Tara I. Chang, MD, MS, FASN

All Publications

• Intensive Blood Pressure Targets and Kidney Disease. Clinical journal of the American Society of Nephrology : CJASN Chang, T. I., Sarnak, M. J. 2018

  View details for DOI 10.2215/CJN.02010218

  View details for PubMedID 29798887

• The Relationship between Intradialytic Hypotension and Hospitalized Mesenteric Ischemia: A Case-Control Study. Clinical journal of the American Society of Nephrology : CJASN Seong, E. Y., Zheng, Y., Winkelmayer, W. C., Montez-Rath, M. E., Chang, T. I. 2018

  Abstract

  BACKGROUND AND OBJECTIVES: Mesenteric ischemia is a rare but devastating condition caused by insufficient blood supply to meet the demands of intestinal metabolism. In patients with ESKD, it can be difficult to diagnose and has a >70% mortality rate. Patients on hemodialysis have a high prevalence of predisposing conditions for mesenteric ischemia, but the contribution of intradialytic hypotension, a potential modifiable risk factor, has not been well described.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used data from the US Renal Data System to identify 626 patients on hemodialysis with a hospitalized mesenteric ischemia event (cases). We selected 2428 controls in up to a 1:4 ratio matched by age, sex, black race, incident dialysis year, diabetes mellitus, coronary artery disease, and peripheral artery disease. We used six different definitions of intradialytic hypotension on the basis of prior studies, and categorized patients as having had intradialytic hypotension if ≥30% of hemodialysis sessions in the 30 days before the event met the specified definition.RESULTS: The proportion of patients with intradialytic hypotension varied depending on its definition: from 19% to 92% of cases and 11% to 94% of controls. Cases had a higher adjusted odds (1.82; 95% confidence interval, 1.47 to 2.26) of having had intradialytic hypotension in the preceding 30 days than controls when using nadir-based intradialytic hypotension definitions such as nadir systolic BP <90 mm Hg. To examine a potential dose-response association of intradialytic hypotension with hospitalized mesenteric ischemia, we categorized patients by the proportion of hemodialysis sessions having intradialytic hypotension, defined using the Nadir90 definition (0%, 1%-9%, 10%-29%, 30%-49%, and ≥50%), and found a direct association of proportion of intradialytic hypotension with hospitalized mesenteric ischemia (P-trend<0.001).CONCLUSIONS: Patients with hospitalized mesenteric ischemia had significantly higher odds of having had intradialytic hypotension in the preceding 30 days than controls, as defined by nadir-based definitions.

  View details for DOI 10.2215/CJN.13891217

  View details for PubMedID 30237215

• Association of Blood Pressure Measurements with Peripheral Arterial Disease Events: A Reanalysis of the ALLHAT Data. Circulation Itoga, N. K., Tawfik, D. S., Lee, C. K., Maruyama, S., Leeper, N. J., Chang, T. I. 2018

  Abstract

  Background -Current guidelines recommend treating hypertension in patients with peripheral arterial disease (PAD) to reduce the risk of cardiac events and stroke, but the effect of reducing blood pressure on lower extremity PAD events is largely unknown. We investigated the association of blood pressure with lower extremity PAD events using data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Methods -ALLHAT investigated the effect of different antihypertensive medication classes (chlorthalidone, amlodipine, lisinopril, or doxazosin) on cardiovascular events. Using these data, the primary outcome in our analysis was time to first lower extremity PAD event, defined as PAD-related hospitalization, procedures, medical treatment, or PAD-related death. Given the availability of longitudinal standardized blood pressure measurements, we analyzed systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) as time-varying categorical variables (reference categories 120-129 mm Hg for SBP, 70-79 mm Hg for DBP, and 45-54 mm Hg for PP) in separate models. We used extended Cox regression with death as a competing risk to calculate the association of each BP component with PAD events, and report the results as sub-distribution hazard ratios (HR) and 95% confidence intervals (CI). Results -The present analysis included 33,357 patients with an average age of 67.4 years, 53.1% men, 59.7% white race, and 36.2% with diabetes mellitus. The median baseline blood pressure was 146/84 mm Hg. Participants were followed for a median of 4.3 (IQR 3.6-5.3) years, during which time 1,489 (4.5%) had a lower extremity PAD event, and 4,148 (12.4%) died. In models adjusted for demographic and clinical characteristics, SBP <120 mm Hg was associated with a 26% (CI 5-52%, P=0.015) higher hazard and SBP≥160 mm Hg was associated with a 21% (CI 0-48%, P=0.050) higher hazard for a PAD event, compared with SBP 120-129 mm Hg. In contrast, lower, but not higher, DBP was associated with higher hazard of PAD events: for DBP <60 mm Hg HR = 1.72 (CI 1.38 - 2.16). PP had a U-shaped association with PAD events. Conclusions -In this re-analysis of data from ALLHAT, we found a higher rate of lower extremity PAD events with higher and lower SBP and PP, and with lower DBP. Given the recent revised blood pressure guidelines advocating lower SBP targets for overall cardiovascular risk reduction, further refinement of optimal blood pressure targets specific to PAD is needed. Clinical Trial Registration -URL: www.clinicaltrials.gov Unique identifier: NCT00000542.

  View details for DOI 10.1161/CIRCULATIONAHA.118.033348

  View details for PubMedID 29930023

• Antihypertensive medication withholding practices in hemodialysis: A survey study of patients and providers. Hemodialysis international. International Symposium on Home Hemodialysis Haase, S. B., Chang, S., Schiller, B., Chertow, G. M., Chang, T. I. 2018

  View details for DOI 10.1111/hdi.12640

  View details for PubMedID 29436151

• Trends in Rates of Lower Extremity Amputation Among Patients With End-Stage Renal Disease Who Receive Dialysis JAMA Internal Medicine Franz, D., Zheng, Y., Leeper, N. J., Chandra, V., Montez-Rath, M., Chang, T. I. 2018

  View details for DOI 10.1001/jamainternmed.2018.2436

• Associations of Glycemic Control With Cardiovascular Outcomes Among US Hemodialysis Patients With Diabetes Mellitus. Journal of the American Heart Association Rhee, J. J., Zheng, Y., Montez-Rath, M. E., Chang, T. I., Winkelmayer, W. C. 2017; 6 (6)

  Abstract

  There is a lack of data on the relationship between glycemic control and cardiovascular end points in hemodialysis patients with diabetes mellitus.We included adult Medicare-insured patients with diabetes mellitus who initiated in-center hemodialysis treatment from 2006 to 2008 and survived for >90 days. Quarterly mean time-averaged glycated hemoglobin (HbA1c) values were categorized into <48 mmol/mol (<6.5%) (reference), 48 to <58 mmol/mol (6.5% to <7.5%), 58 to <69 mmol/mol (7.5% to <8.5%), and ≥69 mmol/mol (≥8.5%). Medicare claims were used to identify outcomes of cardiovascular mortality, nonfatal myocardial infarction (MI), fatal or nonfatal MI, stroke, and peripheral arterial disease. We used Cox models as a function of time-varying exposure to estimate multivariable adjusted hazard ratios and 95%CI for the associations between HbA1c and time to study outcomes in a cohort of 16 387 eligible patients. Patients with HbA1c 58 to <69 mmol/mol (7.5% to <8.5%) and ≥69 mmol/mol (≥8.5%) had 16% (CI, 2%, 32%) and 18% (CI, 1%, 37%) higher rates of cardiovascular mortality (P-trend=0.01) and 16% (CI, 1%, 33%) and 15% (CI, 1%, 32%) higher rates of nonfatal MI (P-trend=0.05), respectively, compared with those in the reference group. Patients with HbA1c ≥69 mmol/mol (≥8.5%) had a 20% (CI, 2%, 41%) higher rate of fatal or nonfatal MI (P-trend=0.02), compared with those in the reference group. HbA1c was not associated with stroke, peripheral arterial disease, or all-cause mortality.Higher HbA1c levels were significantly associated with higher rates of cardiovascular mortality and MI but not with stroke, peripheral arterial disease, or all-cause mortality in this large cohort of hemodialysis patients with diabetes mellitus.

  View details for DOI 10.1161/JAHA.117.005581

  View details for PubMedID 28592463

• Comparative effectiveness of angiotensin receptor blockers vs. angiotensin-converting enzyme inhibitors on cardiovascular outcomes in patients initiating peritoneal dialysis JOURNAL OF NEPHROLOGY Shen, J. I., Saxena, A. B., Montez-Rath, M. E., Leng, L., Chang, T. I., Winkelmayer, W. C. 2017; 30 (2): 281-288

  View details for DOI 10.1007/s40620-016-0340-3

  View details for Web of Science ID 000398460700015

• Drug-Eluting Stents Versus Bare Metal Stents for Percutaneous Coronary Intervention in Kidney Transplant Recipients TRANSPLANTATION Lenihan, C. R., Montez-Rath, M. E., Winkelmayer, W. C., Chang, T. I. 2017; 101 (4): 851-857

  View details for DOI 10.1097/TP.0000000000001446

  View details for Web of Science ID 000398157200042

• Risk profiles for acute health events after incident atrial fibrillation in patients with end-stage renal disease on hemodialysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Airy, M., Chang, T. I., Ding, V. Y., Goldstein, B. A., Bansal, N., Niu, J., Navaneethan, S. D., Turakhia, M. P., Winkelmayer, W. C. 2017

  Abstract

  Little is known about the cardiovascular risks of incident atrial fibrillation/flutter (AF) in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD).We studied older US patients who newly initiated HD for ESRD (2006-11) and who had not previously been diagnosed with AF, stroke, myocardial infarction (MI) or hip fracture. We used Cox regression with AF as a time-varying covariate, adjusted for socio-demographic characteristics and comorbidities to estimate hazard ratios [HRs (95% confidence intervals)] for the events of ischemic stroke, MI and death. Hip fracture served as a negative control outcome.We identified 85 377 older patients (mean age: 76.5 years) who initiated HD; of these, 14.3% were subsequently diagnosed with AF (14.9% thereof as primary diagnosis) and 49.8% died during follow-up. Incident AF was associated with nine times higher adjusted mortality during the first 30 days [9.2 (8.8-9.6)], 5-fold higher mortality between 31 and 90 days [4.6 (4.3-4.8)] and double the mortality beyond 90 days from first AF diagnosis [2.2 (2.1-2.3)]. Incident AF was similarly associated with higher adjusted risk of ischemic stroke: 2.1 (1.6-2.7) during the first 30 days, 2.5 (2.0-3.0) between 31 and 90 days and 1.5 (1.3-1.7) beyond 90 days. Similar findings were obtained for MI. However, the risk of hip fracture was only marginally increased following AF diagnosis [≤30 days: 1.1 (0.7-1.6); 31-90 days: 1.4 (1.0-1.8); >90 days: 1.2 (1.1-1.4)]. All associations were attenuated and the association with hip fracture was null when incident AF was defined by a primary diagnosis code.AF was strongly associated with increased risks of ischemic stroke, MI and death, with risks highest soon after AF diagnosis but extending beyond 90 days.

  View details for DOI 10.1093/ndt/gfx301

  View details for PubMedID 29145634

• Balancing the Evidence: How to Reconcile the Results of Observational Studies vs. Randomized Clinical Trials in Dialysis SEMINARS IN DIALYSIS Shen, J. I., Lum, E. L., Chang, T. I. 2016; 29 (5): 342-346

  Abstract

  Because large randomized clinical trials (RCTs) in dialysis have been relatively scarce, evidence-based dialysis care has depended heavily on the results of observational studies. However, when results from RCTs appear to contradict the findings of observational studies, nephrologists are left to wonder which type of study they should believe. In this editorial, we explore the key differences between observational studies and RCTs in the context of such seemingly conflicting studies in dialysis. Confounding is the major limitation of observational studies, whereas low statistical power and problems with external validity are more likely to limit the findings of RCTs. Differences in the specification of the population, exposure, and outcomes can also contribute to different results among RCTs and observational studies. Rigorous methods are required regardless of what type of study is conducted, and readers should not automatically assume that one type of study design is superior to the other. Ultimately, dialysis care requires both well-designed, well-conducted observational studies and RCTs to move the field forward.

