Bio

Clinical Focus


  • Cardiovascular Disease

Professional Education


  • Residency:Univ Of Ma Med Sch - Worcester (1990) MA
  • Board Certification: Cardiovascular Disease, American Board of Internal Medicine (1993)
  • Fellowship:Duke University Medical Center (1993) NC
  • Board Certification: Internal Medicine, American Board of Internal Medicine (1989)
  • Internship:Univ Of Ma Med Sch - Worcester (1987) MA
  • Medical Education:Tufts University School of Medicine (1986) MA

Publications

Journal Articles


  • 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

  • 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

  • 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

  • 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

  • Radial versus femoral access, bleeding and ischemic events in patients with non-ST-segment elevation acute coronary syndrome managed with an invasive strategy AMERICAN HEART JOURNAL Klutstein, M. W., Westerhout, C. M., Armstrong, P. W., Giugliano, R. P., Lewis, B. S., Gibson, C. M., Lutchmedial, S., Widimsky, P., Steg, P. G., Dalby, A., Zeymer, U., Van de Werf, F., Harrington, R. A., Newby, L. K., Rao, S. V. 2013; 165 (4): 583-?

    Abstract

    Bleeding is a major limitation of antithrombotic therapy among invasively managed non-ST-segment elevation acute coronary syndromes (NSTE-ACS) patients; therefore, we examined the use of radial access and its association with outcomes among NSTE-ACS patients.Clinical characteristics and geographic variation in radial access were examined, as well as its association with bleeding, red blood cell transfusion and ischemic outcomes (96-hour death/myocardial infarction/recurrent ischemic/thrombotic bailout; 30-day death/myocardial infarction; 1-year death) in the EARLY versus delayed, provisional eptifibatide in acute coronary syndromes trial.Of 9126 patients, 13.5% underwent radial-access catheterization. Female sex, age, weight, and prior revascularization were inversely associated with radial access, and its use varied widely by country (2%-97%). There were fewer GUSTO severe/moderate bleeds and red blood cell transfusions in the radial access group; however, it was attenuated after adjustment (odds ratio 0.73, 95% confidence intervals [CI] [0.50-1.06], P = .094 and 1.00 [0.71-1.40] P = .991). Ischemic outcomes did not differ by access site.In this post hoc analysis of a large clinical trial, there was significant international variation in use of radial access for NSTE-ACS patients undergoing invasive management, and it was preferentially used in those at lower risk for bleeding. Radial approach was not associated with a significant reduction in either bleeding or ischemic outcomes. Further study is needed to determine whether wider application of radial approach to acute coronary syndrome patients at high risk for bleeding improves overall outcomes.

    View details for DOI 10.1016/j.ahj.2013.01.009

    View details for Web of Science ID 000317184300021

    View details for PubMedID 23537976

  • Venous thromboembolism prophylaxis: do trial results enable clinicians and patients to evaluate whether the benefits justify the risk? Proceedings of an Ad Hoc Working Group Meeting JOURNAL OF THROMBOSIS AND HAEMOSTASIS Berger, J., Eikelboom, J. W., Quinlan, D. J., Guyatt, G., Buller, H. R., Sobieraj-Teague, M., Harrington, R. A., Hirsh, J. 2013; 11 (4): 778-782

    View details for DOI 10.1111/jth.4900

    View details for Web of Science ID 000317615500027

    View details for PubMedID 23578178

  • ACP Journal Club. PCI using drug-eluting stents had higher mortality than CABG in diabetes and multivessel CAD. Annals of internal medicine Harrington, R. A. 2013; 158 (6): JC8-?
  • 2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards). Circulation Cannon, C. P., Brindis, R. G., Chaitman, B. R., Cohen, D. J., Cross, J. T., Drozda, J. P., Fesmire, F. M., Fintel, D. J., Fonarow, G. C., Fox, K. A., Gray, D. T., Harrington, R. A., Hicks, K. A., Hollander, J. E., Krumholz, H., Labarthe, D. R., Long, J. B., Mascette, A. M., Meyer, C., Peterson, E. D., Radford, M. J., Roe, M. T., Richmann, J. B., Selker, H. P., Shahian, D. M., Shaw, R. E., Sprenger, S., Swor, R., Underberg, J. A., Van de Werf, F., Weiner, B. H., Weintraub, W. S. 2013; 127 (9): 1052-1089

    View details for DOI 10.1161/CIR.0b013e3182831a11

    View details for PubMedID 23357718

  • 2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on clinical data standards (writing committee to develop acute coronary syndromes and coronary artery disease clinical data standards). Journal of the American College of Cardiology Cannon, C. P., Brindis, R. G., Chaitman, B. R., Cohen, D. J., Cross, J. T., Drozda, J. P., Fesmire, F. M., Fintel, D. J., Fonarow, G. C., Fox, K. A., Gray, D. T., Harrington, R. A., Hicks, K. A., Hollander, J. E., Krumholz, H., Labarthe, D. R., Long, J. B., Mascette, A. M., Meyer, C., Peterson, E. D., Radford, M. J., Roe, M. T., Richmann, J. B., Selker, H. P., Shahian, D. M., Shaw, R. E., Sprenger, S., Swor, R., Underberg, J. A., Van de Werf, F., Weiner, B. H., Weintraub, W. S. 2013; 61 (9): 992-1025

    View details for DOI 10.1016/j.jacc.2012.10.005

    View details for PubMedID 23369353

  • A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia. Transfusion Onken, J. E., Bregman, D. B., Harrington, R. A., Morris, D., Acs, P., Akright, B., Barish, C., Bhaskar, B. S., Smith-Nguyen, G. N., Butcher, A., Koch, T. A., Goodnough, L. T. 2013

    Abstract

    BACKGROUND: Many patients receiving oral iron for iron deficiency anemia (IDA) cannot tolerate or fail to respond to therapy, and existing intravenous (IV) iron formulations often require repeated administrations. Ferric carboxymaltose (FCM), a nondextran IV formulation, permits larger single doses. STUDY DESIGN AND METHODS: We evaluated FCM versus oral iron in IDA patients. After 14 days of oral iron, 507 participants responding inadequately to oral iron (hemoglobin [Hb] increase <1?g/dL; Cohort?1) were assigned to Group?A (two doses of FCM, 750?mg, 1 week apart) or Group?B (oral iron, 325?mg, 3?×?day for 14 additional days). Also, 504 subjects not appropriate for oral iron (Cohort?2) were assigned to Group?C (FCM as above) or Group?D (standard-of-care IV iron). The primary efficacy endpoint was change to highest observed Hb from baseline to Day 35. The composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, heart failure, arrhythmias, and hyper- or hypotensive events. RESULTS: Mean (± standard deviation [SD]) Hb increase was significantly greater in Group?A-FCM than Group?B-oral iron: 1.57 (±1.19) g/dL versus 0.80 (±0.80) g/dL (p?=?0.001). Post hoc comparison of Group C-FCM and Group?D-IV standard of care also demonstrated significant mean (±SD) increase in Hb from baseline to highest value by Day 35 in Group?C versus Group?D: 2.90 (±1.64) g/dL versus 2.16 (±1.25) g/dL (p?=?0.001). Safety endpoints occurred in 17 of 499 (3.4%) participants receiving FCM versus 16 of 498 (3.2%) in comparator groups. CONCLUSION: Two 750-mg FCM infusions are safe and superior to oral iron in increasing Hb levels in IDA patients with inadequate oral iron response.

    View details for PubMedID 23772856

  • Quantitative ST-depression in Acute Coronary Syndromes: the PLATO Electrocardiographic Substudy. The American journal of medicine Armstrong, P. W., Westerhout, C. M., Fu, Y., Harrington, R. A., Storey, R. F., Katus, H., James, S., Wallentin, L. 2013; 126 (8): 723-729.e1

    Abstract

    We evaluated whether electrocardiogram (ECG) characteristics were aligned with clinical outcomes and the effect of ticagrelor within the diverse spectrum of non-ST-elevation acute coronary syndrome patients enrolled in the PLATelet inhibition and patient Outcomes (PLATO) trial.There were 8884 PLATO patients who had baseline ECGs assessed by a core laboratory; of these, 4935 had an ECG at hospital discharge that also was assessed. Associations with study treatment on vascular death or myocardial infarction within 1 year were examined.At baseline, most patients had either no or ?0.5 mm of ST-segment depression (57%); 26% had 1.0 mm, and 17% had more extensive depression (>1.0 mm). Across the baseline ST-segment depression strata, there was a consistent treatment benefit with ticagrelor versus clopidogrel on vascular death/myocardial infarction. The extent of residual ST-segment depression at discharge was similar in the treatment groups, and the treatment effect did not differ by the extent of discharge ST-segment depression. There was a progressive increase in vascular death/myocardial infarction with increasing extent of baseline ST-segment depression (1.0 mm [vs no/0.5 mm]: hazard ratio [HR] 1.22; 95% confidence interval [CI], 1.03-1.45; >1.0 mm: HR 1.49; 95% CI, 1.24-1.78; P <.001) and at discharge (HR 1.28; 95% CI, 1.02-1.61; HR 2.13; 95% CI, 1.54-2.95; P <.001).The treatment effect of ticagrelor among non-ST-segment-elevation acute coronary syndrome patients was consistently expressed across all baseline ST-segment depression strata. There was no indication of an anti-ischemic benefit of ticagrelor as reflected on the discharge ECG. Our data affirm the independent prognostic relationship of both baseline and hospital discharge ST-segment depression on outcomes within 1 year in non-ST-segment-elevation acute coronary syndrome patients.

    View details for PubMedID 23795897

  • Response to letter regarding article, "ticagrelor in patients with acute coronary syndromes and stroke: interpretation of subgroups in clinical trials". Stroke; a journal of cerebral circulation James, S. K., Storey, R. F., Pieper, K. S., Cannon, C. P., Becker, R. C., Steg, P. G., Wallentin, L., Harrington, R. A. 2013; 44 (8): e95-6

    View details for PubMedID 23800556

  • 2013 ACCF/AHA Key Data Elements and Definitions for Measuring the Clinical Management and Outcomes of Patients With Acute Coronary Syndromes and Coronary Artery Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards). Critical pathways in cardiology Cannon, C. P., Brindis, R. G., Chaitman, B. R., Cohen, D. J., Cross, J. T., Drozda, J. P., Fesmire, F. M., Fintel, D. J., Fonarow, G. C., Fox, K. A., Gray, D. T., Harrington, R. A., Hicks, K. A., Hollander, J. E., Krumholz, H., Labarthe, D. R., Long, J. B., Mascette, A. M., Meyer, C., Peterson, E. D., Radford, M. J., Roe, M. T., Richmann, J. B., Selker, H. P., Shahian, D. M., Shaw, R. E., Sprenger, S., Swor, R., Underberg, J. A., Van de Werf, F., Weiner, B. H., Weintraub, W. S. 2013; 12 (2): 65-105

    View details for PubMedID 23680811

  • Relationship between postoperative clopidogrel use and subsequent angiographic and clinical outcomes following coronary artery bypass grafting. Journal of thrombosis and thrombolysis Williams, J. B., Lopes, R. D., Hafley, G. E., Bruce Ferguson, T., Mack, M. J., Michael Gibson, C., Harrington, R. A., Peterson, E. D., Smith, P. K., Mehta, R. H., Alexander, J. H. 2013

    Abstract

    Dual antiplatelet therapy with both aspirin and clopidogrel is increasingly used after coronary artery bypass grafting (CABG); however, little is known about the safety or efficacy. We sought to determine the relationship between postoperative clopidogrel and clinical and angiographic outcomes following CABG. We evaluated 3,014 patients from PREVENT IV who underwent CABG at 107 US sites. Postoperative antiplatelet therapy was left to physician discretion. Risk-adjusted angiographic and clinical outcomes were compared in patients taking and not taking clopidogrel 30 days post-CABG. At 30 days, 633 (21 %) patients were taking clopidogrel. Clopidogrel users were more likely to have peripheral vascular (15 vs. 11 %) and cerebrovascular disease (17 vs. 11 %), prior myocardial infarction (MI) (46 vs. 41 %), and off-pump surgery (33 vs. 18 %). Clopidogrel use was associated with statistically insignificant higher graft failure (adjusted odds ratio 1.3; 95 % confidence interval [CI] [1.0, 1.7]; P = 0.05). At 5-year follow-up, clopidogrel use was associated with similar composite rates of death, MI, or revascularization (27 vs. 24 %; adjusted hazard ratio 1.1; 95 % CI [0.9, 1.4]; P = 0.38) compared with those not using clopidogrel. There was an interaction between use of cardiopulmonary bypass and clopidogrel with a trend toward lower 5-year clinical events with clopidogrel in patients undergoing off-pump CABG. In this observational analysis, clopidogrel use was not associated with better 5-year outcomes following CABG. There may be better outcomes with clopidogrel among patients having off-pump surgery. Adequately powered randomized clinical trials are needed to determine the role of dual antiplatelet therapy after CABG.

    View details for PubMedID 23543398

  • Angiographic Outcomes in the PLATO Trial (Platelet Inhibition and Patient Outcomes). JACC. Cardiovascular interventions Kunadian, V., James, S. K., Wojdyla, D. M., Zorkun, C., Wu, J., Storey, R. F., Steg, P. G., Katus, H., Emanuelsson, H., Horrow, J., Maya, J., Wallentin, L., Harrington, R. A., Gibson, C. M. 2013; 6 (7): 671-83

    Abstract

    The PLATO (Platelet Inhibition and Patient Outcomes) angiographic substudy sought to compare the efficacy of ticagrelor versus clopidogrel with respect to angiographic outcomes before and after PCI in the setting of acute coronary syndrome.Greater platelet inhibition has been associated with improved angiographic outcomes before and after percutaneous coronary intervention (PCI). Therefore, it was hypothesized that treatment with ticagrelor, which achieves more rapid, higher, and more consistent platelet inhibition, would be associated with improved angiographic outcomes when compared with those of clopidogrel treatment.The angiographic cohort consists of 2,616 patients drawn from the 18,624-patient PLATO trial. Clopidogrel naïve or pre-treated patients were randomized to 180 mg of ticagrelor or 300 mg of clopidogrel (75 mg for clopidogrel pre-treated patients). PCI patients were administered, as per treatment group: 1) an additional 90 mg of ticagrelor if >24 h following the initial loading dose; or 2) an optional further 300 mg of clopidogrel or placebo (total 600 mg) prior to PCI. The substudy primary endpoint was the incidence of post-PCI TIMI (Thrombolysis In Myocardial Infarction) myocardial perfusion grade 3 (TMPG 3) among patients who received a study drug prior to PCI.In total, 21.3% of patients were pretreated with clopidogrel prior to randomization. There was a short time interval between randomization and PCI (median: 0.68 [interquartile range (IQR): 0.30 to 2.21] h) among all patients. Post-PCI TMPG 3 was similar between the ticagrelor and clopidogrel groups (47.1% vs. 46.9%; p = 0.96). Likewise, the following pre-PCI outcomes were similar in the ticagrelor and clopidogrel groups, respectively: TMPG 3 (30.5% vs. 31.2%), TIMI flow grade 3 (37.1% vs. 39.3%), corrected TIMI frame count (median: 100 vs. 71 frames), TIMI thrombus grade 0 (24.1% vs. 27.6%), minimum lumen diameter (median: 0.3 [IQR: 0.0 to 0.6] vs. 0.3 [IQR: 0.0 to 0.6] mm) and percentage of diameter stenosis (median: 89 [IQR: 78 to 100] vs. 89 [IQR: 77 to 100]).Neither coronary flow nor myocardial perfusion, evaluated on coronary angiograms performed before or following PCI procedures within a few hours after the start of oral antiplatelet treatment in the setting of acute coronary syndromes, demonstrated a difference with ticagrelor versus clopidogrel. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

    View details for PubMedID 23866179

  • Platelet inhibition with cangrelor during PCI. The New England journal of medicine Bhatt, D. L., Harrington, R. A. 2013; 369 (4): 393-4

    View details for PubMedID 23883387

  • Response to letter regarding article, “sustained ventricular tachycardia and ventricular fibrillation complicating non–ST-segment elevation acute coronary syndromes”. Circulation Piccini, J. P., White, J. A., Mehta, R. H., Lokhnygina, Y., Al-Khatib, S. M., Tricoci, P., Califf, R. M., Harrington, R. A., Newby, L. K., Pollack, C. V., Montalescot, G., Van de Werf, F., Gibson, C. M., Giugliano, R. P. 2013; 127 (20): e634

    View details for PubMedID 23833786

  • ACP Journal Club. Intraaortic balloon counterpulsation did not reduce mortality in acute MI with cardiogenic shock. Annals of internal medicine Harrington, R. A. 2012; 157 (12): JC6-11
  • Conversion of Cardiovascular Conference Abstracts to Publications CIRCULATION Fosbol, E. L., Fosbol, P. L., Harrington, R. A., Eapen, Z. J., Peterson, E. D. 2012; 126 (24): 2819-?

    Abstract

    The transition of scientific knowledge from discovery into practice is less than ideal. A key step in this translation occurs when presentations from major meetings are published in peer-reviewed literature, yet the completeness and speed of this process are not known. We performed a systematic and automated evaluation of rates, timing, and correlates of publication from scientific abstracts presented at 3 major cardiovascular conferences.Using an automated computer algorithm, we searched the ISI Web of Science to identify peer-reviewed publications of abstracts presented at the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC) scientific sessions from 2006 to 2008. We compared abstract publication rates and journal impact factor between the 3 meetings using multivariable logistic regression modeling. From 2006 to 2008, 11 365, 5005, and 10 838 abstracts were presented at the AHA, ACC, and ESC meetings, respectively. Overall, 30.6% of presented abstracts were published within 2 years of the conference; ranging from 34.5% for AHA to 29.5% for ACC to 27.0% for ESC (P<0.0001). Five years after conference presentation in 2005, these rates had risen slightly to 49.7% for AHA, 42.6% for ACC, and 37.6% for ESC (P<0.0001). After adjustment for abstract characteristics and contributing countries, abstracts presented at the AHA meeting remained more likely for publication relative to the ESC (adjusted odds ratio, 1.24; 95% confidence interval, 1.16-1.34) and the ACC (adjusted odds ratio, 1.20; 95% confidence interval, 1.11-1.29). Median impact factors for subsequent publications varied from 4.8 (interquartile range, 3.8-10.1) for AHA to 4.0 (interquartile range, 3.1-7.5) for ACC and 3.9 (quartile 1-3, 2.5-5.8) for ESC (P for difference between groups <0.01). Clinical science and population science were less likely to be published compared with basic science.One third of abstracts were translated into publications by 2 years after presentation and less than one half by 5 years after presentation. Our findings suggest that efforts to understand the barriers to publication and to facilitate the rapid dissemination of new knowledge are needed to speed up the transition of scientific discovery into clinical practice.

