Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial

IMPORTANCE: Few cardiovascular outcomes trials have been conducted for obesity treatments. Withdrawal of 2 marketed drugs has resulted in controversy about the cardiovascular safety of obesity agents. OBJECTIVE: To determine whether the combination of naltrexone and bupropion increases major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) compared with placebo in overweight and obese patients. DESIGN, SETTING, AND PARTICIPANTS: Randomized, multicenter, placebo-controlled, double-blind noninferiority trial enrolling 8910 overweight or obese patients at increased cardiovascular risk from June 13, 2012, to January 21, 2013, at 266 US centers. After public release of confidential interim data by the sponsor, the academic leadership of the study recommended termination of the trial and the sponsor agreed. INTERVENTIONS: An Internet-based weight management program was provided to all participants. Participants were randomized to receive placebo (n=4454) or naltrexone, 32 mg/d, and bupropion, 360 mg/d (n=4456). MAIN OUTCOMES AND MEASURES: Time from randomization to first confirmed occurrence of a MACE. The primary analysis planned to assess a noninferiority hazard ratio (HR) of 1.4 after 378 expected events, with a confidential interim analysis after approximately 87 events (25% interim analysis) to assess a noninferiority HR of 2.0 for consideration of regulatory approval. RESULTS: Among the 8910 participants randomized, mean age was 61.0 years (SD, 7.3 years), 54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes, with a median body mass index of 36.6 (interquartile range, 33.1-40.9). For the 25% interim analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropion-treated patients (0.8%; HR, 0.59; 95% CI, 0.39-0.90). After 50% of planned events, MACE occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57-1.34). Adverse effects were more common in the naltrexone-bupropion group, including gastrointestinal events in 14.2% vs 1.9% (P < .001) and central nervous system symptoms in 5.1% vs 1.2% (P < .001). CONCLUSIONS AND RELEVANCE: Among overweight or obese patients at increased cardiovascular risk, based on the interim analyses performed after 25% and 50% of planned events, the upper limit of the 95% CI of the HR for MACE for naltrexone-bupropion treatment, compared with placebo, did not exceed 2.0. However, because of the unanticipated early termination of the trial, it is not possible to assess noninferiority for the prespecified upper limit of 1.4. Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01601704

Volumetric analysis of LAD-diagonal and LCX-obtuse marginal coronary bifurcations: An intravascular ultrasound study

Fecha errónea en el original

Relationship Between Atheroma Regression and Change in Lumen Size After Infusion of Apolipoprotein A-I Milano

ObjectivesThe aim of this study was to determine the relationship between atheroma regression and arterial wall remodeling.BackgroundInfusion of reconstituted high-density lipoprotein (rHDL) containing recombinant apolipoprotein A-I Milano (AIM) has been reported to promote rapid regression of coronary atherosclerosis. The current study analyzed intravascular ultrasound (IVUS) to define the changes that take place in the arterial wall that accompanied atheroma regression in this study.MethodsForty-seven patients, ages 30 to 75 years, after an acute coronary syndrome were randomized to receive five weekly infusions of placebo or rHDL containing either low- or high-dose AIM. External elastic membrane (EEM) and lumen volumes were compared between coronary IVUS studies at baseline and follow-up.ResultsIn comparison with baseline, infusion of rHDL was associated with a 4.6% reduction in EEM volume. Lumen volume did not change. In 10-mm arterial subsegments with the greatest plaque burden at baseline, atheroma volume regressed by 10.9% with a similar reduction in EEM volume but with no change in lumen size. In contrast, EEM and atheroma volume did not change in the 10-mm segments containing the least plaque burden. The reduction in EEM in the most diseased segments was only apparent in subjects who underwent plaque regression. Reduction in EEM volume correlated with the decreased atheroma volume (r = 0.62), but there was no correlation between change in lumen size and change in plaque volume.ConclusionsRemodeling of the arterial wall is a focal and heterogeneous process. After infusion of rHDL containing AIM, regression of coronary atherosclerosis is accompanied by reverse remodeling of the EEM, resulting in no change in luminal dimensions

American College of Cardiology/ European Society of Cardiology international study of angiographic data compression phase III Measurement of image quality differences at varying levels of data compression