  View details for DOI 10.1111/sdi.12518

  View details for Web of Science ID 000388438700003

  View details for PubMedID 27207819

• Antihypertensive Medication Use in Older Patients Transitioning from Chronic Kidney Disease to End-Stage Renal Disease on Dialysis. Clinical journal of the American Society of Nephrology Chang, T. I., Zheng, Y., Montez-Rath, M. E., Winkelmayer, W. C. 2016; 11 (8): 1401-1412

  Abstract

  The transition from CKD to ESRD can be particularly unstable, with high rates of death and hospitalizations. Few studies have examined medication use during this critical period. We examined patterns of antihypertensive medication use from the four quarters before and eight quarters after incident ESRD treated with maintenance dialysis.We used the US Renal Data System to identify patients aged ≥67 years initiating dialysis for ESRD between January 2008 and December 2010 with Medicare Part D and a low-income subsidy. We ascertained the incidence of AKI and hyperkalemia during each quarter on the basis of having at least 1 payment claim for the condition. We used Poisson regression with robust SEMs to formally test for changes in the trend and level of antihypertensive medication use in a series of intervention analyses.The number of antihypertensive drugs used increased as patients neared ESRD, peaking at an average of 3.4 in the quarter immediately preceding dialysis initiation, then declining to 2.2 medications by 2 years later. Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use was stable at approximately 40%, even among patients with coronary disease and systolic heart failure, and did not correlate with AKI or hyperkalemia. Dialysis initiation was associated with a 40% (95% confidence interval, 38% to 43%) lower adjusted level of diuretic use, which continued to decline after ESRD. Three- and four-drug combinations that included a diuretic were most common before ESRD, whereas after ESRD, one- and two-drug β-blocker or calcium-channel blocker-based combinations were most common.The use of antihypertensive medications, particularly angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers and diuretics, may be suboptimal during the transition from CKD to ESRD, especially in patients with coronary disease or systolic heart failure. Future studies are needed to identify strategies to increase the appropriate use of antihypertensive medications during this critical transition period.

  View details for DOI 10.2215/CJN.10611015

  View details for PubMedID 27354656

• Comparative effectiveness of angiotensin receptor blockers vs. angiotensin-converting enzyme inhibitors on cardiovascular outcomes in patients initiating peritoneal dialysis. Journal of nephrology Shen, J. I., Saxena, A. B., Montez-Rath, M. E., Leng, L., Chang, T. I., Winkelmayer, W. C. 2016: -?

  Abstract

  There is evidence that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-II receptor blockers (ARB) may reduce cardiovascular (CV) risk in patients undergoing peritoneal dialysis (PD), but no studies have compared the effectiveness between these drug classes. In this observational cohort study, we compared the association of ARB vs. ACEI use on CV outcomes in patients initiating PD.We identified from the US Renal Data System all adult patients who initiated PD from 2007 to 2011 and participated in Medicare Part D, a federal prescription drug benefits program, for the first 90 days of dialysis. Patients who filled a prescription for an ACEI or ARB in those 90 days were considered users. We excluded patients who used both ACEI and ARB. We applied Cox proportional hazards regression to an inverse probability of treatment-weighted cohort to estimate the hazard ratios (HR) for the combined outcome of all-cause death, ischemic stroke, or myocardial infarction; all-cause mortality; and CV death.Among 1892 patients using either drug class, 39 % were ARB users. We observed 624 events over 2,898 person-years of follow-up, for a composite event rate of 22 events per 100 person-years. We observed no differences between ARB vs. ACEI users: composite outcome HR 0.94, 95 % confidence interval (CI) 0.79-1.11; all-cause mortality HR 0.92, 95 % CI 0.76-1.10; CV death HR: 1.06, 95 % CI 0.80-1.41.We identified no significant difference in the risks of CV events or death between users of ARBs vs. ACEIs in patients initiating PD, thus supporting their mostly interchangeable use in this population.

  View details for PubMedID 27485007

• The Association Between Antihypertensive Medication Nonadherence and Visit-to-Visit Variability of Blood Pressure HYPERTENSION Kronish, I. M., Lynch, A. I., Oparil, S., Whittle, J., Davis, B. R., Simpson, L. M., Krousel-Wood, M., Cushman, W. C., Chang, T. I., Muntner, P. 2016; 68 (1): 39-?

  View details for DOI 10.1161/HYPERTENSIONAHA.115.06960

  View details for Web of Science ID 000377466200014

• Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and cardiovascular outcomes in patients initiating peritoneal dialysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Shen, J. I., Saxena, A. B., Montez-Rath, M. E., Chang, T. I., Winkelmayer, W. C. 2016

  Abstract

  Data on the effectiveness of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in reducing cardiovascular (CV) risk in patients undergoing peritoneal dialysis (PD) are limited. We investigated the association between ACEI/ARB use and CV outcomes in patients initiating PD.In this observational cohort study, we identified from the United States Renal Data System all adult patients who initiated PD from 2007 to 2011 and participated in Medicare Part D, a federal prescription drug benefits program, for the first 90 days of dialysis. Patients who filled a prescription for an ACEI or ARB in those 90 days were considered users. We applied Cox regression to an inverse probability of treatment weighted cohort to estimate the hazard ratios (HRs) for the combined outcome of death, ischemic stroke or myocardial infarction (MI) and each outcome individually.Among 4879 patients, 2063 (42%) used an ACEI/ARB. Patients were followed up for a median of 1.2 years. We recorded 1771 events, for a composite rate of 25 events per 100 person-years. ACEI/ARB use (versus nonuse) was associated with a reduced risk of the composite outcome {HR 0.84 [95% confidence interval (CI) 0.76-0.93]}, all-cause mortality [HR 0.83 (95% CI 0.75-0.92)] and CV death [HR 0.74 (95% CI 0.63-0.87)], but not MI [HR 0.88 (95% CI 0.69-1.12)] or ischemic stroke [HR 1.06 (95% CI 0.79-1.43)]. Results were similar in as-treated analyses. In a subgroup analysis, we did not find any effect modification by residual renal function.ACEI/ARB use is common in patients initiating PD and is associated with a lower risk of fatal CV outcomes.

  View details for PubMedID 27190342

• Drug-Eluting Versus Bare-Metal Stents During PCI in Patients With End-Stage Renal Disease on Dialysis JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Chang, T. I., Montez-Rath, M. E., Tsai, T. T., Hlatky, M. A., Winkelmayer, W. C. 2016; 67 (12): 1459-1469

  View details for DOI 10.1016/j.jacc.2015.10.104

  View details for Web of Science ID 000372408500011

• Drug-Eluting Versus Bare-Metal Stents During PCI in Patients With End-Stage Renal Disease on Dialysis. Journal of the American College of Cardiology Chang, T. I., Montez-Rath, M. E., Tsai, T. T., Hlatky, M. A., Winkelmayer, W. C. 2016; 67 (12): 1459-1469

  Abstract

  In patients undergoing percutaneous coronary intervention (PCI), drug-eluting stents (DES) reduce repeat revascularizations compared with bare-metal stents (BMS), but their effects on death and myocardial infarction (MI) are mixed. Few studies have focused on patients with end-stage renal disease.This study compared mortality and cardiovascular morbidity during percutaneous coronary intervention with DES and with BMS in dialysis patients.We identified 36,117 dialysis patients from the USRDS (United States Renal Data System) who had coronary stenting in the United States between April 23, 2003, and December 31, 2010, and examined the association of DES versus BMS with 1-year outcomes: death; death or MI; and death, MI, or repeat revascularization. We also conducted a temporal analysis by dividing the study period into 3 DES eras: Transitional (April 23, 2003, to June 30, 2004); Liberal (July 1, 2004, to December 31, 2006); and Selective (January 1, 2007, to December 31, 2010).One-year event rates were high, with 38 deaths; 55 death or MI events; and 71 death, MI, or repeat revascularization events per 100 person-years. DES, compared with BMS, were associated with a significant 18% lower risk of death; 16% lower risk of death or MI; and 13% lower risk of death, MI, or repeat revascularization. DES use varied, from 56% in the Transitional era to 85% in the Liberal era and 62% in the Selective era. DES outcomes in the Liberal era were significantly better than in the Transitional Era, but not significantly better than in the Selective Era.DES for percutaneous coronary intervention appears to be safe for use in U.S. dialysis patients and is associated with lower rates of death, MI, and repeat revascularization.

  View details for DOI 10.1016/j.jacc.2015.10.104

  View details for PubMedID 27012407

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

  Abstract

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

  View details for DOI 10.1038/jhh.2015.56

  View details for Web of Science ID 000370449000010

  View details for PubMedID 26040438

• Patterns and Correlates of Baseline Thiazide-Type Diuretic Prescription in the Systolic Blood Pressure Intervention Trial HYPERTENSION Chang, T. I., Evans, G., Cheung, A. K., Cushman, W. C., Diamond, M. J., Dwyer, J. P., Huan, Y., Kitzman, D., Kostis, J. B., Oparil, S., Rastogi, A., Roumie, C. L., Sahay, R., Stafford, R. S., Taylor, A. A., Wright, J. T., Chertow, G. M. 2016; 67 (3): 550-555

  Abstract

  Thiazides and thiazide-type diuretics are recommended as first-line agents for the treatment of hypertension, but contemporary information on their use in clinical practice is lacking. We examined patterns and correlates of thiazide prescription in a cross-sectional analysis of baseline data from participants enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT). We examined baseline prescription of thiazides in 7582 participants receiving at least 1 antihypertensive medication by subgroup, and used log-binomial regression to calculate adjusted prevalence ratios for thiazide prescription (versus no thiazide). Forty-three percent of all participants were prescribed a thiazide at baseline, but among participants prescribed a single agent, the proportion was only 16%. The prevalence of thiazide prescription differed significantly by demographic factors, with younger participants, women, and blacks all having higher adjusted prevalence of thiazide prescription than other corresponding subgroups. Participants in the lowest category of kidney function (estimated glomerular filtration rate <30 mL/min per 1.73 m2) were half as likely to be prescribed a thiazide as participants with preserved kidney function. In conclusion, among persons with hypertension and heightened cardiovascular risk, we found that thiazide prescription varied significantly by demographics and kidney disease status, despite limited evidence about relative differences in effectiveness.

  View details for DOI 10.1161/HYPERTENSIONAHA.115.06851

  View details for Web of Science ID 000369755200017

  View details for PubMedID 26865200

  View details for PubMedCentralID PMC4755350

• Sleep disordered breathing and cardiovascular risk in older patients initiating dialysis in the United States: a retrospective observational study using medicare data BMC NEPHROLOGY Tuohy, C. V., Montez-Rath, M. E., Turakhia, M., Chang, T. I., Winkelman, J. W., Winkelmayer, W. C. 2016; 17

  View details for DOI 10.1186/s12882-016-0229-3

  View details for Web of Science ID 000369620700001

• Visit-to-visit variability of blood pressure and death, end-stage renal disease, and cardiovascular events in patients with chronic kidney disease JOURNAL OF HYPERTENSION Chang, T. I., Tabada, G. H., Yang, J., Tan, T. C., Go, A. S. 2016; 34 (2): 244-252

  View details for DOI 10.1097/HJH.0000000000000779

  View details for Web of Science ID 000369671400014

• Coffee and caffeine consumption and the risk of hypertension in postmenopausal women AMERICAN JOURNAL OF CLINICAL NUTRITION Rhee, J. J., Qin, F., Hedlin, H. K., Chang, T. I., Bird, C. E., Zaslavsky, O., Manson, J. E., Stefanick, M. L., Winkelmayer, W. C. 2016; 103 (1): 210-217

  Abstract

  The associations of coffee and caffeine intakes with the risk of incident hypertension remain controversial.We sought to assess longitudinal relations of caffeinated coffee, decaffeinated coffee, and total caffeine intakes with mean blood pressure and incident hypertension in postmenopausal women in the Women's Health Initiative Observational Study.In a large prospective study, type and amount of coffee and total caffeine intakes were assessed by using self-reported questionnaires. Hypertension status was ascertained by using measured blood pressure and self-reported drug-treated hypertension. The mean intakes of caffeinated coffee, decaffeinated coffee, and caffeine were 2-3 cups/d, 1 cup/d, and 196 mg/d, respectively. Using multivariable linear regression, we examined the associations of baseline intakes of caffeinated coffee, decaffeinated coffee, and caffeine with measured systolic and diastolic blood pressures at annual visit 3 in 29,985 postmenopausal women who were not hypertensive at baseline. We used Cox proportional hazards models to estimate HRs and their 95% CIs for time to incident hypertension.During 112,935 person-years of follow-up, 5566 cases of incident hypertension were reported. Neither caffeinated coffee nor caffeine intake was associated with mean systolic or diastolic blood pressure, but decaffeinated coffee intake was associated with a small but clinically irrelevant decrease in mean diastolic blood pressure. Decaffeinated coffee intake was not associated with mean systolic blood pressure. Intakes of caffeinated coffee, decaffeinated coffee, and caffeine were not associated with the risk of incident hypertension (P-trend > 0.05 for all).In summary, these findings suggest that caffeinated coffee, decaffeinated coffee, and caffeine are not risk factors for hypertension in postmenopausal women.