    View details for DOI 10.1161/CIRCULATIONAHA.112.120535

    View details for Web of Science ID 000312275600010

    View details for PubMedID 23124031

  • Are Central Institutional Review Boards the Solution? The National Heart, Lung, and Blood Institute Working Group's Report on Optimizing the IRB Process ACADEMIC MEDICINE Mascette, A. M., Bernard, G. R., DiMichele, D., Goldner, J. A., Harrington, R., Harris, P. A., Leeds, H. S., Pearson, T. A., Ramsey, B., Wagner, T. H. 2012; 87 (12): 1710-1714

    Abstract

    The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened a working group in June 2011 to examine alternative institutional review board (IRB) models. The working group was held in response to proposed changes in the regulations for government-supported research and the proliferation of multicenter clinical trials where multiple individual reviews may be inefficient. Group members included experts in heart, lung, and blood research, research oversight, bioethics, health economics, regulations, and information technology (IT). The group discussed alternative IRB models, ethical concerns, metrics for evaluating IRBs, IT needs, and economic considerations. Participants noted research gaps in IRB best practices and in metrics. The group arrived at recommendations for process changes, such as defining specific IRB performance requirements in funding announcements, requiring funded researchers to use more efficient alternative IRB models, and developing IT systems to facilitate information sharing and collaboration among IRBs. Despite the success of the National Cancer Institute's central IRB (CIRB), the working group, concerned about the creation costs and unknown cost-efficiency of a new CIRB, and about the risk of shifting the burden of dealing with multiple IRBs from sponsors to research institutions, did not recommend the creation of an NHLBI-funded CIRB.

    View details for DOI 10.1097/ACM.0b013e3182720859

    View details for Web of Science ID 000311836800021

    View details for PubMedID 23095928

  • Transforming Clinical Trials in Cardiovascular Disease Mission Critical for Health and Economic Well-being JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Antman, E. M., Harrington, R. A. 2012; 308 (17): 1743-1744

    View details for Web of Science ID 000310726500017

    View details for PubMedID 23117771

  • Incidence and clinical significance of cardiac biomarker elevation during stem cell mobilization, apheresis, and intramyocardial delivery: An analysis from ACT34-CMI AMERICAN HEART JOURNAL Povsic, T. J., Losordo, D. W., Story, K., Junge, C. E., Schatz, R. A., Harrington, R. A., Henry, T. D. 2012; 164 (5): 689-U86

    Abstract

    Cell therapy is a promising therapeutic for a variety of cardiovascular conditions including refractory angina. Elevation of cardiac biomarkers during cell delivery has been frequently described, but the clinical implications have never been studied.ACT34-CMI was a randomized double-blind study assessing the use of intramyocardial delivery of autologous CD34(+) cells for the treatment of refractory angina. Patients (n = 167) underwent G-CSF-mediated (5 ?g/[kg day] × 5 days) stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5)/kg or 5 × 10(5)/kg CD34(+) cells or placebo. Troponin and creatinine kinase MB were assessed at baseline (n = 161), after cell mobilization and apheresis (n = 153 and 143, respectively), and post-intramyocardial injection (n = 155 and 141, respectively). Major adverse cardiac events (MACE) included death, myocardial infarction, acute congestive heart failure, urgent revascularization, or sustained ventricular arrhythmia.Seven (4.3%) subjects had troponin above the upper limits of normal (ULN) at baseline. Thirty-four (22.2%) and 11 (7.2%) subjects had troponin levels > ULN or >3× ULN after cell mobilization and apheresis, whereas 72 (46.1%) and 39 (25.2%) subjects had troponin elevations > ULN or >3× ULN, respectively, after intramyocardial injections. Age, but no other preprocedural factors, was predictive of troponin elevation. Periprocedural troponin elevation was not associated with an increased risk of MACE during 1 year, especially in cell therapy-treated patients.Troponin elevation is common during stem cell harvesting and intramyocardial administration, is usually asymptomatic, and does not appear to be associated with long-term MACE in subjects undergoing stem cell mobilization and intramyocardial injection.

    View details for DOI 10.1016/j.ahj.2012.06.022

    View details for Web of Science ID 000310783100011

    View details for PubMedID 23137499

  • Road mapping ATLAS ACS 2: are we there yet? EUROPEAN HEART JOURNAL Armstrong, P. W., Harrington, R. A. 2012; 33 (20): 2510-2512

    View details for DOI 10.1093/eurheartj/ehs015

    View details for Web of Science ID 000310167200007

    View details for PubMedID 22297122

  • Association Between Angiographic Complications and Clinical Outcomes Among Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention An EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) Angiographic Substudy JACC-CARDIOVASCULAR INTERVENTIONS Pride, Y. B., Mohanavelu, S., Zorkun, C., Kunadian, V., Giugliano, R. P., Newby, L. K., Braunwald, E., Califf, R. M., Harrington, R. A., Gibson, C. M. 2012; 5 (9): 927-935

    Abstract

    The goal of this analysis was to determine the association between intraprocedural complications and clinical outcomes among patients with high-risk non-ST-segment elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention (PCI).Among patients undergoing PCI for NSTEACS, the relationship between intraprocedural complications and clinical outcomes, independent of epicardial and myocardial perfusion, has not been well characterized.The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) trial enrolled 9,406 patients with high-risk NSTEACS undergoing an early invasive strategy. Of these, 1,452 underwent angiographic assessment in an independent core laboratory and did not have a myocardial infarction (MI) between enrollment and angiography. We assessed the relationship between abrupt closure, loss of side branch(es), distal embolization, and no-reflow phenomenon and 30-day clinical outcomes in these patients.Of the patients, 166 (11.4%) experienced an intraprocedural complication. Baseline clinical characteristics were similar between patients who did and did not have complications. The 30-day composite of death or MI was significantly higher among patients with an intraprocedural complication (28.3% vs. 7.8%, odds ratio [OR]: 4.68, 95% confidence interval [CI]: 3.2 to 7.0, p < 0.001). Individually, both mortality (3.0% vs. 0.9%, OR: 3.60, 95% CI: 1.2 to 10.5, p = 0.019) and MI (27.1% vs. 7.4%, OR: 4.66, 95% CI: 3.1 to 7.0, p < 0.001) were significantly increased. After adjusting for differences in post-PCI epicardial and myocardial perfusion, the association with 30-day death or MI remained significant.Among high-risk NSTEACS patients undergoing an invasive strategy, the incidence of intraprocedural complications is high, and the occurrence of these complications is associated with worse clinical outcomes independent of epicardial and myocardial perfusion. (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-segment Elevation Acute Coronary Syndrome [EARLY ACS]; NCT00089895).

    View details for DOI 10.1016/j.jcin.2012.05.007

    View details for Web of Science ID 000309351600007

    View details for PubMedID 22995880

  • 2012 American College of Cardiology Foundation/Society for Cardiovascular Angiography and Interventions expert consensus document on cardiac catheterization laboratory standards update: American College of Cardiology Foundation Task Force on expert consensus documents Society of Thoracic Surgeons Society for Vascular Medicine. Catheterization and cardiovascular interventions Bashore, T. M., Balter, S., Barac, A., Byrne, J. G., Cavendish, J. J., Chambers, C. E., Hermiller, J. B., Kinlay, S., Landzberg, J. S., Laskey, W. K., McKay, C. R., Miller, J. M., Moliterno, D. J., Moore, J. W., Oliver-McNeil, S. M., Popma, J. J., Gardner 2012; 80 (3): E37-49

    View details for DOI 10.1002/ccd.24466

    View details for PubMedID 22570114

  • Edifoligide and long-term outcomes after coronary artery bypass grafting: PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT IV) 5-year results AMERICAN HEART JOURNAL Lopes, R. D., Williams, J. B., Mehta, R. H., Reyes, E. M., Hafley, G. E., Allen, K. B., Mack, M. J., Peterson, E. D., Harrington, R. A., Gibson, C. M., Califf, R. M., Kouchoukos, N. T., Ferguson, T. B., Lorenz, T. J., Alexander, J. H. 2012; 164 (3): 379-U284

    Abstract

    Edifoligide, an E2F transcription factor decoy, does not prevent vein graft failure or adverse clinical outcomes at 1 year in patients undergoing coronary artery bypass grafting (CABG). We compared the 5-year clinical outcomes of patients in PREVENT IV treated with edifoligide and placebo to identify predictors of long-term clinical outcomes.A total of 3,014 patients undergoing CABG with at least 2 planned vein grafts were enrolled. Kaplan-Meier curves were generated to compare the long-term effects of edifoligide and placebo. A Cox proportional hazards model was constructed to identify factors associated with 5-year post-CABG outcomes. The main outcome measures were death, myocardial infarction (MI), repeat revascularization, and rehospitalization through 5 years.Five-year follow-up was complete in 2,865 patients (95.1%). At 5 years, patients randomized to edifoligide and placebo had similar rates of death (11.7% and 10.7%, respectively), MI (2.3% and 3.2%), revascularization (14.1% and 13.9%), and rehospitalization (61.6% and 62.5%). The composite outcome of death, MI, or revascularization occurred at similar frequency in patients assigned to edifoligide and placebo (26.3% and 25.5%, respectively; hazard ratio 1.03 [95% CI 0.89-1.18], P = .721). Factors associated with death, MI, or revascularization at 5 years included peripheral and/or cerebrovascular disease, time on cardiopulmonary bypass, lung disease, diabetes mellitus, and congestive heart failure.Up to a quarter of patients undergoing CABG will have a major cardiac event or repeat revascularization procedure within 5 years of surgery. Edifoligide does not affect outcomes after CABG; however, common identifiable baseline and procedural risk factors are associated with long-term outcomes after CABG.

    View details for DOI 10.1016/j.ahj.2012.05.019

    View details for Web of Science ID 000308690100015

    View details for PubMedID 22980305

  • Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes-Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial AMERICAN HEART JOURNAL Cornel, J. H., Becker, R. C., Goodman, S. G., Husted, S., Katus, H., Santoso, A., Steg, G., Storey, R. F., Vintila, M., Sun, J. L., Horrow, J., Wallentin, L., Harrington, R., James, S. 2012; 164 (3): 334-U239

    Abstract

    Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits.Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses.Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/nonsmokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/nonsmokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P = .61).In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.

    View details for DOI 10.1016/j.ahj.2012.06.005

    View details for Web of Science ID 000308690100009

    View details for PubMedID 22980299

  • 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: developed in collabration with the American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. journal of thoracic and cardiovascular surgery Holmes, D. R., Mack, M. J., Kaul, S., Agnihotri, A., Alexander, K. P., Bailey, S. R., Calhoon, J. H., Carabello, B. A., Desai, M. Y., Edwards, F. H., Francis, G. S., Gardner, T. J., Kappetein, A. P., Linderbaum, J. A., Mukherjee, C., Mukherjee, D., Otto, C. M., Ruiz, C. E., Sacco, R. L., Smith, D., Thomas, J. D., Harrington, R. A., Bhatt, D. L., Ferrari, V. A., Fisher, J. D., Garcia, M. J., Gardner, T. J., Gentile, F., Gilson, M. F., Hernandez, A. F., Jacobs, A. K., Kaul, S., Linderbaum, J. A., Moliterno, D. J., Weitz, H. H. 2012; 144 (3): e29-84

    View details for DOI 10.1016/j.jtcvs.2012.03.001

    View details for PubMedID 22898522

  • Lecture Halls without Lectures NEW ENGLAND JOURNAL OF MEDICINE Eapen, Z. J., Vavalle, J. P., Harrington, R. A. 2012; 367 (7): 678-678

    View details for Web of Science ID 000307496600025

    View details for PubMedID 22894591

  • Effect of Adenosine-Regulating Agent Acadesine on Morbidity and Mortality Associated With Coronary Artery Bypass Grafting The RED-CABG Randomized Controlled Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Newman, M. F., Ferguson, T. B., White, J. A., Ambrosio, G., Koglin, J., Nussmeier, N. A., Pearl, R. G., Pitt, B., Wechsler, A. S., Weisel, R. D., Reece, T. L., Lira, A., Harrington, R. A. 2012; 308 (2): 157-164

    Abstract

    Ischemia/reperfusion injury remains an important cause of morbidity and mortality after coronary artery bypass graft (CABG) surgery. In a meta-analysis of randomized controlled trials, perioperative and postoperative infusion of acadesine, a first-in-class adenosine-regulating agent, was associated with a reduction in early cardiac death, myocardial infarction, and combined adverse cardiac outcomes in participants undergoing on-pump CABG surgery.To assess the efficacy and safety of acadesine administered in the perioperative period in reducing all-cause mortality, nonfatal stroke, and severe left ventricular dysfunction (SLVD) through 28 days.The Reduction in Cardiovascular Events by Acadesine in Patients Undergoing CABG (RED-CABG) trial, a randomized, double-blind, placebo-controlled, parallel-group evaluation of intermediate- to high-risk patients (median age, 66 years) undergoing nonemergency, on-pump CABG surgery at 300 sites in 7 countries. Enrollment occurred from May 6, 2009, to July 30, 2010.Eligible participants were randomized 1:1 to receive acadesine (0.1 mg/kg per minute for 7 hours) or placebo (both also added to cardioplegic solutions) beginning just before anesthesia induction.Composite of all-cause mortality, nonfatal stroke, or need for mechanical support for SLVD during and following CABG surgery through postoperative day 28.Because results of a prespecified futility analysis indicated a very low likelihood of a statistically significant efficacious outcome, the trial was stopped after 3080 of the originally projected 7500 study participants were randomized. The primary outcome occurred in 75 of 1493 participants (5.0%) in the placebo group and 76 of 1493 (5.1%) in the acadesine group (odds ratio, 1.01 [95% CI, 0.73-1.41]). There were no differences in key secondary end points measured.In this population of intermediate- to high-risk patients undergoing CABG surgery, acadesine did not reduce the composite of all-cause mortality, nonfatal stroke, or SLVD.clinicaltrials.gov Identifier: NCT00872001.

    View details for Web of Science ID 000306219500029

    View details for PubMedID 22782417

  • Usefulness of Medical Conferences JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Antman, E. M., Harrington, R., Tomaselli, G. 2012; 308 (1): 31-32

    View details for DOI 10.1001/jama.2012.6368

    View details for Web of Science ID 000306183000015

    View details for PubMedID 22760283

  • Sustained Ventricular Tachycardia and Ventricular Fibrillation Complicating Non-ST-Segment-Elevation Acute Coronary Syndromes CIRCULATION Piccini, J. P., White, J. A., Mehta, R. H., Lokhnygina, Y., Al-Khatib, S. M., Tricoci, P., Pollack, C. V., Montalescot, G., Van de Werf, F., Gibson, C. M., Giugliano, R. P., Califf, R. M., Harrington, R. A., Newby, L. K. 2012; 126 (1): 41-49

    Abstract

    Ventricular arrhythmias remain a lethal complication of acute coronary syndromes (ACS). However, the incidence and prognosis of sustained ventricular tachycardia/ventricular fibrillation (VT/VF) in contemporary non-ST-segment-elevation (NSTE) ACS populations are not well described.We examined the incidence of VT/VF and subsequent survival among 9211 patients enrolled in the Early Glycoprotein IIb/IIIa Inhibition in NSTE ACS (EARLY ACS) trial. The cumulative incidence of VT/VF was 1.5% (n=141); 0.6% (n=55) had VT/VF ?48 hours after enrollment, and 0.9% (n=86) had VT/VF >48 hours after enrollment. Patients with VT/VF more frequently had prior heart failure, an ejection fraction <30%, and triple-vessel coronary artery disease. Predictors of sustained VT/VF were similar regardless of the timing of VT/VF (?48 versus >48 hours). Patients with VT/VF ?48 hours after enrollment had higher 30-day mortality than those who did not have VT/VF ?48 hours (13.0% versus 2.2%; adjusted odds ratio, 6.73; 95% confidence interval, 2.68-16.9). The increased risk of death associated with VT/VF ?48 hours persisted at 1 year. The risk of mortality, relative to patients without VT/VF, was greater for patients with VT/VF >48 hours (hazard ratio, 20.70; 95% confidence interval, 15.39-27.85) than for those with earlier VT/VF (hazard ratio, 7.45; 95% confidence interval, 4.60-12.08; P=0.0003). The frequency of arrhythmic death was higher in patients with VT/VF than in those without VT/VF (26.4% versus 6.9%).Sustained VT/VF is infrequent after NSTE ACS but is as likely to occur after 48 hours as within the first 48 hours. The marked increase in all-cause death among NSTE ACS patients with both early and late sustained VT/VF raises important considerations for aggressive monitoring beyond 48 hours and interventions to prevent arrhythmic death in these patients.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00089895.

    View details for DOI 10.1161/CIRCULATIONAHA.111.071860

    View details for Web of Science ID 000306977100022

    View details for PubMedID 22645292

  • Highlights from the IV International Symposium of Thrombosis and Anticoagulation (ISTA), October 20-21, 2011, Salvador, Bahia, Brazil JOURNAL OF THROMBOSIS AND THROMBOLYSIS Lopes, R. D., Becker, R. C., Newby, L. K., Peterson, E. D., Hylek, E. M., Granger, C. B., Crowther, M., Wang, T., Carvalho, A. C., Berwanger, O., Giraldez, R. R., Feitosa, G. S., Ribeiro, J. P., Darze, E., Kalil, R. A., Andrande, M., Boas, F. V., Andrade, J., Rocha, A. T., Harrington, R. A., Lopes, A. C., Garcia, D. A. 2012; 34 (1): 143-163

    Abstract

    To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Fourth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, from October 20-21, 2011. 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/s11239-012-0700-3

    View details for Web of Science ID 000305523300023

    View details for PubMedID 22427055

  • Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials JOURNAL OF THROMBOSIS AND THROMBOLYSIS Angiolillo, D. J., Schneider, D. J., Bhatt, D. L., French, W. J., Price, M. J., Saucedo, J. F., Shaburishvili, T., Huber, K., Prats, J., Liu, T., Harrington, R. A., Becker, R. C. 2012; 34 (1): 44-55

    Abstract

    Cangrelor is an intravenous antagonist of the P2Y(12) receptor characterized by rapid, potent, predictable, and reversible platelet inhibition. However, cangrelor was not superior to clopidogrel in reducing the incidence of ischemic events in the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. A prospectively designed platelet function substudy was performed in a selected cohort of patients to provide insight into the pharmacodynamic effects of cangrelor, particularly in regard to whether cangrelor therapy may interfere with the inhibitory effects of clopidogrel. This pre-defined substudy was conducted in a subset of patients from the CHAMPION-PCI trial (n = 230) comparing cangrelor with 600 mg of clopidogrel administered before percutaneous coronary intervention (PCI) and from the CHAMPION-PLATFORM trial (n = 4) comparing cangrelor at the time of PCI and 600 mg clopidogrel given after the PCI. Pharmacodynamic measures included P2Y12 reaction units (PRU) assessed by VerifyNow P2Y12 testing (primary endpoint marker), platelet aggregation by light transmittance aggregometry following 5 and 20 ?mol/L adenosine diphosphate stimuli, and markers of platelet activation determined by flow cytometry. The primary endpoint was the percentage of patients who achieved <20 % change in PRU between baseline and >10 h after PCI. The main trial was stopped early limiting enrollment in the platelet substudy. A total of 167 patients had valid pharmacodynamic assessments for the primary endpoint. The percent of individuals achieving <20 % change in PRU between baseline and >10 h after PCI was higher with cangrelor + clopidogrel (32/84, 38.1 %) compared with placebo + clopidogrel (21/83, 25.3 %), but this was not statistically significant (difference:12.79 %, 95 % CI: -1.18 %, 26.77 %;p = 0.076). All pharmacodynamic markers as well as the prevalence of patients with high on-treatment platelet reactivity were significantly lower in patients treated with cangrelor. A rapid platelet inhibitory effect was achieved during cangrelor infusion and a rapid offset of action after treatment discontinuation. This CHAMPION platelet function substudy represents the largest pharmacodynamic experience with cangrelor, demonstrating its potent P2Y(12) receptor inhibitory effects, and rapid onset/offset of action. Although there was no significant pharmacodynamic interaction when transitioning to clopidogrel therapy, further studies are warranted given that enrollment in this study was limited due to premature interruption of the main trial.

