Bio

Bio


Clinical Focus: Cardiovascular Medicine

Research Focus:

My primary research interest is the design and conduct of multicenter clinical trials and analyses of important clinical cardiac issues using large patient databases. My research focuses on novel anticoagulation agents for the treatment of acute coronary syndromes and atrial fibrillation, the study of agents targeted to protect the myocardium during reperfusion therapy for acute myocardial infarction, and the evaluation of cardiovascular safety of diabetic therapies. I am also interested in the methodology of clinical trials. Current research activities include standardization of the definition of myocardial infarction used in clinical trials, the adjudication of suspected clinical endpoint events by Clinical Event Committees (CEC), and the efficient operational conduct of large multinational clinical trials.

Administrative Focus: Vice Chair of Clinical Research in the Department of Medicine and Member of the Stanford IRB

Professional Training:

1985 Stanford University, BS Chemistry
1989 University of Washington, MD
1993 University of Arizona, Internship/Residency/Chief Residency
1996 Duke University, Fellowship in Cardiology
1996 Duke University, Faculty in Cardiology
2013 Stanford University, Vice Chair of Clinical Research, Department of Medicine

Academic Appointments


Administrative Appointments


  • Vice Chair of Clinical Research, Department of Medicine (2013 - Present)

Research & Scholarship

Clinical Trials


  • Culturally-adapted Diabetes Prevention Lifestyle Intervention for Latinos (E-LITE Latinos) Recruiting

    The purpose of the study is to develop a culturally adapted intervention (CAI) program to improve weight and physical activity in overweight or obese adult Latinos at high risk for developing type 2 diabetes and/or cardiovascular disease (CVD) and to rigorously evaluate the effectiveness and implementation potential of the CAI program.

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  • SPYRAL HTN-OFF MED Study Recruiting

    The purpose of this study is to obtain an assessment of the efficacy and safety of renal denervation in the absence of antihypertensive medications.

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  • SPYRAL HTN-ON MED Study Recruiting

    The purpose of this study is to obtain an assessment of the efficacy and safety of renal denervation in the presence of three standard antihypertensive medications.

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Projects


  • Financial Disclosures, Stanford University

    Full financial disclosures prior to August 1, 2013 can be viewed at https://www.dcri.org/about-us/conflict-of-interest/Mahaffey-COI_2011-2013.pdf .
    Full financial disclosures after August 1, 2013 can be viewed in the attached file - Mahaffey Disclosures Stanford Tracker 20140627.

    Location

    Stanford

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Publications

All Publications


  • The effect of cangrelor and access site on ischaemic and bleeding events: insights from CHAMPION PHOENIX EUROPEAN HEART JOURNAL Gutierrez, J. A., Harrington, R. A., Blankenship, J. C., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Genereux, P., Prats, J., Deliargyris, E. N., Mahaffey, K., White, H. D., Bhatt, D. L. 2016; 37 (14): 1122-1130

    Abstract

    To assess whether the use of the femoral or radial approach for percutaneous coronary intervention (PCI) interacted with the efficacy and safety of cangrelor, an intravenous P2Y12 inhibitor, in CHAMPION PHOENIX.A total of 11 145 patients were randomly assigned in a double-dummy, double-blind manner either to a cangrelor bolus and 2-h infusion or to clopidogrel at the time of PCI. The primary endpoint, a composite of death, myocardial infarction, ischaemia-driven revascularization, or stent thrombosis, and the primary safety endpoint, Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) defined severe bleeding, were evaluated at 48 h. Of the patients undergoing PCI and receiving study drug treatment, a total of 8064 (74%) and 2855 (26%) patients underwent femoral or radial PCI, respectively. Among the femoral cohort, the primary endpoint rate was 4.8% with cangrelor vs. 6.0% with clopidogrel (odds ratio, OR [95% confidence interval, CI] = 0.79 [0.65-0.96]); among the radial cohort, the primary endpoint was 4.4% with cangrelor vs. 5.7% with clopidogrel (OR [95% CI] = 0.76 [0.54-1.06]), P-interaction 0.83. The rate of GUSTO severe bleeding in the femoral cohort was 0.2% with cangrelor vs. 0.1% with clopidogrel (OR [95% CI] = 1.73 [0.51-5.93]). Among the radial cohort, the rate of GUSTO severe bleeding was 0.1% with cangrelor vs. 0.1% with clopidogrel (OR [95% CI] = 1.02 [0.14-7.28]), P-interaction 0.65. The evaluation of safety endpoints with the more sensitive ACUITY-defined bleeding found major bleeding in the femoral cohort to be 5.2% with cangrelor vs. 3.1% with clopidogrel (OR [95% CI] = 1.69 [1.35-2.12]); among the radial cohort the rate of ACUITY major bleeding was 1.5% with cangrelor vs. 0.7% with clopidogrel (OR [95% CI] = 2.17 [1.02-4.62], P-interaction 0.54).In CHAMPION PHOENIX, cangrelor reduced ischaemic events with no significant increase in GUSTO-defined severe bleeding. The absolute rates of bleeding, regardless of the definition, tended to be lower when PCI was performed via the radial artery.http://www.clinicaltrials.gov identifier: NCT01156571.

    View details for DOI 10.1093/eurheartj/ehv498

    View details for Web of Science ID 000373558500011

    View details for PubMedID 26400827

  • Racial/ethnic differences in atrial fibrillation symptoms, treatment patterns, and outcomes: Insights from Outcomes Registry for Better Informed Treatment for Atrial Fibrillation Registry. American heart journal Golwala, H., Jackson, L. R., Simon, D. N., Piccini, J. P., Gersh, B., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L., Fonarow, G. C., Peterson, E. D., Thomas, K. L. 2016; 174: 29-36

    Abstract

    Significant racial/ethnic differences exist in the incidence of atrial fibrillation (AF). However, less is known about racial/ethnic differences in quality of life (QoL), treatment, and outcomes associated with AF.Using data from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we compared clinical characteristics, QoL, management strategies, and long-term outcomes associated with AF among various racial/ethnic groups.We analyzed 9,542 participants with AF (mean age 74 ± 11 years, 43% women, 91% white, 5% black, 4% Hispanic) from 174 centers. Compared with AF patients identified as white race, patients identified as Hispanic ethnicity and those identified as black race were younger, were more often women, and had more cardiac and noncardiac comorbidities. Black patients were more symptomatic with worse QoL and were less likely to be treated with a rhythm control strategy than other racial/ethnic groups. There were no significant racial/ethnic differences in CHA2DS2-VASc stroke or ATRIA bleeding risk scores and rates of oral anticoagulation use were similar. However, racial and ethnic minority populations treated with warfarin spent a lower median time in therapeutic range of international normalized ratio (59% blacks vs 68% whites vs 62% Hispanics, P < .0001). There was no difference in long-term outcomes associated with AF between the 3 groups at a median follow-up of 2.1 years.Relative to white and Hispanic patients, black patients with AF had more symptoms, were less likely to receive rhythm control interventions, and had lower quality of warfarin management. Despite these differences, clinical events at 2 years were similar by race and ethnicity.

    View details for DOI 10.1016/j.ahj.2015.10.028

    View details for PubMedID 26995367

  • Pooled analysis of adverse event collection from 4 acute coronary syndrome trials. American heart journal Zimerman, A., Lopes, R. D., Stebbins, A. L., Guimarães, P. O., Haque, G., Melloni, C., Trollinger, K., James, S. K., Alexander, J. H., Tricoci, P., Roe, M. T., Ohman, E. M., Mahaffey, K. W., Held, C., Tinga, B., Pieper, K. S., Alexander, K. P. 2016; 174: 60-67

    Abstract

    Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied.Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded.In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs.Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.

    View details for DOI 10.1016/j.ahj.2016.01.003

    View details for PubMedID 26995371

  • Pooled analysis of adverse event collection from 4 acute coronary syndrome trials AMERICAN HEART JOURNAL Zimerman, A., Lopes, R. D., Stebbins, A. L., Guimaraes, P. O., Haque, G., Melloni, C., Trollinger, K., James, S. K., Alexander, J. H., Tricoci, P., Roe, M. T., Ohman, E. M., Mahaffey, K. W., Held, C., Tinga, B., Pieper, K. S., Alexander, K. P. 2016; 174: 60-67
  • Racial/ethnic differences in atrial fibrillation symptoms, treatment patterns, and outcomes: Insights from Outcomes Registry for Better Informed Treatment for Atrial Fibrillation Registry AMERICAN HEART JOURNAL Golwala, H., Jackson, L. R., Simon, D. N., Piccini, J. P., Gersh, B., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L., Fonarow, G. C., Peterson, E. D., Thomas, K. L. 2016; 174: 29-36
  • Lessons Learned from EVOLVE for Planning of Future Randomized Trials in Patients on Dialysis CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Parfrey, P. S., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Chertow, G. M. 2016; 11 (3): 539-546

    Abstract

    The effect of the calcimimetic cinacalcet on cardiovascular disease in patients undergoing hemodialysis with secondary hyperparathyroidism was assessed in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events trial. This was the largest (in size) and longest (in duration) randomized controlled clinical trial undertaken in this population. During planning, execution, analysis, and reporting of the trial, many lessons were learned, including those related to the use of a composite cardiovascular primary endpoint, definition of endpoints (particularly heart failure and severe unremitting hyperparathyroidism), importance of age for optimal stratification at randomization, use of unadjusted and adjusted intention-to-treat analysis for the primary outcome, how to respond to a lower-than-predicted event rate during the trial, development of a prespecified analytic plan that accounted for nonadherence and for cointerventions that diminished the power of the trial to observe a treatment effect, determination of the credibility of a subgroup effect, use of adverse effects database to investigate rare diseases, collection of blood for biomarker measurement not designated before trial initiation, and interpretation of the benefits-to-harms ratio for individual patients. It is likely that many of these issues will arise in the planning of future trials in CKD.

    View details for DOI 10.2215/CJN.06370615

    View details for Web of Science ID 000371453100023

    View details for PubMedID 26614406

  • The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial JOURNAL OF HUMAN HYPERTENSION Chang, T. I., AbdAlla, S., London, G. M., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Floege, J., Herzog, C. A., Mahaffey, K. W., Moe, S. M., Parfrey, P. S., Wheeler, D. C., Dehmel, B., Goodman, W. G., Chertow, G. M. 2016; 30 (3): 204-209

    Abstract

    Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2?mm?Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3?mm?Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.

    View details for DOI 10.1038/jhh.2015.56

    View details for Web of Science ID 000370449000010

    View details for PubMedID 26040438

  • Sinus Node Dysfunction Is Associated With Higher Symptom Burden and Increased Comorbid Illness: Results From the ORBIT-AF Registry CLINICAL CARDIOLOGY Jackson, L. R., Kim, S. H., Piccini, J. P., Gersh, B. J., Naccarelli, G. V., Reiffel, J. A., Freeman, J., Thomas, L., Chang, P., Fonarow, G. C., Go, A. S., Mahaffey, K. W., Peterson, E. D., Kowey, P. R. 2016; 39 (2): 119-125

    Abstract

    Patients with sinus node dysfunction (SND) have increased risk of atrial tachyarrhythmias, including atrial fibrillation (AF). To date, treatment patterns and outcomes of patients with SND and AF have not been well described.Patients with SND and AF have higher risk of adverse cardiovascular outcomes.Sinus node dysfunction was defined clinically, based on treating physician. Treatment patterns were described and logistic regression analysis performed to assess outcomes.Overall, 1710 (17.7%) out of 9631 patients had SND at enrollment. Patients with SND and AF had increased comorbid medical illnesses, more severe symptoms (European Heart Rhythm Association class IV: 17.5% vs 13.9%; P = 0.0007), and poorer quality of life (median 12-month Atrial Fibrillation Effect on Quality of Life score: 79.6 vs 85.2; P = 0.0008). There were no differences in AF management strategy between patients with SND and those without (rate control, 69.7% vs 67.7%; rhythm control, 30.0% vs 32.0%; P = 0.11). After adjustment, patients with SND were more likely than those without SND to progress from paroxysmal AF at baseline to persistent or permanent AF at any follow-up, or persistent AF at baseline to permanent AF at any follow-up (odds ratio: 1.23, 95% confidence interval: 1.01-1.49, P = 0.035). However, there was no association between SND and major risk-adjusted outcomes.Sinus node dysfunction is present in 1 of 6 patients with AF and is associated with increased comorbidities and higher symptom burden. However, SND is not associated with an increase in major risk-adjusted outcomes.

    View details for DOI 10.1002/clc.22504

    View details for Web of Science ID 000371415400008

    View details for PubMedID 26720750

  • Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation CIRCULATION Piccini, J. P., Hellkamp, A. S., Washam, J. B., Becker, R. C., Breithardt, G., Berkowitz, S. D., Halperin, J. L., Hankey, G. J., Hacke, W., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Fox, K. A., Patel, M. R. 2016; 133 (4): 352-360

    Abstract

    Patients with atrial fibrillation (AF) often take multiple medications.We examined characteristics and compared adjusted outcomes between rivaroxaban and warfarin according to number of concomitant baseline medications and the presence of combined cytochrome P450 3A4 and P-glycoprotein inhibitors in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study. At baseline, 5101 patients (36%) were on 0 to 4 medications, 7298 (51%) were on 5 to 9, and 1865 (13%) were on ? 10. Although polypharmacy was not associated with higher risk of stroke or non-central nervous system embolism (adjusted hazard ratio, 1.02 for ? 10 versus 0-4 medications; 95% confidence interval, 0.76-1.38), it was associated with higher risks of the combined end point of stroke, non-central nervous system embolism, vascular death, or myocardial infarction (adjusted hazard ratio, 1.41 for ? 10 versus 0-4 medications; 95% confidence interval, 1.18-1.68) and nonmajor clinically relevant or major bleeding (adjusted hazard ratio, 1.47 for ? 10 versus 0-4 medications; 95% confidence interval, 1.31-1.65). There was no significant difference in primary efficacy (adjusted interaction P=0.99) or safety outcomes (adjusted interaction P=0.87) between treatment groups by number of medications. Patients treated with 0 to 4 medications had lower rates of major bleeding with rivaroxaban (adjusted hazard ratio, 0.71; 95% confidence interval, 0.52-0.95; interaction P=0.0074). There was no evidence of differential outcomes in those treated with ? 1 combined cytochrome P450 3A4 and P-glycoprotein inhibitors.In a population of patients with atrial fibrillation, two thirds were on ? 5 medications. Increasing medication use was associated with higher risk of bleeding but not stroke. Rivaroxaban was tolerated across complex patients on multiple medications.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.115.018544

    View details for Web of Science ID 000369259100003

    View details for PubMedID 26673560

  • Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes DIABETES OBESITY & METABOLISM Fulcher, G., Matthews, D. R., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Mathieu, C., Woo, V., Wysham, C., Capuano, G., Desai, M., Shaw, W., Vercruysse, F., Meininger, G., Neal, B. 2016; 18 (1): 82-91

    View details for DOI 10.1111/dom.12589

    View details for Web of Science ID 000367233900011

  • Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF. Journal of the American Heart Association Pokorney, S. D., Piccini, J. P., Stevens, S. R., Patel, M. R., Pieper, K. S., Halperin, J. L., Breithardt, G., Singer, D. E., Hankey, G. J., Hacke, W., Becker, R. C., Berkowitz, S. D., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2016; 5 (3)

    Abstract

    Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions.In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS2 score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P<0.0001) and age ?75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P<0.0001) were associated with higher all-cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C-index 0.677).In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ?7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

    View details for DOI 10.1161/JAHA.115.002197

    View details for PubMedID 26955859

  • The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation EUROPEAN HEART JOURNAL O'Brien, E. C., Simon, D. N., Thomas, L. E., Hylek, E. M., Gersh, B. J., Ansell, J. E., Kowey, P. R., Mahaffey, K. W., Chang, P., Fonarow, G. C., Pencina, M. J., Piccini, J. P., Peterson, E. D. 2015; 36 (46): 3258-3264

    Abstract

    Therapeutic decisions in atrial fibrillation (AF) are often influenced by assessment of bleeding risk. However, existing bleeding risk scores have limitations.We sought to develop and validate a novel bleeding risk score using routinely available clinical information to predict major bleeding in a large, community-based AF population.We analysed data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), a prospective registry that enrolled incident and prevalent AF patients at 176 US sites. Using Cox proportional hazards regression, we identified factors independently associated with major bleeding among patients taking oral anticoagulation (OAC) over a median follow-up of 2 years (interquartile range = 1.6-2.5). We also created a numerical bedside risk score that included the five most predictive risk factors weighted according to their strength of association with major bleeding. The predictive performance of the full model, the simple five-item score, and two existing risk scores (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly, HAS-BLED, and anticoagulation and risk factors in atrial fibrillation, ATRIA) were then assessed in both the ORBIT-AF cohort and a separate clinical trial population, Rivaroxaban Once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET-AF).Among 7411 ORBIT-AF patients taking OAC, the rate of major bleeding was 4.0/100 person-years. The full continuous model (12 variables) and five-factor ORBIT risk score (older age [75+ years], reduced haemoglobin/haematocrit/history of anaemia, bleeding history, insufficient kidney function, and treatment with antiplatelet) both had good ability to identify those who bled vs. not (C-index 0.69 and 0.67, respectively). These scores both had similar discrimination, but markedly better calibration when compared with the HAS-BLED and ATRIA scores in an external validation population from the ROCKET-AF trial.The five-element ORBIT bleeding risk score had better ability to predict major bleeding in AF patients when compared with HAS-BLED and ATRIA risk scores. The ORBIT risk score can provide a simple, easily remembered tool to support clinical decision making.

    View details for DOI 10.1093/eurheartj/ehv476

    View details for Web of Science ID 000370372500013

    View details for PubMedID 26424865

  • Lost to Follow-up and Withdrawal of Consent in Contemporary Global Cardiovascular Randomized Clinical Trials. Critical pathways in cardiology Rodriguez, F., Harrison, R. W., Wojdyla, D., Mahaffey, K. W. 2015; 14 (4): 150-153

    Abstract

    High rates of lost to follow-up (LTFU) and withdrawal of consent (WDC) may introduce uncertainty around the validity of the results of clinical trials. We sought to better understand published proportions of LTFU and WDC in large contemporary cardiovascular clinical trials.Large (>5000 randomized subjects) cardiovascular clinical trials published between 2007 and 2012 in N Engl J Med were systematically reviewed. Data regarding LTFU and WDC were extracted from the primary manuscripts and supplementary online material.Twenty-five published randomized trials were identified. Trials ranged in size from 5518 to 26449 subjects. All trials reported LTFU with 15 separately reporting WDC. The duration of follow-up ranged from 30 days to 6.2 years. The number of subjects LTFU ranged from 8 to 905, and the median proportion of subjects LTFU was 0.23% (interquartile range: 0.12%-0.58%). Individual LTFU proportions varied 300-fold, from 0.03% to 9.7%. Proportions of WDC ranged from 0.02% to 8.3%-a 400-fold difference-with a median of 1.1% (interquartile range: 0.2%-2.6%). WDC occurred more frequently than LTFU in all but 2 studies.Contemporary cardiovascular clinical trials typically have low proportions of LTFU or WDC, but some trials have approximately 10% of subjects with LTFU or WDC. WDC occurred more frequently than LTFU but was only reported in 60% of the trials. These results emphasize the need to standardize reporting of LTFU and WDC as important trial metrics of quality and to develop strategies to minimize their occurrence.

    View details for DOI 10.1097/HPC.0000000000000055

    View details for PubMedID 26569655

  • Efficacy and Safety of Vorapaxar in Non-ST-Segment Elevation Acute Coronary Syndrome Patients Undergoing Noncardiac Surgery JOURNAL OF THE AMERICAN HEART ASSOCIATION van Diepen, S., Tricoci, P., Podder, M., Westerhout, C. M., Aylward, P. E., Held, C., Van de Werf, F., Strony, J., Wallentin, L., Moliterno, D. J., White, H. D., Mahaffey, K. W., Harrington, R. A., Armstrong, P. W. 2015; 4 (12)

    Abstract

    Perioperative antiplatelet agents potentially increase bleeding after non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). The protease-activated receptor 1 antagonist vorapaxar reduced cardiovascular events and was associated with increased bleeding versus placebo in NSTE ACS, but its efficacy and safety in noncardiac surgery (NCS) remain unknown. We aimed to evaluate ischemic, bleeding, and long-term outcomes of vorapaxar in NCS after NSTE ACS.In the TRACER trial, 2202 (17.0%) patients underwent major or minor NCS after NSTE ACS over 1.5 years (median); continuing study treatment perioperatively was recommended. The primary ischemic end point for this analysis was cardiovascular death, myocardial infarction, stent thrombosis, or urgent revascularization within 30 days of NCS. Safety outcomes included 30-day NCS bleeding and GUSTO moderate/severe bleeding. Overall, 1171 vorapaxar and 1031 placebo patients underwent NCS. Preoperative aspirin and thienopyridine use was 96.8% versus 97.7% (P=0.235) and 89.1% versus 86.1% (P=0.036) for vorapaxar versus placebo, respectively. Within 30 days of NCS, no differences were observed in the primary ischemic end point between vorapaxar and placebo groups (3.4% versus 3.9%; adjusted odds ratio 0.81, 95% CI 0.50 to 1.33, P=0.41). Similarly, no differences in NCS bleeding (3.9% versus 3.4%; adjusted odds ratio 1.41, 95% CI 0.87 to 2.31, P=0.17) or GUSTO moderate/severe bleeding (4.2% versus 3.7%; adjusted odds ratio 1.15, 95% CI, 0.72 to 1.83, P=0.55) were observed. In a 30-day landmarked analysis, NCS patients had a higher long-term risk of the ischemic end point (adjusted hazard ratio 1.62, 95% CI 1.33 to 1.97, P<0.001) and GUSTO moderate/severe bleeding (adjusted hazard ratio 5.63, 95% CI 3.98 to 7.97, P<0.001) versus patients who did not undergo NCS, independent of study treatment.NCS after NSTE ACS is common and associated with more ischemic outcomes and bleeding. Vorapaxar after NSTE ACS was not associated with increased perioperative ischemic or bleeding events in patients undergoing NCS.

    View details for DOI 10.1161/JAHA.115.002546

    View details for Web of Science ID 000369947700038

    View details for PubMedID 26672080

  • Impact of cangrelor overdosing on bleeding complications in patients undergoing percutaneous coronary intervention: insights from the CHAMPION trials JOURNAL OF THROMBOSIS AND THROMBOLYSIS Angiolillo, D. J., Bhatt, D. L., Steg, P. G., Stone, G. W., White, H. D., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Liu, T., Mahaffey, K. W., Harrington, R. A. 2015; 40 (3): 317-322
  • Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: The Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial) AMERICAN HEART JOURNAL Bansilal, S., Bloomgarden, Z., Halperin, J. L., Hellkamp, A. S., Lokhnygina, Y., Patel, M. R., Becker, R. C., Breithardt, G., Hacke, W., Hankey, G. J., Nessel, C. C., Singer, D. E., Berkowitz, S. D., Piccini, J. P., Mahaffey, K. W., Fox, K. A. 2015; 170 (4): 675-?

    Abstract

    The prevalence of both atrial fibrillation (AF) and diabetes mellitus (DM) are rising, and these conditions often occur together. Also, DM is an independent risk factor for stroke in patients with AF. We aimed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial.We stratified the ROCKET AF population by DM status, assessed associations with risk of outcomes by DM status and randomized treatment using Cox proportional hazards models, and tested for interactions between randomized treatments. For efficacy, primary outcomes were stroke (ischemic or hemorrhagic) or non-central nervous system embolism. For safety, the primary outcome was major or nonmajor clinically relevant bleeding.The 5,695 patients with DM (40%) in ROCKET AF were younger, were more obese, and had more persistent AF, but fewer had previous stroke (the CHADS2 score includes DM and stroke). The relative efficacy of rivaroxaban and warfarin for prevention of stroke and systemic embolism was similar in patients with (1.74 vs 2.14/100 patient-years, hazard ratio [HR] 0.82) and without (2.12 vs 2.32/100 patient-years, HR 0.92) DM (interaction P = .53). The safety of rivaroxaban vs warfarin regarding major bleeding (HRs 1.00 and 1.12 for patients with and without DM, respectively; interaction P = .43), major or nonmajor clinically relevant bleeding (HRs 0.98 and 1.09; interaction P = .17), and intracerebral hemorrhage (HRs 0.62 and 0.72; interaction P = .67) was independent of DM status. Adjusted exploratory analyses suggested 1.3-, 1.5-, and 1.9-fold higher 2-year rates of stroke, vascular mortality, and myocardial infarction in DM patients.The relative efficacy and safety of rivaroxaban vs warfarin was similar in patients with and without DM, supporting use of rivaroxaban as an alternative to warfarin in diabetic patients with AF.

    View details for DOI 10.1016/j.ahj.2015.07.006

    View details for Web of Science ID 000361575200009

    View details for PubMedID 26386791

  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). Journal of nuclear cardiology Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L. 2015; 22 (5): 1041-1144

    View details for DOI 10.1007/s12350-015-0209-1

    View details for PubMedID 26204990

  • Efficacy and Safety of Canagliflozin Used in Conjunction with Sulfonylurea in Patients with Type 2 Diabetes Mellitus: A Randomized, Controlled Trial. Diabetes therapy : research, treatment and education of diabetes and related disorders Fulcher, G., Matthews, D. R., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Weiss, R., Rosenstock, J., Capuano, G., Desai, M., Shaw, W., Vercruysse, F., Meininger, G., Neal, B. 2015; 6 (3): 289-302

    Abstract

    The efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea monotherapy.The CANagliflozin cardioVascular Assessment Study (CANVAS) is a double-blind, placebo-controlled cardiovascular outcomes study that randomized participants to placebo or canagliflozin 100 or 300 mg once daily in addition to routine therapy. Participants in the CANVAS trial are men and women aged ?30 years with T2DM and a history or high risk of cardiovascular disease, and inadequate glycemic control (glycated hemoglobin [HbA1c] ?7.0% and ?10.5%) on current antihyperglycemic therapies. The primary objective of this prespecified substudy was to assess change from baseline to 18 weeks in HbA1c among patients on sulfonylurea monotherapy.Of the 4330 patients enrolled in CANVAS, 127 met the entry criteria for the sulfonylurea monotherapy substudy (placebo, n = 45; canagliflozin 100 mg, n = 42; canagliflozin 300 mg, n = 40). At 18 weeks, placebo-subtracted changes (95% confidence interval) in HbA1c were -0.74% (-1.15, -0.33; P < 0.001) and -0.83% (-1.24, -0.42; P < 0.001) with canagliflozin 100 and 300 mg, respectively. Relative to placebo, canagliflozin 100 and 300 mg also decreased fasting plasma glucose (FPG; -2.1 mmol/L [-3.0, -1.2] and -2.7 mmol/L [-3.6, -1.7], respectively). Body weight was lower with canagliflozin 300 mg (-1.8% [-3.2, -0.4]; P = 0.014) but unchanged with canagliflozin 100 mg (-0.4% [-1.8, 1.0]; P = 0.557). Canagliflozin 300 mg increased hypoglycemia episodes compared to canagliflozin 100 mg and placebo (15%, 0%, and 4.4%, respectively). Adverse events (AEs) of male and female genital mycotic infections, pollakiuria, and thirst were more common with canagliflozin.Canagliflozin added to ongoing sulfonylurea monotherapy produced improvements in HbA1c, FPG, and body weight, with an increased incidence of AEs consistent with the mechanism of action of SGLT2 inhibition.Janssen Research & Development, LLC.ClinicalTrials.gov NCT01032629.

    View details for DOI 10.1007/s13300-015-0117-z

    View details for PubMedID 26081793

  • Increased Heart Rate Is Associated With Higher Mortality in Patients With Atrial Fibrillation (AF): Results From the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) JOURNAL OF THE AMERICAN HEART ASSOCIATION Steinberg, B. A., Kim, S., Thomas, L., Fonarow, G. C., Gersh, B. J., Holmqvist, F., Hylek, E., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Reiffel, J. A., Chang, P., Peterson, E. D., Piccini, J. P. 2015; 4 (9)

    Abstract

    Most patients with atrial fibrillation (AF) require rate control; however, the optimal target heart rate remains under debate. We aimed to assess rate control and subsequent outcomes among patients with permanent AF.We studied 2812 US outpatients with permanent AF in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation. Resting heart rate was measured longitudinally and used as a time-dependent covariate in multivariable Cox models of all-cause and cause-specific mortality during a median follow-up of 24 months. At baseline, 7.4% (n=207) had resting heart rate <60 beats per minute (bpm), 62% (n=1755) 60 to 79 bpm, 29% (n=817) 80 to 109 bpm, and 1.2% (n=33) ?110 bpm. Groups did not differ by age, previous cerebrovascular disease, heart failure status, CHA2DS2-VASc scores, renal function, or left ventricular function. There were significant differences in race (P=0.001), sinus node dysfunction (P=0.004), and treatment with calcium-channel blockers (P=0.006) and anticoagulation (P=0.009). In analyses of continuous heart rates, lower heart rate ?65 bpm was associated with higher all-cause mortality (adjusted hazard ratio [HR], 1.15 per 5-bpm decrease; 95% CI, 1.01 to 1.32; P=0.04). Similarly, increasing heart rate >65 bpm was associated with higher all-cause mortality (adjusted HR, 1.10 per 5-bpm increase; 95% CI, 1.05 to 1.15; P<0.0001). This relationship was consistent across endpoints and in a broader sensitivity analysis of permanent and nonpermanent AF patients.Among patients with permanent AF, there is a J-shaped relationship between heart rate and mortality. These data support current guideline recommendations, and clinical trials are warranted to determine optimal rate control.URL: http://clinicaltrials.gov/. Unique identifier: NCT01165710.

    View details for DOI 10.1161/JAHA.115.002031

    View details for Web of Science ID 000364152100007

    View details for PubMedID 26370445

  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L., Weintraub, W. S., Bozkurt, B., Fonarow, G. C., Hendel, R. C., Jacobs, J. P., Jneid, H. H., Kutcher, M. A., Lichtman, J. H., Smith, E. E., Tcheng, J. E., Wang, T. Y. 2015; 66 (4): 403-469
  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). Circulation Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L. 2015; 132 (4): 302-361

    View details for DOI 10.1161/CIR.0000000000000156

    View details for PubMedID 25547519

  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). Journal of the American College of Cardiology Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L. 2015; 66 (4): 403-469

    View details for DOI 10.1016/j.jacc.2014.12.018

    View details for PubMedID 25553722

  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards ( Writing Committee to Develop Cardiovascular Endpoints Data Standards) CIRCULATION Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L., Weintraub, W. S., Bozkurt, B., Fonarow, G. C., Hendel, R. C., Jacobs, J. P., Jneid, H. H., Kutcher, M. A., Lichtman, J. H., Smith, E. E., Tcheng, J. E., Wang, T. Y. 2015; 132 (4): 302-361
  • Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial CIRCULATION Moe, S. M., Chertow, G. M., Parfrey, P. S., Kubo, Y., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Herzog, C. A., London, G. M., Mahaffey, K. W., Wheeler, D. C., Stolina, M., Dehmel, B., Goodman, W. G., Floege, J. 2015; 132 (1): 27-39
  • Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Circulation Moe, S. M., Chertow, G. M., Parfrey, P. S., Kubo, Y., Block, G. A., Correa-Rotter, R., Drüeke, T. B., Herzog, C. A., London, G. M., Mahaffey, K. W., Wheeler, D. C., Stolina, M., Dehmel, B., Goodman, W. G., Floege, J. 2015; 132 (1): 27-39

    Abstract

    Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events.This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ?300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ?30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ?30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99).Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.

    View details for DOI 10.1161/CIRCULATIONAHA.114.013876

    View details for PubMedID 26059012

  • Sex-Stratified Trends in Enrollment, Patient Characteristics, Treatment, and Outcomes Among Non-ST-Segment Elevation Acute Coronary Syndrome Patients Insights From Clinical Trials Over 17 Years CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Kragholm, K., Halim, S. A., Yang, Q., Schulte, P. J., Hochman, J. S., Melloni, C., Mahaffey, K. W., Moliterno, D. J., Harrington, R. A., White, H. D., Armstrong, P. W., Ohman, E. M., Van de Werf, F., Tricoci, P., Alexander, J. H., Giugliano, R. P., Newby, L. K. 2015; 8 (4): 357-367
  • Patients' time in therapeutic range on warfarin among US patients with atrial fibrillation: Results from ORBIT-AF registry AMERICAN HEART JOURNAL Pokorney, S. D., Simon, D. N., Thomas, L., Fonarow, G. C., Kowey, P. R., Chang, P., Singer, D. E., Ansell, J., Blanco, R. G., Gersh, B., Mahaffey, K. W., Hylek, E. M., Go, A. S., Piccini, J. P., Peterson, E. D. 2015; 170 (1): 141-U194

    Abstract

    Time in therapeutic range (TTR) of international normalized ratio (INR) of 2.0 to 3.0 is important for the safety and effectiveness of warfarin anticoagulation. There are few data on TTR among patients with atrial fibrillation (AF) in community-based clinical practice.Using the US Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), we examined TTR (using a modified Rosendaal method) among 5,210 patients with AF on warfarin and treated at 155 sites. Patients were grouped into quartiles based on TTR data. Multivariable logistic regression modeling with generalized estimating equations was used to determine patient and provider factors associated with the lowest (worst) TTR.Overall, 59% of the measured INR values were between 2.0 and 3.0, with an overall mean and median TTR of 65% ± 20% and 68% (interquartile range [IQR] 53%-79%). The median times below and above the therapeutic range were 17% (IQR 8%-29%) and 10% (IQR 3%-19%), respectively. Patients with renal dysfunction, advanced heart failure, frailty, prior valve surgery, and higher risk for bleeding (ATRIA score) or stroke (CHA2DS2-VASc score) had significantly lower TTR (P < .0001 for all). Patients treated at anticoagulation clinics had only slightly higher median TTR (69%) than those not (66%) (P < .0001).Among patients with AF in US clinical practices, TTR on warfarin is suboptimal, and those at highest predicted risks for stroke and bleeding were least likely to be in therapeutic range.

    View details for DOI 10.1016/j.ahj.2015.03.017

    View details for Web of Science ID 000356452700018

    View details for PubMedID 26093875

  • Association Between Atrial Fibrillation Symptoms, Quality of Life, and Patient Outcomes Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Freeman, J. V., Simon, D. N., Go, A. S., Spertus, J., Fonarow, G. C., Gersh, B. J., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L. E., Chang, P., Peterson, E. D., Piccini, J. P. 2015; 8 (4): 393-402
  • Digoxin Use and Subsequent Outcomes Among Patients in a Contemporary Atrial Fibrillation Cohort JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Allen, L. A., Fonarow, G. C., Simon, D. N., Thomas, L. E., Marzec, L. N., Pokorney, S. D., Gersh, B. J., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Chang, P., Peterson, E. D., Piccini, J. P. 2015; 65 (25): 2691-2698

    Abstract

    Although digoxin has long been used to treat atrial fibrillation (AF) and heart failure (HF), its safety remains controversial.This study sought to describe digoxin use over time in patients with AF who were stratified by the presence or absence of HF, to characterize the predictors of digoxin use and initiation, and to correlate digoxin use with outcomes.Longitudinal patterns of digoxin use and its association with a variety of outcomes were assessed in a prospective outpatient registry conducted at 174 U.S. sites with enrollment from June 2010 to August 2011.Among 9,619 patients with AF and serial follow-up every 6 months for up to 3 years, 2,267 (23.6%) received digoxin at study enrollment, 681 (7.1%) were initiated on digoxin during follow-up, and 6,671 (69.4%) were never prescribed digoxin. After adjusting for other medications, heart rate was 72.9 beats/min among digoxin users and 71.5 beats/min among nonusers (p < 0.0001). Prevalent digoxin use at registry enrollment was not associated with subsequent onset of symptoms, hospitalization, or mortality (in patients with HF, adjusted hazard ratio [HR] for death: 1.04; without HF, HR: 1.22). Incident digoxin use during follow-up was not associated with subsequent death in patients with HF (propensity adjusted HR: 1.05), but was associated with subsequent death in those without HF (propensity adjusted HR: 1.99).After adjustment for detailed clinical factors, digoxin use in registry patients with AF had a neutral association with outcomes under most circumstances. Because of the multiple conflicting observational reports about digoxin's safety and possible concerns in specific clinical situations, a large pragmatic trial of digoxin therapy in AF is needed.

    View details for DOI 10.1016/j.jacc.2015.04.045

    View details for Web of Science ID 000356775100003

    View details for PubMedID 26112191

  • Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) LANCET Washam, J. B., Stevens, S. R., Lokhnygina, Y., Halperin, J. L., Breithardt, G., Singer, D. E., Mahaffey, K. W., Hankey, G. J., Berkowitz, S. D., Nessel, C. C., Fox, K. A., Califf, R. M., Piccini, J. P., Patel, M. R. 2015; 385 (9985): 2363-2370

    Abstract

    Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767.In 14,171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events per 100 patients-years; hazard ratio 1·17; 95% CI 1·04-1·32; p=0·0093), vascular death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03-1·39, p=0·0201), and sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08-1·70, p=0·0076).Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed.Janssen Research & Development and Bayer HealthCare AG.

    View details for DOI 10.1016/S0140-6736(14)61836-5

    View details for Web of Science ID 000356003700029

  • Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial. Journal of the American Society of Nephrology Moe, S. M., Abdalla, S., Chertow, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Wheeler, D. C., Dehmel, B., Goodman, W. G., Drüeke, T. B. 2015; 26 (6): 1466-1475

    Abstract

    Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ?64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%.

    View details for DOI 10.1681/ASN.2014040414

    View details for PubMedID 25505257

  • Heart rate is associated with progression of atrial fibrillation, independent of rhythm HEART Holmqvist, F., Kim, S., Steinberg, B. A., Reiffel, J. A., Mahaffey, K. W., Gersh, B. J., Fonarow, G. C., Naccarelli, G. V., Chang, P., Freeman, J. V., Kowey, P. R., Thomas, L., Peterson, E. D., Piccini, J. P. 2015; 101 (11): 894-899

    Abstract

    Atrial fibrillation (AF) often progresses from paroxysmal or persistent to more sustained forms, but the rate and predictors of AF progression in clinical practice are not well described.Using the Outcomes Registry for Better Informed Treatment of AF, we analysed the incidence and predictors of progression and tested the discrimination and calibration of the HATCH (hypertension, age, TIA/stroke, chronic obstructive pulmonary disease, heart failure) and CHA?DS?VASc scores for identifying AF progression.Among 6235 patients with paroxysmal or persistent AF at baseline, 1479 progressed, during follow-up (median 18 (IQR 12-24) months). These patients were older and had more comorbidities than patients who did not progress (CHADS? 2.3±1.3 vs 2.1±1.3, p<0.0001). At baseline, patients with AF progression were more often on a rate control as opposed to a rhythm control strategy (66 vs 56%, p<0.0001) and had higher heart rate (72(64-80) vs 68(60-76) bpm, p<0.0001). The strongest predictors of AF progression were AF on the baseline ECG (OR 2.30, 95% CI 1.95 to 2.73, p<0.0001) and increasing age (OR 1.16, 95% CI1.09 to 1.24, p<0.0001, per 10 increase), while patients with lower heart rate (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001, per 10 decrease ?80) were less likely to progress. There was no significant interaction between rhythm on baseline ECG and heart rate (p=0.71). The HATCH and CHA?DS?VASc scores had modest discriminatory power for AF progression (C-indices 0.55 (95% CI 0.53 to 0.58) and 0.55 (95% CI 0.52 to 0.57)).Within 1.5?years, almost a quarter of the patients with paroxysmal or persistent AF progress to a more sustained form. Progression is strongly associated with heart rate, and age.

    View details for DOI 10.1136/heartjnl-2014-307043

    View details for Web of Science ID 000354277600014

    View details for PubMedID 25732748

  • Magnitude of troponin elevation and long-term clinical outcomes in acute coronary syndrome patients treated with and without revascularization. Circulation. Cardiovascular interventions Bagai, A., Huang, Z., Lokhnygina, Y., Harrington, R. A., Armstrong, P. W., Strony, J., White, H. D., Leonardi, S., Held, C., Van de Werf, F., Wallentin, L., Tricoci, P., Mahaffey, K. W. 2015; 8 (6)

    Abstract

    In patients with non-ST-segment-elevation acute coronary syndrome (NSTE ACS), elevated troponin levels identify patients at high risk for adverse outcomes; however, it is unknown whether the magnitude of troponin elevation during hospitalization remains predictive of subsequent events in patients undergoing coronary revascularization.We studied 12?635 patients with NSTE ACS in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) study with at least 1 troponin measurement during index hospitalization. Cox proportional hazards regression was used to examine the relationship between peak troponin level (standardized as the ratio of peak troponin value measured during hospitalization and local laboratory upper reference limit [URL]) and revascularization on all-cause mortality at 2 years. Revascularization (percutaneous coronary intervention or coronary artery bypass graft) was performed during index hospitalization in 8586 patients (68.0%); revascularized patients had higher peak troponin ratios (median, 23 versus 9.5× URL). Among patients that did not undergo revascularization, the mortality rate at 2 years increased in a curvilinear fashion with increasing levels of peak troponin. In contrast, the mortality rate at 2 years remained constant irrespective of peak troponin levels among revascularized patients (P for interaction=0.004). This relationship was unchanged after multivariable adjustment.There is a differential relationship between the magnitude of troponin elevation and long-term mortality in ACS patients treated with and without revascularization. Although prognostically important in patients treated without revascularization, the prognostic implications of peak troponin level seem to be minimal in revascularized patients.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00527943.

    View details for DOI 10.1161/CIRCINTERVENTIONS.115.002314

    View details for PubMedID 26025218

  • Meta-Analysis of Intracranial Hemorrhage in Acute Coronary Syndromes: Incidence, Predictors, and Clinical Outcomes JOURNAL OF THE AMERICAN HEART ASSOCIATION Mahaffey, K. W., Hager, R., Wojdyla, D., White, H. D., Armstrong, P. W., Alexander, J. H., Tricoci, P., Lopes, R. D., Ohman, E. M., Roe, M. T., Harrington, R. A., Wallentin, L. 2015; 4 (6)

    Abstract

    Little is known about the incidence, predictors, or outcomes of intracranial hemorrhage (ICH) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). We aimed to determine the incidence and timing of ICH, characterize the location of ICH, and identify independent baseline predictors of ICH in NSTE ACS patients.We pooled patient-level data from 4 contemporary antithrombotic therapy trials. Multivariable modeling identified independent predictors of ICH. ICHs were adjudicated by a clinical events committee. Of 37 815 patients, 135 (0.4%) had an ICH. The median (25th, 75th percentiles) follow-up was 332 (184, 434) days but differed across trials. Locations of ICH were intracerebral (50%), subdural (31%), subarachnoid (18.5%), and intraventricular (11%). Independent predictors of ICH were older age (HR per 10 years, 1.61; 95% CI, 1.35 to 1.91); prior stroke/transient ischemic attack; HR, 1.95; 95% CI, 1.14 to 3.35), higher systolic blood pressure; HR per 10 mm Hg increase, 1.09; 95% CI, 1.01 to 1.18), and larger number of antithrombotic agents (HR per each additional agent, 2.06; 95% CI, 1.49 to 2.84). Of all ICHs, 45 (33%) were fatal.In patients with NSTE ACS enrolled in recent clinical trials of antithrombotic therapies, ICH was uncommon. Patients with older age, prior transient ischemic attack/stroke, higher systolic blood pressure, or larger number of antithrombotic agents were at increased risk. One-third of patients with ICH died. These data may be useful to trialists and data and safety monitoring committees for trial conduct and monitoring.URL: https://www.clinicaltrials.gov/. Unique identifiers: TRACER: NCT00527943, PLATO: NCT00391872, APPRAISE-2: NCT00831441, TRILOGY ACS: NCT00699998.

    View details for DOI 10.1161/JAHA.114.001512

    View details for Web of Science ID 000357025100007

    View details for PubMedID 26089177

  • Cardiovascular events in acute coronary syndrome patients with peripheral arterial disease treated with ticagrelor compared with clopidogrel: Data from the PLATO Trial EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY Patel, M. R., Becker, R. C., Wojdyla, D. M., Emanuelsson, H., Hiatt, W. R., Horrow, J., Husted, S., Mahaffey, K. W., Steg, P. G., Storey, R. F., Wallentin, L., James, S. K. 2015; 22 (6): 734-742

    Abstract

    To determine the effect of ticagrelor compared to clopidogrel in patients with peripheral artery disease (PAD) and acute coronary syndromes (ACS).PLATO (n = 18,624) was a multicentre, double-blind, randomized trial in ACS, that showed a 16% reduction in cardiovascular death (CV-death), myocardial infarction (MI) and stroke with ticagrelor compared with clopidogrel, without significant increase in overall major bleeding. We performed a post-hoc analysis of cardiovascular and bleeding outcomes in PLATO according to reported PAD status at baseline. At one year, CV death, MI or stroke occurred in 19.3% of patients with PAD (n = 1144) compared to 10.2% in patients without PAD (p < 0.001). The Kaplan-Meier one year event rate for the primary endpoint of CV death, MI or stroke in PAD patients treated with ticagrelor as compared with clopidogrel, was 18% vs 20.6% (HR: 0.85 95% CI 0.64-1.11; for PAD status by treatment interaction, p = 0.99) and for death from any cause 8.7% vs 11.9%, (HR: 0.74 95% CI 0.50-1.08; interaction p = 0.73). PLATO-defined major bleeding event rates at one year were 14.8% for ticagrelor compared to 17.9% for clopidogrel, (HR: 0.81 95% CI 0.59-1.10; interaction p = 0.09).PAD patients have a high rate of ischaemic and bleeding events post ACS. The reduction of CV death, MI or stroke with ticagrelor compared with clopidogrel in PAD patients was consistent with the overall trial result although it did not reach statistical significance. Overall major bleeding was similar between the therapies.

    View details for DOI 10.1177/2047487314533215

    View details for Web of Science ID 000354129500006

  • The future of cardiovascular clinical research in North America and beyond-addressing challenges and leveraging opportunities through unique academic and grassroots collaborations AMERICAN HEART JOURNAL Roe, M. T., Mahaffey, K. W., Ezekowitz, J. A., Alexander, J. H., Goodman, S. G., Hernandez, A., Temple, T., Berdan, L., Califf, R. M., Harrington, R. A., Peterson, E. D., Armstrong, P. W. 2015; 169 (6): 743-750
  • Glycoprotein IIb/IIIa Receptor Inhibitors in Combination With Vorapaxar, a Platelet Thrombin Receptor Antagonist, Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes (from the TRACER Trial) AMERICAN JOURNAL OF CARDIOLOGY Cornel, J. H., Tricoci, P., Lokhnygina, Y., Moliterno, D. J., Wallentin, L., Armstrong, P. W., Aylward, P. E., Clare, R. M., Chen, E., Leonardi, S., de Werf, F. V., White, H. D., Held, C., Strony, J., Mahaffey, K. W., Harrington, R. A. 2015; 115 (10): 1325-1332
  • Glycoprotein IIb/IIIa Receptor Inhibitors in Combination With Vorapaxar, a Platelet Thrombin Receptor Antagonist, Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes (from the TRACER Trial). American journal of cardiology Cornel, J. H., Tricoci, P., Lokhnygina, Y., Moliterno, D. J., Wallentin, L., Armstrong, P. W., Aylward, P. E., Clare, R. M., Chen, E., Leonardi, S., Van de Werf, F., White, H. D., Held, C., Strony, J., Mahaffey, K. W., Harrington, R. A. 2015; 115 (10): 1325-1332

    Abstract

    We evaluated the interaction between protease-activated receptor-1 antagonist vorapaxar and concomitant glycoprotein (GP) IIb/IIIa receptor inhibitors in patients with non-ST-segment elevation acute coronary syndromes who underwent PCI. In Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial, 12,944 patients with non-ST-segment elevation acute coronary syndromes were randomized to vorapaxar or placebo. Administration of GP IIb/IIIa receptor inhibitors was allowed at the treating physician's discretion. We investigated whether use of GP IIb/IIIa receptor inhibitors modified vorapaxar's effect on non-coronary artery bypass grafting (CABG)-related bleeding at 7 days and ischemic events at 30 days. In total, 7,455 patients underwent PCI during index hospitalization. Of these, 2,023 patients (27.1%) received inhibitors and 5,432 (72.9%) did not. Vorapaxar was associated with a numerically higher rate of non-CABG-related moderate/severe Global Use of Strategies to Open Occluded Arteries (GUSTO) bleeding at 7 days compared with placebo in those who did (1.3% vs 1.0%) and did not (0.6% vs 0.4%) receive GP IIb/IIIa receptor inhibitors. Ischemic end point rates at 30 days were not significantly lower with vorapaxar versus placebo. Increased rates of non-CABG GUSTO moderate/severe bleeding were observed in patients who received GP IIb/IIIa receptor inhibitors versus those who did not (adjusted hazard ratio [HR] 1.77, 95% confidence interval [CI] 0.43 to 7.35 in placebo arm; adjusted HR 2.02, 95% CI 0.62 to 6.61 in vorapaxar arm) and in those who received vorapaxar versus placebo (adjusted HR 1.54, 95% CI 0.36 to 6.56 in the GP IIb/IIIa group; adjusted HR 1.34, 95% CI 0.44 to 4.07 in the no-GP IIb/IIIa group). No interaction was found between vorapaxar and inhibitor use up to 7 days (P interaction = 0.89) nor at the end of the treatment (P interaction = 0.74); however, the event rate was low. Also, no interaction was observed for efficacy end points after PCI at 30 days or at the end of the treatment. In conclusion, GP IIb/IIIa receptor inhibitor use plus dual antiplatelet therapy in a population with non-ST-segment elevation myocardial infarction planned for PCI was frequent but did not interact with vorapaxar's efficacy or safety. Nonetheless, GP IIb/IIIa receptor inhibitors and vorapaxar were associated with increased bleeding risk, and their combined use may result in additive effects on bleeding rates.

    View details for DOI 10.1016/j.amjcard.2015.02.043

    View details for PubMedID 25776457

  • The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Clinical journal of the American Society of Nephrology Parfrey, P. S., Drüeke, T. B., Block, G. A., Correa-Rotter, R., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Kubo, Y., Dehmel, B., Goodman, W. G., Chertow, G. M. 2015; 10 (5): 791-799

    Abstract

    The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (?65 years, n=1005) and younger (<65 years, n=2878) patients.Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups.In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

    View details for DOI 10.2215/CJN.07730814

    View details for PubMedID 25710802

  • The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Parfrey, P. S., Drueeke, T. B., Block, G. A., Correa-Rotter, R., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Kubo, Y., Dehmel, B., Goodman, W. G., Chertow, G. M. 2015; 10 (5): 791-799
  • Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation-Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) AMERICAN HEART JOURNAL Holmqvist, F., Guan, N., Zhu, Z., Kowey, P. R., Allen, L. A., Fonarow, G. C., Hylek, E. M., Mahaffey, K. W., Freeman, J. V., Chang, P., Holmes, D. N., Peterson, E. D., Piccini, J. P., Gersh, B. J. 2015; 169 (5): 647-U93

    Abstract

    Obstructive sleep apnea (OSA) is common in patients with atrial fibrillation (AF). Little is known about the impact of OSA on AF treatment and long-term outcomes. We studied whether patients with OSA have a greater likelihood of progressing to more persistent forms of AF or require more hospitalizations and/or worse outcomes compared with patients without OSA.A total of 10,132 patients were enrolled between June 2010 and August 2011 in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) and followed for up to 2 years. The prevalence of OSA and continuous positive airway pressure (CPAP) treatment was captured at baseline. The association between OSA and major cardiovascular outcomes was analyzed using multivariable hierarchical logistic regression modeling and Cox frailty regression model.Of the 10,132 patients with AF, 1,841 had OSA. Patients with OSA were more symptomatic (22% vs 16% severe/disabling symptoms; P < .0001) and more often on rhythm control therapy (35% vs 31%; P = .0037). In adjusted analyses, patients with OSA had higher risk of hospitalization (hazard ratio [HR], 1.12; 95% CI, 1.03-1.22; P = .0078), but no difference in the risks of death (HR, 0.94; 95% CI, 0.77-1.15; P = .54); the composite of CV death, myocardial infarction, and stroke/transient ischemic attack (HR, 1.07; 95% CI, 0.85-1.34; P = .57); major bleeding (HR, 1.18; 95% CI, 0.96-1.46; P = .11); or AF progression (HR, 1.06; 95% CI, 0.89-1.28; P = .51). Patients with OSA on CPAP treatment were less likely to progress to more permanent forms of AF compared with patients without CPAP (HR, 0.66; 95% CI, 0.46-0.94; P = .021).Compared with those without, AF patients with OSA have worse symptoms and higher risks of hospitalization, but similar mortality, major adverse cardiovascular outcome, and AF progression rates.NCT01165710 (http://www.clinicaltrials.gov).

    View details for DOI 10.1016/j.ahj.2014.12.024

    View details for Web of Science ID 000354172400011

    View details for PubMedID 25965712

  • Assessing the treatment effect in a randomized controlled trial with extensive non-adherence: the EVOLVE trial PHARMACEUTICAL STATISTICS Kubo, Y., Sterling, L. R., Parfrey, P. S., Gill, K., Mahaffey, K. W., Gioni, I., Trotman, M., Dehmel, B., Chertow, G. M. 2015; 14 (3): 242-251

    Abstract

    Intention-to-treat (ITT) analysis is widely used to establish efficacy in randomized clinical trials. However, in a long-term outcomes study where non-adherence to study drug is substantial, the on-treatment effect of the study drug may be underestimated using the ITT analysis. The analyses presented herein are from the EVOLVE trial, a double-blind, placebo-controlled, event-driven cardiovascular outcomes study conducted to assess whether a treatment regimen including cinacalcet compared with placebo in addition to other conventional therapies reduces the risk of mortality and major cardiovascular events in patients receiving hemodialysis with secondary hyperparathyroidism. Pre-specified sensitivity analyses were performed to assess the impact of non-adherence on the estimated effect of cinacalcet. These analyses included lag-censoring, inverse probability of censoring weights (IPCW), rank preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE). The relative hazard (cinacalcet versus placebo) of mortality and major cardiovascular events was 0.93 (95% confidence interval 0.85, 1.02) using the ITT analysis; 0.85 (0.76, 0.95) using lag-censoring analysis; 0.81 (0.70, 0.92) using IPCW; 0.85 (0.66, 1.04) using RPSFTM and 0.85 (0.75, 0.96) using IPE. These analyses, while not providing definitive evidence, suggest that the intervention may have an effect while subjects are receiving treatment. The ITT method remains the established method to evaluate efficacy of a new treatment; however, additional analyses should be considered to assess the on-treatment effect when substantial non-adherence to study drug is expected or observed.

    View details for DOI 10.1002/pst.1680

    View details for Web of Science ID 000354417000010

    View details for PubMedID 25851955

  • Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium-Glucose Cotransporter 2, When Used in Conjunction With Insulin Therapy in Patients With Type 2 Diabetes DIABETES CARE Neal, B., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Ways, K., Desai, M., Shaw, W., Capuano, G., Alba, M., Jiang, J., Vercruysse, F., Meininger, G., Matthews, D. 2015; 38 (3): 403-411

    Abstract

    There are limited data about the effects of sodium-glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin.The CANagliflozin CardioVascular Assessment Study is a double-blind, placebo-controlled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined.Individuals receiving insulin at baseline were randomized to receive placebo (n = 690), canagliflozin 100 mg (n = 692), or canagliflozin 300 mg (n = 690). These individuals were 66% male and had a median age of 63 years, mean HbA1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m(2), estimated glomerular filtration rate of 75 mL/min/1.73 m(2), fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA1c with canagliflozin 100 and 300 mg versus placebo were -0.62% (95% CI -0.69, -0.54; -6.8 mmol/mol [95% CI -7.5, -5.9]; P < 0.001) and -0.73% (95% CI -0.81, -0.65; -8.0 mmol/mol [95% CI -8.9, -7.1]; P < 0.001) at 18 weeks and -0.58% (95% CI -0.68, -0.48; -6.3 mmol/mol [95% CI -7.4, -5.2]) and -0.73% (95% CI -0.83, -0.63; -8.0 mmol/mol [95% CI -9.1, -6.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses.Canagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.

    View details for DOI 10.2337/dc14-1237

    View details for Web of Science ID 000350303700024

    View details for PubMedID 25468945

  • Outcomes With Cangrelor Versus Clopidogrel on a Background of Bivalirudin Insights From the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) JACC-CARDIOVASCULAR INTERVENTIONS White, H. D., Bhatt, D. L., Gibson, C. M., Hamm, C. W., Mahaffey, K. W., Price, M. J., Steg, P. G., Stone, G. W., Cortese, B., Wilensky, M., Deliargyris, E. N., Liu, T., Prats, J., Harrington, R. A. 2015; 8 (3): 424-433

    Abstract

    The aim of this study was to examine the efficacy and bleeding outcomes of cangrelor in patients in the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) who underwent percutaneous coronary intervention with bivalirudin.Cangrelor is a potent intravenous P2Y12 inhibitor with rapid onset and offset. In the CHAMPION PHOENIX, cangrelor compared with clopidogrel significantly reduced 48-h ischemic events including stent thrombosis, without increasing major bleeding. Bivalirudin has demonstrated ischemic outcomes similar to those with heparin plus glycoprotein IIb/IIIa inhibition, with reduced bleeding but increased early stent thrombosis.In the modified intent-to-treat population, 2,059 patients (18.8%) received bivalirudin, with 1,014 patients in the cangrelor treatment arm and 1,045 in the clopidogrel treatment arm.At 48 h, the primary endpoint of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis was lower with cangrelor versus clopidogrel (48 [4.7%] vs. 70 [6.7%]; odds ratio [OR]: 0.68, p = 0.047). Death was similar in both arms (2 [0.2%] vs. 2 [0.2%]). Myocardial infarction was reduced by cangrelor (37 [3.6%] vs. 59 [5.6%]; OR: 0.63, p = 0.03), as was death/myocardial infarction (39 [3.8%] vs. 61 [5.8%]; OR: 0.65, p = 0.04). Cangrelor was associated with a nonsignificant trend toward less stent thrombosis (7 [0.7%] vs. 15 [1.4%]; OR: 0.48, p = 0.10), which was evident within 2 h after percutaneous coronary intervention (p = 0.057). GUSTO (Global Use of Strategies to Open Occluded Arteries) severe bleeding was similar in both arms (2 of 1,021 [0.2%] vs. 2 of 1,055 [0.2%]) as were other bleeding definitions and transfusions. Efficacy and safety results were consistent in patients with stable angina, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction (p for interaction: 0.62 and 0.29).Cangrelor may offer an attractive benefit risk profile when used in combination with bivalirudin.

    View details for DOI 10.1016/j.jcin.2014.09.025

    View details for Web of Science ID 000351221300014

    View details for PubMedID 25703887

  • Use and Outcomes Associated With Bridging During Anticoagulation Interruptions in Patients With Atrial Fibrillation: Findings From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation Steinberg, B. A., Peterson, E. D., Kim, S., Thomas, L., Gersh, B. J., Fonarow, G. C., Kowey, P. R., Mahaffey, K. W., Sherwood, M. W., Chang, P., Piccini, J. P., Ansell, J. 2015; 131 (5): 488-494

    Abstract

    Temporary interruption of oral anticoagulation for procedures is often required, and some propose using bridging anticoagulation. However, the use and outcomes of bridging during oral anticoagulation interruptions in clinical practice are unknown.The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry is a prospective, observational registry study of US outpatients with atrial fibrillation. We recorded incident temporary interruptions of oral anticoagulation for a procedure, including the use and type of bridging therapy. Outcomes included multivariable-adjusted rates of myocardial infarction, stroke or systemic embolism, major bleeding, cause-specific hospitalization, and death within 30 days. Of 7372 patients treated with oral anticoagulation, 2803 overall interruption events occurred in 2200 patients (30%) at a median follow-up of 2 years. Bridging anticoagulants were used in 24% (n=665), predominantly low-molecular-weight heparin (73%, n=487) and unfractionated heparin (15%, n=97). Bridged patients were more likely to have had prior cerebrovascular events (22% versus 15%; P=0.0003) and mechanical valve replacements (9.6% versus 2.4%; P<0.0001); however, there was no difference in CHA2DS2-VASc scores (scores ?2 in 94% versus 95%; P=0.5). Bleeding events were more common in bridged than nonbridged patients (5.0% versus 1.3%; adjusted odds ratio, 3.84; P<0.0001). The incidence of myocardial infarction, stroke or systemic embolism, major bleeding, hospitalization, or death within 30 days was also significantly higher in patients receiving bridging (13% versus 6.3%; adjusted odds ratio, 1.94; P=0.0001).Bridging anticoagulation is used in one quarter of anticoagulation interruptions and is associated with higher risk for bleeding and adverse events. These data do not support the use of routine bridging, and additional data are needed to identify best practices concerning anticoagulation interruptions.http://www.clinicaltrials.gov. Unique identifier: NCT01165710.