AbstractOBJECTIVESWe sought to investigate up to which level of Joint Photographic Experts Group (JPEG) data compression the perceived image quality and the detection of diagnostic features remain equivalent to the quality and detectability found in uncompressed coronary angiograms.BACKGROUNDDigital coronary angiograms represent an enormous amount of data and therefore require costly computerized communication and archiving systems. Earlier studies on the viability of medical image compression were not fully conclusive.METHODSTwenty-one raters evaluated sets of 91 cine runs. Uncompressed and compressed versions of the images were presented side by side on one monitor, and image quality differences were assessed on a scale featuring six scores. In addition, the raters had to detect pre-defined clinical features. Compression ratios (CR) were 6:1, 10:1 and 16:1. Statistical evaluation was based on descriptive statistics and on the equivalence t-test.RESULTSAt the lowest CR (CR 6:1), there was already a small (15%) increase in assigning the aesthetic quality score indicating “quality difference is barely discernible—the images are equivalent.” At CR 10:1 and CR 16:1, close to 10% and 55%, respectively, of the compressed images were rated to be “clearly degraded, but still adequate for clinical use” or worse. Concerning diagnostic features, at CR 10:1 and CR 16:1 the error rate was 9.6% and 13.1%, respectively, compared with 9% for the baseline error rate in uncompressed images.CONCLUSIONSCompression at CR 6:1 provides equivalence with the original cine runs. If CR 16:1 were used, one would have to tolerate a significant increase in the diagnostic error rate over the baseline error rate. At CR 10:1, intermediate results were obtained

1015-72 Elevated Plasma Homocysteine: An Important Independent Risk Factor for Coronary Artery Disease in the Elderly

BackgroundHigh plasma homocysteine (HCY) concentration is an established risk factor for premature vascular disease which can be reduced using vitamin therapy. The role of increased homocysteine as a coronary risk factor in the elderly, however, remains uncertain.MethodsWe studied 228 patients with angiographically documented coronary disease (≥ 70% stenosis in at least one major epicardial vessel). These included 136 patients less than, and 92 greater than 65 years old. Patients were compared to 223 healthy controls 199 (&lt;65) and 24 (&gt; 65). The presence of traditional risk factors including hypertension, smoking, hypercholesterolemia and diabetes mellitus were noted. Total fasting plasma homocysteine was measured in all subjects. A gender-adjusted threshold for a high homocysteine level was defined as the 80th percentile for healthy controls (corresponding to a level of 11.7 μmol/L in women and 13.6 μmo1/L in men).ResultsAge&lt;65Age&gt;65PatientsControlsPatientsControlsHomocysteine12.2±4.0*11.0±3.414.2±4.6*11.9±3.6High HCY(%)33*2050†25Odds Ratios2.0*NA2.9*NAConfidence Interval1.2–3.2NA1.0–8.3NA*p&lt;am vs controls†p&lt;0.03ConclusionsHomocysteine concentrations are elevated in patients with coronary artery disease older than 65 years in age. A high value confers an independent three-fold risk for coronary disease in this patient group. Accordingly, intervention studies designed to reduce plasma homocysteine levels should not exclude the elderly

Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial.

BACKGROUND: Diabetes is a multisystem disorder associated with a nearly twofold excess risk for a broad range of adverse cardiovascular outcomes including coronary heart disease, stroke, and cardiovascular death. Liraglutide is a human glucagon-like peptide receptor analog approved for use in patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN: To formally assess the cardiovascular safety of liraglutide, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial was commenced in 2010. LEADER is a phase 3B, multicenter, international, randomized, double-blind, placebo-controlled clinical trial with long-term follow-up. Patients with T2DM at high risk for cardiovascular disease (CVD) who were either drug naive or treated with oral antihyperglycemic agents or selected insulin regimens (human NPH, long-acting analog, or premixed) alone or in combination with oral antihyperglycemics were eligible for inclusion. Randomized patients are being followed for up to 5 years. The primary end point is the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. CONCLUSIONS: LEADER commenced in September 2010, and enrollment concluded in April 2012. There were 9,340 patients enrolled at 410 sites in 32 countries. The mean age of patients was 64.3 ± 7.2 years, 64.3% were men, and mean body mass index was 32.5 ± 6.3 kg/m2. There were 7,592 (81.3%) patients with prior CVD and 1,748 (18.7%) who were high risk but without prior CVD. It is expected that LEADER will provide conclusive data regarding the cardiovascular safety of liraglutide relative to the current standard of usual care for a global population of patients with T2DM