    View details for DOI 10.1007/s11239-012-0737-3

    View details for Web of Science ID 000305523300007

    View details for PubMedID 22569899

  • 2012 ACCF/AATS/SCAI/STS Expert Consensus Document on Transcatheter Aortic Valve Replacement Developed in collaboration with the American Heart Association, American Society of Echocardiography, European Association for CardioThoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Holmes, D. R., Mack, M. J., Kaul, S., Agnihotri, A., Alexander, K. P., Bailey, S. R., Calhoon, J. H., Carabello, B. A., Desai, M. Y., Edwards, F. H., Francis, G. S., Gardner, T. J., Kappetein, A. P., Linderbaum, J. A., Mukherjee, C., Mukherjee, D., Otto, C. M., Ruiz, C. E., Sacco, R. L., Smith, D., Thomas, J. D., Harrington, R. A., Bhatt, D. L., Ferrari, V. A., Fisher, J. D., Garcia, M. J., Gardner, T. J., Gentile, F., Gilson, M. F., Hernandez, A. F., Jacobs, A. K., Kaul, S., Linderbaum, J. A., Moliterno, D. J., Weitz, H. H. 2012; 79 (7): 1023-1082

    View details for DOI 10.1002/ccd.24351

    View details for Web of Science ID 000304753500001

    View details for PubMedID 22294439

  • Pharmacokinetic and Pharmacodynamic Effects of Elinogrel Results of the Platelet Function Substudy From the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention Patients (INNOVATE-PCI) Trial CIRCULATION-CARDIOVASCULAR INTERVENTIONS Angiolillo, D. J., Welsh, R. C., Trenk, D., Neumann, F., Conley, P. B., McClure, M. W., Stephens, G., Kochman, J., Jennings, L. K., Gurbel, P. A., Wojcik, J., Dabrowski, M., Saucedo, J. F., Stumpf, J., Buerke, M., Broderick, S., Harrington, R. A., Rao, S. V. 2012; 5 (3): 347-356

    Abstract

    Elinogrel is the only selective, competitive and reversible platelet P2Y(12) inhibitor available in both intravenous (IV) and oral formulations.This substudy of the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention patients (INNOVATE-PCI) trial evaluated the pharmacokinetic and pharmacodynamic effects of two dosing regimens of IV followed by oral elinogrel (120 mg IV plus 100 mg oral twice daily; 120 mg IV plus 150 mg oral twice daily) versus standard clopidogrel therapy (300-600 mg oral loading dose plus 75 mg oral maintenance dose) in 56 patients undergoing nonurgent PCI. At time of randomization, 71.4% (40/56) of patients were using maintenance clopidogrel therapy. In the acute phase, an IV bolus of elinogrel achieved more rapid and potent antiplatelet effects compared with clopidogrel, which were sustained during the transition from the IV to the oral formulation in the first 24 hours of the peri-PCI period. During chronic therapy, elinogrel achieved similar levels of platelet reactivity compared with clopidogrel before the next oral dose and, although platelet reactivity was lower with elinogrel up to 6 hours after daily oral maintenance dosing, these differences were not statistically significant. These pharmacodynamic effects matched the pharmacokinetic profile of elinogrel. There were no differences in pharmacodynamic and pharmacokinetic effects between the two elinogrel dosing regimens.Compared with clopidogrel, the combination of IV and oral elinogrel achieves more rapid and enhanced antiplatelet effects that were sustained through the transition to oral elinogrel in the peri-PCI period, but these were not significant during chronic dosing in this pilot investigation.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

    View details for DOI 10.1161/CIRCINTERVENTIONS.111.965608

    View details for Web of Science ID 000311707000012

    View details for PubMedID 22619259

  • A Randomized, Double-Blind, Active-Controlled Phase 2 Trial to Evaluate a Novel Selective and Reversible Intravenous and Oral P2Y(12) Inhibitor Elinogrel Versus Clopidogrel in Patients Undergoing Nonurgent Percutaneous Coronary Intervention The INNOVATE-PCI Trial CIRCULATION-CARDIOVASCULAR INTERVENTIONS Welsh, R. C., Rao, S. V., Zeymer, U., Thompson, V. P., Huber, K., Kochman, J., McClure, M. W., Gretler, D. D., Bhatt, D. L., Gibson, C. M., Angiolillo, D. J., Gurbel, P. A., Berdan, L. G., Paynter, G., Leonardi, S., Madan, M., French, W. J., Harrington, R. A. 2012; 5 (3): 336-346

    Abstract

    We evaluated the safety, efficacy, and tolerability of elinogrel, a competitive, reversible intravenous and oral P2Y(12) inhibitor that does not require metabolic activation, in patients undergoing nonurgent percutaneous coronary intervention.In a randomized, double-blind, dose-ranging phase 2b trial, 652 patients received either 300 or 600 mg of clopidogrel pre-percutaneous coronary intervention followed by 75 mg daily or 80 or 120 mg of IV elinogrel followed by 50, 100, or 150 mg oral elinogrel twice daily. Numerous exploratory safety and efficacy end points were assessed and, as such, had no prespecified primary end point, and the study was not powered to conclusively evaluate its objectives. Thrombolysis in myocardial infarction combined bleeding was increased with elinogrel (hazard ratio, 1.98; 95% confidence interval, 1.10 to 3.57), related largely to increased bleeding requiring medical attention (elinogrel 47/408 [11.5%] versus clopidogrel 13/208 [6.3%]) and occurring primarily at the percutaneous coronary intervention access site. Efficacy end points and postprocedure cardiac enzyme were similar, but there was a nonsignificant higher frequency of periprocedural myocardial infarctions in the elinogrel arms (OR, 1.59; 95% confidence interval, 0.79 to 3.48). There was an increased incidence of dyspnea (elinogrel 50/408 [12.3%] versus clopidogrel 8/208 [3.8%]) and transaminase elevation (alanine transferase/aspartate transferase >3× the upper limit of normal; elinogrel 18/408 [4.4%] versus clopidogrel 2/208 [1.0%]) in the elinogrel arms, but there were no cases of heart block, bradycardia, hypotension, or liver failure.In patients undergoing nonurgent percutaneous coronary intervention and in comparison with clopidogrel, intravenous and oral elinogrel therapy did not significantly increase thrombolysis in myocardial infarction major or minor bleeding, although bleeding requiring medical attention was more common. The significance of these findings will need to be more definitively determined in future Phase 3 studies.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

    View details for DOI 10.1161/CIRCINTERVENTIONS.111.964197

    View details for Web of Science ID 000311707000011

    View details for PubMedID 22647518

  • 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

  • Regional Patterns of Use of a Medical Management Strategy for Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Insights From the EARLY ACS Trial CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Roe, M. T., White, J. A., Kaul, P., Tricoci, P., Lokhnygina, Y., Miller, C. D., Van'T Hof, A. W., Montalescot, G., James, S. K., Saucedo, J., Ohman, E. M., Pollack, C. V., Hochman, J. S., Armstrong, P. W., Giugliano, R. P., Harrington, R. A., Van de Werf, F., Califf, R. M., Newby, L. K. 2012; 5 (2): 205-213

    Abstract

    Regional differences in the profile and prognosis of non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients treated with medical management after angiography remain uncertain.Using data from the Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndromes (EARLY ACS) trial, we examined regional variations in the use of an in-hospital medical management strategy in NSTE ACS patients who had significant coronary artery disease (CAD) identified during angiography, factors associated with the use of a medical management strategy, and 1-year mortality rates. Of 9406 patients, 8387 (89%) underwent angiography and had significant CAD; thereafter, 1766 (21%) were treated solely with a medical management strategy (range: 18% to 23% across 4 major geographic regions). Factors most strongly associated with a medical management strategy were negative baseline troponin values, prior coronary artery bypass grafting, lower baseline hemoglobin values, and greater number of diseased vessels; region was not a significant factor. One-year mortality was higher among patients treated with a medical management strategy compared with those who underwent revascularization (7.8% versus 3.6%; adjusted hazard ratio, 1.46; 95% CI, 1.21-1.76), with no significant interaction by region (interaction probability value=0.42).Approximately 20% of NSTE ACS patients with significant CAD in an international trial were treated solely with an in-hospital medical management strategy after early angiography, with no regional differences in factors associated with medical management or the risk of 1-year mortality. These findings have important implications for the conduct of future clinical trials, and highlight global similarities in the profile and prognosis of medically managed NSTE ACS patients.

    View details for DOI 10.1161/CIRCOUTCOMES.111.962332

    View details for Web of Science ID 000302120300014

    View details for PubMedID 22373905

  • 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

  • Relationship Between Vein Graft Failure and Subsequent Clinical Outcomes After Coronary Artery Bypass Surgery CIRCULATION Lopes, R. D., Mehta, R. H., Hafley, G. E., Williams, J. B., Mack, M. J., Peterson, E. D., Allen, K. B., Harrington, R. A., Gibson, C. M., Califf, R. M., Kouchoukos, N. T., Ferguson, T. B., Alexander, J. H. 2012; 125 (6): 749-756

    Abstract

    Vein graft failure (VGF) is common after coronary artery bypass graft surgery, but its relationship with long-term clinical outcomes is unknown. In this retrospective analysis, we examined the relationship between VGF, assessed by coronary angiography 12 to 18 months after coronary artery bypass graft surgery, and subsequent clinical outcomes.Using the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial database, we studied data from 1829 patients who underwent coronary artery bypass graft surgery and had an angiogram performed up to 18 months after surgery. The main outcome measure was death, myocardial infarction, and repeat revascularization through 4 years after angiography. VGF occurred in 787 of 1829 patients (43%). Clinical follow-up was completed in 97% of patients with angiographic follow-up. The composite of death, myocardial infarction, or revascularization occurred more frequently among patients who had any VGF compared with those who had none (adjusted hazard ratio, 1.58; 95% confidence interval, 1.21-2.06; P=0.008). This was due mainly to more frequent revascularization with no differences in death (adjusted hazard ratio, 1.04; 95% confidence interval, 0.71-1.52; P=0.85) or death or myocardial infarction (adjusted hazard ratio, 1.08; 95% confidence interval, 0.77-1.53; P=0.65).VGF is common after coronary artery bypass graft surgery and is associated with repeat revascularization but not with death and/or myocardial infarction. Further investigations are needed to evaluate therapies and strategies for decreasing VGF to improve outcomes in patients undergoing coronary artery bypass graft surgery.

    View details for DOI 10.1161/CIRCULATIONAHA.111.040311

    View details for Web of Science ID 000300605200012

    View details for PubMedID 22238227

  • 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

  • ST-Elevation Acute Coronary Syndromes in the Platelet Inhibition and Patient Outcomes (PLATO) Trial Insights From the ECG Substudy CIRCULATION Armstrong, P. W., Siha, H., Fu, Y., Westerhout, C. M., Steg, P. G., James, S. K., Storey, R. F., Horrow, J., Katus, H., Clemmensen, P., Harrington, R. A., Wallentin, L. 2012; 125 (3): 514-U131

    Abstract

    Ticagrelor, when compared with clopidogrel, reduced the 12-month risk of vascular death/myocardial infarction and stroke in patients with ST-elevation acute coronary syndromes intended to undergo primary percutaneous coronary intervention in the PLATelet inhibition and patient Outcomes (PLATO) trial. This prespecified ECG substudy explored whether ticagrelor's association with vascular death and myocardial infarction within 1 year would be amplified by (1) the extent of baseline ST shift and (2) subsequently associated with fewer residual ST changes at hospital discharge.ECGs were evaluated centrally in a core laboratory in 3122 ticagrelor- and 3084 clopidogrel-assigned patients having at least 1 mm ST-elevation in 2 contiguous leads as identified by site investigators on the qualifying ECG. Patients with greater ST-segment shift at baseline had higher rates of vascular death/myocardial infarction within 1 year. Among those who also had an ECG at hospital discharge (n=4798), patients with ?50% ?ST-deviation (?ST-dev) resolution had higher event-free survival than those with incomplete resolution (6.4% versus 8.8%, adjusted hazard ratio 0.69 (0.54-0.88), P=0.003). The extent of ?ST-dev resolution was similar irrespective of treatment assignment. The benefit of ticagrelor versus clopidogrel on clinical events was consistent irrespective of the extent of baseline ?ST-dev (P(interaction)=0.728). When stratified according to conventional times from symptom onset, ie, ?3 hours, 3 to 6 hours, >6 hours, the extent of baseline ?ST-dev declined progressively over time. As time from symptom onset increased beyond 3 hours, the benefit of ticagrelor appeared to be more pronounced; however, the interaction between time and treatment was not significant (P=0.175).Ticagrelor did not modify ?ST-dev resolution at discharge nor was its benefit affected by the extent of baseline ?ST-dev. These hypothesis-generating observations suggest that the main effects of ticagrelor may not relate to the rapidity or the completeness of acute reperfusion, but rather the prevention of recurrent vascular events by more powerful platelet inhibition or other mechanisms.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.111.047530

    View details for Web of Science ID 000300252800019

    View details for PubMedID 22179530

  • 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

  • Venous thromboembolism prophylaxis: do trial results enable clinicians and patients to evaluate whether the benefits justify the risk? proceedings of an ad hoc working group meeting. Journal of thrombosis and haemostasis : JTH Berger, J., Eikelboom, J. W., Quinlan, D. J., Guyatt, G., Büller, H. R., Sobieraj-Teague, M., Harrington, R. A., Hirsh, J. 2012

    Abstract

    Physicians and patients consider the balance between benefits and risks of treatment when making decisions about the use of anticoagulants for the prevention of venous thromboembolism (VTE). The results of early trials demonstrating the efficacy of heparin compared with placebo or no thromboprophylaxis for the prevention of fatal pulmonary embolism (PE) led to adoption of routine anticoagulant prophylaxis in patients considered to be at increased risk of VTE. More recent trials comparing new anticoagulants with heparin have most commonly used the composite outcome, asymptomatic (or "silent") deep vein thrombosis (DVT), detected by screening venography, and symptomatic (or "patient-important") VTE, as the primary measure of efficacy [1-3]. © 2012 International Society on Thrombosis and Haemostasis.

    View details for PubMedID 22906159

  • Age, treatment, and outcomes in high-risk non-ST-segment elevation acute coronary syndrome patients: Insights from the EARLY ACS trial. International journal of cardiology Lopes, R. D., White, J. A., Tricoci, P., White, H. D., Armstrong, P. W., Braunwald, E., Giugliano, R. P., Harrington, R. A., Lewis, B. S., Brogan, G. X., Gibson, C. M., Califf, R. M., Newby, L. K. 2012

    Abstract

    BACKGROUND: Elderly patients with acute coronary syndromes (ACS) are at high risk for death and recurrent thrombotic events. We evaluated the efficacy and safety of intensive treatment with glycoprotein IIb/IIIa inhibitors in an elderly population, and the relationships between age, timing of administration, and clinical outcomes. METHODS: We used data from high-risk non-ST-segment elevation ACS patients randomized to early eptifibatide vs. delayed provisional use at percutaneous coronary intervention. In multivariable models, we included age×treatment interaction terms to assess whether treatment effect varied by age after adjusting for confounders. RESULTS: Of 9406 patients, 13.9% were aged <55years; 27.6%, 55-64years; 33.2%, 65-74years; and 25.3%, ?75years. For each 10-year age increase, the adjusted odds ratio (OR) (95% confidence interval [CI]) for 96-hour death, myocardial infarction (MI), recurrent ischemia requiring urgent revascularization, or thrombotic bailout was 1.13 (1.04-1.23) and for 30-day death or MI was 1.13 (1.04-1.22). Increasing age was also associated with greater 1-year mortality (adjusted hazard ratio per 10years: 1.44, 95% CI 1.30-1.60). There was no interaction between age and treatment (p interaction=0.99, 0.54, and 0.87, respectively). Increasing age was associated with more non-coronary artery bypass grafting-related TIMI major bleeding (adjusted OR and 95% CI per 10years: 1.54 [1.24-1.92]), GUSTO moderate/severe bleeding (1.52 [1.33-1.75]), and transfusion (1.25 [1.07-1.45]). The amount by which TIMI major bleeding was increased with early vs. delayed provisional eptifibatide use was significantly greater with increasing age (p interaction=0.02), but the age×treatment interactions were not significant for GUSTO moderate/severe bleeding or transfusion (p interaction=0.33 and 0.54, respectively). CONCLUSION: Increasing age was associated with greater risk for ischemic events and more bleeding. Despite higher baseline ischemic risk in older patients, there was no preferential benefit of early vs. delayed provisional eptifibatide use for ischemic outcomes as age increased, but the incremental bleeding risk was amplified.

    View details for PubMedID 22795720

  • Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15years. International journal of cardiology Chan, M. Y., Sun, J. L., Newby, L. K., Lokhnygina, Y., White, H. D., Moliterno, D. J., Théroux, 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. 2012

    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 PubMedID 22341697

  • 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

  • Pulmonary Function in Patients With Acute Coronary Syndrome Treated With Ticagrelor or Clopidogrel (from the Platelet Inhibition and Patient Outcomes [PLATO] Pulmonary Function Substudy) AMERICAN JOURNAL OF CARDIOLOGY Storey, R. F., Becker, R. C., Harrington, R. A., Husted, S., James, S. K., Cools, F., Steg, P. G., Khurmi, N. S., Emanuelsson, H., Lim, S. T., Cannon, C. P., Katus, H. A., Wallentin, L. 2011; 108 (11): 1542-1546

    Abstract

    The Platelet Inhibition and Patient Outcomes (PLATO) trial showed that ticagrelor reduced the risk for cardiovascular events in patients with acute coronary syndromes compared to clopidogrel but was associated with increased incidence of dyspnea. This substudy assessed whether ticagrelor affects pulmonary function in patients with acute coronary syndromes: 199 patients enrolled in the PLATO trial and receiving randomized treatment with ticagrelor 90 mg twice daily (n = 101) or clopidogrel 75 mg/day (n = 98) took part in the pulmonary function substudy. Patients with advanced lung disease, congestive heart failure, or coronary artery bypass graft surgery after the index event were excluded. Pulse oximetry (blood oxygen saturation), spirometry (forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow between 25% and 75% of forced vital capacity before and 20 minutes after inhalation of a ?(2) agonist), lung volumes (total lung capacity, functional residual capacity, residual volume), and diffusion capacity were performed after patients received study medication for 30 to 40 days. Tests were then repeated <10 days before and approximately 30 days after the discontinuation of study medication. After a mean treatment duration of 31 days, there were no differences between the groups for any of the pulmonary function parameters. At the end of treatment (mean 211 days) and after the discontinuation of study medication (mean 32 days after the last dose), there was also no evidence of a change in pulmonary function in either group. For example, forced expiratory volume in 1 second values before ?(2) agonist inhalation in the ticagrelor and clopidogrel groups were 2.81 ± 0.73 and 2.70 ± 0.84 L, respectively, at the first visit and did not change significantly at subsequent visits. In conclusion, no effect of ticagrelor on pulmonary function was seen in this cohort of patients with acute coronary syndromes compared to clopidogrel.