    View details for DOI 10.1161/CIRCULATIONAHA.114.011777

    View details for PubMedID 25499873

  • Centralized adjudication of cardiovascular end points in cardiovascular and noncardiovascular pharmacologic trials: A report from the Cardiac Safety Research Consortium AMERICAN HEART JOURNAL Seltzer, J. H., Turner, J. R., Geiger, M. J., Rosano, G., Mahaffey, K. W., White, W. B., Sabol, M. B., Stockbridge, N., Sager, P. T. 2015; 169 (2): 197-204
  • Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. European heart journal Steinberg, B. A., Hellkamp, A. S., Lokhnygina, Y., Patel, M. R., Breithardt, G., Hankey, G. J., Becker, R. C., Singer, D. E., Halperin, J. L., Hacke, W., Nessel, C. C., Berkowitz, S. D., Mahaffey, K. W., Fox, K. A., Califf, R. M., Piccini, J. P. 2015; 36 (5): 288-296

    Abstract

    Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation (AF). We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation.Patients randomized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (n = 14 264) were grouped by baseline AF category: paroxysmal or persistent. Multivariable adjustment was performed to compare thrombo-embolic events, bleeding, and death between groups, in high-risk subgroups, and across treatment assignment (rivaroxaban or warfarin). Of 14 062 patients, 11 548 (82%) had persistent AF and 2514 (18%) had paroxysmal AF. Patients with persistent AF were marginally older (73 vs. 72, P = 0.03), less likely female (39 vs. 45%, P < 0.0001), and more likely to have previously used vitamin K antagonists (64 vs. 56%, P < 0.0001) compared with patients with paroxysmal AF. In patients randomized to warfarin, time in therapeutic range was similar (58 vs. 57%, P = 0.94). Patients with persistent AF had higher adjusted rates of stroke or systemic embolism (2.18 vs. 1.73 events per 100-patient-years, P = 0.048) and all-cause mortality (4.78 vs. 3.52, P = 0.006). Rates of major bleeding were similar (3.55 vs. 3.31, P = 0.77). Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment (rivaroxaban vs. warfarin, Pinteraction = 0.6).In patients with AF at moderate-to-high risk of stroke receiving anticoagulation, those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF.

    View details for DOI 10.1093/eurheartj/ehu359

    View details for PubMedID 25209598

  • Effects of Cinacalcet on Atherosclerotic and Nonatherosclerotic Cardiovascular Events in Patients Receiving Hemodialysis: The EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Wheeler, D. C., London, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Dehmel, B., Drueeke, T. B., Floege, J., Kubo, Y., Mahaffey, K. W., Goodman, W. G., Moe, S. M., Trotman, M., Abdalla, S., Chertow, G. M., Herzog, C. A. 2015; 4 (1)
  • Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial. Journal of the American Heart Association Singer, D. E., Hellkamp, A. S., Yuan, Z., Lokhnygina, Y., Patel, M. R., Piccini, J. P., Hankey, G. J., Breithardt, G., Halperin, J. L., Becker, R. C., Hacke, W., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2015; 4 (3)

    Abstract

    In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial.We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted.TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported.ClinicalTrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/JAHA.114.001349

    View details for PubMedID 25736441

  • Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial EUROPEAN HEART JOURNAL Breithardt, G., Baumgartner, H., Berkowitz, S. D., Hellkamp, A. S., Piccini, J. P., Stevens, S. R., Lokhnygina, Y., Patel, M. R., Halperin, J. L., Singer, D. E., Hankey, G. J., Hacke, W., Becker, R. C., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2014; 35 (47): 3377-3385

    Abstract

    We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial.ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55-1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75-1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05-1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94-1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban.Many patients with 'non-valvular atrial fibrillation' have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants.

    View details for DOI 10.1093/eurheartj/ehu305

    View details for Web of Science ID 000346406800016

    View details for PubMedID 25148838

  • Effects of Cinacalcet on Atherosclerotic and Nonatherosclerotic Cardiovascular Events in Patients Receiving Hemodialysis: The EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Wheeler, D. C., London, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Dehmel, B., Drueeke, T. B., Floege, J., Kubo, Y., Mahaffey, K. W., Goodman, W. G., Moe, S. M., Trotman, M., Abdalla, S., Chertow, G. M., Herzog, C. A. 2014; 3 (6)
  • Effects of cinacalcet on atherosclerotic and nonatherosclerotic cardiovascular events in patients receiving hemodialysis: the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial. Journal of the American Heart Association Wheeler, D. C., London, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Dehmel, B., Drüeke, T. B., Floege, J., Kubo, Y., Mahaffey, K. W., Goodman, W. G., Moe, S. M., Trotman, M., Abdalla, S., Chertow, G. M., Herzog, C. A. 2014; 3 (6)

    Abstract

    Premature cardiovascular disease limits the duration and quality of life on long-term hemodialysis. The objective of this study was to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms, risk factors for these events, and the effects of cinacalcet, using adjudicated data collected during the EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial.EVOLVE was a randomized, double-blind, placebo-controlled clinical trial that randomized 3883 hemodialysis patients with moderate to severe secondary hyperparathyroidism to cinacalcet or matched placebo for up to 64 months. For this post hoc analysis, the outcome measure was fatal and nonfatal cardiovascular events reflecting atherosclerotic and nonatherosclerotic cardiovascular diseases. During the trial, 1518 patients experienced an adjudicated cardiovascular event, including 958 attributable to nonatherosclerotic disease. Of 1421 deaths during the trial, 768 (54%) were due to cardiovascular disease. Sudden death was the most frequent fatal cardiovascular event, accounting for 24.5% of overall mortality. Combining fatal and nonfatal cardiovascular events, randomization to cinacalcet reduced the rates of sudden death and heart failure. Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events (adjusted relative hazard 0.84, 95% CI 0.74 to 0.96), while the effect of cinacalcet on atherosclerotic events did not reach statistical significance.Accepting the limitations of post hoc analysis, any benefits of cinacalcet on cardiovascular disease in the context of hemodialysis may result from attenuation of nonatherosclerotic processes.Unique identifier: NCT00345839. URL: ClinicalTrials.gov.

    View details for DOI 10.1161/JAHA.114.001363

    View details for PubMedID 25404192

  • Vorapaxar with or without clopidogrel after non-ST-segment elevation acute coronary syndromes: Results from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial AMERICAN HEART JOURNAL Tricoci, P., Lokhnygina, Y., Huang, Z., Van de Werf, F., Cornel, J. H., Chen, E., Wallentin, L., Held, C., Aylward, P. E., Moliterno, D. J., Jennings, L. K., White, H. D., Armstrong, P. W., Harrington, R. A., Strony, J., Mahaffey, K. W. 2014; 168 (6): 869-?
  • Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes HEART Varenhorst, C., Alstrom, U., Braun, O. O., Storey, R. F., Mahaffey, K. W., Bertilsson, M., Cannon, C. P., Scirica, B. M., Himmelmann, A., James, S. K., Wallentin, L., Held, C. 2014; 100 (22): 1762-?
  • Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial AMERICAN HEART JOURNAL Schwartz, G. G., Bessac, L., Berdan, L. G., Bhatt, D. L., Bittner, V., Diaz, R., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Rorick, T., Sasiela, W. J., Shirodaria, C., Szarek, M., Tamby, J., Tricoci, P., White, H., Zeiher, A., Steg, P. G. 2014; 168 (5): 682-689
  • Challenges and Solutions to Pre- and Post-Randomization Subgroup Analyses CURRENT CARDIOLOGY REPORTS Desai, M., Pieper, K. S., Mahaffey, K. 2014; 16 (10)

    Abstract

    Subgroup analyses are commonly performed in the clinical trial setting with the purpose of illustrating that the treatment effect was consistent across different patient characteristics or identifying characteristics that should be targeted for treatment. There are statistical issues involved in performing subgroup analyses, however. These have been given considerable attention in the literature for analyses where subgroups are defined by a pre-randomization feature. Although subgroup analyses are often performed with subgroups defined by a post-randomization feature--including analyses that estimate the treatment effect among compliers--discussion of these analyses has been neglected in the clinical literature. Such analyses pose a high risk of presenting biased descriptions of treatment effects. We summarize the challenges of doing all types of subgroup analyses described in the literature. In particular, we emphasize issues with post-randomization subgroup analyses. Finally, we provide guidelines on how to proceed across the spectrum of subgroup analyses.

    View details for DOI 10.1007/s11886-014-0531-2

    View details for Web of Science ID 000345086700003

    View details for PubMedID 25135344

  • Prognostic implications of creatine kinase-MB measurements in ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention AMERICAN HEART JOURNAL Bagai, A., Schulte, P. J., Granger, C. B., Mahaffey, K. W., Christenson, R. H., Bell, G., Lopes, R. D., Green, C. L., Lincoff, A. M., Armstrong, P. W., Roe, M. T. 2014; 168 (4): 503-?

    Abstract

    Peak creatine kinase (CK)-MB concentration is related to reperfusion success and clinical outcomes after fibrinolytic therapy for acute myocardial infarction. However, prognostic implications of CK-MB measurements after primary percutaneous coronary intervention (PCI), which provides more predictable and consistent reperfusion, are unknown.We pooled 2,042 primary PCI-treated ST-segment elevation myocardial infarction (STEMI) patients from 3 trials with serial core laboratory-determined CK-MB measurements; 1,799 patients (88.1%) who survived to 36 hours and had ?4 CK-MB measurements were studied. Cox regression modeling was performed to quantify the association between peak CK-MB concentration (and area under the time-concentration curve [AUC]) and mortality at 6 months, and death or congestive heart failure at 90 days.The median (25th-75th percentiles) peak CK-MB concentration and AUC measurement through 36 hours were 239 (109-429) ng/mL and 4,263 (2,081-7,124) ng/(mL h), respectively. By multivariable analysis, peak CK-MB concentration and AUC measurement were independently associated with 6-month mortality (adjusted hazard ratio [HR] 1.15, 95% CI 1.05-1.25, per 100-ng/mL increase, P = .002; and adjusted HR 1.09, 95% CI 1.03-1.14, per 1,000-ng/[mL h] increase, P < .001, respectively) and 90-day death or congestive heart failure (adjusted HR 1.26, 95% CI 1.18-1.34, P < .001; and adjusted HR 1.15, 95% CI 1.11-1.19, P < .001, respectively).Peak CK-MB concentration and AUC measurement are independent predictors of 3- to 6-month cardiovascular outcomes in primary PCI-treated STEMI patients. Our findings guide application of these measurements as efficacy end points in early-phase studies evaluating new therapies for STEMI.

    View details for DOI 10.1016/j.ahj.2014.06.008

    View details for Web of Science ID 000343096900016

    View details for PubMedID 25262260

  • Reasons for warfarin discontinuation in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) AMERICAN HEART JOURNAL O'Brien, E. C., Simon, D. N., Allen, L. A., Singer, D. E., Fonarow, G. C., Kowey, P. R., Thomas, L. E., Ezekowitz, M. D., Mahaffey, K. W., Chang, P., Piccini, J. P., Peterson, E. D. 2014; 168 (4): 487-494
  • Vorapaxar in patients with peripheral artery disease and acute coronary syndrome: Insights from Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) AMERICAN HEART JOURNAL Jones, W. S., Tricoci, P., Huang, Z., Moliterno, D. J., Harrington, R. A., Sinnaeve, P. R., Strony, J., Van de Werf, F., White, H. D., Held, C., Armstrong, P. W., Aylward, P. E., Chen, E., Patel, M. R., Mahaffey, K. W. 2014; 168 (4): 588-596
  • Challenges and Priorities for Research A Report From the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on Thrombosis in Pediatric Cardiology and Congenital Heart Disease CIRCULATION McCrindle, B. W., Li, J. S., Manlhiot, C., Tweddell, J. S., Giglia, T. M., Massicotte, M. P., Monagle, P., Krishnamurthy, R., Mahaffey, K. W., Michelson, A. D., Verdun, N., Almond, C. S., Newburger, J. W., Brandao, L. R., Esmon, C. T., Manco-Johnson, M. J., Ichord, R., Ortel, T. L., Chan, A. K., Portman, R., Rose, M., Strony, J., Kaltman, J. R. 2014; 130 (14): 1192-1203
  • Vorapaxar, a platelet thrombin-receptor antagonist, in medically managed patients with non-ST-segment elevation acute coronary syndrome: results from the TRACER trial. European heart journal. Acute cardiovascular care Held, C., Tricoci, P., Huang, Z., Van de Werf, F., White, H. D., Armstrong, P. W., Ambrosio, G., Aylward, P. E., Moliterno, D. J., Wallentin, L., Chen, E., Erkan, A., Jiang, L., Strony, J., Harrington, R. A., Mahaffey, K. W. 2014; 3 (3): 246-256

    Abstract

    This study characterized a medically managed population in a non-ST-segment elevation acute coronary syndrome (NSTEACS) cohort and evaluated prognosis and outcomes of vorapaxar vs. placebo.In the TRACER study, 12,944 NSTEACS patients were treated with standard care and vorapaxar (a novel platelet protease-activated receptor-1 antagonist) or placebo. Of those, 4194 patients (32.4%) did not undergo revascularization during index hospitalization, and 8750 (67.6%) underwent percutaneous coronary intervention or coronary artery bypass grafting. Patients managed medically were heterogeneous with different risk profiles, including 1137 (27.1%) who did not undergo coronary angiography. Patients who underwent angiography but were selected for medical management included those without evidence of significant coronary artery disease (CAD), with prior CAD but no new significant lesions, and with significant lesions who were not treated with revascularization.Cardiovascular event rates were highest among those without angiography and lowest in the group with angiography but without CAD. In the medically managed cohort, 2-year primary outcome (cardiovascular death, myocardial infarction, stroke, recurrent ischaemia with rehospitalization, urgent coronary revascularization) event rates were 16.3% with vorapaxar and 17.0% with placebo (HR 0.99, 95% CI 0.83-1.17), with no interaction between drug and management strategy (p=0.75). Key secondary endpoint (cardiovascular death, myocardial infarction, stroke) rates were 13.4% with vorapaxar and 14.9% with placebo (HR 0.89, 95% CI 0.74-1.07), with no interaction (p=0.58). Vorapaxar increased GUSTO moderate/severe bleeding numerically in medically managed patients (adjusted HR 1.46, 95% CI 0.99-2.15).NSTEACS patients who were initially medically managed had a higher risk-factor burden, and one-third had normal coronary arteries. Outcome in the medically managed cohort was significantly related to degree of CAD, highlighting the importance of coronary angiography. Efficacy and safety of vorapaxar appeared consistent with the overall trial results.

    View details for DOI 10.1177/2048872614527838

    View details for PubMedID 24627331

  • Usefulness and Safety of Vorapaxar in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention (from the TRACER Trial). American journal of cardiology Valgimigli, M., Tricoci, P., Huang, Z., Aylward, P. E., Armstrong, P. W., Van de Werf, F., Leonardi, S., White, H. D., Widimsky, P., Harrington, R. A., Cequier, A., Chen, E., Lokhnygina, Y., Wallentin, L., Strony, J., Mahaffey, K. W., Moliterno, D. J. 2014; 114 (5): 665-673

    Abstract

    The therapeutic potential of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention (PCI) is unknown. This prespecified analysis of a postrandomization subgroup evaluated the effects of vorapaxar compared with placebo among Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) participants undergoing PCI, focusing on the implanted stent type (drug-eluting stent [DES] vs bare-metal stent [BMS]). Among 12,944 recruited patients, 7,479 (57.8%) underwent PCI during index hospitalization, and 3,060 (40.9%) of those patients received exclusively BMS, whereas 4,015 (53.7%) received DES. The median (twenty-fifth, seventy-fifth percentiles) duration of thienopyridine therapy was 133 days (47, 246) with BMS and 221 days (88, 341) with DES. At 2 years among patients undergoing PCI, the primary (cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) and secondary (cardiovascular death, myocardial infarction, or stroke) end points did not differ between vorapaxar and placebo groups, which was consistent with the treatment effect observed in the overall study population (p value for interaction = 0.540). However, the treatment effect trended greater (p value for interaction = 0.069) and the risk for bleeding in patients taking vorapaxar versus placebo appeared attenuated in BMS-only recipients. After adjustment for confounders, the interaction was no longer significant (p value = 0.301). The covariate that mostly explained the stent-type-by-treatment interaction was the duration of clopidogrel therapy. In conclusion, among patients with PCI, the effect of vorapaxar is consistent with the overall TRACER results. Patients who received a BMS underwent shorter courses of clopidogrel therapy and displayed trends toward greater ischemic benefit from vorapaxar and lesser bleeding risk, compared with patients who received a DES.

    View details for DOI 10.1016/j.amjcard.2014.05.054

    View details for PubMedID 25129064

  • Long-term outcomes associated with hospital acquired thrombocytopenia among patients with non-ST-segment elevation acute coronary syndrome AMERICAN HEART JOURNAL Vora, A. N., Chenier, M., Schulte, P. J., Goodman, S., Peterson, E. D., Pieper, K., Jolicoeur, M. E., Mahaffey, K. W., White, H., Wang, T. Y. 2014; 168 (2): 189-?

    Abstract

    Acquired thrombocytopenia after a non-ST-segment-elevation-acute coronary syndrome (NSTE-ACS) has been associated with increased in-hospital mortality and hemorrhagic complications, but longer term outcomes are unclear. We examined the association between thrombocytopenia and long-term outcomes after accounting for thrombocytopenia severity and discharge medication use.Data from 7,435 NSTE-ACS patients enrolled in the SYNERGY trial were analyzed. Severe thrombocytopenia was defined as a nadir platelet count <100 × 10(9)/L or a ? 50% drop from baseline. Mild thrombocytopenia was defined as a nadir platelet count between 100 and 149 × 10(9)/L with a <50% drop from baseline. The primary outcomes of interest were in-hospital GUSTO moderate-severe bleeding and 1-year mortality.Overall, 675 patients (9.1%) developed mild thrombocytopenia and 139 patients (1.9%) developed severe thrombocytopenia. In-hospital bleeding risks were higher in patients with mild (7.7%, adjusted HR 1.63, 95% CI 1.16-2.29) or severe (28.2%, adjusted HR 6.93, 95% CI 4.55-10.56) thrombocytopenia than in patients without thrombocytopenia (5.2%). One-year mortality rates were 6.5%, 8.1%, and 28.1% among patients with no, mild, and severe thrombocytopenia, respectively (log rank P < 0.001) but only severe thrombocytopenia remained significantly associated with increased mortality after adjustment: HR 4.07, 95% CI 2.86-5.78. Patients who developed severe thrombocytopenia were less likely to be discharged on guideline-recommended antiplatelet therapy. The relationship between severe thrombocytopenia and mortality was attenuated by but persisted after adjusting for discharge medication use (HR 2.83, 95% CI 1.49-5.38).Thrombocytopenia occurs commonly during the course of NSTE-ACS care; even mild decreases are associated with clinically meaningful bleeding. Patients who developed severe thrombocytopenia were less likely to be discharged on guideline-recommended antiplatelet therapy; this may contribute to their higher associated long-term mortality.

    View details for DOI 10.1016/j.ahj.2014.04.010

    View details for Web of Science ID 000340207700013

    View details for PubMedID 25066558

  • Population Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Patients with Non-valvular Atrial Fibrillation: Results from ROCKET AF JOURNAL OF CLINICAL PHARMACOLOGY Girgis, I. G., Patel, M. R., Peters, G. R., Moore, K. T., Mahaffey, K. W., Nessel, C. C., Halperin, J. L., Califf, R. M., Fox, K. A., Becker, R. C. 2014; 54 (8): 917-927

    Abstract

    Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20?mg for patients with normal/mildly impaired renal function and 15?mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n?=?161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24?hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF.

    View details for DOI 10.1002/jcph.288

    View details for Web of Science ID 000339163200013

    View details for PubMedID 24668660

  • Outcomes registry for better informed treatment of atrial fibrillation II: Rationale and design of the ORBIT-AF II registry. American heart journal Steinberg, B. A., Blanco, R. G., Ollis, D., Kim, S., Holmes, D. N., Kowey, P. R., Fonarow, G. C., Ansell, J., Gersh, B., Go, A. S., Hylek, E., Mahaffey, K. W., Thomas, L., Chang, P., Peterson, E. D., Piccini, J. P. 2014; 168 (2): 160-167

    Abstract

    Recent clinical trials have demonstrated the safety and efficacy of several non-vitamin K oral anticoagulants (NOACs) for the treatment of atrial fibrillation (AF). However, there are limited data on their use and outcomes in routine clinical practice, particularly among patients newly diagnosed as having AF and patients with AF recently transitioned to a NOAC.ORBIT-AF II is a multicenter, national registry of patients with AF that is enrolling up to 15,000 newly diagnosed patients with AF and/or those with AF recently transitioned to a NOAC from 300 US outpatient practices. These patients will be followed for up to 2 years, including clinical status, outcomes (major adverse cardiovascular events, bleeding), and management of anticoagulation surrounding bleeding events. In addition, detailed data regarding the use of these agents in and around cardiac procedures, their complications, and management of such complications will be collected.The ORBIT-AF II registry will provide valuable insights into the safety and effectiveness of NOACs used in AF in community practice settings.

    View details for DOI 10.1016/j.ahj.2014.04.005

    View details for PubMedID 25066554

  • Independent data monitoring committees: Preparing a path for the future. American heart journal Hess, C. N., Roe, M. T., Gibson, C. M., J Temple, R., Pencina, M. J., Zarin, D. A., Anstrom, K. J., Alexander, J. H., Sherman, R. E., Fiedorek, F. T., Mahaffey, K. W., Lee, K. L., Chow, S., Armstrong, P. W., Califf, R. M. 2014; 168 (2): 135-141 e1

    Abstract

    Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs.

    View details for DOI 10.1016/j.ahj.2014.05.003

    View details for PubMedID 25066551

  • Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. European heart journal Piccini, J. P., Garg, J., Patel, M. R., Lokhnygina, Y., Goodman, S. G., Becker, R. C., Berkowitz, S. D., Breithardt, G., Hacke, W., Halperin, J. L., Hankey, G. J., Nessel, C. C., Mahaffey, K. W., Singer, D. E., Califf, R. M., Fox, K. A. 2014; 35 (28): 1873-1880

    Abstract

    There are no data regarding management and outcomes of major bleeding events in patients treated with oral factor Xa inhibitors.Using data from ROCKET AF, we analysed the management and outcomes of major bleeding overall and according to the randomized treatment. During a median follow-up of 1.9 years, 779 (5.5%) patients experienced major bleeding at a rate of 3.52 events/100 patient-years with a similar event rate in each arm (n = 395 rivaroxaban vs. n = 384 warfarin). The median number of transfused packed red blood cells (PRBC) per episode was similar in both arms [2 (25th, 75th: 2, 4) units]. Overall, few transfusions of whole blood (n = 14), platelets (n = 10), or cryoprecipitate (n = 2) were used. Transfusion of fresh frozen plasma (FFP) was significantly less in the rivaroxaban arm (n = 45 vs. n = 81 units) after adjustment for covariates [odds ratio (OR) 0.43 (95% CI 0.29-0.66); P < 0.0001]. Prothrombin complex concentrates (PCC) were administered less in the rivaroxaban arm (n = 4 vs. n = 9). Outcomes after major bleeding, including stroke or non-central nervous system embolism (4.7% rivaroxaban vs. 5.4% warfarin; HR 0.89; 95% CI 0.42-1.88) and all-cause death (20.4% rivaroxaban vs. 26.1% warfarin; HR 0.69, 95% CI 0.46-1.04) were similar in patients treated with rivaroxaban and warfarin (interaction P = 0.51 and 0.11).Among high-risk patients with atrial fibrillation who experienced major bleeding in ROCKET AF, the use of FFP and PCC was less among those allocated rivaroxaban compared with warfarin. However, use of PRBCs and outcomes after bleeding were similar among patients randomized to rivaroxaban or to warfarin.

    View details for DOI 10.1093/eurheartj/ehu083

    View details for PubMedID 24658769

  • Efficacy and Safety of Rivaroxaban Compared With Warfarin Among Elderly Patients With Nonvalvular Atrial Fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) CIRCULATION Halperin, J. L., Hankey, G. J., Wojdyla, D. M., Piccini, J. P., Lokhnygina, Y., Patel, M. R., Breithardt, G., Singer, D. E., Becker, R. C., Hacke, W., Paolini, J. F., Nessel, C. C., Mahaffey, K. W., Califf, R. M., Fox, K. A. 2014; 130 (2): 138-U45
  • Comparison of Clinical Trial Outcome Patterns in Patients Following Acute Coronary Syndromes and in Patients With Chronic Stable Atherosclerosis CLINICAL CARDIOLOGY Mahaffey, K. W., Wojdyla, D. M., Pieper, K. S., Tricoci, P., Alexander, J. H., Lincoff, A. M., Brennan, D. M., Bhatt, D. L., Wallentin, L., Harrington, R. A. 2014; 37 (6): 337-342

    View details for DOI 10.1002/clc.22255

    View details for Web of Science ID 000337597900003

  • Rivaroxaban for Stroke Prevention in East Asian Patients From the ROCKET AF Trial STROKE Wong, K. S., Hu, D. Y., Oomman, A., Tan, R., Patel, M. R., Singer, D. E., Breithardt, G., Mahaffey, K. W., Becker, R. C., Califf, R., Fox, K. A., Berkowitz, S. D., Hacke, W., Hankey, G. J. 2014; 45 (6): 1739-?

    Abstract

    In Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban was noninferior to dose-adjusted warfarin in preventing stroke or systemic embolism among patients with nonvalvular atrial fibrillation at moderate to high stroke risk. Because of differences in patient demographics, epidemiology, and stroke risk management in East Asia, outcomes and relative effects of rivaroxaban versus warfarin were assessed to determine consistency among East Asians versus other ROCKET AF participants.Baseline demographics and interaction of treatment effects of rivaroxaban and warfarin among patients within East Asia and outside were assessed.A total of 932 (6.5%) ROCKET AF participants resided in East Asia. At baseline, East Asians had lower weight, creatinine clearance, and prior vitamin K antagonist use; higher prevalence of prior stroke; and less congestive heart failure and prior myocardial infarction than other participants. Despite higher absolute event rates for efficacy and safety outcomes in East Asians, the relative efficacy of rivaroxaban (20 mg once daily; 15 mg once daily for creatinine clearance of 30-49 mL/min) versus warfarin with respect to the primary efficacy end point (stroke/systemic embolism) was consistent among East Asians and non-East Asians (interaction P=0.666). Relative event rates for the major or nonmajor clinically relevant bleeding in patients treated with rivaroxaban and warfarin were consistent among East Asians and non-East Asians (interaction P=0.867).Observed relative efficacy and safety of rivaroxaban versus warfarin were similar among patients within and outside East Asia. Rivaroxaban, 20 mg once daily, is an alternative to warfarin for stroke prevention in East Asians with nonvalvular atrial fibrillation.http://www.clinicaltrials.gov. Unique identifier: NCT00123456.

    View details for DOI 10.1161/STROKEAHA.113.002968

    View details for Web of Science ID 000337090700034

    View details for PubMedID 24763930

  • Use and outcomes of antiarrhythmic therapy in patients with atrial fibrillation receiving oral anticoagulation: Results from the ROCKET AF trial HEART RHYTHM Steinberg, B. A., Hellkamp, A. S., Lokhnygina, Y., Halperin, J. L., Breithardt, G., Passman, R., Hankey, G. J., Patel, M. R., Becker, R. C., Singer, D. E., Hacke, W., Berkowitz, S. D., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M., Piccini, J. P. 2014; 11 (6): 925-932

    Abstract

    Antiarrhythmic drugs (AADs) and anticoagulation are mainstays of atrial fibrillation (AF) treatment.To study the use and outcomes of AAD therapy in anticoagulated patients with AF.Patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial (N = 14,264) were stratified by AAD use at baseline: amiodarone, other AAD, or no AAD. Multivariable adjustment was performed to compare stroke, bleeding, and death across AAD groups as well as across treatment assignment (rivaroxaban or warfarin).Of 14,264 patients randomized, 1681 (11.8%) were treated with an AAD (1144 [8%] with amiodarone and 537 [3.8%] with other AADs). Amiodarone-treated patients were less often female (38% vs 48%), had more persistent AF (64% vs 40%), and more concomitant heart failure (71% vs 41%) than were patients receiving other AADs. Patients receiving no AAD more closely resembled amiodarone-treated patients. Time in therapeutic range was significantly lower in warfarin-treated patients receiving amiodarone than in those receiving no AAD (50% vs 58%; P < .0001). Compared with no AAD, neither amiodarone (adjusted hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.74-1.31; P = .9) nor other AADs (adjusted HR 0.66; 95% CI 0.37-1.17; P = .15) were associated with increased mortality. Similar results were observed for embolic and bleeding outcomes. Treatment effects of rivaroxaban vs warfarin in patients receiving no AAD were consistent with results from the overall trial (primary end point: adjusted HR 0.82; 95% CI 0.68-0.98; Pinteraction = .06; safety end point: adjusted HR 1.12; 95% CI 0.90-1.24; Pinteraction = .33).Treatment with AADs was not associated with increased morbidity or mortality in anticoagulated patients with AF. The effect of amiodarone on outcomes in patients receiving rivaroxaban requires further investigation.

    View details for DOI 10.1016/j.hrthm.2014.03.006

    View details for Web of Science ID 000336395600003

  • Lack of concordance between empirical scores and physician assessments of stroke and bleeding risk in atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Circulation Steinberg, B. A., Kim, S., Thomas, L., Fonarow, G. C., Hylek, E., Ansell, J., Go, A. S., Chang, P., Kowey, P., Gersh, B. J., Mahaffey, K. W., Singer, D. E., Piccini, J. P., Peterson, E. D. 2014; 129 (20): 2005-2012

    Abstract

    Physicians treating patients with atrial fibrillation (AF) must weigh the benefits of anticoagulation in preventing stroke versus the risk of bleeding. Although empirical models have been developed to predict such risks, the degree to which these coincide with clinicians' estimates is unclear.We examined 10 094 AF patients enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) registry between June 2010 and August 2011. Empirical stroke and bleeding risks were assessed by using the congestive heart failure, hypertension, age ?75 years, diabetes mellitus, and previous stroke or transient ischemic attack (CHADS2) and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) scores, respectively. Separately, physicians were asked to categorize their patients' stroke and bleeding risks: low risk (<3%); intermediate risk (3%-6%); and high risk (>6%). Overall, 72% (n=7251) in ORBIT-AF had high-risk CHADS2 scores (?2). However, only 16% were assessed as high stroke risk by physicians. Although 17% (n=1749) had high ATRIA bleeding risk (score ?5), only 7% (n=719) were considered so by physicians. The associations between empirical and physician-estimated stroke and bleeding risks were low (weighted Kappa 0.1 and 0.11, respectively). Physicians weighed hypertension, heart failure, and diabetes mellitus less significantly than empirical models in estimating stroke risk; physicians weighted anemia and dialysis less significantly than empirical models when estimating bleeding risks. Anticoagulation use was highest among patients with high stroke risk, assessed by either empirical model or physician estimates. In contrast, physician and empirical estimates of bleeding had limited impact on treatment choice.There is little agreement between provider-assessed risk and empirical scores in AF. These differences may explain, in part, the current divergence of anticoagulation treatment decisions from guideline recommendations.http://www.clinicaltrials.gov. Unique identifier: NCT01165710.

    View details for DOI 10.1161/CIRCULATIONAHA.114.008643

    View details for PubMedID 24682387

  • Lack of Concordance Between Empirical Scores and Physician Assessments of Stroke and Bleeding Risk in Atrial Fibrillation Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry CIRCULATION Steinberg, B. A., Kim, S., Thomas, L., Fonarow, G. C., Hylek, E., Ansell, J., Go, A. S., Chang, P., Kowey, P., Gersh, B. J., Mahaffey, K. W., Singer, D. E., Piccini, J. P., Peterson, E. D. 2014; 129 (20): 2005-?
  • Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation Sherwood, M. W., Douketis, J. D., Patel, M. R., Piccini, J. P., Hellkamp, A. S., Lokhnygina, Y., Spyropoulos, A. C., Hankey, G. J., Singer, D. E., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M., Becker, R. C. 2014; 129 (18): 1850-1859

    Abstract

    During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI.In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non-central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3-30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36-1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80-2.00]; P=0.32).TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation.http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.113.005754

    View details for PubMedID 24552831

  • Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes. The TRACER Pharmacodynamic Substudy. Thrombosis and haemostasis Storey, R. F., Kotha, J., Smyth, S. S., Moliterno, D. J., Rorick, T. L., Moccetti, T., Valgimigli, M., Dery, J. P., Cornel, J. H., Thomas, G. S., Huber, K., Harrington, R. A., Hord, E., Judge, H. M., Chen, E., Strony, J., Mahaffey, K. W., Tricoci, P., Becker, R. C., Jennings, L. K. 2014; 111 (5): 883-891

    Abstract

    Vorapaxar is an antagonist of the protease activated receptor-1 (PAR-1), the principal platelet thrombin receptor. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial evaluated vorapaxar compared to placebo in non-ST-elevation (NSTE)-acute coronary syndrome (ACS) patients. It was the study's objective to assess the pharmacodynamic effects of vorapaxar versus placebo that included aspirin or a thienopyridine or, frequently, a combination of both agents in NSTE-ACS patients. In a substudy involving 249 patients, platelet aggregation was assessed by light transmittance aggregometry (LTA) in 85 subjects (41 placebo, 44 vorapaxar) using the agonists thrombin receptor activating peptide (TRAP, 15 ?M), adenosine diphosphate (ADP, 20 ?M), and the combination of collagen-related peptide (2.5 ?g/ml) + ADP (5 ?M) + TRAP (15 ?M) (CAT). VerifyNow® IIb/IIIa and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assays were performed, and platelet PAR-1 expression, plasma platelet/endothelial and inflammatory biomarkers were determined before and during treatment. LTA responses to TRAP and CAT and VerifyNow results were markedly inhibited by vorapaxar. Maximal LTA response to TRAP (median, interquartile range) 2 hours post loading dose: placebo 68% (53-75%) and vorapaxar 3% (2-6%), p<0.0001. ADP inhibition was greater in the vorapaxar group at 4 hours and one month (p<0.01). In contrast to the placebo group, PAR-1 receptor number in the vorapaxar group at one month was significantly lower than the baseline (179 vs 225; p=0.004). There were significant changes in selected biomarker levels between the two treatment groups. In conclusion, vorapaxar caused a potent inhibition of PAR-1-mediated platelet aggregation. Further studies are needed to explore vorapaxar effect on P2Y12 inhibition, PAR-1 expression and biomarkers and its contribution to clinical outcomes.

    View details for DOI 10.1160/TH13-07-0624

    View details for PubMedID 24402559

  • Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes THROMBOSIS AND HAEMOSTASIS Storey, R. F., Kotha, J., Smyth, S. S., Moliterno, D. J., Rorick, T. L., Moccetti, T., Valgimigli, M., Dery, J. P., Cornel, J. H., Thomas, G. S., Huber, K., Harrington, R. A., Hord, E., Judge, H. M., Chen, E., Strony, J., Mahaffey, K. W., Tricoci, P., Becker, R. C., Jennings, L. K. 2014; 111 (5): 883-891
  • Drivers of hospitalization for patients with atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) AMERICAN HEART JOURNAL Steinberg, B. A., Kim, S., Fonarow, G. C., Thomas, L., Ansell, J., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Hylek, E., Naccarelli, G., Go, A. S., Reiffel, J., Chang, P., Peterson, E. D., Piccini, J. P. 2014; 167 (5): 735-U131
  • Drivers of hospitalization for patients with atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). American heart journal Steinberg, B. A., Kim, S., Fonarow, G. C., Thomas, L., Ansell, J., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Hylek, E., Naccarelli, G., Go, A. S., Reiffel, J., Chang, P., Peterson, E. D., Piccini, J. P. 2014; 167 (5): 735-42 e2

    Abstract

    Atrial fibrillation (AF) is the most common cardiac dysrhythmia and contributes significantly to health care expenditures. We sought to assess the frequency and predictors of hospitalization in patients with AF.The ORBIT-AF registry is a prospective, observational study of outpatients with AF enrolled from June 29, 2010, to August 9, 2011. The current analysis included 9,484 participants with 1-year follow-up. Multivariable, logistic regression was used to identify baseline characteristics that were associated with first cause-specific hospitalization.Overall, 31% of patients with AF studied (n = 2,963) had 1 or more hospitalizations per year and 10% (n = 983) had 2 or more. The most common hospitalization cause was cardiovascular (20 per 100 patient-years vs 3.3 bleeding vs 17 noncardiovascular, nonbleeding). Compared with those not hospitalized, hospitalized patients were more likely to have concomitant heart failure (42% vs 28%, P < .0001), higher mean CHADS2 (1 point for congestive heart failure, hypertension, age ?75, or diabetes; 2 points for prior stroke or transient ischemic attack) scores (2.5 vs 2.2, P < .0001), and more symptoms (baseline European Heart Rhythm Association class severe symptoms 18% vs 13%, P < .0001). In multivariable analysis, heart failure (adjusted hazard ratio [HR] 1.57 for New York Heart Association III/IV vs none, P < .0001), heart rate at baseline (adjusted HR 1.11 per 10-beats/min increase >66, P < .0001), and AF symptom class (adjusted HR 1.37 for European Heart Rhythm Association severe vs none, P < .0001) were the major predictors of incident hospitalization.Hospitalization is common in outpatients with AF and is independently predicted by heart failure and AF symptoms. Improved symptom control, rate control, and comorbid condition management should be evaluated as strategies to reduce health care use in these patients.

    View details for DOI 10.1016/j.ahj.2014.02.003

    View details for PubMedID 24766985

  • Intracranial Hemorrhage Among Patients With Atrial Fibrillation Anticoagulated With Warfarin or Rivaroxaban The Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation STROKE Hankey, G. J., Stevens, S. R., Piccini, J. P., Lokhnygina, Y., Mahaffey, K. W., Halperin, J. L., Patel, M. R., Breithardt, G., Singer, D. E., Becker, R. C., Berkowitz, S. D., Paolini, J. F., Nessel, C. C., Hacke, W., Fox, K. A., Califf, R. M. 2014; 45 (5): 1304-1312

    Abstract

    Intracranial hemorrhage (ICH) is a life-threatening complication of anticoagulation.We investigated the rate, outcomes, and predictors of ICH in 14 264 patients with atrial fibrillation from Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Cox proportional hazards modeling was used.During 1.94 years (median) of follow-up, 172 patients (1.2%) experienced 175 ICH events at a rate of 0.67% per year. The significant, independent predictors of ICH were race (Asian: hazard ratio, 2.02; 95% CI, 1.39-2.94; black: hazard ratio, 3.25; 95% CI, 1.43-7.41), age (1.35; 1.13-1.63 per 10-year increase), reduced serum albumin (1.39; 1.12-1.73 per 0.5 g/dL decrease), reduced platelet count below 210×10(9)/L (1.08; 1.02-1.13 per 10×10(9)/L decrease), previous stroke or transient ischemic attack (1.42; 1.02-1.96), and increased diastolic blood pressure (1.17; 1.01-1.36 per 10 mm Hg increase). Predictors of a reduced risk of ICH were randomization to rivaroxaban (0.60; 0.44-0.82) and history of congestive heart failure (0.65; 0.47-0.89). The ability of the model to discriminate individuals with and without ICH was good (C-index, 0.69; 95% CI, 0.64-0.73).Among patients with atrial fibrillation treated with anticoagulation, the risk of ICH was higher among Asians, blacks, the elderly, and in those with previous stroke or transient ischemic attack, increased diastolic blood pressure, and reduced platelet count or serum albumin at baseline. The risk of ICH was significantly lower in patients with heart failure and in those who were randomized to rivaroxaban instead of warfarin. The external validity of these findings requires testing in other atrial fibrillation populations.

    View details for DOI 10.1161/STROKEAHA.113.004506

    View details for Web of Science ID 000335578100031

  • Ticagrelor Effects on Myocardial Infarction and the Impact of Event Adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Mahaffey, K. W., Held, C., Wojdyla, D. M., James, S. K., Katus, H. A., Husted, S., Steg, P. G., Cannon, C. P., Becker, R. C., Storey, R. F., Khurmi, N. S., Nicolau, J. C., Yu, C., Ardissino, D., Budaj, A., Morais, J., Montgomery, D., Himmelmann, A., Harrington, R. A., Wallentin, L. 2014; 63 (15): 1493-1499

    Abstract

    This study sought to report the treatment effect of ticagrelor on myocardial infarction (MI) and the strategy for and impact of event adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) trial.In PLATO, ticagrelor reduced cardiovascular death, MI, or stroke in patients with acute coronary syndromes (ACS).A clinical events committee (CEC) prospectively defined and adjudicated all suspected MI events, on the basis of events reported by investigators and by triggers on biomarkers. Treatment comparisons used CEC-adjudicated data, and per protocol, excluded silent MI.Overall, 1,299 (610 ticagrelor, 689 clopidogrel) MIs reported by the CEC occurred during the trial. Of these, 1,097 (504 ticagrelor, 593 clopidogrel) contributed to the primary composite endpoint. Site investigators reported 1,198 (580 ticagrelor, 618 clopidogrel) MIs. Ticagrelor significantly reduced overall MI rates (12-month CEC-adjudicated Kaplan-Meier rates: 5.8% ticagrelor, 6.9% clopidogrel; hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.75 to 0.95). Nonprocedural MI (HR: 0.86; 95% CI: 0.74 to 1.01) and MI related to percutaneous coronary intervention or stent thrombosis tended to be lower with ticagrelor. MIs related to coronary artery bypass graft surgery were few, but numerical excess was observed in patients assigned ticagrelor. Analyses of overall MIs using investigator-reported data showed similar results but did not reach statistical significance (HR: 0.88; 95% CI: 0.78 to 1.00).In patients with ACS, ticagrelor significantly reduced the incidence of MI compared with clopidogrel, with consistent results across most MI subtypes. CEC procedures identified more MI endpoints compared with site investigators. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

    View details for DOI 10.1016/j.jacc.2014.01.038

    View details for Web of Science ID 000334285900007

  • Physician practices regarding contraindications to oral anticoagulation in atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. American heart journal O'Brien, E. C., Holmes, D. N., Ansell, J. E., Allen, L. A., Hylek, E., Kowey, P. R., Gersh, B. J., Fonarow, G. C., Koller, C. R., Ezekowitz, M. D., Mahaffey, K. W., Chang, P., Peterson, E. D., Piccini, J. P., Singer, D. E. 2014; 167 (4): 601-609 e1

    Abstract

    Oral anticoagulation (OAC) therapy reduces the risk of thromboembolic events associated with atrial fibrillation (AF), yet a substantial proportion of patients with AF are not prescribed OAC. The aim of this study is to describe the frequencies of and factors associated with OAC contraindications in contemporary clinical practice.We analyzed data from the ORBIT-AF study, a national, prospective, outpatient registry of incident and prevalent AF. Oral anticoagulation contraindications were uniformly collected at enrollment by site personnel using a predefined list. Baseline patient and provider characteristics were compared between participants with and without documented OAC contraindications.From June 2010 to August 2011, 10,130 patients 18 years or older with electrocardiographically documented AF were enrolled at 176 practices. Of these, 1,330 (13.1%) had contraindications documented at the baseline visit: prior bleed (27.7%), patient refusal/preference (27.5%), high bleeding risk (18.0%), frequent falls/frailty (17.6%), need for dual antiplatelet therapy (10.4%), unable to adhere/monitor warfarin (6.0%), comorbid illness (5.3%), prior intracranial hemorrhage (5.0%), allergy (2.4%), occupational risk (0.8%), pregnancy (0.2%), and other (12.6%). Among patients with reported contraindications, 30.3% were taking warfarin or dabigatran, as compared with 83.0% of those without reported contraindications. Besides "patient refusal/preference," being labeled as having frequent falls or being frail was associated with the lowest OAC use among patients with high stroke risk.Contraindications to OAC therapy among patients with AF are common but subjective. Many patients with reported contraindications were receiving OAC, suggesting that the perceived benefit outweighed the potential harm posed by the relative contraindication.

    View details for DOI 10.1016/j.ahj.2013.12.014

    View details for PubMedID 24655711

  • Relationship Between Time in Therapeutic Range and Comparative Treatment Effect of Rivaroxaban and Warfarin: Results From the ROCKET AF Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Piccini, J. P., Hellkamp, A. S., Lokhnygina, Y., Patel, M. R., Harrell, F. E., Singer, D. E., Becker, R. C., Breithardt, G., Halperin, J. L., Hankey, G. J., Berkowitz, S. D., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2014; 3 (2)

    Abstract

    Time in therapeutic range (TTR) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center TTR (cTTR) since such analysis preserves randomized comparisons.TTR was calculated using the Rosendaal method, without exclusion of international normalized ratio (INR) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded. INRs were performed via standardized finger-stick point-of-care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non-central nervous system embolism) was examined by quartiles of cTTR and by cTTR as a continuous function. Centers with the highest cTTRs by quartile had lower-risk patients as reflected by lower CHADS2 scores (P<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (P<0.0001). Sites with higher cTTR were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of cTTRs (P value for interaction=0.71). The hazard of major and non-major clinically relevant bleeding increased with cTTR (P for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold cTTR values.The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cTTR.

    View details for DOI 10.1161/JAHA.113.000521

    View details for Web of Science ID 000336798000039

    View details for PubMedID 24755148

  • Physician practices regarding contraindications to oral anticoagulation in atrial fibrillation: Findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry AMERICAN HEART JOURNAL O'Brien, E. C., Holmes, D. N., Ansell, J. E., Allen, L. A., Hylek, E., Kowey, P. R., Gersh, B. J., Fonarow, G. C., Koller, C. R., Ezekowitz, M. D., Mahaffey, K. W., Chang, P., Peterson, E. D., Piccini, J. P., Singer, D. E. 2014; 167 (4): 601-U229
  • Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome). Journal of the American College of Cardiology Whellan, D. J., Tricoci, P., Chen, E., Huang, Z., Leibowitz, D., Vranckx, P., Marhefka, G. D., Held, C., Nicolau, J. C., Storey, R. F., Ruzyllo, W., Huber, K., Sinnaeve, P., Weiss, A. T., Dery, J., Moliterno, D. J., Van de Werf, F., Aylward, P. E., White, H. D., Armstrong, P. W., Wallentin, L., Strony, J., Harrington, R. A., Mahaffey, K. W. 2014; 63 (11): 1048-1057

    Abstract

    This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG).Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients.Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method.Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%).In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943).

    View details for DOI 10.1016/j.jacc.2013.10.048

    View details for PubMedID 24211500

  • Association of Aspirin Dose and Vorapaxar Safety and Efficacy in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (from the TRACER Trial) AMERICAN JOURNAL OF CARDIOLOGY Mahaffey, K. W., Huang, Z., Wallentin, L., Storey, R. F., Jennings, L. K., Tricoci, P., White, H. D., Armstrong, P. W., Aylward, P. E., Molitemo, D. J., Van de Werf, F., Chen, E., Leonardi, S., Rorick, T., Held, C., Strony, J., Harrington, R. A. 2014; 113 (6): 936-944

    Abstract

    Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial compared vorapaxar and placebo in 12,944 high-risk patients with non-ST-segment elevation acute coronary syndrome. We explored aspirin (ASA) use and its association with outcomes. Kaplan-Meier event rates were compared in groups defined by ASA dose (low, medium, and high). Landmark analyses with covariate adjustment were performed for 0 to 30, 31 to 180, and 181 to 365 days. Of 12,515 participants, 7,523, 1,049, and 3,943 participants were treated with low-, medium-, and high-dose ASA at baseline, respectively. Participants enrolled in North America versus elsewhere were more often treated with a high dose at baseline (66% vs 19%) and discharge (60% vs 3%). Unadjusted cardiovascular death, myocardial infarction, stroke, hospitalization for ischemia, or urgent revascularization event rates tended to be higher with higher baseline ASA (18.45% low, 19.13% medium, and 20.27% high; p for trend = 0.15573). Unadjusted and adjusted hazard ratios (95% confidence intervals) for effect of vorapaxar on cardiovascular (unadjusted p for interaction = 0.065; adjusted p for interaction = 0.140) and bleeding (unadjusted p for interaction = 0.915; adjusted p for interaction = 0.954) outcomes were similar across groups. Landmark analyses showed similar safety and efficacy outcomes with vorapaxar and placebo by ASA dose at each time point except for 0 to 30 days, when vorapaxar tended to be worse for efficacy (hazard ratio 1.13, 95% confidence interval 0.89 to 1.44, p for interaction = 0.0157). In conclusion, most TRACER participants were treated with low-dose ASA, although a high dose was common in North America. High-dose participants tended to have higher rates of ischemic and bleeding outcomes. Although formal statistical testing did not reveal heterogeneity in vorapaxar's effect across dose subgroups, consistent trends support use of low-dose ASA with other antiplatelet therapies.

    View details for DOI 10.1016/j.amjcard.2013.11.052

    View details for Web of Science ID 000333476700006

  • Factors Associated With Major Bleeding Events JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Goodman, S. G., Wojdyla, D. M., Piccini, J. P., White, H. D., Paolini, J. F., Nessel, C. C., Berkowitz, S. D., Mahaffey, K. W., Patel, M. R., Sherwood, M. W., Becker, R. C., Halperin, J. L., Hacke, W., Singer, D. E., Hankey, G. J., Breithardt, G., Fox, K. A., Califf, R. M. 2014; 63 (9): 891-900
  • Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). Journal of the American College of Cardiology Goodman, S. G., Wojdyla, D. M., Piccini, J. P., White, H. D., Paolini, J. F., Nessel, C. C., Berkowitz, S. D., Mahaffey, K. W., Patel, M. R., Sherwood, M. W., Becker, R. C., Halperin, J. L., Hacke, W., Singer, D. E., Hankey, G. J., Breithardt, G., Fox, K. A., Califf, R. M. 2014; 63 (9): 891-900

    Abstract

    This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin.The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model.The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, ?75 years; pinteraction = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) ?90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk.Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767).

    View details for DOI 10.1016/j.jacc.2013.11.013

    View details for PubMedID 24315894

  • Impact of intraprocedural stent thrombosis during percutaneous coronary intervention: insights from the CHAMPION PHOENIX Trial (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). Journal of the American College of Cardiology Généreux, P., Stone, G. W., Harrington, R. A., Gibson, C. M., Steg, P. G., Brener, S. J., Angiolillo, D. J., Price, M. J., Prats, J., Lasalle, L., Liu, T., Todd, M., Skerjanec, S., Hamm, C. W., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2014; 63 (7): 619-629

    Abstract

    This study sought to evaluate the clinical impact of intraprocedural stent thrombosis (IPST), a relatively new endpoint.In the prospective, double-blind, active-controlled CHAMPION PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial, cangrelor significantly reduced periprocedural and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI), including IPST.An independent core laboratory blinded to treatment assignment performed a frame-by-frame angiographic analysis in 10,939 patients for the development of IPST, defined as new or worsening thrombus related to stent deployment at any time during the procedure. Adverse events were adjudicated by an independent, blinded clinical events committee.IPST developed in 89 patients (0.8%), including 35 of 5,470 (0.6%) and 54 of 5,469 (1.0%) patients in the cangrelor and clopidogrel arms, respectively (odds ratio: 0.65; 95% confidence interval: 0.42 to 0.99; p = 0.04). Compared to patients without IPST, IPST was associated with a marked increase in composite ischemia (death, myocardial infarction [MI], ischemia-driven revascularization, or new-onset out-of-laboratory stent thrombosis [Academic Research Consortium]) at 48 h and at 30 days (29.2% vs. 4.5% and 31.5% vs. 5.7%, respectively; p < 0.0001 for both). After controlling for potential confounders, IPST remained a strong predictor of all adverse ischemic events at both time points.In the large-scale CHAMPION PHOENIX trial, the occurrence of IPST was strongly predictive of subsequent adverse cardiovascular events. The potent intravenous adenosine diphosphate antagonist cangrelor substantially reduced IPST, contributing to its beneficial effects at 48 h and 30 days. (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX]; NCT01156571).

    View details for DOI 10.1016/j.jacc.2013.10.022

    View details for PubMedID 24184169

  • Release kinetics of circulating cardiac myosin binding protein-C following cardiac injury AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Kuster, D. W., Cardenas-Ospina, A., Miller, L., Liebetrau, C., Troidl, C., Nef, H. M., Moellmann, H., Hamm, C. W., Pieper, K. S., Mahaffey, K. W., Kleiman, N. S., Stuyvers, B. D., Marian, A. J., Sadayappan, S. 2014; 306 (4): H547-H556

    Abstract

    Diagnosis of myocardial infarction (MI) is based on ST-segment elevation on electrocardiographic evaluation and/or elevated plasma cardiac troponin (cTn) levels. However, troponins lack the sensitivity required to detect the onset of MI at its earliest stages. Therefore, to confirm its viability as an ultra-early biomarker of MI, this study investigates the release kinetics of cardiac myosin binding protein-C (cMyBP-C) in a porcine model of MI and in two human cohorts. Release kinetics of cMyBP-C were determined in a porcine model of MI (n = 6, pigs, either sex) by measuring plasma cMyBP-C level serially from 30 min to 14 days after coronary occlusion, with use of a custom-made immunoassay. cMyBP-C plasma levels were increased from baseline (76 ± 68 ng/l) at 3 h (767 ± 211 ng/l) and peaked at 6 h (2,418 ± 780 ng/l) after coronary ligation. Plasma cTnI, cTnT, and myosin light chain-3 levels were all increased 6 h after ligation. In a cohort of patients (n = 12) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy, cMyBP-C was significantly increased from baseline (49 ± 23 ng/l) in a time-dependent manner, peaking at 4 h (560 ± 273 ng/l). In a cohort of patients with non-ST segment elevation MI (n = 176) from the SYNERGY trial, cMyBP-C serum levels were significantly higher (7,615 ± 4,514 ng/l) than those in a control cohort (416 ± 104 ng/l; n = 153). cMyBP-C is released in the blood rapidly after cardiac damage and therefore has the potential to positively mark the onset of MI.

    View details for DOI 10.1152/ajpheart.00846.2013

    View details for Web of Science ID 000331895000009

    View details for PubMedID 24337456

  • Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION Wallentin, L., Lindholm, D., Siegbahn, A., Wernroth, L., Becker, R. C., Cannon, C. P., Cornel, J. H., Himmelmann, A., Giannitsis, E., Harrington, R. A., Held, C., Husted, S., Katus, H. A., Mahaffey, K. W., Steg, P. G., Storey, R. F., James, S. K. 2014; 129 (3): 293-303

    Abstract

    Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high-sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial.Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels. Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively. NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS and hs-TnT ?14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT <14.0 ng/L, there was no difference between ticagrelor and clopidogrel in the noninvasive groupHs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively. Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed patients, but no apparent benefit was seen at normal hs-TnT.URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.113.004420

    View details for Web of Science ID 000329880700006

  • Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial EUROPEAN HEART JOURNAL Mahaffey, K. W., Stevens, S. R., White, H. D., Nessel, C. C., Goodman, S. G., Piccini, J. P., Patel, M. R., Becker, R. C., Halperin, J. L., Hacke, W., Singer, D. E., Hankey, G. J., Califf, R. M., Fox, K. A., Breithardt, G. 2014; 35 (4): 233-241

    Abstract

    We investigated the prevalence of prior myocardial infarction (MI) and incidence of ischaemic cardiovascular (CV) events among atrial fibrillation (AF) patients.In ROCKET AF, 14 264 patients with nonvalvular AF were randomized to rivaroxaban or warfarin. The key efficacy outcome for these analyses was CV death, MI, and unstable angina (UA). This pre-specified analysis was performed on patients while on treatment. Rates are per 100 patient-years. Overall, 2468 (17%) patients had prior MI at enrollment. Compared with patients without prior MI, these patients were more likely to be male (75 vs. 57%), on aspirin at baseline (47 vs. 34%), have prior congestive heart failure (78 vs. 59%), diabetes (47 vs. 39%), hypertension (94 vs. 90%), higher mean CHADS2 score (3.64 vs. 3.43), and fewer prior strokes or transient ischaemic attacks (46 vs. 54%). CV death, MI, or UA rates tended to be lower in patients assigned rivaroxaban compared with warfarin [2.70 vs. 3.15; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73-1.00; P = 0.0509]. CV death, MI, or UA rates were higher in those with prior MI compared with no prior MI (6.68 vs. 2.19; HR 3.04, 95% CI 2.59-3.56) with consistent results for CV death, MI, or UA for rivaroxaban compared with warfarin in prior MI compared with no prior MI (P interaction = 0.10).Prior MI was common and associated with substantial risk for subsequent cardiac events. Patients with prior MI assigned rivaroxaban compared with warfarin had a non-significant 14% reduction of ischaemic cardiac events.

    View details for DOI 10.1093/eurheartj/eht428

    View details for Web of Science ID 000330837300008

  • Gastrointestinal ulcers, role of aspirin, and clinical outcomes: pathobiology, diagnosis, and treatment. Journal of multidisciplinary healthcare Cryer, B., Mahaffey, K. W. 2014; 7: 137-146

    Abstract

    Peptic ulcer disease is a major cause of morbidity and mortality in the US with more than six million diagnoses annually. Ulcers are reported as the most common cause of hospitalization for upper gastrointestinal (GI) bleeding and are often a clinical concern due to the widespread use of aspirin and nonsteroidal anti-inflammatory drugs, both of which have been shown to induce ulcer formation. The finding that Helicobacter pylori infection (independent of aspirin use) is associated with the development of ulcers led to a more thorough understanding of the causes and pathogenesis of ulcers and an improvement in therapeutic options. However, many patients infected with H. pylori are asymptomatic and remain undiagnosed. Complicating matters is a current lack of understanding of the association between aspirin use and asymptomatic ulcer formation. Low-dose aspirin prescriptions have increased, particularly for cardioprotection. Unfortunately, the GI side effects associated with aspirin therapy continue to be a major complication in both symptomatic and asymptomatic patients. These safety concerns should be important considerations in the decision to use aspirin and warrant further education. The medical community needs to continue to improve awareness of aspirin-induced GI bleeding to better equip physicians and improve care for patients requiring aspirin therapy.