  View details for DOI 10.3945/ajcn.115.120147

  View details for Web of Science ID 000367869500025

  View details for PubMedCentralID PMC4691674

• Medication adherence and visit-to-visit variability of systolic blood pressure in African Americans with chronic kidney disease in the AASK trial JOURNAL OF HUMAN HYPERTENSION Hong, K., Muntner, P., Kronish, I., Shilane, D., Chang, T. I. 2016; 30 (1): 73-78

  Abstract

  Lower adherence to antihypertensive medications may increase visit-to-visit variability of blood pressure (VVV of BP), a risk factor for cardiovascular events and death. We used data from the African American Study of Kidney Disease and Hypertension (AASK) trial to examine whether lower medication adherence is associated with higher systolic VVV of BP in African Americans with hypertensive chronic kidney disease (CKD). Determinants of VVV of BP were also explored. AASK participants (n=988) were categorized by self-report or pill count as having perfect (100%), moderately high (75-99%), moderately low (50-74%) or low (<50%) proportion of study visits with high medication adherence over a 1-year follow-up period. We used multinomial logistic regression to examine determinants of medication adherence, and multivariable-adjusted linear regression to examine the association between medication adherence and systolic VVV of BP, defined as the coefficient of variation or the average real variability (ARV). Participants with lower self-reported adherence were generally younger and had a higher prevalence of comorbid conditions. Compared with perfect adherence, moderately high, moderately low and low adherence was associated with 0.65% (±0.31%), 0.99% (±0.31%) and 1.29% (±0.32%) higher systolic VVV of BP (defined as the coefficient of variation) in fully adjusted models. Results were qualitatively similar when using ARV or when using pill counts as the measure of adherence. Lower medication adherence is associated with higher systolic VVV of BP in African Americans with hypertensive CKD; efforts to improve medication adherence in this population may reduce systolic VVV of BP.

  View details for DOI 10.1038/jhh.2015.26

  View details for Web of Science ID 000367734100013

  View details for PubMedID 25833706

• Comparative outcomes of predominant facility-level use of ferumoxytol versus other intravenous iron formulations in incident hemodialysis patients NEPHROLOGY DIALYSIS TRANSPLANTATION Airy, M., Mandayam, S., Mitani, A. A., Chang, T. I., Ding, V. Y., Brookhart, M. A., Goldstein, B. A., Winkelmayer, W. C. 2015; 30 (12): 2068-2075

  Abstract

  Ferumoxytol was first approved for clinical use in 2009 solely based on data from trial comparisons with oral iron on biochemical anemia efficacy end points. To compare the rates of important patient outcomes (infection, cardiovascular events and death) between facilities predominantly using ferumoxytol versus iron sucrose (IS) or ferric gluconate (FG) in patients with end-stage renal disease (ESRD)-initiating hemodialysis (HD).Using the United States Renal Data System, we identified all HD facilities that switched (almost) all patients from IS/FG to ferumoxytol (July 2009-December 2011). Each switching facility was matched with three facilities that continued IS/FG use. All incident ESRD patients subsequently initiating HD in these centers were studied and assigned their facility exposure. They were followed for all-cause mortality, cardiovascular hospitalization/death or infectious hospitalization/death. Follow-up ended at kidney transplantation, switch to peritoneal dialysis, transfer to another facility, facility switch to another iron formulation and end of database (31 December 2011). Cox proportional hazards regression was then used to estimate adjusted hazard ratios [HR (95% confidence intervals)].In July 2009-December 2011, 278 HD centers switched to ferumoxytol; 265 units (95.3%) were matched with 3 units each that continued to use IS/FG. Subsequently, 14 206 patients initiated HD, 3752 (26.4%) in ferumoxytol and 10 454 (73.6%) in IS/FG centers; their characteristics were very similar. During 6433 person-years, 1929 all-cause, 726 cardiovascular and 191 infectious deaths occurred. Patients in ferumoxytol (versus IS/FG) facilities experienced similar all-cause [0.95 (0.85-1.07)], cardiovascular [0.99 (0.83-1.19)] and infectious mortality [0.88 (0.61-1.25)]. Among 5513 Medicare (Parts A + B) beneficiaries, cardiovascular events [myocardial infarction, stroke and cardiovascular death; 1.05 (0.79-1.39)] and infectious events [hospitalization/death; 0.96 (0.85-1.08)] did not differ between the iron exposure groups.In incident HD patients, ferumoxytol showed similar short- to mid-term safety profiles with regard to cardiovascular, infectious and mortality outcomes compared with the more commonly used intravenous iron formulations IS and FG.

  View details for DOI 10.1093/ndt/gfv305

  View details for Web of Science ID 000368453700020

  View details for PubMedID 26311216

• Outcomes After Warfarin Initiation in a Cohort of Hemodialysis Patients With Newly Diagnosed Atrial Fibrillation. American journal of kidney diseases Shen, J. I., Montez-Rath, M. E., Lenihan, C. R., Turakhia, M. P., Chang, T. I., Winkelmayer, W. C. 2015; 66 (4): 677-688

  Abstract

  Although warfarin is indicated to prevent ischemic strokes in most patients with atrial fibrillation (AF), evidence supporting its use in hemodialysis patients is limited. Our aim was to examine outcomes after warfarin therapy initiation, relative to no warfarin use, following incident AF in a large cohort of hemodialysis patients who had comprehensive prescription drug coverage through Medicare Part D.Retrospective observational cohort study.Patients in the US Renal Data System undergoing maintenance hemodialysis who had AF newly diagnosed in 2007 to 2011, with Medicare Part D coverage, who had no recorded history of warfarin use.Warfarin therapy initiation, identified by a filled prescription within 30 days of the AF event.Death, ischemic stroke, hemorrhagic stroke, severe gastrointestinal bleeding, and composite outcomes.HRs estimated by applying Cox regression to an inverse probability of treatment and censoring-weighted cohort.Of 12,284 patients with newly diagnosed AF, 1,838 (15%) initiated warfarin therapy within 30 days; however, ∼70% discontinued its use within 1 year. In intention-to-treat analyses, warfarin use was marginally associated with a reduced risk of ischemic stroke (HR, 0.68; 95% CI, 0.47-0.99), but not with the other outcomes. In as-treated analyses, warfarin use was associated with reduced mortality (HR, 0.84; 95% CI, 0.73-0.97).Short observation period, limited number of nonfatal events, limited generalizability of results to more affluent patients.In hemodialysis patients with incident AF, warfarin use was marginally associated with reduced risk of ischemic stroke, and there was a signal toward reduced mortality in as-treated analyses. These results support clinical equipoise regarding the use of warfarin in hemodialysis patients and underscore the need for randomized trials to fill this evidence gap.

  View details for DOI 10.1053/j.ajkd.2015.05.019

  View details for PubMedID 26162653

• Classifying individuals based on a densely captured sequence of vital signs: An example using repeated blood pressure measurements during hemodialysis treatment JOURNAL OF BIOMEDICAL INFORMATICS Goldstein, B. A., Chang, T. I., Winkelmayer, W. C. 2015; 57: 219-224

  Abstract

  Electronic Health Records (EHRs) present the opportunity to observe serial measurements on patients. While potentially informative, analyzing these data can be challenging. In this work we present a means to classify individuals based on a series of measurements collected by an EHR. Using patients undergoing hemodialysis, we categorized people based on their intradialytic blood pressure. Our primary criteria were that the classifications were time dependent and independent of other subjects. We fit a curve of intradialytic blood pressure using regression splines and then calculated first and second derivatives to come up with four mutually exclusive classifications at different time points. We show that these classifications relate to near term risk of cardiac events and are moderately stable over a succeeding two-week period. This work has general application for analyzing dense EHR data.

  View details for DOI 10.1016/j.jbi.2015.08.010

  View details for Web of Science ID 000363437500020

  View details for PubMedID 26277118

• Longer-term Outcomes of Darbepoetin Alfa Versus Epoetin Alfa in Patients With ESRD Initiating Hemodialysis: A Quasi-experimental Cohort Study AMERICAN JOURNAL OF KIDNEY DISEASES Winkelmayer, W. C., Chang, T. I., Mitani, A. A., Wilhelm-Leen, E. R., Ding, V., Chertow, G. M., Brookhart, M. A., Goldstein, B. A. 2015; 66 (1): 106-113

  Abstract

  Adequately powered studies directly comparing hard clinical outcomes of darbepoetin alfa (DPO) versus epoetin alfa (EPO) in patients undergoing dialysis are lacking.Observational, registry-based, retrospective cohort study; we mimicked a cluster-randomized trial by comparing mortality and cardiovascular events in US patients initiating hemodialysis therapy in facilities (almost) exclusively using DPO versus EPO.Nonchain US hemodialysis facilities; each facility switching from EPO to DPO (2003-2010) was matched for location, profit status, and facility type with one EPO facility. Patients subsequently initiating hemodialysis therapy in these facilities were assigned their facility-level exposure.DPO versus EPO.All-cause mortality, cardiovascular mortality; composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke.Unadjusted and adjusted HRs from Cox proportional hazards regression models.Of 508 dialysis facilities that switched to DPO, 492 were matched with a similar EPO facility; 19,932 (DPO: 9,465 [47.5%]; EPO: 10,467 [52.5%]) incident hemodialysis patients were followed up for 21,918 person-years during which 5,550 deaths occurred. Almost all baseline characteristics were tightly balanced. The demographics-adjusted mortality HR for DPO (vs EPO) was 1.06 (95% CI, 1.00-1.13) and was materially unchanged after adjustment for all other baseline characteristics (HR, 1.05; 95% CI, 0.99-1.12). Cardiovascular mortality did not differ between groups (HR, 1.05; 95% CI, 0.94-1.16). Nonfatal outcomes were evaluated among 9,455 patients with fee-for-service Medicare: 4,542 (48.0%) in DPO and 4,913 (52.0%) in EPO facilities. During 10,457 and 10,363 person-years, 248 and 372 events were recorded, respectively, for strokes and MIs. We found no differences in adjusted stroke or MI rates or their composite with cardiovascular death (HR, 1.10; 95% CI, 0.96-1.25).Nonrandom treatment assignment, potential residual confounding.In incident hemodialysis patients, mortality and cardiovascular event rates did not differ between patients treated at facilities predominantly using DPO versus EPO.

  View details for DOI 10.1053/j.ajkd.2015.02.339

  View details for Web of Science ID 000356730600020

  View details for PubMedID 25943715

• Coronary artery bypass graft type and outcomes in maintenance dialysis. journal of cardiovascular surgery Shilane, D., Hlatky, M. A., Winkelmayer, W. C., Chang, T. I. 2015; 56 (3): 463-471

  Abstract

  Aim: Patients with end-stage renal disease (ESRD) on maintenance dialysis have a high burden of coronary disease. Prior studies in non-dialysis patients show better outcomes in coronary artery bypass surgery using the internal mammary artery (IMA) compared with the saphenous vein graft (SVG), but less is known about outcomes in ESRD. We sought to compare the effectiveness of multivessel bypass grafting using IMA versus SVG in patients on maintenance dialysis in the United States. Methods: Cohort study using data from the United States Renal Data System to examine IMA versus SVG in patients on maintenance dialysis undergoing multivessel coronary revascularization. We used Cox proportional hazards regression with multivariable adjustment in the full cohort and in a propensity-score matched cohort. The primary outcome was death from any cause; the secondary outcome was a composite of non-fatal myocardial infarction or death. Results: Overall survival rates were low in this patient population (5-year survival in the matched cohort 25.3%). Use of the IMA compared to SVG was associated with lower risk of death (adjusted hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.84-0.92) and lower risk of the composite outcome (adjusted HR 0.89; CI 0.85-0.93). Results did not materially change in analyses using the propensity-score matched cohort. We found similar results irrespective of patient sex, age, race, or the presence of diabetes, peripheral vascular disease or heart failure. Conclusion: Although overall survival rates were low, IMA was associated with lower risk of mortality and cardiovascular morbidity compared to SVG in patients on dialysis.