    View details for DOI 10.1016/j.amjcard.2011.07.015

    View details for Web of Science ID 000297880000004

    View details for PubMedID 21890085

  • Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes EUROPEAN HEART JOURNAL Storey, R. F., Becker, R. C., Harrington, R. A., Husted, S., James, S. K., Cools, F., Steg, P. G., Khurmi, N. S., Emanuelsson, H., Cooper, A., Cairns, R., Cannon, C. P., Wallentin, L. 2011; 32 (23): 2945-2953

    Abstract

    AIMS To describe the incidence of dyspnoea and its associations with demographic characteristics and clinical outcomes in patients with acute coronary syndromes (ACS) treated with ticagrelor or clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) study. METHODS AND RESULTS In the PLATO study, 18 624 patients were randomized to receive either clopidogrel [300-600 mg loading dose (LD), 75 mg daily] or ticagrelor (180 mg LD, 90 mg b.i.d.). The occurrence of reported dyspnoea adverse events (AEs) was analysed in the 18 421 patients who received at least one dose of study medication in relation to demographic characteristics, clinical outcomes and other associations of patients with and without dyspnoea. A total of 1339 ticagrelor-treated patients (14.5%) and 798 clopidogrel-treated patients (8.7%) had a dyspnoea AE following randomization, with respectively 39 (0.4%) and 24 (0.3%) classified as severe in intensity. Excluding dyspnoea AEs occurring after the secondary endpoint of myocardial infarction (MI), the yearly rates of the efficacy endpoints in dyspnoea AE patients in the ticagrelor and clopidogrel groups were: for the primary composite of CV death, MI, and stroke, 8.8 and 10.4% (unadjusted P = 0.25; adjusted P = 0.54); for CV death, 3.1 and 4.8% (unadjusted P = 0.024; adjusted P = 0.18); and for total death 3.7 and 6.2% (unadjusted P = 0.004; adjusted P = 0.06), respectively. CONCLUSIONS Ticagrelor-related dyspnoea is usually mild or moderate in intensity and does not appear to be associated with differences concerning any efficacy or safety outcomes with ticagrelor compared with clopidogrel therapy in ACS patients.

    View details for DOI 10.1093/eurheartj/ehr231

    View details for Web of Science ID 000297647400009

    View details for PubMedID 21804104

  • Safety and efficacy of adjusted-dose eptifibatide in patients with acute coronary syndromes and reduced renal function AMERICAN HEART JOURNAL Melloni, C., James, S. K., White, J. A., Giugliano, R. P., Harrington, R. A., Huber, K., Tricoci, P., Armstrong, P. W., Van de Werf, F., Montalescot, G., Califf, R. M., Newby, L. K. 2011; 162 (5)

    Abstract

    Dose adjustment of renally excreted antithrombotic drugs is recommended for patients with reduced renal function. We examined the influence of dose modification on bleeding and efficacy.Based on initial study drug infusion rate, Early GP IIb/IIIa Inhibition in non-ST-segment elevation acute coronary syndromes (EARLY ACS) patients were categorized into groups: standard dose (2 ?g/kg/min; estimated creatinine clearance [eCrCl] ?50 ml/min), adjusted dose (1 ?g/kg/min; eCrCl <50 ml/min, per protocol), excess dose (2 ?g/kg/min; eCrCl <50 ml/min). We explored relationships among initial dosing, randomized treatment assignment, and bleeding and ischemic end points (96-h composite of death, myocardial infarction [MI], recurrent ischemia requiring urgent revascularization or thrombotic bailout, and 30-d death or MI).Of 8,708 patients with eCrCl and dosing data, 19% had eCrCl <50 ml/min. Of these, 13% received adjusted dose eptifibatide and 6% received an excess dose. Across all dosing groups, no significant reductions were found in ischemic end points between early versus delayed provisional eptifibatide (OR 1.14, 95% CI 0.80-1.65; OR 1.13, 95% CI 0.81-1.56, respectively, for 96-h and 30-d composite end points). Bleeding risk was not significantly increased in the early versus delayed provisional treatment group in either the adjusted (OR 1.50, 95% CI 0.95-2.39) or excess dose group (OR 1.67, 95% CI 0.85-3.39). There were no significant interactions between dose group and treatment strategy on bleeding or efficacy.Similar to observations in practice, despite guidelines recommendations and protocol guidance, 34% of EARLY ACS patients with reduced renal function failed to receive an appropriately adjusted study drug infusion. Use of an appropriately adjusted eptifibatide infusion was not associated with expected reductions in bleeding among patients with renal insufficiency.

    View details for DOI 10.1016/j.ahj.2011.08.020

    View details for Web of Science ID 000297247800014

    View details for PubMedID 22093205

  • Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome NEW ENGLAND JOURNAL OF MEDICINE Alexander, J. H., Lopes, R. D., James, S., Kilaru, R., He, Y., Mohan, P., Bhatt, D. L., Goodman, S., Verheugt, F. W., Flather, M., Huber, K., Liaw, D., Husted, S. E., Lopez-Sendon, J., De Caterina, R., Jansky, P., Darius, H., Vinereanu, D., Cornel, J. H., Cools, F., Atar, D., Luis Leiva-Pons, J., Keltai, M., Ogawa, H., Pais, P., Parkhomenko, A., Ruzyllo, W., Diaz, R., White, H., Ruda, M., Geraldes, M., Lawrence, J., Harrington, R. A., Wallentin, L. 2011; 365 (8): 699-708

    Abstract

    Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome.We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events.The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo.The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

    View details for DOI 10.1056/NEJMoa1105819

    View details for Web of Science ID 000294205300005

    View details for PubMedID 21780946

  • Biomedical Innovation: A Risky Business at Risk SCIENCE TRANSLATIONAL MEDICINE Stack, R. S., Harrington, R. A. 2011; 3 (96)

    Abstract

    Regulatory and financial challenges conspire to stall the development and market approval of breakthrough medical products. Inconsistent parameters are used to assess the safety and efficacy of drugs, biologics, and devices; this glitch in the system introduces uncertainty, slows or blocks product approvals, and increases the costs of product development. Here, we consider how to balance the benefits and risks to the public in the assessment of innovative medical products. We also discuss the Institute of Medicine's recent report on the medical device approval process.

    View details for DOI 10.1126/scitranslmed.3002459

    View details for Web of Science ID 000293953100002

    View details for PubMedID 21849662

  • American Industry and the U.S. Cardiovascular Clinical Research Enterprise An Appropriate Analogy? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Califf, R. M., Harrington, R. A. 2011; 58 (7): 677-680

    View details for DOI 10.1016/j.jacc.2011.03.048

    View details for Web of Science ID 000293455300004

    View details for PubMedID 21816302

  • Intramyocardial, Autologous CD34+Cell Therapy for Refractory Angina CIRCULATION RESEARCH Losordo, D. W., Henry, T. D., Davidson, C., Lee, J. S., Costa, M. A., Bass, T., Mendelsohn, F., Fortuin, F. D., Pepine, C. J., Traverse, J. H., Amrani, D., Ewenstein, B. M., Riedel, N., Story, K., Barker, K., Povsic, T. J., Harrington, R. A., Schatz, R. A. 2011; 109 (4): 428-U235

    Abstract

    A growing number of patients with coronary disease have refractory angina. Preclinical and early-phase clinical data suggest that intramyocardial injection of autologous CD34+ cells can improve myocardial perfusion and function.Evaluate the safety and bioactivity of intramyocardial injections of autologous CD34+ cells in patients with refractory angina who have exhausted all other treatment options.In this prospective, double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053), 167 patients with refractory angina received 1 of 2 doses (1×10(5) or 5×10(5) cells/kg) of mobilized autologous CD34+ cells or an equal volume of diluent (placebo). Treatment was distributed into 10 sites of ischemic, viable myocardium with a NOGA mapping injection catheter. The primary outcome measure was weekly angina frequency 6 months after treatment. Weekly angina frequency was significantly lower in the low-dose group than in placebo-treated patients at both 6 months (6.8±1.1 versus 10.9±1.2, P=0.020) and 12 months (6.3±1.2 versus 11.0±1.2, P=0.035); measurements in the high-dose group were also lower, but not significantly. Similarly, improvement in exercise tolerance was significantly greater in low-dose patients than in placebo-treated patients (6 months: 139±151 versus 69±122 seconds, P=0.014; 12 months: 140±171 versus 58±146 seconds, P=0.017) and greater, but not significantly, in the high-dose group. During cell mobilization and collection, 4.6% of patients had cardiac enzyme elevations consistent with non-ST segment elevation myocardial infarction. Mortality at 12 months was 5.4% in the placebo-treatment group with no deaths among cell-treated patients.Patients with refractory angina who received intramyocardial injections of autologous CD34+ cells (10(5) cells/kg) experienced significant improvements in angina frequency and exercise tolerance. The cell-mobilization and -collection procedures were associated with cardiac enzyme elevations, which will be addressed in future studies.

    View details for DOI 10.1161/CIRCRESAHA.111.245993

    View details for Web of Science ID 000293504100011

    View details for PubMedID 21737787

  • 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

  • Saphenous Vein Grafts With Multiple Versus Single Distal Targets in Patients Undergoing Coronary Artery Bypass Surgery One-Year Graft Failure and Five-Year Outcomes From the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) IV Trial CIRCULATION Mehta, R. H., Ferguson, T. B., Lopes, R. D., Hafley, G. E., Mack, M. J., Kouchoukos, N. T., Gibson, C. M., Harrington, R. A., Califf, R. M., Peterson, E. D., Alexander, J. H. 2011; 124 (3): 280-288

    Abstract

    Limited information exists on the intermediate-term graft patency and 5-year clinical outcomes of patients receiving saphenous vein grafts with multiple (m-SVG) versus single distal targets (s-SVG) during coronary artery bypass graft (CABG) surgery in the current era.We studied the association of the use of m-SVG versus s-SVG conduits with 1-year SVG failure (defined as ?75% angiographic stenosis) and 5-year clinical events (death; death or myocardial infarction [MI]; and death, MI, or revascularization) in 3014 patients undergoing their first CABG surgery enrolled in the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV. Of 3014 patients enrolled in PREVENT IV, 1045 (34.7%) had ?1 m-SVGs during CABG. Vein graft failure at 1-year was higher for m-SVG compared with s-SVG (adjusted odds ratio 1.24, 95% confidence interval 1.03 to 1.48). At 5 years, the adjusted composite of death, MI (including perioperative MI), or revascularization (hazard ratio 1.15, 95% confidence interval 1.00 to 1.31) and death or MI (hazard ratio 1.21, 95% confidence interval 1.03 to 1.43) were significantly higher in patients receiving m-SVGs.In patients undergoing first CABG surgery, the use of m-SVG was associated with a higher 1-year vein graft failure rate and trends toward worse clinical outcomes. Additional studies are needed to better understand the most appropriate conduit to improve long-term graft patency and clinical outcomes of patients undergoing CABG surgery. In the meantime, these data should encourage the use of s-SVG over m-SVG when feasible.

    View details for DOI 10.1161/CIRCULATIONAHA.110.991299

    View details for Web of Science ID 000292819300010

    View details for PubMedID 21709060

  • Dose Selection for a Direct and Selective Factor IXa Inhibitor and its Complementary Reversal Agent: Translating Pharmacokinetic and Pharmacodynamic Properties of the REG1 System to Clinical Trial Design JOURNAL OF THROMBOSIS AND THROMBOLYSIS Povsic, T. J., Cohen, M. G., Chan, M. Y., Zelenkofske, S. L., WARGIN, W. A., Harrington, R. A., Alexander, J. H., Rusconi, C. P., Becker, R. C. 2011; 32 (1): 21-31

    Abstract

    We performed detailed pharmacokinetic and pharmacodynamic modeling of REG1, an anticoagulation system composed of the direct factor IXa (FIXa) inhibitor pegnivacogin (RB006) and its matched active control agent anivamersen (RB007), with a focus on level of target inhibition to translate phase 1 results to phase 2 dose selection. We modeled early-phase clinical data relating weight-adjusted pegnivacogin dose and plasma concentration to prolongation of the activated partial thromboplastin time (aPTT). Using an in vitro calibration curve, percent FIXa inhibition was determined and related to aPTT prolongation and pegnivacogin dose and concentration. Similar methods were applied to relate anivamersen dose and level of reversal of pegnivacogin anticoagulation. Combined early-phase data suggested that ?0.75 mg/kg pegnivacogin was associated with >99% inhibition of FIX activity and prolongation of plasma aPTT values ?2.5 times above baseline, leading to selection of a 1 mg/kg dose for a phase 2a elective percutaneous coronary intervention study to achieve a high intensity of anticoagulation and minimize intersubject variability. Phase 2 validated our predictions, demonstrating 1 mg/kg pegnivacogin yielded plasma concentrations ?25 ?g/ml and >99% inhibition of FIX activity. The relationship between the anivamersen to pegnivacogin dose ratio and degree of pegnivacogin reversal was also validated. Our approach decreased the need for extensive dose-response studies, reducing the duration, complexity and cost of clinical development. The 1 mg/kg pegnivacogin dose and a range of anivamersen dose ratios are being tested in the phase 2b RADAR study (NCT00932100).

    View details for DOI 10.1007/s11239-011-0588-3

    View details for Web of Science ID 000292832800003

    View details for PubMedID 21503856

  • Upstream Use of Small-Molecule Glycoprotein IIb/IIIa Inhibitors in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes A Systematic Overview of Randomized Clinical Trials CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Tricoci, P., Newby, L. K., Hasselblad, V., Kong, D. F., Giugliano, R. P., White, H. D., Theroux, P., Stone, G. W., Moliterno, D. J., Van de Werf, F., Armstrong, P. W., Prabhakaran, D., Rasoul, S., Bolognese, L., durand, e., Braunwald, E., Califf, R. M., Harrington, R. A. 2011; 4 (4): 448-458

    Abstract

    The use of upstream small-molecule glycoprotein (GP) IIb/IIIa inhibitors in non-ST-segment elevation acute coronary syndromes (NSTE ACS) has been studied in multiple randomized clinical trials. We systematically reviewed the effect of upstream GP IIb/IIIa inhibitor use in NSTE ACS as reported in published clinical trials.Randomized clinical trials of upstream small-molecule GP IIb/IIIa inhibitors in NSTE ACS were identified through a PubMed and EMBASE search and were included if they contained 30-day outcome data. Odds ratios were generated from the published data and pooled by means of random effects modeling. The primary outcome measures were 30-day death and 30-day death or myocardial infarction. Primary safety measures were major bleeding and transfusion during the index hospitalization. Twelve clinical trials were included, evaluating tirofiban, eptifibatide, and lamifiban. Of these, 7 evaluated upstream GP IIb/IIIa inhibitors versus placebo (n=24 031) and 5 evaluated a strategy of upstream GP IIb/IIIa inhibitors versus upstream placebo with later provisional use at the time of percutaneous coronary intervention (n=19 643). Overall, upstream GP IIb/IIIa inhibitor use was associated with an 11% reduction in 30-day death/myocardial infarction (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.83 to 0.95) but no significant mortality effect (OR, 0.93; 95% CI, 0.83 to 1.05). The risk of major bleeding was 23% higher in patients treated with upstream GP IIb/IIIa inhibitors (OR, 1.23; 95% CI, 1.02 to 1.48). Results were similar when only trials comparing upstream GP IIb/IIIa inhibitors versus placebo were considered: 30-day death/myocardial infarction (OR, 0.88; 95% CI, 0.81 to 0.95); 30-day death (OR, 0.89; 95% CI, 0.76 to 1.03); and major bleeding (OR, 1.17; 95% CI, 0.88 to 1.54). Upstream versus selective use at percutaneous coronary intervention trended toward lower 30-day death/myocardial infarction (OR, 0.91; 95% CI, 0.82 to 1.01) but had no effect on mortality (OR, 1.00; 95% CI, 0.81 to 1.23) and increased major bleeding risk by 34% (OR, 1.34; 95% CI, 1.10 to 1.63).In NSTE ACS, treatment with upstream small-molecule GP IIb/IIIa inhibitors provides a significant but modest ischemic benefit when compared with initial placebo. Compared with delayed, selective use at percutaneous coronary intervention, early upstream use is associated with a trend toward fewer ischemic events. However, these modest benefits are associated with an increased risk of bleeding.

    View details for DOI 10.1161/CIRCOUTCOMES.110.960294

    View details for Web of Science ID 000292872500012

    View details for PubMedID 21712522

  • Dueling Registries? An Alternative Perspective and the Case for Competitive Collaboration CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Harrington, R. A. 2011; 4 (4): 486-487
  • ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents Developed in Collaboration With the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION Aronow, W. S., Fleg, J. L., Pepine, C. J., Artinian, N. T., Bakris, G., Brown, A. S., Ferdinand, K. C., Forciea, M. A., Frishman, W. H., Jaigobin, C., Kostis, J. B., Mancia, G., Oparil, S., Ortiz, E., Reisin, E., Rich, M. W., Schocken, D. D., Weber, M. A., Wesley, D. J., Harrington, R. A., Bates, E. R., Bhatt, D. L., Bridges, C. R., Eisenberg, M. J., Ferrari, V. A., Fisher, J. D., Gardner, T. J., Gentile, F., Gilson, M. F., Hlatky, M. A., Jacobs, A. K., Kaul, S., Moliterno, D. J., Mukherjee, D., Rosenson, R. S., Stein, J. H., Weitz, H. H., Wesley, D. J. 2011; 5 (4): 259-352

    View details for DOI 10.1016/j.jash.2011.06.001

    View details for Web of Science ID 000293866000007

    View details for PubMedID 21771565

  • Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial BRITISH MEDICAL JOURNAL James, S. K., Roe, M. T., Cannon, C. P., Cornel, J. H., Horrow, J., Husted, S., Katus, H., Morais, J., Steg, P. G., Storey, R. F., Stevens, S., Wallentin, L., Harrington, R. A. 2011; 342

    Abstract

    To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy.Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial.862 centres in 43 countries.5216 (28%) of 18,624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management.Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615).Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year.2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel.In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy.Clinical trials NCT00391872.

    View details for DOI 10.1136/bmj.d3527

    View details for Web of Science ID 000291933200003

    View details for PubMedID 21685437

  • ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation Aronow, W. S., Fleg, J. L., Pepine, C. J., Artinian, N. T., Bakris, G., Brown, A. S., Ferdinand, K. C., Forciea, M. A., Frishman, W. H., Jaigobin, C., Kostis, J. B., Mancia, G., Oparil, S., Ortiz, E., Reisin, E., Rich, M. W., Schocken, D. D., Weber, M. A., Wesley, D. J., Harrington, R. A. 2011; 123 (21): 2434-2506

    View details for DOI 10.1161/CIR.0b013e31821daaf6

    View details for PubMedID 21518977

  • Intravenous Erythropoietin in Patients With ST-Segment Elevation Myocardial Infarction REVEAL: A Randomized Controlled Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Najjar, S. S., Rao, S. V., Melloni, C., Raman, S. V., Povsic, T. J., Melton, L., Barsness, G. W., Prather, K., Heitner, J. F., Kilaru, R., Gruberg, L., Hasselblad, V., Greenbaum, A. B., Patel, M., Kim, R. J., Talan, M., Ferrucci, L., Longo, D. L., Lakatta, E. G., Harrington, R. A. 2011; 305 (18): 1863-1872

    Abstract

    Acute ST-segment elevation myocardial infarction (STEMI) is a leading cause of morbidity and mortality. In experimental models of MI, erythropoietin reduces infarct size and improves left ventricular (LV) function.To evaluate the safety and efficacy of a single intravenous bolus of epoetin alfa in patients with STEMI.A prospective, randomized, double-blind, placebo-controlled trial with a dose-escalation safety phase and a single dose (60,000 U of epoetin alfa) efficacy phase; the Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial was conducted at 28 US sites between October 2006 and February 2010, and included 222 patients with STEMI who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy.Participants were randomly assigned to treatment with intravenous epoetin alfa or matching saline placebo administered within 4 hours of reperfusion.Infarct size, expressed as percentage of LV mass, assessed by cardiac magnetic resonance (CMR) imaging performed 2 to 6 days after study medication administration (first CMR) and again 12 ± 2 weeks later (second CMR).In the efficacy cohort, the infarct size did not differ between groups on either the first CMR scan (n = 136; 15.8% LV mass [95% confidence interval {CI}, 13.3-18.2% LV mass] for the epoetin alfa group vs 15.0% LV mass [95% CI, 12.6-17.3% LV mass] for the placebo group; P = .67) or on the second CMR scan (n = 124; 10.6% LV mass [95% CI, 8.4-12.8% LV mass] vs 10.4% LV mass [95% CI, 8.5-12.3% LV mass], respectively; P = .89). In a prespecified analysis of patients aged 70 years or older (n = 21), the mean infarct size within the first week (first CMR) was larger in the epoetin alfa group (19.9% LV mass; 95% CI, 14.0-25.7% LV mass) than in the placebo group (11.7% LV mass; 95% CI, 7.2-16.1% LV mass) (P = .03). In the safety cohort, of the 125 patients who received epoetin alfa, the composite outcome of death, MI, stroke, or stent thrombosis occurred in 5 (4.0%; 95% CI, 1.31%-9.09%) but in none of the 97 who received placebo (P = .04).In patients with STEMI who had successful reperfusion with primary or rescue PCI, a single intravenous bolus of epoetin alfa within 4 hours of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Subgroup analyses raised concerns about an increase in infarct size among older patients.clinicaltrials.gov Identifier: NCT00378352.