    View details for DOI 10.2147/JMDH.S54324

    View details for PubMedID 24741318

  • Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF EUROPEAN HEART JOURNAL Jones, W. S., Hellkamp, A. S., Halperin, J., Piccini, J. P., Breithardt, G., Singer, D. E., Fox, K. A., Hankey, G. J., Mahaffey, K. W., Califf, R. M., Patel, M. R. 2014; 35 (4): 242-249

    Abstract

    Vascular disease is included in a risk scoring system to predict stroke in patients with non-valvular atrial fibrillation (AF). This post hoc analysis of ROCKET AF aimed to determine the absolute rates of stroke and bleeding, and the relative effectiveness and safety of rivaroxaban vs. warfarin in patients with and without peripheral artery disease (PAD). Peripheral artery disease was defined on the case-report form as the presences of intermittent claudication, amputation for arterial insufficiency, vascular reconstruction, bypass surgery, or percutaneous intervention to the extremities, or previously documented abdominal aortic aneurysm.ROCKET AF was a double-blind, double-dummy, randomized-controlled trial comparing rivaroxaban and warfarin for the prevention of stroke or systemic embolism. A total of 839 (5.9%) patients in ROCKET AF had PAD. Patients with and without PAD had similar rates of stroke or systemic embolism [HR: 1.04, 95% CI (0.72, 1.50), P = 0.84] and major or non-major clinically relevant (NMCR) bleeding [HR: 1.11, 95% CI (0.96, 1.28), P = 0.17], respectively. The efficacy of rivaroxaban when compared with warfarin for the prevention of stroke or systemic embolism was similar in patients with PAD (HR: 1.19, 95% CI: 0.63-2.22) and without PAD (HR: 0.86, 95% CI: 0.73-1.02; interaction P = 0.34). There was a significant interaction for major or NMCR bleeding in patients with PAD treated with rivaroxaban compared with warfarin (HR: 1.40, 95% CI: 1.06-1.86) compared with those without PAD (HR: 1.03, 95% CI: 0.95-1.11; interaction P = 0.037).Patients with PAD in ROCKET AF did not have a statistically significant higher risk of stroke or systemic embolism than patients without PAD, and there were similar efficacy outcomes in patients treated with rivaroxaban and warfarin. In PAD patients, there was a higher risk of major bleeding or NMCR bleeding with rivaroxaban when compared with warfarin (interaction P = 0.037). Further investigation is warranted to validate this subgroup analysis and determine the optimal treatment in this high-risk cohort of AF patients with PAD.

    View details for DOI 10.1093/eurheartj/eht492

    View details for Web of Science ID 000330837300010

    View details for PubMedID 24302273

  • Reduction in Overall Occurrences of Ischemic Events With Vorapaxar: Results From TRACER. Journal of the American Heart Association White, H. D., Huang, Z., Tricoci, P., Van de Werf, F., Wallentin, L., Lokhnygina, Y., Moliterno, D. J., Aylward, P. E., Mahaffey, K. W., Armstrong, P. W. 2014; 3 (4)

    Abstract

    Clinical trials traditionally use time-to-first-event analysis embedded within the composite endpoint of cardiovascular death (CVD), myocardial infarction (MI), or stroke. However, many patients have >1 event, and this approach may not reflect overall experience. We addressed this by analyzing all cardiovascular events in TRACER.TRACER randomized 12 944 patients with non-ST-segment elevation acute coronary syndromes to placebo or to protease-activated receptor 1 antagonist vorapaxar with a median follow-up of 502 days (interquartile range, 349 to 667). Analysis of vorapaxar's effect on recurrent CVD, MI, or stroke was prespecified using the Wei, Lin, and Weissfeld approach. Vorapaxar did not reduce the first occurrence of the primary endpoint of CVD, MI, stroke, revascularization, or rehospitalization for recurrent ischemia, but reduced the secondary composite endpoint of CVD, MI, or stroke (14.7% vorapaxar vs. 16.4% placebo; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.02; number needed to treat [NNT], 81). Recurrent secondary events occurred in 2.7% of patients. Vorapaxar reduced overall occurrences of ischemic events, first and subsequent (HR, 0.88; 95% CI, 0.80 to 0.98; P=0.02; NNT, 51). Also, there was a trend indicating that vorapaxar reduced the expanded endpoint, including revascularization and rehospitalization for recurrent ischemia (HR, 0.92; 95% CI, 0.84 to 1.01; P=0.09). Vorapaxar increased overall occurrences of moderate and severe Global Use of Strategies to Open Occluded Coronary Arteries bleeding (HR, 1.42; 95% CI, 1.21 to 1.66; P<0.001) and Thrombolysis in Myocardial Infarction clinically significant bleeding (HR, 1.550; 95% CI, 1.403 to 1.713; P<0.001).Vorapaxar reduced overall occurrences of ischemic events, but increased bleeding. These exploratory findings broaden our understanding of vorapaxar's potential and expand our understanding of the value of capturing recurrent events.ClinicalTrials.gov. Unique identifier: NCT00527943.

    View details for DOI 10.1161/JAHA.114.001032

    View details for PubMedID 25012288

  • Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data LANCET Steg, P. G., Bhatt, D. L., Hamm, C. W., Stone, G. W., Gibson, C. M., Mahaffey, K. W., Leonardi, S., Liu, T., Skerjanec, S., Day, J. R., Iwaoka, R. S., Stuckey, T. D., Gogia, H. S., Gruberg, L., French, W. J., White, H. D., Harrington, R. A. 2013; 382 (9909): 1981-1992

    Abstract

    Cangrelor is a potent, rapid-acting, reversible intravenous platelet inhibitor that was tested for percutaneous coronary intervention (PCI) in three large, double-blind, randomised trials. We did a pooled analysis of data from three trials that assessed the effectiveness of cangrelor against either clopidogrel or placebo in PCI.This prespecified, pooled analysis of patient-level data from three trials (CHAMPION-PCI, CHAMPION-PLATFORM, and CHAMPION-PHOENIX) compared cangrelor with control (clopidogrel or placebo) for prevention of thrombotic complications during and after PCI. Trial participants were patients undergoing PCI for ST-elevation myocardial infarction (11.6%), non-ST-elevation acute coronary syndromes (57.4%), and stable coronary artery disease (31.0%). Efficacy was assessed in the modified intention-to-treat population of 24,910 patients, with a prespecified primary efficacy composite of death, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis at 48 h. The primary safety outcome was non-coronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe or life-threatening bleeding at 48 h.Cangrelor reduced the odds of the primary outcome by 19% (3.8% for cangrelor vs 4.7% for control; odds ratio [OR] 0.81, 95% CI 0.71-0.91, p=0.0007), and stent thrombosis by 41% (0.5% vs 0.8%, OR 0.59, 95% CI 0.43-0.80, p=0.0008). Cangrelor reduced the odds of the secondary triple composite (all-cause death, myocardial infarction, or ischaemia-driven revascularisation at 48 h) by 19% (3.6% vs 4.4%, OR 0.81, 95% CI 0.71-0.92, p=0.0014). Efficacy outcomes were consistent across the trials and main patient subsets. These benefits were maintained at 30 days. There was no difference in the primary safety outcome (0.2% in both groups), in GUSTO moderate bleeding (0.6% vs 0.4%), or in transfusion (0.7% vs 0.6%), but cangrelor increased GUSTO mild bleeding (16.8% vs 13.0%, p<0.0001).Compared with control (clopidogrel or placebo), cangrelor reduced PCI periprocedural thrombotic complications, at the expense of increased bleeding.The Medicines Company.

    View details for DOI 10.1016/S0140-6736(13)61615-3

    View details for Web of Science ID 000328223700025

  • Early Adoption of Dabigatran and Its Dosing in US Patients With Atrial Fibrillation: Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation JOURNAL OF THE AMERICAN HEART ASSOCIATION Steinberg, B. A., Holmes, D. N., Piccini, J. P., Ansell, J., Chang, P., Fonarow, G. C., Gersh, B., Mahaffey, K. W., Kowey, P. R., Ezekowitz, M. D., Singer, D. E., Thomas, L., Peterson, E. D., Hylek, E. M. 2013; 2 (6)

    Abstract

    Dabigatran is a novel oral anticoagulant approved for thromboprophylaxis in atrial fibrillation. Adoption patterns of this new agent in community practice are unknown.We studied patterns of dabigatran use among patients enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry between June 2010 and August 2011 and followed for 12 months. Among 9974 atrial fibrillation patients included, 1217 (12%) were treated with dabigatran during the study. Overall, patients receiving dabigatran were younger (median age 72 versus 75 years, P<0.0001), more likely to be white (92% versus 89%, P=0.005), more likely to have private insurance (33% versus 25%, P<0.0001), and less likely to have prior cardiovascular disease (4% versus 33%, P<0.0001). They had more new-onset atrial fibrillation (8.8% versus 4.1%, P<0.0001), lower CHADS2 scores (estimated risk based on the presence of congestive heart failure, hypertension, aged ?75 years, diabetes mellitus, and prior stroke or transient ischemic attack; mean 2.0 versus 2.3, P<0.0001), and lower Anticoagulation and Risk Factors in Atrial Fibrillation scores (mean 2.4 versus 2.8, P<0.0001). More than half (n=14/25, 56%) of patients with severe kidney disease were not prescribed reduced dosing, whereas 10% (n=91/920) with preserved renal function received lower dosing. Among patients not on dabigatran at baseline, 8% had dabigatran initiated during follow-up. Patient education was significantly associated with switching from warfarin to dabigatran (adjusted odds ratio for postgraduate 1.73, P=0.007), whereas antiarrhythmic drug use significantly correlated with de novo adoption of dabigatran (adjusted odds ratio 2.4, P<0.0001).Patients receiving dabigatran were younger and at a lower risk of stroke and bleeding. Patients appeared to drive switching from warfarin, whereas clinical characteristics influenced de novo start of dabigatran. These data suggest cautious early uptake of dabigatran, and more careful attention to dosing adjustments is warranted.Clinicaltrials.gov. Unique identifier: NCT01165710.

    View details for DOI 10.1161/JAHA.113.000535

    View details for Web of Science ID 000330177900042

    View details for PubMedID 24275632

  • 5-Year Results of a Randomized Comparison of XIENCE V Everolimus-Eluting and TAXUS Paclitaxel-Eluting Stents Final Results From the SPIRIT III Trial (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) JACC-CARDIOVASCULAR INTERVENTIONS Gada, H., Kirtane, A. J., Newman, W., Sanz, M., Hermiller, J. B., Mahaffey, K. W., Cutlip, D. E., Sudhir, K., Hou, L., Koo, K., Stone, G. W. 2013; 6 (12): 1263-1266

    Abstract

    This study sought to evaluate the long-term safety and efficacy of everolimus-eluting stents (EES) and paclitaxel-eluting stents (PES) in patients with obstructive coronary artery disease.The use of EES compared to PES has been shown to result in improved clinical outcomes in patients undergoing PCI. However, there have been concerns regarding the durability of these benefits over longer-term follow-up.SPIRIT III was a prospective, multicenter trial in which 1,002 patients were randomized 2:1 to EES versus PES. Endpoints included ischemia-driven target vessel failure (TVF) (death, myocardial infarction (MI), or ischemia-driven target vessel revascularization [TVR]), the pre-specified primary endpoint), target lesion failure (TLF) (cardiac death, target-vessel MI, or ischemia-driven target lesion revascularization [TLR]), major adverse cardiac events (MACE) (cardiac death, MI, or ischemia-driven TLR), their individual components and stent thrombosis.Five-year follow-up was available in 91.9% of patients. Treatment with EES versus PES resulted in lower 5-year Kaplan-Meier rates of TVF (19.3% vs. 24.5%, p = 0.05), TLF (12.7% vs. 19.0%, p = 0.008), and MACE (13.2% vs. 20.7%, p = 0.007). EES also resulted in reduced rates of all-cause death (5.9% vs. 10.1%, p = 0.02), with nonsignificantly different rates of MI, stent thrombosis, and TLR, and no evidence of late catch-up of TLR over time.At 5 years after treatment, EES compared to PES resulted in durable benefits in composite safety and efficacy measures as well as all-cause mortality. Additionally, the absolute difference in TLR between devices remained stable over time without deterioration of effect during late follow-up.

    View details for DOI 10.1016/j.jcin.2013.07.009

    View details for Web of Science ID 000328458800007

    View details for PubMedID 24239202

  • The Clinical Course of Treated Hyperparathyroidism Among Patients Receiving Hemodialysis and the Effect of Cinacalcet: The EVOLVE Trial JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Parfrey, P. S., Chertow, G. M., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Dehmel, B., Trotman, M., Modafferi, D. M., Goodman, W. G. 2013; 98 (12): 4834-4844

    Abstract

    The clinical course of secondary hyperparathyroidism (sHPT) in patients on hemodialysis is not well described, and the effect of the calcimimetic cinacalcet on disease progression is uncertain.Our objective was to describe 1) the clinical course of sHPT in patients treated with phosphate binders and/or vitamin D sterols and 2) the impact of cinacalcet on the occurrence of severe unremitting HPT, defined by the persistence of markedly elevated PTH concentrations together with hypercalcemia or parathyroidectomy (PTX).This was a randomized, double-blind, placebo-controlled, global, multicenter clinical trial.Of 5755 patients screened with moderate to severe sHPT, 3883 patients on hemodialysis were included in the trial.Outcomes included PTX; severe, unremitting HPT; and use of commercial cinacalcet (a protocol violation). Intervention: Intervention was cinacalcet (30-180 mg daily) or placebo for up to 64 months.In the 1935 patients randomized to placebo, 278 patients (14%) underwent PTX (median PTH 1872 pg/mL within the previous 12 weeks from surgery). Age, sex, geographic region, co-morbidity, calcium-containing phosphate binder use, and baseline serum calcium, phosphorus, and PTH concentrations were associated with PTX. Commercial cinacalcet was started in 443 (23%) patients (median PTH 1108 pg/mL before treatment began). Severe unremitting HPT developed in 470 patients (24%). In a multivariable Cox model, the relative hazard (comparing patients randomized to cinacalcet versus placebo) of severe unremitting HPT was 0.31 (95% confidence interval = 0.26-0.37). The relative hazard differed little when adjusted by baseline clinical characteristics.Severe unremitting HPT develops frequently in patients on hemodialysis despite conventional therapy, and cinacalcet substantially reduces its occurrence.

    View details for DOI 10.1210/jc.2013-2975

    View details for Web of Science ID 000328477200057

  • Prognostic implications of left ventricular end-diastolic pressure during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: Findings from the Assessment of Pexelizumab in Acute Myocardial Infarction study AMERICAN HEART JOURNAL Bagai, A., Armstrong, P. W., Stebbins, A., Mahaffey, K. W., Hochman, J. S., Weaver, W. D., Patel, M. R., Granger, C. B., Lopes, R. D. 2013; 166 (5): 913-919

    Abstract

    Left ventricular end-diastolic pressure (LVEDP) is frequently measured during primary percutaneous coronary intervention (PCI). However, little is known of this measurement's utility in predicting outcomes or informing treatment decisions. We sought to determine the prognostic value of LVEDP measured during primary PCI for ST-segment elevation myocardial infarction (STEMI).We studied 1,909 (33.2%) of 5,745 STEMI patients in whom LVEDP was measured during primary PCI in the APEX-AMI trial. Cox regression analysis was used to evaluate whether LVEDP was an independent predictor of mortality and the composite of death, cardiogenic shock, or congestive heart failure (CHF) at 90 days.The median (25th, 75th percentiles) LVEDP level was 22 mm Hg (16, 29); compared with patients with LVEDP ? 22 mm Hg, those with LVEDP > 22 mm Hg had higher rates of CHF (7.3% vs 3.1%, P < .001), cardiogenic shock (4.6% vs 1.7%, P < .001), and death (4.1% vs 2.2%, P = .014) at 90 days. After multivariable adjustment, LVEDP was associated with increased risk of mortality through 90 days (adjusted hazard ratio 1.22, 95% CI 1.02-1.46, per 5-mmHg increase, P = .044) and the composite of death, cardiogenic shock, or CHF within the first 2 days (adjusted hazard ratio 1.40, 95% CI 1.23-1.59, per 5-mm Hg increase, P < .001), but not from day 3 to 90 (P = .25).Left ventricular end-diastolic pressure measured during primary PCI for STEMI is an independent predictor of inhospital and longer term cardiovascular outcomes. Measuring LVEDP may be useful to stratify patient risk and guide postinfarct treatment.

    View details for DOI 10.1016/j.ahj.2013.08.006

    View details for Web of Science ID 000326233500018

    View details for PubMedID 24176448

  • Prognostic relevance of baseline pro- and anti-inflammatory markers in STEMI: An APEX AMI substudy INTERNATIONAL JOURNAL OF CARDIOLOGY van Diepen, S., Newby, L. K., Lopes, R. D., Stebbins, A., Hasselblad, V., James, S., Roe, M. T., Ezekowitz, J. A., Moliterno, D. J., Neumann, F., Reist, C., Mahaffey, K. W., Hochman, J. S., Hamm, C. W., Armstrong, P. W., Granger, C. B., Theroux, P. 2013; 168 (3): 2127-2133

    Abstract

    Plaque rupture, acute ischemia, and necrosis in acute coronary syndromes are accompanied by concurrent pro- and anti-inflammatory cascades. Whether STEMI clinical prediction models can be improved with the addition of baseline inflammatory biomarkers remains unknown.In an APEX-AMI trial substudy, 772 patients had a panel of 9 inflammatory serum biomarkers, high sensitivity C reactive protein (hsCRP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measured at baseline after randomization. Baseline biomarkers were incorporated into a clinical prediction model for a composite of 90-day death, shock, or heart failure. Incremental prognostic value was assessed using Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI).Individually, several biomarkers were independent predictors of clinical outcome: hsCRP (hazard ratio [HR] 1.12; 95% confidence interval [CI], 1.03-1.21; p=0.007, per doubling), NT-proBNP (HR 1.14; 95% CI, 1.06-1.23; p<0.001, per doubling), interleukin (IL)-6 (HR 1.26; 95% CI, 1.12-1.41;p<0.001, per doubling), and inducible protein-10 (IP-10) (HR 0.86; 95% CI, 0.76-0.98; p<0.025, per doubling). The addition of baseline NT-proBNP (NRI 8.6%, p=0.028; IDI 0.030, p<0.001) and IL-6 (NRI 8.8%, p=0.012; IDI 0.036, p<0.001) improved the clinical risk prediction model and the addition of hsCRP (NRI 6.5%, p=0.069; IDI 0.018, p=0.004) yielded minimal improvement. After incorporating NT-proBNP into the model, the remaining biomarkers added little additional predictive value.Multiple inflammatory biomarkers independently predicted 90-day death, shock or heart failure; however, they added little value to a clinical prediction model that included NT-proBNP. Future studies of inflammatory biomarkers in STEMI should report incremental value in a prediction model that includes NT-proBNP.

    View details for DOI 10.1016/j.ijcard.2013.01.004

    View details for Web of Science ID 000326184400068

    View details for PubMedID 23394896

  • Response to Letter Regarding Article, "Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation: Validation of the R(2)CHADS(2) Index in the ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study Cohorts" CIRCULATION Piccini, J. P., Stevens, S. R., Chang, Y., Singer, D. E., Lokhnygina, Y., Go, A. S., Patel, M. R., Mahaffey, K. W., Halperin, J. L., Breithardt, G., Hankey, G. J., Hacke, W., Becker, R. C., Nessel, C. C., Fox, K. A., Califf, R. M. 2013; 128 (11): E172-E173
  • Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective, Randomized PLATO Trial CIRCULATION Steg, P. G., Harrington, R. A., Emanuelsson, H., Katus, H. A., Mahaffey, K. W., Meier, B., Storey, R. F., Wojdyla, D. M., Lewis, B. S., Maurer, G., Wallentin, L., James, S. K. 2013; 128 (10): 1055-1065
  • A novel approach to systematically implement the universal definition of myocardial infarction: insights from the CHAMPION PLATFORM trial HEART Leonardi, S., Truffa, A. A., Neely, M. L., Tricoci, P., White, H. D., Gibson, C. M., Wilson, M., Stone, G. W., Harrington, R. A., Bhatt, D. L., Mahaffey, K. W. 2013; 99 (17): 1282-1287

    Abstract

    OBJECTIVE: To reassess the efficacy of cangrelor efficacy using the universal definition of myocardial infarction (MI). DESIGN: We adopted a novel approach to systematically implement the universal definition of MI. Two physicians blinded to treatment allocation reviewed plots of CK-MB and troponin values in relation to time of randomisation and percutaneous coronary intervention (PCI) to identify patients with stable or falling biomarkers pre-PCI (ie, primary cohort), and those with post-PCI CK-MB elevations. SETTING: The CHAMPION PLATFORM trial. PATIENTS: Non-ST-elevation acute coronary syndromes (95%) and stable angina patients (5%). INTERVENTIONS: Cangrelor versus placebo. MAIN OUTCOME MEASURES: The efficacy of cangrelor compared with placebo using the reclassified events (type 4a MI) and the original clinical events committee-adjudicated (CEC PCI-MI) results was investigated. RESULTS: Of 5295 patients, 3406 (64.4%) were in the primary cohort. Type 4a MI occurred in 4.3% (226 events/5295 patients) while original CEC PCI-MI occurred in 6.5% (344 events/5295 patients), a significant difference (p<0.0001). Using the reclassified MI events, the primary composite endpoint of death, MI, or ischaemia-driven revascularisation through 48 h occurred in 5.4% of patients (4.9% cangrelor, 6.0% placebo; OR 0.80; 95% CI 0.63 to 1.02) as opposed to 7.5% of the primary analyses (7.0% cangrelor, 8.0% placebo; OR 0.87; 95% CI 0.71 to 1.07). CONCLUSIONS: Systematic, strict implementation of the universal MI definition with emphasis on baseline assessment may enhance discrimination in detecting PCI-MI and may allow for more rigorous assessment of interventions in patients undergoing early PCI.

    View details for DOI 10.1136/heartjnl-2012-303103

    View details for Web of Science ID 000323162800012

    View details for PubMedID 23434768

  • The Systemic Inflammatory Response Syndrome in Patients With ST-Segment Elevation Myocardial Infarction CRITICAL CARE MEDICINE van Diepen, S., Vavalle, J. P., Newby, L. K., Clare, R., Pieper, K. S., Ezekowitz, J. A., Hochman, J. S., Mahaffey, K. W., Armstrong, P. W., Granger, C. B. 2013; 41 (9): 2080-2087

    Abstract

    To assess whether systemic inflammatory response syndrome is associated with morbidity and mortality in ST-elevation myocardial infarction.Secondary analysis of multicenter randomized controlled trials.Complement and reduction of infarct size after angioplasty or lytics project patients (n=1,903) with ST-elevation myocardial infarction undergoing fibrinolysis or mechanical reperfusion.None.The prevalence of systemic inflammatory response syndrome was described in the 1,186 patients (64.4%) with data available for all systemic inflammatory response syndrome criteria. Using multiple imputations for the 1,843 patients (96.8%) with available endpoints, we compared the 90-day prevalence of death, shock, heart failure, or stroke between patients with and without systemic inflammatory response syndrome at presentation and at 24 hours post admission. Systemic inflammatory response syndrome was defined as ?2 of 1) heart rate>90 beats/min, 2) respiratory rate>20 breaths/min, 3) body temperature>38 or <36°C, or 4) leukocyte count>12 or<4×10/L. At presentation, 25.0% of patients met systemic inflammatory response syndrome criteria; at 24 hours, 8.1% of patients met systemic inflammatory response syndrome criteria. The primary outcome was more frequent among patients with systemic inflammatory response syndrome at presentation (31.0% vs 16.7%; adjusted hazard ratio, 1.78 [95% CI, 1.35-2.34]; p<0.001) and at 24 hours (36.7% vs 11.1%; adjusted hazard ratio, 2.84 [95% CI, 2.03-3.97]; p<0.001). Mortality at 90 days was also higher among patients with systemic inflammatory response syndrome at either time point. Each additional systemic inflammatory response syndrome criterion was independently associated with 90-day outcomes at the time of presentation (adjusted hazard ratio, 1.41 per systemic inflammatory response syndrome criteria [95% CI, 1.24-1.61]; p<0.001) and at 24 hours (adjusted hazard ratio, 1.72 per systemic inflammatory response syndrome criteria [95% CI, 1.47-2.01]; p<0.001).The diagnosis of systemic inflammatory response syndrome and the cumulative number of systemic inflammatory response syndrome criteria were independently associated with 90-day clinical outcomes in a population of patients with ST-elevation myocardial infarction. The independent association of this simple composite measure of the inflammatory response with outcomes underscores the importance of the clinical inflammatory response in ST-elevation myocardial infarction.

    View details for DOI 10.1097/CCM.0b013e31828a67b2

    View details for Web of Science ID 000330537600003

    View details for PubMedID 23760155

  • Use and Associated Risks of Concomitant Aspirin Therapy With Oral Anticoagulation in Patients With Atrial Fibrillation Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry CIRCULATION Steinberg, B. A., Kim, S., Piccini, J. P., Fonarow, G. C., Lopes, R. D., Thomas, L., Ezekowitz, M. D., Ansell, J., Kowey, P., Singer, D. E., Gersh, B., Mahaffey, K. W., Hylek, E., Go, A. S., Chang, P., Peterson, E. D. 2013; 128 (7): 721-728

    Abstract

    The role of concomitant aspirin (ASA) therapy in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) is unclear. We assessed concomitant ASA use and its association with clinical outcomes among AF patients treated with OAC.The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry enrolled 10 126 AF patients from 176 US practices from June 2010 through August 2011. The study population was limited to those on OAC (n=7347). Hierarchical multivariable logistic regression models were used to assess factors associated with concomitant ASA therapy. Primary outcomes were 6-month bleeding, hospitalization, ischemic events, and mortality. Overall, 35% of AF patients (n=2543) on OAC also received ASA (OAC+ASA). Patients receiving OAC+ASA were more likely to be male (66% versus 53%; P<0.0001) and had more comorbid illness than those on OAC alone. More than one third of patients (39%) receiving OAC+ASA did not have a history of atherosclerotic disease, yet 17% had elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding risk scores (?5). Major bleeding (adjusted hazard ratio, 1.53; 95% confidence interval, 1.20-1.96) and bleeding hospitalizations (adjusted hazard ratio, 1.52; 95% confidence interval, 1.17-1.97) were significantly higher in those on OAC+ASA compared with those on OAC alone. Rates of ischemic events were low.Patients with AF receiving OAC are often treated with concomitant ASA, even when they do not have cardiovascular disease. Use of OAC+ASA was associated with significantly increased risk for bleeding, emphasizing the need to carefully determine if and when the benefits of concomitant ASA outweigh the risks in AF patients already on OAC.URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01165710.

    View details for DOI 10.1161/CIRCULATIONAHA.113.002927

    View details for Web of Science ID 000323102400016

    View details for PubMedID 23861512

  • Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)-A randomized placebo-controlled trial AMERICAN HEART JOURNAL Neal, B., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Stein, P., Desai, M., Shaw, W., Jiang, J., Vercruysse, F., Meininger, G., Matthews, D. 2013; 166 (2): 217-?

    Abstract

    Sodium glucose co-transporter 2 inhibition is a novel mode of treatment for type 2 diabetes mellitus (T2DM). The sodium glucose co-transporter 2 inhibitor canagliflozin lowered blood glucose, blood pressure, and body weight, with increased risk of urogenital infections in Phase 2 studies. Effects on macrovascular complications of diabetes remain to be determined. CANVAS is a double-blind, placebo-controlled trial designed to evaluate the effects of canagliflozin on the risk of cardiovascular disease and to assess safety and tolerability in patients with inadequately controlled T2DM and increased cardiovascular risk. The first of 2 planned phases randomized 4,330 individuals to placebo, canagliflozin 100 or 300 mg (1:1:1) with planned follow-up of about 2 years to substantiate potential cardiovascular protection by assessing key biomarkers and to achieve initial safety objectives. By the end of mid-September 2012, a total of 7174 patient-years of follow-up were accrued. Mean baseline age was 62 years, duration of diabetes 13 years; hemoglobin A1c 8.2%, fasting plasma glucose 9.3 mmol/L, and body mass index 32 kg/m(2). Of the participants, 34% are female and 57% had a history of atherosclerotic vascular disease. Participants will be followed up to achieve primary safety and tolerability objectives and to investigate secondary outcomes. The planned second phase will not be undertaken. CANVAS will define the effects of canagliflozin on biomarkers and provide data on cardiovascular safety against established regulatory parameters.

    View details for DOI 10.1016/j.ahj.2013.05.007

    View details for Web of Science ID 000322629000005

    View details for PubMedID 23895803

  • Provider Specialty and Atrial Fibrillation Treatment Strategies in United States Community Practice: Findings From the ORBIT-AF Registry JOURNAL OF THE AMERICAN HEART ASSOCIATION Fosbol, E. L., Holmes, D. N., Piccini, J. P., Thomas, L., Reiffel, J. A., Mills, R. M., Kowey, P., Mahaffey, K., Gersh, B. J., Peterson, E. D. 2013; 2 (4)

    Abstract

    The prevalence of atrial fibrillation (AF) continues to increase; however, there are limited data describing the division of care among practitioners in the community and whether care differs depending on provider specialty.Using the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) Registry, we described patient characteristics and AF management strategies in ambulatory clinic practice settings, including electrophysiology (EP), general cardiology, and primary care. A total of 10 097 patients were included; of these, 1544 (15.3%) were cared for by an EP provider, 6584 (65.2%) by a cardiology provider, and 1969 (19.5%) by an internal medicine/primary care provider. Compared with those patients who were cared for by cardiologists or internal medicine/primary care providers, patients cared for by EP providers were younger (median age, 73 years [interquartile range, IQR, 64, 80 years, Q1, Q3] versus 75 years [IQR, 67, 82 years] for cardiology and versus 76 years [IQR, 68, 82 years] for primary care). Compared with cardiology and internal medicine/primary care providers, EP providers used rhythm control (versus rate control) management more often (44.2% versus 29.7% and 28.8%, respectively, P<0.0001; adjusted odds ratio [OR] EP versus cardiology, 1.66 [95% confidence interval, CI, 1.05 to 2.61]; adjusted OR for internal medicine/primary care versus cardiology, 0.91 [95% CI, 0.65 to 1.26]). Use of oral anticoagulant therapy was high across all providers, although it was higher for cardiology and EP providers (overall, 76.1%; P=0.02 for difference between groups).Our data demonstrate important differences between provider specialties, the demographics of the AF patient population treated, and treatment strategies-particularly for rhythm control and anticoagulation therapy.

    View details for DOI 10.1161/JAHA.113.000110

    View details for Web of Science ID 000326340900011

    View details for PubMedID 23868192

  • Methodology of a reevaluation of cardiovascular outcomes in the RECORD trial: Study design and conduct AMERICAN HEART JOURNAL Lopes, R. D., Dickerson, S., Hafley, G., Burns, S., Tourt-Uhlig, S., White, J., Newby, L. K., Komajda, M., McMurray, J., Bigelow, R., Home, P. D., Mahaffey, K. W. 2013; 166 (2): 208-?

    Abstract

    In 2010, after regulatory review of rosiglitazone licensing, the US Food and Drug Administration (FDA) requested a reevaluation of cardiovascular end points in the RECORD trial.Automated screening of the original clinical trial database and manual case report form review were performed to identify all potential cardiovascular and noncardiovascular deaths, and nonfatal myocardial infarction (MI) and stroke events. Search techniques were used to find participants lost to follow-up, and sites were queried for additional source documents. Suspected events underwent blinded adjudication using both original RECORD end point definitions and new FDA end point definitions, before analysis by the Duke Clinical Research Institute.The reevaluation effort included an additional 328 person-years of follow-up. Automated screening identified 396 suspected deaths, 2,052 suspected MIs, and 468 suspected strokes. Manual review of documents by Duke Clinical Research Institute clinical events classification (CEC) coordinators identified an additional 31 suspected deaths, 49 suspected MIs, and 28 suspected strokes. There were 127 CEC queries issued requesting additional information on suspected deaths; 43 were closed with no site response, 61 were closed with a response that no additional data were available, and additional data were received for 23. Seventy CEC queries were issued requesting additional information for suspected MI and stroke events; 31 were closed with no site response, 20 were closed with a response that no additional data were available, and 19 resulted in additional data.Comprehensive procedures were used for rigorous event reascertainment and readjudication in a previously completed open-label, global clinical trial. These procedures used in this unique situation were consistent with other common approaches in the field, were enhanced to address the FDA concerns about the original RECORD trial results, and could be considered by clinical trialists designing event readjudication protocols for drug development programs that have been completed.

    View details for DOI 10.1016/j.ahj.2013.05.005

    View details for Web of Science ID 000322629000004

    View details for PubMedID 23895802

  • Results of a reevaluation of cardiovascular outcomes in the RECORD trial AMERICAN HEART JOURNAL Mahaffey, K. W., Hafley, G., Dickerson, S., Burns, S., Tourt-Uhlig, S., White, J., Newby, L. K., Komajda, M., McMurray, J., Bigelow, R., Home, P. D., Lopes, R. D. 2013; 166 (2): 240-?

    Abstract

    The US Food and Drug Administration (FDA) required a reevaluation of cardiovascular (CV) outcomes in the RECORD trial. This provided an opportunity to assess the implications of event adjudication by 2 groups and quantify the differences as well as to use new FDA end point definitions in development.Original data were used to systematically identify all potential deaths, myocardial infarctions (MIs), and strokes. Site investigators were approached for additional source documents and information about participants lost to follow-up. Suspected events were adjudicated using standard procedures, and the results were compared with the original trial outcomes.Follow-up for mortality was 25,833 person-years, including an additional 328 person-years identified during the reevaluation effort. A total of 184 CV or unknown-cause deaths (88 rosiglitazone, 96 metformin/sulfonylurea), 128 participants with an MI (68 rosiglitazone, 60 metformin/sulfonylurea), and 113 participants with a stroke (50 rosiglitazone, 63 metformin/sulfonylurea) were included. The hazard ratio (HR) for rosiglitazone versus metformin/sulfonylurea for the end point of CV (or unknown cause) death, MI, or stroke was 0.95 (95% CI 0.78-1.17) compared with 0.93 (95% CI 0.74-1.15) for the original RECORD results. Treatment comparisons for MI (HR 1.13, 95% CI 0.80-1.59) and mortality (HR 0.86, 95% CI 0.68-1.08) were also the same compared with the original RECORD results. Sensitivity analyses were also consistent with the original RECORD results. Analyses using the FDA definitions showed similar results.Only a modest number of additional person-years of follow-up were ascertained from this reevaluation of CV end points in RECORD. Observed HRs and CIs from these analyses using the original RECORD or new FDA end point definitions showed similar treatment effects of rosiglitazone compared with the original RECORD results.

    View details for DOI 10.1016/j.ahj.2013.05.004

    View details for Web of Science ID 000322629000008

    View details for PubMedID 23895806

  • Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years INTERNATIONAL JOURNAL OF CARDIOLOGY Chan, M. Y., Sun, J., Newby, L. K., Lokhnygina, Y., White, H. D., Moliterno, D. J., Theroux, P., Ohman, E. M., Simoons, M. L., Mahaffey, K. W., Pieper, K. S., Giugliano, R. P., Armstrong, P. W., Califf, R. M., Van de Werf, F., Harrington, R. A. 2013; 167 (2): 548-554

    Abstract

    BACKGROUND: Data are limited on whether clinical trials have randomized higher-risk patients over time and how trends in risk profiles and evidence-based pharmacotherapies have influenced trial outcomes. We quantified changes in baseline risk, treatment, and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) randomized in 9 phase 3 clinical trials of antithrombotic therapy over 15years. METHODS: We studied 58,771 patients in GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B, PRISM, PRISM-PLUS, GUSTO IV-ACS, SYNERGY, and EARLY ACS. Patient-level data were mapped to 3 pre-specified 5-year randomization periods. Temporal trends in GRACE score-predicted mortality were compared with trends in observed mortality. RESULTS: Over time, in-hospital and discharge use of thienopyridines (p=0.001), statins (p<0.0001), and angiotensin-converting enzyme inhibitors (p<0.0001) increased, and hospital length-of-stay decreased (p=0.024). Blood transfusion use increased (8.3% [1994-98], 10.7% [1999-2003], 13% [2004-08], p=0.0002) despite stable rates of severe bleeding (0.9% [1994-98], 1.4% [1999-2003] and 1.1% [2004-08], p=0.127) and coronary artery bypass grafting (12.4% [1994-98], 13.7% [1999-2003] 13.1% [2004-08], p=0.880). Although predicted 6-month mortality increased (6.9% [1994-98], 9.0% [1999-2003], 7.9% [2004-08], p=0.017), observed 6-month mortality decreased (6.7% [1994-98], 5.8% [1999-2003], 5.1% [2004-08], p=0.025). Thirty-day myocardial infarction rates remained stable (9.2% [1994-98], 9.3% [1999-2003], 10% [2004-08], p=0.539). CONCLUSIONS: Despite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study.

    View details for DOI 10.1016/j.ijcard.2012.01.065

    View details for Web of Science ID 000320768800050

    View details for PubMedID 22341697

  • Cardiac Troponin After Percutaneous Coronary Intervention and 1-Year Mortality in Non-ST-Segment Elevation Acute Coronary Syndrome Using Systematic Evaluation of Biomarker Trends JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tricoci, P., Leonardi, S., White, J., White, H. D., Armstrong, P. W., Montalescot, G., Giugliano, R. P., Gibson, C. M., Van de Werf, F., Califf, R. M., Harrington, R. A., Braunwald, E., Mahaffey, K. W., Newby, L. K. 2013; 62 (3): 242-251

    Abstract

    OBJECTIVES: We reviewed cardiac troponin (cTn) trends during non-ST-segment elevation acute coronary syndrome (NSTE ACS) in patients undergoing percutaneous coronary intervention (PCI) in EARLY ACS and SYNERGY and studied the relationship between post-PCI cTn and mortality. BACKGROUND: The prognostic value of cTn post-PCI is controversial. In patients with NSTE ACS, it is especially difficult to distinguish between cTn elevations due to PCI or index myocardial infarction (MI). METHODS: Time and cTn (indexed by upper limit of normal [ULN]) data pairs were plotted for 10,199 patients and independently reviewed by 2 physicians to identify patients in whom post-PCI cTn elevation could be distinguished from that of index MI. Post-PCI cTn peak was identified for each plot, and its relationship with 1-year mortality was evaluated using Cox modeling, correcting for 15 clinical variables from the EARLY ACS 1-year mortality model (including baseline cTn). We used an identical methodology to assess the association between creatine kinase-MB (CK-MB) and 1-year mortality. RESULTS: Patients with cTn (re)elevation post-PCI not evaluable were identified and excluded from further analysis (4198 [41%] with cTn rising prior to PCI; 229 [2%] with missing cTn). Among the remainder (N=5772 [57%]), in the multivariable model, peak cTn post-PCI was associated with a 7% increase in mortality (hazard ratio [HR] for 10x ULN increase, 1.07; 95% confidence interval [CI], 1.02-1.11; p=0.0038). Peak post-PCI CK-MB was significantly associated with 1-year mortality (HR for 1x ULN increase, 1.13; 95% CI, 1.05-1.21; p=0.0013). CONCLUSIONS: We used a methodology that differentiated post-PCI cTn (re)elevation from that of presenting MI in more than half of patients with NSTE ACS undergoing PCI. This identified a highly significant relationship between post-PCI cTn and 1-year mortality, with implication for both incorporating a cTn post-PCI MI definition and preventing PCI-related myonecrosis.

    View details for DOI 10.1016/j.jacc.2013.04.043

    View details for Web of Science ID 000321695500011

    View details for PubMedID 23684676

  • Use of Evidence-based Cardiac Prevention Therapy Among Outpatients with Atrial Fibrillation AMERICAN JOURNAL OF MEDICINE Hess, P. L., Kim, S., Piccini, J. P., Allen, L. A., Ansell, J. E., Chang, P., Freeman, J. V., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Thomas, L., Peterson, E. D., Fonarow, G. C. 2013; 126 (7): 625-?

    Abstract

    Patients with atrial fibrillation often have cardiovascular risk factors or known comorbid disease, yet the use of evidence-based primary and secondary prevention cardiac therapy among atrial fibrillation outpatients is unknown.Using baseline data collected between June 2010 and August 2011 from 174 sites participating in ORBIT-AF, a US national registry of patients with atrial fibrillation coordinated from Durham, NC, we examined professional guideline-recommended evidence-based therapy use for cardiovascular comorbid conditions and risk factors. Multivariable logistic regression was used to identify factors associated with receipt of all indicated evidence-based therapy.Among 10,096 enrolled patients, 93.5% were eligible for one or more evidence-based therapies. Among those eligible, 46.6% received all indicated therapies: 62.3% received an antiplatelet agent, 72.3% received a beta-blocker, 59.5% received an angiotensin-converting enzyme or angiotensin receptor blocker, 15.3% received an aldosterone antagonist, 65.7% received a statin, and 58.8% received an implantable cardioverter-defibrillator. A minority of patients with coronary artery disease, diabetes mellitus, heart failure, and peripheral vascular disease received all indicated therapies (25.1%, 43.2%, 42.5%, and 43.4%, respectively). A total of 52.4% of patients had controlled hypertension and 74.6% of patients with hyperlipidemia received a statin. Factors associated with nonreceipt of all indicated therapies included frailty, comorbid illness, geographic region, and antiarrhythmic drug therapy.The majority of eligible atrial fibrillation outpatients did not receive all guideline-recommended therapies for cardiovascular comorbid conditions and risk factors. This represents a potential opportunity to improve atrial fibrillation patients' quality of care and outcomes.

    View details for DOI 10.1016/j.amjmed.2013.01.037

    View details for Web of Science ID 000320649800028

    View details for PubMedID 23787195

  • Highlights from the fifth international symposium of thrombosis and anticoagulation (ISTA V), October 18-19, 2012, Belo Horizonte, Minas Gerais, Brazil. Journal of thrombosis and thrombolysis Lopes, R. D., Becker, R. C., Newby, L. K., Peterson, E. D., Hylek, E. M., Giugliano, R., Granger, C. B., Mahaffey, K. W., Carvalho, A. C., Berwanger, O., Giraldez, R. R., Feitosa-Filho, G. S., Barbosa, M. M., da Consolacao V Moreira, M., Kalil, R. A., Freitas, M., de Campos Guerra, J. C., Barros, M. V., da Rocha Rodrigues, T., Lopes, A. C., Garcia, D. A. 2013; 36 (1): 115-130

    Abstract

    To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Fifth International Symposium of Thrombosis and Anticoagulation was held in Belo Horizonte, Minas Gerais, Brazil, on October 18-19, 2012. This scientific program was developed by clinicians for clinicians and was promoted by three major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, and Hospital do Coração Research Institute. Comprising 2 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

    View details for DOI 10.1007/s11239-013-0906-z

    View details for PubMedID 23494487

  • Risks and Benefits of Anticoagulation in Atrial Fibrillation: Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Cullen, M. W., Kim, S., Piccini, J. P., Ansell, J. E., Fonarow, G. C., Hylek, E. M., Singer, D. E., Mahaffey, K. W., Kowey, P. R., Thomas, L., Go, A. S., Lopes, R. D., Chang, P., Peterson, E. D., Gersh, B. J. 2013; 6 (4): 461-469

    Abstract

    Patients with atrial fibrillation (AF) at the highest stroke risk derive the largest benefit from oral anticoagulation (OAC). Those with the highest stroke risk have been paradoxically less likely to receive OAC. This study assessed the association between stroke and bleeding risk on rates of OAC.We analyzed OAC use among 10,098 patients with AF from 174 community-based outpatient practices enrolled in 2010-2011 in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). OAC was defined as warfarin or dabigatran use at study enrollment. Stroke and bleeding risk were calculated using congestive heart failure, hypertension, age, diabetes mellitus, prior stroke (CHADS?), and anticoagulation and risk factors in AF (ATRIA) scores, respectively. The mean subject age was 73 years; 58% were men. Overall, 76% of patients received OAC (71% warfarin and 5% dabigatran). The use of OAC increased among those with higher CHADS? scores, from 53% for CHADS?=0 to 80% for CHADS??2 (P<0.001). OAC use fell slightly with increasing ATRIA bleeding risk score, from 81% for ATRIA=3 to 73% for ATRIA?5 (P<0.001). A significant interaction existed between ATRIA and CHADS? scores (P=0.021). Among those with low bleeding risk, use of OAC increased significantly with increasing stroke risk. Among those with high bleeding risk, CHADS? stroke risk had a smaller impact on use of OAC.In community-based outpatients with AF, use of OAC was high and driven by not only predominantly stroke but also bleeding risk. Stroke risk significantly affects OAC use among those with low bleeding risk, whereas those with high bleeding risk demonstrate consistently lower use of OAC regardless of stroke risk.

    View details for DOI 10.1161/CIRCOUTCOMES.113.000127

    View details for Web of Science ID 000321898000014

    View details for PubMedID 23759473

  • Highlights from the fifth international symposium of thrombosis and anticoagulation (ISTA V), october 18-19, 2012, Belo Horizonte, Minas Gerais, Brazil JOURNAL OF THROMBOSIS AND THROMBOLYSIS Lopes, R. D., Becker, R. C., Newby, L. K., Peterson, E. D., Hylek, E. M., Giugliano, R., Granger, C. B., Mahaffey, K. W., Carvalho, A. C., Berwanger, O., Giraldez, R. R., Feitosa-Filho, G. S., Barbosa, M. M., Moreira, M. d., Kalil, R. A., Freitas, M., de Campos Guerra, J. C., Lins Barros, M. V., Rodrigues, T. d., Lopes, A. C., Garcia, D. A. 2013; 36 (1): 115-130
  • Efficacy and Safety of Rivaroxaban in Patients With Heart Failure and Nonvalvular Atrial Fibrillation Insights From ROCKET AF CIRCULATION-HEART FAILURE van Diepen, S., Hellkamp, A. S., Patel, M. R., Becker, R. C., Breithardt, G., Hacke, W., Halperin, J. L., Hankey, G. J., Nessel, C. C., Singer, D. E., Berkowitz, S. D., Califf, R. M., Fox, K. A., Mahaffey, K. W. 2013; 6 (4): 740-747

    Abstract

    In Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), rivaroxaban was noninferior to warfarin for the prevention of stroke and systemic embolic events and significantly reduced intracranial bleeding in patients with nonvalvular atrial fibrillation. We explore the safety and efficacy of rivaroxaban in patients with heart failure (HF).A total of 9033 (63.7%) patients had HF. The primary efficacy analysis was rates of stroke or systemic embolism (per 100 patient-years) by intention to treat. The safety outcomes were major or nonmajor clinically relevant bleeding and hemorrhagic stroke during treatment. Patients with HF were younger (72 versus 74 years), more likely to have persistent atrial fibrillation (83.0% versus 77.6%), and had higher mean CHADS2 scores (3.7 versus 3.1). The efficacy of rivaroxaban compared with warfarin was similar in patients with HF (1.90 versus 2.09) and without HF (2.10 versus 2.54; P-interaction=0.62). The risk of major or nonmajor clinically relevant bleeding with rivaroxaban was similar to warfarin in patients with HF (14.22 versus 14.02) and without HF (16.12 versus 15.35; P-interaction=0.99). A reduction in hemorrhagic stroke was observed with rivaroxaban in patients with HF as in the overall trial (adjusted hazard ratio, 0.38; 95% confidence interval, 0.19-0.76; P-interaction=0.067). Among patients with HF, the efficacy of rivaroxaban was similar, irrespective of ejection fraction <40 or ? 40% (P-interaction=0.38), New York Heart Association class I-II versus III-IV (P-interaction=0.68), HF preserved or reduced ejection fraction (P-interaction=0.35), or CHADS2 score 2 versus ? 3 (P-interaction=0.48).Treatment-related outcomes were similar in patients with and without HF and across HF subgroups. These findings support the use of rivaroxaban as an alternative to warfarin in patients with atrial fibrillation and HF. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCHEARTFAILURE.113.000212

    View details for Web of Science ID 000335157800023

    View details for PubMedID 23723250

  • End of Study Transition From Study Drug to Open-Label Vitamin K Antagonist Therapy: The ROCKET AF Experience CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Mahaffey, K. W., Hellkamp, A. S., Patel, M. R., Hannan, K. L., Schwabe, K., Nessel, C. C., Berkowitz, S. D., Halperin, J. L., Hankey, G. J., Becker, R. C., Piccini, J. P., Breithardt, G., Hacke, W., Singer, D. E., Califf, R. M., Fox, K. A. 2013; 6 (4): 470-478

    Abstract

    To evaluate the previously reported excess of thromboembolic events during the 30 days after the end of study (EOS) visit when participants transitioned from blinded therapy to open-label vitamin K antagonist.At the EOS visit, open-label vitamin K antagonist was recommended, and the international normalized ratio (INR) was not to be measured until 3 days later to preserve blinding. We analyzed transition strategies, clinical outcomes, and INR values. Event rates are per 100 patient-years. A total of 9248 (65%) participants were taking study drug at EOS, and, between days 3 and 30, an excess of stroke and systemic embolic events were observed in participants assigned to rivaroxaban (rivaroxaban 22 events, event rate 6.42; warfarin 6 events, event rate 1.73; hazard ratio, 3.72; 95% confidence interval, 1.51-9.16; P=0.0044). No INR values were reported for ?5% of participants transitioned to warfarin. By 30 days after EOS, 83% of the warfarin group and 52% of the rivaroxaban group had ?1 therapeutic INR value. Median time to first therapeutic INR was 3 days in the warfarin group and 13 days in the rivaroxaban group.The excess of events at EOS was likely because of a period of inadequate anticoagulation in rivaroxaban participants switched to vitamin K antagonist therapy. If transition from rivaroxaban to vitamin K antagonist is needed, timely monitoring and careful dosing should be used to ensure consistent and adequate anticoagulation.

    View details for DOI 10.1161/CIRCOUTCOMES.113.000132

    View details for Web of Science ID 000321898000015

    View details for PubMedID 23759472

  • Prognostic Significance of Bleeding Location and Severity Among Patients With Acute Coronary Syndromes JACC-CARDIOVASCULAR INTERVENTIONS Vavalle, J. P., Clare, R., Chiswell, K., Rao, S. V., Petersen, J. L., Kleiman, N. S., Mahaffey, K. W., Wang, T. Y. 2013; 6 (7): 709-717

    Abstract

    This study sought to determine if there is an association between bleed location and clinical outcomes in acute coronary syndromes (ACS) patients.The prognostic significance of bleeding location among ACS patients undergoing cardiac catheterization is not well known.We analyzed in-hospital bleeding events among 9,978 patients randomized in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) study. Bleeding events were categorized by location as access site, systemic, surgical, or superficial, and severity was graded using the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definition. We assessed the association of each bleeding location and severity with 6-month risk of death or myocardial infarction using a multicovariate-adjusted Cox proportional hazard model.A total of 4,900 bleeding events were identified among 3,694 ACS patients with in-hospital bleeding. Among 4,679 GUSTO mild/moderate bleeding events, only surgical and systemic bleeds were associated with an increased risk of 6-month death or myocardial infarction (adjusted hazard ratio [HR]: 2.52 [95% confidence interval (CI): 2.16 to 2.94, and 1.40 [95% CI: 1.16 to 1.69], respectively). Mild/moderate superficial and access-site bleeds were not associated with downstream risk (adjusted HR: 1.17 [95% CI: 0.97 to 1.40], and 0.96 [95% CI: 0.82 to 1.12], respectively). Among 221 GUSTO severe bleeds, surgical bleeds were associated with the highest risk (HR: 5.27 [95% CI: 3.80 to 7.29]), followed by systemic (HR: 4.48 [95% CI: 2.98 to 6.72]), and finally access-site bleeds (HR: 3.57 [95% CI: 2.35 to 5.40]).Among ACS patients who develop in-hospital bleeding, systemic and surgical bleeding are associated with the highest risks of adverse outcomes regardless of bleeding severity. Although the most frequent among bleeds, GUSTO mild/moderate access-site bleeding is not associated with increased risk. These data underscore the importance of strategies to minimize overall bleeding risk beyond vascular access site management.

    View details for DOI 10.1016/j.jcin.2013.03.010

    View details for Web of Science ID 000322129400013

    View details for PubMedID 23866183

  • Clinical Outcomes With Rivaroxaban in Patients Transitioned From Vitamin K Antagonist Therapy A Subgroup Analysis of a Randomized Trial ANNALS OF INTERNAL MEDICINE Mahaffey, K. W., Wojdyla, D., Hankey, G. J., White, H. D., Nessel, C. C., Piccini, J. P., Patel, M. R., Berkowitz, S. D., Becker, R. C., Halperin, J. L., Singer, D. E., Califf, R. M., Fox, K. A., Breithardt, G., Hacke, W. 2013; 158 (12): 861-?

    Abstract

    In ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), a large randomized, clinical trial, rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation.To determine the efficacy and safety of rivaroxaban compared with warfarin among vitamin K antagonist (VKA)-naive and VKA-experienced patients.Prespecified subgroup analysis. (ClinicalTrials.gov: NCT00403767).Global.14,264 persons with atrial fibrillation.Interaction of the relative treatment effect of rivaroxaban and warfarin on stroke or systemic embolism among VKA-naive and VKA-experienced patients.Overall, 7897 (55.4%) patients were VKA-experienced and 6367 (44.6%) were VKA-naive. The effect of rivaroxaban versus warfarin on stroke or systemic embolism was consistent: Rates per 100 patient-years of follow-up were 2.32 versus 2.87 for VKA-naive patients (hazard ratio [HR], 0.81 [95% CI, 0.64 to 1.03]) and 1.98 versus 2.09 for VKA-experienced patients (HR, 0.94 [CI, 0.75 to 1.18]; interaction P = 0.36). During the first 7 days, rivaroxaban was associated with more bleeding than warfarin (HR in VKA-naive patients, 5.83 [CI, 3.25 to 10.44], and in VKA-experienced patients, 6.66 [CI, 3.83 to 11.58]; interaction P = 0.53). After 30 days, rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients (HR, 0.84 [CI, 0.74 to 0.95]) and similar bleeding in VKA-experienced patients (HR, 1.06 [CI, 0.96 to 1.17]; interaction P = 0.003).The trial was not designed to detect differences in these subgroups.The efficacy of rivaroxaban in VKA-experienced and VKA-naive patients was similar to that of the overall trial. There were more bleeding events within 7 days of study drug initiation with rivaroxaban, but after 30 days, rivaroxaban was associated with less bleeding in VKA-naive patients and similar bleeding in VKA-experienced patients. This information may be useful to clinicians considering a transition to rivaroxaban for patients receiving VKA therapy.Johnson & Johnson and Bayer HealthCare.

    View details for Web of Science ID 000320645000014

    View details for PubMedID 23778903

  • Effect of vorapaxar on myocardial infarction in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA.CER) trial EUROPEAN HEART JOURNAL Leonardi, S., Tricoci, P., White, H. D., Armstrong, P. W., Huang, Z., Wallentin, L., Aylward, P. E., Moliterno, D. J., Van de Werf, F., Chen, E., Providencia, L., Nordrehaug, J. E., Held, C., Strony, J., Rorick, T. L., Harrington, R. A., Mahaffey, K. W. 2013; 34 (23): 1723-1731

    Abstract

    AimsThe TRA·CER trial compared vorapaxar, a novel platelet protease-activated receptor (PAR)-1 antagonist, with placebo in 12 944 patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS). In this analysis, we explored the effect of vorapaxar on myocardial infarction (MI).Methods and resultsA blinded, independent central endpoint adjudication committee prospectively defined and classified MI according to the universal MI definition, including peak cardiac marker value (creatine kinase-MB [CK-MB] and/or troponin). Because the trial failed to meet its primary endpoint, these analyses are considered exploratory. During a median follow-up of 502 days, 1580 MIs occurred in 1319 patients. The majority (n = 1025, 64.9%) were type 1 (spontaneous) MI, followed by type 4a [percutaneous coronary intervention (PCI)-related] MI (n = 352; 22.3%). Compared with placebo, vorapaxar reduced the hazard of a first MI of any type by 12% [hazard ratio (HR), 0.88; 95% confidence interval (CI), 0.79-0.98; P = 0.021] and the hazard of total number of MIs (first and subsequent) by 14% (HR, 0.86; 95% CI, 0.77-0.97; P = 0.014), an effect that was sustained over time. Vorapaxar reduced type 1 MI by 17% (HR, 0.83; 95% CI, 0.73-0.95; P = 0.007). Type 4a MIs were not significantly reduced by vorapaxar (HR, 0.90; 95% CI, 0.73-1.12; P = 0.35). Vorapaxar effect was consistent across MI sizes defined by peak cardiac marker elevations and across key clinical subgroups; however, in patients not treated with thienopyridine at baseline (HR, 0.65; 95% CI, 0.46-0.92) compared with patients who received thienopyridine (HR, 0.91; 95% CI, 0.81-1.02), there was a trend towards a higher effect (Pint = 0.077).ConclusionThe PAR-1 antagonist vorapaxar was associated with a reduction of MI, including total number of infarctions. This reduction was sustained over time and was mostly evident in type 1 MI, the most common type of MI observed.

    View details for DOI 10.1093/eurheartj/eht104

    View details for Web of Science ID 000320408500009

    View details for PubMedID 23530022

  • Quantification of the effect of clopidogrel on enzymatic infarct size related to a percutaneous coronary intervention in patients with acute coronary syndromes: insights from the CHAMPION percutaneous coronary intervention trial CORONARY ARTERY DISEASE Leonardi, S., Stebbins, A., Lopes, R. D., Lokhnygina, Y., Todd, M., Bhatt, D. L., Stone, G. W., Lincoff, A. M., Dauerman, H. L., Gibson, C. M., White, H. D., Parikh, K. H., Gruberg, L., Herrmann, H. C., McLaurin, B. T., Goodman, S. G., Mahaffey, K. W. 2013; 24 (4): 321-327

    Abstract

    Using data from the CHAMPION percutaneous coronary intervention (PCI), we determined the relationship between clopidogrel started at least 5 days before PCI (maintenance of clopidogrel) and PCI-related enzymatic infarct size.Clopidogrel is recommended in patients with acute coronary syndrome (ACS) managed with PCI, but its effect on PCI-related myonecrosis in contemporary patients has not been quantified.Patients with ACS (with or without ST-segment elevation) who underwent PCI and had at least three creatine kinase-MB (CK-MB) samples after PCI were included. Enzymatic infarct size was defined as the peak CK-MB concentration indexed by its upper limit of normal. Associations between maintenance clopidogrel and enzymatic infarct size were explored using multivariable linear regression (with and without missing data imputation) and propensity score analysis using inverse probability weighting.Of 8877 patients randomized, 6327 (71.3%) were included (median age 61 years, 73% male, 13% ACS with ST-segment elevation). Of these 6327 patients, 2015 (31.8%) were on maintenance clopidogrel. After multivariable adjustment, maintenance clopidogrel was associated with a reduction in enzymatic infarct size {?=-0.63; 47% decrease in peak CK-MB [95% confidence interval (CI) 35, 56%]}. Multivariable linear regression with multiple imputations and inverse probability weighting propensity score analysis yielded similar results, with maintenance clopidogrel associated with 44% (95% CI 33, 53%) and 29% (95% CI 24, 33%) infarct size reductions.In this subgroup analysis of modern ACS patients, clopidogrel maintenance was independently associated with smaller enzymatic infarct size after PCI. These results are consistent with previous observations suggesting a benefit of clopidogrel on the procedural outcome and quantify this benefit.

    View details for DOI 10.1097/MCA.0b013e32835f2fbd

    View details for Web of Science ID 000318154600010

    View details for PubMedID 23442944

  • Heart failure complicating non-ST-segment elevation acute coronary syndrome: timing, predictors, and clinical outcomes. JACC. Heart failure Bahit, M. C., Lopes, R. D., Clare, R. M., Newby, L. K., Pieper, K. S., Van de Werf, F., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Diaz, R., Ohman, E. M., White, H. D., James, S., Granger, C. B. 2013; 1 (3): 223-229

    Abstract

    This study sought to describe the occurrence and timing of heart failure (HF), associated clinical factors, and 30-day outcomes in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS).Little is known about HF-complicating NSTE-ACS.Using pooled patient-level data from 7 clinical trials from 1994 to 2008, we describe the occurrence and timing of HF, associated clinical factors, and 30-day outcomes in NSTE-ACS patients. HF at presentation was defined as Killip classes II to III; patients with Killip class IV or cardiogenic shock were excluded. New in-hospital cases of HF included new pulmonary edema. After adjusting for baseline variables, we created logistic regression models to identify clinical factors associated with HF at presentation and to determine the association between HF and 30-day mortality.Of 46,519 NSTE-ACS patients, 4,910 (10.6%) had HF at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization. A total of 40,415 (86.9%) had no HF at any time. Patients presenting with or developing HF during hospitalization were older, more often female, and had a higher risk of death at 30 days than patients without HF (adjusted odds ratio [OR]: 1.74; 95% confidence interval: 1.35 to 2.26). Older age, higher presenting heart rate, diabetes, prior myocardial infarction (MI), and enrolling MI were significantly associated with HF during hospitalization.In this large cohort of NSTE-ACS patients, presenting with or developing HF during hospitalization was associated with an increased risk of 30-day mortality. Research targeting new strategies to prevent and manage HF in this high-risk population is needed.

