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Acharjee S.,Einstein Medical Center Philadelphia | Boden W.E.,Albany Medical College | Hartigan P.M.,Cooperative Studies Program Coordinating Center | Teo K.K.,McMaster University | And 8 more authors.
Journal of the American College of Cardiology | Year: 2013

Objectives This study sought to assess the independent effect of high-density lipoprotein-cholesterol (HDL-C) level on cardiovascular risk in patients with stable ischemic heart disease (SIHD) who were receiving optimal medical therapy (OMT). Background Although low HDL-C level is a powerful and independent predictor of cardiovascular risk, recent data suggest that this may not apply when low-density lipoprotein-cholesterol (LDL-C) is reduced to optimal levels using intensive statin therapy. Methods We performed a post-hoc analysis in 2,193 men and women with SIHD from the COURAGE trial. The primary outcome measure was the composite of death from any cause or nonfatal myocardial infarction (MI). The independent association between HDL-C levels measured after 6 months on OMT and the rate of cardiovascular events after 4 years was assessed. Similar analyses were performed separately in subjects with LDL-C levels below 70 mg/dl (1.8 mmol/l). Results In the overall population, the rate of death/MI was 33% lower in the highest HDL-C quartile as compared with the lowest quartile, with quartile of HDL-C being a significant, independent predictor of death/MI (p = 0.05), but with no interaction for LDL-C category (p = 0.40). Among subjects with LDL-C levels <70 mg/dl, those in the highest quintile of HDL-C had a 65% relative risk reduction in death or MI as compared with the lowest quintile, with HDL-C quintile demonstrating a significant, inverse predictive effect (p = 0.02). Conclusions In this post-hoc analysis, patients with SIHD continued to experience incremental cardiovascular risk associated with low HDL-C levels despite OMT during long-term follow-up. This relationship persisted and appeared more prominent even when LDL-C was reduced to optimal levels with intensive dyslipidemic therapy. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657). © 2013 by the American College of Cardiology Foundation.


Wilt T.J.,University of Minnesota | Brawer M.K.,Urologic | Jones K.M.,Cooperative Studies Program Coordinating Center | Barry M.J.,Massachusetts General Hospital | And 15 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. METHODS: From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostatecancer mortality. RESULTS: During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P = 0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P = 0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P = 0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P = 0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. CONCLUSIONS: Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.) Copyright © 2012 Massachusetts Medical Society.


Stergiopoulos K.,State University of New York at Stony Brook | Boden W.E.,Samuel ratton Medical Center | Hartigan P.,Cooperative Studies Program Coordinating Center | Mobius-Winkler S.,University of Leipzig | And 5 more authors.
JAMA Internal Medicine | Year: 2014

IMPORTANCE Myocardial ischemia in patients with stable coronary artery disease (CAD) has been repeatedly associated with impaired survival. However, it is unclear if revascularization with percutaneous coronary intervention (PCI) to relieve ischemia improves outcomes compared with medical therapy (MT). OBJECTIVE The objective of this study was to compare the effect of PCI and MT with MT alone exclusively in patients with stable CAD and objectively documented myocardial ischemia on clinical outcomes. DATA SOURCES MEDLINE, Cochrane, and PubMed databases from 1970 to November 2012. Unpublished data were obtained from investigators. STUDY SELECTION Randomized clinical trials of PCI and MT vs MT alone for stable coronary artery disease in which stents and statins were used in more than 50% of patients. DATA EXTRACTION For studies in which myocardial ischemia diagnosed by stress testing or fractional flow reserve was required for enrollment, descriptive and quantitative data were extracted from the published report. For studies in which myocardial ischemia was not a requirement for enrollment, authors provided data for only those patients with ischemia determined by stress testing prior to randomization. The outcomes analyzed included death from any cause, nonfatal myocardial infarction (MI), unplanned revascularization, and angina. Summary odds ratios (ORs) were obtained using a random-effects model. Heterogeneity was assessed using the Q statistic and I2. RESULTS In 5 trials enrolling 5286 patients, myocardial ischemia was diagnosed in 4064 patients by exercise stress testing, nuclear or echocardiographic stress imaging, or fractional flow reserve. Follow-up ranged from 231 days to 5 years (median, 5 years). The respective event rates for PCI with MT vs MT alone for death were 6.5%and 7.3%(OR, 0.90 [95%CI, 0.71-1.16); for nonfatal MI, 9.2%and 7.6%(OR, 1.24 [95%CI, 0.99-1.56]); for unplanned revascularization, 18.3%and 28.4%(OR, 0.64 [95%CI, 0.35-1.17); and for angina, 20.3%and 23.3%(OR, 0.91 [95%CI, 0.57-1.44]). CONCLUSIONS AND RELEVANCE In patients with stable CAD and objectively documented myocardial ischemia, PCI with MT was not associated with a reduction in death, nonfatal MI, unplanned revascularization, or angina compared with MT alone. Copyright © 2014 American Medical Association. All rights reserved.