  View details for PubMedID 24343371

• Association of Spontaneous Bleeding and Myocardial Infarction With Long-Term Mortality After Percutaneous Coronary Intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kazi, D. S., Leong, T. K., Chang, T. I., Solomon, M. D., Hlatky, M. A., Go, A. S. 2015; 65 (14): 1411-1420

  Abstract

  Platelet inhibition after percutaneous coronary intervention (PCI) reduces the risk of myocardial infarction (MI) but increases the risk of bleeding. MIs and bleeds during the index hospitalization for PCI are known to negatively affect long-term outcomes. The impact of spontaneous bleeding occurring after discharge on long-term mortality is unknown.This study sought to examine, in a real-world cohort, the association between spontaneous major bleeding or MI after PCI and long-term mortality.We conducted a retrospective cohort study of patients ≥30 years of age who underwent a PCI between 1996 and 2008 in an integrated healthcare delivery system. We used extended Cox regression to examine the associations of spontaneous bleeding and MI with all-cause mortality, after adjustment for time-updated demographics, comorbidities, periprocedural events, and longitudinal medication exposure.Among 32,906 patients who had a PCI and survived the index hospitalization, 530 had bleeds and 991 had MIs between 7 and 365 days post-discharge. There were 4,048 deaths over a mean follow-up of 4.42 years. The crude annual death rate after a spontaneous bleed (9.5%) or MI (7.6%) was higher than among patients who experienced neither event (2.6%). Bleeding was associated with an increased rate of death (adjusted hazard ratio [HR]: 1.61, 95% confidence interval [CI]: 1.30 to 2.00), similar to that after an MI (HR: 1.91; 95% CI: 1.62 to 2.25). The association of bleeding with death remained significant after additional adjustment for the longitudinal use of antiplatelet agents.Spontaneous bleeding after a PCI was independently associated with higher long-term mortality, and conveyed a risk comparable to that of an MI during follow-up. This tradeoff between efficacy and safety bolsters the argument for personalizing antiplatelet therapy after PCI on the basis of the patient's long-term risk of both thrombotic and bleeding events.

  View details for DOI 10.1016/j.jacc.2015.01.047

  View details for Web of Science ID 000352419100005

  View details for PubMedID 25857906

• Visit-to-Visit Variability of Systolic Blood Pressure and Cardiovascular Disease CURRENT HYPERTENSION REPORTS Hussein, W. F., Chang, T. I. 2015; 17 (4)

  Abstract

  Visit-to-visit variability of blood pressure (VVV of BP) is gaining interest as a prognostic marker for stroke, cardiovascular disease, and all-cause mortality. In this review, we discuss different metrics used to define VVV of BP, explore the potential sources of this phenomenon including patient characteristics and antihypertensive medication classes, and discuss recent evidence of its relation with cardiovascular outcomes. Current evidence relies on secondary analyses of clinical trials or on observational studies, none of which was designed to examine VVV of BP specifically. More research is required to develop standardized definitions of VVV of BP, to confirm the value of VVV as a prognostic indicator, and to ascertain whether efforts to reduce VVV of BP in addition to mean BP will improve outcomes.

  View details for DOI 10.1007/s11906-014-0527-8

  View details for Web of Science ID 000351563900004

  View details for PubMedID 25754319

• Correlates and outcomes of warfarin initiation in kidney transplant recipients newly diagnosed with atrial fibrillation. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Lenihan, C. R., Montez-Rath, M. E., Shen, J. I., Scandling, J. D., Turakhia, M. P., Chang, T. I., Winkelmayer, W. C. 2015; 30 (2): 321-329

  Abstract

  In the kidney transplant population with atrial fibrillation (AF), evidence regarding the effectiveness and safety of warfarin treatment is lacking. We used fee-for-service Medicare claims to identify kidney transplant recipients with newly diagnosed AF from the United States Renal Data System. Warfarin use within 30 days of AF diagnosis was ascertained from Medicare Part D prescription claims (2007-11) or using a validated algorithm (1997-2011). The study end points were (i) the composite of death, stroke or gastrointestinal bleed, (ii) death and (iii) death-censored graft failure. Warfarin user and non-user groups were balanced using inverse probability of treatment weighting and hazard ratios were (HRs) estimated using Cox regression. Among 718 subjects with an indication for anticoagulation, 24% initiated warfarin treatment within 30 days of AF diagnosis. Age was the only independent correlate of warfarin use [odds ratio = 1.02 per year; 95% confidence interval (95% CI) 1.01-1.04]. In the larger cohort of 6492 patients with AF, warfarin use [(23.5%) versus non-use (76.5%)] was associated with small and non-significant reductions in the composite of death, stroke or gastrointestinal bleed (HR = 0.92; 95% CI 0.83-1.02), death (HR = 0.92; 95% CI 0.82-1.02) and death-censored graft failure (HR = 0.90; 95% CI 0.76-1.08). Our study suggests the need for clinical trials of warfarin use in the kidney transplant population with AF.

  View details for DOI 10.1093/ndt/gfu323

  View details for PubMedID 25335507

• Thienopyridine use after coronary stenting in low income patients enrolled in medicare part D receiving maintenance dialysis. Journal of the American Heart Association Chang, T. I., Montez-Rath, M. E., Shen, J. I., Solomon, M. D., Chertow, G. M., Winkelmayer, W. C. 2014; 3 (5)

  Abstract

  Coronary stenting in patients on dialysis has increased by nearly 50% over the past decade, despite heightened risks of associated stent thrombosis and bleeding relative to the general population. We examined clopidogrel, prasugrel or ticlopidine use after percutaneous coronary intervention (PCI) with stenting in patients on dialysis. We conducted 3-, 6-, and 12-month landmark analyses to test the hypothesis that thienopyridine discontinuation prior to those time points would be associated with higher risks of death, myocardial infarction, or repeat revascularization, and a lower risk of major bleeding episodes compared with continued thienopyridine use.Using the US Renal Data System, we identified 8458 patients on dialysis with Medicare Parts A+B+D undergoing PCI with stenting between July 2007 and December 2010. Ninety-nine percent of all thienopyridine prescriptions were for clopidogrel. At 3 months, 82% of patients who received drug-eluting stents (DES) had evidence of thienopyridine use. These proportions fell to 62% and 40% at 6 and 12 months, respectively. In patients who received a bare-metal stent (BMS), 70%, 34%, and 26% of patients had evidence of thienopyridine use at 3, 6, and 12 months, respectively. In patients who received a DES, there was a suggestion of higher risks of death or myocardial infarction associated with thienopyridine discontinuation in the 3-, 6-, and 12-months landmark analyses, but no higher risk of major bleeding episodes. In patients who received a BMS, there were no differences in death or cardiovascular events, and possibly lower risk of major bleeding with thienopyridine discontinuation in the 3- and 6-month landmark analyses.The majority of patients on dialysis who undergo PCI discontinue thienopyridines before 1 year regardless of stent type. While not definitive, these data suggest that longer-term thienopyridine use may be of benefit to patients on dialysis who undergo PCI with DES.

  View details for DOI 10.1161/JAHA.114.001356

  View details for PubMedID 25336465

• Thienopyridine use after coronary stenting in low income patients enrolled in medicare part D receiving maintenance dialysis. Journal of the American Heart Association Chang, T. I., Montez-Rath, M. E., Shen, J. I., Solomon, M. D., Chertow, G. M., Winkelmayer, W. C. 2014; 3 (5)

  View details for DOI 10.1161/JAHA.114.001356

  View details for PubMedID 25336465

• Acute Kidney Injury After CABG Versus PCI: An Observational Study Using 2 Cohorts. Journal of the American College of Cardiology Chang, T. I., Leong, T. K., Boothroyd, D. B., Hlatky, M. A., Go, A. S. 2014; 64 (10): 985-994

  Abstract

  Acute kidney injury (AKI) is a known complication after coronary revascularization, but few studies have directly compared the incidence of AKI after coronary artery bypass surgery (CABG) or after percutaneous coronary intervention (PCI) in similar patients.The aim of this study was to investigate whether multivessel CABG compared with PCI as an initial revascularization strategy is associated with a higher risk for AKI.A retrospective analysis of patients undergoing first documented coronary revascularization was conducted using 2 complementary cohorts: 1) Kaiser Permanente Northern California, a diverse, integrated health care delivery system; and 2) Medicare beneficiaries, a large, nationally representative older cohort. AKI was defined in the Kaiser Permanente Northern California cohort by an increase in serum creatinine of ≥0.3 mg/dl or ≥150% above baseline and in the Medicare cohort by discharge diagnosis codes and the use of dialysis.The incidence of AKI was 20.4% in the Kaiser Permanente Northern California cohort and 6.2% in the Medicare cohort. The incidence of AKI requiring dialysis was <1%. CABG was associated with a 2- to 3-fold significantly higher adjusted odds for developing AKI compared with PCI in both cohorts.AKI is common after multivessel coronary revascularization and is more likely after CABG than after PCI. The risk for AKI should be considered when choosing a coronary revascularization strategy, and ways to prevent AKI after coronary revascularization are needed.

  View details for DOI 10.1016/j.jacc.2014.04.077

  View details for PubMedID 25190232

• The Association of Gender to Cardiovascular Outcomes After Coronary Artery Revascularization in Patients With End-Stage Renal Disease CLINICAL CARDIOLOGY Krishnaswami, A., Chang, T. I., Jang, J. J., Leong, T. K., Go, A. S. 2014; 37 (9): 546-551

  View details for DOI 10.1002/clc.22306

  View details for Web of Science ID 000342236900006

• Beta-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease. Journal of the American College of Cardiology Andersson, C., Shilane, D., Go, A. S., Chang, T. I., Kazi, D., Solomon, M. D., Boothroyd, D. B., Hlatky, M. A. 2014; 64 (3): 247-252

  Abstract

  The effectiveness of beta-blockers for preventing cardiac events has been questioned for patients who have coronary heart disease (CHD) without a prior myocardial infarction (MI).The purpose of this study was to assess the association of beta-blockers with outcomes among patients with new-onset CHD.We studied consecutive patients discharged after the first CHD event (acute coronary syndrome or coronary revascularization) between 2000 and 2008 in an integrated healthcare delivery system who did not use beta-blockers in the year before entry. We used time-varying Cox regression models to determine the hazard ratio (HR) associated with beta-blocker treatment and used treatment-by-covariate interaction tests (pint) to determine whether the association differed for patients with or without a recent MI.A total of 26,793 patients were included, 19,843 of whom initiated beta-blocker treatment within 7 days of discharge from their initial CHD event. Over an average of 3.7 years of follow-up, 6,968 patients had an MI or died. Use of beta-blockers was associated with an adjusted HR for mortality of 0.90 (95% confidence limits [CL]: 0.84 to 0.96), and an adjusted HR for death or MI of 0.92 (CL: 0.87 to 0.97). The association between beta-blockers and outcomes differed significantly between patients with and without a recent MI (HR for death: 0.85 vs. 1.02, pint = 0.007; and HR for death or MI: 0.87 vs. 1.03, pint = 0.005).Use of beta-blockers among patients with new-onset CHD was associated with a lower risk of cardiac events only among patients with a recent MI.

  View details for DOI 10.1016/j.jacc.2014.04.042

  View details for PubMedID 25034059

• Temporal trends in mortality after coronary artery revascularization in patients with end-stage renal disease. The Permanente journal Krishnaswami, A., Leong, T. K., Hlatky, M. A., Chang, T. I., Go, A. S. 2014; 18 (3): 11-16

  Abstract

  Recent studies that have assessed the comparative effectiveness between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients with end-stage renal disease (ESRD) that have included analyses of temporal trends in mortality have noted mixed results.We conducted an observational longitudinal cohort study of all adults with ESRD undergoing CABG or PCI within Kaiser Permanente Northern California. The primary predictor, index period of revascularization, was categorized into 3 periods: 1996-1999 (reference), 2000-2003, and 2004-2008, with the primary outcome being 3-year all-cause mortality. A multivariable Cox regression model with the assumption of independent censoring was used to determine the adjusted relative risk of the primary predictor.Among 1015 ESRD patients, 3-year mortality showed no significant change in the 2000-2003 period but was lower during the 2004-2008 period with an adjusted hazard ratio of 0.66 (95% confidence interval: 0.49-0.88; trend test p = 0.01). No change in 30-day mortality was noted. Further adjustment for receipt of medications at baseline and after revascularization did not materially affect risk estimates. No significant interactions were observed between the type of revascularization (CABG or PCI) and the period of the index revascularization.Among a high-risk cohort of patients with ESRD and coronary artery disease within Kaiser Permanente Northern California who were referred for coronary revascularization by either CABG or PCI, the relative risk of mortality in the 2004-2008 period decreased by 34% compared with the 1996-1999 period, with the benefit primarily in the decrease in late mortality.