    View details for DOI 10.1016/j.jchf.2013.02.007

    View details for PubMedID 24621874

  • Outcomes After Cardioversion and Atrial Fibrillation Ablation in Patients Treated With Rivaroxaban and Warfarin in the ROCKET AF Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Piccini, J. P., Stevens, S. R., Lokhnygina, Y., Patel, M. R., Halperin, J. L., Singer, D. E., Hankey, G. J., Hacke, W., Becker, R. C., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M., Breithardt, G. 2013; 61 (19): 1998-2006

    Abstract

    This study sought to investigate the outcomes following cardioversion or catheter ablation in patients with atrial fibrillation (AF) treated with warfarin or rivaroxaban.There are limited data on outcomes following cardioversion or catheter ablation in AF patients treated with factor Xa inhibitors.We compared the incidence of electrical cardioversion (ECV), pharmacologic cardioversion (PCV), or AF ablation and subsequent outcomes in patients in a post hoc analysis of the ROCKET AF (Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation) trial.Over a median follow-up of 2.1 years, 143 patients underwent ECV, 142 underwent PCV, and 79 underwent catheter ablation. The overall incidence of ECV, PCV, or AF ablation was 1.45 per 100 patient-years (n = 321; 1.44 [n = 161] in the warfarin arm, 1.46 [n = 160] in the rivaroxaban arm). The crude rates of stroke and death increased in the first 30 days after cardioversion or ablation. After adjustment for baseline differences, the long-term incidence of stroke or systemic embolism (hazard ratio [HR]: 1.38; 95% confidence interval [CI]: 0.61 to 3.11), cardiovascular death (HR: 1.57; 95% CI: 0.69 to 3.55), and death from all causes (HR: 1.75; 95% CI: 0.90 to 3.42) were not different before and after cardioversion or AF ablation. Hospitalization increased after cardioversion or AF ablation (HR: 2.01; 95% CI: 1.51 to 2.68), but there was no evidence of a differential effect by randomized treatment (p value for interaction = 0.58). The incidence of stroke or systemic embolism (1.88% vs. 1.86%) and death (1.88% vs. 3.73%) were similar in the rivaroxaban-treated and warfarin-treated groups.Despite an increase in hospitalization, there were no differences in long-term stroke rates or survival following cardioversion or AF ablation. Outcomes were similar in patients treated with rivaroxaban or warfarin. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation [ROCKET AF]; NCT00403767).

    View details for DOI 10.1016/j.jacc.2013.02.025

    View details for Web of Science ID 000318910300011

    View details for PubMedID 23500298

  • Methods of creatine kinase-MB analysis to predict mortality in patients with myocardial infarction treated with reperfusion therapy TRIALS Lopes, R. D., Lokhnygina, Y., Hasselblad, V., Newby, K. L., Yow, E., Granger, C. B., Armstrong, P. W., Hochman, J. S., Mills, J. S., Ruzyllo, W., Mahaffey, K. W. 2013; 14

    Abstract

    Larger infarct size measured by creatine kinase (CK)-MB release is associated with higher mortality and has been used as an important surrogate endpoint in the evaluation of new treatments for ST-segment elevation myocardial infarction (STEMI). Traditional approaches to quantify infarct size include the observed CK-MB peak and calculated CK-MB area under the curve (AUC). We evaluated alternative approaches to quantifying infarct size using CK-MB values, and the relationship between infarct size and clinical outcomes.Of 1,850 STEMI patients treated with reperfusion therapy in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) (percutaneous coronary intervention (PCI)-treated) and the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) (fibrinolytic-treated) trials, 1,718 (92.9%) (COMMA, n = 868; COMPLY, n = 850) had at least five of nine protocol-required CK-MB measures. In addition to traditional methods, curve-fitting techniques were used to determine CK-MB AUC and estimated peak CK-MB. Cox proportional hazards modeling assessed the univariable associations between infarct size and mortality, and the composite of death, heart failure, shock and stroke at 90 days.In COMPLY, CK-MB measures by all methods were significantly associated with higher mortality (hazard ratio range per 1,000 units increase: 1.09 to 1.13; hazard ratio range per 1 standard deviation increase: 1.41 to 1.62; P <0.01 for all analyses). In COMMA, the associations were similar but did not reach statistical significance. For the composite outcome of 90-day death, heart failure, shock and stroke, the associations with all CK-MB measures were statistically significant in both the COMMA and COMPLY trials.Sophisticated curve modeling is an alternative to infarct-size quantification in STEMI patients, but it provides information similar to that of more traditional methods. Future studies will determine whether the same conclusion applies in circumstances other than STEMI, or to studies with different frequencies and patterns of CK-MB data collection.

    View details for DOI 10.1186/1745-6215-14-123

    View details for Web of Science ID 000319397900001

    View details for PubMedID 23782531

  • Incorporation of bleeding as an element of the composite end point in clinical trials of antithrombotic therapies in patients with non-ST-segment elevation acute coronary syndrome: Validity, pitfalls, and future approaches AMERICAN HEART JOURNAL Subherwal, S., Ohman, E. M., Mahaffey, K. W., Rao, S. V., Alexander, J. H., Wang, T. Y., Alexander, K. P., Hasselblad, V., Roe, M. T. 2013; 165 (5): 644-?

    Abstract

    With the large number of antithrombotic therapies available and under investigation for the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS), practice guidelines now stress the importance of selecting an antithrombotic strategy according to the efficacy and safety profiles of the chosen agent. Contemporary trials have incorporated bleeding along with ischemic end points into a composite end point commonly referred to as net clinical benefit, which allows for simultaneous evaluation of the differences between benefit and harm for an investigational antithrombotic therapy. However, incorporating major bleeding into a composite end point that includes ischemic events is not warranted and is associated with many pitfalls. In this article, we discuss the validity of combining efficacy and safety end points to form a net clinical benefit composite end point with the traditional time-to-event analysis for trials evaluating antithrombotic therapies for NSTE ACS. We describe alternative statistical approaches for concurrent assessment of the safety and efficacy of antithrombotic therapies used to treat patients with NSTE ACS.

    View details for DOI 10.1016/j.ahj.2012.11.012

    View details for Web of Science ID 000318724000005

    View details for PubMedID 23622901

  • Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events NEW ENGLAND JOURNAL OF MEDICINE Bhatt, D. L., Stone, G. W., Mahaffey, K. W., Gibson, C. M., Steg, P. G., Hamm, C. W., Price, M. J., Leonardi, S., Gallup, D., Bramucci, E., Radke, P. W., Widimsky, P., Tousek, F., Tauth, J., Spriggs, D., McLaurin, B. T., Angiolillo, D. J., Genereux, P., Liu, T., Prats, J., Todd, M., Skerjanec, S., White, H. D., Harrington, R. A. 2013; 368 (14): 1303-1313

    Abstract

    The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects.In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours.The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups.Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.).

    View details for DOI 10.1056/NEJMoa1300815

    View details for Web of Science ID 000316989900007

    View details for PubMedID 23473369

  • Left Bundle Branch Block in Non-ST-Segment Elevation Acute Coronary Syndromes Incidence, Angiographic Characteristics, and Clinical Outcomes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rose, J. J., Newby, L. K., Broderick, S., Chiswell, K., Van de Werf, F., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Ohman, E. M., Giugliano, R. P., Goodman, S. G., White, H. D., Califf, R. M., Granger, C. B., Lopes, R. D. 2013; 61 (13): 1461-1463

    View details for DOI 10.1016/j.jacc.2012.12.032

    View details for Web of Science ID 000317191200017

    View details for PubMedID 23500249

  • Rate versus rhythm control for management of atrial fibrillation in clinical practice: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry AMERICAN HEART JOURNAL Steinberg, B. A., Holmes, D. N., Ezekowitz, M. D., Fonarow, G. C., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Reiffel, J., Chang, P., Peterson, E. D., Piccini, J. P. 2013; 165 (4): 622-629

    Abstract

    All patients with atrial fibrillation (AF) require optimization of their ventricular rate. Factors leading to use of additional rhythm control in clinical practice have not been thoroughly defined.The ORBIT-AF registry enrolled patients with AF from a broad range of practice settings and collected data on rate versus rhythm control, as indicated by the treating physician. Multivariable logistic regression analysis was performed to identify factors associated with each strategy.Of 10,061 patients enrolled, 6,859 (68%) were managed with rate only control versus 3,202 (32%) with rhythm control. Patients managed with rate control were significantly older and more likely to have hypertension, heart failure, prior stroke, and gastrointestinal bleeds. They also had fewer AF-related symptoms (41% with no symptoms vs 31% for rhythm control). Systemic anticoagulation was prescribed for 5,448 (79%) rate-control patients versus 2,219 (69%) rhythm-control patients (P < .0001). After multivariable adjustment, patients with higher symptom scores (severe symptoms vs. none, OR 1.62, 95% CI 1.41-1.87) and those referred to electrophysiologists (OR 1.64, 95% CI 1.45-1.85) were more likely to be managed with a rhythm control strategy.In this outpatient registry of US clinical practice, the majority of patients with AF were managed with rate control alone. Patients with more symptoms and who were treated by an electrophysiologist were more likely to receive rhythm-control therapies. A significant proportion of AF patients, regardless of treatment strategy, were not treated with anticoagulation for thromboembolism prophylaxis.

    View details for DOI 10.1016/j.ahj.2012.12.019

    View details for Web of Science ID 000317184300026

    View details for PubMedID 23537981

  • Dynamic modeling of 90-day mortality in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention AMERICAN HEART JOURNAL Westerhout, C. M., Pieper, K. S., James, S. K., Mahaffey, K. W., Van de Werf, F., Califf, R. M., Granger, C. B., Armstrong, P. W. 2013; 165 (3): 354-?

    Abstract

    Dynamic risk models update the risk profile of ST-elevation myocardial infarction (STEMI) patients over the acute period following the event and have implications to clinical practice and research.Multivariable survival models were developed in 5,745 STEMI patients undergoing primary percutaneous coronary intervention (PCI) enrolled in the APEX-AMI trial to predict 90-day mortality from 4 clinically relevant times: baseline, 2 hours, 24 hours, and 96 hours. Culprit coronary thrombolysis in myocardial infarction flow grade, 30-minute post-PCI worst-lead ST-elevation residual, and in-hospital clinical events were considered in the models. The 90-day mortality was 4.7%; the cumulative proportion of mortality occurring within 2, 24, and 96 hours was 8%, 22%, and 40% respectively. Relative to the baseline risk factors, age and systolic blood pressure remained highly ranked in the post-baseline models. However, the relative importance of heart rate, Killip class, and creatinine declined, whereas markers of coronary reperfusion and in-hospital events (shock, congestive heart failure) became increasingly influential. The c-index increased from 0.819 at baseline to 0.847 at 96 hours. Over the forecasting periods, the proportion of "low-risk" (<1.1% 90-day mortality) patients increased from 20% to 49%. This approach derived from an unfolding series of models reveals the shifting levels of mortality risk from baseline to 96 hours.This novel approach in STEMI patients undergoing primary PCI demonstrates the dynamic nature of risk over time and may prove useful in understanding risk and in clinical decision making.

    View details for DOI 10.1016/j.ahj.2012.12.001

    View details for Web of Science ID 000315710500019

    View details for PubMedID 23453104

  • Outcomes of Discontinuing Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation Analysis From the ROCKET AF Trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Patel, M. R., Hellkamp, A. S., Lokhnygina, Y., Piccini, J. P., Zhang, Z., Mohanty, S., Singer, D. E., Hacke, W., Breithardt, G., Halperin, J. L., Hankey, G. J., Becker, R. C., Nessel, C. C., Berkowitz, S. D., Califf, R. M., Fox, K. A., Mahaffey, K. W. 2013; 61 (6): 651-658

    Abstract

    The purpose of this study was to understand the possible risk of discontinuation in the context of clinical care.Rivaroxaban is noninferior to warfarin for preventing stroke in atrial fibrillation patients. Concerns exist regarding possible increased risk of stroke and non-central nervous system (CNS) thromboembolic events early after discontinuation of rivaroxaban.We undertook a post-hoc analysis of data from the ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation, n = 14,624) for stroke or non-CNS embolism within 30 days after temporary interruptions of 3 days or more, early permanent study drug discontinuation, and end-of-study transition to open-label therapy.Stroke and non-CNS embolism occurred at similar rates after temporary interruptions (rivaroxaban: n = 9, warfarin: n = 8, 6.20 vs. 5.05/100 patient-years, hazard ratio [HR]: 1.28, 95% confidence interval [CI]: 0.49 to 3.31, p = 0.62) and after early permanent discontinuation (rivaroxaban: n = 42, warfarin: n = 36, 25.60 vs. 23.28/100 patient-years, HR: 1.10, 95% CI: 0.71 to 1.72, p = 0.66). Patients transitioning to open-label therapy at the end of the study had more strokes with rivaroxaban (n = 22) versus warfarin (n = 6, 6.42 vs. 1.73/100 patient-years, HR: 3.72, 95% CI: 1.51 to 9.16, p = 0.0044) and took longer to reach a therapeutic international normalized ratio with rivaroxaban versus warfarin. All thrombotic events within 30 days of any study drug cessation (including stroke, non-CNS embolism, myocardial infarction, and vascular death) were similar between groups (HR: 1.02, 95% CI: 0.83 to 1.26, p = 0.85).In atrial fibrillation patients who temporarily or permanently discontinued anticoagulation, the risk of stroke or non-CNS embolism was similar with rivaroxaban or warfarin. An increased risk of stroke and non-CNS embolism was observed in rivaroxaban-treated patients compared with warfarin-treated patients after the end of the study, underscoring the importance of therapeutic anticoagulation coverage during such a transition.

    View details for DOI 10.1016/j.jacc.2012.09.057

    View details for Web of Science ID 000314660700010

    View details for PubMedID 23391196

  • Impact of Global Geographic Region on Time in Therapeutic Range on Warfarin Anticoagulant Therapy: Data From the ROCKET AF Clinical Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Singer, D. E., Hellkamp, A. S., Piccini, J. P., Mahaffey, K. W., Lokhnygina, Y., Pan, G., Halperin, J. L., Becker, R. C., Breithardt, G., Hankey, G. J., Hacke, W., Nessel, C. C., Patel, M. R., Califf, R. M., Fox, K. A. 2013; 2 (1)

    Abstract

    Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial.TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i-TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i-TTR was 55.2% (SD 21.3%) and the median i-TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i-TTR, dominant determinants were previous warfarin use (mean i-TTR of 61.1% for warfarin-experienced versus 47.4% in VKA-naïve patients) and geographic region where patients were managed (mean i-TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i-TTRs had INR distributions shifted toward lower INR values and had longer inter-INR test intervals.Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i-TTR in global studies of warfarin. Regional differences in mean i-TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing.URL: ClinicalTrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/JAHA.112.000067

    View details for Web of Science ID 000326336800033

    View details for PubMedID 23525418

  • Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation Validation of the R(2)CHADS(2) Index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) Study Cohorts CIRCULATION Piccini, J. P., Stevens, S. R., Chang, Y., Singer, D. E., Lokhnygina, Y., Go, A. S., Patel, M. R., Mahaffey, K. W., Halperin, J. L., Breithardt, G., Hankey, G. J., Hacke, W., Becker, R. C., Nessel, C. C., Fox, K. A., Califf, R. M. 2013; 127 (2): 224-?

    Abstract

    We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial.In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance ?30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R(2)CHADS(2)) improved net reclassification index by 6.2% compared with CHA(2)DS(2)VASc (C statistic=0.578) and by 8.2% compared with CHADS(2) (C statistic=0.575). The inclusion of creatinine clearance <60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R(2)CHADS(2) in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS(2).In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function.URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.112.107128

    View details for Web of Science ID 000313637200019

    View details for PubMedID 23212720

  • Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis NEW ENGLAND JOURNAL OF MEDICINE Chertow, G. M., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Floege, J., Goodman, W. G., Herzog, C. A., Kubo, Y., London, G. M., Mahaffey, K. W., Mix, T. C., Moe, S. M., Trotman, M., Wheeler, D. C., Parfrey, P. S. 2012; 367 (26): 2482-2494
  • Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. New England journal of medicine Chertow, G. M., Block, G. A., Correa-Rotter, R., Drüeke, T. B., Floege, J., Goodman, W. G., Herzog, C. A., Kubo, Y., London, G. M., Mahaffey, K. W., Mix, T. C., Moe, S. M., Trotman, M., Wheeler, D. C., Parfrey, P. S. 2012; 367 (26): 2482-2494

    Abstract

    Disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to extraskeletal (including vascular) calcification among patients with chronic kidney disease. It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients.In this clinical trial, we randomly assigned 3883 patients with moderate-to-severe secondary hyperparathyroidism (median level of intact parathyroid hormone, 693 pg per milliliter [10th to 90th percentile, 363 to 1694]) who were undergoing hemodialysis to receive either cinacalcet or placebo. All patients were eligible to receive conventional therapy, including phosphate binders, vitamin D sterols, or both. The patients were followed for up to 64 months. The primary composite end point was the time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event. The primary analysis was performed on the basis of the intention-to-treat principle.The median duration of study-drug exposure was 21.2 months in the cinacalcet group, versus 17.5 months in the placebo group. The primary composite end point was reached in 938 of 1948 patients (48.2%) in the cinacalcet group and 952 of 1935 patients (49.2%) in the placebo group (relative hazard in the cinacalcet group vs. the placebo group, 0.93; 95% confidence interval, 0.85 to 1.02; P=0.11). Hypocalcemia and gastrointestinal adverse events were significantly more frequent in patients receiving cinacalcet.In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis. (Funded by Amgen; EVOLVE ClinicalTrials.gov number, NCT00345839.).

    View details for DOI 10.1056/NEJMoa1205624

    View details for PubMedID 23121374

  • Comparison of the Prognosis of Spontaneous and Percutaneous Coronary Intervention-Related Myocardial Infarction JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Leonardi, S., Thomas, L., Neely, M. L., Tricoci, P., Lopes, R. D., White, H. D., Armstrong, P. W., Giugliano, R. P., Antman, E. M., Califf, R. M., Newby, L. K., Mahaffey, K. W. 2012; 60 (22): 2296-2304

    Abstract

    This study compared prognoses of myocardial infarction related to percutaneous coronary intervention (PCI, procedural MI) using increasing creatine kinase-myocardial band (CK-MB) thresholds with spontaneous MI.Procedural MI usually is defined by a CK-MB elevation of more than 3 times the upper limit of normal (ULN), but higher thresholds have been proposed.Patients from the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) study and the SYNERGY (Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors) study treated with PCI were included. The primary end point was 1-year all-cause mortality from 24 h after PCI. To determine an enzymatic threshold for procedural MI with a prognosis similar to that of spontaneous MI, we redefined procedural MI using increasing CK-MB thresholds and compared corresponding hazard ratios with those of spontaneous MI (CK-MB more than twice the ULN). Hazard ratios for mortality for procedural and spontaneous MI were calculated using Cox proportional hazards regression and Global Registry of Acute Cardiac Events covariates for risk adjustment.Nine thousand eighty-seven patients who underwent PCI (46.8%) were included; 773 procedural MI and 239 spontaneous MI occurred within 30 days. Adjusted hazard ratios for 1-year death were 1.39 (95% confidence interval [CI]: 1.01 to 1.89) for procedural MI and 5.37 (95% CI: 3.90 to 7.38) for spontaneous MI. The CK-MB threshold for procedural MI that achieved the same prognosis as spontaneous MI was 27.7 times the ULN (95% CI: 13.9 to 58.4), but this differed between the SYNERGY study (57.9 times the ULN, 95% CI: 17.9 to 63.6) and the EARLY-ACS study (20.4 times the ULN, 95% CI: 5.16 to 24.2). Of all procedural MI, 49 (6%) had CK-MB elevations of 27.7 or more times the ULN.The current enzymatic definition of procedural MI (CK-MB more than 3 times the ULN) used in clinical trials is less strongly associated with death than that of spontaneous MI. Procedural MI achieves similar prognosis for 1-year mortality when much higher CK-MB thresholds are applied.

    View details for DOI 10.1016/j.jacc.2012.09.005

    View details for Web of Science ID 000311680500007

    View details for PubMedID 23122801

  • ESC Guidelines on the management of acute myocardial infarction with persistent ST-segment elevation KARDIOLOGIA POLSKA Steg, G., James, S. K., Atar, D., Badano, L. P., Lundquist, C. B., Borger, M. A., Di Mario, C., Dickstein, K., Ducrocq, G., Fernandes-Aviles, F., Gershlick, A. H., Gianuzzi, P., Halvorsen, S., Huber, K., Juni, P., Kastrati, A., Knuuti, J., Lenzen, M. J., Mahaffey, K. W., Valgimigli, M., van't Hof, A., Widimsky, P., Zahger, D. 2012; 70: S255-S318
  • Factors Contributing to the Lower Mortality With Ticagrelor Compared With Clopidogrel in Patients Undergoing Coronary Artery Bypass Surgery JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Varenhorst, C., Alstrom, U., Scirica, B. M., Hogue, C. W., Asenblad, N., Storey, R. F., Steg, G., Horrow, J., Mahaffey, K. W., Becker, R. C., James, S., Cannon, C. P., Brandrup-Wognsen, G., Wallentin, L., Held, C. 2012; 60 (17): 1623-1630

    Abstract

    This study investigated the differences in specific causes of post-coronary artery bypass graft surgery (CABG) deaths in the PLATO (Platelet Inhibition and Patient Outcomes) trial.In the PLATO trial, patients assigned to ticagrelor compared with clopidogrel and who underwent CABG had significantly lower total and cardiovascular mortality.In the 1,261 patients with CABG performed within 7 days after stopping study drug, reviewers blinded to treatment assignment classified causes of death into subcategories of vascular and nonvascular, and specifically identified bleeding or infection events that either caused or subsequently contributed to death.Numerically more vascular deaths occurred in the clopidogrel versus the ticagrelor group related to myocardial infarction (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2). Clopidogrel was also associated with an excess of nonvascular deaths related to infection (8 vs. 2). Among factors directly causing or contributing to death, bleeding and infections were more common in the clopidogrel group compared with the ticagrelor group (infections: 16 vs. 6, p < 0.05, and bleeding: 27 vs. 9, p < 0.01, for clopidogrel and ticagrelor, respectively).The mortality reduction with ticagrelor versus clopidogrel following CABG in the PLATO trial was associated with fewer deaths from cardiovascular, bleeding, and infection complications. (Platelet Inhibition and Patient Outcomes [PLATO]; NCT00391872).

    View details for DOI 10.1016/j.jacc.2012.07.021

    View details for Web of Science ID 000310199700006

    View details for PubMedID 23021325

  • ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation EUROPEAN HEART JOURNAL Steg, P. G., James, S. K., Atar, D., Badano, L. P., Blomstrom-Lundqvist, C., Borger, M. A., Di Mario, C., Dickstein, K., Ducrocq, G., Fernandez-Aviles, F., Gershlick, A. H., Giannuzzi, P., Halvorsen, S., Huber, K., Juni, P., Kastrati, A., Knuuti, J., Lenzen, M. J., Mahaffey, K. W., Valgimigli, M., van't Hof, A., Widimsky, P., Zahger, D. 2012; 33 (20): 2569-2619

    View details for DOI 10.1093/eurheartj/ehs215

    View details for Web of Science ID 000310167200015

    View details for PubMedID 22922416

  • Antithrombotic therapy for atrial fibrillation and coronary artery disease in older patients AMERICAN HEART JOURNAL Hess, C. N., Broderick, S., Piccini, J. P., Alexander, K. P., Newby, L. K., Shaw, L. K., Mahaffey, K. W., Alexander, J. H., Peterson, E. D., Granger, C. B., Lopes, R. D. 2012; 164 (4): 607-615

    Abstract

    Older patients with atrial fibrillation (AF) and coronary artery disease (CAD) face high risk of stroke and bleeding with antithrombotic therapy. Balancing safe and effective use of aspirin, clopidogrel, and warfarin in this population is important.From the Duke Databank for Cardiovascular Disease, we identified patients with AF ?65 years old with angiographically confirmed CAD from 2000 to 2010. Antithrombotic use was described across age and Congestive heart failure, Hypertension, Age >75 years, Diabetes, prior Stroke/transient ischemic attack (CHADS(2)) stroke risk and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding scores. Death and the composite of death, myocardial infarction, and stroke by antithrombotic strategy were reported.Of 2,122 patients ?65 years old with AF and CAD, 477 (22.5%) were ?80 years old; 1,133 (53.4%) had acute coronary syndromes. Overall rates of aspirin, clopidogrel, and warfarin use were 83.4%, 34.6%, and 38.9%, respectively. Compared with patients 65 to 79 years old, more patients ?80 years old were at high stroke risk (CHADS(2) ?2, 84.7% vs 57.8%) and high bleeding risk (ATRIA 5-10, 55.8% vs 23.3%). Warfarin use in both age groups increased with higher CHADS(2) scores and decreased with higher ATRIA scores. Of patients ?80 years old with CHADS(2) ?2, 150 (38.2%) received warfarin. Antithrombotic strategy was not associated with improved 1-year adjusted outcomes.Among older patients with AF and CAD, overall warfarin use was low. Patients ?80 years old at highest stroke risk received warfarin in similar proportions to the overall cohort. Further investigation into optimizing antithrombotic strategies in this population is warranted.

    View details for DOI 10.1016/j.ahj.2012.07.004

    View details for Web of Science ID 000310506000026

    View details for PubMedID 23067921

  • Ticagrelor Versus Clopidogrel in Elderly Patients With Acute Coronary Syndromes A Substudy From the Prospective Randomized PLATelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Husted, S., James, S., Becker, R. C., Horrow, J., Katus, H., Storey, R. F., Cannon, C. P., Heras, M., Lopes, R. D., Morais, J., Mahaffey, K. W., Bach, R. G., Wojdyla, D., Wallentin, L. 2012; 5 (5): 680-688

    Abstract

    Elderly patients with acute coronary syndrome are at high risk of recurrent ischemic events and death, and for both antithrombotic therapy and catheter-based complications. This prespecified analysis investigates the effect and treatment-related complications of ticagrelor versus clopidogrel in elderly patients (?75 years of age) with acute coronary syndrome compared with those <75 years of age.The association between age and the primary composite outcome, as well as major bleeding were evaluated in the PLATelet inhibition and patient Outcomes (PLATO) trial using Cox proportional hazards. Similar models were used to evaluate the interaction of age with treatment effects. Hazard ratios were adjusted for baseline characteristics. The clinical benefit of ticagrelor over clopidogrel was not significantly different between patients aged ?75 years of age (n=2878) and those <75 years of age (n=15 744) with respect to the composite of cardiovascular death, myocardial infarction, or stroke (interaction P=0.56), myocardial infarction (P=0.33), cardiovascular death (P=0.47), definite stent thrombosis (P=0.81), or all-cause mortality (P=0.76). No increase in PLATO-defined overall major bleeding with ticagrelor versus clopidogrel was observed in patients aged ?75 years (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27) or patients aged <75 years (hazard ratio, 1.04; 95% confidence interval, 0.94-1.15). Dyspnea and ventricular pauses were more common during ticagrelor than clopidogrel treatment, with no evidence of an age-by-treatment interaction.The significant clinical benefit and overall safety of ticagrelor compared with clopidogrel in acute coronary syndrome patients in the PLATO cohort were not found to depend on age.

    View details for DOI 10.1161/CIRCOUTCOMES.111.964395

    View details for Web of Science ID 000309109000015

    View details for PubMedID 22991347

  • Search for a diagnostic/prognostic biomarker for the brain cancer glioblastoma multiforme by 2D-DIGE-MS technique MOLECULAR AND CELLULAR BIOCHEMISTRY Banerjee, H. n., Mahaffey, K., Riddick, E., Banerjee, A., Bhowmik, N., Patra, M. 2012; 367 (1-2): 59-63

    Abstract

    The prognosis of patients with glioblastoma multiforme, the most malignant adult glial brain tumor, remains poor in spite of advances in treatment procedures, including surgical resection, irradiation, and chemotherapy. Genetic heterogeneity of glioblastoma warrants extensive studies to gain a thorough understanding of the biology of this tumor. While there have been several studies of global transcript profiling of glioma with the identification of gene signatures for diagnosis and disease management, translation into clinics is yet to happen. In the present study, we report a novel proteomic approach by using two-dimensional difference gel electrophoresis followed by spot picking and analysis of proteins/peptides by Mass spectrometry. We report at least ten different novel proteins/peptides as identified by this technique which are differentially expressed in this cancer and could be of further importance for diagnostic, therapeutic, and prognostic approaches.

    View details for DOI 10.1007/s11010-012-1319-6

    View details for Web of Science ID 000305683100007

    View details for PubMedID 22547198

  • Baseline characteristics of subjects enrolled in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial NEPHROLOGY DIALYSIS TRANSPLANTATION Chertow, G. M., Correa-Rotter, R., Block, G. A., Drueke, T. B., Floege, J., Goodman, W. G., Herzog, C. A., Kubo, Y., London, G. M., Mahaffey, K. W., Mix, T., Moe, S. M., Wheeler, D. C., Parfrey, P. S. 2012; 27 (7): 2872-2879

    Abstract

    Secondary hyperparathyroidism (sHPT) and other abnormalities associated with chronic kidney disease-mineral bone disorder can contribute to dystrophic (including vascular) calcification. Dietary modification and variety of medications can be used to attenuate the severity of sHPT. However, it is unknown whether any of these approaches can reduce the high risks of death and cardiovascular disease in patients with end-stage renal disease.The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial was designed to test the hypothesis that treatment with the calcimimetic agent cinacalcet compared with placebo (on a background of conventional therapy including phosphate binders +/- vitamin D sterols) reduces time to death or non-fatal cardiovascular events (specifically myocardial infarction, unstable angina, heart failure and peripheral arterial disease events) among patients on hemodialysis with sHPT. This report describes baseline characteristics of enrolled subjects with a focus on regional variation.There were 3883 subjects randomized from 22 countries, including the USA, Canada, Australia, three Latin American nations, Russia and 15 European nations. The burden of overt cardiovascular disease at baseline was high (e.g. myocardial infarction 12.4%, heart failure 23.3%). The median plasma parathyroid hormone concentration at baseline was 692 pg/mL (10%, 90% range, 363-1694 pg/mL). At baseline, 87.2% of subjects were prescribed phosphate binders and 57.5% were prescribed activated vitamin D derivatives. Demographic data, comorbid conditions and baseline laboratory data varied significantly across regions.EVOLVE enrolled 3883 subjects on hemodialysis with moderate to severe sHPT. Inclusion of subjects from multiple global regions with varying degrees of disease severity will enhance the external validity of the trial results.

    View details for DOI 10.1093/ndt/gfr777

    View details for Web of Science ID 000306669100039

    View details for PubMedID 22529163

  • Baseline NT-proBNP and biomarkers of inflammation and necrosis in patients with ST-segment elevation myocardial infarction: insights from the APEX-AMI trial JOURNAL OF THROMBOSIS AND THROMBOLYSIS van Diepen, S., Roe, M. T., Lopes, R. D., Stebbins, A., James, S., Newby, L. K., Moliterno, D. J., Neumann, F., Ezekowitz, J. A., Mahaffey, K. W., Hochman, J. S., Hamm, C. W., Armstrong, P. W., Theroux, P., Granger, C. B. 2012; 34 (1): 106-113

    Abstract

    Coronary plaque rupture is associated with a systemic inflammatory response. The relationship between baseline N-terminal pro B-type natriuretic peptide (NT-proBNP), a prognostic marker in patients with acute coronary syndromes, and systemic inflammatory mediators in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) is not well described. Of 5,745 STEMI patients treated with primary PCI in the APEX-AMI trial, we evaluated the relationship between baseline NT-proBNP levels and baseline levels of inflammatory markers and markers of myonecrosis in a subset of 772 who were enrolled in a biomarker substudy. Spearman correlations (r (s)) were calculated between baseline NT-proBNP levels and a panel of ten systemic inflammatory biomarkers. Interleukin (IL)-6, a pro-inflammatory cytokine, was significantly positively correlated with NT-proBNP (r (s) = 0.317, P < 0.001). In a sensitivity analysis excluding all heart failure patients, the correlation between baseline IL-6 and NT-proBNP remained significant (n = 651, r (s) = 0.296, P < 0.001). A positive association was also observed with high sensitivity C-reactive protein (r (s) = 0.377, P < 0.001) and there was a weak negative correlation with the anti-inflammatory cytokine IL-10 (r (s) = -0.109, P = 0.003). No other significant correlations were observed among the other testes inflammatory cytokines and chemokines. In STEMI patients undergoing primary PCI, the pro-inflammatory cytokine IL-6 was modestly correlated with baseline NT-proBNP levels. This relationship remained significant in patients without heart failure. This finding is consistent with pre-clinical and clinical research suggesting that systemic inflammation may influence NT-proBNP expression independently of myocardial stretch.

    View details for DOI 10.1007/s11239-012-0691-0

    View details for Web of Science ID 000305523300015

    View details for PubMedID 22307842

  • Activated partial thromboplastin time measurement is not associated with clinical outcomes in patients with high-risk non-ST-segment elevation acute coronary syndromes treated with unfractionated heparin JOURNAL OF THROMBOSIS AND THROMBOLYSIS Thomas, M. P., Mahaffey, K. W., Chiswell, K., Cohen, M., Kontos, M. C., Antman, E. M., Ferguson, J. J., Califf, R. M., Goodman, S. G., Becker, R. C. 2012; 34 (1): 114-119

    Abstract

    Our objective was to determine the association of activated partial thromboplastin time (aPTT) with recurrent ischemic events and non-coronary artery bypass surgery-related thrombolysis in myocardial infarction major bleeding. We studied 4,985 patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS) participating in SYNERGY, a prospective, randomized, international trial designed to emulate contemporary practice wherein unfractionated heparin (UFH) is given intravenously and titrated according to a weight-adjusted dosing nomogram to a target aPTT of 1.5-2 times the upper limit of normal (approximately 50-70 s). Aspirin was administered to 95% of patients, clopidogrel to 63%, and glycoprotein IIb/IIIa receptor inhibitors to 58%. More than 90% of patients underwent early coronary angiography, and 69% were revascularized. Used as a time-dependent covariate, aPTT was evaluated as a predictor of time to ischemic or major hemorrhagic events in proportional hazards regression models. Using discrete variable analysis, aPTT was categorized as persistently below a lower threshold of anticoagulation (<50 vs. ?50 s) for recurrent ischemic events and above an upper threshold (>70 vs. ?70 s) for major hemorrhagic events. UFH treatment lasted a median of 42 (30, 78) h. At >6-12 (n = 3,021), >12-24 (n = 3,406), and >24-48 (n = 2,497) h, 34, 41, and 46% of patients achieved the target aPTT range, respectively. Both before and after adjusting for baseline predictors of anticoagulant response and risk score (age, hypertension, diabetes, smoking, ST depression, and renal function), no significant relationship between aPTT values and recurrent ischemic events or major bleeding was found. No relationship was observed between clinical outcomes and aPTT values persistently above or below the designated thresholds. Measurements of aPTT were not associated with clinical outcomes among patients with NSTE ACS treated with UFH. The required intensity of anticoagulation for benefit may be relatively modest when UFH is administered concomitantly with dual or triple platelet-directed therapy, particularly in patients undergoing early coronary revascularization.

    View details for DOI 10.1007/s11239-012-0693-y

    View details for Web of Science ID 000305523300016

    View details for PubMedID 22323092

  • Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic Attack CIRCULATION James, S. K., Storey, R. F., Khurmi, N. S., Husted, S., Keltai, M., Mahaffey, K. W., Maya, J., Morais, J., Lopes, R. D., Nicolau, J. C., Pais, P., Raev, D., Lopez-Sendon, J. L., Stevens, S. R., Becker, R. C. 2012; 125 (23): 2914-?

    Abstract

    Patients with acute coronary syndromes and history of stroke or transient ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial hemorrhages.We evaluated treatment effects of ticagrelor versus clopidogrel in patients with acute coronary syndrome with and without a history of prior stroke or TIA in the PLATelet inhibition and patient Outcomes (PLATO) trial. Of the 18 624 randomized patients, 1152 (6.2%) had a history of stroke or TIA. Such patients had higher rates of myocardial infarction (11.5% versus 6.0%), death (10.5% versus 4.9%), stroke (3.4% versus 1.2%), and intracranial bleeding (0.8% versus 0.2%) than patients without prior stroke or TIA. Among patients with a history of stroke or TIA, the reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results: 19.0% versus 20.8% (hazard ratio, 0.87; 95% confidence interval, 0.66-1.13; interaction P=0.84) and 7.9% versus 13.0% (hazard ratio, 0.62; 95% confidence interval, 0.42-0.91). The overall PLATO-defined bleeding rates were similar: 14.6% versus 14.9% (hazard ratio, 0.99; 95% confidence interval, 0.71-1.37), and intracranial bleeding occurred infrequently (4 versus 4 cases, respectively).Patients with acute coronary syndrome with a prior history of ischemic stroke or TIA had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality.URL: http://www.clinicatrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.111.082727

    View details for Web of Science ID 000306975100030

    View details for PubMedID 22572911

  • Rationale and design of the Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON PHOENIX trial AMERICAN HEART JOURNAL Leonardi, S., Mahaffey, K. W., White, H. D., Gibson, C. M., Stone, G. W., Steg, P. G., Hamm, C. W., Price, M. J., Todd, M., Dietrich, M., Gallup, D., Liu, T., Skerjanec, S., Harrington, R. A., Bhatt, D. L. 2012; 163 (5): 768-?

    Abstract

    Despite robust efficacy in the reduction of ischemic events in patients who require percutaneous coronary intervention (PCI), current P2Y(12) inhibitors have limitations. In particular, they require hours to be effective, and they can only be administered orally. Cangrelor is an intravenous, potent, and reversible P2Y(12) inhibitor with fast onset and offset of action. We designed CHAMPION PHOENIX to evaluate the efficacy and safety of cangrelor in patients with atherosclerosis undergoing PCI.The CHAMPION PHOENIX is a randomized, double-blind, double-dummy, superiority trial comparing cangrelor with clopidogrel standard of care in approximately 10,900 patients who have not previously received a P2Y(12) inhibitor and who require PCI, including patients with stable angina and with acute coronary syndromes (with or without ST-segment elevation). The primary objective of the study is to demonstrate that cangrelor will reduce the incidence of the composite of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis in the 48 hours after randomization compared with clopidogrel without excessive periprocedural bleeding. The key secondary objective is to demonstrate that cangrelor will reduce the incidence of stent thrombosis. Myocardial infarction will be defined according to the universal MI definition, adapting the definition of PCI-related (type 4a) MI. Bleeding will be assessed according to the thrombolysis in myocardial infarction, GUSTO, and Bleeding Academic Research Consortium (BARC) scales.The CHAMPION PHOENIX may establish the role of cangrelor in the care of patients who require PCI across the spectrum of stable and unstable coronary diseases in the setting of current treatment strategies.

    View details for DOI 10.1016/j.ahj.2012.02.018

    View details for Web of Science ID 000304261000011

    View details for PubMedID 22607853

  • Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF LANCET NEUROLOGY Hankey, G. J., Patel, M. R., Stevens, S. R., Becker, R. C., Breithardt, G., Carolei, A., Diener, H., Donnan, G. A., Halperin, J. L., Mahaffey, K. W., Mas, J., Massaro, A., Norrving, B., Nessel, C. C., Paolini, J. F., Roine, R. O., Singer, D. E., Wong, L., Califf, R. M., Fox, K. A., Hacke, W. 2012; 11 (4): 315-322

    Abstract

    In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA).In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2·0-3·0). Patients and investigators were masked to treatment allocation. Between Dec 18, 2006, and June 17, 2009, 14?264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767.7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2·79% rivaroxaban vs 2·96% warfarin; hazard ratio [HR] 0·94, 95% CI 0·77-1·16) and those without (1·44%vs 1·88%; 0·77, 0·58-1·01; interaction p=0·23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13·31% rivaroxaban vs 13·87% warfarin; HR 0·96, 95% CI 0·87-1·07) and those without (16·69%vs 15·19%; 1·10, 0·99-1·21; interaction p=0·08).There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF.Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare.

    View details for DOI 10.1016/S1474-4422(12)70042-X

    View details for Web of Science ID 000301999600007

    View details for PubMedID 22402056

  • Prediction of enzymatic infarct size in ST-segment elevation myocardial infarction CORONARY ARTERY DISEASE Mills, J. S., Mahaffey, K. W., Lokhnygina, Y., Nicolau, J. C., Ruzyllo, W., Adams, P. X., Todaro, T. G., Armstrong, P. W., Granger, C. B. 2012; 23 (2): 118-125

    Abstract

    Predictors of adverse outcomes following myocardial infarction (MI) are well established; however, little is known about what predicts enzymatically estimated infarct size in patients with acute ST-elevation MI. The Complement And Reduction of INfarct size after Angioplasty or Lytics trials of pexelizumab used creatine kinase (CK)-MB area under the curve to determine infarct size in patients treated with primary percutaneous coronary intervention (PCI) or fibrinolysis.Prediction of infarct size was carried out by measuring CK-MB area under the curve in patients with ST-segment elevation MI treated with reperfusion therapy from January 2000 to April 2002. Infarct size was calculated in 1622 patients (PCI=817; fibrinolysis=805). Logistic regression was used to examine the relationship between baseline demographics, total ST-segment elevation, index angiographic findings (PCI group), and binary outcome of CK-MB area under the curve greater than 3000 ng/ml.Large infarcts occurred in 63% (515) of the PCI group and 69% (554) of the fibrinolysis group. Independent predictors of large infarcts differed depending on mode of reperfusion. In PCI, male sex, no prior coronary revascularization and diabetes, decreased systolic blood pressure, sum of ST-segment elevation, total (angiographic) occlusion, and nonright coronary artery culprit artery were independent predictors of larger infarcts (C index=0.73). In fibrinolysis, younger age, decreased heart rate, white race, no history of arrhythmia, increased time to fibrinolytic therapy in patients treated up to 2 h after symptom onset, and sum of ST-segment elevation were independently associated with a larger infarct size (C index=0.68).Clinical and patient data can be used to predict larger infarcts on the basis of CK-MB quantification. These models may be helpful in designing future trials and in guiding the use of novel pharmacotherapies aimed at limiting infarct size in clinical practice.

    View details for DOI 10.1097/MCA.0b013e32834e4f8f

    View details for Web of Science ID 000300406400007

    View details for PubMedID 22217457

  • Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor Insights From the Platelet Inhibition and Patient Outcomes Trial CIRCULATION Goodman, S. G., Clare, R., Pieper, K. S., Nicolau, J. C., Storey, R. F., Cantor, W. J., Mahaffey, K. W., Angiolillo, D. J., Husted, S., Cannon, C. P., James, S. K., Kilhamn, J., Steg, P. G., Harrington, R. A., Wallentin, L. 2012; 125 (8): 978-986

    Abstract

    The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear.We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n=6539) compared with those not on a PPI (n=12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04-1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07-1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79-1.23; ticagrelor, HR, 0.89; 95% CI, 0.73-1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12-1.49; ticagrelor, HR, 1.30; 95% CI, 1.14-1.49).The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events.http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.111.032912

    View details for Web of Science ID 000300951700013

    View details for PubMedID 22261200

  • Reduced immediate ischemic events with cangrelor in PCI: A pooled analysis of the CHAMPION trials using the universal definition of myocardial infarction AMERICAN HEART JOURNAL White, H. D., Chew, D. P., Dauerman, H. L., Mahaffey, K. W., Gibson, C. M., Stone, G. W., Gruberg, L., Harrington, R. A., Bhatt, D. L. 2012; 163 (2): 182-U275

    Abstract

    There is a clinical need for an intravenous P2Y(12) inhibitor in patients with acute coronary syndromes (ACS) for patients who are unable to take oral medications or might benefit from a rapidly reversible compound. As the time from admission to percutaneous coronary intervention (PCI) shortens, establishing the benefit of novel therapies impacting ischemic events is increasingly challenging. Cangrelor, an intravenous potent rapidly acting P2Y(12) inhibitor, bolus 30 ?g/Kg plus infusion of 4 ?g/Kg/min, was compared to a 600-mg loading dose of clopidogrel either before or early after PCI in patients with ACS undergoing PCI in The CHAMPION (Cangrelor versus standard tHerapy to Achieve optimal Management of Platelet InhibitiON) PLATFORM and PCI studies.As both CHAMPION studies used similar inclusion/exclusion criteria and death, myocardial infarction, or ischemia-driven revascularization (including stent thrombosis) at 48 hours as their primary end points, the studies were pooled. The clinical events committee adjudicated myocardial infarction. The universal definition was used to define myocardial infarction.A total of 13 049 patients were included. Cangrelor had no effect on the primary end point with the original MI definition (P = .646). With the use of the universal definition, the primary end point was decreased with cangrelor (odds ratio 0.82, 95% confidence interval 0.68-0.99, P = .037). Stent thrombosis was reduced from 0.4% to 0.2% (odds ratio 0.44, 95% confidence interval 0.22-0.87, P = .018). Thrombolysis in Myocardial Infarction major bleeding and transfusions were not increased with cangrelor.With the use of the universal definition of myocardial infarction, cangrelor was associated with a significant reduction in early ischemic events when compared with clopidogrel in patients with non-ST-elevation ACS undergoing PCI.

    View details for DOI 10.1016/j.ahj.2011.11.001

    View details for Web of Science ID 000300226600009

    View details for PubMedID 22305835

  • Clopidogrel and PPI Interaction: Clinically Relevant or Not? CURRENT CARDIOLOGY REPORTS Harrison, R. W., Mahaffey, K. W. 2012; 14 (1)
  • Promises of PAR-1 inhibition in acute coronary syndrome. Current cardiology reports Leonardi, S., Tricoci, P., Mahaffey, K. W. 2012; 14 (1): 32-39

    Abstract

    Platelet activation is a key process in the pathogenesis of acute coronary syndromes (ACS). Of the many triggers involved in this process, three are presumed to be critical: thromboxane A(2) (TBXA(2)) via the TBXA(2) receptor, adenosine diphosphate via the P2Y(12) receptor, and thrombin via the protease-activated receptor (PAR)-1. Despite the effective inhibition of the first two pathways with aspirin and an expanding family of P2Y(12) inhibitors, the incidence of recurrent ischemic events remains high after ACS. PAR-1 inhibitors are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preclinical data and phase 2 clinical trials in patients with stable and unstable coronary disease support the potential of these compounds to improve clinical outcome. In this review we discuss the rationale for developing this novel class of agents with a focus on the two compounds in most advanced clinical development, vorapaxar (SCH 530348) and atopaxar (E5555).

    View details for DOI 10.1007/s11886-011-0232-z

    View details for PubMedID 22160877

  • Promise of factor Xa inhibition in atrial fibrillation. Current cardiology reports Al-Khatib, S. M., Alexander, J. H., Lopes, R. D., Mahaffey, K. W., Patel, M. R., Granger, C. B. 2012; 14 (1): 70-78

    Abstract

    Randomized clinical trials have conclusively demonstrated that warfarin prevents stroke in patients with atrial fibrillation. This evidence led the American College of Cardiology, the American Heart Association, and the European Society of Cardiology to designate warfarin as a Class I indication in patients at moderate to high risk for stroke. Despite the evidence from randomized clinical trials and clear practice guidelines, warfarin is underutilized in many eligible patients. This is, at least in part, due to the many challenges associated with warfarin use that have led to the development of many new anticoagulants including direct thrombin inhibitors and factor Xa inhibitors. In this article, we review the complexities of anticoagulation in patients with atrial fibrillation, underscoring the challenges related to warfarin use, and present an overview of new anticoagulants particularly, factor Xa inhibitors, with special emphasis on emerging data from randomized clinical trials on their efficacy and safety in the management of atrial fibrillation.

    View details for DOI 10.1007/s11886-011-0230-1

    View details for PubMedID 22109539

  • Promises of PAR-1 Inhibition in Acute Coronary Syndrome CURRENT CARDIOLOGY REPORTS Leonardi, S., Tricoci, P., Mahaffey, K. W. 2012; 14 (1)
  • Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes NEW ENGLAND JOURNAL OF MEDICINE Tricoci, P., Huang, Z., Held, C., Moliterno, D. J., Armstrong, P. W., Van de Werf, F., White, H. D., Aylward, P. E., Wallentin, L., Chen, E., Lokhnygina, Y., Pei, J., Leonardi, S., Rorick, T. L., Kilian, A. M., Jennings, L. H., Ambrosio, G., Bode, C., Cequier, A., Cornel, J. H., Diaz, R., Erkan, A., Huber, K., Hudson, M. P., Jiang, L., Jukema, J. W., Lewis, B. S., Lincoff, A. M., Montalescot, G., Nicolau, J. C., Ogawa, H., Pfisterer, M., Carlos Prieto, J., Ruzyllo, W., Sinnaeve, P. R., Storey, R. F., Valgimigli, M., Whellan, D. J., Widimsky, P., Strony, J., Harrington, R. A., Mahaffey, K. W. 2012; 366 (1): 20-33

    Abstract

    Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation.In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization.Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups.In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

    View details for DOI 10.1056/NEJMoa1109719

    View details for Web of Science ID 000299968800004

    View details for PubMedID 22077816

  • Pattern of liver enzyme elevations in acute ST-elevation myocardial infarction CORONARY ARTERY DISEASE Lofthus, D. M., Stevens, S. R., Armstrong, P. W., Granger, C. B., Mahaffey, K. W. 2012; 23 (1): 22-30

    Abstract

    Liver enzyme elevations occur with ST-segment elevation myocardial infarction (STEMI); however, their significance in the modern era is not well-defined. The incidence of liver enzyme elevations in STEMI, temporal trends, correlations with creatine kinase-MB (CK-MB), and associations with clinical outcomes were evaluated.The Complement Inhibition in Myocardial Infarction Treated with Angioplasty and Complement Inhibition in Myocardial Infarction Treated with Thrombolytics trials evaluated 1903 patients with STEMI. A core lab analyzed liver enzymes at baseline, days 1, 6, and 14, and CK-MB measured sequentially over 72 h. The GUSTO model for 30-day mortality was used to predict clinical endpoints.A total of 1783 patients were included in the analysis. Aspartate transaminase (AST) was elevated above the upper limit of normal in 85.6% and alanine transaminase (ALT) was elevated in 48.2% of patients at baseline or day 1. CK-MB area under the curve correlated with maximum AST (r=0.727) and maximum ALT (r=0.456). Both AST and ALT elevations were independent predictors of worse outcomes in multivariable adjusted analysis, even after adjustment for CK-MB. Hazard ratios and 95% confidence intervals of AST elevation were 1.12 (1.05-1.19) for all-cause mortality, and 1.08 (1.02-1.13) for the composite endpoint of death, congestive heart failure, shock, or stroke. Hazard ratios and 95% confidence intervals of ALT elevation were 1.15 (1.04-1.27) for mortality and 1.47 (1.10-1.98) for the composite endpoint.AST and ALT elevations are common in STEMI. Both markers are correlated with CK-MB area under the curve, but independently associated with worse mortality and clinical outcomes.

    View details for DOI 10.1097/MCA.0b013e32834e4ef1

    View details for Web of Science ID 000298410100004

    View details for PubMedID 22113063

  • Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial EUROPEAN HEART JOURNAL Becker, R. C., Bassand, J. P., Budaj, A., Wojdyla, D. M., James, S. K., Cornel, J. H., French, J., Held, C., Horrow, J., Husted, S., Lopez-Sendon, J., Lassila, R., Mahaffey, K. W., Storey, R. F., Harrington, R. A., Wallentin, L. 2011; 32 (23): 2933-2944

    Abstract

    AIMS More intense platelet-directed therapy for acute coronary syndrome (ACS) may increase bleeding risk. The aim of the current analysis was to determine the rate, clinical impact, and predictors of major and fatal bleeding complications in the PLATO study. METHODS AND RESULTS PLATO was a randomized, double-blind, active control international, phase 3 clinical trial in patients with acute ST elevation and non-ST-segment elevation ACS. A total of 18 624 patients were randomized to either ticagrelor, a non-thienopyridine, reversibly binding platelet P2Y(12) receptor antagonist, or clopidogrel in addition to aspirin. Patients randomized to ticagrelor and clopidogrel had similar rates of PLATO major bleeding (11.6 vs. 11.2%; P = 0.43), TIMI major bleeding (7.9 vs. 7.7%, P = 0.56) and GUSTO severe bleeding (2.9 vs. 3.1%, P = 0.22). Procedure-related bleeding rates were also similar. Non-CABG major bleeding (4.5 vs. 3.8%, P = 0.02) and non-procedure-related major bleeding (3.1 vs. 2.3%, P = 0.05) were more common in ticagrelor-treated patients, primarily after 30 days on treatment. Fatal bleeding and transfusion rates did not differ between groups. There were no significant interactions for major bleeding or combined minor plus major bleeding between treatment groups and age ?75 years, weight <60 kg, region, chronic kidney disease, creatinine clearance <60 mL/min, aspirin dose >325 mg on the day of randomization, pre-randomization clopidogrel administration, or clopidogrel loading dose. CONCLUSION Ticagrelor compared with clopidogrel was associated with similar total major bleeding but increased non-CABG and non-procedure-related major bleeding, primarily after 30 days on study drug treatment. Fatal bleeding was low and did not differ between groups.

    View details for DOI 10.1093/eurheartj/ehr422

    View details for Web of Science ID 000297647400008

    View details for PubMedID 22090660

  • Determinants of plasma vitamin D levels in patients with acute coronary syndromes EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Rodriguez, G., Starr, A. Z., Czernuszewicz, G. Z., Manhas, A., Alhariri, A., Willerson, J. T., Reist, C. J., Pieper, K., Mahaffey, K. W., Marian, A. J., Kleiman, N. S. 2011; 41 (12): 1299-1309

    Abstract

    Vitamin D is implicated in various biological functions ranging from cellular proliferation to immunity. Vitamin D deficiency is associated with an increased risk of several diseases including coronary atherosclerosis.We measured plasma 25(OH)D3 level in 224 patients with acute coronary syndromes (ACS) and 209 control individuals by ELISA. We genotyped the study populations for 11 single nucleotide polymorphisms (SNPs) in seven genes involved in vitamin D biosynthesis and metabolism by 5' nuclease assays.The mean and median plasma 25(OH)D3 levels were not significantly different between patients with ACS and controls (median: 22·06 vs. 22·24 ng mL(-1) , respectively, P = 0·618). Plasma 25(OH)D3 level was < 20 ng mL(-1) in 175/433 (40%) and < 30 ng mL(-1) in 333/433 (77%) participants. Only four individuals had plasma 25(OH)D3 levels of above 60 ng mL(-1) . African-American and Hispanic populations, women and those with diabetes mellitus had significantly lower plasma 25(OH)D3 levels. In multivariable regression analysis, age, sex, diabetes mellitus, body weight, rs2762933 (CYP24A1) and rs6055987 (PLCB1) SNPs were independent predictors of plasma 25(OH)D3 level in the Caucasian population.We found no difference in mean plasma vitamin D levels between patients with ACS and controls. Differences in population characteristics between the two study groups including medications use and the lack of data on vitamin D, calcium and multivitamin supplements intake as well as the relatively small sample size of the populations could confound the results. Ethnic background, sex, age, body weight and SNPs in CYP24A1 and PLCB1 were independent determinants of plasma vitamin D levels.

    View details for DOI 10.1111/j.1365-2362.2011.02540.x

    View details for Web of Science ID 000297146400006

    View details for PubMedID 21615392

  • Mode of Death and Hospitalization from the Second Follow-Up Serial Infusions of Nesiritide (FUSION II) Trial and Comparison of Clinical Events Committee Adjudicated Versus Investigator Reported Outcomes AMERICAN JOURNAL OF CARDIOLOGY O'Connor, C. M., Fiuzat, M., Lindenfeld, J., Miller, A., Lombardi, C., Carson, P., Shaw, L. K., Wang, L., Connolly, P., Mills, R., Yancy, C., Mahaffey, K. 2011; 108 (10): 1449-1457

    Abstract

    The aim of this study was to evaluate the mode of death and hospitalizations in advanced heart failure (HF) patients with renal dysfunction and to examine the rate of concordance between events reported by the clinical events committee and site investigators (using case report forms) in the Second Follow-Up Serial Infusions of Nesiritide (FUSION II) trial. Little is known about the cause of death and hospitalization in patients with advanced HF. FUSION II was a randomized, double-blind, placebo-controlled trial evaluating outpatient nesiritide infusions versus placebo, with 911 patients with advanced HF (New York Heart Association class III or IV) and renal dysfunction enrolled. There were 151 deaths and 1,041 hospitalizations at 24 weeks. The clinical events committee classified events as cardiac, renal, cardiorenal, other or noncardiovascular, or unknown. Kappa statistics and McNemar tests were used to assess agreement (overall and by individual modes of death and hospitalization indications). In conclusion, the most common cause of death or hospitalization was cardiac related, with 70% of deaths and 60% of hospitalizations due to cardiac causes. There was 74% agreement (26% disagreement) on cardiac cause of death (? = 0.40, McNemar p = 0.001) and 75% agreement (25% disagreement) between the investigators and the clinical events committee on cardiac classification for hospitalization (? = 0.49, McNemar p <0.0001).

    View details for DOI 10.1016/j.amjcard.2011.06.065

    View details for Web of Science ID 000297435100013

    View details for PubMedID 21890092

  • Outcomes registry for better informed treatment of atrial fibrillation: Rationale and design of ORBIT-AF AMERICAN HEART JOURNAL Piccini, J. P., Fraulo, E. S., Ansell, J. E., Fonarow, G. C., Gersh, B. J., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L. E., Kong, M. H., Lopes, R. D., Mills, R. M., Peterson, E. D. 2011; 162 (4): 606-U54

    Abstract

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with an increased risk of stroke, heart failure, and death. Data on contemporary treatment patterns and outcomes associated with AF in clinical practice are limited.The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation is a multicenter, prospective, ambulatory-based registry of incident and prevalent AF. The registry will be a nationwide collaboration of health care providers, including internists, primary care physicians, cardiologists, and electrophysiologists. Initial target enrollment is approximately 10,000 patients to be recruited from approximately 200 US outpatient practices. Enrolled patients will be observed for ?2 years. A patient-reported outcomes substudy in ?1,500 patients will provide serial quality-of-life assessments. The goal is to characterize treatment and outcomes of patients with AF, thereby promoting better quality of AF care and improved patient outcomes.The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation will provide insights into "real-world" treatment including rate and rhythm control, stroke prevention, transitions to new therapies, and clinical and patient-centered outcomes among patients with AF in community practice settings (ClinicalTrials.gov NCT01165710).