    View details for Web of Science ID 000290438800023

    View details for PubMedID 21558517

  • The Incidence of Bradyarrhythmias and Clinical Bradyarrhythmic Events in Patients With Acute Coronary Syndromes Treated With Ticagrelor or Clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) Trial Results of the Continuous Electrocardiographic Assessment Substudy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Scirica, B. M., Cannon, C. P., Emanuelsson, H., Michelson, E. L., Harrington, R. A., Husted, S., James, S., Katus, H., Pais, P., Raev, D., Spinar, J., Steg, P. G., Storey, R. F., Wallentin, L. 2011; 57 (19): 1908-1916

    Abstract

    The aim of this study was to determine whether ticagrelor increased the risk of ventricular pauses compared with clopidogrel and whether these pauses were associated with any clinical bradycardic events in patients presenting with acute coronary syndromes.Ticagrelor, an oral reversibly binding P2Y(12) inhibitor, provides more potent and consistent inhibition of platelet aggregation than clopidogrel but in a phase II study was associated with increased risk for ventricular pauses. A prospective continuous electrocardiographic (cECG) assessment was therefore performed within the PLATO (Platelet Inhibition and Patient Outcomes) study comparing ticagrelor and clopidogrel in patients hospitalized with acute coronary syndromes.Patients in the cECG assessment had planned 7-day cECG recording initiated at the time of randomization (week 1), which was within 24 h of symptom onset, and then repeated at 1 month after randomization during the convalescent phase. The principal safety endpoint was the incidence of ventricular pauses lasting at least 3 s. Investigators also reported symptomatic bradycardic adverse events during the entire study duration (median 277 days).A total of 2,908 patients were included in the cECG assessment, of whom 2,866 (98.5%) had week 1 recordings, 1,991 (68.4%) had 1-month recordings, and 1,949 (67.0%) had both. During the first week after randomization, ventricular pauses ?3 s occurred more frequently in patients receiving ticagrelor than clopidogrel (84 [5.8%] vs. 51 [3.6%]; relative risk: 1.61; p = 0.006). At 1 month, pauses ?3 s occurred overall less frequently and were similar between treatments (2.1% vs. 1.7%). Most were ventricular pauses, and the greatest excess associated with ticagrelor were asymptomatic, sinoatrial nodal in origin (66%), and nocturnal. There were no differences between ticagrelor and clopidogrel in the incidence of clinically reported bradycardic adverse events, including syncope, pacemaker placement, and cardiac arrest.In the PLATO cECG assessment, more patients treated with ticagrelor compared with clopidogrel had ventricular pauses, which were predominantly asymptomatic, sinoatrial nodal in origin, and nocturnal and occurred most frequently in the acute phase of acute coronary syndromes. There were no apparent clinical consequences related to the excess in ventricular pauses in patients assigned to ticagrelor. (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

    View details for DOI 10.1016/j.jacc.2010.11.056

    View details for Web of Science ID 000290210100010

    View details for PubMedID 21545948

  • The PLATO trial reveals further opportunities to improve outcomes in patients with acute coronary syndrome. Editorial on Serebruany. "Viewpoint: Paradoxical excess mortality in the PLATO trial should be independently verified" (Thromb Haemost 2011; 105.5). Thrombosis and haemostasis Wallentin, L., Becker, R. C., James, S. K., Harrington, R. A. 2011; 105 (5): 760-762

    View details for DOI 10.1160/TH11-03-0162

    View details for PubMedID 21394383

  • Upstream Clopidogrel Use and the Efficacy and Safety of Early Eptifibatide Treatment in Patients With Acute Coronary Syndrome An Analysis From the Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) Trial CIRCULATION Wang, T. Y., White, J. A., Tricoci, P., Giugliano, R. P., Zeymer, U., Harrington, R. A., Montalescot, G., James, S. K., Van de Werf, F., Armstrong, P. W., Braunwald, E., Califf, R. M., Newby, L. K. 2011; 123 (7): 722-730

    Abstract

    In the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, routine preangiography eptifibatide use was not superior to delayed provisional use but led to more bleeding. This analysis examines efficacy and safety of early eptifibatide in the setting of concurrent upstream clopidogrel use.In EARLY-ACS, clopidogrel use and timing were determined by treating physicians, but randomization to early eptifibatide versus placebo was stratified by the intent to use upstream clopidogrel. Among 9166 non-ST-elevation acute coronary syndrome patients who underwent coronary angiography, intent to use upstream clopidogrel was declared in 6895 (75%), and 7068 (77%) received upstream clopidogrel. After multivariable adjustment, intended upstream clopidogrel use did not differentially influence the effect of early eptifibatide on the primary end point of 96-hour death/myocardial infarction/recurrent ischemia requiring urgent revascularization/thrombotic bailout (interaction P=0.988). Early eptifibatide use reduced 30-day death/myocardial infarction among patients with intended upstream clopidogrel (adjusted odds ratio 0.85; 95% confidence interval 0.73 to 0.99) but not among those without intended upstream clopidogrel use (adjusted odds ratio 1.02; 95% confidence interval 0.80 to 1.30). However, the clopidogrel by randomized treatment interaction term was not significant (P=0.23). Thrombolysis in Myocardial Infarction major bleeding risk was increased with early eptifibatide in the setting of upstream clopidogrel use. Results were similar using actual clopidogrel treatment strata.Routine early eptifibatide use, compared with delayed provisional use, may be associated with lower 30-day ischemic risk in non-ST-elevation acute coronary syndrome patients also treated with clopidogrel before angiography. The benefit-risk ratio of intensive platelet inhibition with combined early use of antiplatelet agents needs further evaluation in prospective randomized trials.

    View details for DOI 10.1161/CIRCULATIONAHA.110.958041

    View details for Web of Science ID 000287588000011

    View details for PubMedID 21300952

  • 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

  • Impact of Recovery of Renal Function on Long-Term Mortality After Coronary Artery Bypass Grafting AMERICAN JOURNAL OF CARDIOLOGY Mehta, R. H., Honeycutt, E., Patel, U. D., Lopes, R. D., Shaw, L. K., Glower, D. D., Harrington, R. A., Califf, R. M., Sketch, M. H. 2010; 106 (12): 1728-1734

    Abstract

    Whether prognosis differs in acute renal failure (ARF) after coronary artery bypass grafting (CABG) in patients with and without recovery of renal function is not known. We studied patients who had CABG at Duke University Medical Center (1995 to 2008). ARF was defined as an increase in peak creatinine ?50% after CABG or ?0.7 mg/dl above baseline or need for new dialysis. Patients were categorized into 3 groups: (1) no ARF after CABG, (2) ARF after CABG and completely recovered renal function at day 7 (return of creatinine to no higher than baseline and no dialysis), or (3) ARF after CABG with no recovery of renal function at day 7 (creatinine no higher than baseline or new dialysis). Main outcome measurement was risk-adjusted long-term mortality (excluding death ?7 days). ARF after CABG occurred in 2,083 of 10,415 patients (20%) and completely recovered in 703 (33.7%). Risk-adjusted mortality was highest in patients with ARF without recovery of renal function (hazard ratios 1.47, 95% confidence interval 1.34 to 1.62) and intermediate in those with ARF but completely recovered renal function (hazard ratios 1.21, 95% confidence interval 1.07 to 1.37, referent no-ARF group). Mortality was lower in patients with ARF compared to those without complete recovery of renal function (p = 0.0083). In conclusion, in patients with ARF after CABG, complete recovery of renal function was associated with significantly lower long-term mortality compared to those without such recovery, although this was significantly higher than in those without ARF. Thus, major emphasis should be on prevention of ARF in patients undergoing CABG.

    View details for DOI 10.1016/j.amjcard.2010.07.045

    View details for Web of Science ID 000285735000010

    View details for PubMedID 21126617

  • Patterns of discharge antiplatelet therapy and late outcomes among 8,582 patients with bleeding during acute coronary syndrome: A pooled analysis from PURSUIT, PARAGON-A, PARAGON-B, and SYNERGY AMERICAN HEART JOURNAL Chan, M. Y., Sun, J. L., Wang, T. Y., Lopes, R. D., Jolicoeur, M. E., Pieper, K. S., Rao, S. V., Newby, L. K., Mahaffey, K. W., Harrington, R. A., Peterson, E. D. 2010; 160 (6): 1056-U95

    Abstract

    Major bleeding during an acute coronary syndrome (ACS) is associated with increased late ischemic events. Patients with bleeding are often discharged without antiplatelet therapy (AT). The association between discharge AT use and late ischemic outcomes among ACS patients with bleeding is uncertain.We examined discharge AT use among 8,582 ACS patients with in-hospital bleeding from a total of 26,451 patients enrolled in 4 randomized trials. After adjusting for the propensity to receive AT, we compared 6-month postdischarge outcomes between patients discharged with and those discharged without AT.Almost 1 in 10 patients with bleeding was discharged without AT (n=826). Compared with those receiving discharge AT, those not receiving discharge AT had a higher risk of 6-month death, myocardial infarction, and stroke (14.3% vs 7.8%, propensity-adjusted hazard ratio [HR]=1.36, 95% confidence interval=1.01-1.85). Nonuse of AT at discharge was associated with worse outcomes among patients treated with percutaneous coronary intervention compared with those treated without it (adjusted HR=4.22 vs 1.13, interaction P=.0003). Discharge monotherapy was associated with worse outcomes than dual AT among patients receiving stents (adjusted HR=1.78, 95% CI=1.04-3.03).Bleeding occurred commonly among patients with ACS. AT was often not used in these patients at discharge, and lack of discharge AT was associated with an increased risk of 6-month ischemic events. These data raise the possibility that lack of AT use among patients with in-hospital bleeding may contribute to their excess risk of long-term ischemic outcomes.

    View details for DOI 10.1016/j.ahj.2010.09.001

    View details for Web of Science ID 000285187600015

    View details for PubMedID 21146658

  • ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac computed tomography. A report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. Journal of the American College of Cardiology Taylor, A. J., Cerqueira, M., Hodgson, J. M., Mark, D., Min, J., O'Gara, P., Rubin, G. D., Kramer, C. M., Berman, D., Brown, A., Chaudhry, F. A., Cury, R. C., Desai, M. Y., Einstein, A. J., Gomes, A. S., Harrington, R., Hoffmann, U., Khare, R., Lesser, J., McGann, C., Rosenberg, A., Schwartz, R., Shelton, M., Smetana, G. W., Smith, S. C. 2010; 56 (22): 1864-1894

    Abstract

    The American College of Cardiology Foundation (ACCF), along with key specialty and subspecialty societies, conducted an appropriate use review of common clinical scenarios where cardiac computed tomography (CCT) is frequently considered. The present document is an update to the original CCT/cardiac magnetic resonance (CMR) appropriateness criteria published in 2006, written to reflect changes in test utilization, to incorporate new clinical data, and to clarify CCT use where omissions or lack of clarity existed in the original criteria (1). The indications for this review were drawn from common applications or anticipated uses, as well as from current clinical practice guidelines. Ninety-three clinical scenarios were developed by a writing group and scored by a separate technical panel on a scale of 1 to 9 to designate appropriate use, inappropriate use, or uncertain use. In general, use of CCT angiography for diagnosis and risk assessment in patients with low or intermediate risk or pretest probability for coronary artery disease (CAD) was viewed favorably, whereas testing in high-risk patients, routine repeat testing, and general screening in certain clinical scenarios were viewed less favorably. Use of noncontrast computed tomography (CT) for calcium scoring was rated as appropriate within intermediate- and selected low-risk patients. Appropriate applications of CCT are also within the category of cardiac structural and functional evaluation. It is anticipated that these results will have an impact on physician decision making, performance, and reimbursement policy, and that they will help guide future research.

    View details for DOI 10.1016/j.jacc.2010.07.005

    View details for PubMedID 21087721

  • Ticagrelor Versus Clopidogrel in Patients With ST-Elevation Acute Coronary Syndromes Intended for Reperfusion With Primary Percutaneous Coronary Intervention A Platelet Inhibition and Patient Outcomes (PLATO) Trial Subgroup Analysis CIRCULATION Steg, P. G., James, S., Harrington, R. A., Ardissino, D., Becker, R. C., Cannon, C. P., Emanuelsson, H., Finkelstein, A., Husted, S., Katus, H., Kilhamn, J., Olofsson, S., Storey, R. F., Weaver, D., Wallentin, L. 2010; 122 (21): 2131-2141

    Abstract

    Aspirin and clopidogrel are recommended for patients with acute coronary syndromes (ACS) or undergoing coronary stenting. Ticagrelor, a reversible oral P2Y12-receptor antagonist, provides faster, greater, and more consistent platelet inhibition than clopidogrel and may be useful for patients with acute ST-segment elevation (STE) ACS and planned primary percutaneous coronary intervention.Platelet Inhibition and Patient Outcomes (PLATO), a randomized, double-blind trial, compared ticagrelor with clopidogrel for the prevention of vascular events in 18 624 ACS patients. This report concerns the 7544 ACS patients with STE or left bundle-branch block allocated to either ticagrelor 180-mg loading dose followed by 90 mg twice daily or clopidogrel 300-mg loading dose (with provision for 300 mg clopidogrel at percutaneous coronary intervention) followed by 75 mg daily for 6 to 12 months. The reduction of the primary end point (myocardial infarction, stroke, or cardiovascular death) with ticagrelor versus clopidogrel (10.8% versus 9.4%; hazard ratio [HR], 0.87; 95% confidence interval, 0.75 to 1.01; P=0.07) was consistent with the overall PLATO results. There was no interaction between presentation with STE/left bundle-branch block and randomized treatment (interaction P=0.29). Ticagrelor reduced several secondary end points, including myocardial infarction alone (HR, 0.80; P=0.03), total mortality (HR, 0.82; P=0.05), and definite stent thrombosis (HR, 0.66; P=0.03). The risk of stroke, low in both groups, was higher with ticagrelor (1.7% versus 1.0%; HR,1.63; 95% confidence interval, 1.07 to 2.48; P=0.02). Ticagrelor did not affect major bleeding (HR, 0.98; P=0.76).In patients with STE-ACS and planned primary percutaneous coronary intervention, the effects of ticagrelor were consistent with those observed in the overall PLATO trial.URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.109.927582

    View details for Web of Science ID 000284471800013

    View details for PubMedID 21060072

  • Design and rationale of the Reduction of Infarct Expansion and Ventricular Remodeling with Erythropoietin after Large Myocardial Infarction (REVEAL) trial AMERICAN HEART JOURNAL Melloni, C., Rao, S. V., Povsic, T. J., Melton, L., Kim, R. J., Kilaru, R., Patel, M. R., Talan, M., Ferrucci, L., Longo, D. L., Lakatta, E. G., Najjar, S. S., Harrington, R. A. 2010; 160 (5): 795-U39

    Abstract

    Acute myocardial infarction (MI) remains a leading cause of death despite advances in pharmacologic and percutaneous therapies. Animal models of ischemia/reperfusion have demonstrated that single-dose erythropoietin may reduce infarct size, decrease apoptosis, and increase neovascularization, possibly through mobilization of endothelial progenitor cells.REVEAL is a randomized, double-blind, placebo-controlled, multicenter trial evaluating the effects of epoetin ? on infarct size and left ventricular remodeling in patients with large MIs. The trial comprises a dose-escalation safety phase and a single-dose efficacy phase using the highest acceptable epoetin ? dose up to 60,000 IU. Up to 250 ST-segment elevation myocardial infarction patients undergoing primary or rescue percutaneous coronary intervention will be randomized to intravenous epoetin ? or placebo within 4 hours of successful reperfusion. The primary study end point is infarct size expressed as a percentage of left ventricular mass, as measured by cardiac magnetic resonance imaging 2 to 6 days post study medication administration. Secondary end points will assess changes in endothelial progenitor cell numbers and changes in indices of ventricular remodeling.The REVEAL trial will evaluate the safety and efficacy of the highest tolerated single dose of epoetin ? in patients who have undergone successful rescue or primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction.

    View details for DOI 10.1016/j.ahj.2010.09.007

    View details for Web of Science ID 000284458700004

    View details for PubMedID 21095264

  • Effect of apixaban, an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome THROMBOSIS AND HAEMOSTASIS Becker, R. C., Alexander, J. H., Newby, L. K., Yang, H., Barrett, Y., Mohan, P., Wang, J., Harrington, R. A., Wallentin, L. C. 2010; 104 (5): 976-983

    Abstract

    Apixaban is an oral, direct factor Xa inhibitor under development for secondary prevention in acute coronary syndrome (ACS). Apixaban's effect on D-dimer and prothrombin fragment 1.2 (F1.2) (coagulation activity biomarkers ) was determined in a randomised, double-blinded, placebo-controlled, phase 2 study. Patients (n=1,715) with either ST- segment elevation or non-ST-segment elevation ACS received either placebo or apixaban 2.5 mg twice daily, 10 mg once daily, 10 mg twice daily or 20 mg once daily for six months. Samples were obtained at baseline (before study drug administration), week 3 and week 26. Apixaban plasma concentrations were measured directly by liquid chromatography/mass spectometry, and anti-Xa activity was determined using apixaban as a reference standard. D-dimer and F 1.2 were measured using ELISA-based methods. Most patients had elevated D-dimer and F1.2 levels at baseline. Both coagulation activity biomarkers decreased by week 3 in all treatment groups, but to a greater degree with apixaban than placebo (p<0.001). In a multivariable analysis, apixaban was independently associated with a change in biomarkers over time (p<0.0001). While the overall decrease did not differ significantly among the three highest apixaban doses, F1.2 was suppressed more rapidly by the 10 mg once daily than the 2.5 mg twice daily dose (p<0.05). There was a strong and direct relationship between apixaban plasma concentrations and anti-Xa-apixaban levels, and an inverse relationship for both measures with coagulation activity biomarkers. In conclusion, the oral direct factor Xa inhibitor apixaban significantly reduced coagulation activity biomarkers among patients with ACS. The 10 mg once daily dose reduced thrombin generation (F 1.2) and fibrin formation (D-dimer) more rapidly and robustly than the 2.5 mg twice daily dose. The effect on both D-dimer and F 1.2 was apixaban concentration-and factor Xa inhibition dependent, durable and provided general guidance for dose selection in phase 3 investigation.

