• Coronary Artery Disease
• Cardiology Clinical Trials

Observational studies have suggested that spontaneously higher high-density lipoprotein cholesterol (HDL-C) levels are associated with lower cardiovascular (CV) risk; however, it is uncertain whether raising HDL-C by a pharmacologic approach reduces the risk. The cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib raised HDL-C by approximately 30% in Phase 2 trials [Lüscher TF et al. Eur Heart 2012; Fayad ZA et al. Lancet 2011] without affecting blood pressure (BP) or neurohormones. The objective of the Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome [dal-OUTCOMES; NCT00658515; Schwartz GG et al. N Engl J Med 2012] presented by Gregory G. Schwartz, MD, PhD, VA Medical Center and University of Colorado School of Medicine, Denver, Colorado, USA, was to compare the effects of dalcetrapib versus placebo in patients with recent acute coronary syndrome (ACS).

Following a single-blind placebo run-in period of 4 to 12 weeks, patients with recent ACS were randomized to dalcetrapib (n=7938) versus placebo (n=7933) in addition to evidence-based background therapy. Patients with triglycerides >400 mg/dL or under treatment with niacin, fibrates, or bile acid sequestrants were excluded. The primary composite endpoint was time to first occurrence of coronary heart disease death, nonfatal myocardial infarction (MI), ischemic stroke, hospitalization for unstable angina, and cardiac arrest with resuscitation. Secondary endpoints were all-cause mortality and coronary revascularization. The study was terminated for futility at the second prespecified interim analysis (median follow-up 31 months) with 1135 primary endpoint events (71% of projected) since the probability of demonstrating a benefit with dalcetrapib was <20%.

Baseline characteristics, concurrent treatments, and baseline lipid levels were well balanced between the treatment groups. Dalcetrapib raised HDL-C from 43 mg/dL to 59 mg/dL compared with only a slight increase from 43 mg/dL to 45 mg/dL in the placebo group. Low-density lipoprotein cholesterol (LDL-C) averaged 76 mg/dL at baseline in both groups and differed minimally between groups during the study. Despite the effect of dalcetrapib on HDL-C, there was no significant difference in the cumulative percentage of patients reaching the primary endpoint with dalcetrapib (3-year event rate 9.2%) versus placebo (9.1%; HR, 1.04; 95% CI, 0.93 to 1.16; p=0.52).

There were no significant differences in the dalcetrapib versus placebo group in any of the individual components of the primary composite outcome or in the secondary outcomes (Table 1).

Analysis of the annualized event rates relative to baseline or on-treatment HDL-C levels showed that there was no association between baseline HDL-C and risk of the primary endpoint. Mean systolic BP was 0.6 mm Hg higher in patients treated with dalcetrapib versus placebo (p<0.001). After 3 months on assigned treatment, the median high sensitivity C-reactive protein (hs-CRP) level was 0.2 mg/L higher in the dalcetrapib versus placebo group (p<0.001).

In this study dalcetrapib raised HDL-C by about 30% with a minimal effect on LDL-C, but had no effect on the risk of major CV events in patients with recent ACS. HDL-C concentration did not predict risk in this study population. Slightly higher systolic BP and CRP caused by dalcetrapib might represent adverse effects of CETP inhibition. This is now the second large trial with a CETP inhibitor that failed to show benefit (see MD Conference Express Coverage of AHA 2007 Issue coverage of the ILLUMINATE trial). The REVEAL-HPS 3/TIMI 55 trial continues to test anacetrapib, which has more robust LDL-C lowering in addition to its HDL-C raising effects, in an ongoing trial of 30,000 patients with established vascular disease.

Together with the recently terminated AIM-HIGH study in which niacin raised HDL-C by approximately 15% but had no effect on CV events [The AIM-HIGH Investigators. N Engl J Med 2011], the dal-OUTCOMES study challenges the long-held assumption that raising HDL-C concentration favorably modifies CV risk. However, HDL-C concentration may not reflect HDL function, such as reverse cholesterol transport from tissues to liver. It remains to be determined whether measures of HDL function bore a relationship to risk in dal-OUTCOMES and/or were affected by dalcetrapib treatment.

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