    View details for DOI 10.1016/j.ahj.2011.07.001

    View details for Web of Science ID 000295925100007

    View details for PubMedID 21982650

  • Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment EUROPEAN HEART JOURNAL Fox, K. A., Piccini, J. P., Wojdyla, D., Becker, R. C., Halperin, J. L., Nessel, C. C., Paolini, J. F., Hankey, G. J., Mahaffey, K. W., Patel, M. R., Singer, D. E., Califf, R. M. 2011; 32 (19): 2387-2394

    Abstract

    Patients with non-valvular atrial fibrillation (AF) and renal insufficiency are at increased risk for ischaemic stroke and bleeding during anticoagulation. Rivaroxaban, an oral, direct factor Xa inhibitor metabolized predominantly by the liver, preserves the benefit of warfarin for stroke prevention while causing fewer intracranial and fatal haemorrhages.We randomized 14 264 patients with AF in a double-blind trial to rivaroxaban 20 mg/day [15 mg/day if creatinine clearance (CrCl) 30-49 mL/min] or dose-adjusted warfarin (target international normalized ratio 2.0-3.0). Compared with patients with CrCl >50 mL/min (mean age 73 years), the 2950 (20.7%) patients with CrCl 30-49 mL/min were older (79 years) and had higher event rates irrespective of study treatment. Among those with CrCl 30-49 mL/min, the primary endpoint of stroke or systemic embolism occurred in 2.32 per 100 patient-years with rivaroxaban 15 mg/day vs. 2.77 per 100 patient-years with warfarin [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.57-1.23] in the per-protocol population. Intention-to-treat analysis yielded similar results (HR 0.86; 95% CI 0.63-1.17) to the per-protocol results. Rates of the principal safety endpoint (major and clinically relevant non-major bleeding: 17.82 vs. 18.28 per 100 patient-years; P = 0.76) and intracranial bleeding (0.71 vs. 0.88 per 100 patient-years; P = 0.54) were similar with rivaroxaban or warfarin. Fatal bleeding (0.28 vs. 0.74% per 100 patient-years; P = 0.047) occurred less often with rivaroxaban.Patients with AF and moderate renal insufficiency have higher rates of stroke and bleeding than those with normal renal function. There was no evidence of heterogeneity in treatment effect across dosing groups. Dose adjustment in ROCKET-AF yielded results consistent with the overall trial in comparison with dose-adjusted warfarin.

    View details for DOI 10.1093/eurheartj/ehr342

    View details for Web of Science ID 000295684300017

    View details for PubMedID 21873708

  • Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation NEW ENGLAND JOURNAL OF MEDICINE Patel, M. R., Mahaffey, K. W., Garg, J., Pan, G., Singer, D. E., Hacke, W., Breithardt, G., Halperin, J. L., Hankey, G. J., Piccini, J. P., Becker, R. C., Nessel, C. C., Paolini, J. F., Berkowitz, S. D., Fox, K. A., Califf, R. M. 2011; 365 (10): 883-891

    Abstract

    The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin.In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism.In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group.In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).

    View details for Web of Science ID 000294595600004

    View details for PubMedID 21830957

  • Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION Mahaffey, K. W., Wojdyla, D. M., Carroll, K., Becker, R. C., Storey, R. F., Angiolillo, D. J., Held, C., Cannon, C. P., James, S., Pieper, K. S., Horrow, J., Harrington, R. A., Wallentin, L. 2011; 124 (5): 544-U78

    Abstract

    In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (P=0.045), with less effect of ticagrelor in North America than in the rest of the world.Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose ?300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort.The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.111.047498

    View details for Web of Science ID 000293338400014

    View details for PubMedID 21709065

  • Highlights from the III International Symposium of Thrombosis and Anticoagulation (ISTA), October 14-16, 2010, Sao Paulo, Brazil JOURNAL OF THROMBOSIS AND THROMBOLYSIS Lopes, R. D., Becker, R. C., Alexander, J. H., Armstrong, P. W., Califf, R. M., Chan, M. Y., Crowther, M., Granger, C. B., Harrington, R. A., Hylek, E. M., James, S. K., Jolicoeur, E. M., Mahaffey, K. W., Newby, L. K., Peterson, E. D., Pieper, K. S., Van de Werf, F., Wallentin, L., White, H. D., Carvalho, A. C., Giraldez, R. R., Guimaraes, H. P., Nader, H. B., Kalil, R. A., Bizzachi, J. M., Lopes, A. C., Garcia, D. A. 2011; 32 (2): 242-266

    Abstract

    To discuss and share knowledge around advances in the care of patients with thrombotic disorders, the Third International Symposium of Thrombosis and Anticoagulation was held in São Paulo, Brazil, from October 14-16, 2010. This scientific program was developed by clinicians for clinicians, and was promoted by four major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, the Canadian VIGOUR Centre, and the Uppsala Clinical Research Center. Comprising 3 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

    View details for DOI 10.1007/s11239-011-0592-7

    View details for Web of Science ID 000292833000017

    View details for PubMedID 21547405

  • Cardiogenic shock and heart failure post-percutaneous coronary intervention in ST-elevation myocardial infarction: Observations from "Assessment of Pexelizumab in Acute Myocardial Infarction" AMERICAN HEART JOURNAL French, J. K., Armstrong, P. W., Cohen, E., Kleiman, N. S., O'Connor, C. M., Hellkamp, A. S., Stebbins, A., Holmes, D. R., Hochman, J. S., Granger, C. B., Mahaffey, K. W. 2011; 162 (1): 89-97

    Abstract

    Mortality after ST-elevation myocardial infarction (STEMI) has reduced with reperfusion by primary percutaneous coronary intervention (PCI), which may have impacted on the adverse outcomes of cardiogenic shock (CS) and congestive heart failure (CHF).In the APEX-AMI trial, 5,745 patients with STEMI and planned primary PCI were randomly assigned pexelizumab or matching placebo. Post-randomization CS or CHF was adjudicated by a clinical endpoints committee. Treatment assignment to pexelizumab did not influence either endpoint or mortality rates. Cardiogenic shock developed in 196 patients (3.4%) at a median of 6.0 hours (interquartile range 3.9-28.3) post-randomization, and mortality at 90 days was 54.6%. Congestive heart failure occurred in 254 of patients (4.4%) at a median of 2.6 days (IQR 1.0-16.6), and mortality through 90 days was 10.2%; mortality among those with neither endpoint was 2.1%. Patients with CS or CHF were older, were more often female, and had more hypertension and diabetes, but smoked less compared with non-CS/CHF patients (all P < .05). Independent mortality predictors among those with CS or CHF were hyperlipidemia and a history of angina (interaction P = .011 and .008, respectively); procedural predictors among survivors to PCI were pre-PCI Thrombolysis In Myocardial Infarction (TIMI) flow 0-1 and post-PCI TIMI flow <3 (P = .013 and <.0001, respectively).Survival after CS remains poor despite aggressive reperfusion. Both CS and CHF remain the major causes of death among STEMI patients undergoing primary PCI. Future studies should examine treatments that aim to reduce mortality in these highest risk patients.

    View details for DOI 10.1016/j.ahj.2011.04.009

    View details for Web of Science ID 000292542400022

    View details for PubMedID 21742094

  • Inference on treatment effects from a randomized clinical trial in the presence of premature treatment discontinuation: the SYNERGY trial BIOSTATISTICS Zhang, M., Tsiatis, A. A., Davidian, M., Pieper, K. S., Mahaffey, K. W. 2011; 12 (2): 258-269

    Abstract

    The Superior Yield of the New Strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) was a randomized, open-label, multicenter clinical trial comparing 2 anticoagulant drugs on the basis of time-to-event endpoints. In contrast to other studies of these agents, the primary, intent-to-treat analysis did not find evidence of a difference, leading to speculation that premature discontinuation of the study agents by some subjects may have attenuated the apparent treatment effect and thus to interest in inference on the difference in survival distributions were all subjects in the population to follow the assigned regimens, with no discontinuation. Such inference is often attempted via ad hoc analyses that are not based on a formal definition of this treatment effect. We use SYNERGY as a context in which to describe how this effect may be conceptualized and to present a statistical framework in which it may be precisely identified, which leads naturally to inferential methods based on inverse probability weighting.

    View details for DOI 10.1093/biostatistics/kxq054

    View details for Web of Science ID 000288800600006

    View details for PubMedID 20797983

  • The Impact of Postrandomization Crossover of Therapy in Acute Coronary Syndromes Care CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Mahaffey, K. W., Pieper, K. S., Lokhnygina, Y., Califf, R. M., Antman, E. M., Kleiman, N. S., Goodman, S. G., White, H. D., Rao, S. V., Hochman, J. S., Cohen, M., Col, J. J., Roe, M. T., Ferguson, J. J. 2011; 4 (2): 211-U119

    Abstract

    In the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) study, patients assigned enoxaparin or unfractionated heparin (UFH) were treated with alternative anticoagulant therapy after randomization at physician discretion, a practice made possible because the trial was open label. Using SYNERGY as an example, we demonstrate the difficulty of evaluating the effect of postrandomization events in clinical trials and discuss possible methodology.Patients with and without postrandomization crossovers were characterized and event rates analyzed. Statistical modeling was performed using inverse probability weighting and landmark analyses to evaluate the potential impact of postrandomization crossovers on event rates and treatment effect. Of 9978 SYNERGY patients, 9613 (96.3%) received at least 1 dose of randomized therapy and are included in these analyses. Of these, 740 (7.7%; 554 enoxaparin; 186 UFH) had postrandomization crossover. Crossover patients had higher unadjusted rates of 30-day death/myocardial infarction (MI) (18.9% versus 14.0%), thrombolysis in MI (TIMI) bleeding (16.9% versus 7.6%), Global Use of Strategies to Open Occluded Coronary Arteries bleeding (4.5% versus 2.3%), and transfusions (32.3% versus 15.2%). Adjustment for timing of crossover relative to the events attenuated the difference noted in death/MI but accentuated the association with TIMI bleeding. After adjustment using the inverse probability weighting technique, only a modest difference in the absolute treatment effect was observed between enoxaparin and UFH on death/MI (0.6% [unadjusted] versus 0.8% [adjusted]) and TIMI major bleeding (1.5% [unadjusted] versus 1.0% [adjusted]). The landmark analysis indicated a significant association between crossover from enoxaparin to UFH and TIMI bleeding but not in the other direction, and no crossover association was found in death/MI.Postrandomization events in clinical trials are accompanied by substantial confounders that require careful consideration. In SYNERGY, postrandomization crossovers occurred in nearly 10% of patients, abetted by the open-label trial design. These patients had increased incidence of bleeding and death/MI, but after adjustment using several modeling techniques, only a modest impact of postrandomization crossovers on treatment effect was observed. The usual methods of analyzing end points cannot adequately address biases in changing treatment in these patients. The potential biases of membership in a postrandomization subgroup, as well as the methods used to account for the biases, should be considered when weighing the strength of results. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00043784.

    View details for DOI 10.1161/CIRCOUTCOMES.109.853598

    View details for Web of Science ID 000288372200013

    View details for PubMedID 21304094

  • Mortality Implications of Primary Percutaneous Coronary Intervention Treatment Delays: Insights From the Assessment of Pexelizumab in Acute Myocardial Infarction Trial CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Hudson, M. P., Armstrong, P. W., O'Neil, W. W., Stebbins, A. L., Weaver, W. D., Widimsky, P., Aylward, P. E., Ruzyllo, W., Holmes, D., Mahaffey, K. W., Granger, C. B. 2011; 4 (2): 183-192

    Abstract

    Prior studies demonstrate a direct relationship between treatment delays to primary percutaneous intervention and mortality in patients with ST-segment elevation myocardial infarction (STEMI). This analysis compared the relationship of symptom onset-to-balloon time and door-to-balloon time on mortality in patients with STEMI.We analyzed different treatment delays (symptom onset-to-balloon time, door-to-balloon time) and mortality in 5745 STEMI patients. Baseline characteristics, flow grade, 90-day mortality, and clinical outcomes were compared in patients stratified by treatment delay. Multivariable logistic regression modeling was performed to assess the independent and relative effect of each treatment delay on 90-day mortality. Female sex, increased age, and worse thrombolysis in myocardial infarction flow grade were significantly associated with longer symptom onset-to-balloon times and door-to-balloon times. Longer symptom onset-to-balloon time was significantly associated with worse 90-day mortality (3.7%, 4.2%, and 6.5% for time delays <3 hours, 3 to 5 hours, and >5 hours, respectively, P<0.0001). Similarly, longer door-to-balloon times were significantly associated with worse 90-day mortality (3.2%, 4.0%, 4.6%, and 5.3% for delays <60 minutes, 60 to 90 minutes, 90 to 120 minutes, and ?120 minutes respectively, P<0.0001). In a multivariate model of 90-day mortality, door-to-balloon time (?(2) 6.0, P<0.014), and symptom onset-to-hospital arrival (?(2) 9.8, P<0.007) remained independent determinants.Both symptom onset-to-balloon time and hospital door-to-balloon time are strongly associated with 90-day mortality following STEMI. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00091637.

    View details for DOI 10.1161/CIRCOUTCOMES.110.945311

    View details for Web of Science ID 000288372200009

    View details for PubMedID 21304097

  • Strategic lessons from the clinical event classification process for the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial CONTEMPORARY CLINICAL TRIALS Mahaffey, K. W., Wampole, J. L., Stebbins, A., Berdan, L. G., Mcafee, D., Rorick, T. L., French, J. K., Kleiman, N. S., O'Connor, C. M., Cohen, E. A., Granger, C. B., Armstrong, P. W. 2011; 32 (2): 178-187

    Abstract

    Independent adjudication of clinical trial events is traditionally performed by physicians on a clinical event classification (CEC) committee.The experience of the centralized CEC group of the APEX-AMI trial is described. This group adjudicated key secondary pre-specified outcome measures of congestive heart failure (CHF) and cardiogenic shock through 90 days using an algorithmic approach for some events.Data were collected via an electronic data capture (EDC) tool on all subjects, and additional information was provided via EDC for patients identified by site investigators with CHF or shock. Two strategies were used to adjudicate potential events: 1) a computer algorithm (followed by physician confirmation) analyzed data to determine whether events met trial end point definitions; or 2) physician review was used if EDC data were inadequate to allow classification by algorithm.Of 5745 patients, 282 suspected cardiogenic shock and 465 suspected CHF events were identified. The computer algorithm or physicians confirmed 196/282 cardiogenic shock and 277/465 CHF end points. Overall, 242/742 (32.6%) of suspected events were classified by algorithm. Of the 500 events not resolved by computer algorithm, the CEC physicians agreed with site investigator assessments in 126/277 (45%) of CHF and 151/196 (77%) of cardiogenic shock events. The CEC committee completed adjudication of all suspected 30- and 90-day CHF and cardiogenic shock events within 7 days of the last patient 30-day follow-up visit and within 1 day of the last patient 90-day follow-up visit. Only 27% of patients required source document collection in addition to EDC-collected information.A complementary approach of a computerized assessment and physician review was used in the CEC effort of the APEX-AMI trial. The algorithm categorized approximately one third of suspected CHF/cardiogenic shock events. The APEX-AMI CEC experience shows that an algorithmic approach may be a useful strategy for end point evaluation but requires validation.

    View details for DOI 10.1016/j.cct.2010.12.013

    View details for Web of Science ID 000288056700006

    View details for PubMedID 21220052

  • Association of Myocardial Enzyme Elevation and Survival Following Coronary Artery Bypass Graft Surgery JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Domanski, M. J., Mahaffey, K., Hasselblad, V., Brener, S. J., Smith, P. K., Hillis, G., Engoren, M., Alexander, J. H., Levy, J. H., Chaitman, B. R., Broderick, S., Mack, M. J., Pieper, K. S., Farkouh, M. E. 2011; 305 (6): 585-591

    Abstract

    Several small studies have suggested that cardiac enzyme elevation in the 24 hours following coronary artery bypass graft (CABG) surgery is associated with worse prognosis, but a definitive study is not available. Also, the long-term prognostic impact of small increases of perioperative enzyme has not been reported.To quantify the relationship between peak post-CABG elevation of biomarkers of myocardial damage and early, intermediate-, and long-term mortality, including determining whether there is a threshold below which elevations lack prognostic significance.Studies (randomized clinical trials or registries) of patients undergoing CABG surgery in which postprocedural biomarker and mortality data were collected and included. A search of the PubMed database was performed in July 2008 using the search terms coronary artery bypass, troponin, CK-MB, and mortality.Studies evaluating mortality and creatine kinase (CK-MB), troponin, or both were included. One study investigator declined to participate and 3 had insufficient data.Two independent reviewers determined study eligibility. The principal investigator from each eligible study was contacted to request his/her participation. Once institutional review board approval for the use of these data for this purpose was obtained, we requested patient-level data from each source. Data were examined to ensure that cardiac markers had been measured within 24 hours after CABG surgery, key baseline covariates, and mortality were available.A total of 18,908 patients from 7 studies were included. Follow-up varied from 3 months to 5 years. Mortality was found to be a monotonically increasing function of the CK-MB ratio. The 30-day mortality rates by categories of CK-MB ratio were 0.63% (95% confidence interval [CI], 0.36%-1.02%) for 0 to <1, 0.86% (95% CI, 0.49%-1.40%) for 1 to <2, 0.95% (95% CI, 0.72%-1.22%) for 2 to <5, 2.09% (95% CI, 1.69%-2.57%) for 5 to <10, 2.78% (95% CI, 2.12%-3.58%) for 10 to <20, and 7.06% (95% CI, 5.46%-8.96%) for 20 to ?40. Of the variables considered, the CK-MB ratio was the strongest independent predictor of death to 30 days and remained significant even after adjusting for a wide range of baseline risk factors (?(2) = 143, P < .001; hazard ratio [HR] for each 5 point-increment above the upper limits of normal [ULN] = 1.12; 95% CI, 1.10-1.14). This result was strongest at 30 days, but the adjusted association persisted from 30 days to 1 year (?(2) = 24; P < .001; HR for each 5-point increment above ULN = 1.17; 95% CI, 1.10-1.24) and a trend was present from 1 year to 5 years (?(2) = 2.8; P = .10; HR for each 5-point increment above ULN = 1.05; 95% CI, 0.99-1.11). Similar analyses using troponin as the marker of necrosis led to the same conclusions (?(2) = 142 for 0-30 days and ?(2) = 40 for 30 days to 6 months, both P < .001; HR for each 50 points above the ULN = 1.28; 95% CI, 1.23-1.33 and 1.15; 95% CI, 1.10-1.21, respectively).Among patients who had undergone CABG surgery, elevation of CK-MB or troponin levels within the first 24 hours was independently associated with increased intermediate- and long-term risk of mortality.

    View details for Web of Science ID 000287080500023

    View details for PubMedID 21304084

  • Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery Results From the PLATO (Platelet Inhibition and Patient Outcomes) Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Held, C., Asenblad, N., Bassand, J. P., Becker, R. C., Cannon, C. P., Claeys, M. J., Harrington, R. A., Horrow, J., Husted, S., James, S. K., Mahaffey, K. W., Nicolau, J. C., Scirica, B. M., Storey, R. F., Vintila, M., Ycas, J., Wallentin, L. 2011; 57 (6): 672-684

    Abstract

    The purpose of this study is to evaluate the efficacy and safety of ticagrelor and clopidogrel in patients with acute coronary syndrome undergoing coronary artery bypass graft surgery (CABG), as a post-randomization strategy.Ticagrelor is a novel, reversibly binding, oral, direct-acting P2Y(12)-receptor antagonist. In the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized 18,624 patients with acute coronary syndromes, ticagrelor compared with clopidogrel significantly reduced the risk of the primary composite end point of cardiovascular (CV) death, myocardial infarction, or stroke (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.77 to 0.92; p < 0.001). This report investigated the outcomes of patients treated with CABG during the trial.In total, 1,899 patients underwent CABG post-randomization. The protocol recommended ticagrelor/placebo to be withheld for 24 to 72 h and clopidogrel/placebo for 5 days preoperatively. In all, 1,261 patients underwent CABG and were receiving study drug treatment <7 days before surgery. The statistical analysis was based on events occurring from the CABG procedure until the end of the study, excluding 3 patients with CABG after study end.In the 1,261 patient cohort, the relative reduction of primary composite end point at 12 months (10.6% [66 of 629] with ticagrelor versus 13.1% [79 of 629] with clopidogrel; HR: 0.84; 95% CI: 0.60 to 1.16; p = 0.29) was consistent with the results of the whole trial. Total mortality was reduced from 9.7% (58 of 629) to 4.7% (29 of 629; HR: 0.49; 95% CI: 0.32 to 0.77; p < 0.01), CV death from 7.9% (47 of 629) to 4.1% (25 of 629; HR: 0.52; 95% CI: 0.32 to 0.85; p < 0.01), and non-CV death numerically from 2.0% to 0.7% (p = 0.07). There was no significant difference in CABG-related major bleeding between the randomized treatments.In the subgroup of patients undergoing CABG within 7 days after the last study drug intake, ticagrelor compared with clopidogrel was associated with a substantial reduction in total and CV mortality without excess risk of CABG-related bleeding.

    View details for DOI 10.1016/j.jacc.2010.10.029

    View details for Web of Science ID 000286880100006

    View details for PubMedID 21194870

  • Heparin-associated anti-Xa activity and platelet-derived prothrombotic and proinflammatory biomarkers in moderate to high-risk patients with acute coronary syndrome JOURNAL OF THROMBOSIS AND THROMBOLYSIS Becker, R. C., Mahaffey, K. W., Yang, H., Marian, A. J., Furman, M. I., Lincoff, A. M., Hazen, S. L., Petersen, J. L., Reist, C. J., Kleiman, N. S. 2011; 31 (2): 146-153

    Abstract

    Heparin compounds, to include fractionated and unfractionated preparations, exert both antithrombotic and antiinflammatory effects through combined inhibition of factor Xa and thrombin. The contribution of modulated platelet activity in vivo is less clearly defined. The SYNERGY library was a prospectively designed repository for candidate clinical, hemostatic, platelet, and molecular biomarkers from patients participating in SYNERGY--a large-scale, randomized clinical trial evaluating the comparative benefits of unfractionated heparin (UFH) and enoxaparin in high-risk patients with acute coronary syndrome (ACS). Samples were collected from 201 patients enrolled at 26 experienced, participating sites and shipped to established core laboratories for analysis of platelet, endothelium-derived, inflammatory and coagulation activity biomarkers. Tissue factor pathway inhibitor (TFPI)--a vascular endothelial cell-derived factor Xa regulatory protein-correlated directly with plasma anti-Xa activity (unadjusted: r = 0.23, P < 0.0001; adjusted: ? = 0.10; P = 0.001), as did TFPI-fXa complexes (unadjusted: r = 0.34, P < 0.0001; adjusted: ? = 0.38; P = < 0.0001). In contrast, there was a direct and inverse relationship between anti-Xa activity and two platelet-derived biomarkers-plasminogen activator inhibitor-1 (unadjusted: r = -0.18, P = 0.0012; adjusted: ? = -0.10; P = 0.021) and soluble CD40 ligand (unadjusted: r = -0.11, P = 0.05; adjusted: ? = -0.13; P = 0.049). All measured analyte relationships persisted after adjustment for age, creatinine clearance, weight, sex, and duration of treatment. Differences in biomarkers between patients receiving UFH and those randomized to enoxaparin were not observed. The ability of heparin compounds to affect the prothrombotic and proinflammatory states which characterize ACS may involve factor Xa-related modulation of platelet activation and expression. Whether this potentially beneficial effect is direct or indirect and achieved, at least in part, through the release of endothelial cell-derived coagulation regulatory proteins will require further investigation.

    View details for DOI 10.1007/s11239-010-0532-y

    View details for Web of Science ID 000286467400003

    View details for PubMedID 21086021

  • ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use AMERICAN JOURNAL OF GASTROENTEROLOGY Abraham, N. S., Hlatky, M. A., Antman, E. M., Bhatt, D. L., Bjorkman, D. J., Clark, C. B., Furberg, C. D., Johnson, D. A., Kahi, C. J., Laine, L., Mahaffey, K. W., Quigley, E. M., Scheiman, J., Sperling, L. S., Tomaselli, G. F. 2010; 105 (12): 2533-2549

    View details for DOI 10.1038/ajg.2010.445

    View details for Web of Science ID 000284940900004

    View details for PubMedID 21131924

  • Independent Adjudication of Symptomatic Heart Failure With the Use of Doxorubicin and Cyclophosphamide Followed by Trastuzumab Adjuvant Therapy: A Combined Review of Cardiac Data From the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 Clinical Trials JOURNAL OF CLINICAL ONCOLOGY Russell, S. D., Blackwell, K. L., Lawrence, J., Pippen, J. E., Roe, M. T., Wood, F., Paton, V., Holmgren, E., Mahaffey, K. W. 2010; 28 (21): 3416-3421

    Abstract

    An independent Adjuvant Cardiac Review and Evaluation Committee (ACREC) systematically reviewed cases of symptomatic heart failure events to uniformly define the cardiac event rate across two large trials (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-31 and North Central Cancer Treatment Group [NCCTG] N9831) that assessed the addition of trastuzumab to standard adjuvant chemotherapy.The committee was composed of six independent oncologists and cardiologists. A retrospective review of patients with a cardiac event was performed by the primary investigators of the trials. The ACREC prospectively established criteria for determining a symptomatic heart failure event. Recovery status was determined from documented resolution of signs and symptoms. Potential risk factors were also assessed.Medical records for a total of 173 patients were reviewed: 40 in the chemotherapy-alone arm and 133 in the trastuzumab arm. Trastuzumab-treated patients had a 2.0% incidence of symptomatic heart failure events compared with 0.45% in the chemotherapy-alone arm. Complete or partial recovery was observed in 86.1% of trastuzumab-treated patients with symptomatic heart failure events. Of five patients who died, only one patient had received trastuzumab. Independent predictors for cardiac events were age older than 50 years, a low ejection fraction at the start of paclitaxel treatment, and trastuzumab treatment.The incidence of symptomatic heart failure events is 2.0% in patients treated with adjuvant trastuzumab, and the majority of these patients recover with appropriate treatment.

    View details for DOI 10.1200/JCO.2009.23.6950

    View details for Web of Science ID 000280003700004

    View details for PubMedID 20530275

  • Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation CURRENT OPINION IN CARDIOLOGY Piccini, J. P., Lopes, R. D., Mahaffey, K. W. 2010; 25 (4): 312-320

    Abstract

    Prevention of stroke and systemic emboli is paramount in the management of atrial fibrillation. Although warfarin is the predominant anticoagulant used in patients with atrial fibrillation, it has significant limitations that have impeded appropriate use of stroke prophylaxis in eligible patients with atrial fibrillation. Consequently, much research has been focused on finding an alternative to warfarin. We review the potential alternatives in development and evaluate the current evidence concerning their safety and efficacy.Oral direct factor Xa inhibitors are potentially well tolerated and effective replacements for warfarin. These agents do not require cofactors and offer selective inhibition at a critical step of amplification in the coagulation cascade. Multiple direct anti-factor Xa agents are currently undergoing evaluation in phase I, II, and III trials. Early results suggest that these novel anticoagulants have favorable pharmacokinetic and pharmacodynamic profiles with minimal-to-no requirements for therapeutic monitoring. Two direct factor Xa inhibitors are emerging from phase II trials (betrixaban and YM150) and three are being evaluated in phase III trials (apixaban, edoxaban, and rivaroxaban) for the prevention of stroke and systemic emboli in patients with atrial fibrillation. The phase III trials of apixaban and rivaroxaban have completed enrollment and are in the follow-up phase.Given the growing population of patients with atrial fibrillation, there is a great interest in finding new therapies for oral anticoagulation. The direct factor Xa inhibitors may offer several promising alternatives to warfarin therapy.

    View details for DOI 10.1097/HCO.0b013e32833a524f

    View details for Web of Science ID 000278569800004

    View details for PubMedID 20520539

  • Enoxaparin 0.3 mg/kg IV Supplement for Patients Transitioning to PCI after Subcutaneous Enoxaparin Therapy for NSTE ACS: A Subgroup Analysis from the SYNERGY Trial CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Cohen, M., Levine, G. N., Pieper, K. S., Lan, L., Antman, E. M., Aylward, P. E., White, H. D., Kleiman, N. S., Califf, R. M., Mahaffey, K. W. 2010; 75 (6): 928-935

    Abstract

    To explore clinical and bleeding outcomes in patients enrolled in the SYNERGY trial who had percutaneous coronary intervention (PCI) based on adherence to the dosing regimens of enoxaparin mandated by the protocol.In SYNERGY, 4,687 patients underwent PCI during index hospitalization. Patients in the subcutaneous (sc) enoxaparin group were to be given an 0.3 mg/kg IV bolus immediately before PCI if balloon inflation occurred > or = 8 hr after their last sc dose of enoxaparin.The incidence of the 1 degrees efficacy end point (death/myocardial infarction [MI] post PCI and through 30 days), and the rates of post-PCI in-hospital TIMI major and GUSTO severe bleeding were compared between patients randomized to unfractionated heparin (UFH) and those randomized to sc enoxaparin who did or did not receive a supplemental IV bolus of enoxaparin in accord with protocol-mandates.A total of 4,687 patients had PCI; 2,323 were assigned sc enoxaparin and 1,332 received protocol-mandated IV enoxaparin bolus, while 215 enoxaparin patients received inappropriate IV therapy (either receiving IV enoxaparin before the 8-hr protocol time or not receiving the IV enoxaparin as directed after 8 hr). Death or MI occurring post PCI through 30-day follow-up tended to be lower in the enoxaparin patients who were treated according to protocol than in those who were not (12.3% vs. 14.4%; adjusted P = 0.25), as was TIMI major bleeding (3.0% vs. 4.7%, adjusted P = 0.08).These exploratory analyses show that patients in SYNERGY who received the protocol-mandated supplemental IV bolus of 0.3 mg/kg enoxaparin before PCI performed 8-12 hr after their last sc enoxaparin dose tended to have improved outcomes compared with those who did not. Strategies to ensure adherence to dosing guidelines of enoxaparin during PCI should be considered.

    View details for DOI 10.1002/ccd.22340

    View details for Web of Science ID 000277396200026

    View details for PubMedID 20432399

  • A Systematic Assessment of Cardiovascular Outcomes in the Saxagliptin Drug Development Program for Type 2 Diabetes POSTGRADUATE MEDICINE Frederich, R., Alexander, J. H., Fiedorek, F. T., Donovan, M., Berglind, N., Harris, S., Chen, R., Wolf, R., Mahaffey, K. W. 2010; 122 (3): 16-27

    Abstract

    The objective was to assess the relative risk (RR) for cardiovascular (CV) events across all 8 randomized phase 2/3 trials evaluating saxagliptin in patients with type 2 diabetes mellitus.Cardiovascular events (death, myocardial infarction [MI], stroke, revascularization procedures, and cardiac ischemia) were reported by investigators through standard adverse event reporting procedures and were systematically identified. Post hoc blinded adjudication of all deaths, MIs, and strokes was performed using prespecified endpoint definitions by an independent clinical events committee (CEC).A total of 4607 randomized and treated patients (n = 3356 treated with saxagliptin [2.5-100 mg/d]; n = 1251, comparator [n = 656, placebo; n = 328, metformin; n = 267, uptitrated glyburide]) were included. The median ages were 54 years (saxagliptin) and 55 years (comparator) (interquartile range, 47-61 each); 51% were female, 73% were white, 52% were hypertensive, 44% had hypercholesterolemia, 39% had a smoking history, 20% had a first-degree family member with premature coronary heart disease, and 12% had prior CV disease. Cardiovascular events were experienced by 61 patients (38 [1.1%], saxagliptin; 23 [1.8%], comparator), and CV death/MI/stroke events were reported by investigators in 41 patients: 23 (0.7%), saxagliptin; 18 (1.4%), comparator (relative risk, 95% confidence interval [CI], 0.44 [0.24-0.82]). The CEC reviewed 147 patients with potential CV events and identified a total of 40 patients with CV death/MI/stroke: 22 (0.7%), saxagliptin; 18 (1.4%), comparator (RR, 0.43 [0.23-0.80]). Component proportions for CV death, MI, and stroke were (saxagliptin vs comparator): 7 (0.2%) vs 10 (0.8%), 8 (0.2%) vs 8 (0.6%), and 11 (0.3%) vs 5 (0.4%), respectively.No increased risk of CV death/MI/stroke was observed in patients randomly assigned saxagliptin across a broad drug development program. Although this systematic overview has inherent and important limitations, the data support a potential reduction in CV events with saxagliptin. The hypothesis of CV protection with saxagliptin will be tested prospectively in a large randomized clinical outcome trial evaluating saxagliptin compared with standard of care in patients with type 2 diabetes at increased risk for CV events.

    View details for Web of Science ID 000281249000002

    View details for PubMedID 20463410

  • Prognostic utility of quantifying evolutionary ST-segment depression on early follow-up electrocardiogram in patients with non-ST-segment elevation acute coronary syndromes EUROPEAN HEART JOURNAL Yan, R. T., Yan, A. T., Mahaffey, K. W., White, H. D., Pieper, K., Sun, J., Pepine, C. J., Biasucci, L. M., Gulba, D. C., Lopez-Sendon, J., Goodman, S. G. 2010; 31 (8): 958-966

    Abstract

    Although ST-segment depression (STD) on the admission electrocardiogram (ECG) confers adverse prognosis in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), the implications of STD on follow-up ECG remain uncertain. We determined the prognostic significance of STD on follow-up ECG performed within 12-24 h of admission and whether its quantitative evaluation can further refine risk stratification.The admission and follow-up ECGs of 3877 patients in the SYNERGY trial were analysed for the presence (>or=1 mm) and extent (maximum magnitude on any single lead) of STD. Of the 1110 patients presenting with STD on admission, 534 (48.1%) with persistent STD at follow-up had higher mortality at 30 days (7.1 vs. 3.6%, P = 0.01) and 6 months (10.7 vs. 5.2%, P = 0.001) than those with normalized STD. Among 2767 patients without STD on admission, 174 (6.3%) developed new STD on follow-up ECG and experienced increased mortality compared with those without such interval change (30 days: 4.0 vs. 1.7%, P = 0.035; 6 months: 8.0 vs. 3.3%, P = 0.001). After adjustment for established clinical prognosticators and the extent of STD on admission, every 1 mm increment of STD on the follow-up ECG independently predicted a graded increase in 30-day mortality [hazards ratio (HR) = 1.60, 95% confidence interval (CI) = 1.29-1.98, P < 0.0001], and death/myocardial infarction at 30 days (HR = 1.19, 95% CI = 1.03-1.36, P = 0.017) and 6 months (HR = 1.17, 95% CI = 1.03-1.32, P = 0.016).The magnitude of STD on a routine 12-24 h follow-up ECG provides incremental prognostic information beyond established clinical prognosticators and the extent of STD on admission. Incorporating a follow-up ECG and its quantitative evaluation for STD may further refine risk stratification of patients with NSTE-ACS.

    View details for DOI 10.1093/eurheartj/ehp548

    View details for Web of Science ID 000277278900018

    View details for PubMedID 20034973

  • Obesity in patients with non-ST-segment elevation acute coronary syndromes: Results from the SYNERGY trial INTERNATIONAL JOURNAL OF CARDIOLOGY Mahaffey, K. W., Tonev, S. T., Spinler, S. A., Levine, G. N., Gallo, R., Ducas, J., Goodman, S. G., Antman, E. M., Becker, R. C., Langer, A., White, H. D., Aylward, P. E., Col, J. J., Ferguson, J. J., Califf, R. M. 2010; 139 (2): 123-133

    Abstract

    Obese patients are at increased risk of acute coronary syndromes (ACS). We evaluated the prevalence of obesity in a large ACS population, as well as the relationship between body mass index (BMI) and the use of cardiac medications and procedures, clinical outcomes, and treatment effects between enoxaparin and unfractionated heparin (UFH).Using the database of the SYNERGY trial, we identified 9978 patients in 12 countries who were randomly assigned to receive enoxaparin or UFH. Patient weight at baseline and 30-day follow-up was recorded. BMI information was available on 9837 patients. BMI was analyzed in clinically meaningful categories (<20, 20-25, 30-35, > or =35 kg/m(2)) and as a continuous variable.Thirty-two percent of patients were obese (BMI> or =30), with a greater proportion of patients with obesity from North America (36%) compared with other regions. Enoxaparin was dosed as 1 mg/kg regardless of body weight without maximum. The first dose of enoxaparin was underdosed in 15% of patients assigned enoxaparin, and obese patients were more likely to be underdosed than non-obese patients. Obese patients were younger, less often white, had more diabetes, hypertension, hyperlipidemia, family history of coronary artery disease, and congestive heart failure but fewer strokes, less peripheral vascular disease, and less often smoked. After adjustment, increased BMI was not an independent predictor of bleeding outcomes or 30-day death/myocardial infarction (MI), but increased BMI was predictive of lower 1-year mortality in the subgroup of patients with BMI at baseline below approximately 30 kg/m(2). No statistical interaction term was observed between obesity and randomized therapy for the outcomes of death/MI at 30 days and 6 months; death at 30 days, 6 months, and 1 year; and GUSTO or TIMI bleeding.Nearly one third of patients in SYNERGY were obese. Despite multiple comorbidities, obese patients had better unadjusted short- and long-term outcomes. After adjustment, higher BMI was not an independent predictor of in-hospital bleeding events or 30-day death/MI, but increased BMI was an independent predictor of 1-year mortality in patients with lower BMI but not in heavier patients. No interaction between the randomized treatment and obesity for efficacy and safety outcomes was observed across the range of BMI in this dataset. Standard dosing of enoxaparin should be used in patients without extreme obesity due to limited outcome data in these patients.

    View details for DOI 10.1016/j.ijcard.2008.10.008

    View details for Web of Science ID 000274955700004

    View details for PubMedID 19012977

  • Resolution of ST-segment depression: a new prognostic marker in ST-segment elevation myocardial infarction EUROPEAN HEART JOURNAL Tjandrawidjaja, M. C., Fu, Y., Westerhout, C. M., White, H. D., Todaro, T. G., Van de Werf, F., Mahaffey, K. W., Wagner, G. S., Granger, C. B., Armstrong, P. W. 2010; 31 (5): 573-581

    Abstract

    To evaluate the prognostic impact of ST depression resolution among patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI in the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial.In this study, 4729 of 5745 patients had analysable ECGs demonstrating concomitant ST-segment depression. Resolution of summation operatorST elevation (STE-R) and summation operatorST depression (STD-R) on 30 min post-PCI ECGs was dichotomized into those with > or =50 vs. <50% ST-segment resolution. Overall, 1143 patients (24%) had STD-R<50%. These patients had higher risk characteristics including older age, female sex, diabetes, hypertension, prior CHF/MI, Killip class >I, triple vessel disease, and less frequent TIMI 3 flow in the culprit coronary vessel post-PCI. After multivariable adjustment and accounting for STE-R, STD-R<50% remained an independent predictor for 90 day death and the composite of death, cardiogenic shock, or CHF. When compared with patients with both STE-R and STD-R> or =50%, patients with both STE-R and STD-R<50% had the worst outcomes [hazard ratios (HR) 90 day death: 2.54; 95% confidence intervals (CI): 1.71-3.77; HR 90 day composite: 2.18; 95% CI: 1.63-2.91].When ST depression is present in STEMI patients undergoing primary PCI, STD-R<50% provides independent prognostic value that is incremental to STE-R.

    View details for DOI 10.1093/eurheartj/ehp494

    View details for Web of Science ID 000275241900015

    View details for PubMedID 19952006

  • Influence of clinical trial participation on subsequent antithrombin use. Clinical cardiology Shah, B. R., Peterson, E. D., Chen, A. Y., Mahaffey, K. W., DeLong, E. R., Ohman, E. M., Pollack, C. V., Gibler, W. B., Roe, M. T. 2010; 33 (3): E49-55

    Abstract

    Results from the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial showed that the low-molecular-weight heparin (LMWH) enoxaparin was non-inferior compared with unfractionated heparin (UFH) in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) managed invasively.We explored the influence of SYNERGY trial site participation on subsequent patterns of heparin use for NSTE-ACS patients treated in routine practice.We examined temporal patterns of LMWH use compared with UFH use among 122 764 patients with NSTE-ACS enrolled in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) quality improvement initiative between January 1, 2002 and June 30, 2006, to determine whether site participation in SYNERGY influenced the type of heparin used before and after publication of the SYNERGY results in July 2004.A total of 118 out of 388 (30%) U.S. hospitals participating in CRUSADE simultaneously participated in SYNERGY. SYNERGY sites in the CRUSADE registry were more likely to have a teaching affiliation and have more hospital beds than non-SYNERGY centers in the registry. There was no difference in the proportion of patients treated with LMWH at SYNERGY and non-SYNERGY sites prior to July 2004 compared with after July 2004. However, at SYNERGY sites, there was a slight decrease in the proportion of patients treated with both UFH and LMWH within 24 hours of presentation.The results of the SYNERGY trial did not appear to influence temporal patterns of LMWH use at sites in the CRUSADE registry. Furthermore, site participation in the SYNERGY trial did not alter patterns of LMWH use for NSTE-ACS after publication of the trial results in July 2004.

    View details for DOI 10.1002/clc.20581

    View details for PubMedID 20127904

  • Warfarin Use and Outcomes in Patients with Atrial Fibrillation Complicating Acute Coronary Syndromes AMERICAN JOURNAL OF MEDICINE Lopes, R. D., Starr, A., Pieper, C. F., Al-Khatib, S. M., Newby, L. K., Mehta, R. H., Van de Werf, F., Mahaffey, K. W., Armstrong, P. W., Harrington, R. A., White, H. D., Wallentin, L., Granger, C. B. 2010; 123 (2): 134-140

    Abstract

    We examined warfarin use at discharge (according to Congestive heart failure, Hypertension, Age>75 years, Diabetes, Prior Stroke/transient ischemic attack score and bleeding risk) and its association with 6-month death or myocardial infarction in patients with post-acute coronary syndrome atrial fibrillation.Of the 23,208 patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network A, and Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors trials, 4.0% (917 patients) had atrial fibrillation as an in-hospital complication and were discharged alive. Cox proportional hazards models were performed to assess 6-month outcomes after discharge.Overall, 13.5% of patients with an acute coronary syndrome complicated by atrial fibrillation received warfarin at discharge. Warfarin use among patients with atrial fibrillation had no relation with estimated stroke risk; similar rates were observed across Congestive heart failure, Hypertension, Age>75 years, Diabetes, Prior Stroke/transient ischemic attack (CHADS(2)) scores (0, 13%; 1, 14%; > or = 2, 13%) and across different bleeding risk categories (low risk, 11.9%; intermediate risk, 13.3%; high risk, 11.1%). Among patients with in-hospital atrial fibrillation, warfarin use at discharge was independently associated with a lower risk of death or myocardial infarction within 6 months of discharge (hazard ratio 0.39; 95% confidence interval, 0.15-0.98).Warfarin is associated with better 6-month outcomes among patients with atrial fibrillation complicating an acute coronary syndrome, but its use is not related to CHADS(2) score or bleeding risk.

    View details for DOI 10.1016/j.amjmed.2009.09.015

    View details for Web of Science ID 000274346200011

    View details for PubMedID 20103022

  • Mechanical Complications After Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction (from APEX-AMI) AMERICAN JOURNAL OF CARDIOLOGY French, J. K., Hellkamp, A. S., Armstrong, P. W., Cohen, E., Kleiman, N. S., O'Connor, C. M., Holmes, D. R., Hochman, J. S., Granger, C. B., Mahaffey, K. W. 2010; 105 (1): 59-63

    Abstract

    A decrease in mechanical complications after ST-elevation myocardial infarction may have contributed to improved survival rates associated with reperfusion by primary percutaneous coronary intervention (PCI). Mechanical complications occurred in 52 of 5,745 patients (0.91%) in the largest reported randomized trial in which primary PCI was the reperfusion strategy. The frequencies were 0.52% (30) for cardiac free-wall rupture (tamponade), 0.17% (10) for ventricular septal rupture, and 0.26% (15) for papillary muscle rupture (3 patients had 2 complications). Ninety-day survival rates were 37% (11) for cardiac free-wall rupture, 20% (2) for ventricular septal rupture, and 73.3% (11) for papillary muscle rupture. These mechanical complications occurred at a median of 23.5 hours (interquartile range 5.0 to 76.8) after symptom onset and were associated with 44% (23 of 52) survival through 90 days, which accounted for 11% of the 90-day mortality. Factors associated with mechanical complications were older age, female gender, Q waves, presence of radiologic pulmonary edema, and increased prerandomization troponin levels. In conclusion, rates of mechanical complications are lower with primary PCI than those previously reported after fibrinolytic therapy.

    View details for DOI 10.1016/j.amjcard.2009.08.653

    View details for Web of Science ID 000278136200010

    View details for PubMedID 20102891

  • Intravenous Platelet Blockade with Cangrelor during PCI. NEW ENGLAND JOURNAL OF MEDICINE Bhatt, D. L., Lincoff, A. M., Gibson, C. M., Stone, G. W., McNulty, S., Montalescot, G., Kleiman, N. S., Goodman, S. G., White, H. D., Mahaffey, K. W., Pollack, C. V., Manoukian, S. V., Widimsky, P., Chew, D. P., Cura, F., Manukov, I., Tousek, F., Jafar, M. Z., Arneja, J., Skerjanec, S., Harrington, R. A. 2009; 361 (24): 2330-2341

    Abstract

    Intravenous cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) receptor antagonist, might reduce ischemic events during percutaneous coronary intervention (PCI).In this double-blind, placebo-controlled study, we randomly assigned 5362 patients who had not been treated with clopidogrel to receive either cangrelor or placebo at the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a composite of death, myocardial infarction, or ischemia-driven revascularization at 48 hours. Enrollment was stopped when an interim analysis concluded that the trial would be unlikely to show superiority for the primary end point.The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%) and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P=0.17) (modified intention-to-treat population adjusted for missing data). In the cangrelor group, as compared with the placebo group, two prespecified secondary end points were significantly reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31; 95% CI, 0.11 to 0.85; P=0.02), and the rate of death from any cause, from 0.7% to 0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P=0.02). There was no significant difference in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the placebo group, P=0.13), though major bleeding on one scale was increased in the cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas.The use of periprocedural cangrelor during PCI was not superior to placebo in reducing the primary end point. The prespecified secondary end points of stent thrombosis and death were lower in the cangrelor group, with no significant increase in the rate of transfusion. Further study of intravenous ADP blockade with cangrelor may be warranted. (ClinicalTrials.gov number, NCT00385138.)

    View details for DOI 10.1056/NEJMoa0908629

    View details for Web of Science ID 000272547600007

    View details for PubMedID 19915222

  • Platelet Inhibition with Cangrelor in Patients Undergoing PCI. NEW ENGLAND JOURNAL OF MEDICINE Harrington, R. A., Stone, G. W., McNulty, S., White, H. D., Lincoff, A. M., Gibson, C. M., Pollack, C. V., Montalescot, G., Mahaffey, K. W., Kleiman, N. S., Goodman, S. G., Amine, M., Angiolillo, D. J., Becker, R. C., Chew, D. P., French, W. J., Leisch, F., Parikh, K. H., Skerjanec, S., Bhatt, D. L. 2009; 361 (24): 2318-2329

    Abstract

    Cangrelor, a nonthienopyridine adenosine triphosphate analogue, is an intravenous blocker of the adenosine diphosphate receptor P2Y(12). This agent might have a role in the treatment of patients who require rapid, predictable, and profound but reversible platelet inhibition.We performed a large-scale international trial comparing cangrelor with 600 mg of oral clopidogrel administered before percutaneous coronary intervention (PCI) in patients with acute coronary syndromes. The primary efficacy end point was a composite of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours.We enrolled 8877 patients, and 8716 underwent PCI. At 48 hours, cangrelor was not superior to clopidogrel with respect to the primary composite end point, which occurred in 7.5% of patients in the cangrelor group and 7.1% of patients in the clopidogrel group (odds ratio, 1.05; 95% confidence interval [CI], 0.88 to 1.24; P=0.59). Likewise, cangrelor was not superior at 30 days. The rate of major bleeding (according to Acute Catheterization and Urgent Intervention Triage Strategy criteria) was higher with cangrelor, a difference that approached statistical significance (3.6% vs. 2.9%; odds ratio, 1.26; 95% CI, 0.99 to 1.60; P=0.06), but this was not the case with major bleeding (according to the Thrombolysis in Myocardial Infarction criteria) or severe or life-threatening bleeding (according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria). A secondary exploratory end point of death from any cause, Q-wave myocardial infarction, or ischemia-driven revascularization showed a trend toward a reduction with cangrelor, but it was not significant (0.6% vs. 0.9%; odds ratio, 0.67; 95% CI, 0.39 to 1.14; P=0.14).Cangrelor, when administered intravenously 30 minutes before PCI and continued for 2 hours after PCI, was not superior to an oral loading dose of 600 mg of clopidogrel, administered 30 minutes before PCI, in reducing the composite end point of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. (ClinicalTrials.gov number, NCT00305162.)

    View details for DOI 10.1056/NEJMoa0908628

    View details for Web of Science ID 000272547600006

    View details for PubMedID 19915221

  • Comparison of Site-Reported and Core Laboratory-Reported Creatine Kinase-MB Values in Non-ST-Segment Elevation Acute Coronary Syndrome (from the International Trial SYNERGY) AMERICAN JOURNAL OF CARDIOLOGY Linefsky, J. P., Lin, M., Pieper, K. S., Reist, C. J., Berdan, L. G., Antman, E. M., Goodman, S. G., French, J. K., Guneri, S., Roe, M. T., Newby, L. K., Harrington, R. A., Ferguson, J. J., Califf, R. M., Mahaffey, K. W. 2009; 104 (10): 1330-1335

    Abstract

    The effect of nonstandardized creatine kinase (CK)-MB assays on the assessment of myocardial infarction (MI) end points in multicenter international trials has not been evaluated. We compared the site-reported and corresponding core laboratory CK-MB measures from 5 countries participating in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Samples for CK-MB were collected locally, with corresponding samples sent to a core laboratory at enrollment and after recurrent ischemic events, percutaneous coronary intervention, or coronary artery bypass grafting. The measured values were compared to the reported assay upper limits of normal (ULN) used at the site (or core laboratory for the core laboratory samples). The CK-MB results were available locally and from the core laboratory for 913 patients, constituting 4,693 time-matched laboratory values. The agreement between the core and site laboratory CK-MB/ULN ratio was moderate (concordance correlation coefficient 0.45) and varied considerably by geographic location and site. The CK-MB values were elevated (>or=2 times the ULN) by the core laboratory but normal (<2 times the ULN) by local standards in 708 instances (15%). There were 162 MI end points according to the core laboratory values versus 91 MI end points using the site-reported CK-MB data (kappa statistic 0.48). Compared with patients with no MI by the core or site laboratory values, patients with MI, as determined by both the core and the site laboratories, had significantly lower unadjusted 1-year survival rates (80.6% vs 93.5%, p <0.0001). Patients with MI, as determined by the core laboratory but not by the site laboratory, showed a trend toward a lower 1-year survival rate (89.8% vs 93.5%, p = 0.20). In conclusion, a substantial variation in CK-MB ratios and MI outcomes between the site and core laboratory data was observed in the SYNERGY trial. More MI outcomes were identified by the core laboratory, and patients with MI as defined by core laboratory data had lower 1-year survival, making these events potentially clinically important.

    View details for DOI 10.1016/j.amjcard.2009.06.056

    View details for Web of Science ID 000271998500003

    View details for PubMedID 19892046

  • Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes NEW ENGLAND JOURNAL OF MEDICINE Wallentin, L., Becker, R. C., Budaj, A., Cannon, C. P., Emanuelsson, H., Held, C., Horrow, J., Husted, S., James, S., Katus, H., Mahaffey, K. W., Scirica, B. M., Skene, A., Steg, P. G., Storey, R. F., Harrington, R. A. 2009; 361 (11): 1045-1057

    Abstract

    Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation.At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)

    View details for DOI 10.1056/NEJMoa0904327

    View details for Web of Science ID 000269659400007

    View details for PubMedID 19717846

  • The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale AMERICAN HEART JOURNAL Harrington, R. A., Van de Werf, F., Armstrong, P. W., Aylward, P., Veltri, E., Mahaffey, K. W., Moliterno, D. J., Strony, J., Wallentin, L., White, H. D., Diaz, R., Huber, K., Nicolau, J. C., Carlos Prieto, J., Isaza, D., Widimsky, P., Grande, P., Nieminen, M., Montalescot, G., Bode, C., Wong, L., Ofner, P., Lewis, B. S., Ambrosio, G., Valgimigli, M., Ogawa, H., Yamaguchi, J., Jukema, J. W., Cornel, J. H., Nordrehaug, J. E., Ruzyllo, W., Providencia, L., Tan, H., Dalby, A., Seung-Jung, P., Betriu, A., Cequier, A., Held, C., Pfisterer, M., Ming-Fong, C., Timurkaynak, T., Storey, R. F., Chen, E., Hudson, M. P., Lincoff, A. M., Morrow, D. A., Tricoci, P., Whellan, D. 2009; 158 (3): 327-U5

    Abstract

    The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA*CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features.TRA*CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least 1 year. The TRA*CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention.TRA*CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies.

    View details for DOI 10.1016/j.ahj.2009.07.001

    View details for Web of Science ID 000269641200002

    View details for PubMedID 19699853

  • Influence of body mass index on the efficacy of revascularization in patients with coronary artery disease JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Turer, A. T., Mahaffey, K. W., Honeycutt, E., Tuttle, R. H., Shaw, L. K., Sketch, M. H., Smith, P. K., Califf, R. M., Alexander, J. H. 2009; 137 (6): 1468-1474

    Abstract

    We examined the effect of body mass index on the association between revascularization strategy and survival in patients with coronary artery disease.Using the Duke Database for Cardiovascular Disease, we selected 22,877 patients who underwent cardiac catheterization from January 1986 to August 2004 and were found to have significant coronary artery disease. Patients were categorized into three coronary disease management groups: no revascularization, percutaneous coronary intervention, and coronary artery bypass surgery. Propensity scoring was used to control for coronary artery revascularization strategy. The relationship between body mass index, coronary disease treatment, and survival was assessed via Cox multivariable models adjusting for baseline demographic, clinical, and angiographic characteristics.The median body mass index was 27.2 kg/m(2) (24.4-30.4) in the overall cohort, 27.1 kg/m(2) (24.1-30.3) in the no revacularization group, 27.4 kg/m(2) (24.8-30.9) in the percutaneous intervention group, and 26.9 kg/m(2) (24.4-30.1) in the coronary bypass group. Body mass index was a significant, but weak, predictor of revascularization, with higher indexes predicting lower rates of coronary bypass. Thirty-day survival did not differ across body mass indexes among treatment groups, but survival curves appeared to separate over longer-term follow-up. An inverted U-shaped survival function was noted across all time points after 30 days, with the lowest risk of death at a body mass index of approximately 26 kg/m(2) (independent of revascularization strategy). Coronary bypass was associated with the highest survival at all later time points, whereas no revascularization was associated with the lowest.Extremes of body mass index are associated with lower long-term survival in patients with significant coronary disease. Revascularization, particularly with coronary bypass, is consistently associated with the best survival across the spectrum of body mass indexes.

    View details for DOI 10.1016/j.jtcvs.2008.11.047

    View details for Web of Science ID 000266275200026

    View details for PubMedID 19464466

  • Baseline Q-Wave Surpasses Time From Symptom Onset as a Prognostic Marker in ST-Segment Elevation Myocardial Infarction Patients Treated With Primary Percutaneous Coronary Intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Armstrong, P. W., Fu, Y., Westerhout, C. M., Hudson, M. P., Mahaffey, K. W., White, H. D., Todaro, T. G., Adams, P. X., Aylward, P. E., Granger, C. B. 2009; 53 (17): 1503-1509

    Abstract

    We assessed the incremental value of baseline Q waves over time from symptom onset as a marker of clinical outcome in ST-segment elevation myocardial infarction (STEMI).Time from symptom onset is a central focus in STEMI patients. The presence of Q waves on the baseline electrocardiogram (ECG) has been suggested to be of incremental value to time from symptom onset in evaluating clinical outcomes.We evaluated baseline Q waves and ST-segment resolution 30 min after primary percutaneous intervention (PCI) ECGs in 4,530 STEMI patients without prior infarction. Additionally, peak biomarkers; 90-day mortality; and the composite of death, congestive heart failure (CHF), or cardiogenic shock were assessed.Fifty-six percent of patients had baseline Q waves: they were older, more frequently male and diabetic, and had a more advanced Killip class. Patients with baseline Q waves had greater mortality and a higher composite rate of death, CHF, and shock versus patients without baseline Q waves at 90 days (5.3% vs. 2.1% and 12.1% vs. 4.8%, respectively, both p < 0.001). Complete ST-segment resolution was highest, whereas 90-day mortality and the composite outcome were lowest among those randomized < or =3 h without baseline Q waves. After multivariable adjustment, baseline Q-wave but not time from symptom onset was significantly associated with a 78% relative increase in the hazard of 90-day mortality and a 90% relative increase in the hazard of death, shock, and CHF.Baseline Q waves in STEMI patients treated with primary PCI provide an independent prognostic marker of clinical outcome. These data might be useful in designing future clinical trials as well as in evaluating patients for triage and potential transfer for planned primary PCI. (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction [APEX-AMI]; NCT00091637).

    View details for DOI 10.1016/j.jacc.2009.01.046

    View details for Web of Science ID 000265515100004

    View details for PubMedID 19389560

  • Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study LANCET Becker, R. C., Moliterno, D. J., Jennings, L. K., Pieper, K. S., Pei, J., Niederman, A., Ziada, K. M., Berman, G., Strony, J., Joseph, D., Mahaffey, K. W., Van de Werf, F., Veltri, E., Harrington, R. A. 2009; 373 (9667): 919-928

    Abstract

    An antithrombotic drug is needed that safely reduces cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We therefore assessed the tolerability and safety of SCH 530348-an oral platelet protease-activated receptor-1 antagonist.We randomly assigned patients aged 45 years or older and undergoing non-urgent PCI or coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio in a multicentre international study. Those in the SCH 530348 group who subsequently underwent PCI (primary PCI cohort) continued taking an oral maintenance dose (0.5 mg, 1.0 mg, or 2.5 mg per day), and patients in the placebo group continued placebo for 60 days. The primary endpoint was the incidence of clinically significant major or minor bleeding according to the thrombolysis in myocardial infarction (TIMI) scale. Both investigators and patients were unaware of treatment allocation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00132912.257 patients were assigned to placebo and 773 to SCH 530348. The primary endpoint occurred in 2 (2%) of 129, 3 (3%) of 120, and 7 (4%) of 173 patients, respectively, in the SCH 530348 10 mg, 20 mg, and 40 mg groups compared with 5 (3%) of 151 patients in the placebo group (p=0.5786). TIMI major plus minor bleeding occurred in 3 (2%) of 136, 5 (4%) of 139, and 4 (3%) of 138 patients given SCH 530348 0.5 mg, 1.0 mg, and 2.5 mg once per day, respectively (p=0.7561).Oral SCH 530348 was generally well tolerated and did not cause increased TIMI bleeding, even when administered concomitantly with aspirin and clopidogrel. Further testing in phase III trials to accurately define the safety and efficacy of SCH 530348 is warranted.

    View details for Web of Science ID 000264158700033

    View details for PubMedID 19286091

  • Integrating ancillary studies in a large clinical trial: The design and rationale of the APEX library CONTEMPORARY CLINICAL TRIALS Mahaffey, K. W., Reist, C. J., Fu, Y., Brener, S. J., Theroux, P., Patel, M. R., Stebbins, A., Westerhout, C. M., Todaro, T. G., Adams, P. X., Granger, C. B., Armstrong, P. W. 2008; 29 (6): 887-895

    Abstract

    The APEX library was a coordinated and integrated set of ancillary analyses and substudies that were a part of the large APEX-AMI trial. The library included electrocardiogram, angiographic, blood biomarker, genetics, and MRI components. Operationally, the goals and administration of the APEX library were developed concurrently with the design of the parent trial. The goal recruitment in the library was met due to this approach. These data will provide important insights into the pathobiology of acute myocardial infarction and the relationships between inflammation, thrombosis, genetics, and classic clinical markers from angiograms, electrocardiograms, and patient demographics. In conclusion, the APEX library is an example of successful collaboration among academic trial leaders, site investigators, and pharmaceutical sponsors. The operational paradigm of this effort should be considered in future investigations so that important advances in clinical care of disease can be realized efficiently.