    View details for DOI 10.1160/TH10.04.0247

    View details for Web of Science ID 000284522600016

    View details for PubMedID 20806117

  • Study design and rationale for the clinical outcomes of the STABILITY Trial (STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease AMERICAN HEART JOURNAL White, H., Held, C., Stewart, R., Watson, D., Harrington, R., Budaj, A., Steg, P. G., Cannon, C. P., Krug-Gourley, S., Wittes, J., Trivedi, T., Tarka, E., Wallentin, L. 2010; 160 (4): 655-U289

    Abstract

    Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with increased risk of cardiovascular (CV) events. Direct inhibition of this proinflammatory enzyme with darapladib may benefit CV patients when given as an adjunct to standard of care, including lipid-lowering and antiplatelet therapies.STABILITY is a randomized, placebo-controlled, double-blind, international, multicenter, event-driven trial. The study has randomized 15,828 patients with chronic coronary heart disease (CHD) receiving standard of care to darapladib enteric-coated (EC) tablets, 160 mg or placebo.The primary end point is the composite of major adverse cardiovascular events (MACE): CV death, nonfatal myocardial infarction, and nonfatal stroke. The key secondary end points will include major coronary events, total coronary events, individual components of MACE, and all-cause mortality. Prespecified substudies include 24-hour ambulatory blood pressure monitoring, albuminuria progression, changes in cognitive function, and pharmacokinetic and biomarker analyses. Health economic outcomes and characterization of baseline lifestyle risk factors also will be assessed. The study will continue until 1,500 primary end points have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be 2.75 years.STABILITY will assess whether direct inhibition of Lp-PLA(2) with darapladib added to the standard of care confers clinical benefit to patients with CHD.

    View details for DOI 10.1016/j.ahj.2010.07.006

    View details for Web of Science ID 000282677300015

    View details for PubMedID 20934559

  • Ticagrelor Versus Clopidogrel in Acute Coronary Syndromes in Relation to Renal Function Results From the Platelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION James, S., Budaj, A., Aylward, P., Buck, K. K., Cannon, C. P., Cornel, J. H., Harrington, R. A., Horrow, J., Katus, H., Keltai, M., Lewis, B. S., Parikh, K., Storey, R. F., Szummer, K., Wojdyla, D., Wallentin, L. 2010; 122 (11): 1056-1067

    Abstract

    Reduced renal function is associated with a poorer prognosis and increased bleeding risk in patients with acute coronary syndromes and may therefore alter the risk-benefit ratio with antiplatelet therapies. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor compared with clopidogrel reduced the primary composite end point of cardiovascular death, myocardial infarction, and stroke at 12 months but with similar major bleeding rates.Central laboratory serum creatinine levels were available in 15 202 (81.9%) acute coronary syndrome patients at baseline, and creatinine clearance, estimated by the Cockcroft Gault equation, was calculated. In patients with chronic kidney disease (creatinine clearance <60 mL/min; n=3237), ticagrelor versus clopidogrel significantly reduced the primary end point to 17.3% from 22.0% (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.65 to 0.90) with an absolute risk reduction greater than that of patients with normal renal function (n=11 965): 7.9% versus 8.9% (HR, 0.90; 95% CI, 0.79 to 1.02). In patients with chronic kidney disease, ticagrelor reduced total mortality (10.0% versus 14.0%; HR, 0.72; 95% CI, 0.58 to 0.89). Major bleeding rates, fatal bleedings, and non-coronary bypass-related major bleedings were not significantly different between the 2 randomized groups (15.1% versus 14.3%; HR, 1.07; 95% CI, 0.88 to 1.30; 0.34% versus 0.77%; HR, 0.48; 95% CI, 0.15 to 1.54; and 8.5% versus 7.3%; HR, 1.28; 95% CI, 0.97 to 1.68). The interactions between creatinine clearance and randomized treatment on any of the outcome variables were nonsignificant.In acute coronary syndrome patients with chronic kidney disease, ticagrelor compared with clopidogrel significantly reduces ischemic end points and mortality without a significant increase in major bleeding but with numerically more non-procedure-related bleeding.URL:http://www.clinicatrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.109.933796

    View details for Web of Science ID 000281877800002

    View details for PubMedID 20805430

  • President's page: the ACC reconfirms commitment to transparent relationships with industry. Journal of the American College of Cardiology Brindis, R., Harrington, R. 2010; 56 (11): 900-902

    View details for DOI 10.1016/j.jacc.2010.08.001

    View details for PubMedID 20813288

  • First Clinical Application of an Actively Reversible Direct Factor IXa Inhibitor as an Anticoagulation Strategy in Patients Undergoing Percutaneous Coronary Intervention CIRCULATION Cohen, M. G., Purdy, D. A., Rossi, J. S., Grinfeld, L. R., Myles, S. K., Aberle, L. H., Greenbaum, A. B., Fry, E., Chan, M. Y., Tonkens, R. M., Zelenkofske, S., Alexander, J. H., Harrington, R. A., Rusconi, C. P., Becker, R. C. 2010; 122 (6): 614-622

    Abstract

    The ideal anticoagulant should prevent ischemic complications without increasing the risk of bleeding. Controlled anticoagulation is possible with the REG1 system, an RNA aptamer pair comprising the direct factor IXa inhibitor RB006 and its active control agent RB007.This phase 2a study included a roll-in group (n=2) treated with REG1 plus glycoprotein IIb/IIIa inhibitors followed by 2 groups randomized 5:1 to REG1 or unfractionated heparin. In group 1 (n=12), RB006 was partially reversed with RB007 after percutaneous coronary intervention and fully reversed 4 hours later. In group 2 (n=12), RB006 was fully reversed with RB007 immediately after percutaneous coronary intervention. Femoral sheaths were removed after complete reversal. Patients were pretreated with aspirin and clopidogrel. End points included major bleeding within 48 hours; composite of death, myocardial infarction, or urgent target vessel revascularization within 14 days; and pharmacodynamic measures. All cases were successful, with final Thrombolysis in Myocardial Infarction grade 3 flow and no angiographic thrombotic complications. There were 2 ischemic end points in the REG1 group and 1 in the unfractionated heparin group, with 1 major bleed in the unfractionated heparin group. Median activated clotting time values rose from 151 to 236 seconds after RB006. Administration of the partial RB007 dose reversed anticoagulation to an intermediate activated clotting time value of 186 seconds. Complete reversal with RB007 returned the median activated clotting time value to 144 seconds. Both reversal strategies enabled scheduled femoral sheath removal.This study demonstrates the clinical translation of a novel platform of anticoagulation targeting factor IXa and its active reversal to percutaneous coronary intervention and provides the basis for further investigation.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715455.

    View details for DOI 10.1161/CIRCULATIONAHA.109.927756

    View details for Web of Science ID 000280757300008

    View details for PubMedID 20660806

  • Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y(12)-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI) AMERICAN HEART JOURNAL Leonardi, S., Rao, S. V., Harrington, R. A., Bhatt, D. L., Gibson, C. M., Roe, M. T., Kochman, J., Huber, K., Zeymer, U., Madan, M., Gretler, D. D., McClure, M. W., Paynter, G. E., Thompson, V., Welsh, R. C. 2010; 160 (1): 65-72

    Abstract

    Despite current dual-antiplatelet therapy with aspirin and clopidogrel, adverse clinical events continue to occur during and after percutaneous coronary intervention (PCI). The failure of clopidogrel to provide optimal protection may be related to delayed onset of action, interpatient variability in its effect, and an insufficient level of platelet inhibition. Furthermore, the irreversible binding of clopidogrel to the P2Y(12) receptor for the life span of the platelet is associated with increased bleeding risk especially during urgent or emergency surgery. Novel antiplatelet agents are required to improve management of patients undergoing PCI. Elinogrel is a potent, direct-acting (ie, non-prodrug), selective, competitive, and reversible P2Y(12) inhibitor available in both intravenous and oral formulations. The INNOVATE-PCI study is a phase 2 randomized, double-blind, clopidogrel-controlled trial to evaluate the safety, tolerability, and preliminary efficacy of this novel antiplatelet agent in patients undergoing nonurgent PCI.

    View details for DOI 10.1016/j.ahj.2010.04.008

    View details for Web of Science ID 000279440400011

    View details for PubMedID 20598974

  • Randomized Evaluation of efficacy and safety of ferric carboxymaltose in Patients with iron deficiency Anaemia and Impaired Renal function (REPAIR-IDA): rationale and study design NEPHROLOGY DIALYSIS TRANSPLANTATION Szczech, L. A., Bregman, D. B., Harrington, R. A., Morris, D., Butcher, A., Koch, T. A., Goodnough, L. T., Wolf, M., Onken, J. E. 2010; 25 (7): 2368-2375

    Abstract

    Patients with iron deficiency anaemia (IDA) in the setting of non-dialysis-dependent chronic kidney disease (NDD-CKD) may benefit from treatment with intravenous (IV) iron. Ferric carboxymaltose (FCM) is a novel IV iron formulation designed to permit larger infusions compared to currently available IV standards such as Venofer(R) (iron sucrose).The primary objective of REPAIR-IDA is to estimate the cardiovascular safety and efficacy of FCM (two doses at 15 mg/kg to a maximum of 750 mg per dose) compared to Venofer(R) (1000 mg administered as five infusions of 200 mg) in subjects who have IDA and NDD-CKD. REPAIR-IDA is a multi-centre, randomized, active-controlled, open-label study. Eligible patients must have haemoglobin (Hgb) < or = 11.5 g/dL and CKD defined as (1) GFR < 60 mL/min/1.73 m(2) on two occasions or (2) GFR < 90 mL/min/1.73 m(2) and either evidence of renal injury by urinalysis or elevated Framingham cardiovascular risk score. Two thousand and five hundred patients will be randomized to FCM or Venofer(R) in a 1:1 ratio. The primary efficacy endpoint is mean change in Hgb from baseline to the highest observed Hgb between baseline and Day 56. The primary safety endpoint is the proportion of subjects experiencing at least one of the following events: death due to any cause, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring hospitalization, congestive heart failure requiring hospitalization or medical intervention, arrhythmias, hypertension or hypotension during the 120 days following randomization.REPAIR-IDA will assess the efficacy and safety of two 750-mg infusions of FCM compared to an FDA-approved IV iron regimen in patients with NDD-CKD at increased risk for cardiovascular disease.

    View details for DOI 10.1093/ndt/gfq218

    View details for Web of Science ID 000279189400051

    View details for PubMedID 20466657

  • There Is a Role for Industry-Sponsored Education in Cardiology CIRCULATION Harrington, R. A., Califf, R. M. 2010; 121 (20): 2221-2227
  • An update on the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) design AMERICAN HEART JOURNAL Califf, R. M., Lokhnygina, Y., Cannon, C. P., Stepanavage, M. E., McCabe, C. H., Musliner, T. A., Pasternak, R. C., Blazing, M. A., Giugliano, R. P., Harrington, R. A., Braunwald, E. 2010; 159 (5): 705-709

    View details for DOI 10.1016/j.ahj.2010.03.004

    View details for Web of Science ID 000277243300001

    View details for PubMedID 20435175

  • Changes in Inflammatory Biomarkers in Patients Treated With Ticagrelor or Clopidogrel CLINICAL CARDIOLOGY Husted, S., Storey, R. F., Harrington, R. A., Emanuelsson, H., Cannon, C. P. 2010; 33 (4): 206-212

    Abstract

    Inflammation is a key factor in the development of atherosclerotic disease and acute coronary syndromes (ACS). The P2Y(12) receptor antagonists ticagrelor (AZD6140) and clopidogrel may have anti-inflammatory effects. The objective of this analysis from the Dose Confirmation Study Assessing Anti-Platelet Effects of AZD6140 vs Clopidogrel in NSTEMI 2 (DISPERSE 2) trial was to compare ticagrelor and clopidogrel for effects on the inflammatory biomarkers C-reactive protein (CRP), interleukin 6 (IL-6), myeloperoxidase (MPO), and soluble CD40 ligand (sCD40L).Ticagrelor inhibits the P2Y(12) receptor and inflammation to a greater extent than clopidogrel in nonST-segment elevation ACS (NSTE-ACS) patients.In a double-blind, double-dummy, multicenter trial, 990 patients who had been hospitalized within the previous 48 hours with NSTE-ACS were randomized to receive ticagrelor 90 mg twice daily, ticagrelor 180 mg twice daily, or clopidogrel 300 mg initially and then 75 mg once daily. Within the ticagrelor groups, patients were also randomized to receive or not receive a loading dose of ticagrelor 270 mg initially. All patients received standard treatment for ACS, which included 325 mg aspirin initially and 75 to 100 mg aspirin each day subsequently. Inflammatory biomarkers were measured at baseline, upon hospital discharge, and after 4 weeks.Inflammatory biomarker measurements were not significantly different among treatment groups at baseline, discharge, and 4 weeks.Ticagrelor and clopidogrel appeared not to differ in this study with respect to the inflammatory biomarkers CRP, IL-6, MPO, and sCD40L in patients with NSTE-ACS.

    View details for DOI 10.1002/clc.20732

    View details for Web of Science ID 000277113300004

    View details for PubMedID 20394040

  • Towards a new order in cardiovascular medicine: re-engineering through global collaboration EUROPEAN HEART JOURNAL Califf, R. M., Armstrong, P. W., Granger, C. B., Harrington, R. A., Lee, K., Simess, R. J., Van de Werf, F., Wallentin, L., White, H. D. 2010; 31 (8): 911-917

    View details for DOI 10.1093/eurheartj/ehp550

    View details for Web of Science ID 000277278900010

    View details for PubMedID 20130014

  • Metabolic Syndrome Is Not Associated With Increased Mortality or Cardiovascular Risk in Nondiabetic Patients With a New Diagnosis of Coronary Artery Disease CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Petersen, J. L., Yow, E., Aljaroudi, W., Shaw, L. K., Goyal, A., McGuire, D. K., Peterson, E. D., Harrington, R. A. 2010; 3 (2): 165-172

    Abstract

    Metabolic syndrome (MetSyn) is associated with increased cardiovascular risk in the general population. Its prognostic implications are less well defined in patients with coronary artery disease.We analyzed patients in the Duke Database for Cardiovascular Disease with a diagnosis of incident obstructive coronary artery disease. Diabetes mellitus (DM) was classified as a clinical history of DM, use of hypoglycemic drugs, or fasting glucose of >or=126 mg/dL. MetSyn was defined as having 3 of 5 characteristics: fasting glucose >or=100 and <126 mg/dL, low high-density lipoprotein cholesterol (men, <40 mg/dL; women, <50 mg/dL), triglycerides >150 mg/dL, blood pressure >or=130/85 mm Hg, or use of antihypertensive therapy, or body mass index >or=27. Death, myocardial infarction, or stroke was assessed at 6 months, 1 year, then annually. Cox proportional hazards models were generated to compare mortality and cardiovascular events between groups. The primary cohort consisted of 5744 patients; 1831 (31.9%) had DM, 2491 (43.4%) had MetSyn, and 1422 (24.7%) had no DM/MetSyn. Median follow-up was 5 years. Compared with no DM/MetSyn patients, DM patients had a higher adjusted risk for mortality (hazard ratio, 1.47; 95% CI, 1.28 to 1.69) but MetSyn patients did not (hazard ratio, 0.94; 95% CI, 0.81 to 1.08). Similar results were found for the combined end points of death or myocardial infarction, and death, myocardial infarction, or stroke.In a population of consecutive patients with a new diagnosis of coronary artery disease by angiography, MetSyn without DM was not an independent predictor of mortality or cardiovascular events.

    View details for DOI 10.1161/CIRCOUTCOMES.109.864447

    View details for Web of Science ID 000276080200010

    View details for PubMedID 20179266

  • 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

  • Comparison of ticagrelor with clopidogrel in patients with planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study LANCET Cannon, C. P., Harrington, R. A., James, S., Ardissino, D., Becker, R. C., Emanuelsson, H., Husted, S., Katus, H., Keltai, M., Khurmi, N. S., Kontny, F., Lewis, B. S., Steg, P. G., Storey, R. F., Wojdyla, D., Wallentin, L. 2010; 375 (9711): 283-293

    Abstract

    Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients.At randomisation, an invasive strategy was planned for 13 408 (72.0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300-600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6-12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00391872.6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 [event rate at 360 days 9.0%] vs 668 [10.7%], hazard ratio 0.84, 95% CI 0.75-0.94; p=0.0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 [11.6%] vs 689 [11.5%], 0.99 [0.89-1.10]; p=0.8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 [3.2%] vs 185 [2.9%], 0.91 [0.74-1.12]; p=0.3785).Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned.

    View details for DOI 10.1016/S0140-6736(09)62191-7

    View details for Web of Science ID 000274069300029

    View details for PubMedID 20079528

  • 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

  • Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Early Rapid ReversAl of Platelet ThromboSis with Intravenous Elinogrel before PCI to Optimize REperfusion in Acute Myocardial Infarction (ERASE MI) pilot trial AMERICAN HEART JOURNAL Berger, J. S., Roe, M. T., Gibson, C. M., Kilaru, R., Green, C. L., Melton, L., Blankenship, J. D., Metzger, D. C., Granger, C. B., Gretler, D. D., Grines, C. L., Huber, K., Zeymer, U., Buszman, P., Harrington, R. A., Armstrong, P. W. 2009; 158 (6): 998-U145

    Abstract

    Inhibition of the P2Y12 ADP-receptor with oral antiplatelet agents given to patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is associated with improved outcomes, but this strategy is limited by the time required for maximal antiplatelet effect after administration. We examined the safety and tolerability of a novel, direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, versus placebo when administered to STEMI patients before primary PCI.The ERASE MI trial was a pilot, phase IIA, randomized, double-blind, placebo-controlled, dose-escalation study designed to evaluate the safety and tolerability of escalating doses (10, 20, 40, and 60 mg) of elinogrel administered as a single intravenous bolus before the start of the diagnostic angiogram preceding primary PCI. Patients were randomly assigned in a 1:1 manner to either elinogrel or placebo within each dosing group; and all patients received a 600-mg clopidogrel loading dose, followed by a second 300-mg clopidogrel loading dose 4 hours after PCI. The major outcome, in-hospital bleeding, was assessed with the Thrombolysis in Myocardial Infarction and Global Strategies to Open Occluded Coronary Arteries bleeding scales. Pre-PCI corrected Thrombolysis in Myocardial Infarction frame count and ST-segment resolution were also evaluated.Seventy patients were randomized in the dose-escalation study, but the dose-confirmation phase was not started because the trial was prematurely terminated for administrative reasons. The incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel versus placebo. No differences in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction frame count, or ST resolution were demonstrated between elinogrel and placebo.With the limitations of a small study sample size, this pilot study provided preliminary data on the feasibility and tolerability of escalating doses of a direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, as an adjunctive therapy for primary PCI for STEMI.