  View details for DOI 10.7812/TPP/14-003

  View details for PubMedID 25102514

• Comparative Effectiveness of Clopidogrel in Medically Managed Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. Journal of the American College of Cardiology Solomon, M. D., Go, A. S., Shilane, D., Boothroyd, D. B., Leong, T. K., Kazi, D. S., Chang, T. I., Hlatky, M. A. 2014; 63 (21): 2249-2257

  Abstract

  This study sought to examine the effectiveness of clopidogrel in real-world, medically managed patients with unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI).Although clinical trials have demonstrated the efficacy of clopidogrel to reduce cardiovascular (CV) morbidity and mortality in medically managed patients with UA or NSTEMI, the effectiveness of clopidogrel in actual clinical practice is less certain.A retrospective cohort study was conducted of Kaiser Permanente Northern California members without known coronary artery disease or prior clopidogrel use who presented with UA or NSTEMI between 2003 and 2008 and were medically managed (i.e., no percutaneous coronary intervention or coronary artery bypass grafting during the index hospitalization or within 7 days post-discharge). Over 2 years of follow-up, we measured the association between clopidogrel use and all-cause mortality, hospital stay for MI, and a composite endpoint of death or MI using propensity-matched multivariable Cox analyses.We identified 16,365 patients with incident UA (35%) or NSTEMI (65%); 36% of these patients were prescribed clopidogrel within 7 days of discharge. In 8,562 propensity score-matched patients, clopidogrel users had lower rates of all-cause mortality (8.3% vs. 13.0%; p < 0.01; adjusted hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.54 to 0.72) and the composite of death or MI (13.5% vs. 17.4%; p < 0.01; HR: 0.74, CI: 0.66 to 0.84), but not MI alone (6.7% vs. 7.2%; p = 0.30; HR: 0.93, CI: 0.78 to 1.11), compared with nonusers of clopidogrel. The association between clopidogrel use and the composite of death or MI was significant only among patients presenting with NSTEMI (HR: 0.67; CI: 0.59 to 0.76; pint < 0.01), not among those presenting with UA (HR: 1.25; CI: 0.94 to 1.67).In a large, community-based cohort of patients who were medically managed after UA/NSTEMI, clopidogrel use was associated with a lower risk of death and MI, particularly among patients with NSTEMI.

  View details for DOI 10.1016/j.jacc.2014.02.586

  View details for PubMedID 24703914

• Near-Term Prediction of Sudden Cardiac Death in Older Hemodialysis Patients Using Electronic Health Records CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Goldstein, B. A., Chang, T. I., Mitani, A. A., Assimes, T. L., Winkelmayer, W. C. 2014; 9 (1): 82-91

  Abstract

  Sudden cardiac death is the most common cause of death among individuals undergoing hemodialysis. The epidemiology of sudden cardiac death has been well studied, and efforts are shifting to risk assessment. This study aimed to test whether assessment of acute changes during hemodialysis that are captured in electronic health records improved risk assessment.Data were collected from all hemodialysis sessions of patients 66 years and older receiving hemodialysis from a large national dialysis provider between 2004 and 2008. The primary outcome of interest was sudden cardiac death the day of or day after a dialysis session. This study used data from 2004 to 2006 as the training set and data from 2007 to 2008 as the validation set. The machine learning algorithm, Random Forests, was used to derive the prediction model.In 22 million sessions, 898 people between 2004 and 2006 and 826 people between 2007 and 2008 died on the day of or day after a dialysis session that was serving as a training or test data session, respectively. A reasonably strong predictor was derived using just predialysis information (concordance statistic=0.782), which showed modest but significant improvement after inclusion of postdialysis information (concordance statistic=0.799, P<0.001). However, risk prediction decreased the farther out that it was forecasted (up to 1 year), and postdialytic information became less important.Subtle changes in the experience of hemodialysis aid in the assessment of sudden cardiac death and are captured by modern electronic health records. The collected data are better for the assessment of near-term risk as opposed to longer-term risk.

  View details for DOI 10.2215/CJN.03050313

  View details for Web of Science ID 000329364700013

  View details for PubMedID 24178968

• Visit-to-visit systolic blood pressure variability and outcomes in hemodialysis JOURNAL OF HUMAN HYPERTENSION Chang, T. I., Flythe, J. E., Brunelli, S. M., Muntner, P., Greene, T., Cheung, A. K., Chertow, G. M. 2014; 28 (1): 18-24

  Abstract

  Visit-to-visit blood pressure variability (VTV-BPV) is an independent risk factor for cardiovascular events and death in the general population. We sought to determine the association of VTV-BPV with outcomes in patients on hemodialysis, using data from a National Institutes of Health-sponsored randomized trial (the HEMO study). We used the coefficient of variation (CV) and the average real variability in systolic blood pressure (SBP) as metrics of VTV-BPV. In all, 1844 out of 1846 randomized subjects had at least three visits with SBP measurements and were included in the analysis. Median follow-up was 2.5 years (interquartile range 1.3-4.3 years), during which time there were 869 deaths from any cause and 408 (adjudicated) cardiovascular deaths. The mean pre-dialysis SBP CV was 9.9±4.6%. In unadjusted models, we found a 31% higher risk of death from any cause per 10% increase in VTV-BPV. This association was attenuated after multivariable adjustment but remained statistically significant. Similarly, we found a 28% higher risk of cardiovascular death per 10% increase in VTV-BPV, which was attenuated and no longer statistically significant in fully adjusted models. The associations among VTV-BPV, death and cardiovascular death were modified by baseline SBP. In a diverse, well-dialyzed cohort of patients on maintenance hemodialysis, VTV-BPV, assessed using metrics of variability in pre-dialysis SBP, was associated with a higher risk of all-cause mortality and a trend toward higher risk of cardiovascular mortality, particularly in patients with a lower baseline SBP.Journal of Human Hypertension advance online publication, 27 June 2013; doi:10.1038/jhh.2013.49.

  View details for DOI 10.1038/jhh.2013.49

  View details for Web of Science ID 000327940600005

• Contemporary Incidence, Predictors, and Outcomes of Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Interventions JACC-CARDIOVASCULAR INTERVENTIONS Tsai, T. T., Patel, U. D., Chang, T. I., Kennedy, K. F., Masoudi, F. A., Matheny, M. E., Kosiborod, M., Amin, A. P., Messenger, J. C., Rumsfeld, J. S., Spertus, J. A. 2014; 7 (1): 1-9

  Abstract

  This study sought to examine the contemporary incidence, predictors and outcomes of acute kidney injury in patients undergoing percutaneous coronary interventions.Acute kidney injury (AKI) is a serious and potentially preventable complication of percutaneous coronary interventions (PCIs) that is associated with adverse outcomes. The contemporary incidence, predictors, and outcomes of AKI are not well defined, and clarifying these can help identify high-risk patients for proactive prevention.A total of 985,737 consecutive patients underwent PCIs at 1,253 sites participating in the National Cardiovascular Data Registry Cath-PCI registry from June 2009 through June 2011. AKI was defined on the basis of changes in serum creatinine level in the hospital according to the Acute Kidney Injury Network (AKIN) criteria. Using multivariable regression analyses with generalized estimating equations, we identified patient characteristics associated with AKI.Overall, 69,658 (7.1%) patients experienced AKI, with 3,005 (0.3%) requiring new dialysis. On multivariable analyses, the factors most strongly associated with development of AKI included ST-segment elevation myocardial infarction (STEMI) presentation (odds ratio [OR]: 2.60; 95% confidence interval [CI]: 2.53 to 2.67), severe chronic kidney disease (OR: 3.59; 95% CI: 3.47 to 3.71), and cardiogenic shock (OR: 2.92; 95% CI: 2.80 to 3.04). The in-hospital mortality rate was 9.7% for patients with AKI and 34% for those requiring dialysis compared with 0.5% for patients without AKI (p < 0.001). After multivariable adjustment, AKI (OR: 7.8; 95% CI: 7.4 to 8.1, p < 0.001) and dialysis (OR: 21.7; 95% CI: 19.6 to 24.1; p < 0.001) remained independent predictors of in-hospital mortality.Approximately 7% of patients undergoing a PCI experience AKI, which is strongly associated with in-hospital mortality. Defining strategies to minimize the risk of AKI in patients undergoing PCI are needed to improve the safety and outcomes of the procedure.

  View details for DOI 10.1016/j.jcin.2013.06.016

  View details for Web of Science ID 000330953100003

  View details for PubMedCentralID PMC4122507

• Incremental prognostic information from kidney function in patients with new onset coronary heart disease AMERICAN HEART JOURNAL Hlatky, M. A., Shilane, D., Chang, T. I., Boothroyd, D., Go, A. S. 2014; 167 (1): 86-92

  Abstract

  Prognostic factors are usually evaluated by their statistical significance rather than by their clinical utility. Risk reclassification measures the extent to which a novel marker adds useful information to a prognostic model. The extent to which estimated glomerular filtration rate (eGFR) adds information about prognosis among patients with coronary heart disease is uncertain.We studied patients in an integrated health care delivery system with newly diagnosed coronary heart disease. We developed a model of the risk of death over 2 years of follow-up and then added eGFR to the model and measured changes in C-index, net reclassification improvement, and integrated discrimination improvement.Almost half of the 31,533 study patients had reduced eGFR (<60 mL/min per 1.73 m(2)). Mortality was significantly higher among patients who had lower levels of eGFR, even after adjustment for baseline characteristics (P < .0001). The addition of eGFR to the prognostic model increased the C-index from 0.837 to 0.843, the net reclassification improvement by 3.2% (P < .0001), and integrated discrimination improvement by 1.3% (P = .007).Estimated glomerular filtration rate is an informative prognostic factor among patients with incident coronary heart disease, independent of other clinical characteristics.

  View details for DOI 10.1016/j.ahj.2013.10.006

  View details for Web of Science ID 000328458600013

  View details for PubMedID 24332146

• Multivessel coronary revascularization and outcomes in kidney transplant recipients. Transplant international Lenihan, C. R., Montez-Rath, M. E., Winkelmayer, W. C., Chang, T. I. 2013; 26 (11): 1080-1087

  Abstract

  Coronary artery disease is a major cause of morbidity and mortality in the kidney transplant population. We compared the long-term outcomes of coronary artery bypass graft (CABG) surgery with percutaneous coronary intervention (PCI) for multivessel coronary disease in a contemporary cohort of US kidney transplant recipients. From the U.S. Renal Data System, we identified all adult kidney transplant patients with ≥6 months of Medicare A+B undergoing first recorded multivessel coronary revascularization from 1997 to 2009. The associations of CABG versus PCI with death and the composite of death or myocardial infarction (MI) were compared using proportional hazards regression. Of the 2272 patients included in the study, 1594 underwent CABG and 678 underwent PCI. The estimated 5-year survival rate was 55% [95% confidence interval (CI) 53% to 57%] following coronary revascularization, with no significant association between revascularization type and death [adjusted hazard ratio (aHR) = 1.08; CI 0.94-1.23] or the composite of death or MI (aHR = 1.07; CI 0.96-1.18). Separate propensity score-matched analyses yielded similar results. In this analysis of kidney transplant recipients undergoing multivessel coronary revascularization, we found no difference between CABG and PCI in terms of survival or the composite of death and MI.