    View details for DOI 10.1016/j.cct.2008.06.003

    View details for Web of Science ID 000260990300010

    View details for PubMedID 18644468

  • ST-segment recovery and outcome after primary percutaneous coronary intervention for ST-elevation myocardial infarction - Insights from the Assessment of PEXelizumab in Acute Myocardial Infarction (APEX-AMI) trial CIRCULATION Buller, C. E., Fu, Y., Mahaffey, K. W., Todaro, T. G., Adams, P., Westerhout, C. M., White, H. D., 't Hof, A. W., de Werf, F. J., Wagner, G. S., Granger, C. B., Armstrong, P. W. 2008; 118 (13): 1335-1346

    Abstract

    Primary percutaneous coronary angioplasty is an effective and widely adopted treatment for acute myocardial infarction. A simple method of determining prognosis after primary percutaneous coronary intervention (PCI) would facilitate appropriate care and expedite hospital discharge. Thus, we determined the prognostic importance of various measures of ST-segment-elevation recovery after primary PCI in a large, contemporary cohort of patients with ST-elevation myocardial infarction.We analyzed ECG data describing the magnitude and extent of ST-segment elevation and deviation before and early after (ie, 30 minutes) primary PCI in the study cohort of 4866 subjects with electrocardiographically high-risk ST-elevation myocardial infarction enrolled in the Assessment of PEXelizumab in Acute Myocardial Infarction (APEX-AMI) trial. Associations among 6 methods for calculating ST-segment recovery, biomarker estimates of infarct size (ie, peak creatine kinase, creatine kinase-MB, and troponin I and T), and prespecified clinical outcomes (ie, rates of 90-day death and 90-day death, heart failure, or shock) were examined. All ST-segment-recovery methods provided strong prognostic information regarding clinical outcomes. A simple ST-segment-recovery method of residual ST-segment elevation measurement in the most affected lead on the post-PCI ECG performed as well as complex methods that required comparison of pre- and post-PCI ECGs or calculation of summed ST-segment deviation in multiple leads (ie, worst-lead residual ST elevation: adjusted hazard ratio for 90-day death rate [reference <1 mm]: 1 to <2 mm, 1.23 [95% CI 0.74 to 2.03]; > or =2 mm, 2.22 [95% CI 1.35 to 3.65], corrected c-index=0.832; 90-day death/congestive heart failure/shock [reference <1 mm]: 1 to <2 mm, 1.55 [95% CI 1.06 to 2.26]; > or =2 mm, 2.33 [95% CI 1.59 to 3.41], corrected c-index=0.802). Biomarker estimates of infarct size declined in association with enhanced ST-segment recovery.An ECG performed early after primary PCI is a simple, widely available, inexpensive, and powerful prognostic tool applicable to patients with ST-elevation myocardial infarction.

    View details for DOI 10.1161/CIRCULATIONAHA.108.767772

    View details for Web of Science ID 000259402300006

    View details for PubMedID 18779444

  • Impact of perioperative myocardial infarction on angiographic and clinical outcomes following coronary artery bypass grafting (from PRoject of Ex-vivo Vein Graft ENgineering via Transfection [PREVENT] IV) AMERICAN JOURNAL OF CARDIOLOGY Yau, J. M., Alexander, J. H., Hafley, G., Mahaffey, K. W., Mack, M. J., Kouchoukos, N., Goyal, A., Peterson, E. D., Gibson, C. M., Califf, R. M., Harrington, R. A., Ferguson, T. B. 2008; 102 (5): 546-551

    Abstract

    Myocardial infarction (MI) after coronary artery bypass grafting (CABG) is associated with significant morbidity and mortality. Frequency, management, mechanisms, and angiographic and clinical outcomes associated with perioperative MI remain poorly understood. PREVENT IV was a multicenter, randomized, placebo-controlled trial of edifoligide in 3,014 patients undergoing CABG. Angiographic and 2-year clinical follow-up were complete for 1,920 and 2,956 patients, respectively. Perioperative MI was defined as creatinine kinase-MB increase >or=10 times the upper limit of normal or >or=5 times the upper limit of normal with new 30-ms Q waves within 24 hours of surgery. Baseline characteristics, in-hospital management, and angiographic and clinical outcomes of patients with and without perioperative MI were compared. Perioperative MI occurred in 294 patients (9.8%). Patients with perioperative MI had longer surgery (250 vs 230 minutes; p <0.001), more on-pump surgery (83% vs 78%; p = 0.048), and worse target-artery quality (p <0.001). Patients with perioperative MI more frequently underwent angiography within 30 days of enrollment (1.7% vs 0.6%; p = 0.021). One-year angiographic vein graft failure occurred in 62.4% of patients with and 43.8% of patients without perioperative MI (p <0.001). Two-year composite clinical outcome (death, MI, or revascularization) was worse in patients with perioperative MI before (19.4% vs 15.2%; p = 0.039) and after (hazard ratio 1.33, 95% confidence interval 1.00 to 1.76, p = 0.046) adjusting for differences in significant predictors. In conclusion, perioperative MI was relatively common, was associated with worse outcomes, and mechanisms other than vein graft failure accounted for a substantial proportion of these MIs. Further research is needed into the prevention and treatment of perioperative MI in patients undergoing CABG.

    View details for DOI 10.1016/j.amjcard.2008.04.069

    View details for Web of Science ID 000258784500008

    View details for PubMedID 18721510

  • Outcomes in elderly patients with acute coronary syndromes randomized to enoxaparin vs. unfractionated heparin: results from the SYNERGY trial EUROPEAN HEART JOURNAL Lopes, R. D., Alexander, K. P., Marcucci, G., White, H. D., Spinler, S., Col, J., Aylward, P. E., Califf, R. M., Mahaffey, K. W. 2008; 29 (15): 1827-1833

    Abstract

    Elderly patients are at high risk from non-ST-segment elevation acute coronary syndromes (NSTE ACS) as well as from treatment-related complications. Age-associated changes in physiology may alter the risk and benefit expected from therapy. The SYNERGY database was used to study the influence of age on treatment outcomes with enoxaparin vs. unfractionated heparin (UFH) in patients with high-risk NSTE ACS.Age was analysed as a continuous and categorical variable (<65, 65-74, and >or=75 years, and <75 and >or=75 years) for descriptive purposes. Logistic regression was used to adjust the outcomes of 30-day death, death or myocardial infarction (MI), and major bleeding for baseline characteristics. Odds ratios compared outcomes by age and by treatment within age groups. Model interaction terms were used to test for statistically different outcomes by treatment and age. Overall, 9977 randomized patients had age information, of whom 25.5% (2540) were >or=75 years of age. Elderly patients (>or=75 years) had more cardiovascular risk factors, prior cardiac disease, and higher acuity at presentation. After adjustment, advanced age (per 10 years) was associated with 30-day death or MI [risk odds ratios (ROR): 1.14, P = 0.002], 30-day death (ROR: 1.54, P < 0.0001), and 1-year death (ROR: 1.47, P < 0.0001), as well with TIMI major bleeding (ROR: 1.21, P = 0.001), GUSTO severe bleeding (ROR: 1.20, P = 0.047), and transfusion (ROR: 1.04, P = 0.324). Although there was a higher rate of GUSTO severe bleeding noted with enoxaparin in elderly patients, the overall relationships between treatment (UFH or enoxaparin) and outcomes did not vary significantly as a function of the patient's age.Although higher rates of adverse events are seen in the oldest subgroup (age >or=75 years) treated with enoxaparin, statistical comparisons confirm similar efficacy and safety of enoxaparin and UFH across age subgroups as was demonstrated overall in SYNERGY.

    View details for DOI 10.1093/eurheartj/ehn236

    View details for Web of Science ID 000258137200010

    View details for PubMedID 18519426

  • Initial risk stratification and presenting characteristics of patients with evolving myocardial infarctions EMERGENCY MEDICINE JOURNAL Miller, C. D., Fermann, G. J., Lindsell, C. J., Mahaffey, K. W., Peacock, W. F., Pollack, C. V., Hollander, J. E., Diercks, D. B., Gibler, W. B., Hoekstra, J. W. 2008; 25 (8): 492-497

    Abstract

    To describe the presenting characteristics and risk stratification of patients presenting to the emergency department with chest pain who have a normal initial troponin level followed by a raised troponin level within 12 h (evolving myocardial infarction (EMI)).Data from the Internet Tracking Registry for Acute Coronary Syndromes (i*trACS), a registry of patients presenting with undifferentiated chest pain, were used. This analysis included patients without ST segment elevation with at least two troponin assay results < or = 12 h apart. Patients were stratified into three groups: EMI (initial troponin assay negative, second troponin assay positive), non-ST elevation myocardial infarction (NSTEMI) (initial troponin assay positive) and no MI (all troponin assays negative).Of 4136 eligible patients, 5% had EMI, 8% had NSTEMI and 87% had no MI. Patients with EMI were more similar to those with NSTEMI than those with no MI with respect to demographic characteristics, presentation, admission patterns and revascularisation. The initial ECG in patients with EMI was most commonly non-diagnostic (51%), but physicians' initial impressions commonly reflected MI, unstable angina or high-risk chest pain (76%). This risk assessment was followed by a high rate of critical care admissions (32%) and revascularisation (percutaneous coronary intervention 17%) among patients with EMI.Patients with EMI appear similar at presentation to those with NSTEMI. Patients with EMI are perceived as being at high risk, evidenced by similar diagnostic impressions, admission practices and revascularisation rates to patients with NSTEMI.

    View details for DOI 10.1136/emj.2007.052183

    View details for Web of Science ID 000257922500009

    View details for PubMedID 18660397

  • Prevalence, Predictors, and Impact of Conservative Medical Management for Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Who Have Angiographically Documented Significant Coronary Disease JACC-CARDIOVASCULAR INTERVENTIONS Chan, M. Y., Mahaffey, K. W., Sun, L. J., Pieper, K. S., White, H. D., Aylward, P. E., Ferguson, J. J., Califf, R. M., Roe, M. T. 2008; 1 (4): 369-378

    Abstract

    We sought to characterize the utilization and impact of a conservative medical management strategy for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) and significant coronary artery disease on early angiography.Practice guidelines recommend an early invasive management strategy for NSTE ACS, but revascularization procedures may not always be performed after early angiography, even when significant coronary artery disease is present.We evaluated 8,225 intermediate- to high-risk NSTE ACS patients with at least 1 coronary lesion >50% stenosis on early angiography from the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trial (2001 to 2003), comparing patients treated with conservative medical management with those who underwent in-hospital percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within 7 days of randomization.A total of 2,633 patients (32%) were medically managed, 4,294 (52%) underwent PCI, and 1,298 (16%) underwent CABG. The strongest independent predictors of conservative medical management versus any intervention were prior CABG, lower body weight, lack of a reinfarction between randomization and catheterization, and 3-vessel disease. With conservative medical management, the cumulative risk of 1-year mortality after discharge increased rapidly during the first 90 days and thereafter remained higher at 7.7% compared with that seen in patients treated with PCI (3.6%) or CABG (6.2%).One-third of patients with NSTE ACS and significant coronary disease on early angiography were managed without in-hospital revascularization in the SYNERGY trial, and these patients had an increased risk of late mortality. These findings highlight the need for novel treatment approaches for NSTE ACS patients who are not candidates for revascularization. (SYNERGY trial; NCT00043784).

    View details for Web of Science ID 000207586200005

    View details for PubMedID 19463332

  • Smoking status and antithrombin therapy in patients with non-ST-segment elevation acute coronary syndrome AMERICAN HEART JOURNAL Leung, S., Gallup, D., Mahaffey, K. W., Cohen, M., Antman, E. M., Goodman, S. G., Harrington, R. A., Langer, A., Aylward, P., Ferguson, J. J., Califf, R. M. 2008; 156 (1): 177-184

    Abstract

    Smoking remains a major public health issue. We investigated the incidence of smoking and outcomes in high-risk patients with acute coronary syndromes. Differences in treatment effect of antithrombin therapies were also investigated.Using data from SYNERGY, patients were categorized by their self-reported smoking status. They were followed at 30 days and 6 months for death, nonfatal myocardial infarction (MI), revascularization procedures, stroke, and need for rehospitalization, and at 1 year for occurrences of death.Overall, 9,971 patients were evaluated, of whom 2,404 (24%) were current smokers, 3,491 (35%) were former smokers, and 4076 (41%) had never smoked. Current smokers were younger (median age 61 years, interquartile range [IQR] 52-67) than former smokers (median age 69 years, IQR 63-75) and never smokers (median age 70 years, IQR 64-77) and had fewer additional coronary artery disease risk factors (hypertension, diabetes, hypercholesterolemia). The 30-day death/MI rate was similar for former versus never smokers (15% vs 13.6%, P = .079) and for current versus never smokers (14% vs 13.6%, P = .585). Adjusted odds ratios for 30-day death/MI in patients receiving enoxaparin compared with those receiving unfractionated heparin were 1.065 (95% CI 0.883-1.283, P = .51) in never smokers, 1.034 (95% CI 0.853-1.254, P = .733) in former smokers, and 0.742 (95% CI 0.582-0.948, P = .017) in current smokers. A significant interaction for treatment and smoking status was found at 30 days (P = .0215), but not at 6 months (P = .1381) or 1 year (P = .1054). One-year unadjusted mortality rates were higher for former versus never smokers (9.1% vs 6.7%, P = .0002) but were similar for current versus never smokers (6.5% vs 6.7%, P = .7226). On follow-up at 30 days, 62.3% (n =1397) of current smokers reported not smoking.Smokers with non-ST-segment elevation acute coronary syndrome are generally younger and have fewer cardiac risk factors. A significant interaction of smoking and enoxaparin was seen at 30 days, but not sustained at 6 months and 1 year. More than 60% of smokers quit within 30 days of their cardiac event. There was little difference in outcomes from 30 days to 1 year for these smokers who quit versus those who did not.

    View details for DOI 10.1016/j.ahj.2008.02.002

    View details for Web of Science ID 000257329900025

    View details for PubMedID 18585514

  • Management of acute coronary syndromes in patients with renal dysfunction CURRENT OPINION IN CARDIOLOGY Melloni, C., Mahaffey, K. W. 2008; 23 (4): 320-326

    Abstract

    Chronic kidney disease is becoming common among patients with acute coronary syndromes and is associated with substantial cardiovascular morbidity and mortality. Often, patients with chronic kidney disease are excluded from clinical trials, so in clinical practice physicians may not have definitive evidence to support treatment decisions.Recent studies have shown that chronic kidney disease is an independent risk factor for outcomes in patients with acute coronary syndromes and that there is a stepwise increase in mortality with progressive decline of glomerular filtration rate. It has been demonstrated that the use of aggressive treatment strategies in these patients may be associated with improved outcome that is similar to, if not higher than, in those patients without renal disease. Yet, although critical for the correct dose adjustment of many antithrombotic and antiplatelet therapies, accurate renal function estimation often is not done.Chronic kidney disease is common, and the stages of chronic kidney disease are strongly related to the risk of adverse in-hospital outcomes and to the use of evidence-based therapies. Many antithrombotic drugs are eliminated mainly by the kidneys, so an accurate assessment of renal function is required in all patients with acute coronary syndromes for a proper dose adjustment. There is a clear need for clinical trials in patients with moderate-to-severe kidney dysfunction to further refine their optimal management in the setting of acute coronary syndromes.

    View details for Web of Science ID 000256868200006

    View details for PubMedID 18520715

  • Rivaroxaban, an oral direct factor Xa inhibitor EXPERT OPINION ON INVESTIGATIONAL DRUGS Piccini, J. P., Patel, M. R., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2008; 17 (6): 925-937

    Abstract

    Rivaroxaban is a small molecule, direct Factor Xa inhibitor and may be a potentially attractive alternative to vitamin K antagonists. Rivaroxaban is being investigated for the prevention and treatment of venous and arterial thrombosis. A broad search of Medline, clinicaltrials.gov and the annual proceedings of the American Society of Hematology and the International Society on Thrombosis and Hemostasis was conducted. This review addresses the findings of this systematic search, including the need for new oral anticoagulants, the development and pharmacology of rivaroxaban, and the results of completed as well as ongoing trials with rivaroxaban. At present, the safety and efficacy of rivaroxaban for the prophylaxis and treatment of venous thromboembolism has been evaluated in Phase II and Phase III trials involving over 24,000 patients. Additionally, rivaroxaban is being evaluated for the treatment of pulmonary embolism, secondary prevention after acute coronary syndromes and the prevention of stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation. The drug may have its greatest impact in providing a much-needed and attractive alternative to warfarin. Further data (especially large Phase III trials) are required.

    View details for DOI 10.1517/13543784.17.6.925

    View details for Web of Science ID 000256576800009

    View details for PubMedID 18491993

  • Coronary artery bypass surgery in patients with acute coronary syndromes is difficult to predict AMERICAN HEART JOURNAL Chew, D. P., Mahaffey, K. W., White, H. D., Huang, Z., Hockstra, J. W., Ferguson, J. J., Califf, R. M., Aylward, P. E. 2008; 155 (5): 841-847

    Abstract

    Although the use of clopidogrel in patients "unlikely" to require coronary artery bypass grafting (CABG) is recommended in current guidelines of acute coronary syndrome (ACS) management, an important minority of patients require CABG. We assessed the ability to predict need for CABG from demographics known at the time of ACS presentation, using data from SYNERGY.Patients undergoing CABG at any time after the index angiogram were included. Early CABG was defined as surgery <72 hours after angiography. The relationship between cessation of enoxaparin and glycoprotein IIb/IIIa inhibition, CABG timing, and 30-day death or MI and bleeding events was assessed. Demographic and clinical factors and geographic location were assessed as predictors of early CABG or CABG at any time. The discriminatory utility is reported with the c-index.Of the 9053 patients undergoing angiography, 1793 (18.1%) received CABG. Early CABG (n = 972) was associated with more bleeding events (39.2% vs 29.4%, P < .001) but not death or MI. The risk of bleeding events diminished when surgery was delayed >18 hours after cessation of enoxaparin and glycoprotein IIb/IIIa inhibition. Clinical factors associated with early CABG included diabetes and lack of prior CABG or clopidogrel. However, overall the logistic regression model had poor discriminatory ability to predict patients likely to require CABG in the setting of an ACS presentation (c-index 0.671).It is difficult to predict those high-risk patients with ACS who will undergo surgical revascularization based on baseline clinical characteristics.

    View details for DOI 10.1016/j.ahj.2007.12.002

    View details for Web of Science ID 000256001500007

    View details for PubMedID 18440330

  • Comparison of an everolimus-eluting stent and a paclitaxel-eluting stent in patients with coronary artery disease - A randomized trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Stone, G. W., Midei, M., Newman, W., Sanz, M., Hermiller, J. B., Williams, J., Farhat, N., Mahaffey, K. W., Cutlip, D. E., Fitzgerald, P. J., Sood, P., Su, X., Lansky, A. J. 2008; 299 (16): 1903-1913

    Abstract

    A thin, cobalt-chromium stent eluting the antiproliferative agent everolimus from a nonadhesive, durable fluoropolymer has shown promise in preliminary studies in improving clinical and angiographic outcomes in patients with coronary artery disease.To evaluate the safety and efficacy of an everolimus-eluting stent compared with a widely used paclitaxel-eluting stent. Design, Setting, andThe SPIRIT III trial, a prospective, randomized, single-blind, controlled trial enrolling patients at 65 academic and community-based US institutions between June 22, 2005, and March 15, 2006. Patients were 1002 men and women undergoing percutaneous coronary intervention in lesions 28 mm or less in length and with reference vessel diameter between 2.5 and 3.75 mm. Angiographic follow-up was prespecified at 8 months in 564 patients and completed in 436 patients. Clinical follow-up was performed at 1, 6, 9, and 12 months.Patients were randomized 2:1 to receive the everolimus-eluting stent (n = 669) or the paclitaxel-eluting stent (n = 333).The primary end point was noninferiority or superiority of angiographic in-segment late loss. The major secondary end point was noninferiority assessment of target vessel failure events (cardiac death, myocardial infarction, or target vessel revascularization) at 9 months. An additional secondary end point was evaluation of major adverse cardiac events (cardiac death, myocardial infarction, or target lesion revascularization) at 9 and 12 months.Angiographic in-segment late loss was significantly less in the everolimus-eluting stent group compared with the paclitaxel group (mean, 0.14 [SD, 0.41] mm vs 0.28 [SD, 0.48] mm; difference, -0.14 [95% CI, -0.23 to -0.05]; P < or = .004). The everolimus stent was noninferior to the paclitaxel stent for target vessel failure at 9 months (7.2% vs 9.0%, respectively; difference, -1.9% [95% CI, -5.6% to 1.8%]; relative risk, 0.79 [95% CI, 0.51 to 1.23]; P < .001). The everolimus stent compared with the paclitaxel stent resulted in significant reductions in composite major adverse cardiac events both at 9 months (4.6% vs 8.1%; relative risk, 0.56 [95% CI, 0.34 to 0.94]; P = .03) and at 1 year (6.0% vs 10.3%; relative risk, 0.58 [95% CI, 0.37 to 0.90]; P = .02), due to fewer myocardial infarctions and target lesion revascularization procedures.In this large-scale, prospective randomized trial, an everolimus-eluting stent compared with a paclitaxel-eluting stent resulted in reduced angiographic late loss, noninferior rates of target vessel failure, and fewer major adverse cardiac events during 1 year of follow-up.clinicaltrials.gov Identifier: NCT00180479.

    View details for Web of Science ID 000255163800024

    View details for PubMedID 18430909

  • Prediction of one-year survival in high-risk patients with acute coronary syndromes: Results from the SYNERGY trial JOURNAL OF GENERAL INTERNAL MEDICINE Mahaffey, K. W., Yang, Q., Pieper, K. S., Antman, E. M., White, H. D., Goodman, S. G., Cohen, M., Kleiman, N. S., Langer, A., Aylward, P. E., Col, J. J., Reist, C., Ferguson, J. J., Califf, R. M. 2008; 23 (3): 310-316

    Abstract

    Despite advances in pharmacologic therapy and invasive management strategies for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), these patients still suffer substantial morbidity and mortality.The objective of this study was to analyze independent predictors of 1-year mortality in patients with high-risk NSTE ACS.A total of 9,978 patients were assigned to receive enoxaparin or unfractionated heparin (UFH) in this prospective, randomized, open-label, international trial.Vital status at 1 year was collected. Univariable and multivariable predictors of 1-year mortality were identified. Three different multivariable regression models were constructed to identify: (1) predictors of 30-day mortality; (2) predictors of 1-year mortality; (3) predictors of 1-year mortality in 30-day survivors. The last model is the focus of this paper.Overall, 9,922 (99.4%) of patients had 1-year follow-up. Of the 56 patients (37 UFH-assigned and 19 enoxaparin-assigned) without 1-year data, 11 patients were excluded because of withdrawal of consent, and 45 could not be located. One-year mortality was 7.5% (7.7% enoxaparin-assigned patients; 7.3% UFH-assigned patients; P = 0.4). In patients surviving 30 days after enrollment, independent predictors of 1-year mortality included factors known at baseline such as increased age, male sex, decreased weight, having ever smoked, decreased creatinine clearance, ST-segment depression, history of diabetes, history of angina, congestive heart failure, coronary artery bypass grafting, increased heart rate, rales, increased hematocrit, lowered hemoglobin, and higher platelet count. Factors predictive of mortality during the hospitalization and 30-day follow-up period were decreased weight at 30 days from baseline, atrial fibrillation, decreased nadir platelet, no use of beta-blockers and statins up to 30 days, and not receiving an intervention (c-index = 0.82).Easily determined baseline clinical characteristics can be used to predict 1-year mortality with reasonable discriminative power. These models corroborate prior work in a contemporary aggressively managed population. A model to predict 1-year mortality in patients surviving at least 30 days may be quite helpful to healthcare providers in setting expectations and goals with patients after ACS.

    View details for DOI 10.1007/s11606-007-0498-4

    View details for Web of Science ID 000253214000015

    View details for PubMedID 18196350

  • Patients with non-ST-elevation acute coronary syndromes undergoing coronary artery bypass grafting in the modern era of antithrombotic therapy AMERICAN HEART JOURNAL Chew, D. P., Huang, Z., Pieper, K. S., White, H., Mahaffey, K. W., Ferguson, J. J., Califf, R. M., Aylward, P. G. 2008; 155 (2): 239-244

    Abstract

    Many high-risk patients with non-ST-elevation acute coronary syndromes within the SYNERGY trial required coronary artery bypass grafting (CABG) for optimal revascularization. We explored the clinical outcomes among high-risk patients undergoing CABG and the impact of modern pharmacology.We evaluated 180-day rates of death and myocardial infarction (MI) and 30-day GUSTO severe bleeding among patients undergoing CABG, contrasting them with patients undergoing percutaneous coronary intervention (PCI) or medical management. The relationships between perioperative MI, bleeding events, and 6-month mortality were explored. The effect of random assignment to unfractionated heparin or enoxaparin and the relationships between use of clopidogrel and glycoprotein IIb/IIIa inhibitors and clinical outcomes were assessed.Death or MI at 6 months was more common among patients requiring CABG (CABG 31.2%, PCI 15.9%, medical 9.9%). Thirty-day GUSTO severe bleeding was also higher (CABG 6.4%, PCI 1.1%, medical 0.9%). Perioperative MI and GUSTO severe bleeding were associated with excess 6-month mortality (hazard ratio 2.1, 95% CI 1.27-3.53 and hazard ratio 7.6, CI 4.78-12.09, respectively). Randomization to enoxaparin was not associated with an increase in bleeding or a reduction in death or MI. No differences in ischemic outcomes were observed among patients given glycoprotein IIb/IIIa inhibition or clopidogrel.High-risk patients still commonly require CABG with greater bleeding and ischemic event rates observed. Current definitions of perioperative MI and GUSTO severe bleeding portend an increased in 6-month mortality among CABG patients. Modern pharmacotherapies do not appear to impact these higher event rates.

    View details for DOI 10.1016/j.ahj.2007.10.002

    View details for Web of Science ID 000252812800008

    View details for PubMedID 18215592

  • Time to coronary angiography and outcomes among patients with high-risk non-ST-segment-elevation acute coronary syndromes: Results from the SYNERGY trial CIRCULATION Tricoci, P., Lokhnygina, Y., Berdan, L. G., Steinhubl, S. R., Gulba, D. C., White, H. D., Kleiman, N. S., Aylward, P. E., Langer, A., Califf, R. M., Ferguson, J. J., Antman, E. M., Newby, L. K., Harrington, R. A., Goodman, S. G., Mahaffey, K. W. 2007; 116 (23): 2669-2677

    Abstract

    Optimal timing for an early invasive strategy in patients with non-ST-segment-elevation acute coronary syndrome remains unclear. We evaluated the relationship between time from hospital admission to coronary angiography and outcomes in high-risk patients with non-ST-segment-elevation acute coronary syndrome who underwent angiography within 48 hours of admission.Data from 10 027 patients enrolled in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial were analyzed. Patients were grouped by 6-hour intervals of time from hospital admission to coronary angiography. Primary outcomes were 30-day death or myocardial infarction, in-hospital Thrombolysis In Myocardial Infarction (TIMI) and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) major bleeding, and blood transfusion. Adjusted estimates of event rates were obtained by use of a multivariable methodology that included possible confounders through baseline and accounted for propensity of time to angiography. The landmark method was used to calculate odds ratios and 95% confidence intervals of outcomes for each time period adjusted for baseline and postbaseline clinical events. Overall, 9216 patients (92%) underwent angiography, 6352 (63%) within 48 hours. Unadjusted and adjusted rates of death/myocardial infarction increased with increasing time to angiography. The adjusted odds ratio for death/myocardial infarction in patients receiving angiography in <6 hours was 0.56 (95% confidence interval 0.41 to 0.74), whereas after 30 hours, there was no significant benefit compared with further delayed angiography. Major bleeding and transfusion did not vary significantly across time-to-angiography intervals.A decrease in the time to coronary angiography was associated with fewer ischemic outcomes and no increase in bleeding. Randomized clinical trials are needed to provide definitive evidence on optimal timing of coronary angiography but are difficult to design and conduct. Ongoing trials should instead clarify whether delaying angiography to administer aggressive upstream antithrombotic therapies is effective in the current setting of non-ST-segment-elevation acute coronary syndrome management.

    View details for DOI 10.1161/CIRCULATIONAHA.107.690081

    View details for Web of Science ID 000251361400005

    View details for PubMedID 18025532

  • Evaluation of cinacalcet therapy to lower cardiovascular events (EVOLVE): Rationale and design overview CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chertow, G. M., Pupim, L. B., Block, G. A., Correa-Rotter, R., Drueke, T. B., Floege, J., Goodman, W. G., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Albizem, M., Olson, K., Klassen, P., Parfrey, P. 2007; 2 (5): 898-905

    Abstract

    The dramatically high rates of mortality and cardiovascular morbidity observed among dialysis patients highlights the importance of identifying and implementing strategies to lower cardiovascular risk in this population. Results from clinical trials undertaken thus far, including trials on lipid reduction, normalization of hematocrit, and increased dialysis dosage, have been unsuccessful. Available data indicate that abnormalities in calcium and phosphorus metabolism, as a result of either secondary hyperparathyroidism alone or the therapeutic measures used to manage secondary hyperparathyroidism, are associated with an increased risk for death and cardiovascular events. However, no prospective trials have evaluated whether interventions that modify these laboratory parameters result in a reduction in adverse cardiovascular outcomes.Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events is a global, phase 3, double-blind, randomized, placebo-controlled trial evaluating the effects of cinacalcet on mortality and cardiovascular events in hemodialysis patients with secondary hyperparathyroidism. Approximately 3800 patients from 22 countries will be randomly assigned to cinacalcet or placebo. Flexible use of traditional therapies will be permitted. The primary end point is the composite of time to all-cause mortality or first nonfatal cardiovascular event (myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular disease, including lower extremity revascularization and nontraumatic amputation).The study will be event driven (terminated at 1882 events) with an anticipated duration of approximately 4 yr.Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events will determine whether management of secondary hyperparathyroidism with cinacalcet reduces the risk for mortality and cardiovascular events in hemodialysis patients.

    View details for DOI 10.2215/CJN.04381206

    View details for Web of Science ID 000249039500007

    View details for PubMedID 17702710

  • Baseline glucose and left ventricular remodeling after acute myocardial infarction JOURNAL OF DIABETES AND ITS COMPLICATIONS Nicolau, J. C., Maia, L. N., Vitola, J. V., Mahaffey, K. W., Machado, M. N., Ramires, J. A. 2007; 21 (5): 294-299

    Abstract

    In patients with acute myocardial infarction (AMI), the mechanisms behind the increased mortality related to glucose levels (GL) are poorly understood. The main purpose of this study is to analyze the relationship between baseline glucose and left ventricular enlargement (LVE). We analyzed 52 patients with a first ST-elevation AMI <24 h of evolution. Glucose levels were obtained upon admission (median time, 3 h after the beginning of chest pain). The median GL was 123.5 mg/dl, and patients above this limit were considered hyperglycemic (n=26). Left ventricular enlargement was analyzed comparing two radionuclide ventriculographies, the first obtained within 4 days post-AMI (median, 55 h) and the second 6 months later (median, 188.5 days), taking into account the difference in the obtained end-systolic volumes. Myocardial reperfusion was evaluated comparing ST resolution between a first ECG done immediately upon hospital arrival with a second ECG performed 2 h after treatment. By univariate analysis, LVE correlated significantly with baseline hyperglycemia (P<.001), failed reperfusion by ECG criteria (P<.001), and no use of ACE inhibitors or AT1 blockers (P=.046) and aspirin (P=.046). A history of previous diabetes did not correlate significantly with LVE at 6 months. In the adjusted model, basal hyperglycemia (P<.001) and failed reperfusion (P=.001) were the only variables independently correlated with LVE. In conclusion, baseline glucose is a powerful and independent predictor of LVE after AMI, which reinforces the importance of a tight glucose control during the initial phase of the disease.

    View details for DOI 10.1016/j.jdiacomp.2006.01.003

    View details for Web of Science ID 000249622500004

    View details for PubMedID 17825753

  • Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis EUROPEAN HEART JOURNAL Murphy, S. A., Gibson, C. M., Morrow, D. A., de Werf, F. V., Menown, I. B., Goodman, S. G., Mahaffey, K. W., Cohen, M., McCabe, C. H., Antman, E. M., Braunwald, E. 2007; 28 (17): 2077-2086

    Abstract

    To determine whether the low-molecular weight heparin enoxaparin remains favourable when compared with unfractionated heparin (UFH) among patients with acute coronary syndromes (ACS) when incorporating efficacy and safety of these adjunctive therapies using a net clinical endpoint.We performed a meta-analysis of randomized trials of enoxaparin vs. UFH in ST-elevation-MI (STEMI) or non-ST-elevation-ACS (NSTEACS) (n = 49,088 patients in 12 trials). The net clinical endpoint was defined as death, MI, or major bleeding by 30 days. Death or myocardial infarction (MI) was significantly reduced with enoxaparin when compared with UFH (9.8 vs. 11.4%, OR 0.84, P < 0.001). The net clinical endpoint occurred less frequently with enoxaparin than UFH (12.5 vs. 13.5%, OR 0.90, P = 0.051). Major bleeding was higher with enoxaparin (4.3 vs. 3.4%, OR 1.25, P = 0.019). Among STEMI trials, the net clinical endpoint was significantly lower with enoxaparin (OR 0.84, P = 0.015), but there was no difference in NSTEACS trials (OR 0.97).When compared with UFH, enoxaparin was associated with superior efficacy as adjunctive antithrombin therapy among >49 000 patients across the ACS spectrum. Although bleeding was increased with enoxaparin, this increase was offset by a reduction in death or MI. The net clinical benefit in favour of enoxaparin was evident among the STEMI population and was neutral among the NSTEACS population.

    View details for DOI 10.1093/eurheartj/ehm224

    View details for Web of Science ID 000249763800009

    View details for PubMedID 17600038

  • Treatment and outcomes of patients with evolving myocardial infarction: experiences from the SYNERGY trial EUROPEAN HEART JOURNAL Miller, C. D., Banerjee, A., Mahaffey, K. W., Kontos, M. C., Fermann, G., Pollack, C. V., Antman, E., Aylward, P., Goodman, S. G., Santos, R., Ferguson, J. J., Califf, R. M., Hoekstra, J. W. 2007; 28 (9): 1079-1084

    Abstract

    Patients with myocardial infarction (MI) presenting immediately after symptom onset may be treated less aggressively due to their non-elevated troponin status. We compared the initial treatment and clinical outcomes of patients presenting with evolving MI (EMI) with those presenting with MI.This study analysed data from the Superior Yield of the New strategy of Enoxaparin, Revascularisation, and Glycoprotein IIb/IIIa inhibitors (SYNERGY) trial, which enrolled patients meeting at least two of the following: age >or= 60 years, elevated cardiac biomarkers, or ST-segment changes. Patients were stratified by troponin results obtained within 12 h of presentation: EMI [initial troponin (-), second troponin (+)], MI [initial troponin (+)], and no MI at enrolment [first and second troponin (-)]. Comparisons were made using Wilcoxon rank-sum and chi(2) tests. Of the 8,309 patients with complete data, 5,503 (66%) had MI, 1,686 (20%) had EMI, and 1,120 (13%) had no MI. Treatment patterns prior to enrolment were similar among EMI and MI patients [aspirin (88 vs. 86%), beta-blockers (62 vs. 61%), heparin (83 vs. 81%), and glycoprotein IIb/IIIa inhibitors (23 vs. 24%)]. Similar rates of percutaneous coronary intervention (48 vs. 50%) and coronary artery bypass grafting (21 vs. 22%) were seen after enrolment. Patients presenting with MI had a higher rate of death or recurrent MI compared with patients with EMI [16 vs. 13%, adjusted OR 1.22 (95% CI 1.04, 1.44)].Initial treatment patterns were similar among patients with EMI and MI in the SYNERGY trial. Patients with EMI had lower rates of death or re-infarction at 30 days compared with patients presenting with positive troponin results.

    View details for DOI 10.1093/eurheartj/ehm016

    View details for Web of Science ID 000247071200013

    View details for PubMedID 17405770

  • Publication or presentation of results from multicenter clinical trials: Evidence from an academic medical center AMERICAN HEART JOURNAL Turer, A. T., Mahaffey, K. W., Compton, K. L., Califf, R. M., Schulman, K. A. 2007; 153 (4): 674-680

    Abstract

    Nonpublication of research results threatens the integrity of clinical research, but the extent of nonpublication and factors associated with publication remain poorly documented. We sought to examine rates of publication or presentation of research findings from multicenter clinical trials and determine what factors are associated with dissemination of results.We conducted a follow-up study of 217 prospective, multicenter clinical trials of treatment approved in 1998 by the institutional review board of a large academic medical center, of which 197 had enrolled participants and were not known to be ongoing. Follow-up included searches of the literature and the Internet and telephone and e-mail inquiries to investigators and research sponsors. The main outcome measures were manuscript publication or other presentation of research results.Results of 110 (56%) out of 197 multicenter clinical trials have been published in the peer-reviewed literature. Results of 87 (44%) studies have not been published, and results of 52 (26%) studies have not been disseminated in any form. The rate of dissemination of trial results was highest for studies that were phase 3 (81%), lowest risk (86%), and investigational (76%). The dissemination rate was lowest for studies that were supported by internal funds (50%). However, none of these associations were statistically significant.Results of almost half of the multicenter clinical trials conducted in part at a large academic medical center have never been published. Mechanisms to ensure public dissemination of clinical trial results are needed.

    View details for DOI 10.1016/j.ahj.2007.01.005

    View details for Web of Science ID 000245784200035

    View details for PubMedID 17383311

  • Creatine kinase-MB elevation after coronary artery bypass grafting surgery in patients with non-ST-segment elevation acute coronary syndromes predict worse outcomes: results from four large clinical trials EUROPEAN HEART JOURNAL Mahaffey, K. W., Roe, M. T., Kilaru, R., Alexander, J. H., Van de Werf, F., Califf, R. M., Simoons, M. L., Topol, E. J., Harrington, R. A. 2007; 28 (4): 425-432

    Abstract

    To assess the significance of creatine kinase (CK)-MB elevations in outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) who have undergone coronary artery bypass grafting (CABG) surgery.This analysis includes data from 26 465 patients with NSTE ACS enrolled in four major trials. In total, 4626 (17.5%) of patients had CABG within 30 days. Patients were excluded if CK-MB was elevated within 24 h before surgery and there was no CK-MB measured after surgery. Overall, 4401 patients were included in these analyses. The incidence of mortality increased with peak CK-MB ratios of 0-1, >1-3, >3-5, >5-10, and>10x the upper limit of normal measured at the local lab (P<0.001 across categories): 1.1, 2.8, 2.4, 3.1, and 10.8% in hospital; 1.1, 3.0, 2.9, 3.5, and 10.2% at 30 days; and 1.6, 4.4, 4.7, 6.0, and 10.9% at 180 days. Multivariable predictors of 6-month mortality included age, heart rate and randomization, peak CK-MB ratio, time to CABG, prior angina, signs of congestive heart failure and randomization, three- and two-vessel coronary disease, enrolment infarction, ST-segment depression at enrolment, female sex, experimental treatment, and systolic blood pressure.CK-MB elevations after CABG are independently associated with increased risk of mortality in patients with NSTE ACS.

    View details for DOI 10.1093/eurheartj/ehl483

    View details for Web of Science ID 000245177000010

    View details for PubMedID 17267458

  • Methylmercury exposure and health effects in humans: A worldwide concern AMBIO Mergler, D., Anderson, H. A., Chan, L. H., Mahaffey, K. R., Murray, M., Sakamoto, M., Stern, A. H. 2007; 36 (1): 3-11

    Abstract

    The paper builds on existing literature, highlighting current understanding and identifying unresolved issues about MeHg exposure, health effects, and risk assessment, and concludes with a consensus statement. Methylmercury is a potent toxin, bioaccumulated and concentrated through the aquatic food chain, placing at risk people, throughout the globe and across the socioeconomic spectrum, who consume predatory fish or for whom fish is a dietary mainstay. Methylmercury developmental neurotoxicity has constituted the basis for risk assessments and public health policies. Despite gaps in our knowledge on new bioindicators of exposure, factors that influence MeHg uptake and toxicity, toxicokinetics, neurologic and cardiovascular effects in adult populations, and the nutritional benefits and risks from the large number of marine and freshwater fish and fish-eating species, the panel concluded that to preserve human health, all efforts need to be made to reduce and eliminate sources of exposure.

    View details for Web of Science ID 000244817800003

    View details for PubMedID 17408186

  • Racial differences among high-risk patients presenting with non-ST-segment elevation acute coronary syndromes (results from the SYNERGY trial) AMERICAN JOURNAL OF CARDIOLOGY Echols, M. R., Mahaffey, K. W., Banerjee, A., Pieper, K. S., Stebbins, A., Lansky, A., Cohen, M. G., Velazquez, E., Santos, R., Newby, L. K., Gurfinkel, E. P., Biasucci, L., Ferguson, J. J., Califf, R. M. 2007; 99 (3): 315-321

    Abstract

    Management and outcomes of patients with acute coronary syndromes (ACSs) may vary according to patient race and ethnicity. To assess racial differences in presentation and outcome in high-risk North American patients with non-ST-segment elevation (NSTE) ACS, we analyzed baseline racial/ethnic differences and all-cause death or nonfatal myocardial infarction (MI) in 6,077 white, 586 African-American, and 344 Hispanic patients through 30-day, 6-month, and 1-year follow-up. Frequencies of hypertension were 66% for whites, 83% for African-Americans, and 78% for Hispanics (overall p <0.001). Use of angiography was similar across groups. Use of percutaneous coronary intervention (46% for whites, 41% for African-Americans, and 45% for Hispanics, overall p = 0.046) and coronary artery bypass grafting (20% for whites, 16% for African-Americans, and 22% for Hispanics, overall p = 0.044) differed. African-American patients had significantly fewer diseased vessels compared with white patients (p = 0.0001). Thirty-day death or MI was 14% for whites, 10% for African-Americans, and 14% for Hispanics (overall p = 0.034). After adjustment for baseline variables, African-American patients had lower 30-day death or MI compared with white patients (odds ratio 0.73, 95% confidence interval 0.55 to 0.98). There were no differences in 6-month death or MI across racial/ethnic groups. In conclusion, baseline clinical characteristics differed across North American racial/ethnic groups in the SYNERGY trial. African-American patients had significantly better adjusted 30-day outcomes but similar 6-month outcomes compared with white patients.

    View details for DOI 10.1016/j.amjcard.2006.08.031

    View details for Web of Science ID 000243947900005

    View details for PubMedID 17261389

  • Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Cantor, W. J., Mahaffey, K. W., Huang, Z., Das, P., Gulba, D. C., Glezer, S., Gallo, R., Ducas, J., Cohen, M., Antman, E. M., Langer, A., Kleiman, N. S., White, H. D., Chisholm, R. J., Harrington, R. A., Ferguson, J. J., Califf, R. M., Goodman, S. G. 2007; 69 (1): 73-83

    Abstract

    Our objective was to analyze the impact of arterial access site, sheath size, timing of sheath removal, and use of access site closure devices on high-risk patients with acute coronary syndromes (ACS).In the SYNERGY trial, 9,978 patients with ACS were randomly assigned to receive enoxaparin or unfractionated heparin.This analysis includes 9,404 patients for whom sheath access information was obtained for the first PCI procedure or diagnostic catheterization. Comparisons of baseline, angiographic, and procedural characteristics were carried out according to access site and sheath size.Overall, 9,404 (94%) patients underwent angiography at a median of 21 hr (25th and 75th percentiles: 5, 42) and 4,687 (50%) underwent PCI at a median of 23 hr (6,49) of enrollment. The access site was femoral for 94.9% of cases, radial for 4.4%, and brachial for 0.7%. Radial access was associated with fewer transfusions than femoral access (0.9% vs. 4.8%, P=0.007). For femoral access, the rates of noncoronary artery bypass grafting (CABG)-related TIMI major bleeding by sheath size was 1.5% for 4 or 5 French (Fr), 1.6% for 6 Fr, 3.3% for 7 Fr, and 3.8% for >or=8 Fr (P<0.0001). After adjustment for baseline characteristics, femoral access site, larger sheath size, and delayed sheath removal were independent predictors of need for transfusion.Smaller sheaths, radial access, and timely sheath removal may mitigate the bleeding risk associated with potent antithrombotic/platelet therapy and early catheterization.

    View details for DOI 10.1002/ccd.20897

    View details for Web of Science ID 000243330300015

    View details for PubMedID 17139670

  • A subgroup analysis of the impact of prerandomization antithrombin therapy on outcomes in the SYNERGY trial: Enoxaparin versus unfractionated heparin in non-ST-segment elevation acute coronary syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Cohen, M., Mahaffey, K. W., Pieper, K., Pollack, C. V., Antman, E. M., Hoekstra, J., Goodman, S. G., Langer, A., Col, J. J., White, H. D., Califf, R. M., Ferguson, J. J. 2006; 48 (7): 1346-1354

    Abstract

    The purpose of this study was to compare the effect of receiving pretreatment with antithrombin before randomization as well as overall efficacy and safety of enoxaparin versus unfractionated heparin (UFH) in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trial.The SYNERGY trial results demonstrated noninferiority in outcomes with enoxaparin compared with UFH. Randomized treatment was independent of prerandomization treatment.Analyses were first performed on the 4 prerandomization subgroups: patients who received no antithrombin therapy and those who were treated with enoxaparin or UFH or both. Then, we focused on the subgroup of patients who received no pretreatment or were pretreated with and randomized to the same drug. Of the 9,978 patients, 2,440 did not receive prerandomization therapy and 6,138 received consistent therapy through randomization. The primary end point was the composite of death and nonfatal myocardial infarction (MI) at 30 days.After adjustment for differences among the subgroups, no significant difference in the association between the 4 pretreatment groups and death or MI remained (p = 0.171). The randomized treatment effect on 30-day death or MI tended to vary with pretreatment (p = 0.055 for interaction test after adjustment). Patients who received consistent therapy with enoxaparin had significantly less death or MI than patients randomized to UFH (adjusted p = 0.041) with a trend toward increased bleeding.Treatment with antithrombin therapy before randomization had potential impact on comparison of study drug effects. After adjustment for differences in baseline characteristics between subgroups, consistent therapy with enoxaparin might be superior to UFH in reducing death or nonfatal MI, with a modest excess in bleeding.

    View details for DOI 10.1016/j.jacc.2006.05.058

    View details for Web of Science ID 000240924400010

    View details for PubMedID 17010793

  • Effect of pexelizumab on mortality in patients with acute myocardial infarction or undergoing coronary artery bypass surgery: A systematic overview AMERICAN HEART JOURNAL Mahaffey, K. W., Van de Werf, F., Shernan, S. K., Granger, C. B., Verrier, E. D., Filloon, T. G., Todaro, T. G., Adams, P. X., Levy, J. H., Hasselblad, V., Armstrong, P. W. 2006; 152 (2): 291-296

    Abstract

    Recent trials evaluating the C5 complement inhibitor, pexelizumab, have shown that modulation of inflammation during ischemia/reperfusion in patients with acute myocardial infarction (MI) or undergoing coronary artery bypass graft (CABG) surgery may improve clinical outcomes.We performed a systematic overview of individual patient data from all completed randomized controlled trials of pexelizumab to evaluate the effect on all-cause mortality at 30 and 180 days after treatment. We used a random effects model and included all 5916 patients randomized in 4 clinical trials. Patients received placebo, pexelizumab bolus only or pexelizumab bolus followed by a 24-hour infusion.A significant reduction in mortality at 30 days was observed in patients treated with bolus plus infusion (n = 2476) compared with placebo (n = 2492) (2.9% vs 4.2%; relative risk [RR], 0.70; 95% confidence interval [CI], 0.52-0.95; P = .02), with no interaction according to disease state of CABG or acute MI (P for interaction .33). A trend toward a reduction in mortality was observed in patients who received bolus plus infusion or bolus only (n = 3429) compared with placebo (n = 2476) (3.5% vs 4.2%; RR, 0.85; 95% CI, 0.66-1.0975; P = .215), but not in patients who received bolus only (n = 937) compared with placebo (n = 937) (5.2% vs 5.4%; RR, 0.96; 95% CI, 0.66-1.41; P = .918). The mortality benefit with bolus plus infusion compared with placebo persisted through 180 days (P = .05).Pexelizumab reduced 30-day mortality in this systematic evaluation. Bolus plus infusion dose is being studied in ongoing trials in acute MI and CABG populations.

    View details for DOI 10.1016/j.ahj.2006.03.027

    View details for Web of Science ID 000239573000017

    View details for PubMedID 16875911

  • Prognosis of patients taking selective serotonin reuptake inhihitors before coronary artery bypass grafting AMERICAN JOURNAL OF CARDIOLOGY Xiong, G. L., Jiang, W., Clare, R., Shaw, L. K., Smith, P. K., Mahaffey, K. W., O'Connor, C. M., Krishnan, K. R., Newby, L. K. 2006; 98 (1): 42-47

    Abstract

    Depression is increasingly recognized as an independent prognostic risk factor in patients with coronary artery disease and coronary artery bypass grafting (CABG). The use of selective serotonin reuptake inhibitors (SSRIs) for depression in patients with cardiac disease is becoming more prevalent. We examined the long-term outcomes of patients on SSRIs before CABG. We prospectively examined collected data in the Duke Databank for Cardiovascular Disease from January 1, 1999 to December 31, 2003. The median and maximum follow-up periods were 3 and 6 years, respectively. We screened patients who underwent CABG (n = 5,364) and excluded those who underwent simultaneous CABG and valvular surgery (n = 570). SSRI antidepressants included fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, venlafaxine, and clomipramine, and their use was determined from the inpatient pharmacy records during the index hospitalization. Outcomes included event-free survival from all-cause mortality, rehospitalization, and a composite end point of all-cause mortality or rehospitalization. Of 4,794 CABG-only patients, 246 (5.1%) took SSRIs before CABG. The SSRI group had a higher prevalence of diabetes, hypercholesterolemia, hypertension, cerebrovascular disease, peripheral vascular disease, and previous cardiovascular intervention. After adjustment for baseline differences, patients on SSRIs before CABG had increased risks of mortality, rehospitalization, and the composite end point (hazard ratio 1.61, 95% confidence interval 1.17 to 2.21, p = 0.003; hazard ratio 1.52, 95% confidence interval 1.30 to 1.77, p <0.0001; and hazard ratio 1.46, 95% confidence interval 1.26 to 1.70, p <0.0001, respectively). In conclusion, SSRI use before CABG was associated with a higher risk of long-term post-CABG mortality and rehospitalization. The explanation behind these findings requires further research.

    View details for DOI 10.1016/j.amjcard.2006.01.051

    View details for Web of Science ID 000238896900010

    View details for PubMedID 16784918

  • Statin use and sex-specific stroke outcomes in patients with vascular disease STROKE Bushnell, C. D., Griffin, J., Newby, L. K., Goldstein, L. B., Mahaffey, K. W., Graffagnino, C. A., Harrington, R. A., White, H. D., Simes, R. J., Califf, R. M., Topol, E. J., Easton, J. D. 2006; 37 (6): 1427-1431

    Abstract

    Although statins reduce the risk of stroke in patients with coronary heart disease, possible differing effects of statins on stroke outcomes based on sex remain uncertain. We investigated the relationships between statin use and sex-specific stroke incidence, severity, and mortality.Data from 3 trials of oral glycoprotein IIb/IIIa inhibitors (first and second Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events postacute cOroNary sYndromes [SYMPHONY] and Blockade of the glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion [BRAVO]) were pooled and stroke outcomes compared among 8191 baseline statin users versus 14,752 nonusers. Time-to-event data were modeled with proportional hazards regression. Stroke severity was assessed retrospectively with the Canadian Neurological Scale (CNS) based on records with scoreable neurological examinations.A total of 217 subjects had strokes (0.95%). Statin users had a lower risk of stroke in unadjusted (hazard ratio [HR], 0.69; 95% CI, 0.51 to 0.92) and risk-adjusted models (HR, 0.72; 95% CI, 0.53 to 0.97). There was no difference in stroke mortality with statin use (P=0.8). CNS scores could be assigned to 106 of the subjects, with no difference in severity among statin users and nonusers (median CNS=10.5 in users versus CNS=9.75 in nonusers; P=0.14). Women had more severe strokes than men (median CNS=10.5 in men versus 9.5 in women; Poisson regression P=0.035). Women had more severe strokes after adjustment for statin use (P=0.03) and the combination of statin use, atrial fibrillation, and age (P=0.03).In patients included in these clinical trials of oral glycoprotein IIb/IIIa inhibitors, statin use is associated with a reduced risk of stroke but not severity or mortality. Women had more severe strokes than men, a difference that was not explained by baseline characteristics or statin use.

    View details for DOI 10.1161/01.STR.0000221315.60282.ca

    View details for Web of Science ID 000237925000027

    View details for PubMedID 16645137

  • Comparing classifications of death in the Mode Selection Trial: Agreement and disagreement among site investigators and a clinical events committee CONTEMPORARY CLINICAL TRIALS Petersen, J. L., Haque, G., Hellkarnp, A. S., Flaker, G. C., Estes, N. A., Marchlinski, F. E., McAnulty, J. H., Greenspon, A. J., Marinchak, R. A., Lee, K. L., Lamas, G. A., Mahaffey, K. W. 2006; 27 (3): 260-268

    Abstract

    Clinical events committees (CECs) are the current standard for endpoint adjudication in clinical trials. However, little data exist with which to compare CEC and site investigator determinations or to evaluate internal agreement among CEC members. Using data from the Mode Selection Trial in Sinus Node Dysfunction (MOST), we analyzed classifications of death in order to compare internal agreement among CEC physician reviewers and agreement between the CEC and site investigators. Death was classified at 2 levels: by major cause (cardiac, noncardiac, or unknown) and by minor subclassification of the major classifications. Reviewer agreement was tabulated at the major and minor levels, and standard and weighted kappa statistics were calculated. Disagreement at both levels was also determined. Individual decision-making was tabulated in terms of frequency in classifying death as unknown. All 404 deaths were classified by the CEC. Site investigators determined major classifications in 382 cases and minor classification in 379 cases. The CEC and the site investigators disagreed in classifying 41 cases (10.7%) at the major level and 117 (30.9%) at the minor level. CEC reviewers disagreed internally at the major level in 64 cases (15.8%), at the minor level in 63 cases (15.6%), and at any level in 127 cases (31.4%) (kappa = 0.60, 95% confidence interval (CI) [0.55, 0.66]; weighted kappa = 0.66, 95% CI [0.62, 0.75]). In resolving internal disagreements, the full CEC agreed with 1 of 2 CEC reviewers in 85.9% of cases. Disagreements occurred between site investigators and CEC reviewers in classifying deaths. Endpoint determination and decision-making varied among individual CEC reviewers, but second-tier reviews by the full CEC resolved all disagreements. These findings support continued use of CECs for endpoint adjudication in clinical trials.

    View details for DOI 10.1016/j.cct.2006.02.002

    View details for Web of Science ID 000237791900006

    View details for PubMedID 16574497

  • Prognostic significance of the change in glucose level in the first 24 h after acute myocardial infarction: results from the CARDINAL study EUROPEAN HEART JOURNAL Goyal, A., Mahaffey, K. W., Garg, J., Nicolau, J. C., Hochman, J. S., Weaver, W. D., Theroux, P., Oliveira, G. B., Todaro, T. G., Mojcik, C. F., Armstrong, P. W., Granger, C. B. 2006; 27 (11): 1289-1297

    Abstract

    In acute myocardial infarction (AMI), baseline hyperglycaemia predicts adverse outcomes, but the relation between subsequent change in glucose levels and outcomes is unclear. We evaluated the prognostic significance of baseline glucose and the change in glucose in the first 24 h following AMI.We analysed 1469 AMI patients with baseline and 24 h glucose data from the CARDINAL trial database. Baseline glucose and the 24 h change in glucose (24 h glucose level subtracted from baseline glucose) were included in multivariable models for 30- and 180-day mortality. By 30 and 180 days, respectively, 45 and 74 patients had died. In the multivariable 30-day mortality model, neither baseline glucose nor the 24 h change in glucose predicted mortality in diabetic patients (n=250). However, in nondiabetic patients (n=1219), higher baseline glucose predicted higher mortality [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04-1.20, per 0.6 mmol/L increase], and a greater 24 h change in glucose predicted lower mortality (HR 0.91, 95% CI 0.86-0.96, for every 0.6 mmol/L drop in glucose in the first 24 h) at 30 days. Baseline glucose and the 24 h change in glucose remained significant multivariable mortality predictors at 180 days in nondiabetic patients.Both higher baseline glucose and the failure of glucose levels to decrease in the first 24 h after AMI predict higher mortality in nondiabetic patients.

    View details for DOI 10.1093/eurheartj/ehi884

    View details for Web of Science ID 000238679300009

    View details for PubMedID 16611669

  • Low-molecular-weight heparin compared with unfractionated heparin for patients with non-ST-segment elevation acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors: Results from the CRUSADE initiative JOURNAL OF THROMBOSIS AND THROMBOLYSIS Singh, K. P., Roe, M. T., Peterson, E. D., Chen, A. Y., Mahaffey, K. W., Goodman, S. G., Harrington, R. A., Smith, S. C., Gibler, W. B., Ohman, E. M., Pollack, C. V. 2006; 21 (3): 211-220

    Abstract

    Both heparin and glycoprotein (GP) IIb/IIIa inhibitor therapy and early invasive management strategies are recommended by the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the treatment of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). However, controversy exists about which form of heparin-unfractionated (UF) or low-molecular-weight (LMW)-is preferable. We sought to compare the efficacy and safety of these treatment strategies in a large contemporary population of patients with NSTE ACS.Using data from the CRUSADE Initiative, we evaluated LMWH and UFH in high-risk NSTE ACS patients (positive cardiac markers and/or ischemic ST-segment changes) who had received early (< 24 hours) GP IIb/IIIa inhibitor therapy and underwent early invasive management. In-hospital outcomes were compared among treatment groups.From a total of 11,358 patients treated at 407 hospitals in the US from January 2002-June 2003, 6881 (60.6%) received UFH and 4477 (39.4%) received LMWH. Patients treated with UFH were more often admitted to a cardiology inpatient service (73.6% vs. 65.5%, P < 0.0001) and more frequently underwent diagnostic catheterization (91.8% vs. 85.9%, P < 0.0001) and percutaneous coronary intervention (PCI) (69.7% vs. 56.9%, P < 0.0001) than patients treated with LMWH. The point estimate of the adjusted risk of in-hospital death or reinfarction was slightly lower among patients treated with LMWH (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.67-0.99) and the risk of red blood cell transfusion was similar (OR 1.01, 95% CI 0.89-1.15). Among patients who underwent PCI within 48 hours, adjusted rates of death (OR 1.14, 95% CI 0.71-1.85), death or reinfarction (OR 0.93, 0.67-1.31), and transfusion (OR 1.16, 0.89-1.50) were similar. Patients who underwent PCI more than 48 hours into hospitalization had reduced rates of death (OR 0.64, 0.46-0.88), death or reinfarction (OR 0.57, 0.44-0.73), and transfusion (OR 0.66, 0.52-0.84).In routine clinical practice, patients treated with GP IIb/IIIa inhibitors have slightly improved outcomes and similar bleeding risks with LMWH than with UFH. These findings are consistent with current ACC/AHA guidelines but raise important questions about the safety and effectiveness of antithrombotic therapy in real-world clinical practice. Using data from the CRUSADE Initiative, we evaluated low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) in high-risk patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) who received early (<24 hours) glycoprotein (GP) IIb/IIIa inhibitors and early invasive management. In-hospital outcomes were compared among treatment groups. LMWH was associated with slightly improved clinical outcomes and similar rates of transfusion compared with UFH. Our results support the current ACC/AHA guidelines recommendations but raise concerns about the safety and efficacy of UFH in the setting of background use of upstream GP IIb/IIIa inhibitors for patients with NSTE ACS in routine clinical practice.

    View details for DOI 10.1007/s11239-006-5708-0

    View details for Web of Science ID 000237437200001

    View details for PubMedID 16683212

  • Concerning the mechanism of pexelizumab's benefit in acute myocardial infarction AMERICAN HEART JOURNAL Armstrong, P. W., Mahaffey, K. W., Chang, W. C., Weaver, W. D., Hochman, J. S., Theroux, P., Rollins, S., Todaro, T. G., Granger, C. B. 2006; 151 (4): 787-790

    Abstract

    The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial previously demonstrated an unexpected dose-dependent reduction in 90-day mortality after bolus/infusion of pexelizumab despite no reduction in the primary end point of myocardial infarction (MI) size. We examined whether the mortality benefit was related to established modulators of clinical benefit such as baseline demographics, time to treatment from symptom onset, myocardial perfusion post-percutaneous coronary intervention (PCI), and extent of ST resolution.Eight hundred fourteen patients were randomized into 3 groups; (1) placebo, (2) pexelizumab bolus 2.0 mg/kg and placebo infusion for 20 hours, and (3) pexelizumab bolus 2.0 and 0.05 mg/kg per hour infusion for 20 hours commencing 4 hours after the bolus. Subjects presented with ST elevation MI within 6 hours of symptom onset and underwent PCI, creatine kinase (CK), and CK-MB measurements taken sequentially to define CK-MB area under the curve (AUC) and sequential ECG's defined ST resolution and QRS infarct size. Whereas mortality for both placebo and bolus pexelizumab groups rose during later time after presentation, it remained low and did not change appreciably during the 6-hour randomization window when patients received pexelizumab bolus infusion. Amplification of the mortality benefit was evident in patients with the highest quartile of hemodynamic compromise, that is, heart rate > or = 90 beat/min and systolic blood pressure < or = 118 mm Hg (3.2% vs 11.3% P = .004). A significant interaction between treatment assignment and hemodynamic status (P = .013) existed after adjusting for age, race, and MI location. Clinical benefit was not related to infarct size, extent of ST elevation, or evidence of angiographic or electrocardiographic reperfusion.These data raise the possibility that the clinical benefit of pexelizumab is mediated through novel pathways such as reduction in apoptosis or other mechanisms.

    View details for DOI 10.1016/j.ahj.2005.06.008

    View details for Web of Science ID 000236721000008

    View details for PubMedID 16569534

  • N-terminal pro-brain natriuretic peptide and the timing, extent and mortality in ST elevation myocardial infarction CANADIAN JOURNAL OF CARDIOLOGY Ezekowitz, J. A., Theroux, P., Chang, W. C., Mahaffey, K. W., Granger, C. B., Weaver, W. D., Hochman, J. S., Armstrong, P. W. 2006; 22 (5): 393-397

    Abstract

    While natriuretic peptides have demonstrated diagnostic and prognostic potential in cardiac disorders, little is known about their relationship with the onset and quantification of myocardial infarction. The relationship of serial N-terminal pro-brain natriuretic peptide (NT-proBNP) with duration from symptom onset, infarct size and prognosis in ST elevation myocardial infarction (STEMI) patients treated with primary percutaneous intervention was examined.Three hundred thirty-one STEMI patients in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial, which evaluated pexelizumab versus placebo, were studied. NT-proBNP (pg/mL) was measured at randomization, 24 h and 72 h; creatine kinase-MB area under the curve was measured at 72 h; and QRS score was assessed at discharge. Prognosis was ascertained from the 90-day composite clinical outcome of death, shock, stroke and congestive heart failure. Multivariate logistical regression was used to adjust for baseline characteristics for models at randomization, 24 h and 72 h. NT-proBNP was higher in patients with longer time from symptom onset (P<0.001) and correlated with measures of infarct size, including the area under the curve (P<0.001) and QRS score (P<0.001). Patients reaching the primary end point had markedly higher NT-proBNP at each sampling period (P<0.001). NT-proBNP at all time points was the strongest independent predictor of the primary end point in the multivariate model: in the 24 h model, only age and 24 h NT-proBNP (C-index 0.83); and only age, Killip class and NT-proBNP was in the 72 h model (C-index 0.85).Higher NT-proBNP at 24 h correlated with larger infarct size and worse clinical outcomes. NT-proBNP at baseline, 24 h and 72 h after presentation with acute STEMI, is an independent predictor of a poor outcome and adds clinically useful prognostic information.

    View details for Web of Science ID 000236992200004

    View details for PubMedID 16639474

  • A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rao, S. V., O'Grady, K., Pieper, K. S., Granger, C. B., Newby, L. K., Mahaffey, K. W., Moliterno, D. J., Lincof, A. M., Armstrong, P. W., Van de Werf, F., Califf, R. M., Harrington, R. A. 2006; 47 (4): 809-816

    Abstract

    The goal of this study was to determine the association between Thrombolysis In Myocardial Infarction (TIMI) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding and clinical outcomes.There are limited data on the relative utility of either scale at predicting clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes (ACS).Pooled data from two randomized trials of patients with ACS (n = 15,454) were analyzed to determine the association between TIMI and GUSTO bleeding and 30-day and 6-month death/myocardial infarction (MI) using Cox proportional hazards modeling that included bleeding as a time-dependent covariate.There was a stepwise increase in the adjusted hazard of 30-day death/MI with worsening GUSTO bleeding (hazard ratio [95% confidence interval], GUSTO mild 1.20 [1.05 to 1.37]; moderate 3.28 [2.88 to 3.73]; severe 5.57 [4.33 to 7.17]), and an increased risk with all three levels of TIMI bleeding (TIMI minimal 1.84 [1.63 to 2.08]; TIMI minor 1.64 [1.31 to 2.04]; major 1.45 [1.23 to 1.70]). When both bleeding scales were included in the same model, the risk with GUSTO bleeding persisted; however, the association between TIMI bleeding and outcome was no longer significant.Both scales identify ACS patients with bleeding complications at risk for adverse outcomes. In a model that included both definitions, the risk with GUSTO bleeding persisted while the risk with TIMI bleeding did not. This suggests that bleeding assessed with clinical criteria is more important than that assessed by laboratory criteria in terms of outcomes. Future clinical trials should consider using a combination of the GUSTO bleeding scale and the need for transfusion to assess bleeding complications.

    View details for DOI 10.1016/j.jacc.2005.09.060

    View details for Web of Science ID 000235422900021

    View details for PubMedID 16487850

  • Forecasting mortality: dynamic assessment of risk in ST-segment elevation acute myocardial infarction EUROPEAN HEART JOURNAL Chang, W. C., Kaul, P., Fu, Y. L., Westerhout, C. M., Granger, C. B., Mahaffey, K. W., Wallentin, L., Van de Werf, F., Armstrong, P. W. 2006; 27 (4): 419-426

    Abstract

    To demonstrate the feasibility and clinical utility of developing dynamic risk assessment models for ST-segment elevation myocardial infarction (STEMI) patients.In 6066 STEMI patients enrolled in the Assessment of the Safety and Efficacy of a New Thrombolytic-3 (ASSENT-3) trial with complete electrocardiographic data, we assessed the probability of 30-day mortality over the following forecasting periods beginning at day 0 (baseline), 3 h, day 2, and day 5 using multiple-logistic regression. These models were validated and simplified in independent samples of 1622 similar fibrinolytic-treated patients from the ASSENT-3 PLUS trial and in 814 STEMI patients undergoing primary percutaneous coronary intervention in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial. The discriminatory power of these predictive models, from baseline to day 5, was excellent (c-statistics 0.80 to 0.87); and their predictive ability was supported by strong gradients in mortality outcomes as the risk score increased. Dynamic modelling also provided information on the change in prognosis over time which may be used to advise more appropriate therapeutic decisions, e.g. the identification of high-risk patients for possible co-interventions.Dynamic modelling for STEMI patients enhances the risk assessment and stratification and should provide valuable ongoing guidance for their management.

    View details for DOI 10.1093/eurheartj/ehi700

    View details for Web of Science ID 000235278100010

    View details for PubMedID 16407373

  • Elevated creatine kinase-MB with normal creatine kinase predicts worse outcomes in patients with acute coronary syndromes: Results from 4 large clinical trials AMERICAN HEART JOURNAL Galla, J. M., Mahaffey, K. W., Sapp, S. K., Alexander, J. H., Roe, M. T., Ohman, E. M., Granger, C. B., Armstrong, P. W., Harrington, R. A., White, H. D., Simoons, M. L., Newby, L. K., Califf, R. M., Topol, E. J. 2006; 151 (1): 16-24

    Abstract

    The degree to which elevated creatine kinase (CK)-MB in the presence of normal CK is predictive of outcome is not well understood despite having been studied for decades. This analysis examined whether normal CK with elevated CK-MB in patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) is an independent predictor of worse outcomes. A concomitant goal was to contribute insight to the debate over how patients with NSTE ACS should be managed.Data for 25,960 patients from the GUSTO IIb, PARAGON A and B, and PURSUIT trials were analyzed. Of these patients, 6402 were excluded from primary analysis because of missing (unmeasured) biomarkers. Patients with complete laboratory data (n = 19,558) were grouped by CK and CK-MB results. To confirm the primary analysis results, data from patients with missing biomarkers were used in an imputation model.Patients were categorized in 1 of 4 groups: normal CK + normal CK-MB; normal CK + elevated CK-MB; elevated CK + normal CK-MB; or elevated CK + elevated CK-MB. For the primary outcome, 180-day death, or myocardial infarction, Kaplan-Meier estimates were 14.9%, 20.8%, 14.5%, and 18.2%, respectively. Regardless of total CK, elevated CK-MB was associated with a 25% to 49% increased relative risk of worse outcomes. Findings from the analyses were verified by the multivariable model.CK-MB remains a reliable marker for myocardial necrosis and a strong predictor of worse prognosis. All patients with ACS should have CK-MB measurement to search for cardiac ischemia. Patients with elevated CK-MB should receive aggressive management commensurate with their increased risks.

    View details for DOI 10.1016/j.ahj.2005.01.045

    View details for Web of Science ID 000234485100003

    View details for PubMedID 16368286

  • High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin - Outcomes at 6 months and 1 year in the SYNERGY trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Mahaffey, K. W., Cohen, M., Garg, J., Antman, E., Kleiman, N. S., Goodman, S. G., Berdan, L. G., Reist, C. J., Langer, A., White, H. D., Aylward, P. E., Col, J. J., Ferguson, J. J., Califf, R. M. 2005; 294 (20): 2594-2600

    Abstract

    The SYNERGY trial comparing enoxaparin and unfractionated heparin in high-risk patients with acute coronary syndromes (ACS) showed that enoxaparin was not inferior to unfractionated heparin in reducing death or nonfatal myocardial infarction (MI) at 30 days.To evaluate continued risk in this patient cohort through 6-month and 1-year follow-up.Overall, 9978 patients were randomized from August 2001 through December 2003 in 487 hospitals in 12 countries. Patients were followed up for 6 months and for 1 year.Six-month outcomes were death, nonfatal MI, revascularization procedures, stroke, and site-investigator-reported need for rehospitalization; 1-year outcome was all-cause death.Six-month and 1-year follow-up data were available for 9957 (99.8%) and 9608 (96.3%) of 9978 patients, respectively; 541 patients (5.4%) had died at 6 months and 739 (7.4%) at 1 year. Death or nonfatal MI at 6 months occurred in 872 patients receiving enoxaparin (17.6%) vs 884 receiving unfractionated heparin (17.8%) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.89-1.07; P = .65). In the subgroup of patients receiving consistent therapy, ie, only enoxaparin or unfractionated heparin during the index hospitalization (n = 6138), a reduction in death or nonfatal MI with enoxaparin was maintained at 180 days (HR, 0.85; 95% CI, 0.75-0.95; P = .006). Rehospitalization within 180 days occurred in 858 patients receiving enoxaparin (17.9%) and 911 receiving unfractionated heparin (19.0%) (HR, 0.94; 95% CI, 0.85-1.03; P = .17). One-year all-cause death rates were similar in the 2 treatment groups (380/4974 [7.6%] for enoxaparin vs 359/4948 [7.3%] for unfractionated heparin; HR, 1.06; 95% CI, 0.92-1.22; P = .44). One-year death rates in patients receiving consistent therapy were also similar (251/3386 [7.4%] for enoxaparin vs 213/2720 [7.8%] for unfractionated heparin; HR, 0.95; 95% CI, 0.79-1.14; P = .55).In the SYNERGY trial, patients continued to experience adverse cardiac events through long-term follow-up. The effect of enoxaparin on death or MI compared with that of unfractionated heparin at 6 months was similar to that observed at 30 days in the overall trial and in the consistent-therapy group. One-year death rates were also similar in both groups. High-risk patients with ACS remain susceptible to continued cardiac events despite aggressive therapies.ClinicalTrials.gov Identifier: NCT00043784.

    View details for Web of Science ID 000233436200024

    View details for PubMedID 16304073

  • Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Rao, S. V., O'Grady, K., Pieper, K. S., Granger, C. B., Newby, L. K., Van de Werf, F., Mahaffey, K. W., Califf, R. M., Harrington, R. A. 2005; 96 (9): 1200-1206

    Abstract

    Bleeding is a complication of current therapies for acute coronary syndrome (ACS). No studies have examined the effect of bleeding events on clinical outcomes. We analyzed pooled data from 4 multicenter, randomized clinical trials of patients who had ACS (n = 26,452) to determine an association between bleeding severity as measured by the GUSTO scale and 30-day and 6-month mortality rates using Cox proportional hazards modeling that incorporated bleeding as a time-dependent covariate. The analysis was repeated to examine procedure- and non-procedure-related bleeding and after censoring at the time of coronary artery bypass grafting. Of all the patients included, 27.6% had > or =1 bleeding episode. Patients who bled were older and sicker at presentation than were those who did not bleed. Unadjusted rates of 30-day and 6-month mortality increased as bleeding severity increased. There were stepwise increases in the adjusted hazards of 30-day mortality (mild bleeding, hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.3 to 1.9; moderate bleeding, HR 2.7, 95% CI l 2.3 to 3.4; severe bleeding, HR 10.6, 95% CI 8.3 to 13.6) and 6-month mortality (mild bleeding, HR 1.4, 95% CI 1.2 to 1.6; moderate bleeding, HR 2.1, 95% CI 1.8 to 2.4; severe bleeding, HR 7.5, 95% CI 6.1 to 9.3) as bleeding severity increased. Results were consistent after censoring for coronary artery bypass grafting and for procedure- and non-procedure-related bleeds. In conclusion, the GUSTO bleeding classification identifies patients who are at risk for short- and long-term adverse events. Therapies that minimize bleeding risk and maintain an anticoagulant effect may improve outcomes among patients who have ACS.

    View details for DOI 10.1016/j.amjcard.2005.06.056

    View details for Web of Science ID 000233343500005

    View details for PubMedID 16253582

  • Utilization of catheterization and revascularization procedures in patients with non-ST segment elevation acute coronary syndrome over the last decade CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Levine, G. N., Lincoff, A. M., Ferguson, J. J., Mahaffey, K. W., Goodman, S. G., Cannon, C. P., Theroux, P., Fox, K. A. 2005; 66 (2): 149-157

    Abstract

    The degree to which catheterization and revascularization procedures are utilized in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) during hospitalization has broad implications with respect to initial pharmacotherapeutic decisions (upfront therapies), treatment and hospital transfer protocols, guideline recommendations, and allocation of training, material, and financial resources. Analysis of data from multiple trials and registries of patients with NSTE-ACS has the potential to assess more broadly utilization of invasive and revascularization procedures and provide a wide angle or bird's-eye view of the management of such patients, complementing the data obtained from any one trial or registry. We therefore undertook a systematic overview of all large trials and registries of patients with NSTE-ACS conducted over the last decade that were deemed appropriate to provide information on catheterization and revascularization procedures. Although not unexpectedly the percentage of patients with NSTE-ACS managed with cardiac catheterization, percutaneous coronary intervention (PCI), and coronary artery bypass grafting varies in different clinical trials and registries, general findings and trends were still discernable from these studies. During the initial treatment period, the majority of patients were ultimately treated with medical therapy alone (e.g., without revascularization). The percentage of those NSTE-ACS patients undergoing diagnostic cardiac catheterization who were then managed with PCI increased over the last decade and now stands at approximately 50%. Of NSTE-ACS patients who undergo revascularization, the percentage of those patients who are revascularized via PCI similarly increased, and PCI is currently the revascularization procedure utilized in approximately three-fourths of patients undergoing revascularization. The percentages of patients undergoing invasive and revascularization procedures were consistently higher in the U.S. cohorts of study subjects when compared to non-U.S. cohorts of study subjects.

    View details for DOI 10.1002/ccd.20469

    View details for Web of Science ID 000232387600001

    View details for PubMedID 16152646

  • Heart failure on admission and the risk of stroke following acute myocardial infarction: the VALIANT registry EUROPEAN HEART JOURNAL Szummer, K. E., Solomon, S. D., Velazquez, E. J., Kilaru, R., McMurray, J., Rouleau, J. L., Mahaffey, K. W., Maggioni, A. P., Califf, R. M., Pfeffer, M. A., White, H. D. 2005; 26 (20): 2114-2119

    Abstract

    We sought to assess the relative contribution of heart failure (HF) on admission for an acute myocardial infarction (MI) to the subsequent in-hospital stroke risk.The VALsartan In Acute myocardial iNfarcTion (VALIANT) registry enrolled 5573 consecutive MI patients at 84 international sites from 1999 to 2001. We calculated odds ratios (ORs) for stroke and adjusted for baseline characteristics, Killip Class, and risk factors for stroke, such as diabetes and prior HF. In-hospital stroke occurred in 81 (1.5%) patients. HF was present on admission in 38% of patients who developed a stroke and in 24% who did not (P=0.001). Older age (OR 1.03 increase/year, 95% confidence interval (CI) 1.01-1.04), Killip Class III (OR 1.66, CI 0.86-3.19) or IV (OR 4.85, CI 1.69-13.93), history of hypertension (OR 1.73, CI 1.06-2.82), and history of stroke (OR 1.89, CI 1.06-3.37) were more common in patients who had in-hospital stroke. In-hospital mortality in patients with and without stroke was 27.2 and 6.5%, respectively (P<0.001).Patients with stroke after MI have a dismal prognosis. The presence of HF on admission for an acute MI increases in-hospital stroke risk. HF treatments may modify the risk of stroke.

    View details for DOI 10.1093/eurheartj/ehi352

    View details for Web of Science ID 000232278500010

    View details for PubMedID 15972293

  • Electrocardiographic infarct size assessment after thrombolysis: Insights from the Acute Myocardial Infarction STudy ADenosine (AMISTAD) trial AMERICAN HEART JOURNAL Barbagelata, A., Di Carli, M. F., Califf, R. M., Garg, J., Birnbaum, Y., Grinfeld, L., Gibbons, R. J., Granger, C. B., Goodman, S. G., Wagner, G. S., Mahaffey, K. W. 2005; 150 (4): 659-665

    Abstract

    Noninvasive methods are needed to evaluate reperfusion success in patients with acute myocardial infarction (MI). The AMISTAD trial was analyzed to compare MI size and myocardial salvage determined by electrocardiogram (ECG) with technetium Tc 99m sestamibi single-photon emission computerized tomography (SPECT) imaging.Of 236 patients enrolled in AMISTAD, 166 (70 %) with no ECG confounding factors and no prior MI were included in this analysis. Of these, group 1 (126 patients, 53%) had final infarct size (FIS) available by both ECG and SPECT. Group 2 (56 patients, 24%) had myocardium at risk, FIS, and salvage index (SI) assessed by both SPECT and ECG techniques. Aldrich/Clemmensen scores for myocardium at risk and the Selvester QRS score for final MI size were used. Salvage index was calculated as follows: SI = (myocardium at risk-FIS)/(myocardium at risk).In group 1, FIS was 15% (6, 24) as measured by ECG and 11% (2, 27) as measured by SPECT. In the adenosine group, FIS was 12% (6, 21) and 11% (2, 22). In the placebo group, FIS was 16.5% (7.5, 24) and 11.5% (3.0, 38.5) by ECG and SPECT, respectively. The overall correlation between SPECT and ECG for FIS was 0.58 (P = .0001): 0.60 in the placebo group (P = .0001) and 0.54 (P = .0001) in the adenosine group. In group 2, myocardium at risk was 23% (17, 30) and 26% (10, 50) with ECG and SPECT, respectively (P = .0066). Final infarct size was 17% (6, 21) and 12% (1, 24) (P < .0001). The SI was 29% (-7, 57) and 46% (15, 79) with ECG and SPECT, respectively (P = .0510).The ECG measurement of infarct size has a moderate relationship with SPECT infarct size measurements in the population with available assessments. This ECG algorithm must further be validated on clinical outcomes.

    View details for DOI 10.1016/j.ahj.2004.10.014

    View details for Web of Science ID 000232953300007

    View details for PubMedID 16209961

  • Prognostic significance of blood markers of inflammation in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty and effects of pexelizumab, a C5 inhibitor: a substudy of the COMMA trial EUROPEAN HEART JOURNAL Theroux, P., Armstrong, P. W., Mahaffey, K. W., Hochman, J. S., Malloy, K. J., Rollins, S., Nicolau, J. C., Lavoie, J., Luong, T. M., Burchenal, J., Granger, C. B. 2005; 26 (19): 1964-1970

    Abstract

    Pexelizumab, a monoclonal antibody inhibiting C5, reduced 90 day mortality and shock in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial without apparent reductions in infarct size. Inflammation is a critical component of ST-elevation myocardial infarction (STEMI); this substudy examines prognostic values of selected markers and treatment effects.C-reactive protein, interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha) serum levels were assessed in 337 patients enrolled in either the placebo or the pexelizumab 24 h infusion group. Higher C-reactive protein and IL-6 levels at baseline, 24 h, and 72 h were strongly associated with increased subsequent death (P<0.002 at baseline and 24 h, P<0.02 at 72 h); and all baseline marker levels with death or cardiogenic shock (P<0.03) within 90 days. C-reactive protein and IL-6 levels were similar at baseline, but significantly lower 24 h later with pexelizumab, when compared with placebo (17.1 vs. 25.5 mg/L, P=0.03 and 51.0 vs. 63.8 pg/mL, P=0.04, respectively). At 72 h, corresponding levels were similar, whereas TNF-alpha was slightly higher (P=0.04) in the treated group.Inflammation markers and their serial changes predict death and shock in patients with STEMI undergoing primary angioplasty. Pexelizumab reduced C-reactive protein and IL-6, suggesting treatment benefits mediated through anti-inflammatory effects.

    View details for DOI 10.1093/eurheartj/ehi292

    View details for Web of Science ID 000232103200008

    View details for PubMedID 15872036

  • Enzyme estimates of infarct size correlate with functional and clinical outcomes in the setting of ST-segment elevation myocardial infarction CURRENT CONTROLLED TRIALS IN CARDIOVASCULAR MEDICINE Turer, A. T., Mahaffey, K. W., Gallup, D., Weaver, W. D., Christenson, R. H., Every, N. R., Ohman, E. M. 2005; 6

    Abstract

    Cardiac biomarkers are routinely obtained in the setting of suspected myocardial ischemia and infarction. Evidence suggests these markers may correlate with functional and clinical outcomes, but the strength of this correlation is unclear. The relationship between enzyme measures of myocardial necrosis and left ventricular performance and adverse clinical outcomes were explored.Creatine kinase (CK) and CK-MB data were analyzed, as were left ventricular ejection fraction (LVEF) by angiogram, and infarct size by single-photon emission computed tomography (SPECT) imaging in patients in 2 trials: Prompt Reperfusion In Myocardial-infarction Evolution (PRIME), and Efegatran and Streptokinase to Canalize Arteries Like Accelerated Tissue plasminogen activator (ESCALAT). Both trials evaluated efegatran combined with thrombolysis for treating acute ST-segment elevation myocardial infarction (STEMI).Peak CK and CK area-under-the-curve (AUC) correlated significantly with SPECT-determined infarct size 5 to 10 days after enrollment. Peak CK had a statistically significant correlation with LVEF, but CK-AUC and LVEF correlation were less robust. Statistically significant correlations exist between SPECT-determined infarct size and peak CK-MB and CK-MB AUC. However, there was no correlation with LVEF for peak CK-MB and CK-MB AUC. The combined outcome of congestive heart failure and death were significantly associated with CK AUC, CK-MB AUC, peak CK, and peak CK-MB measurements.Peak CK and CK-MB values and AUC calculations have significant correlation with functional outcomes (LVEF- and SPECT-determined infarct size) and death or CHF outcomes in the setting of STEMI. Cardiac biomarkers provide prognostic information and may serve as valid endpoint measurements for phase II clinical trials.

    View details for DOI 10.1186/1468-6708-6-12

    View details for Web of Science ID 000232280400001

    View details for PubMedID 16115321

  • Characterization of myocardial infarction as an end point in two large trials of acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Mahaffey, K. W., Roe, M. T., Kilaru, R., French, J. K., Alexander, J. H., Berdan, L. G., Van de Werf, F., Simoons, M. L., Weaver, W. D., White, H. D., Lincoff, A. M., Kleiman, N. S., Topol, E. J., Harrington, R. A. 2005; 95 (12): 1404-1408

    Abstract

    Myocardial infarction (MI) is a key component of composite end points in trials that evaluate new therapies in non-ST-segment elevation acute coronary syndromes. Types of MI events in these trials have not been well characterized. A similar clinical-events classification process adjudicated all suspected MI end points in the PURSUIT and PARAGON B trials. All MI end points were classified as nonprocedural, related to percutaneous coronary intervention, or related to coronary artery bypass grafting. A total of 16,173 patients was enrolled in the 2 trials, and 1,802 MI end points occurred during a 30-day follow-up. Nearly 66% of MI end points were not related to percutaneous coronary intervention or coronary artery bypass grafting. Patients who had MI compared with those who did not had higher 30-day mortality rates (13.6% vs 2.3%, p <0.001) and 6-month mortality rates (18.4% vs 4.4%, p <0.001). Patients who had been randomized to glycoprotein IIb/IIIa inhibition showed trends toward fewer MI events regardless of type. Two-thirds of MI end points in 2 large trials of acute coronary syndrome were not related to procedure. All MI types were associated with worse short- and long-term outcomes. Characterization of the type of MI provides an opportunity for more informed interpretation of clinical trial results and improved planning for future trials.

    View details for DOI 10.1016/j.amjcard.2005.02.005

    View details for Web of Science ID 000229952900002

    View details for PubMedID 15950560

  • Clinical use of enoxaparin in the management of non-ST segment elevation acute coronary syndromes EXPERT OPINION ON PHARMACOTHERAPY Galla, J. M., Mahaffey, K. W. 2005; 6 (7): 1241-1251

    Abstract

    Enoxaparin (Lovenox; Roule-Poulenc Rorer, Inc.), a low molecular weight heparin (LMWH), is commonly used in the management of non-ST-segment elevation acute coronary syndromes (NSTE ACS) based on clinical trial outcomes. It is one of a group of glycosaminoglycan compounds that accelerate the inactivation of factor Xa by inducing a conformational change in antithrombin. In contrast to unfractionated heparin (UFH), LMWH have greater bioavailability, a more predictable anticoagulant response, longer half-life and a higher proportion of anti-factor Xa to anti-factor IIa activity. As a consequence, laboratory monitoring of the anticoagulant effect is typically unnecessary. Antithrombin therapy with LMWH or UFH has the highest-level recommendation (IA) in the 2002 professional guidelines for the management of unstable angina and non-ST-elevation myocardial infarction, where enoxaparin has a IIA recommendation over UFH unless early coronary artery bypass surgery is planned. In a recent systematic overview of > 20,000 patients with NSTE ACS from six clinical trials, including conservative and invasively managed patients, enoxaparin provided a statistically significant reduction in 30-day death or nonfatal myocardial infarction (MI) compared with UFH with no significant excess in transfusions, or major bleeding. These data support the role of enoxaparin as an anti-coagulant in patients with NSTE ACS.

    View details for DOI 10.1517/146566566.6.7.1241

    View details for Web of Science ID 000230945100017

    View details for PubMedID 15957976

  • A perspective on trials comparing enoxaparin and unfractionated heparin in the treatment of non-ST-elevation acute coronary syndromes AMERICAN HEART JOURNAL Califf, R. M., Petersen, J. L., Hasselblad, V., Mahaffey, K. W., Ferguson, J. J. 2005; 149 (4): S91-S99

    Abstract

    Non-ST-elevation (NSTE) acute coronary syndrome (ACS) is a serious, acute illness characterized by a high rate of death and morbid events, and antithrombin therapy is integral to its management. Contemporary guidelines from the American College of Cardiology/American Heart Association call for use of low-molecular-weight heparin or unfractionated heparin (UFH).A systematic overview of six randomized, controlled trials comparing enoxaparin to UFH in the treatment of NSTE ACS was performed using a random-effects empirical Bayes model. Efficacy end points included the incidence of death or the composite of death and myocardial infarction (MI) at 30 days. Safety end points included major bleeding and transfusion at 7 days.For the aggregate of 21,946 patients, the incidence of the composite of death and MI at 30 days was lower in enoxaparin-treated patients (10.1% vs 11.0% for UFH, OR 0.91, 95% CI 0.83-0.99, number need to treat 107). For the 9,835 patients in these trials who received no prerandomization antithrombin therapy, the composite of death and MI at 30 days occurred in 8.0% and 9.4% of enoxaparin- and UFH-treated patients, respectively (OR 0.81, 95% CI 0.70-0.94, number need to treat 94). There was no significant difference in the incidence of death at 30 days in either population. A nonsignificant trend toward higher rates of major bleeding was seen at 7 days for enoxaparin-treated patients, in both the overall safety population and the population of patients who did not receive antithrombin treatment before randomization, but there was no difference in blood transfusions.In a systematic overview of six randomized, controlled trials comparing enoxaparin to UFH in the treatment of NSTE ACS in approximately 22,000 patients, the use of enoxaparin rather than UFH was associated with a modest reduction in the incidence of the composite of death and MI at 30 days without a significant increase in the rate of major bleeding or transfusion at 7 days.

    View details for DOI 10.1016/j.ahj.2005.02.021

    View details for Web of Science ID 000228754500003

    View details for PubMedID 16124953

  • Exploring the role of enoxaparin in the management of high-risk patients with non-ST-elevation acute coronary syndromes: The SYNERGY trial AMERICAN HEART JOURNAL Mahaffey, K. W., Ferguson, J. J. 2005; 149 (4): S81-S90

    Abstract

    In patients with non-ST-elevation acute coronary syndromes (NSTE ACS), enoxaparin has been shown to be superior to unfractionated heparin (UFH) and is associated with a reduction in ischemic end points with nonsignificant increases in bleeding. However, the critical trials comparing enoxaparin with UFH were conducted before the widespread use of early invasive management and the availability of clopidogrel and glycoprotein IIb/IIIa receptor antagonists.SYNERGY was an international, multicenter, randomized, open-label trial that compared enoxaparin with UFH in high-risk NSTE ACS patients managed with an early invasive strategy. For enrollment, 2 out of 3 high-risk features were required: age > or =60 years, elevated cardiac biomarkers, or ST-segment changes. The primary efficacy end point was death/myocardial infarction (MI) at 30 days. The primary safety end point was inhospital major bleeding or stroke through 30 days.The incidence of death/MI at 30 days was 14.0% in the enoxaparin group and 14.5% in the UFH group (hazard ratio 0.96, 95% CI 0.86-1.06), demonstrating noninferiority of enoxaparin relative to UFH. Enoxaparin was associated with a small but significant excess of Thrombolysis In Myocardial Infarction (TIMI) major bleeding, but there was no statistically significant increase in Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) severe bleeding or the rate of transfusion. There was no difference in complications of percutaneous coronary intervention. Interpretation of trial results was complicated by widespread use of enoxaparin or UFH before randomization, and by postrandomization crossover to the nonrandomized agent.In patients with NSTE ACS, including high-risk patients proceeding rapidly to catheterization, enoxaparin is an effective and safe alternative to UFH.

    View details for DOI 10.1016/j.ahj.2005.02.023

    View details for Web of Science ID 000228754500002

    View details for PubMedID 16124952

  • Prognostic usefulness of White Blood Cell count and temperature in acute myocardial infarction (from the CARDINAL Trial) AMERICAN JOURNAL OF CARDIOLOGY Patel, M. R., Mahaffey, K. W., Armstrong, P. W., Weaver, W. D., Tasissa, G., Hochman, J. S., Todaro, T. G., Malloy, K. J., Rollins, S., Theroux, P., Ruzyllo, W., Nicolau, J. C., Granger, C. B. 2005; 95 (5): 614-618

    Abstract

    White blood cell (WBC) count and temperature are 2 global measures of inflammation that are systematically gathered and easily identifiable in a clinical setting, unlike many other markers of inflammation being investigated in patients with coronary artery disease. The prognostic usefulness of the WBC count and temperature were evaluated in a large acute myocardial infarction trial, the Complement And ReDuction of INfarct size after Angioplasty or Lytics program. Baseline and serial measurements of WBC counts and temperature were correlated with infarct size and clinical outcome.

    View details for Web of Science ID 000227156400013

    View details for PubMedID 15721102

  • Platelet glycoprotein IIb/IIIa receptor antagonists in non-ST segment elevation acute coronary syndromes - A review and guide to patient selection DRUGS Atwater, B. D., Roe, M. T., Mahaffey, K. W. 2005; 65 (3): 313-324

    Abstract

    Platelet glycoprotein (Gp) IIb/IIIa receptor antagonists improve outcomes in patients with acute coronary syndromes without persistent ST-segment elevation, but relative effects depend on appropriate patient selection. Recent data from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines) quality improvement initiative suggests that GpIIb/IIIa antagonists are underused in clinical practice. The relationship between GpIIb/IIIa inhibition and the magnitude of clinical benefit in the setting of acute coronary syndromes is complex. Several key factors should be considered for proper patient selection, including accurate patient risk stratification, incorporation of these agents with an early invasive management strategy and the concomitant use of other anti-thrombotic therapies. Current practice guidelines for the treatment of patients with non-ST-segment elevation acute coronary syndromes support the integration of an early invasive management with optimal pharmacological therapy, including GpIIb/IIIa antagonists.

    View details for Web of Science ID 000227006600002

    View details for PubMedID 15669877

  • Incidence and characteristics of stroke during 90-day follow-up in patients stabilized after an acute coronary syndrome AMERICAN HEART JOURNAL Kassem-Moussa, H., Mahaffey, K. W., Graffagnino, C., Tasissa, G., Sila, C. A., Simes, R. J., White, H. D., Califf, R. M., Bhapkar, M. V., Newby, L. K. 2004; 148 (3): 439-446

    Abstract

    Stroke is a rare but serious event that complicates the course of patients with acute coronary syndromes (ACS). The type, outcome, and risk factors of stroke occurring in stabilized patients with ACS have not been previously reported.We evaluated stroke incidence, subtypes, and outcomes, in addition to demographics and clinical risk characteristics associated with stroke among patients enrolled in the Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes (SYMPHONY) and 2nd SYMPHONY trials.Of 15,904 stabilized patients with ACS, 113 (0.71%) had a stroke over a median follow-up of 90 days. The majority of strokes occurred within 30 days of presentation, and the time course for stroke occurrence paralleled that of myocardial (re)infarction. Most strokes were ischemic (78%), and 52% resulted in moderate or severe disability or death. Patients with stroke were older and more often had hypertension, diabetes, peripheral vascular disease, and atrial fibrillation. Among patients with stroke who had cardiac catheterization, percutaneous coronary intervention, or coronary artery bypass grafting, stroke occurred predominantly after the procedure. No difference in occurrence or type of stroke was observed in the assigned treatment groups. In multivariable modeling age, heart failure, prior stroke, left bundle branch block, and systolic blood pressure predicted the occurrence of stroke.In patients stabilized after presenting with a spectrum of ACS and treated with sibrafiban and/or aspirin, stroke occurred in fewer than 1% within 90 days but carried a significant mortality and morbidity risk.

    View details for DOI 10.1016/j.ahj.2004.01.028

    View details for Web of Science ID 000224339600010

    View details for PubMedID 15389230

  • Coordinated series of studies to evaluate characteristics and mechanisms of acute coronary syndromes in high-risk patients randomly assigned to enoxaparin or unfractionated heparin: Design and rationale of the SYNERGY Library AMERICAN HEART JOURNAL Petersen, J. L., Mahaffey, K. W., Becker, R. C., Goodman, S. G., Kleiman, N. S., Marian, A. J., Stone, G. W., Lansky, A. J., Lincoff, A. M., Hazen, S. L., Nessel, C. C., Toro-Figueroa, L., Tate, L., Reist, C. J., Cohen, M., Califf, R. M., Ferguson, J. J. 2004; 148 (2): 269-276

    Abstract

    Clinical trials and accompanying substudies in patients with acute coronary syndromes (ACS) have over the last several years yielded a wealth of knowledge about the pathophysiology and management of this high-risk condition. The Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is a large-scale, randomized, controlled trial evaluating the effect of enoxaparin and unfractionated heparin on death and myocardial infarction in high-risk patients presenting with non-ST-segment elevation ACS. The SYNERGY Library has been designed as a coordinated series of investigations with simultaneous data acquisition on the same cohort of approximately 500 SYNERGY patients at 60 centers in North America. Specifically, electrocardiograms, coronary arteriograms, inflammatory markers, coagulation studies, and genetic samples will be collected and processed at core laboratory facilities, and the results will be stored in a central repository. This novel strategy for substudy investigation is unprecedented in cardiovascular clinical trials. The goal is to gain significant understanding about this patient population, discover new principles of pathophysiology, identify novel pharmacologic targets, and streamline further drug development. It is hoped that the SYNERGY Library will serve as a model for future substudy design to maximize academic insight within the framework of a large-scale, multicenter trial.

    View details for DOI 10.1016/j.ahj.2004.03.022

    View details for Web of Science ID 000223494000013

    View details for PubMedID 15308996

  • Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-segment elevation acute coronary syndromes - A systematic overview JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Petersen, J. L., Mahaffey, K. W., Hasselblad, V., Antman, E. M., Cohen, M., Goodman, S. G., Langer, A., Blazing, M. A., Le-Moigne-Amrani, A., de Lemos, J. A., Nessel, C. C., Harrington, R. A., Ferguson, J. J., Braunwald, E., Califf, R. M. 2004; 292 (1): 89-96

    Abstract

    Antithrombin therapy has become a guidelines-recommended standard of care in the treatment of acute coronary syndromes (ACS), but recent trials comparing use of enoxaparin and unfractionated heparin in ACS have yielded less robust efficacy and safety results than have earlier trials of these antithrombin therapies.To systematically evaluate the end points of all-cause death and nonfatal myocardial infarction (MI), transfusion, and major bleeding observed in the 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in treatment of ACS.The primary data sets for ESSENCE, A to Z, and SYNERGY were available at the Duke Clinical Research Institute. Baseline characteristics and event frequencies for TIMI 11B, ACUTE II, and INTERACT were provided by the principal investigator of each study.All 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in non-ST-segment elevation ACS were selected for analysis.Efficacy and safety end points were extracted from the overall trial populations and the subpopulation receiving no antithrombin therapy prior to randomization.Systematic evaluation of the outcomes for 21 946 patients was performed using a random-effects empirical Bayes model. No significant difference was found in death at 30 days for enoxaparin vs unfractionated heparin (3.0% vs 3.0%; odds ratio [OR], 1.00; 95% confidence interval [CI], 0.85-1.17). A statistically significant reduction in the combined end point of death or nonfatal MI at 30 days was observed for enoxaparin vs unfractionated heparin in the overall trial populations (10.1% vs 11.0%; OR, 0.91; 95% CI, 0.83-0.99; number needed to treat, 107). A statistically significant reduction in the combined end point of death or MI at 30 days was also observed for enoxaparin in the populations receiving no prerandomization antithrombin therapy (8.0% vs 9.4%; OR, 0.81; 95% CI, 0.70-0.94; number needed to treat, 72). No significant difference was found in blood transfusion (OR, 1.01; 95% CI, 0.89-1.14) or major bleeding (OR, 1.04; 95% CI, 0.83-1.30) at 7 days after randomization in the overall safety population or in the population of patients receiving no prerandomization antithrombin therapy.In a systematic overview of approximately 22 000 patients across the spectrum of ACS, enoxaparin is more effective than unfractionated heparin in preventing the combined end point of death or MI.

    View details for Web of Science ID 000222448100032

    View details for PubMedID 15238596

  • Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy - Primary results of the SYNERGY randomized trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ferguson, J. J., Califf, R. M., Antman, E. M., Cohen, M., Grines, C. L., Goodman, S., Kereiakes, D. J., Langer, A., Mahaffey, K. W., Langer, A., Mahaffey, K. W., Nessel, C. C., Armstrong, P. W., Avezum, A., Aylward, P., Becker, R. C., Biasucci, L., Borzak, S., Col, J., Frey, M. J., Fry, E., Gulba, D. C., Guneri, S., Gurfinkel, E., Harrington, R., Hochman, J. S., Kleiman, N. S., Leon, M. B., Lopez-Sendon, J. L., Pepine, C. J., Ruzyllo, W., Steinhubl, S. R., Teirstein, P. S., Toro-Figueroa, L., White, H. 2004; 292 (1): 45-54

    Abstract

    Enoxaparin has demonstrated advantages over unfractionated heparin in low- to moderate-risk patients with non-ST-segment elevation acute coronary syndromes (ACS) treated with a conservative strategy.To compare the outcomes of patients treated with enoxaparin vs unfractionated heparin and to define the role of enoxaparin in patients with non-ST-segment elevation ACS at high risk for ischemic cardiac complications managed with an early invasive approach.The Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was a prospective, randomized, open-label, multicenter, international trial conducted between August 2001 and December 2003. A total of 10 027 high-risk patients with non-ST-segment elevation ACS to be treated with an intended early invasive strategy were recruited.Subcutaneous enoxaparin (n = 4993) or intravenous unfractionated heparin (n = 4985) was to be administered immediately after enrollment and continued until the patient required no further anticoagulation, as judged by the treating physician.The primary efficacy outcome was the composite clinical end point of all-cause death or nonfatal myocardial infarction during the first 30 days after randomization. The primary safety outcome was major bleeding or stroke.The primary end point occurred in 14.0% (696/4993) of patients assigned to enoxaparin and 14.5% (722/4985) of patients assigned to unfractionated heparin (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.86-1.06). No differences in ischemic events during percutaneous coronary intervention (PCI) were observed between enoxaparin and unfractionated heparin groups, respectively, including similar rates of abrupt closure (31/2321 [1.3%] vs 40/2364 [1.7%]), threatened abrupt closure (25/2321 [1.1%] vs 24/2363 [1.0%]), unsuccessful PCI (81/2281 [3.6%] vs 79/2328 [3.4%]), or emergency coronary artery bypass graft surgery (6/2323 [0.3%] vs 8/2363 [0.3%]). More bleeding was observed with enoxaparin, with a statistically significant increase in TIMI (Thrombolysis in Myocardial Infarction) major bleeding (9.1% vs 7.6%, P =.008) but nonsignificant excess in GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Arteries) severe bleeding (2.7% vs 2.2%, P =.08) and transfusions (17.0% vs 16.0%, P =.16).Enoxaparin was not superior to unfractionated heparin but was noninferior for the treatment of high-risk patients with non-ST-segment elevation ACS. Enoxaparin is a safe and effective alternative to unfractionated heparin and the advantages of convenience should be balanced with the modest excess of major bleeding.

    View details for Web of Science ID 000222448100026

    View details for PubMedID 15238590

  • The evaluation and management of dyslipidemia and impaired glucose metabolism during acute coronary syndromes. Current cardiology reports Goyal, A., Petersen, J. L., Mahaffey, K. W. 2004; 6 (4): 300-307

    Abstract

    Dyslipidemia and hyperglycemia are common among patients presenting with acute coronary syndromes (ACS), and patients with ACS and metabolic disorders are at increased risk for worse outcomes. Although guidelines for the diagnosis and management of dyslipidemia, diabetes, and the metabolic syndrome have been published, these guidelines have not specifically focused on the ACS patient population. Recent observational registries and clinical trials have advanced the appreciation of these disorders in ACS populations and data from these studies support aggressive efforts to diagnose and treat dyslipidemia and hyperglycemia in patients admitted for ACS.

    View details for PubMedID 15182608

  • Risk factors for intracranial hemorrhage and nonhemorrhagic stroke after fibrinolytic therapy (from the GUSTO-I trial) AMERICAN JOURNAL OF CARDIOLOGY Kandzari, D. E., Granger, C. B., Simoons, M. L., White, H. D., Simes, J., Mahaffey, K. W., Gore, J., Weaver, W. D., Longstreth, W. T., Stebbins, A., Lee, K. L., Califf, R. M., Topol, E. J. 2004; 93 (4): 458-461

    Abstract

    Of 592 patients in the Global Utilization of Streptokinase and tPA for Occluded Arteries-I trial who had a stroke during initial hospitalization, the risk for intracranial hemorrhage was significantly greater in those with recent facial or head trauma (odds ratio 13.0, 95% confidence interval 3.4 to 85.5); dementia was additionally associated with an increased risk for intracranial hemorrhage (odds ratio 3.4, 95% confidence interval 1.2 to 10.2). Because facial or head trauma may greatly influence treatment decisions, this risk factor should be incorporated into models designed to estimate the risks and benefits of fibrinolytic therapy.

    View details for DOI 10.1016/j.amjcard.2003.10.043

    View details for Web of Science ID 000188968800016

    View details for PubMedID 14969623

  • Creatine kinase-MB elevation after percutaneous coronary intervention predicts adverse outcomes in patients with acute coronary syndromes EUROPEAN HEART JOURNAL Roe, M. T., Mahaffey, K. W., Kilaru, R., Alexander, J. H., Akkerhuis, K. M., Simoons, M. L., Harrington, R. A., Tardiff, B. E., Granger, C. B., Ohman, E. M., Moliterno, D. J., Lincoff, A. M., Armstrong, P. W., Van de Werf, F., Califf, R. M., Topol, E. J. 2004; 25 (4): 313-321

    Abstract

    To study the relationship between outcomes and peak creatine kinase (CK)-MB levels after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS).Peak CK-MB ratios (peak CK-MB level/upper limit of normal [ULN]) after PCI were analysed in 6164 patients with NSTE ACS from four randomized trials who underwent in-hospital PCI. We excluded 696 patients with elevated CK or CK-MB levels <24h before PCI; the primary analysis included 2384 of the remaining 5468 patients (43.6%) with CK-MB levels measured <==24h after PCI. The incidence of in-hospital heart failure (0.1%, 0.8%, 3.4%, 4.1%, and 6.1%; P<0.001), arrhythmias (0.8%, 1.9%, 6.9%, 4.1%, and 7.9%; P<0.001), cardiogenic shock (0.1%, 1.3%, 2.0%, 2.3%, and 2.6%; P=0.004), and mortality through 6 months (2.1%, 2.4%, 4.9%, 4.1%, and 5.7%, P=0.005) was increased with peak CK-MB ratios of 0-1, 1-3, 3-5, 5-10, and >10xULN, respectively. The continuous peak CK-MB ratio after PCI significantly predicted adjusted 6-month mortality (risk ratio, 1.06 per unit increase above ULN; 95% confidence interval, 1.01-1.11; P=0.017).Greater CK-MB elevation after PCI is independently associated with adverse outcomes in NSTE ACS. These results underscore the adverse implications of elevated CK-MB levels after PCI in this high-risk population.

    View details for DOI 10.1016/j.ehj.2003.12.009

    View details for Web of Science ID 000220194100007

    View details for PubMedID 14984920

  • Integrating antithrombin and antiplatelet therapies with early invasive management for non-ST-segment elevation acute coronary syndromes AMERICAN JOURNAL OF MEDICINE Rebeiz, A. G., Roe, M. T., Alexander, J. H., Mahaffey, K. W., Granger, C. B., Peterson, E. D., Califf, R. M., Harrington, R. A. 2004; 116 (2): 119-129

    Abstract

    Non-ST-segment elevation acute coronary syndromes are a dramatic manifestation of coronary artery disease. Multiple clinical trials have shown that early cardiac catheterization improves clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes. Many antithrombotic agents effectively manage unstable coronary syndromes and serve as adjuncts to percutaneous coronary intervention. Yet, the growing number of pharmacologic agents makes early management of non-ST-segment elevation acute coronary syndromes increasingly complex. We review the current evidence regarding the optimal integration of early antithrombotic and antiplatelet therapies with early coronary angiography and subsequent revascularization.

    View details for DOI 10.1016/j.amjmed.2003.09.028

    View details for Web of Science ID 000188246900008

    View details for PubMedID 14715326

  • Prognostic importance of new small Q waves following non-ST-elevation acute coronary syndromes AMERICAN JOURNAL OF MEDICINE Alexander, J. H., Harrington, R. A., Bhapkar, M., Mahaffey, K. W., Lincoff, A. M., Ohman, E. M., Klootwijk, P., Pahlm, O., Henden, B., Deckers, J. W., Simoons, M. L., Califf, R. M., Wagner, G. S. 2003; 115 (8): 613-619

    Abstract

    To investigate the prognostic importance of new small Q waves following an acute coronary syndrome.We assessed 6-month mortality in 10501 patients with non-ST-elevation acute coronary syndromes who had survived 30 days and had both admission and 30-day electrocardiograms. Patients were stratified by whether they had no new Q waves (n = 9447), new 30- to 40-ms Q waves (n = 733), or new > or =40-ms Q waves (n = 321).Mortality was higher in patients with 30- to 40-ms Q waves than in those with no new Q waves (3.4% [25/733] vs. 2.4% [227/9447], P = 0.005), and even higher in those with > or =40-ms Q waves (5.3% [17/321], P = 0.002). After adjustment for baseline risk predictors, mortality remained higher in patients with new 30- to 40-ms Q waves (odds ratio [OR] = 1.30; 95% confidence interval [CI]: 0.85 to 1.98; P = 0.23) and those with new > or =40-ms Q waves (OR = 1.87; 95% CI: 1.13 to 3.09; P = 0.01).Patients with new small Q waves following a non-ST-elevation acute coronary syndrome are at increased risk of adverse outcomes. These small Q waves should be considered diagnostic of myocardial infarction. Further research should investigate whether even smaller QRS changes are prognostically important.

    View details for DOI 10.1016/j.amjmed.2003.08.007

    View details for Web of Science ID 000186883800003

    View details for PubMedID 14656613

  • Current perspectives on reperfusion therapy for acute ST-segment elevation myocardial infarction: integrating pharmacologic and mechanical reperfusion strategies AMERICAN HEART JOURNAL Waters, R. E., Mahaffey, K. W., Granger, C. B., Roe, M. T. 2003; 146 (6): 958-968

    Abstract

    The therapeutic approach to patients with acute ST-segment elevation myocardial infarction (STEMI) has advanced rapidly over the past decade. Intravenous fibrinolytic therapy remains the most common form of reperfusion therapy worldwide, since fibrinolytics are associated with a dramatic reduction in mortality rates. However, primary percutaneous coronary intervention (PCI) is associated with improved outcomes and less bleeding complications compared with fibrinolytic therapy, but it is not widely available. Adjunctive therapies with intracoronary stents, glycoprotein (GP) IIb/IIIa inhibitors, and more potent antithrombin agents have shown great promise for the initial treatment of STEMI and have stimulated further investigation of combined pharmacological/mechanical reperfusion strategies that may be synergistic. Although the optimal combination of fibrinolytics, antiplatelet agents, antithrombins, and mechanical reperfusion at hospitals with and without primary PCI facilities remains elusive, results from recent studies suggest that such a combined approach may facilitate transfer of patients with STEMI from a referral hospital to an invasive hospital for definitive primary PCI after administration of a potent pharmacologic regimen designed to enhance early infarct-related artery reperfusion. Thus, as the reperfusion era continues to evolve, the ideal treatment strategy for patients with STEMI is being redefined to integrate pharmacologic and mechanical approaches to reperfusion.

    View details for DOI 10.1016/S0002-8703(03)00439-3

    View details for Web of Science ID 000187080200009

    View details for PubMedID 14660986

  • The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study: main results. journal of invasive cardiology Mahaffey, K. W., Lewis, B. E., Wildermann, N. M., Berkowitz, S. D., Oliverio, R. M., Turco, M. A., Shalev, Y., Ver Lee, P., Traverse, J. H., Rodriguez, A. R., Ohman, E. M., Harrington, R. A., Califf, R. M. 2003; 15 (11): 611-616

    Abstract

    Up to 5% of patients given heparin develop heparin-induced thrombocytopenia (HIT). These patients may need anticoagulation for acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI), a clinical challenge given the limited alternatives. In a prospective, open-label study, we evaluated the safety and efficacy of bivalirudin in patients with HIT or HIT with thrombotic syndrome (HITTS) undergoing PCI. Patients aged 18 years were enrolled in 24 centers in 2 countries. Bivalirudin was given 5 minutes before PCI (1 mg/kg bolus; 2.5 mg/kg/hour infusion for 4 hours [high-dose group] or 0.75 mg/kg bolus; 1.75 mg/kg/hour infusion [low-dose group]). Clinical and hematological measures were assessed within 24 hours after starting bivalirudin, just before PCI, just before sheath removal, and 48 hours after treatment or at discharge, whichever occurred first. The primary endpoint was major bleeding 48 hours after discontinuation or until discharge, whichever occurred first. From July 1999 to February 2003, 52 patients were recruited. Procedural success (TIMI grade 3 flow and < 50% stenosis) was achieved in 98% of patients, and clinical success (absence of death, emergency bypass surgery, or Q-wave infarction) was achieved in 96%. One high-dose patient who underwent elective bypass surgery had major bleeding (1.9%; 95% CI: 0.05 10.65%), and 7 patients had minor bleeding. No patient had significant thrombocytopenia (platelet count < 50 109/L) after treatment. One patient in the low-dose group died from cardiac arrest ~46 hours after uncomplicated PCI. Bivalirudin appeared safe and provided effective anticoagulation during PCI. These data, and extensive experience with bivalirudin in PCI, support its use in high-risk patients with HIT requiring PCI.

    View details for PubMedID 14608128

  • Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarction - The COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial CIRCULATION Mahaffey, K. W., Granger, C. B., Nicolau, J. C., Ruzyllo, W., Weaver, W. D., Theroux, P., Hochman, J. S., Filloon, T. G., Mojcik, C. F., Todaro, T. G., Armstrong, P. W. 2003; 108 (10): 1176-1183

    Abstract

    Complement activation mediates myocardial damage that occurs during ischemia and reperfusion through multiple pathways. We performed 2 separate, parallel, double-blind, placebo-controlled trials to determine the effects of pexelizumab (a novel C5 complement monoclonal antibody fragment) on infarct size in patients receiving reperfusion therapy: COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) and COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA). The COMPLY trial is reported here.Overall, 943 patients with acute ST-segment elevation myocardial infarction (MI) (20% with isolated inferior MI) receiving fibrinolysis were randomly assigned <6 hours after symptom onset to placebo, pexelizumab 2.0-mg/kg bolus, or pexelizumab 2.0-mg/kg bolus plus 0.05 mg/kg per h for 20 hours. Infarct size determined by creatine kinase-MB area under the curve was the primary analysis, which included patients who received at least some study drug and fibrinolysis (n=920). The median infarct size did not differ by treatment (placebo, 5230; bolus, 4952; bolus plus infusion, 5557 [ng/mL] x h; bolus versus placebo, P=0.85; bolus plus infusion versus placebo, P=0.81), nor did the 90-day composite incidence of death, new or worsening congestive heart failure, shock, or stroke (placebo, 18.6%; bolus, 18.4%; bolus plus infusion, 19.7%). Pexelizumab inhibited complement for 4 hours with bolus-only dosing and for 20 to 24 hours with bolus-plus-infusion dosing, with no increase in infections.When used adjunctively with fibrinolysis, pexelizumab blocked complement activity but reduced neither infarct size by creatine kinase-MB assessment nor adverse clinical outcomes.

    View details for DOI 10.1161/01.CIR.0000087404.53661.F8

    View details for Web of Science ID 000185187800004

    View details for PubMedID 12925455

  • Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction - The COMplement inhibition in myocardial infarction treated with angioplasty (COMMA) trial CIRCULATION Granger, C. B., Mahaffey, K. W., Weaver, W. D., Theroux, P., Hochman, J. S., Filloon, T. G., Rollins, S., Todaro, T. G., Nicolau, J. C., Ruzyllo, W., Armstrong, P. W. 2003; 108 (10): 1184-1190

    Abstract

    Complement, activated during myocardial ischemia and reperfusion, causes myocardial damage through multiple processes. The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial was performed to determine the effect of pexelizumab, a C5 complement inhibitor, on infarct size in patients with ST-segment-elevation myocardial infarction (MI) undergoing primary percutaneous coronary intervention.In COMMA, 960 patients with MI (20% isolated inferior MI) were randomized to placebo, pexelizumab 2.0-mg/kg bolus, or pexelizumab 2.0-mg/kg bolus and 0.05-mg/kg per h infusion for 20 hours. Infarct size by creatine kinase-MB area under the curve, the primary outcome, did not differ significantly between groups (placebo median, 4393; bolus pexelizumab, 4526; bolus plus infusion pexelizumab, 4713 [ng/mL] x h; P=0.89 for bolus versus placebo; P=0.76 for bolus plus infusion versus placebo), nor did the composite of 90-day death, new or worsening heart failure, shock, or stroke (placebo, 11.1%; bolus, 10.7%; bolus plus infusion, 8.5%). The ninety-day mortality rate was significantly lower with pexelizumab bolus plus infusion (1.8% versus 5.9% with placebo; nominal P=0.014); the bolus-only group had an intermediate mortality rate (4.2%).In patients with ST-elevation MI undergoing percutaneous coronary intervention, pexelizumab had no measurable effect on infarct size. However, the significant reduction in mortality suggests that pexelizumab may benefit patients through alternative novel mechanisms and provides impetus for additional investigation.

    View details for DOI 10.1161/01.CIR.0000087447.12918.85

    View details for Web of Science ID 000185187800005

    View details for PubMedID 12925454

  • Does the discharge ECG provide additional prognostic insight(s) in non-ST elevation ACS patients from that acquired on admission? European heart journal HERSI, A., Fu, Y., Wong, B., Mahaffey, K. W., Harrington, R. A., Califf, R. M., Van de Werf, F., Armstrong, P. W. 2003; 24 (6): 522-531

    Abstract

    Although the prognostic value of admission ST changes in patients with non-ST elevation acute coronary syndrome (ACS) is established, the utility of the discharge ECG is unknown. Accordingly, using the PARAGON-B Troponin substudy, we assessed the prevalence of ST depression on both admission and discharge ECG, the likelihood of developing new Q-waves at discharge and the additional prognostic value of these changes.Nine hundred and eighteen patients were studied; 542 patients (59%) had admission ST downward arrow > or =1mm and 376 patients (41%) did not and their 6-month mortality was 4.4 vs 0.8%, P=0.002, respectively. Of patients with ST downward arrow on admission, 320 (59%) normalized their ST segment at discharge. Of patients without ST downward arrow on admission, 35 (9.3%) developed new ST downward arrow at discharge. Patients with persistent ST downward arrow on discharge had a higher 6-month mortality (6.0 vs 0.9%), (re)MI (16.3 vs 7.4%), and death/(re)MI (20.0 vs 8.3%) than those who never had ST downward arrow (all P< or =0.002). Two hundred and fifty-six patients had Q-waves on admission whereas by discharge 320 had Q-waves. Patients with Q-waves on discharge vs those without had a higher mortality (4.8 vs 1.9%), (re)MI (13.8 vs 8.3%), and death/(re)MI (16.4 vs 9.6%) at 6 months (all P< or =0.021).This study highlights that the dynamic ECG changes which occur between admission and discharge in non-ST elevation ACS patients allows further risk stratification in determining the likelihood of 6-month death and/or re(MI).