    View details for DOI 10.1016/j.ahj.2009.10.010

    View details for Web of Science ID 000273051100016

    View details for PubMedID 19958867

  • Standardized reporting of bleeding complications for clinical investigations in acute coronary syndromes: A proposal from the Academic Bleeding Consensus (ABC) Multidisciplinary Working Group AMERICAN HEART JOURNAL Rao, S. V., Eikelboom, J., Steg, P. G., Lincoff, A. M., Weintraub, W. S., Bassand, J., Rao, A. K., Gibson, C. M., Petersen, J. L., Mehran, R., Manoukian, S. V., Charnigo, R., Lee, K. L., Moscucci, M., Harrington, R. A. 2009; 158 (6): 881-U16

    Abstract

    Clinical trials of antithrombotic agents for the treatment of ACS routinely assess bleeding as a safety endpoint, but variation in bleeding definitions makes comparison of the relative safety of these agents difficult.The ABC Multidisciplinary Working Group, an informal working group comprising clinical researchers and representatives from the US Food and Drug Administration, the National Institutes of Health, and the pharmaceutical industry, sought to develop a consensus approach to measuring the incidence and severity of bleeding complications during clinical trials of acute coronary syndromes (ACS). A meeting of the ABC was convened in April 2008 in Washington, DC, with the goal of developing a consensus approach to measuring the incidence and severity of hemorrhagic complications during clinical trials of ACS. Relevant literature on bleeding was reviewed through a series of short lectures and intensive group discussion.Using existing evidence on bleeding and outcomes as well as clinical judgment, criteria for the assessment of bleeding were developed through expert consensus. This consensus statement divides bleeding-related data elements into three categories: essential, recommended, and optional.The ABC Group recommendations for collection and reporting of bleeding complications provide a framework for consistency in the collection of information on hemorrhagic complications in trials of ACS. Widespread adoption of the statement recommendations will facilitate understanding of the mechanisms of adverse outcomes after bleeding and comparisons of the relative safety of antithrombotic agents, as well as the interpretation of safety results from future studies.

    View details for DOI 10.1016/j.ahj.2009.10.008

    View details for Web of Science ID 000273051100001

    View details for PubMedID 19958852

  • 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

  • Enoxaparin Versus Unfractionated Heparin in Elective Percutaneous Coronary Intervention 1-Year Results From the STEEPLE (SafeTy and Efficacy of Enoxaparin in Percutaneous coronary intervention patients, an internationaL randomized Evaluation) Trial JACC-CARDIOVASCULAR INTERVENTIONS Montalescot, G., Gallo, R., White, H. D., Cohen, M., Steg, G., Aylward, P. E., Bode, C., Chiariello, M., King, S. B., Harrington, R. A., Desmet, W. J., Macaya, C., Steinhubl, S. R. 2009; 2 (11): 1083-1091

    Abstract

    Our purpose was to evaluate long-term mortality and identify factors associated with 1-year mortality in patients who underwent elective percutaneous coronary intervention (PCI).While long-term outcomes in PCI patients have been reported previously, limited data are currently available regarding the comparative long-term outcomes in PCI patients who receive enoxaparin versus intravenous unfractionated heparin (UFH).We conducted a follow-up analysis of clinical outcomes at 1 year in patients enrolled in the STEEPLE (SafeTy and Efficacy of Enoxaparin in Percutaneous coronary intervention patients, an internationaL randomized Evaluation) trial of 3,528 patients undergoing elective PCI. Patients were randomized to receive either intravenous 0.50-mg/kg or 0.75-mg/kg enoxaparin or intravenous UFH during elective PCI procedures. All-cause mortality at 1 year after index PCI was the main outcome measure.Mortality rates were 1.4%, 2.0%, and 1.5% from 1 month to 1 year, and 2.3%, 2.2%, and 1.9% from randomization to 1 year, after index PCI in patients receiving 0.50 mg/kg enoxaparin, 0.75 mg/kg enoxaparin, and UFH, respectively. Multivariate analysis identified nonfatal myocardial infarction and/or urgent target vessel revascularization up to 30 days after index PCI (hazard ratio: 3.5, 95% confidence interval: 1.7 to 7.3; p < 0.001), and major bleeding within 48 h (hazard ratio: 3.0, 95% confidence interval: 1.1 to 8.5; p = 0.04) as the strongest independent risk factors for 1-year mortality.The 1-year mortality rates were low and comparable between patients receiving enoxaparin and UFH during elective PCI. Periprocedural ischemic or bleeding events were the strongest independent predictors of 1-year mortality. (The STEEPLE Trial; NCT00077844).

    View details for DOI 10.1016/j.jcin.2009.08.016

    View details for Web of Science ID 000275913800008

    View details for PubMedID 19926048

  • Patterns of management of atrial fibrillation complicating coronary artery bypass grafting: Results from the PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT-IV) Trial AMERICAN HEART JOURNAL Al-Khatib, S. M., Hafley, G., Harrington, R. A., Mack, M. J., Ferguson, T. B., Peterson, E. D., Califf, R. M., Kouchoukos, N. T., Alexander, J. H. 2009; 158 (5): 792-798

    Abstract

    Current practice related to the management of atrial fibrillation (AF) complicating coronary artery bypass grafting (CABG) is uncertain.We examined management of post-CABG AF in the PREVENT-IV trial, and we explored patterns of use of postoperative rhythm versus rate control and anticoagulation for AF by geographic region and type of site. We also compared outcomes of patients who developed post-CABG AF (663) with those who did not (2,131).The incidence of AF was 24%. Post-CABG AF was treated with a rhythm control strategy in 81% of patients and with warfarin in 23% of patients. Although there were significant variations across sites in the management of post-CABG AF, patterns of use of postoperative rhythm versus rate control and anticoagulation did not differ by geographic region or by whether or not the enrolling site was an academic institution. Mortality was higher in patients with post-CABG AF than patients without AF at 30 days (1.5% vs 0.7%, P = .01) but not at 3 years (6.9% vs 4.9%, P = .41). There was a trend toward a higher risk of mortality or stroke at 30 days in patients with AF (2.4% vs 1.9%, P = .08).Although a rhythm control strategy was used in most of the patients in this trial and the overall rate of use of warfarin was low, the significance of these findings is uncertain because of the lack of data from randomized clinical trials. The substantial variations in the management of post-CABG AF across sites are likely because of definitive data on the most effective therapies, highlighting the need for clinical trials on rate versus rhythm control and on anticoagulation for AF in this setting.

    View details for DOI 10.1016/j.ahj.2009.09.003

    View details for Web of Science ID 000271275400016

    View details for PubMedID 19853700

  • Catheter thrombosis and percutaneous coronary intervention: fundamental perspectives on blood, artificial surfaces and antithrombotic drugs JOURNAL OF THROMBOSIS AND THROMBOLYSIS Chan, M. Y., Weitz, J. I., Merhi, Y., Harrington, R. A., Becker, R. C. 2009; 28 (3): 366-380

    Abstract

    Recent reports of catheter thrombosis among patients undergoing percutaneous coronary intervention (PCI) have had a significant impact on the development of new antithrombotic therapies. The overall incidence of this complication is unknown, mainly because of underreporting in contemporary clinical trials of coronary intervention. The etiology and pathophysiology of catheter thrombosis is also poorly understood. Introduction of a catheter or guidewire may not provoke the intense thrombotic response that follows angioplasty or stenting, but factors such as catheter materials and device size, equipment surface properties, flow conditions, procedural time and complexity, as well as the antiplatelet and anticoagulant drugs administered during the procedure influence the likelihood, rate and clinical impact of thrombosis. The crucial role of cellular interactions involving tissue-factor bearing cells and platelets in the process of thrombosis also needs to be critically explored when considering blood contact with an exogenous material. Focusing on the inherently prothrombotic environment of percutaneous coronary intervention, we review the physiologic underpinnings of catheter and guidewire thrombosis, and explore the effect of antithrombotic drugs at the interface between blood and material surfaces. We also propose a clinical classification for the diagnosis and investigation of catheter thrombosis in clinical trials of anticoagulant therapy and PCI.

    View details for DOI 10.1007/s11239-009-0375-6

    View details for Web of Science ID 000269860600021

    View details for PubMedID 19597766

  • 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

  • Antithrombotics in Acute Coronary Syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Bonaca, M. P., Steg, P. G., Feldman, L. J., Canales, J. F., Ferguson, J. J., Wallentin, L., Califf, R. M., Harrington, R. A., Giugliano, R. P. 2009; 54 (11): 969-984

    Abstract

    Antithrombotic agents are an integral component of the medical regimens and interventional strategies currently recommended to reduce thrombotic complications in patients with acute coronary syndromes (ACS). Despite great advances with these therapies, associated high risks for thrombosis and hemorrhage remain as the result of complex interactions involving patient comorbidities, drug combinations, multifaceted dosing adjustments, and the intricacies of the care environment. As such, the optimal combinations of antithrombotic therapies, their timing, and appropriate targeted subgroups remain the focus of intense research. During the last several years a number of new antithrombotic treatments have been introduced, and new data regarding established therapies have come to light. Although treatment guidelines include the most current available data, subsequent findings can be challenging to integrate. This challenge is compounded by the complexity associated with different efficacy and safety measures and the variability in study populations, presenting syndromes, physician, and patient preferences. In this work we review recent data regarding clinically available antiplatelet and anticoagulation agents used in the treatment of patients with ACS. We address issues including relative efficacy, safety, and timing of therapies with respect to conservative and invasive treatment strategies. In specific cases we will highlight remaining questions and controversies and ongoing trials, which will hopefully shed light in these areas. In addition to reviewing existing agents, we take a look forward at the most promising new antithrombotics currently in late-stage clinical development and their potential role in the context of ACS management.

    View details for DOI 10.1016/j.jacc.2009.03.083

    View details for Web of Science ID 000269477500001

    View details for PubMedID 19729112

  • Sex Differences in Mortality Following Acute Coronary Syndromes JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Berger, J. S., Elliott, L., Gallup, D., Roe, M., Granger, C. B., Armstrong, P. W., Simes, R. J., White, H. D., Van de Werf, F., Topol, E. J., Hochman, J. S., Newby, L. K., Harrington, R. A., Califf, R. M., Becker, R. C., Douglas, P. S. 2009; 302 (8): 874-882

    Abstract

    Conflicting information exists about whether sex differences modulate short-term mortality following acute coronary syndromes (ACS).To investigate the relationship between sex and 30-day mortality in ACS, and to determine whether this relationship was modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates.A convenience sample of patients pooled from 11 independent, international, randomized ACS clinical trials between 1993 and 2006 whose databases are maintained at the Duke Clinical Research Institute, Durham, North Carolina. Of 136 247 patients, 38 048 (28%) were women; 102 004 (26% women) with ST-segment elevation myocardial infarction (STEMI), 14 466 (29% women) with non-STEMI (NSTEMI), and 19 777 (40% women) with unstable angina.Thirty-day mortality following ACS.Thirty-day mortality was 9.6% in women and 5.3% in men (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.83-2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR, 1.06; 95% CI, 0.99-1.15). A significant sex by type of ACS interaction was demonstrated (P < .001). In STEMI, 30-day mortality was higher among women (adjusted OR, 1.15; 95% CI, 1.06-1.24), whereas in NSTEMI (adjusted OR, 0.77; 95% CI, 0.63-0.95) and unstable angina, mortality was lower among women (adjusted OR, 0.55; 95% CI, 0.43-0.70). In a cohort of 35 128 patients with angiographic data, women more often had nonobstructive (15% vs 8%) and less often had 2-vessel (25% vs 28%) and 3-vessel (23% vs 26%) coronary disease, regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (P for interaction = .70).Sex-based differences existed in 30-day mortality among patients with ACS and vary depending on clinical presentation. However, these differences appear to be largely explained by clinical differences at presentation and severity of angiographically documented disease.

    View details for Web of Science ID 000269260100021

    View details for PubMedID 19706861

  • Premature Release of Data from Clinical Trials of Ezetimibe NEW ENGLAND JOURNAL OF MEDICINE Califf, R. M., Harrington, R. A., Blazing, M. A. 2009; 361 (7): 712-717

    View details for Web of Science ID 000268884100015

    View details for PubMedID 19675335

  • Endoscopic versus Open Vein-Graft Harvesting in Coronary-Artery Bypass Surgery NEW ENGLAND JOURNAL OF MEDICINE Lopes, R. D., Hafley, G. E., Allen, K. B., Ferguson, T. B., Peterson, E. D., Harrington, R. A., Mehta, R. H., Gibson, C. M., Mack, M. J., Kouchoukos, N. T., Califf, R. M., Alexander, J. H. 2009; 361 (3): 235-244

    Abstract

    Vein-graft harvesting with the use of endoscopy (endoscopic harvesting) is a technique that is widely used to reduce postoperative wound complications after coronary-artery bypass grafting (CABG), but the long-term effects on the rate of vein-graft failure and on clinical outcomes are unknown.We studied the outcomes in patients who underwent endoscopic harvesting (1753 patients) as compared with those who underwent graft harvesting under direct vision, termed open harvesting (1247 patients), in a secondary analysis of 3000 patients undergoing CABG. The method of graft harvesting was determined by the surgeon. Vein-graft failure was defined as stenosis of at least 75% of the diameter of the graft on angiography 12 to 18 months after surgery (data were available in an angiographic subgroup of 1817 patients and 4290 grafts). Clinical outcomes included death, myocardial infarction, and repeat revascularization. Generalized estimating equations were used to adjust for baseline covariates associated with vein-graft failure and to account for the potential correlation between grafts within a patient. Cox proportional-hazards modeling was used to assess long-term clinical outcomes.The baseline characteristics were similar between patients who underwent endoscopic harvesting and those who underwent open harvesting. Patients who underwent endoscopic harvesting had higher rates of vein-graft failure at 12 to 18 months than patients who underwent open harvesting (46.7% vs. 38.0%, P<0.001). At 3 years, endoscopic harvesting was also associated with higher rates of death, myocardial infarction, or repeat revascularization (20.2% vs. 17.4%; adjusted hazard ratio, 1.22; 95% confidence interval [CI], 1.01 to 1.47; P=0.04), death or myocardial infarction (9.3% vs. 7.6%; adjusted hazard ratio, 1.38; 95% CI, 1.07 to 1.77; P=0.01), and death (7.4% vs. 5.8%; adjusted hazard ratio, 1.52; 95% CI, 1.13 to 2.04; P=0.005).Endoscopic vein-graft harvesting is independently associated with vein-graft failure and adverse clinical outcomes. Randomized clinical trials are needed to further evaluate the safety and effectiveness of this harvesting technique.

    View details for Web of Science ID 000267976100004

    View details for PubMedID 19605828

  • A new generation of antiplatelet agents CURRENT OPINION IN CARDIOLOGY Sellers, M. B., Tricoci, P., Harrington, R. A. 2009; 24 (4): 307-312

    Abstract

    Since the development and market entry of clopidogrel, a platelet ADP blocker, physicians have had few new antiplatelet options available to them for the treatment of acute and chronic coronary disease, specifically in the setting of acute coronary syndromes, percutaneous coronary intervention, and chronic stent management. Over the years, limitations of current antiplatelet regimens have emerged, establishing a need for novel antiplatelet drugs. This article discusses potential new targets for platelet inhibition and reviews innovative antiplatelet therapies under investigation.There are five main categories of antiplatelet therapies currently undergoing clinical study, consisting of the thienopyridines (P2Y12 receptor antagonists), cyclopentyltriazolopyrimidines (P2Y12 receptor antagonists), anti-von Willebrand factor aptamers, thrombin receptor (protease-activated receptor-1) antagonists, and thromboxane receptor antagonists. Early studies of these agents are discussed.Each of these new antiplatelet therapies has a unique profile that is aimed at improving clinical response with hopes of incremental efficacy and decreased complications, specifically bleeding.

    View details for DOI 10.1097/HCO.0b013e32832e2b44

    View details for Web of Science ID 000267279500006

    View details for PubMedID 19509485

  • Apixaban, an Oral, Direct, Selective Factor Xa Inhibitor, in Combination With Antiplatelet Therapy After Acute Coronary Syndrome Results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) Trial CIRCULATION Alexander, J. H., Becker, R. C., Bhatt, D. L., Cools, F., Crea, F., Dellborg, M., Fox, K. A., Goodman, S. G., Harrington, R. A., Huber, K., Husted, S., Lewis, B. S., Lopez-Sendon, J., Mohan, P., Montalescot, G., Ruda, M., Ruzyllo, W., Verheugt, F., Wallentin, L., Darius, H., Simoons, M., Boersma, E., DeLemos, J., Spencer, F. 2009; 119 (22): 2877-U39

    Abstract

    After an acute coronary syndrome, patients remain at risk of recurrent events. Apixaban, an oral direct factor Xa inhibitor, is a novel anticoagulant that may reduce these events but also poses a risk of bleeding.Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) was a phase 2, double-blind, placebo-controlled, dose-ranging study. Patients (n=1715) with recent ST-elevation or non-ST-elevation acute coronary syndrome were randomized to 6 months of placebo (n=611) or 1 of 4 doses of apixaban: 2.5 mg twice daily (n=317), 10 mg once daily (n=318), 10 mg twice daily (n=248), or 20 mg once daily (n=221). Nearly all patients received aspirin; 76% received clopidogrel. The primary outcome was International Society of Thrombosis and Hemostasis major or clinically relevant nonmajor bleeding. A secondary outcome was cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke. At the recommendation of the Data Monitoring Committee, the 2 higher-dose apixaban arms were discontinued because of excess total bleeding. Compared with placebo, apixaban 2.5 mg twice daily (hazard ratio, 1.78; 95% confidence interval, 0.91 to 3.48; P=0.09) and 10 mg once daily (hazard ratio, 2.45; 95% confidence interval, 1.31 to 4.61; P=0.005) resulted in a dose-dependent increase in major or clinically relevant nonmajor bleeding. Apixaban 2.5 mg twice daily (hazard ratio, 0.73; 95% confidence interval, 0.44 to 1.19; P=0.21) and 10 mg once daily (hazard ratio, 0.61; 95% confidence interval, 0.35 to 1.04; P=0.07) resulted in lower rates of ischemic events compared with placebo. The increase in bleeding was more pronounced and the reduction in ischemic events was less evident in patients taking aspirin plus clopidogrel than in those taking aspirin alone.We observed a dose-related increase in bleeding and a trend toward a reduction in ischemic events with the addition of apixaban to antiplatelet therapy in patients with recent acute coronary syndrome. The safety and efficacy of apixaban may vary depending on background antiplatelet therapy. Further testing of apixaban in patients at risk of recurrent ischemic events is warranted.

    View details for DOI 10.1161/CIRCULATIONAHA.108.832139

    View details for Web of Science ID 000266777900004

    View details for PubMedID 19470889

  • Careers for Clinician Investigators CIRCULATION Harrington, R. A., Califf, R. M., Hodgson, P. K., Peterson, E. D., Roe, M. T., Mark, D. B. 2009; 119 (22): 2945-2950
  • Coronary artery bypass graft failure after on-pump and off-pump coronary artery bypass: findings from PREVENT IV ANNALS OF THORACIC SURGERY Magee, M. J., Alexander, J. H., Hafley, G., Ferguson, T. B., Gibson, C. M., Harrington, R. A., Peterson, E. D., Califf, R. M., Kouchoukos, N. T., Herbert, M. A., Mack, M. J. 2008; 85 (2): 494-500

    Abstract

    This analysis compares 1-year vein graft patency and major adverse cardiac and cerebral events (MACCE [death, myocardial infarction, or stroke]) in on-pump and off-pump patients enrolled in PREVENT IV (the PRoject of Ex-vivo Vein graft ENgineering via Transfection IV).The PREVENT IV was a multicenter (107 sites) randomized trial of edifoligide to prevent vein graft failure from neointimal hyperplasia in 3,014 patients undergoing primary, isolated coronary artery bypass grafting (CABG) with at least two vein grafts. One-year angiographic follow-up was completed on 1,920 patients (4,736 grafts) with MACCE follow-up on 99.4% of enrolled patients.In all, 2,377 procedures (78.9%) were on pump and 637 (21.1%) were off pump. On-pump patients had more chronic lung disease (17% versus 11%; p < 0.001), congestive heart failure (10% versus 7%; p = 0.03), lower mean ejection fraction (50% versus 55%; p < 0.001), and worse target artery quality (good 63.8% versus 68.1%; fair 26.4% versus 22.7%; poor 9.8% versus 9.2%; p < 0.001). Vein graft failure (more than 75% graft stenosis) in on- versus off-pump patients was 25.3% versus 25.7% (p = 0.62). After adjusting for differences in significant predictors of vein graft failure (target artery quality, surgery time, endoscopic vein harvest, more than 1 distal anastomosis/graft, and patient weight), the odds of vein graft failure was 0.82 (95% confidence interval: 0.67 to 1.00; p = 0.05) for on-pump versus off-pump patients. One-year mortality for on- versus off-pump patients was 3.3% versus 2.5% (p = 0.30); and MACCE was 15.4% versus 11.3% (p = 0.01). The adjusted hazard ratio for 1-year MACCE was 1.31 (95% confidence interval: 1.01-1.69; p = 0.01) for on pump versus off pump.Observed saphenous vein failure rate was 25% in both groups. One-year clinical outcomes (MACCE) were better with off-pump than with on-pump CABG, suggesting benefits not related to vein graft patency.