Carson J.L.,University of New Brunswick | Terrin M.L.,University of Maryland, Baltimore | Noveck H.,University of New Brunswick | Sanders D.W.,University of Western Ontario | And 14 more authors.
New England Journal of Medicine | Year: 2011

Background: The hemoglobin threshold at which postoperative red-cell transfusion is warranted is controversial. We conducted a randomized trial to determine whether a higher threshold for blood transfusion would improve recovery in patients who had undergone surgery for hip fracture. Methods: We enrolled 2016 patients who were 50 years of age or older, who had either a history of or risk factors for cardiovascular disease, and whose hemoglobin level was below 10 g per deciliter after hip-fracture surgery. We randomly assigned patients to a liberal transfusion strategy (a hemoglobin threshold of 10 g per deciliter) or a restrictive transfusion strategy (symptoms of anemia or at physician discretion for a hemoglobin level of <8 g per deciliter). The primary outcome was death or an inability to walk across a room without human assistance on 60-day follow-up. Results: A median of 2 units of red cells were transfused in the liberal-strategy group and none in the restrictive-strategy group. The rates of the primary outcome were 35.2% in the liberal-strategy group and 34.7% in the restrictive-strategy group (odds ratio in the liberal-strategy group, 1.01; 95% confidence interval [CI], 0.84 to 1.22), for an absolute risk difference of 0.5 percentage points (95% CI, -3.7 to 4.7). The rates of in-hospital acute coronary syndrome or death were 4.3% and 5.2%, respectively (absolute risk difference, -0.9%; 99% CI, -3.3 to 1.6), and rates of death on 60-day follow-up were 7.6% and 6.6%, respectively (absolute risk difference, 1.0%; 99% CI, -1.9 to 4.0). The rates of other complications were similar in the two groups. Conclusions: A liberal transfusion strategy, as compared with a restrictive strategy, did not reduce rates of death or inability to walk independently on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk. (Funded by the National Heart, Lung, and Blood Institute; FOCUS ClinicalTrials.gov number, NCT00071032.) Copyright © 2011 Massachusetts Medical Society. All rights reserved.


Azad N.,Hines Veterans Administration Hospital | Agrawal L.,Hines Veterans Administration Hospital | Emanuele N.V.,Hines Veterans Administration Hospital | Klein R.,University of Wisconsin - Madison | And 2 more authors.
Diabetologia | Year: 2014

Aims/hypothesis: The aim of this study was to test the hypothesis that intensive glycaemic control (INT) and higher plasma C-peptide levels in patients with poorly controlled diabetes would be associated with better eye outcomes. Methods: The incidence and progression of diabetic retinopathy (DR) was assessed by grading seven-field stereoscopic fundus photographs at baseline and 5 years later in 858 of 1,791 participants in the Veterans Affairs Diabetes Trial (VADT). Results: After adjustment for all covariates, risk of progression (but not incidence) of DR increased by 30% for each 1% increase in baseline HbA 1c (OR 1.3; 95% CI 1.123, 1.503; p∈=∈0.0004). Neither assignment to INT nor age was independently associated with DR in the entire cohort. However, INT showed a biphasic interaction with age. The incidence of DR was decreased in INT participants ≤55 years of age (OR 0.49; 95% CI 0.24, 1.0) but increased in those ≥70 years old (OR 2.88; 95% CI 1.0, 8.24) (p∈=∈0.0043). The incidence of DR was reduced by 67.2% with each 1 pmol/ml increment in baseline C-peptide (OR 0.328; 95% CI 0.155, 0.7; p∈=∈0.0037). Baseline C-peptide was also an independent inverse risk factor for the progression of DR, with a reduction of 47% with each 1 pmol/ml increase in C-peptide (OR 0.53; 95% CI 0.305, 0.921; p∈=∈0.0244). Conclusions/interpretation: Poor glucose control at baseline was associated with an increased risk of progression of DR. INT was associated with a decreased incidence of DR in younger patients but with an increased risk of DR in older patients. Higher C-peptide at baseline was associated with reduced incidence and progression of DR. © 2014 Springer-Verlag Berlin Heidelberg (outside the USA).


Saremi A.,Phoenix VA Health Care System | Bahn G.D.,Cooperative Studies Program Coordinating Center | Reaven P.D.,Phoenix VA Health Care System
Diabetes Care | Year: 2016

OBJECTIVE To determine whether a link exists between serious hypoglycemia and progression of atherosclerosis in a substudy of the Veterans Affairs Diabetes Trial (VADT) and to examine whether glycemic control during the VADT modified the association between serious hypoglycemia and coronary artery calcium (CAC) progression. RESEARCH DESIGN AND METHODS Serious hypoglycemia was defined as severe episodes with loss of consciousness or requiring assistance or documented glucose <50 mg/dL. Progression of CAC was determined in 197 participants with baseline and follow-up computed tomography scans. RESULTS During an average follow-up of 4.5 years between scans, 97 participants reported severe hypoglycemia (n = 23) or glucose <50mg/dL (n = 74). Serious hypoglycemia occurred more frequently in the intensive therapy group than in the standard treatment group (74%vs. 21%, P <0.01). Serious hypoglycemiawas not associated with progression of CAC in the entire cohort, but the interaction between serious hypoglycemia and treatment was significant (P <0.01). Participants with serious hypoglycemia in the standard therapy group, but not in the intensive therapy group, had ∼50% greater progression of CAC than those without serious hypoglycemia (median 11.15 vs. 5.4 mm 3, P = 0.02). Adjustment for all baseline differences, including CAC, or time-varying risk factors during the trial, did not change the results. Examining the effect of serious hypoglycemia by on-trial HbA1c levels (cutoff 7.5%) yielded similar results. In addition, a dose-response relationship was found between serious hypoglycemia and CAC progression in the standard therapy group only. CONCLUSIONS Despite a higher frequency of serious hypoglycemia in the intensive therapy group, serious hypoglycemia was associated with progression of CAC in only the standard therapy group. © 2016 by the American Diabetes Association.


Zhou B.,Yale University | Zhou B.,Cooperative Studies Program Coordinating Center | Fine J.,University of North Carolina at Chapel Hill | Latouche A.,French National Conservatory of Arts and Crafts | Labopin M.,Paris University
Biostatistics | Year: 2012

A population average regression model is proposed to assess the marginal effects of covariates on the cumulative incidence function when there is dependence across individuals within a cluster in the competing risks setting. This method extends the Fine-Gray proportional hazards model for the subdistribution to situations, where individuals within a cluster may be correlated due to unobserved shared factors. Estimators of the regression parameters in the marginal model are developed under an independence working assumption where the correlation across individuals within a cluster is completely unspecified. The estimators are consistent and asymptotically normal, and variance estimation may be achieved without specifying the form of the dependence across individuals. A simulation study evidences that the inferential procedures perform well with realistic sample sizes. The practical utility of the methods is illustrated with data from the European Bone Marrow Transplant Registry. The Author 2011. Published by Oxford University Press. All rights reserved.


Zhou B.,Yale University | Zhou B.,Cooperative Studies Program Coordinating Center | Fine J.,University of North Carolina at Chapel Hill | Laird G.,Bristol Myers Squibb
Statistics in Medicine | Year: 2013

This paper concerns using modified weighted Schoenfeld residuals to test the proportionality of subdistribution hazards for the Fine-Gray model, similar to the tests proposed by Grambsch and Therneau for independently censored data. We develop a score test for the time-varying coefficients based on the modified Schoenfeld residuals derived assuming a certain form of non-proportionality. The methods perform well in simulations and a real data analysis of breast cancer data, where the treatment effect exhibits non-proportional hazards. © 2013 John Wiley & Sons, Ltd.


Li X.,Cooperative Studies Program Coordinating Center | Hedeker D.,University of Illinois at Chicago
Statistics in Medicine | Year: 2012

In studies using ecological momentary assessment (EMA), or other intensive longitudinal data collection methods, interest frequently centers on changes in the variances, both within-subjects and between-subjects. For this, Hedeker et al. (Biometrics 2008; 64: 627-634) developed an extended two-level mixed-effects model that treats observations as being nested within subjects and allows covariates to influence both the within-subjects and between-subjects variance, beyond their influence on means. However, in EMA studies, subjects often provide many responses within and across days. To account for the possible systematic day-to-day variation, we developed a more flexible three-level mixed-effects location scale model that treats observations within days within subjects, and allows covariates to influence the variance at the subject, day, and observation level (over and above their usual effects on means) using a log-linear representation throughout. We provide details of a maximum likelihood solution and demonstrate how SAS PROC NLMIXED can be used to achieve maximum likelihood estimates in an alternative parameterization of our proposed three-level model. The accuracy of this approach using NLMIXED was verified by a series of simulation studies. Data from an adolescent mood study using EMA were analyzed to demonstrate this approach. The analyses clearly show the benefit of the proposed three-level model over the existing two-level approach. The proposed model has useful applications in many studies with three-level structures where interest centers on the joint modeling of the mean and variance structure. © 2012 John Wiley & Sons, Ltd.


Saremi A.,Phoenix VA Health Care System | Bahn G.,Cooperative Studies Program Coordinating Center | Reaven P.D.,Phoenix VA Health Care System
Diabetes Care | Year: 2012

OBJECTIVE - To determine the effect of statin use on progression of vascular calcification in type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS - Progression of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) was assessed according to the frequency of statin use in 197 participants with T2DM. RESULTS - After adjustment for baseline CAC and other confounders, progression of CAC was significantly higher in more frequent statin users than in less frequent users (mean ± SE, 8.2 ± 0.5 mm 3 vs. 4.2 ± 1.1 mm3; P < 0.01). AAC progression was in general not significantly increased with more frequent statin use; in a subgroup of participants initially not receiving statins, however, progression of both CAC and AAC was significantly increased in frequent statin users. CONCLUSIONS - More frequent statin use is associated with accelerated CAC in T2DM patients with advanced atherosclerosis. © 2012 by the American Diabetes Association.

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