  View details for DOI 10.1111/tri.12168

  View details for PubMedID 23957580

• Use and safety of heparin-free maintenance hemodialysis in the USA NEPHROLOGY DIALYSIS TRANSPLANTATION Shen, J. I., Mitani, A. A., Chang, T. I., Winkelmayer, W. C. 2013; 28 (6): 1589-1602

  Abstract

  BACKGROUND: Although heparin is used to anticoagulate the extracorporeal circuit for most patients on maintenance hemodialysis (HD), some patients undergo heparin-free HD. We describe the determinants of heparin-free HD and its association with adverse outcomes using data from a national dialysis provider merged with Medicare claims. METHODS: We identified patients aged ≥67 years with no recent history of warfarin use who initiated maintenance HD from 2007 to 2008. We applied the Cox regression to a propensity score-matched cohort to estimate the hazards of all-cause mortality, bleeding (gastrointestinal hemorrhage, hemorrhagic stroke, other hemorrhage), atherothrombosis (ischemic stroke, myocardial infarction) and venous thromboembolism (VTE) (deep vein thrombosis, pulmonary embolism). RESULTS: Among 12 468 patients, 836 (6.7%) were dialyzed heparin-free. In multivariable-adjusted analyses, a history of gastrointestinal bleeding, hemorrhagic stroke and lower hemoglobin and platelet counts were associated with higher odds of heparin-free HD. Heparin-free HD use also varied as much as 4-fold by facility region. We found no significant association of heparin-free HD with all-cause mortality [hazard ratio (HR) 1.08; 95% confidence interval (CI): 0.94-1.26], bleeding (HR 1.15; 95% CI: 0.83-1.60), atherothrombosis (HR 1.09, 95% CI: 0.90-1.31) or VTE (HR 1.23, 95% CI: 0.93-1.64) compared with HD with heparin. CONCLUSIONS: Patient markers of increased risk of bleeding and facility region associated with heparin-free HD use. Despite the potential benefits of avoiding heparin use, heparin-free HD was not significantly associated with decreased hazards of death, bleeding or thrombosis, suggesting that it may be no safer than HD with heparin.

  View details for DOI 10.1093/ndt/gft067

  View details for Web of Science ID 000321057700040

  View details for PubMedID 23563280

• Association of Intradialytic Blood Pressure Variability With Increased All-Cause and Cardiovascular Mortality in Patients Treated With Long-term Hemodialysis AMERICAN JOURNAL OF KIDNEY DISEASES Flythe, J. E., Inrig, J. K., Shafi, T., Chang, T. I., Cape, K., Dinesh, K., Kunaparaju, S., Brunelli, S. M. 2013; 61 (6): 966-974

  Abstract

  Blood pressure is known to fluctuate widely during hemodialysis; however, little is known about the association between intradialytic blood pressure variability and outcomes.Retrospective observational cohort.A random sample of 6,393 adult, thrice-weekly, in-center, maintenance hemodialysis patients dialyzing at 1,026 dialysis units within a single large dialysis organization.Intradialytic systolic blood pressure (SBP) variability. This was calculated using a mixed linear effects model. Peridialytic SBP phenomena were defined as starting SBP (regression intercept), systematic change in SBP over the course of dialysis (2 regression slopes), and random intradialytic SBP variability (absolute regression residual).All-cause and cardiovascular mortality.SBPs (n = 631,922) measured during hemodialysis treatments (n = 78,961) during the first 30 days in the study. Outcome data were obtained from the dialysis unit electronic medical record and were considered beginning on day 31.High (ie, greater than the median) versus low SBP variability was associated with greater risk of all-cause mortality (adjusted HR, 1.26; 95% CI, 1.08-1.47). The association between high SBP variability and cardiovascular mortality was even more potent (adjusted HR, 1.32; 95% CI, 1.01-1.72). A dose-response trend was observed across quartiles of SBP variability for both all-cause (P = 0.001) and cardiovascular (P = 0.04) mortality.Inclusion of patients from a single large dialysis organization, over-representation of African Americans and patients with diabetes and heart failure, and lack of standardized SBP measurements.Greater intradialytic SBP variability is associated independently with increased all-cause and cardiovascular mortality. Further prospective studies are needed to confirm findings and identify means of reducing SBP variability to facilitate randomized study.

  View details for DOI 10.1053/j.ajkd.2012.12.023

  View details for Web of Science ID 000318999200018

  View details for PubMedID 23474007

• Comparative effectiveness of multivessel coronary bypass surgery and multivessel percutaneous coronary intervention: a cohort study. Annals of internal medicine Hlatky, M. A., Boothroyd, D. B., Baker, L., Kazi, D. S., Solomon, M. D., Chang, T. I., Shilane, D., Go, A. S. 2013; 158 (10): 727-734

  Abstract

  Chinese translationRandomized trials of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) suggest that patient characteristics modify the effect of treatment on mortality.To assess whether clinical characteristics modify the comparative effectiveness of CABG versus PCI in an unselected, general patient population.Observational treatment comparison using propensity score matching and Cox proportional hazards models.United States, 1992 to 2008.Medicare beneficiaries aged 66 years or older.Multivessel CABG or multivessel PCI.The CABG-PCI hazard ratio (HR) for all-cause mortality, with prespecified treatment-by-covariate interaction tests, and the absolute difference in life-years of survival in clinical subgroups after CABG or PCI, both over 5 years of follow-up.Among 105 156 propensity score-matched patients, CABG was associated with lower mortality than PCI (HR, 0.92 [95% CI, 0.90 to 0.95]; P < 0.001). Association of CABG with lower mortality was significantly greater (interaction P ≤ 0.002 for each) among patients with diabetes (HR, 0.88), a history of tobacco use (HR, 0.82), heart failure (HR, 0.84), and peripheral arterial disease (HR, 0.85). The overall predicted difference in survival between CABG and PCI treatment over 5 years was 0.053 life-years (range, -0.017 to 0.579 life-years). Patients with diabetes, heart failure, peripheral arterial disease, or tobacco use had the largest predicted differences in survival after CABG, whereas those with none of these factors had slightly better survival after PCI.Treatments were chosen by patients and physicians rather than being randomly assigned.Multivessel CABG is associated with lower long-term mortality than multivessel PCI in the community setting. This association is substantially modified by patient characteristics, with improvement in survival concentrated among patients with diabetes, tobacco use, heart failure, or peripheral arterial disease.National Heart, Lung, and Blood Institute.

  View details for DOI 10.7326/0003-4819-158-10-201305210-00639

  View details for PubMedID 23609014

• Comparative effectiveness of coronary artery bypass grafting and percutaneous coronary intervention for multivessel coronary disease in a community-based population with chronic kidney disease. American heart journal Chang, T. I., Leong, T. K., Kazi, D. S., Lee, H. S., Hlatky, M. A., Go, A. S. 2013; 165 (5): 800-808 e2

  Abstract

  Randomized clinical trials comparing coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) have largely excluded patients with chronic kidney disease (CKD), leading to uncertainty about the optimal coronary revascularization strategy. We sought to test the hypothesis that an initial strategy of CABG would be associated with lower risks of long-term mortality and cardiovascular morbidity compared with PCI for the treatment of multivessel coronary heart disease in the setting of CKD.We created a propensity score-matched cohort of patients aged ≥30 years with no prior dialysis or renal transplant who received multivessel coronary revascularization between 1996 and 2008 within a large integrated health care delivery system in northern California. We used extended Cox regression to examine death from any cause, acute coronary syndrome, and repeat revascularization.Coronary artery bypass grafting was associated with a significantly lower adjusted rate of death than PCI across all strata of estimated glomerular filtration rate (eGFR) (in mL/min per 1.73 m(2)): the adjusted hazard ratio (HR) was 0.81, 95% CI 0.68 to 1.00 for patients with eGFR ≥60; HR 0.73 (CI 0.56-0.95) for eGFR of 45 to 59; and HR 0.87 (CI 0.67-1.14) for eGFR <45. Coronary artery bypass grafting was also associated with significantly lower rates of acute coronary syndrome and repeat revascularization at all levels of eGFR compared with PCI.Among adults with and without CKD, multivessel CABG was associated with lower risks of death and coronary events compared with multivessel PCI.

  View details for DOI 10.1016/j.ahj.2013.02.012

  View details for PubMedID 23622918

• Risk Factors for ESRD in Individuals With Preserved Estimated GFR With and Without Albuminuria: Results From the Kidney Early Evaluation Program (KEEP) AMERICAN JOURNAL OF KIDNEY DISEASES Chang, T. I., Li, S., Chen, S., Peralta, C. A., Shlipak, M. G., Fried, L. F., Whaley-Connell, A. T., McCullough, P. A., Tamura, M. K. 2013; 61 (4): S4-S11

  Abstract

  Given the increasing costs and poor outcomes of end-stage renal disease (ESRD), we sought to identify risk factors for ESRD in people with preserved estimated glomerular filtration rate (eGFR), with or without albuminuria, who were at high risk of ESRD.This cohort study included participants in the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) with eGFR ≥ 60 mL/min/1.73 m(2) at baseline stratified by the presence or absence of albuminuria. The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate eGFR. Urine was tested for albuminuria by semiquantitative dipstick. The outcome was the development of treated chronic kidney failure, defined as initiation of maintenance dialysis therapy or kidney transplantation, determined by linkage to the US Renal Data System. We used a Cox model with the Fine-Gray method to assess risk factors for treated chronic kidney failure while accounting for the competing risk of death.During a median follow-up of 4.8 years, 126 of 13,923 participants with albuminuria (16/10,000 patient-years) and 56 of 109,135 participants without albuminuria (1.1/10,000 patient-years) developed treated chronic kidney failure. Diabetes was a strong risk factor for developing treated chronic kidney failure in participants with and without albuminuria (adjusted HRs of 9.3 [95% CI, 5.7-15.3] and 7.8 [95% CI, 4.1-14.8], respectively). Black race, lower eGFR, and higher systolic blood pressure also were associated with higher adjusted risks of developing treated chronic kidney failure.In a diverse high-risk cohort of KEEP participants with preserved eGFR, we showed that diabetes, higher systolic blood pressure, lower eGFR, and black race were risk factors for developing treated chronic kidney failure irrespective of albuminuria status, although the absolute risk of kidney failure in participants without albuminuria was very low. Our findings support testing for kidney disease in high-risk populations, which often have otherwise unrecognized kidney disease.

  View details for DOI 10.1053/j.ajkd.2012.12.016

  View details for Web of Science ID 000317270600002

  View details for PubMedID 23507268

• Effectiveness of beta-Blockers in Heart Failure With Left Ventricular Systolic Dysfunction and Chronic Kidney Disease JOURNAL OF CARDIAC FAILURE Chang, T. I., Yang, J., Freeman, J. V., Hlatky, M. A., Go, A. S. 2013; 19 (3): 176-182

  Abstract

  Establishing medication effectiveness outside of a randomized trial requires careful study design to mitigate selection bias. Previous observational studies of β-blockers in patients with chronic kidney disease and heart failure have had methodologic limitations that may have introduced bias. We examined whether initiation of β-blocker therapy was associated with better outcomes among patients with chronic kidney disease and newly diagnosed heart failure with left ventricular systolic dysfunction.We identified 668 adults in the Kaiser Permanente Northern California system from 2006 to 2008 with chronic kidney disease, incident heart failure, left ventricular systolic dysfunction, and no previous β-blocker use. We defined chronic kidney disease as estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2) or proteinuria, and we excluded patients receiving dialysis. We used extended Cox regression to assess the association of treatment with death and the combined end point of death or heart failure hospitalization. Initiation of β-blocker therapy was associated with a significantly lower crude risk of death (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.35-0.63), but this association was attenuated and no longer significant after multivariable adjustment (HR 0.75, CI 0.51-1.12). β-Blocker therapy was significantly associated with a lower risk of death or heart failure hospitalization even after adjustment for potential confounders (HR 0.67, CI 0.51-0.88).β-Blocker therapy is associated with lower risk of death or heart failure hospitalization among patients with chronic kidney disease, incident heart failure, and left ventricular systolic dysfunction.

  View details for DOI 10.1016/j.cardfail.2013.01.006

  View details for Web of Science ID 000316529900005

  View details for PubMedID 23482078

• Comparative Effectiveness Research in Heart Failure Therapies Women, Elderly Patients, and Patients with Kidney Disease HEART FAILURE CLINICS Shah, R. U., Chang, T. I., Fonarow, G. C. 2013; 9 (1): 79-?