    View details for DOI 10.1016/j.athoracsur.2007.10.008

    View details for Web of Science ID 000252664900023

    View details for PubMedID 18222251

  • First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology - A phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity CIRCULATION Dyke, C. K., Steinhubl, S. R., Kleiman, N. S., Cannon, R. O., Aberle, L. G., Lin, M., Myles, S. K., Melloni, C., Harrington, R. A., Alexander, J. H., Becker, R. C., Rusconi, C. P. 2006; 114 (23): 2490-2497

    Abstract

    Selectivity, titratability, rapidity of onset, and active reversibility are desirable pharmacological properties of anticoagulant therapy administered for acute indications and collectively represent an attractive platform to maximize patient safety. A novel anticoagulation system (REG1, Regado Biosciences), developed using a protein-binding oligonucleotide to factor IXa (drug, RB006) and its complementary oligonucleotide antidote (RB007), was evaluated in healthy volunteers. The primary objective was to determine the safety profile and to characterize the pharmacodynamic responses in this first-in-human study.Regado 1a was a subject-blinded, dose-escalation, placebo-controlled study that randomized 85 healthy volunteers to receive a bolus of drug or placebo followed 3 hours later by a bolus of antidote or placebo. Pharmacodynamic samples were collected serially. Subject characteristics were the following: median age, 32 years (interquartile range, 23 to 39 years); female gender, 35%; and median weight, 79 kg (interquartile range, 70 to 87 kg). No significant differences were found in median hemoglobin, platelet, creatinine, or liver function studies. There were no significant bleeding signals associated with RB006, and overall, both drug and antidote were well tolerated. One serious adverse event, an episode of transient encephalopathy, occurred in a subject receiving the low intermediate dose of RB006. The subject's symptoms resolved rapidly, and no further sequelae occurred. A predictable dose-pharmacodynamic response, reflected in activated partial thromboplastin time measurements, was seen after administration of the bolus of drug, with a clear correlation between the peak posttreatment activated partial thromboplastin time and post hoc weight-adjusted dose of drug (correlation coefficient, 0.725; P<0.001). In subjects treated with drug, antidote administration reversed the pharmacological activity of the drug, with a rapid (mean time, 1 to 5 minutes across all dose levels) and sustained return of activated partial thromboplastin time to within the normal range. The activated clotting time followed a similar anticoagulant response and reversal pattern. As anticipated, prothrombin time remained unchanged compared with baseline.These observations represent a first-in-human experience of an RNA aptamer and its complementary oligonucleotide antidote used as an anticoagulant system. The findings contribute to an emerging platform of selective, actively reversible anticoagulant drugs for use among patients with thrombotic disorders of the venous and arterial circulations.

    View details for DOI 10.1161/CIRUCLATIONAHA.106.668434

    View details for Web of Science ID 000243477500013

    View details for PubMedID 17101847

  • Impact of internal mammary artery conduit on long-term outcomes after percutaneous intervention of saphenous vein graft CIRCULATION Mehta, R. H., Honeycutt, E., Peterson, E. D., Granger, C. B., Halabi, A. R., Shaw, L. K., Smith, P. K., Califf, R. M., Harrington, R. A., Sketch, M. H. 2006; 114: I396-I401

    Abstract

    The influence of an internal mammary artery (IMA) graft on long-term outcomes after percutaneous saphenous vein graft (SVG) intervention is currently unknown.To examine the impact of IMA on outcomes in patients undergoing SVG interventions, we analyzed 2119 patients from the Duke Cardiovascular Disease Database (1986-2003) with prior coronary artery bypass surgery undergoing cardiac catheterization who had at least 1 SVG graft. Patients were categorized into 4 groups: group I, SVG intervention and patent IMA; group II, no SVG intervention and patent IMA; group III, SVG intervention without patent IMA; and group IV, no SVG intervention without patent IMA. At a median follow-up of 4.8 years (interquartile range, 2.1 to 8.8 years), adjusted survival rates in groups I, II, III, and IV were 72.8%, 72.3%, 64.5%, and 58.9%, respectively. Multivariate Cox proportional hazards modeling showed similar survival for groups I and II (P=0.63) and for groups III and IV (P=0.33). The presence of IMA graft was related to lower long-term mortality (adjusted hazard ratio [HR], 0.69; 95% CI, 0.58 to 0.82), whereas SVG intervention was not associated with long-term mortality (adjusted HR, 0.94; 95% CI, 0.81 to 1.10). In contrast, the adjusted event-free rates for nonfatal myocardial infarction were lower in the SVG intervention groups (groups I and III) than in the non-SVG intervention groups (groups II and IV) (HR for SVG intervention versus no SVG intervention, 3.19; 95% CI, 2.18 to 4.66), with the presence of patent IMA conferring no significant benefit on this outcome (HR, 1.37; 95% CI, 0.91 to 2.08).In patients undergoing SVG interventions, survival, but not nonfatal myocardial infarction, is favorably influenced by the presence of patent IMA. In contrast, SVG intervention had no measurable survival benefit but was associated with an increased risk of nonfatal myocardial infarction.

    View details for DOI 10.1161/CIRCULATIONAHA.105.000349

    View details for Web of Science ID 000238688200064

    View details for PubMedID 16820607

  • Care of non-ST-segment elevation patients: Insights from the CRUSADE national quality improvement initiative AMERICAN HEART JOURNAL Ohman, E. M., Roe, M. T., Smith, S. C., Brindis, R. G., Christenson, R. H., Harrington, R. A., Gibler, W. B., Peterson, E. D. 2004; 148 (5): S34-S39

    Abstract

    Acute coronary syndromes (ACS), including non-ST-segment elevation (NSTE) ACS, represent a significant source of morbidity and mortality in the United States. To address this widespread, serious health problem, the American College of Cardiology and the American Heart Association (ACC/AHA) published guidelines for the treatment of NSTE ACS, which include unstable angina (UA) and NSTE myocardial infarction (NSTEMI). These ACC/AHA guidelines are intended to help physicians make appropriate decisions when diagnosing and treating patients with NSTE ACS.

    View details for DOI 10.1016/j.ahj.2004.09.013

    View details for Web of Science ID 000225160900003

    View details for PubMedID 15514632

  • Immediate coronary artery bypass surgery after platelet inhibition with eptifibatide: Results from PURSUIT ANNALS OF THORACIC SURGERY Dyke, C. M., Bhatia, D., Lorenz, T. J., Marso, S. P., Tardiff, B. E., Hogeboom, C., Harrington, R. A. 2000; 70 (3): 866-871

    Abstract

    The platelet GP IIb/IIIa inhibitor eptifibatide improves outcomes in patients with acute coronary syndromes. Patients requiring emergent coronary artery bypass grafting, however, may be at increased risk for bleeding if exposed to eptifibatide. Data from the PURSUIT trial were reviewed to assess this risk in patients undergoing coronary surgery immediately after exposure to eptifibatide.In PURSUIT, 10,948 patients who presented with non-ST segment elevation acute coronary syndromes were prospectively randomized to receive eptifibatide (180 microg/kg bolus plus 2 microg/kg/min infusion) or placebo. A total of 78 patients underwent immediate coronary artery bypass surgery within 2 hours of cessation of study drug (placebo, n = 46; eptifibatide, n = 32). Clinical outcome, bleeding, and transfusion requirements within this subset were examined.Major bleeding was not different between groups, occurring in 64% of patients receiving placebo and 63% of patients receiving eptifibatide. The incidence of blood transfusion was similar as well (57% vs 59%). Postoperative thrombocytopenia occurred less often after eptifibatide exposure. Perioperative myocardial infarction was significantly reduced in patients who received eptifibatide (46% vs 22%, p < 0.05). There was no difference in perioperative stroke (2.2% vs 6.3%) or mortality (6.3% vs 6.5%).Patients may safely undergo coronary artery bypass surgery within 2 hours of discontinuation of eptifibatide. Eptifibatide infusion in the immediate preoperative period had no adverse clinical effects, but did significantly decrease the incidence of perioperative myocardial infarction. Additionally, platelet counts after surgery were higher in the group of patients who received eptifibatide, perhaps indicative of a platelet-sparing effect during cardiopulmonary bypass.

    View details for Web of Science ID 000089447400046

    View details for PubMedID 11016325

  • Dose-finding, safety, and tolerability study of an oral platelet glycoprotein IIb/IIIa inhibitor, lotrafiban, in patients with coronary or cerebral atherosclerotic disease CIRCULATION Harrington, R. A., Armstrong, P. W., Graffagnino, C., Van de Werf, F., Kereiakes, D. J., Sigmon, K. N., Card, T., Joseph, D. M., Samuels, R., Granett, J., Chan, R., Califf, R. M., Topol, E. J. 2000; 102 (7): 728-735

    Abstract

    Antiplatelet therapy is the mainstay of the treatment and secondary prevention of cardiovascular and cerebrovascular ischemic events. We assessed the safety, tolerability, and pharmacodynamics of lotrafiban, an oral platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strategy in patients with cerebrovascular or cardiovascular disease.Overall, 451 patients with a recent cardiovascular or cerebrovascular acute ischemic event were randomized in a double-blind fashion to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregation and clinical events. The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated early because of excess major bleeding. Protocol-defined thrombocytopenia (<100 000 platelets/microL) occurred in 5 lotrafiban-treated patients (1.4%, 95% CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three lotrafiban-treated patients had a nadir platelet count <20 000/microL (0.9%, 95% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platelet aggregation; 5 mg lotrafiban did not differ significantly from placebo, whereas 100 mg inhibited aggregation by nearly 100%.-Lotrafiban provides dose-dependent platelet inhibition when administered to a range of patients with atherosclerosis. The level of platelet inhibition appears to correlate with bleeding risk and drug tolerability.

    View details for Web of Science ID 000088748100003

    View details for PubMedID 10942739

  • Glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: Pathophysiologic foundation and clinical findings AMERICAN HEART JOURNAL Kleiman, N. S., Lincoff, A. M., Ohman, E. M., Harrington, R. A. 1998; 136 (4): S32-S42

    Abstract

    The pathophysiologic basis for potent platelet inhibition in the acute coronary syndromes has been established. In the setting of PTCA for unstable angina and non-Q-wave myocardial infarction, there are clear data for a benefit of GP IIb/IIIa inhibition, whereas for primary PTCA in evolving myocardial infarction, preliminary data are very encouraging and a large-scale clinical trial is nearly completed. Glycoprotein IIb/IIIa inhibition as an adjunct to medical therapy for unstable angina is also the subject of encouraging preliminary data, and 3 large-scale clinical trials have just been completed. Preliminary data have also been accrued for GP IIb/IIIa inhibition as conjunctive therapy with thrombolytic agents, and large clinical trials are now commencing.

    View details for Web of Science ID 000076408000004

    View details for PubMedID 9778086

  • Relation between inhibition of platelet aggregation and clinical outcomes AMERICAN HEART JOURNAL Harrington, R. A., Kleiman, N. S., Granger, C. B., Ohman, E. M., Berkowitz, S. D. 1998; 136 (4): S43-S50

    Abstract

    Despite a clinical trials experience in excess of 30,000 randomized patients, there is no definitive answer or agreement as to the relation between the level of inhibition of platelet aggregation and clinical outcome. Work with abciximab in the setting of percutaneous intervention would suggest that a level of platelet inhibition in excess of 80% provides the most favorable clinical benefit. Whether this applies to the small molecule inhibitors such as eptifibatide, tirofiban, and lamifiban is unknown and will require testing of the hypothesis in large-scale clinical trials. In the acute coronary syndromes, only the peptide and nonpeptide inhibitors have been studied independent of a need for percutaneous intervention. The level of platelet inhibition required to achieve maximal clinical benefit is unknown and awaits data from the large-scale unstable angina and myocardial infarction trials. Issues of combining heparin with GP IIb/IIIa inhibition and the platelet-altering effects of thrombolysis must be considered when examining what might be the optimal level of platelet inhibition that provides maximal efficacy while maintaining safety. Long-term therapy with the oral platelet inhibitors poses a particular challenge in determining an optimal level of treatment that renders clinical effectiveness while preserving safety. Large, ongoing clinical trials with these agents should provide insight into this question. Finally, given the complexity of using such potent therapies in any individual patient, there is a need for improved monitoring of the platelet inhibitory effect. Standard platelet aggregometry has its problems and limitations, as described, and is not a test that has wide-scale applicability. Whole blood aggregometry and other methods of rapidly assessing platelet function at the point of care have promise in this arena. In a clinical trial, such technology might allow better delineation of the population's pharmacodynamic response to an agent because it could be more widely applied and therefore more patients would be studied. In clinical practice, patients could be dosed individually so that a range of platelet inhibition could be achieved that was believed to provide optimal benefit and safety.

    View details for Web of Science ID 000076408000005

    View details for PubMedID 9778087

  • Prognostic value of congestive heart failure history in patients undergoing percutaneous coronary interventions JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Anderson, R. D., Ohman, E. M., Holmes, D. R., Harrington, R. A., Barsness, G. W., Wildermann, N. M., Phillips, H. R., Topol, E. J., Califf, R. M. 1998; 32 (4): 936-941

    Abstract

    We sought to determine the prognostic significance of a history of congestive heart failure above that provided by baseline ejection fraction in patients undergoing percutaneous coronary interventions.Left ventricular function is a known predictor of survival in patients with coronary artery disease, as is a history of congestive heart failure. The contribution of heart failure history independent of left ventricular function is unknown.Data were pooled from four interventional trials and the Duke University database. The combined dataset included 5,260 patients undergoing percutaneous interventions, 334 with and 4,926 without a history of heart failure. Patients were defined by the treating physician as having a clinical history of heart failure at the time of enrollment.The 30-day and 6-month mortality were higher in patients with a clinical history of congestive heart failure than in those without such a history (2% vs. <1%, p=0.002 at 30 days, 5% vs. 1%, p=0.001 at 6 months). Heart failure history did not influence the incidence of myocardial infarction, use of angioplasty or the use of bypass surgery during follow-up. Multivariable analysis revealed that heart failure history added significantly to ejection fraction in predicting intermediate-term (6-month) mortality (p=0.01). Stepwise logistic regression also revealed heart failure history to be an independent predictor of 6-month mortality (odds risk 1.9, 95% confidence interval 1.1 to 3.5).A clinical history of congestive heart failure is associated with increased early and intermediate-term mortality in patients undergoing percutaneous revascularization. Congestive heart failure history appears to provide prognostic information independent of that available from a patient's left ventricular function. These findings suggest that patients with a clinical history of congestive heart failure who undergo a percutaneous intervention should be closely monitored, especially those with the lowest ejection fractions.

    View details for Web of Science ID 000076214000011

    View details for PubMedID 9768714

  • Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Berkowitz, S. D., Sane, D. C., Sigmon, K. N., Shavender, J. H., Harrington, R. A., Tcheng, J. E., Topol, E. J., Califf, R. M. 1998; 32 (2): 311-319

    Abstract

    This study sought to determine the frequency of thrombocytopenia and its relation with clinical outcomes in high risk patients undergoing percutaneous coronary revascularization who received either the platelet glycoprotein (GP) IIb/IIIa receptor antagonist abciximab (ReoPro, c7E3 Fab) or conventional therapy.The development of thrombocytopenia on exposure to GPIIb/IIIa antagonists threatens the utility and economic viability of this drug class for patients with vascular disease.We analyzed data from the Evaluation of c7E3 for the Prevention of Ischemic Complications trial (EPIC), a 2,099-patient, randomized trial of placebo, abciximab bolus or abciximab bolus plus a 12-h infusion during high-risk coronary revascularization.Thrombocytopenia (nadir platelet count <100 x 10(9)/ liter) developed in 81 patients (3.9%) during their hospital stay, with 19 (0.9%) developing severe (<50 x 10(9)/liter) thrombocytopenia. Both thrombocytopenia and severe thrombocytopenia were more frequent in the bolus-plus-infusion arm (5.2% and 1.6%, respectively) than in the bolus-only and placebo arms combined (p = 0.020 and p = 0.025, respectively). Acute profound thrombocytopenia developed in two patients in the bolus-plus-infusion arm. Patients with thrombocytopenia experienced more unfavorable clinical outcomes than those who did not develop thrombocytopenia, regardless of treatment assignment, but those with thrombocytopenia who received abciximab had fewer worse outcomes at 30 days. Multivariable logistic modeling revealed a lower baseline platelet count, older age and lighter weight to be important predictors of thrombocytopenia. In a logistic regression model, bolus-plus-infusion treatment was a significant predictor of thrombocytopenia (p = 0.016) and remained so after adjustment for procedures and baseline risk factors (p = 0.0077).Thrombocytopenia was associated with adverse clinical outcomes and excessive bleeding, but patients receiving abciximab fared better than those receiving placebo.

    View details for Web of Science ID 000075273200003

    View details for PubMedID 9708455

Conference Proceedings


  • Randomized, Double-Blind, Placebo-Controlled Trial of Autologous CD34+Cell Therapy for Refractory Angina: 2-Year Safety Analysis Losordo, D. W., Henry, T. D., Schatz, R. A., Lee, J. S., Costa, M., Bass, T., Schaer, G. L., Mendelsohn, F., Davidson, C., Waksman, R., Soukas, P. A., Simon, D., Chronos, N., Fortuin, F. D., Huang, P. P., Weintraub, N., Yeung, A., Rosenfield, K., Wong, S. C., Taussig, A., Raval, A. N., Sherman, W., Kereiakes, D., Strumpf, R. K., Port, S., Pieper, K., Ewenstein, B., Story, K. O., Barker, K. B., Harrington, R. A. LIPPINCOTT WILLIAMS & WILKINS. 2010
  • Autologous CD34+Cell Therapy for Refractory Angina: 12 Month Results of the Phase II ACT34-CMI Study Losordo, D. W., Henry, T., Schatz, R. A., Lee, J. S., Costa, M., Bass, T., Schaer, G., Niederman, A., Mendelsohn, F., Davidson, C., Waksman, R., Soukas, P. A., Simon, D., Chronos, N., Fortuin, F. D., Huang, P. P., Weintraub, N., Yeung, A., Rosenfield, K., Wong, S. C., Taussig, A., Rava, A. N., Sherman, W., Kereiakes, D., Strumpf, R. K., Port, S., Pieper, K., Adams, P. X., Harrington, R. LIPPINCOTT WILLIAMS & WILKINS. 2009: S1132-S1132

Stanford Medicine Resources: