Anacetrapib reduces major coronary events in high-risk CVD patients
Late-breaking results from a multinational trial show for the first time that adding anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, to intensive statin therapy reduces cardiovascular (CV) events in high-risk patients, with the possibility of providing greater benefit with longer duration of treatment.
Results of the REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification) trial, presented at the European Society of Cardiology Congress 2017 held in Barcelona, Spain, showed that adding anacetrapib (100 mg daily) to effective doses of atorvastatin produced a 9 percent proportional reduction in the incidence of the primary outcome of major coronary event (a composite of coronary death, MI, or coronary revascularization) vs placebo (10.8 vs 11.8 percent; p=0.004) at the end of 4 years. [N Engl J Med 2017; doi:10.1056/NEJMoa1706444]
Coronary death or MI was reduced by 11 percent with anacetrapib vs placebo (6.1 vs 6.9 percent; p=0.008), while coronary revascularization was reduced by 10 percent (7.1 vs 7.9 percent; p=0.01).
The double-blind, placebo-controlled trial included 30,449 men and women aged over 50 years with established atherosclerotic vascular disease recruited from more than 400 hospitals in the UK, US, Canada, China, Germany, Italy, and Scandinavia. The patients were effectively stabilized on atorvastatin (20 or 80 mg; 10 or 20mg daily in China; mean baseline HDL-cholesterol [HDL-C], LDL-cholesterol [LDL-C] and non–HDL-C were 1.0, 1.6 and 2.4 mmol/L, respectively).
“The findings of REVEAL are in marked contrast to the disappointing results of previous trials of other CETP inhibitors, which were stopped after about 2 years due to unexpected hazards or an apparent lack of efficacy,” said REVEAL’s co-principal investigator Professor Martin Landray of the University of Oxford, UK.
“The full effects of anacetrapib were not seen until after the first year, like in statin trials. Furthermore, the proportional reduction in coronary death or MI relative to the absolute reduction in non-HDL-C was similar to that shown in other LDL-C–lowering trials, suggesting that the large increase in HDL-C levels produced by anacetrapib does not have much impact on risk,” he remarked.
“Nevertheless, the possible contribution of HDL-C–raising to CV benefit is not excluded if anacetrapib-induced lowering of LDL particle species engenders elevation in the atherogenicity and concentrations of specific LDL particle subfractions, as shown in earlier studies,” commented discussant Professor John Chapman of the University of Pierre and Marie Curie, France.
At trial midpoint, HDL-C and non–HDL-C levels were 104 percent higher (+1.1 mmol/L) and 18 percent lower, respectively, in the anacetrapib vs control group. The mean LDL-C level was 41 percent lower in the anacetrapib vs control group as measured using direct assay (which underestimated the LDL-C level among patients treated with anacetrapib), and 17 percent lower as measured by beta quantification in a randomly selected subgroup of 2,000 patients. Adding anacetrapib to statin therapy also slightly reduced the risk of new-onset diabetes mellitus (5.3 percent vs 6 percent with placebo; p=0.05).
“Anacetrapib was well tolerated. There was no evidence of major clinical safety issues, no increase in death, cancer or other serious medical events, and no effect on the liver, macular degeneration or cognitive function. The small increase in blood pressure observed did not translate to hypertensive serious adverse events, and the small reduction in kidney function also did not result in renal failure adverse events,” reiterated Landray.