    View details for PubMedID 12643885

  • Evaluation of a novel point-of-care enoxaparin monitor with central laboratory anti-Xa levels THROMBOSIS RESEARCH Saw, J., Kereiakes, D. J., Mahaffey, K. W., Applegate, R. J., Braden, G. A., Brent, B. N., Brodie, B. R., Groce, J. B., Levine, G. N., Leya, F., Moliterno, D. J. 2003; 112 (5-6): 301-306

    Abstract

    Measurement of enoxaparin's anticoagulant activity has been limited to specialized coagulation laboratories and has been impractical for areas needing rapid results, such as during coronary angioplasty. A new point-of-care device, Rapidpoint ENOX, was recently developed to measure clotting times with enoxaparin use.To correlate ENOX times with anti-Xa levels among patients receiving enoxaparin.A total of 166 patients receiving enoxaparin for the prevention of deep venous thrombosis or as treatment during acute coronary syndromes or angioplasty were prospectively studied. Citrated and non-citrated whole-blood (CWB and NCWB) samples were obtained at baseline and peak enoxaparin activity. ENOX times were measured with whole-blood, and the Stachrom anti-Xa assay was performed on the plasma from the remainder of the samples. The Pearson correlation coefficient was used to assess the relationship between these two assays.There was a strong linear correlation between the ENOX times and the anti-Xa activities for both CWB (r=0.89, p<0.001) and NCWB (r=0.82, p<0.001) when considering all 332 samples (baseline and peak). When baseline samples were excluded, the correlation remained strong for CWB ENOX times and anti-Xa levels (r=0.84, p<0.001), but was only moderate for NCWB (r=0.73, p<0.001). A CWB ENOX time of /=200 s corresponded to anti-Xa levels >/=0.8 IU/ml in 96% (93/96) of patients.Rapidpoint ENOX times correlate strongly to anti-Xa activities measured by the Stachrom Heparin Assays for citrated whole-blood samples. This novel test can be used for rapid bedside measurements of enoxaparin anticoagulant activity.

    View details for DOI 10.1016/j.thromres.2004.01.006

    View details for Web of Science ID 000220595700008

    View details for PubMedID 15041274

  • Promise of combined low-molecular-weight heparin and platelet glycoprotein IIb/IIIa inhibition: Results from platelet IIb/IIIa antagonist for the reduction of Acute Coronary Syndrome Events in a Global Organization Network B (PARAGON b) AMERICAN HEART JOURNAL Mukherjee, D., Mahaffey, K. W., Moliterno, D. J., Harrington, R. A., Yadav, J. S., Pieper, K. S., Gallup, D., Dyke, C., Roe, M. T., Berdan, L., Lauer, M. S., MANTTARI, M., White, H. D., Califf, R. M., Topol, E. J. 2002; 144 (6): 995-1002

    Abstract

    Low-molecular-weight heparin (LMWH) has a more predictable anticoagulant effect than unfractionated heparin (UFH), is easier to administer, and does not require monitoring. Minimal data are available on LMWH combined with platelet glycoprotein (GP) IIb/IIIa inhibitors.In the Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network B (PARAGON B) trial, patients with an acute coronary syndrome were randomized to receive the IIb/IIIa inhibitor lamifiban or a placebo. To rigorously explore the potential benefits of LWMH and GP IIb/IIIa inhibition, we analyzed the rates of ischemic complications and safety outcomes in PARAGON B.Approximately one fifth of the patients received LMWH (805 vs 4395 UFH). For the overall cohort, the incidence of death/myocardial infarction (MI)/severe recurrent ischemia (SRI) was 12.2%, and this composite end point was numerically lowest in the lamifiban with LMWH group (10.2%). Similarly, the incidence of death/MI was 11.0% for the entire cohort and lowest in the lamifiban and LMWH group (9.0%). The lower event rate for patients taking LMWH in the lamifiban group was sustained at 6 months, with a lower revascularization rate (51.5% vs 42.8%) and a lower composite of death/MI (13.8% vs 11.9%). Bleeding was comparable in the 2 heparin groups (1.4% with UFH vs 0.9% with LMWH). The propensity adjusted odds ratio for 30-day revascularization was significantly lower with LMWH (odds ratio 0.67, 95% CI 0.57-0.79, P <.001). There were no significant differences in death/MI/SRI at 30 days (P =.465), death/MI at 30 days (P =.264), and stroke at 30 days with the type of heparin use (P =.201) after propensity risk adjustment.In the PARAGON B trial, use of LMWH in conjunction with a GP IIb/IIIa inhibitor was safe and associated with a lower revascularization rate. These findings support the rationale and promise for combining GP IIb/IIIa blockers and LMWH for future management of acute coronary syndrome.

    View details for DOI 10.1067/mhj.2002.126118

    View details for Web of Science ID 000180186200008

    View details for PubMedID 12486423

  • Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction NEW ENGLAND JOURNAL OF MEDICINE Aviles, R. J., Askari, A. T., Lindahl, B., Wallentin, L., Jia, G., Ohman, E. M., Mahaffey, K. W., Newby, L. K., Califf, R. M., Simoons, M. L., Topol, E. J., Lauer, M. S., Berger, P. 2002; 346 (26): 2047-2052

    Abstract

    Among patients with suspected acute coronary syndromes, cardiac troponin T levels have prognostic value. However, there is concern that renal dysfunction may impair the prognostic value, because cardiac troponin T may be cleared by the kidney.We analyzed the outcomes in 7033 patients enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries IV trial who had complete base-line data on troponin T levels and creatinine clearance rates. The troponin T level was considered abnormal if it was 0.1 ng per milliliter or higher, and creatinine clearance was assessed in quartiles. The primary end point was a composite of death or myocardial infarction within 30 days.Death or myocardial infarction occurred in 581 patients. Among patients with a creatinine clearance above the 25th percentile value of 58.4 ml per minute, an abnormally elevated troponin T level was predictive of an increased risk of myocardial infarction or death (7 percent vs. 5 percent; adjusted odds ratio, 1.7; 95 percent confidence interval, 1.3 to 2.2; P<0.001). Among patients with a creatinine clearance in the lowest quartile, an elevated troponin T level was similarly predictive of increased risk (20 percent vs. 9 percent; adjusted odds ratio, 2.5; 95 percent confidence interval, 1.8 to 3.3; P<0.001). When the creatinine clearance rate was considered as a continuous variable and age, sex, ST-segment depression, heart failure, previous revascularization, diabetes mellitus, and other confounders had been accounted for, elevation of the troponin T level was independently predictive of risk across the entire spectrum of renal function.Cardiac troponin T levels predict short-term prognosis in patients with acute coronary syndromes regardless of their level of creatinine clearance.

    View details for Web of Science ID 000176411900005

    View details for PubMedID 12087140

  • The SYNERGY trial: Study design and rationale AMERICAN HEART JOURNAL Ferguson, J. J., Califf, R. M., Antman, E. M., Cohen, M., Grines, C. L., Kereiakes, D. J., Langer, A., Mahaffey, K. W., Nessel, C. C., Rios-Nogales, L. 2002; 143 (6): 952-960

    Abstract

    Enoxaparin was shown to be superior to unfractionated heparin in the patients with non-ST-segment elevation acute coronary syndromes (ACS) in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events study and the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. However, enoxaparin has had limited acceptance in clinical practice, in part because of the contemporary management of these patients, which includes glycoprotein IIb/IIIa inhibition and the use of early invasive management strategies.The Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is an 8000-patient, prospective, randomized, open-label, multicenter investigation of enoxaparin compared with unfractionated heparin in patients at high risk with non-ST-segment elevation ACS treated with an early invasive strategy. The primary efficacy end point is death or nonfatal myocardial infarction 30 days after enrollment.The SYNERGY trial is the largest study currently planned for the acute therapy of patients with non-ST-segment elevation ACS and the first large trial since the publication of the revised American College of Cardiology/American Heart Association guidelines for the management of these patients. In addition to evaluating the potential superiority of enoxaparin over unfractionated heparin, this investigation will provide important observations of current treatment strategies in patients with ACS.

    View details for DOI 10.1067/mhj.2002.122120

    View details for Web of Science ID 000176525400008

    View details for PubMedID 12075248

  • Safety and efficacy of only 2 weeks of ticlopidine therapy in patients at increased risk of coronary stent thrombosis: Results from the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial AMERICAN HEART JOURNAL Berger, P. B., Mahaffey, K. W., Meier, S. J., Buller, C. E., Batchelor, W., Fry, E. T., Zidar, J. P. 2002; 143 (5): 841-846

    Abstract

    Controversy exists regarding the frequency of late stent thrombosis among patients treated with intracoronary stents and the most appropriate duration of treatment with a thienopyridine that is required to prevent this complication.We analyzed the frequency of stent thrombosis and other ischemic events in the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial. In the ATLAST trial, 1102 patients at increased risk of stent thrombosis (ST-elevation myocardial infarction within 48 hours, diffuse distal disease, a large amount of thrombus, acute closure, residual dissection, etc) were randomly assigned to receive either enoxaparin (40 or 60 mg given every 12 hours for 14 days) or placebo; all patients received aspirin (325 mg daily) and ticlopidine (250 mg twice daily) for only 14 days.The primary end point, the 30-day combined incidence of death, nonfatal myocardial infarction, and urgent revascularization, was reached in 2.3% of patients (1.8% of patients taking enoxaparin vs 2.7% of patients taking placebo; P =.295). However, during the 15th through 30th days, the frequency of ischemic events was only 0.73%, and only 0.27% (3/1102) of patients had possible stent thrombosis (95% CI 0.06, 0.77).The frequency of stent thrombosis and other adverse ischemic events in the 15th through 30th days after stent placement in even high-risk stent patients treated with ticlopidine for only 2 weeks is low whether or not enoxaparin is administered.

    View details for DOI 10.1067/mhj.2002.121929

    View details for Web of Science ID 000176063800015

    View details for PubMedID 12040346

  • Experience with glycoprotein IIb/IIIa antagonists in patients with acute coronary syndromes. Journal of interventional cardiology Kandzari, D. E., Mahaffey, K. W. 2002; 15 (2): 121-129

    View details for PubMedID 12063807

  • Misreporting of myocardial infarction end points: Results of adjudication by a central clinical events committee in the PARAGON-B trial AMERICAN HEART JOURNAL Mahaffey, K. W., Roe, M. T., Dyke, C. K., Newby, L. K., Kleiman, N. S., Connolly, P., Berdan, L. G., Sparapani, R., Lee, K. L., Armstrong, P. W., Topol, E. J., Califf, R. M., Harrington, R. A. 2002; 143 (2): 242-248
  • Misreporting of myocardial infarction end points: results of adjudication by a central clinical events committee in the PARAGON-B trial. Second Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network Trial. American heart journal Mahaffey, K. W., Roe, M. T., Dyke, C. K., Newby, L. K., Kleiman, N. S., Connolly, P., Berdan, L. G., Sparapani, R., Lee, K. L., Armstrong, P. W., Topol, E. J., Califf, R. M., Harrington, R. A. 2002; 143 (2): 242-248

    Abstract

    Myocardial (re)infarction (MI), a common trial end point, can be difficult to identify because of inconclusive signs and symptoms. We examined disagreement between investigator and clinical events committee (CEC) reporting of MIs in an international, randomized trial.The primary end point of the PARAGON-B trial was a 30-day composite of death, MI (CEC adjudicated), or ischemia-driven intervention. If CEC and investigator determinations of MI differed, we sent investigators event summaries and rationales for CEC decisions and asked whether they now agreed with the CEC assessment. If they still disagreed, they were to provide a rationale and supporting data. Such cases were reviewed, and a final decision was made.Overall, 1736 of 5225 (33%) patients had suspected MIs; the CEC adjudicated 483 of 1736 (28%) as MIs. In 404 patients (23%), investigator and CEC assessments of MI differed; 270 MIs were identified by the CEC but not investigators, and 134 were identified by investigators but not the CEC. Most disagreements concerned periprocedural MIs, but some reflected clinical ischemia and enzyme elevations. Letters for 382 disagreements were sent and returned by investigators, and investigators came to agree with CEC assessments in 307 cases (80%). For the other 75 cases (20%), after review the investigators' assessments were confirmed in 10 cases, and the original CEC decisions were supported in the other 65 cases.Investigators misreport MI end points, but most later agree with CEC assessments. These data support standard, independent adjudication of suspected MIs for accurate reporting, which may affect evaluations of therapies, sample-size calculations, and event-rate comparisons across trials.

    View details for PubMedID 11835026

  • Grade III ischemia on presentation with acute myocardial infarction predicts rapid progression of necrosis and less myocardial salvage with thrombolysis CARDIOLOGY Birnbaum, Y., Mahaffey, K. W., Criger, D. A., Gates, K. B., Barbash, G. I., Barbagelata, A., Clemmensen, P., Sgarbossa, E. B., Gibbons, R. J., Rahman, M. A., Califf, R. M., Granger, C. B., Wagner, G. S. 2002; 97 (3): 166-174

    Abstract

    We assessed the relation between baseline electrocardiographic ischemia grades and initial myocardial area at risk (AR) and final infarct size (IS) in 49 patients who had undergone (99m)Tc sestamibi single-photon emission computed tomography before and 6 +/- 1 days after thrombolysis. Patients were classed as having grade III ischemia (ST segment elevation with terminal QRS distortion, n = 19) or grade II ischemia (ST elevation but no terminal QRS distortion, n = 30). We compared AR and IS by baseline ischemia grade and treatment (adenosine vs. placebo) and assessed relations of infarction index (IS/AR ratio x100) to time to thrombolysis, baseline ischemia grade, and adenosine therapy. Time to thrombolysis was similar for grade II and grade III. For placebo- treated patients, the median AR did not differ significantly between grade II (38%) and grade III patients (46%, p = 0.47), nor did median IS (16 vs. 40%, p = 0.096), but the median infarction index was 66 vs. 90% (p = 0.006). For adenosine-treated patients, median AR (21 vs. 26%, p = 0.44), median IS (5 vs. 17%, p = 0.15), and their ratio (31 vs. 67%, p = 0.23) did not differ significantly between grade II and grade III patients. The infarction index independently related to grade III ischemia (p = 0.0121) and adenosine therapy (p = 0.045). Infarct size related to baseline ischemia grade and was reduced by adenosine treatment. Necrosis progressed slowlier with baseline grade II versus III ischemia, which could offer more time for myocardial salvage with reperfusion.

    View details for Web of Science ID 000176567200009

    View details for PubMedID 12077570

  • A randomized, placebo-controlled trial of enoxaparin after high-risk coronary stenting: The ATLAST trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Batchelor, W. B., Mahaffey, K. W., Berger, P. B., DEUTSCH, E., Meier, S., Hasselblad, V., Fry, E. T., Teirstein, P. S., Ross, A. M., Binanay, C. A., Zidar, J. P. 2001; 38 (6): 1608-1613

    Abstract

    We performed a multicenter, double-blind placebo-controlled trial to examine the efficacy and safety of enoxaparin in patients at high risk for stent thrombosis (ST).The optimal antithrombotic regimen for such patients is unknown.We randomized 1,102 patients with clinical, angiographic or ultrasonographic features associated with an increased risk of ST to receive either twice-daily injections of weight-adjusted enoxaparin or placebo for 14 days after stenting. All patients received aspirin and ticlopidine. The primary end point was a 30-day composite end point of death, myocardial infarction (MI) or urgent revascularization.The target enrollment for the study was 2,000 patients. However, the trial was terminated prematurely at 1,102 patients after interim analysis revealed an unexpectedly low event rate. The primary outcome occurred in 1.8% enoxaparin-treated patients versus 2.7% treated with placebo (odds ratio [OR] 0.66; 95% confidence interval [CI] 0.29 to 1.5, p = 0.30); for death or MI the rates were 0.9% vs. 2.2%, respectively (OR 0.41, 95% CI 0.14 to 1.2, p =0.13); and for MI, 0.4% vs. 1.6%, respectively (OR 0.22, 95% CI 0.05 to 0.99, p = 0.04). The groups had comparable rates of major bleeding (3.3% for enoxaparin, 1.6% for placebo, p =0.08), but minor nuisance bleeding was increased with enoxaparin (25% vs. 5.1%, p < 0.001).The clinical outcomes of patients at increased risk of ST are more favorable than previously reported, rendering routine oral antiplatelet therapy adequate for most. However, given its relative safety and potential to reduce the risk of subsequent infarction, a 14-day course of enoxaparin may be considered for carefully selected patients.

    View details for Web of Science ID 000172254600005

    View details for PubMedID 11704394

  • Atrial fibrillation and mortality among patients with acute coronary syndromes without ST-segment elevation: results from the PURSUIT trial. American journal of cardiology Al-Khatib, S. M., Pieper, K. S., Lee, K. L., Mahaffey, K. W., Hochman, J. S., Pepine, C. J., Kopecky, S. L., Akkerhuis, M., Stepinska, J., Simoons, M. L., Topol, E. J., Califf, R. M., Harrington, R. A. 2001; 88 (1): A7-?

    View details for PubMedID 11423065

  • Disagreements between central clinical events committee and site investigator assessments of myocardial infarction endpoints in an international clinical trial: review of the PURSUIT study CURRENT CONTROLLED TRIALS IN CARDIOVASCULAR MEDICINE Mahaffey, K. W., Harrington, R. A., Akkerhuis, M., Kleiman, N. S., Berdan, L. G., Crenshaw, B. S., Tardiff, B. E., Granger, C. B., DeJong, I., Bhapkar, M., Widimsky, P., Corbalon, R., Lee, K. L., Deckers, J. W., Simoons, M. L., Topol, E. J., Califf, R. M. 2001; 2 (4): 187-194
  • Systematic adjudication of myocardial infarction end-points in an international clinical trial CURRENT CONTROLLED TRIALS IN CARDIOVASCULAR MEDICINE Mahaffey, K. W., Harrington, R. A., Akkerhuis, M., Kleiman, N. S., Berdan, L. G., Crenshaw, B. S., Tardiff, B. E., Granger, C. B., DeJong, I., Bhapkar, M., Widimsky, P., Corbalon, R., Lee, K. L., Deckers, J. W., Simoons, M. L., Topol, E. J., Califf, R. M. 2001; 2 (4): 180-186
  • Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial LANCET Tcheng, J. E., O'Shea, J. C., Cohen, E. A., Pacchiana, C. M., Kitt, M. M., Lorenz, T. J., Greenberg, S., Strony, J., Califf, R. M., Buller, C., Cantor, W. J., Joseph, D. M., Kitt, M. M., Lincoff, A. M., Madan, M., Popma, J., Teirstein, P., Cohen, E., Balleza, L., Parsons, P., Lui, H., Young, J., Fox, R., Labinaz, M., Jelley, J., Williams, J., Cohen, D., Trovato, M., Smith, J., Henry, P., Chisholm, R., O'Donnell, D., Talley, J. D., Pacheco, R., Timmis, S., Muraka, A., Mann, T., Cubeddu, G., Tannenbaum, M., Greene, J., Santoian, E., Wash, M., Sheldon, S., Pronesti, L., Jain, A., Alonzo, M., Seidelin, P., Richards, J., Lopez, M., Dittenber, R., Johnson, K., Levine, G., Maresh, K., Ferrando, T., Sarembock, I., Snyder, L., Kieval, J., Herlan, L., Miller, M., Bembridge, D., Nair, R., Hickel, L., Kiernan, F., Murphy, D., Cloutier, J., Conn, E., Beardsley, J., Ritchie, M., Cragen, D., Jafar, M. Z., Counihan, P., Rosenfelder, D., Ducas, J., Montebruno, L., Carere, R., Radons, B., Williams, L., Owens, W., Dougal, R., Feldman, R., Audrain, D., Karamali, A., Smith, M., Blankenship, J., Demko, S. L., Thompson, M., Gacoich, G., Chiodo, V., Noll, P., Ledley, G., Miller, C., Felten, W., Garner, B., Chandler, A. B., Easler, P., Albin, G., Page, A., Maddox, W., Allen, S., Gilchrist, I., Moore, R., Zimmerman, H., Curtis, M., Hildebrand, K., Greene, R., Healy, E., Meengs, W., Carson, D., George, J., Roncevich, T., Aharonian, V., Browning, R., Kostuk, W., Carr, S., Feit, F., Gostomsky, B., BUTMAN, S., Hannah, E., Hassel, C. D., Hartley, D., Shook, T., Hiller-Mullin, S., Brill, D., Dillion, M., Armstrong, B., Kerns, D., Pichard, A., Okubagzi, P., Nasser, T., Driver, L., GARRETT, J., Boltey, L., Stouffer, G., Potter, M., Amidon, T., Eggert, S., Taussig, A., Potter, K., Natarajan, M., Tartaglia, C., WERNER, J., Dunlap, T., Harrold-Runge, P., Davidson, C., Goodreau, L., Herzog, W., Calamunci, N., Slater, A., Tormey, D., Phillips, W., White, D., Sridhar, K., WHITE, J., Goodman, D., Buchbinder, M., Nasser, V., Rapeport, K., Vorman, P., Weiner, B., Borbone, M., Shadoff, N., Paap, C., Rehman, A., Haag, E., Burchenal, J., Kioussopoulos, K., Senior, D., Senior, J., Piana, R., Kirshenbaum, J., Chan, S., Chowdry, A., Kraft, P., Clark, V., Fox, M., DEUTSCH, E., Shannon, T., Quesada, R., Brotherton, J., Murrin, C., Cinderella, J., Hearne, S., Seefried, V., Farah, T., Pakstis, D., Bartolet, B., Bond, C., Debarardinis, C., Montory, D., Smith, G., Gray, D., Phillips, P., Hathaway, S., Manoukian, S., Patrick, C., Yakubov, S., Brooks, J., Block, P., Block, B., Muhlestein, J. B., Kim, S., Shalev, Y., Schmidt, W., Resar, J., Citro, K., Stine, R., Zumbuhl, J., Moreyra, A., Kreiger, S., Berger, P., Cannon, C. P., Fisher, L., Hasselblad, V., Foster, A., Joseph, D., Madan, M., McLendon, C., Rund, M., Tillery, N., Wood, F., Mahaffey, K. W., Irwin, C., Kulick, D., Johnson, N., Chen, J., Greenberg, S., Hogeboom, C., Lorenz, T. J., Terifay, R., Strony, J., Veltri, E. 2000; 356 (9247): 2037-2044

    Abstract

    The platelet glycoprotein IIb/IIIa inhibitors, although effective in reducing ischaemic complications of percutaneous coronary intervention, are used in few coronary stent implantation procedures. ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) is a randomised, placebo-controlled trial to assess whether a novel, double-bolus dose of eptifibatide could improve outcomes of patients undergoing coronary stenting.We recruited 2064 patients undergoing stent implantation in a native coronary artery. Immediately before percutaneous coronary intervention, patients were randomly allocated to receive eptifibatide, given as two 180 microg/kg boluses 10 min apart and a continuous infusion of 2.0 microg/kg/min for 18-24 h, or placebo, in addition to aspirin, heparin, and a thienopyridine. The primary endpoint was the composite of death, myocardial infarction, urgent target vessel revascularisation, and thrombotic bailout glycoprotein IIb/IIIa inhibitor therapy within 48 h after randomisation. The key secondary endpoint was the composite of death, myocardial infarction, or urgent target vessel revascularisation at 30 days.The trial was terminated early for efficacy. The primary endpoint was reduced from 10.5% (108 of 1024 patients on placebo [95% CI 8.7-12.4%]) to 6.6% (69 of 1040 [5.1-8.1%]) with treatment (p=0.0015). The key 30 day secondary endpoint was also reduced, from 10.5% (107 of 1024 patients on placebo [8.6-12.3%]) to 6.8% (71 of 1040 [5.3-8.4%]; p=0.0034). There was consistency in reduction of events across all components of the composite endpoint and among the major subgroups. Major bleeding was infrequent but arose more often with eptifibatide than placebo (1.3%, 13 of 1040 [0.7-2.1%]) vs 0.4%, 4 of 1024 [0.1-1.0%]; p=0.027).Routine glycoprotein IIb/IIIa inhibitor pretreatment with eptifibatide substantially reduces ischaemic complications in coronary stent intervention and is better than a strategy of reserving treatment to the bailout situation.

    View details for Web of Science ID 000165994300009

    View details for PubMedID 11145489

  • Bivalirudin in patients with heparin-induced thrombocytopenia undergoing percutaneous coronary intervention. journal of invasive cardiology Campbell, K. R., Mahaffey, K. W., Lewis, B. E., Weitz, J. I., Berkowitz, S. D., Ohman, E. M., Califf, R. M. 2000; 12: 14F-9

    View details for PubMedID 11156729

  • Geographic variability in outcomes within an international trial of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes - Results from PURSUIT EUROPEAN HEART JOURNAL Akkerhuis, K. M., Deckers, J. W., Boersma, E., Harrington, R. A., Stepinska, J., Mahaffey, K. W., Wilcox, R. G., Lincoff, A. M., Keltai, M., Topol, E. J., Califf, R. M., Simoons, M. L. 2000; 21 (5): 371-381

    Abstract

    Variations in outcome of patients from different geographic regions have been observed in many large international trials. We analysed the factors that might contribute to the geographic variations in patient outcome and treatment effect as observed in the PURSUIT trial.In PURSUIT, 9461 patients with acute coronary syndromes without persistent ST-elevation were randomized to the platelet inhibitor eptifibatide or placebo for 72 h in 27 countries in four geographic regions: Western (n=3697) and Eastern Europe (n=1541) as well as North (n=3827) and Latin America (n=396). The primary end-point was the 30-day composite of death or myocardial infarction. In the initial univariate analysis, the treatment effect appeared greater in N. America than in W. Europe, while no benefit was apparent in L. America and E. Europe. However, the confidence intervals were wide and overlapping. To study these differences, a subdivision in an early and late patient outcome and treatment effect was made. Accordingly, we analysed the rate of death or infarction at 72 h censored for percutaneous coronary intervention and the rate between 3 and 30 days, respectively. Additional analyses were performed with different definitions of myocardial infarction using progressively higher thresholds of CK(-MB) elevation. Multivariable analysis was used to evaluate the relation between region and outcome and to determine the adjusted odds ratios for the eptifibatide treatment effect.Major differences in baseline demographics were apparent among the four regions; in particular, more patients from E. Europe had characteristics associated with impaired outcome. Interventional treatment also varied considerably, with more patients from N. America undergoing revascularization. Despite differences in the 72 h event rate, eptifibatide showed a consistent trend towards a reduction in the composite end-point among all four regions and for all definitions of infarction. Relative reductions ranged from 17-42% in W. Europe, 23-35% in N. America, 0-33% in E. Europe, and 55-82% in L. America. After multivariable adjustment, the pattern of benefit with eptifibatide was consistent among the regions. In patients undergoing percutaneous coronary intervention during study drug infusion in W. Europe (n=266) and N. America (n=931), the relative reduction in myocardial infarction during medical therapy ranged from 56-75% in W. Europe and 14-67% in N. America, while the reduction in procedure-related events ranged from 12-44% and 25-61% for different definitions of infarction. After multivariable adjustment neither benefit nor rebound were apparent after study drug discontinuation, or after 3 days in all regions, except in L. America. In general, the differences in outcome and treatment effect were greatest when the protocol definition of myocardial infarction (CK(-MB) >1 upper normal limit) was applied. Under stricter definitions, these differences became smaller and disappeared with the investigator's assessment.The analysis suggests that the apparent differences in patient outcome and eptifibatide treatment effect can be explained largely by differences in baseline demographics and adjunctive treatment strategies as well as by the methodology of myocardial infarction definition and the adjudication process.

    View details for Web of Science ID 000085515100010

    View details for PubMedID 10666351

  • Cost-effectiveness of platelet glycoprotein IIb/IIIa inhibition with eptifibatide in patients with non-ST-elevation acute coronary syndromes CIRCULATION Mark, D. B., Harrington, R. A., Lincoff, A. M., Califf, R. M., Nelson, C. L., Tsiatis, A. A., Buell, H., Mahaffey, K. W., Davidson-Ray, L., Topol, E. J. 2000; 101 (4): 366-371

    Abstract

    In the PURSUIT trial, eptifibatide significantly reduced the 30-day incidence of death and myocardial infarction relative to placebo in 9461 patients with an acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction).We conducted a 2-part prospective economic substudy of the 3522 US patients enrolled in PURSUIT: (1) an empirical intention-to-treat comparison of medical costs (hospital plus physician) up to 6 months after hospitalization and (2) a lifetime cost-effectiveness analysis. The base-case cost-effectiveness ratio was expressed as the 1996 US dollars required to add 1 life-year with eptifibatide therapy. The 2 treatment arms had equivalent resource consumption and medical costs (exclusive of the cost of the eptifibatide regimen) during the index (enrollment) hospitalization (P=0.78) and up to 6 months afterward (P=0.60). The average wholesale price of the eptifibatide regimen was $1217, but a typical hospital discounted price was $1014. The estimated life expectancy from randomization in the US patients was 15.96 years for eptifibatide and 15.85 years for placebo, an incremental difference of 0.111. The incremental cost-effectiveness ratio for eptifibatide therapy in US PURSUIT patients was $16 491 per year of life saved. This result was robust through a wide range of sensitivity analyses. The cost-utility ratio for eptifibatide (using time trade-off defined utilities) was $19 693 per added quality-adjusted life-year.Based on the results observed in the US PURSUIT patients, the routine addition of eptifibatide to standard care for non-ST-elevation acute coronary syndrome patients is economically attractive by conventional standards.

    View details for Web of Science ID 000085064400011

    View details for PubMedID 10653826

  • Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction - Results of a multicenter, randomized, placebo-controlled trial: The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Mahaffey, K. W., Puma, J. A., Barbagelata, N. A., DiCarli, M. F., Leesar, M. A., Browne, K. F., Eisenberg, P. R., Bolli, R., Casas, A. C., Molina-Viamonte, V., Orlandi, C., Blevins, R., Gibbons, R. J., Califf, R. M., Granger, C. B. 1999; 34 (6): 1711-1720

    Abstract

    The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial was designed to test the hypothesis that adenosine as an adjunct to thrombolysis would reduce myocardial infarct size.Reperfusion therapy for acute myocardial infarction (MI) has been shown to reduce mortality, but reperfusion itself also may have deleterious effects.The AMISTAD trial was a prospective, open-label trial of thrombolysis with randomization to adenosine or placebo in 236 patients within 6 h of infarction onset. The primary end point was infarct size as determined by Tc-99 m sestamibi single-photon emission computed tomography (SPECT) imaging 6+/-1 days after enrollment based on multivariable regression modeling to adjust for covariates. Secondary end points were myocardial salvage index and a composite of in-hospital clinical outcomes (death, reinfarction, shock, congestive heart failure or stroke).In all, 236 patients were enrolled. Final infarct size was assessed in 197 (83%) patients. There was a 33% relative reduction in infarct size (p = 0.03) with adenosine. There was a 67% relative reduction in infarct size in patients with anterior infarction (15% in the adenosine group vs. 45.5% in the placebo group) but no reduction in patients with infarcts located elsewhere (11.5% for both groups). Patients randomized to adenosine tended to reach the composite clinical end point more often than those assigned to placebo (22% vs. 16%; odds ratio, 1.43; 95% confidence interval, 0.71 to 2.89).Many agents thought to attenuate reperfusion injury have been unsuccessful in clinical investigation. In this study, adenosine resulted in a significant reduction in infarct size. These data support the need for a large clinical outcome trial.

    View details for Web of Science ID 000083778300011

    View details for PubMedID 10577561

  • Neurosurgical evacuation of intracranial hemorrhage after thrombolytic therapy for acute myocardial infarction: Experience from the GUSTO-I Trial AMERICAN HEART JOURNAL Mahaffey, K. W., Granger, C. B., Sloan, M. A., Green, C. L., Gore, J. M., Weaver, W. D., White, H. D., Simoons, M. L., Barbash, G. I., Topol, E. J., Califf, R. M. 1999; 138 (3): 493-499

    Abstract

    Intracranial hemorrhage is an uncommon but very dangerous complication in patients receiving thrombolytic therapy for acute myocardial infarction. Neurosurgical evacuation is often an available treatment option. However, the association between neurosurgical evacuation and clinical outcomes in these patients has yet to be determined.The GUSTO-I trial randomly assigned 41,021 patients with acute myocardial infarction to 1 of 4 thrombolytic strategies in 1081 hospitals in 15 countries. A total of 268 patients (0.65%) had an intracranial hemorrhage. We assessed differences in clinical characteristics, neuroimaging features, Glasgow coma scale scores, functional status (disabled: moderate or severe deficit; not disabled: no or minor deficit) and 30-day mortality rate between the 46 patients who underwent neurosurgical evacuation and the 222 patients who did not.Mortality rate at 30 days for all patients with intracranial hemorrhage was 60%; an additional 27% were disabled. Evacuation was associated with significantly higher 30-day survival (65% versus 35%, P <.001) and a trend toward improved functional status (nondisabling stroke: 20% versus 12%, P =.15).Although intracranial hemorrhage is uncommon after thrombolysis for acute myocardial infarction, 87% of patients die or have disabling stroke. Although not definitive, these data indicate that neurosurgical evacuation may be associated with improved clinical outcomes. Physicians treating such patients should consider early neurosurgical consultation and intervention in these patients.

    View details for Web of Science ID 000082401900019

    View details for PubMedID 10467200

  • Stroke in patients with acute coronary syndromes - Incidence and outcomes in the platelet glycoprotein IIb/IIIa in unstable angina: Receptor suppression using integrilin therapy (PURSUIT) trial CIRCULATION Mahaffey, K. W., Harrington, R. A., Simoons, M. L., Granger, C. B., Graffagnino, C., Alberts, M. J., Laskowitz, D. T., MILLER, J. M., Sloan, M. A., Berdan, L. G., MacAulay, C. M., Lincoff, A. M., Deckers, J., Topol, E. J., Califf, R. M. 1999; 99 (18): 2371-2377

    Abstract

    The incidence of stroke in patients with acute coronary syndromes has not been clearly defined because few trials in this patient population have been large enough to provide stable estimates of stroke rates.We studied the 10 948 patients with acute coronary syndromes without persistent ST-segment elevation who were randomly assigned to placebo or the platelet glycoprotein IIb/IIIa receptor inhibitor eptifibatide in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial to determine stroke rates, stroke types, clinical outcomes in patients with stroke, and independent baseline clinical predictors for nonhemorrhagic stroke. Stroke occurred in 79 (0.7%) patients, with 66 (0.6%) nonhemorrhagic, 6 intracranial hemorrhages, 3 cerebral infarctions with hemorrhagic conversion, and 4 of uncertain cause. There were no differences in stroke rates between patients who received placebo and those assigned high-dose eptifibatide (odds ratios and 95% confidence intervals 0.82 [0.59, 1.14] and 0.70 [0.49, 0.99], respectively). Of the 79 patients with stroke, 17 (22%) died within 30 days, and another 26 (32%) were disabled by hospital discharge or 30 days, whichever came first. Higher heart rate was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by older age, prior anterior myocardial infarction, prior stroke or transient ischemic attack, and diabetes mellitus. These factors were used to develop a simple scoring nomogram that can predict the risk of nonhemorrhagic stroke.Stroke was an uncommon event in patients with acute coronary syndromes in the PURSUIT trial. These strokes are, however, associated with substantial morbidity and mortality rates. The majority of strokes were of nonhemorrhagic causes. Eptifibatide was not associated with an increase in intracranial hemorrhage, and no significant effect on nonhemorrhagic stroke was observed. We developed a useful nomogram for assigning baseline nonhemorrhagic stroke risk in this patient population.

    View details for Web of Science ID 000080143300005

    View details for PubMedID 10318656

  • Effects of stroke on medical resource use and costs in acute myocardial infarction CIRCULATION Tung, C. Y., Granger, C. B., Sloan, M. A., Topol, E. J., KNIGHT, J. D., Weaver, W. D., Mahaffey, K. W., White, H., Clapp-Channing, N., Simoons, M. L., Gore, J. M., Califf, R. M., Mark, D. B. 1999; 99 (3): 370-376

    Abstract

    Stroke occurs concurrently with myocardial infarction (MI) in approximately 30 000 US patients each year. This number is expected to rise with the increasing use of thrombolytic therapy for MI. However, no data exist for the economic effect of stroke in the setting of acute MI (AMI). The purpose of this prospective study was to assess the effect of stroke on medical resource use and costs in AMI patients in the United States.Medical resource use and cost data were prospectively collected for 2566 randomly selected US GUSTO I patients (from 23 105 patients) and for the 321 US GUSTO I patients who developed non-bypass surgery-related stroke during the baseline hospitalization. Follow-up was for 1 year. All costs are expressed in 1993 US dollars. During the baseline hospitalization, stroke was associated with a reduction in cardiac procedure rates and an increase in length of stay, despite a hospital mortality rate of 37%. Together with stroke-related procedural costs of $2220 per patient, the baseline medical costs increased by 44% ($29 242 versus $20 301, P<0.0001). Follow-up medical costs were substantially higher for stroke survivors ($22 400 versus $5282, P<0.0001), dominated by the cost of institutional care. The main determinant for institutional care was discharge disability status. The cumulative 1-year medical costs for stroke patients were $15 092 higher than for no-stroke patients. Hemorrhagic stroke patients had a much higher hospital mortality rate than non-hemorrhagic stroke patients (53% versus 15%, P<0.001), which was associated with approximately $7200 lower mean baseline hospitalization cost. At discharge, hemorrhagic stroke patients were more likely to be disabled (68% versus 46%, P=0.002).In this first large prospective economic study of stroke in AMI patients, we found that strokes were associated with a 60% ($15 092) increase in cumulative 1-year medical costs. Baseline hospitalization costs were 44% higher because of longer mean lengths of stay. Stroke type was a key determinant of baseline cost. Follow-up costs were more than quadrupled for stroke survivors because of the need for institutional care. Disability level was the main determinant of institutional care and thus of follow-up costs.

    View details for Web of Science ID 000078211300009

    View details for PubMedID 9918523

  • Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tardiff, B. E., Califf, R. M., Tcheng, J. E., Lincoff, A. M., Sigmon, K. N., Harrington, R. A., Mahaffey, K. W., Ohman, E. M., Teirstein, P. S., Blankenship, J. C., Kitt, M. M., Topol, E. J. 1999; 33 (1): 88-96

    Abstract

    We examined the relations of elevated creatine kinase (CK) and its myocardial band isoenzyme (CK-MB) to clinical outcomes after percutaneous coronary intervention (PCI) in patients enrolled in Integrilin (eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II (trial) (IMPACT-II), a trial of the platelet glycoprotein IIb/IIIa inhibitor eptifibatide.Elevation of cardiac enzymes often occurs after PCI, but its clinical implications are uncertain.Patients undergoing elective, scheduled PCI for any indication were analyzed. Parallel analyses investigated CK (n=3,535) and CK-MB (n=2,341) levels after PCI (within 4 to 20 h). Clinical outcomes at 30 days and 6 months were stratified by postprocedure CK and CK-MB (multiple of the site's upper normal limit).Overall, 1,779 patients (76%) had no CK-MB elevation; CK-MB levels were elevated to 1 to 3 times the upper normal limit in 323 patients (13.8%), to 3 to 5 times normal in 84 (3.6%), to 5 to 10 times normal in 86 (3.7%), and to >10 times normal in 69 patients (2.9%). Elevated CK-MB was associated with an increased risk of death, reinfarction, or emergency revascularization at 30 days, and of death, reinfarction, or surgical revascularization at 6 months. Elevated total CK to above three times normal was less frequent, but its prognostic significance paralleled that seen for CK-MB. The degree of risk correlated with the rise in CK or CK-MB, even for patients with successful procedures not complicated by abrupt closure.Elevations in cardiac enzymes, including small increases (between one and three times normal) often not considered an infarction, are associated with an increased risk for short-term adverse clinical outcomes after successful or unsuccessful PCI.

    View details for Web of Science ID 000078088300015

    View details for PubMedID 9935014

  • The use of tomographic myocardial perfusion scanning to evaluate an electrocardiographic salvage estimation method in patients with acute myocardial infarction: An AMISTAD substudy JOURNAL OF ELECTROCARDIOLOGY Barbagelata, A., Di Carli, M. F., Sgarbossa, E. B., Califf, R. M., Clemmensen, P., Criger, D. A., Gates, K. B., Gibbons, R. J., Casabe, H., Granger, C. B., Wagner, G. S., Mahaffey, K. W. 1999; 32: 111-113

    View details for Web of Science ID 000085220300023

    View details for PubMedID 10688313

  • Prediction of 30-day mortality among patients with thrombolysis-related intracranial hemorrhage CIRCULATION Sloan, M. A., Sila, C. A., Mahaffey, K. W., Granger, C. B., Longstreth, W. T., Koudstaal, P., White, H. D., Gore, J. M., Simoons, M. L., Weaver, W. D., Green, C. L., Topol, E. J., Califf, R. M. 1998; 98 (14): 1376-1382

    Abstract

    Limited information exists on risk factors for mortality after thrombolysis-related intracranial hemorrhage. We wished to determine the characteristics associated with 30-day mortality after thrombolysis-related intracranial hemorrhage.We performed an observational analysis within a randomized trial of 4 thrombolytic therapies, conducted in 1081 hospitals in 15 countries. Patients presented with ST-segment elevation within 6 hours of symptom onset. Our population was composed of the 268 patients who had primary intracranial hemorrhage after thrombolysis. With univariable and multivariable analyses, we identified clinical and brain imaging characteristics that would predict 30-day mortality among these patients. CT or MRI were available for 240 patients (90%). The 30-day mortality rate was 59.7%. Glasgow Coma Scale score, age, time from thrombolysis to symptoms of intracranial hemorrhage, hydrocephalus, herniation, mass effect, intraventricular extension, and volume and location of intracranial hemorrhage were significant univariable predictors. Multivariable analysis of 170 patients with complete data, 98 of whom died, identified the following independent, significant predictors: Glasgow Coma Scale score (chi2, 19.3; P<0. 001), time from thrombolysis to intracranial hemorrhage (chi2, 15.8; P<0.001), volume of intracranial hemorrhage (chi2, 11.6; P<0.001), and baseline clinical predictors of mortality in the overall GUSTO-I trial (chi2, 10.3; P=0.001). The final model had a C-index of 0.931.This model provides excellent discrimination between patients who are likely to live and those who are likely to die after thrombolytic-related intracranial hemorrhage; this may aid in making decisions about the appropriate level of care for such patients.

    View details for Web of Science ID 000076219500005

    View details for PubMedID 9760291

  • Comparison of the ABC/2 estimation technique to computer-assisted volumetric analysis of intraparenchymal and subdural hematomas complicating the GUSTO-1 trial STROKE Gebel, J. M., Sila, C. A., Sloan, M. A., Granger, C. B., Weisenberger, J. P., Green, C. L., Topol, E. J., Mahaffey, K. W. 1998; 29 (9): 1799-1801

    Abstract

    The volume of an intracerebral hemorrhage has been shown to be an important independent predictor of mortality in several reports. A technique for estimating hematoma volume, known as the ABC/2 method, has been proven a reliable, simple bedside technique for the volume measurement of intraparenchymal intracerebral hemorrhage. Subdural hematomas also carry a significant mortality risk but are more amenable to surgical evacuation. A reliable, simple bedside measurement of subdural hematoma volume may prove a valuable tool in prognostication and management of patients with this entity.Computed tomographic (CT) brain scans of 244 patients suffering from intracranial hemorrhage in the GUSTO-1 trial were systematically reviewed. The volumes of 298 intraparenchymal hematomas were measured by the ABC/2 technique, and the volumes of 44 subdural hematomas were measured by an adaptation of this technique and compared to computer-assisted volumetric analysis.Excellent correlation between the techniques were achieved for both subdural (r=0.842; slope, 0.982) and intraparenchymal hematoma volume measurements (r=0.929; slope, 1.11).The ABC/2 method is a simple and accurate technique for the measurement of intraparenchymal hematoma volume, and a simple adaptation allows for a similarly accurate measurement of subdural hematoma volume as well.

    View details for Web of Science ID 000075651800008

    View details for PubMedID 9731597

  • Risk factors for in-hospital nonhemorrhagic stroke in patients with acute myocardial infarction treated with thrombolysis CIRCULATION Mahaffey, K. W., Granger, C. B., Sloan, M. A., Thompson, T. D., Gore, J. M., Weaver, W. D., White, H. D., Simoons, M. L., Barbash, G. I., Topol, E. J., Califf, R. M. 1998; 97 (8): 757-764

    Abstract

    Nonhemorrhagic stroke occurs in 0.1% to 1.3% of patients with acute myocardial infarction who are treated with thrombolysis, with substantial associated mortality and morbidity. Little is known about the risk factors for its occurrence.We studied the 247 patients with nonhemorrhagic stroke who were randomly assigned to one of four thrombolytic regimens within 6 hours of symptom onset in the GUSTO-I trial. We assessed the univariable and multivariable baseline risk factors for nonhemorrhagic stroke and created a scoring nomogram from the baseline multivariable modeling. We used time-dependent Cox modeling to determine multivariable in-hospital predictors of nonhemorrhagic stroke. Baseline and in-hospital predictors were then combined to determine the overall predictors of nonhemorrhagic stroke. Of the 247 patients, 42 (17%) died and another 98 (40%) were disabled by 30-day follow-up. Older age was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by higher heart rate, history of stroke or transient ischemic attack, diabetes, previous angina, and history of hypertension. These factors remained statistically significant predictors in the combined model, along with worse Killip class, coronary angiography, bypass surgery, and atrial fibrillation/flutter.Nonhemorrhagic stroke is a serious event in patients with acute myocardial infarction who are treated with thrombolytic, antithrombin, and antiplatelet therapy. We developed a simple nomogram that can predict the risk of nonhemorrhagic stroke on the basis of baseline clinical characteristics. Prophylactic anticoagulation may be an important treatment strategy for patients with high probability for nonhemorrhagic stroke, but further study is needed.

    View details for Web of Science ID 000072200800009

    View details for PubMedID 9498539

  • Thrombolysis-related intracranial hemorrhage - A radiographic analysis of 244 cases from the GUSTO-1 trial with clinical correlation STROKE Gebel, J. M., Sila, C. A., Sloan, M. A., Granger, C. B., Mahaffey, K. W., Weisenberger, J., Green, C. L., White, H. D., Gore, J. M., Weaver, W. D., Califf, R. M., Topol, E. J. 1998; 29 (3): 563-569

    Abstract

    Intracranial hemorrhage (ICH) is a serious complication of thrombolytic therapy. We systematically reviewed the radiographic features of 244 cases of symptomatic ICH complicating thrombolysis for acute myocardial infarction in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, correlated these observations with clinical data, and speculated on hemorrhage pathogenesis.CT scans from 244 patients suffering symptomatic ICH were systematically reviewed for selected radiographic features, including ICH type, location, hematoma characteristics, mass effect features, hydrocephalus, and preexisting lesions. Hematoma volume was estimated by computer-assisted volumetric analysis. Data from this analysis were correlated with clinical data including hypertension, anticoagulation, age, thrombolytic regimen, and ICH timing.Most hemorrhages were large (median [25th, 75th percentile] volume, 72 mL [39, 118]), solitary (66%), lobar (77%), confluent (80%), and intraparenchymal (82%) with a blood/fluid level (82%) and little edema (median [25th, 75th percentile] volume, 9 mL [5, 16]). Hydrocephalus (P<.001), any one mass effect feature (P<.001), intraventricular hemorrhage (P=.022), mottled hematoma appearance (P=.050), and hematoma blood/fluid level (P<.001) were associated with higher hemorrhage volume in the radiographic analysis, as were older age (P=.005), treatment with combined streptokinase and tissue plasminogen activator (P=.034), and hemorrhage onset 8 to 13 hours after treatment (P=.008) in the clinical analysis. Subdural hemorrhage was a high-volume subgroup whose risk increased with antecedent trauma (P=.026) or syncope (P=.006). Deep intraparenchymal hemorrhage was associated with hypertension (P=.016), and multifocal ICH occurred significantly earlier after treatment (P=.002).Although the majority of postthrombolytic ICH are large, solitary, and supratentorial, the spectrum is diverse. Features of mass effect reflected the large volumes, and hematoma characteristics of mottling and blood/fluid levels were frequent. Thrombolysis-related coagulopathy and age appear to be the most important identifiable factors in the genesis of postthrombolytic ICH, but the hemorrhage subtype seen may reflect an interaction with other factors such as hypertension, ICH timing, antecedent head trauma, and syncope.

    View details for Web of Science ID 000072348900001

    View details for PubMedID 9506593

  • Diabetic retinopathy should not be a contraindication to thrombolytic therapy for acute myocardial infarction: Review of ocular hemorrhage incidence and location in the GUSTO-I trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Mahaffey, K. W., Granger, C. B., Toth, C. A., White, H. D., Stebbins, A. L., Barbash, G. I., Vahanian, A., Topol, E. J., Califf, R. M. 1997; 30 (7): 1606-1610

    Abstract

    This study sought to evaluate the incidence of ocular hemorrhage in patients with and without diabetes after thrombolytic therapy for acute myocardial infarction.Ocular hemorrhage after thrombolysis has been reported rarely. However, there is concern that the risk is increased in patients with diabetes. In fact, diabetic hemorrhagic retinopathy has been identified as a contraindication to thrombolytic therapy without clear evidence that these patients have an increased risk for ocular hemorrhage.We identified all suspected ocular hemorrhages from bleeding complications reported in patients enrolled in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I trial. Additional information was collected on a one-page data form. We compared the incidence and location of ocular hemorrhages in patients with and without diabetes.There were 40,899 patients (99.7%) with information about diabetic history and ocular bleeding. Twelve patients (0.03%) had an ocular hemorrhage. Intraocular hemorrhage was confirmed in only one patient. There were 6,011 patients (15%) with diabetes, of whom only 1 had an ocular hemorrhage (eyelid hematoma after a documented fall). The upper 95% confidence intervals for the incidence of intraocular hemorrhage in patients with and without diabetes were 0.05% and 0.006%, respectively.Ocular hemorrhage and, more important, intraocular hemorrhage after thrombolytic therapy for acute myocardial infarction is extremely uncommon. The calculated upper 95% confidence interval for the incidence of intraocular hemorrhage in patients with diabetes was only 0.05%. We conclude that diabetic retinopathy should not be considered a contraindication to thrombolysis in patients with an acute myocardial infarction.

    View details for Web of Science ID A1997YH37900003

    View details for PubMedID 9385883

  • A comparison of reteplase with alteplase for acute myocardial infarction NEW ENGLAND JOURNAL OF MEDICINE Topol, E., Califf, R., Ohman, E., Wilcox, R., Grinfeld, L., Aylward, P., Simes, R., Probst, P., VandeWerf, F., ARMSTRONG, P., HEIKKILA, J., Vahanian, A., Bode, C., Ostor, E., Ardissino, D., Deckers, J., White, H., Sadowski, Z., SEABRAGOMES, R., Dalby, A., Betriu, A., Emanuelsson, H., Hartford, M., Follath, D., Hampton, J., Bates, E., Gibler, W., Gore, J., Granger, C., Guerci, A., Hochman, J., Holmes, D., Kleiman, N., Moliterno, D., Morris, D., Smalling, R., Weaver, W., Neuhaus, K., Cheitlin, M., Debono, D., Fisher, L., Frye, R., Jensen, G., Alberts, M., Mahaffey, K., Miller, J., Sloan, M. 1997; 337 (16): 1118-1123
  • Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization NEW ENGLAND JOURNAL OF MEDICINE Topol, E. J., Califf, R. M., Lincoff, A. M., Tcheng, J. E., Cabot, C. F., Weisman, H. F., Kereiakes, D., Lausten, D., Runyon, J. P., Howard, W., Kelly, T., Muncy, D., Timmis, G., SAFIAN, M., Davey, D., Kleiman, N. S., Rose, D., Basinger, L., Rouse, C., Kramer, J., Wilson, R., Talley, J. D., Boyles, M., Navetta, F. I., LeBueuf, R., Kraft, P., Dvorak, L., Smigla, R. M., Ferguson, J., Harlan, M., Browne, K., Telatnik, M., Blankenship, J., Demko, L., Ivanhoe, R. J., Jackson, C., Shadoff, N., Goebel, S., Taylor, M., Cleary, E., GACIOCH, G., Chiodo, V., Bates, E., QUAIN, L., Snyder, H., Bass, T. A., Rohman, C., Gradman, A., Boltey, L., Tannenbaum, M., Stengl, D., Gordon, P., Wright, N., Cummins, F., Nonnweiler, J., Aversano, T., PELTZER, L., Bear, P., Craig, M. B., HATTEL, L., Tooke, G., Anderson, H. V., Weigelt, L., Hettleman, B., Kennedy, S., Teirstein, P. S., Claire, D., Sarembock, I., Sayre, S., Davidson, C. J., Schaechter, A., Aguirre, F., Stonner, T., Azrin, M., BODETT, J., Barry, M. B., Worley, S., Frey, L. A., SPRIGGS, D. J., Wahl, S. A., Weston, M. W., Yedinak, K., George, B., Smith, D., Gilliland, C., Smith, D., Ricci, D. R., Fox, R., Hartman, C., Lunow, S., Farah, T., Petruolo, S., Sander, G., Stevens, A., Delise, K., Reen, B., Whisnant, D., Henderson, L., Heuser, R., Swiderski, K., Kaluzniak, M., Larkin, T., JACKSON, B. J., Popma, J., Prunka, N., Sanz, M., Mayer, D., Mackey, K., Burton, J., Hogg, N., Brown, R., Stevens, K., French, W., Wang, S., Adelman, A. G., Foulger, V., Weber, S., Gottlieb, R., Lavoie, J., King, S., Frerichs, F., Hollywood, L., Ducas, J., Schick, U., Hochman, J. S., Slater, J., Tormey, D., ONEILL, B. J., Foshay, K., Fitzgerald, N., Cheung, P. K., Bedard, D., Knudtson, M. L., Galbraith, D., Watt, H., Samaha, J., Hamilton, B., Klein, L. W., Hebson, L., Almond, D., WHITE, J., Rosenberg, M. J., Teully, S., UNKS, M., Rodgers, K., Faxon, D., Gore, J., Kelsey, S., Lee, K., Sane, D., Walters, L., Booth, J., Cannata, R., Castle, V., Cohen, H., DeLuca, S., Kutner, M., Knuth, T., McCollough, T., McPherson, J., Melton, J., Miller, D., Pulliam, M., Sapp, S., Sigmon, K. N., Montague, E., Alexander, K., Augostini, R., Bajzer, C., Bart, B., Belli, G., Carlson, J., Challapalli, R., Crenshaw, B., Dawson, I., Dickey, A., Echols, A., Erickson, B., FONTANA, M. B., Ghaffari, S., Gordon, C., Granger, C., Grano, G., Grimm, R., Johnson, T., Juran, N., Kingsley, A., Kruse, K., Lauer, M., Mahaffey, K., Malone, K., Mark, D., Marwick, T., Migrino, R., Miller, J., Newby, K., Pace, C., Peterson, E., Rabbani, R., Ragan, J., Rimmerman, C., Rodkey, S., Savor, V., Shaw, W. F., Sila, C., Silver, M., Tan, W., Tobiasz, D., Vandervoort, P., Wang, C. W., Ward, C., Waters, J., Wiehle, D., Winchell, M., Underwood, D., Clemons, P., Heupler, S., Powers, J., Rubin, D., Sgarbossa, E., Steinhubl, S., Moliterno, D., Debowey, D., Balazs, E., Crowe, T., Ivanc, T., Ols, L., POLISZCZUK, R., VILSACK, H., Witherspoon, B., DAVIDSONRAY, L., Anderson, K. M., Giel, K. M., Musco, M. H., Stoner, G. L. 1997; 336 (24): 1689-1696
  • Overview of randomized trials of intravenous heparin in patients with acute acute myocardial infarction treated with thrombolytic therapy AMERICAN JOURNAL OF CARDIOLOGY Mahaffey, K. W., Granger, C. B., Collins, R., OCONNOR, C. M., Ohman, E. M., Bleich, S. D., Col, J. J., Califf, R. M. 1996; 77 (8): 551-556

    Abstract

    Intravenous heparin is routinely given after thrombolytic therapy for patients with acute myocardial infarction in the United States and in some, but by no means all, other countries. Several trials have documented improved infarct-artery patency in patients treated with heparin; however, none was large enough individually to assess the effect of heparin on clinical outcomes. We performed a systematic overview of the 6 randomized controlled trials (1,735 patients) to summarize the available data concerning the risks and benefits of intravenous heparin versus no heparin after thrombolytic therapy. Mortality before hospital discharge was 5.1% for patients allocated to intravenous heparin compared with 5.6% for controls (relative risk reduction of 9%, odds ratio 0.91, 95% confidence interval 0.59 to 1.39). Similar rates of recurrent ischemia and reinfarction were observed among those allocated to heparin therapy or control. The rates of total stroke, intracranial hemorrhage, and severe bleeding were similar in patients allocated to heparin; however, the risk of any severity of bleeding was significantly higher (22.7% vs 16.2%; odds ratio 1.55, 95% confidence interval 1.21 to 1.98). There was no significant difference in the observed effects of heparin between patients receiving tissue-type plasminogen activator and those receiving streptokinase or anisoylated plasminogen streptokinase activator complex, or between patients who did and did not receive aspirin. The findings of this overview demonstrate that insufficient clinical outcome data are available to support or to refute the routine use of intravenous heparin therapy after thrombolysis. It is not known if these findings are due to lack of statistical power, inappropriate levels of anticoagulation, or lack of benefit of intravenous heparin. Large randomized studies of heparin (and of new antithrombotic regimens) are needed to establish the role of such therapy.

    View details for Web of Science ID A1996UD08300001

    View details for PubMedID 8610601

  • RAPID BIOASSAY SYSTEM FOR LEAD USING YOUNG JAPANESE QUAIL JOURNAL OF ENVIRONMENTAL PATHOLOGY AND TOXICOLOGY Stone, C. L., Mahaffey, K. R., FOX, M. R. 1979; 2 (3): 767-779

    Abstract

    A rapid bioassay of lead was established in young japanese quail. Each group of 10 day-old birds received deionized water and a purified diet ad libitum for 2 wk. The diet contained 0.2 microgram lead/g. Lead acetate was added to give 14.8, 34.4, 51.2, 74.4, 234, 563, or 1223 microgram total lead/g by analysis. The duodenum, kidneys, liver and tibias were assayed for lead. Consumption of a diet containing either 563 or 1223 ppm lead caused a decrease (P less than or equal to 0.05) in body weight after 1 wk and an increase in free erythrocyte protoporphyrin after 2wk. Inhibition of red blood cell delta-aminolevulinic acid dehydratase (RBC-ALAD) activity occurred in birds consuming as little as 14.8 ppm lead. Packed cell volumes and hemoglobin concentrations were not affected by the dietary treatments. Lead concentrations in tissues from birds fed the lowest level of added lead were greater than those found in the corresponding tissues of control birds. The concentration of lead in the tibia showed the most distinguishable group means and the most nearly linear response; the highest slope was between 14.8 and 110 ppm dietary lead, using log-log transformations. The rapid bioassay is suitable for investigating high lead foods.

    View details for Web of Science ID A1979GM37600014

    View details for PubMedID 422934

  • DELTA-AMINOLEVULINIC-ACID DEHYDRATASE - SENSITIVE INDICATOR OF LEAD-EXPOSURE IN JAPANESE QUAIL POULTRY SCIENCE Stone, C. L., FOX, M. R., Jones, A. L., Mahaffey, K. R. 1977; 56 (1): 174-181
  • INFLUENCE OF ETHANOL INGESTION ON LEAD TOXICITY IN RATS FED ISOCALORIC DIETS ARCHIVES OF ENVIRONMENTAL HEALTH Mahaffey, K. R., Goyer, R. A., Wilson, M. H. 1974; 28 (4): 217-222

    View details for Web of Science ID A1974S835100007

    View details for PubMedID 4814957

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