  View details for DOI 10.1016/j.hfc.2012.09.003

  View details for Web of Science ID 000313137800008

  View details for PubMedID 23168319

• Multivessel Coronary Artery Bypass Grafting Versus Percutaneous Coronary Intervention in ESRD JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chang, T. I., Shilane, D., Kazi, D. S., Montez-Rath, M. E., Hlatky, M. A., Winkelmayer, W. C. 2012; 23 (12): 2042-2049

  Abstract

  Thirty to sixty percent of patients with ESRD on dialysis have coronary heart disease, but the optimal strategy for coronary revascularization is unknown. We used data from the United States Renal Data System to define a cohort of 21,981 patients on maintenance dialysis who received initial coronary revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) between 1997 and 2009 and had at least 6 months of prior Medicare coverage as their primary payer. The primary outcome was death from any cause, and the secondary outcome was a composite of death or myocardial infarction. Overall survival rates were consistently poor during the study period, with unadjusted 5-year survival rates of 22%-25% irrespective of revascularization strategy. Using multivariable-adjusted proportional hazards regression, we found that CABG compared with PCI associated with significantly lower risks for both death (HR=0.87, 95% CI=0.84-0.90) and the composite of death or myocardial infarction (HR=0.88, 95% CI=0.86-0.91). Results were similar in analyses using a propensity score-matched cohort. In the absence of data from randomized trials, these results suggest that CABG may be preferred over PCI for multivessel coronary revascularization in appropriately selected patients on maintenance dialysis.

  View details for DOI 10.1681/ASN.2012060554

  View details for Web of Science ID 000311819000017

  View details for PubMedID 23204445

  View details for PubMedCentralID PMC3507369

• Preoperative Statin Use and Postoperative Acute Kidney Injury AMERICAN JOURNAL OF MEDICINE Brunelli, S. M., Waikar, S. S., Bateman, B. T., Chang, T. I., Lii, J., Garg, A. X., Winkelmayer, W. C., Choudhry, N. K. 2012; 125 (12): 1195-?

  Abstract

  Acute kidney injury is a frequent postoperative complication that confers increased mortality, morbidity, and costs. The purpose of this study was to evaluate whether preoperative statin use is associated with a decreased risk of postoperative acute kidney injury.We assembled a retrospective cohort of 98,939 patients who underwent a major open abdominal, cardiac, thoracic, or vascular procedure between 2000 and 2010. Statin users were pair-matched to nonusers on the basis of surgery type, baseline kidney function, days from admission until surgery, and propensity score based on demographics, comorbid conditions, and concomitant medications. Acute kidney injury was defined based on changes in serum creatinine measurements applying Acute Kidney Injury Network and Risk-Injury-Failure staging systems, and on the need for renal replacement therapy. Associations between statin use and acute kidney injury were estimated by conditional logistic regression.Across various acute kidney injury definitions, statin use was consistently associated with a decreased risk: adjusted odds ratios (95% confidence intervals) varied from 0.74 (0.58-0.95) to 0.80 (0.71-0.90). Associations were similar among diabetics and nondiabetics, and across strata of baseline kidney function. The protective association of statins was most pronounced among patients undergoing vascular surgery and least among patients undergoing cardiac surgery.Preoperative statin use is associated with a decreased risk of postoperative acute kidney injury. Future randomized clinical trials are needed to determine causality.

  View details for DOI 10.1016/j.amjmed.2012.06.021

  View details for Web of Science ID 000311217600020

  View details for PubMedID 23062398

• Comparative effectiveness research: what is it and why do we need it in nephrology? NEPHROLOGY DIALYSIS TRANSPLANTATION Chang, T. I., Winkelmayer, W. C. 2012; 27 (6): 2156-2161

  Abstract

  The USA leads other industrialized countries in health care spending but lags behind in terms of health outcomes. There has been growing interest in comparative effectiveness research (CER) as a means to identify best practices to create a more efficient and effective health care system. Two key concepts of CER are that it should (i) compare two or more alternative tests, therapies or procedures and (ii) be conducted in persons, clinical settings and conditions that are representative of the real world. The goal of CER is to provide evidence for clinicians, patients, policy makers and others to make informed decisions that will ultimately improve the overall health of specific subgroups and of the population as a whole. In this narrative review, we first describe the strengths and limitations of various types of studies that constitute CER, including randomized clinical trials, observational studies and systematic reviews, providing examples from the nephrology literature. Because of the concerns regarding confounding in observational CER, we also provide an overview of methods to reduce confounding in these types of studies. Finally, we will discuss why CER pertaining to kidney disease care needs to be a top priority in order to move our field from a largely opinion-based specialty to an evidence-based specialty.

  View details for DOI 10.1093/ndt/gfs154

  View details for Web of Science ID 000304832100008

  View details for PubMedID 22649210

• Use of Secondary Prevention Medications among Adults with Reduced Kidney Function CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chang, T. I., Gao, L., Brown, T. M., Safford, M. M., Judd, S. E., McClellan, W. M., Limdi, N. A., Muntner, P., Winkelmayer, W. C. 2012; 7 (4): 604-611

  Abstract

  Persons with kidney disease often have cardiovascular disease, but they are less likely to use recommended medications for secondary prevention. The hypothesis was that participants with reduced estimated GFR have lower use of medications recommended for secondary prevention of cardiovascular events (antiplatelet agents, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, β-blockers, and statins) and lower medication adherence than participants with preserved estimated GFR.In this cross-sectional analysis, we analyzed data from 6913 participants in the Reasons for Geographic and Racial Differences in Stroke study with a history of cardiovascular disease. Medication use was ascertained by an in-home pill bottle review. Medication adherence was assessed using a validated four-item scale.Among participants with a history of cardiovascular disease, 59.8% used antiplatelet agents, 49.9% used angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, 41.6% used β-blockers, and 53.0% used statins. Compared with the referent group (estimated GFR ≥60 ml/min per 1.73 m(2)), participants with estimated GFR <45 ml/min per 1.73 m(2) were more likely to use angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (adjusted prevalence ratio=1.14, 95% confidence interval=1.06-1.23), β-blockers (adjusted prevalence ratio=1.20, 95% confidence interval=1.09-1.32), and statins (adjusted prevalence ratio=1.10, 95% confidence interval=1.01-1.19). Antiplatelet agent use did not differ by estimated GFR category; 30% of participants reported medication nonadherence across all categories of estimated GFR.Among participants with a history of cardiovascular disease, mild to moderate reductions in estimated GFR were associated with similar and even more frequent use of medications for secondary prevention compared with participants with preserved estimated GFR. Overall medication use and adherence were suboptimal.

  View details for DOI 10.2215/CJN.11441111

  View details for Web of Science ID 000302281900013

  View details for PubMedID 22344513

• Blood Pressure Components and End-stage Renal Disease in Persons With Chronic Kidney Disease The Kidney Early Evaluation Program (KEEP) ARCHIVES OF INTERNAL MEDICINE Peralta, C. A., Norris, K. C., Li, S., Chang, T. I., Tamura, M. K., Jolly, S. E., Bakris, G., McCullough, P. A., Shlipak, M. 2012; 172 (1): 41-47

  Abstract

  Treatment of hypertension is difficult in chronic kidney disease (CKD), and blood pressure goals remain controversial. The association between each blood pressure component and end-stage renal disease (ESRD) risk is less well known.We studied associations of systolic and diastolic blood pressure (SBP and DBP, respectively) and pulse pressure (PP) with ESRD risk among 16,129 Kidney Early Evaluation Program (KEEP) participants with an estimated glomerular filtration rate of 60 mL/min/1.73 m(2) using Cox proportional hazards. We estimated the prevalence and characteristics associated with uncontrolled hypertension (SBP ≥ 150 or DBP ≥ 90 mm Hg).The mean (SD) age of participants was 69 (12) years; 25% were black, 6% were Hispanic, and 43% had diabetes mellitus. Over 2.87 years, there were 320 ESRD events. Higher SBP was associated with higher ESRD risk, starting at SBP of 140 mm Hg or higher. After sex and age adjustment, compared with SBP lower than 130 mm Hg, hazard ratios (HRs) were 1.08 (95% CI, 0.74-1.59) for SBP of 130 to 139 mm Hg, 1.72 (95% CI, 1.21-2.45) for SBP of 140 to 149 mm Hg, and 3.36 (95% CI, 2.51-4.49) for SBP of 150 mm Hg or greater. After full adjustment, HRs for ESRD were 1.27 (95% CI, 0.88-1.83) for SBP of 140 to 149 mm Hg and 1.36 (95% CI, 1.02-1.85) for SBP of 150 mm Hg or higher. Persons with DBP of 90 mm Hg or higher were at higher risk for ESRD compared with persons with DBP of 60 to 74 mm Hg (HR, 1.81; 95% CI, 1.33-2.45). Higher PP was also associated with higher ESRD risk (HR, 1.44 [95% CI, 1.00-2.07] for PP ≥ 80 mm Hg compared with PP < 50 mm Hg). Adjustment for SBP attenuated this association. More than 33% of participants had uncontrolled hypertension (SBP ≥ 150 mm Hg or DBP ≥ 90 mm Hg), mostly due to isolated systolic hypertension (54%).In this large, diverse, community-based sample, we found that high SBP seemed to account for most of the risk of progression to ESRD. This risk started at SBP of 140 mm Hg rather than the currently recommended goal of less than 130 mm Hg, and it was highest among those with SBP of at least 150 mm Hg. Treatment strategies that preferentially lower SBP may be required to improve BP control in CKD.

  View details for Web of Science ID 000298958900008

  View details for PubMedID 22232147

• Systolic Blood Pressure and Mortality in Patients on Hemodialysis CURRENT HYPERTENSION REPORTS Chang, T. I. 2011; 13 (5): 362-369

  Abstract

  Hypertension is extremely common in patients with end-stage renal disease who are receiving hemodialysis, and cardiovascular disease remains the leading cause of death in these patients. However, optimal blood pressure management strategies in this high-risk population are still controversial. This review first discusses the complex association of systolic blood pressure with clinical outcomes in patients on hemodialysis, with a focus on several recent studies. Next, it updates the reader on issues related to optimal timing and methods of blood pressure measurement, appropriate blood pressure targets, and pharmacologic and nonpharmacologic hypertension treatment strategies for patients on hemodialysis.

  View details for DOI 10.1007/s11906-011-0223-x

  View details for Web of Science ID 000295167300007

  View details for PubMedID 21800233

• Chronic Kidney Disease and Cardiovascular Therapeutics Time to Close the Evidence Gaps JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Chang, T. I., Chertow, G. M. 2011; 58 (11): 1162-1164

  View details for DOI 10.1016/j.jacc.2011.06.010

  View details for Web of Science ID 000294449200013

  View details for PubMedID 21884955

• Angiotensin-converting enzyme inhibitors and cardiovascular outcomes in patients on maintenance hemodialysis AMERICAN HEART JOURNAL Chang, T. I., Shilane, D., Brunelli, S. M., Cheung, A. K., Chertow, G. M., Winkelmayer, W. C. 2011; 162 (2): 324-330

  Abstract

  Persons with end-stage renal disease (ESRD) on hemodialysis carry an exceptionally high burden of cardiovascular disease. Angiotensin-converting enzyme inhibitors (ACEIs) are recommended for patients on dialysis, but there are few data regarding their effectiveness in ESRD.We conducted a secondary analysis of results of the HEMO study, a randomized trial of dialysis dose and membrane flux in patients on maintenance hemodialysis. We focused on the nonrandomized exposure of ACEI use, using proportional hazards regression and a propensity score analysis. The primary outcome was all-cause mortality. Secondary outcomes examined in the present analysis were cardiovascular hospitalization, heart failure hospitalization, and the composite outcomes of death or cardiovascular hospitalization and death or heart failure hospitalization.In multivariable-adjusted analyses, there were no significant associations among ACEI use and mortality (hazard ratio 0.97, 95% CI 0.82-1.14), cardiovascular hospitalization, and either composite outcome. Angiotensin-converting enzyme inhibitor use was associated with a higher risk of heart failure hospitalization (hazard ratio 1.41, 95% CI 1.11-1.80). In the propensity score-matched cohort, ACEI use was not significantly associated with any outcomes, including heart failure hospitalization.In a well-characterized cohort of patients on maintenance hemodialysis, ACEI use was not significantly associated with mortality or cardiovascular morbidity. The higher risk of heart failure hospitalization associated with ACEI use may not only reflect residual confounding but also highlights gaps in evidence when applying treatments proven effective in the general population to patients with ESRD. Our results underscore the need for definitive trials in ESRD to inform the treatment of cardiovascular disease.

  View details for DOI 10.1016/j.ahj.2011.05.004

  View details for Web of Science ID 000293729400016

  View details for PubMedID 21835294

• Angiotensin Converting Enzyme Inhibitors in Hemodialysis Chang, T. I., Shilane, D., Brunelli, S. M., Cheung, A. K., Chertow, G. M., Winkelmayer, W. C. WILEY PERIODICALS, INC. 2011: S15–S15

  View details for Web of Science ID 000294946600034

• Intradialytic Hypotension and Vascular Access Thrombosis JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chang, T. I., Paik, J., Greene, T., Desai, M., Bech, F., Cheung, A. K., Chertow, G. M. 2011; 22 (8): 1526-1533

  Abstract

  Identifying potential modifiable risk factors to reduce the incidence of vascular access thrombosis in hemodialysis could reduce considerable morbidity and health care costs. We analyzed data from a subset of 1426 HEMO study subjects to determine whether more frequent intradialytic hypotension and/or lower predialysis systolic BP were associated with higher rates of vascular access thrombosis. Our primary outcome measure was episodes of vascular access thrombosis occurring within a given 6-month period during HEMO study follow-up. There were 2005 total episodes of vascular access thrombosis during a median 3.1 years of follow-up. The relative rate of thrombosis of native arteriovenous fistulas for the highest quartile of intradialytic hypotension was approximately twice that of the lowest quartile, independent of predialysis systolic BP and other covariates. There was no significant association of intradialytic hypotension with prosthetic arteriovenous graft thrombosis after multivariable adjustment. Higher predialysis systolic BP was associated with a lower rate of fistula and graft thrombosis, independent of intradialytic hypotension and other covariates. In conclusion, more frequent episodes of intradialytic hypotension and lower predialysis systolic BP associate with increased rates of vascular access thrombosis. These results underscore the importance of including vascular access patency in future studies of BP management in hemodialysis.

  View details for DOI 10.1681/ASN.2010101119

  View details for Web of Science ID 000294083300019

  View details for PubMedID 21803971

  View details for PubMedCentralID PMC3148707

• Kidney Function and Long-Term Medication Adherence after Myocardial Infarction in the Elderly CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chang, T. I., Desai, M., Solomon, D. H., Winkelmayer, W. C. 2011; 6 (4): 864-869

  Abstract

  The association of kidney function with long-term outpatient medication adherence in the elderly remains understudied.A cohort of 2103 patients over the age of 65 years enrolled in a pharmacy benefits program after hospital discharge for myocardial infarction was studied. Using linear mixed effects models, the association of baseline kidney function with long-term adherence to recommended medications after myocardial infarction was examined, including angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), β-blockers, and statins. The primary outcome measure was the percentage of days covered as calculated by pharmacy refill data for 12 serial 3-month intervals (totaling 36 months of follow-up).Overall long-term adherence to ACEIs/ARBs, β-blockers, and statins was poor. The mean percentage of days covered by 36 months was only 50% to 60% for all three medication classes. Patients with baseline kidney dysfunction had significantly lower long-term ACEI/ARB and β-blocker adherence compared with patients with higher baseline kidney function. Long-term statin adherence did not vary by baseline level of kidney function.Long-term medication adherence after myocardial infarction in the elderly is low, especially in patients with kidney dysfunction. Future strategies to improve medication adherence should pay special attention to the elderly with kidney dysfunction because they may be especially vulnerable to its adverse clinical consequences.

  View details for DOI 10.2215/CJN.07290810

  View details for Web of Science ID 000289223600025

  View details for PubMedID 21233459

• Systolic blood pressure and mortality in prevalent haemodialysis patients in the HEMO study JOURNAL OF HUMAN HYPERTENSION Chang, T. I., Friedman, G. D., Cheung, A. K., Greene, T., Desai, M., Chertow, G. M. 2011; 25 (2): 98-105

  Abstract

  Previous studies of blood pressure and mortality in haemodialysis have yielded mixed results, perhaps due to confounding by comorbid conditions. We hypothesized that after improved accounting for confounding factors, higher systolic blood pressure (SBP) would be associated with higher all-cause mortality. We conducted a secondary analysis of data from the haemodialysis study, a randomized trial in prevalent haemodialysis patients. We used three proportional hazard models to determine the relative hazard at different levels of SBP: (1) Model-BL used baseline SBP; (2) Model-TV used SBP as a time-varying variable; and (3) Model-TV-Lag added a 3-month lag to Model-TV to de-emphasize changes in SBP associated with acute illness. In all the models, pre-dialysis SBP <120 mm Hg was associated with a higher risk of mortality compared with the referent group (140-159 mm Hg); higher pre-dialysis SBP was not associated with higher risk of mortality. In conclusion, we observed a robust association between lower pre-dialysis SBP and higher risk for all-cause and cardiovascular mortality in a well-characterized cohort of prevalent haemodialysis patients. Randomized clinical trials are needed to define optimal blood pressure targets in the haemodialysis population.

  View details for DOI 10.1038/jhh.2010.42

  View details for Web of Science ID 000286179500005

  View details for PubMedID 20410919

• Blood Pressure Control in Type 2 Diabetes Mellitus AMERICAN JOURNAL OF KIDNEY DISEASES Chang, T. I., Cheung, A. K., Chertow, G. M. 2010; 56 (6): 1029-1031

  View details for DOI 10.1053/j.ajkd.2010.08.007

  View details for Web of Science ID 000284401800006

  View details for PubMedID 20870328

• Updated comorbidity assessments and outcomes in prevalent hemodialysis patients HEMODIALYSIS INTERNATIONAL Chang, T. I., Paik, J., Greene, T., Miskulin, D. C., Chertow, G. M. 2010; 14 (4): 478-485

  Abstract

  When evaluating clinical characteristics and outcomes in patients on hemodialysis, the prevalence and severity of comorbidity may change over time. Knowing whether updated assessments of comorbidity enhance predictive power will assist the design of future studies. We conducted a secondary data analysis of 1846 prevalent hemodialysis patients from 15 US clinical centers enrolled in the HEMO study. Our primary explanatory variable was the Index of Coexistent Diseases score, which aggregates comorbidities, as a time-constant and time-varying covariate. Our outcomes of interest were all-cause mortality, time to first hospitalization, and total hospitalizations. We used Cox proportional hazards regression. Accounting for an updated comorbidity assessment over time yielded a more robust association with mortality than accounting for baseline comorbidity alone. The variation explained by time-varying comorbidity assessments on time to death was greater than age, baseline serum albumin, diabetes, or any other covariates. There was a less pronounced advantage of updated comorbidity assessments on determining time to hospitalization. Updated assessments of comorbidity significantly strengthen the ability to predict death in patients on hemodialysis. Future studies in dialysis should invest the necessary resources to include repeated assessments of comorbidity.

  View details for DOI 10.1111/j.1542-4758.2010.00468.x

  View details for Web of Science ID 000283174100021

  View details for PubMedID 20955281

• Kidney Disease and Antihypertensive Medication Adherence: The Need for Improved Measurement Tools AMERICAN JOURNAL OF KIDNEY DISEASES Chang, T. I., Winkelmayer, W. C. 2010; 56 (3): 423-426

  View details for DOI 10.1053/j.ajkd.2010.05.006

  View details for Web of Science ID 000281203200002

  View details for PubMedID 20728787

• Kidney Disease, Hospitalized Hypertension, and Cardiovascular Events: Cause or Consequence? CIRCULATION Chertow, G. M., Chang, T. I. 2010; 121 (20): 2160-2161

  View details for DOI 10.1161/CIRCULATIONAHA.110.956904

  View details for Web of Science ID 000278018500002

  View details for PubMedID 20458007

• GFR estimating equations, CKD prevalence and the public health JOURNAL OF INTERNAL MEDICINE Chang, T. I., Chertow, G. M. 2010; 267 (4): 354-356

  View details for DOI 10.1111/j.1365-2796.2009.02172.x

  View details for Web of Science ID 000275518600002

  View details for PubMedID 20433581

• Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects DIABETOLOGIA Chang, T. I., Horal, M., Jain, S. K., Wang, F., Patel, R., Loeken, M. R. 2003; 46 (4): 538-545

  Abstract

  Maternal diabetes increases oxidative stress in embryos. Maternal diabetes also inhibits expression of embryonic genes, most notably, Pax-3, which is required for neural tube closure. Here we tested the hypothesis that oxidative stress inhibits expression of Pax-3, thereby providing a molecular basis for neural tube defects induced by diabetic pregnancy.Maternal diabetes-induced oxidative stress was blocked with alpha-tocopherol (vitamin E), and oxidative stress was induced with the complex III electron transport inhibitor, antimycin A, using pregnant diabetic or non-diabetic mice, primary cultures of neurulating mouse embryo tissues, or differentiating P19 embryonal carcinoma cells. Pax-3 expression was assayed by quantitative RT-PCR, and neural tube defects were scored by visual inspection. Oxidation-induced DNA fragmentation in P19 cells was assayed by electrophoretic analysis.Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and alpha-tocopherol blocked these effects. In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects. In cultured embryo tissues, high glucose-inhibited Pax-3 expression, and this effect was blocked by alpha-tocopherol and GSH-ethyl ester, and Pax-3 expression was inhibited by culture with antimycin A. In differentiating P19 cells, antimycin A inhibited Pax-3 induction but did not induce DNA strand breaks.Oxidative stress inhibits expression of Pax-3, a gene that is essential for neural tube closure. Impaired expression of essential developmental control genes could be the central mechanism by which neural tube defects occur during diabetic pregnancy, as well as other sources of oxidative stress.

  View details for DOI 10.1007/s00125-003-1063-2

  View details for Web of Science ID 000183198600015

  View details for PubMedID 12739027

• Evidence that elevated glucose causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy DIABETES Fine, E. L., Horal, M., Chang, T. I., Fortin, G., Loeken, M. R. 1999; 48 (12): 2454-2462

  Abstract

  Congenital malformations, including neural tube defects (NTDs), are significantly increased in the offspring of diabetic mothers. We previously reported that in the embryos of a mouse model of diabetic pregnancy, NTDs are associated with reduced expression of the gene Pax-3, which encodes a transcription factor that regulates neural tube development, and that reduced expression of Pax-3 leads to neuroepithelial apoptosis. In this study, we used three approaches to test whether glucose alone could be responsible for these adverse effects of diabetes on embryonic development. First, primary culture of embryo tissue in medium containing 15 mmol/l glucose inhibited Pax-3 expression compared with culture in medium containing 5 mmol/l glucose. Second, inducing hyperglycemia in pregnant mice by subcutaneous glucose administration significantly inhibited Pax-3 expression (P < 0.05), as demonstrated by quantitative reverse transcription-polymerase chain reaction assay of Pax-3 mRNA, and also increased neural tube apoptosis (P < 0.05). NTDs were significantly increased in glucose-injected pregnancies when blood glucose levels were >250 mg/dl (P < 0.002) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.37). Third, phlorizin administration to pregnant diabetic mice reduced blood glucose levels and the rate of NTDs. As seen with glucose-injected pregnancies, the rate of NTDs in phlorizin-treated diabetic pregnancies was related to the severity of hyperglycemia, since NTDs were significantly increased in severely hyperglycemic (>250 mg/dl) diabetic pregnancies (P < 0.001) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.35). These two findings, that elevated glucose alone can cause the changes in Pax-3 expression observed during diabetic pregnancy and that the NTD rate rises with significant increases in blood glucose levels, suggest that congenital malformations associated with diabetic pregnancy are caused by disruption of regulatory gene expression in the embryo in response to elevated glucose.

  View details for Web of Science ID 000083880900025

  View details for PubMedID 10580436

• Genotoxicity and diabetic embryopathy: Impaired expression of developmental control genes as a cause of defective morphogenesis SEMINARS IN REPRODUCTIVE ENDOCRINOLOGY Chang, T. I., Loeken, M. R. 1999; 17 (2): 153-165

  Abstract

  Since the advent of insulin therapy for diabetes mellitus, the survival of mothers with diabetes prior to pregnancy and their offspring has greatly improved. Nevertheless, the observation that the earliest stages of organogenesis can be impaired in the offspring of women with diabetes raises the question of how abnormal fuel metabolism disturbs embryogenesis. Research into this process has been made possible in recent years by advances in molecular biology which makes it possible to study gene expression in early embryos, and by the availability of genetically engineered mutant mouse strains. Using these approaches, a model is emerging in which elevated glucose, by disturbing expression of genes which regulate embryonic development and cell cycle progression, causes premature cell death of emerging organ structures, thereby causing defective morphogenesis. Investigation into the signaling mechanisms by which excess glucose metabolism exhibits toxic effects on embryo gene expression will explain how diabetic embryopathy occurs on a molecular and cellular level, as well as increase our understanding of the role of metabolic homeostasis in proper embryonic development.

  View details for Web of Science ID 000083025700006

  View details for PubMedID 10528366