Larger benefit of CETP inhibitor with longer follow-up

Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease

Literature - HPS3/TIMI55-REVEAL Collaborative group: Sammons E, Hopewell JC, Chen F et al., - Eur Heart J. 2021, doi: 10.1093/eurheartj/ehab863

The benefit of the CETP inhibitor anacetrapib on major coronary events increases with longer follow-up, shown in a post-trial analysis of patients who had been randomized to anacetrapib compared to those on placebo in the REVEAL trial.

Introduction and methods


The cholesterol ester transfer protein (CETP) inhibitor anacetrapib lowers non-HDL-c, in particular LDL-c. In the HPS3/TIMI55-REVEAL trial , addition of anacetrapib to intensive statin therapy reduced the risk of major coronary events by 9% (95%CI: 3-15%, P=0.004) compared to placebo during a median follow-up of 4.1 years [1.2]. It is slowly eliminated from the circulation because of its accumulation in adipose tissue, which explains lipid-modifying effects years after stopping prolonged treatment [3-5].

In this study, the efficacy and safety are reported of an additional 2 years follow-up following the discontinuation of treatment in the REVEAL study.

Study design

In the REVEAL trial, 30,449 patients ≥50 years with pre-existing ASCVD were randomized to anacetrapib or matching placebo in addition to atorvastatin regimen. After the final follow-up visit, treatment with anacetrapib or placebo and atorvastatin was stopped. In the post-trial follow-up, participants and their doctors remained blinded to the previous randomized treatment. During the post-trial period, information was collected for 26,129 consenting participants by telephone interview or medical record review. Follow-up was a median of 4.1 years for the in -trial period, 2.3 years for the post-trial period and 6.3 years for the combined periods.


The pre-specified outcome for this analysis was the first major coronary event, which was the composite of coronary death, myocardial infarction, or coronary revascularization) during the combined in-trial and post-trial follow-up period.

Main results

First major coronary event

  • During the post-trial follow-up, there was a further reduction in first major coronary events in patients who had been randomized to anacetrapib compared to those allocated to placebo (RR 0.80, 95%CI:0.71-0.90, P<0.001).
  • During combined follow-up, randomization to anacetrapib for a median of 4.1 years resulted in a 12% reduction in the rate of first major coronary events (RR 0.88, 95%CI:0.83-0.93, P<0.001) with larger reductions in the later years of follow-up (Pfor trend across RR by year of first event=0.01).

Secondary CV outcomes

  • Reduction in the first major atherosclerotic event during the in-trial period was 7% (RR 0.93, 95%CI:0.86-1.00, P=0.052), was 16% in the post-trial period (RR 0.84, 95%CI:0.75-0.95, P=0.005), leading to a overall risk reduction of 9% (RR 0.91, 95%CI:0.85-0.96, P=0.002).
  • Major vascular events were reduced by 7% during the in-trial period (RR 0.93, 95%CI: 0.88-0.99, P=0.02), by 18% in the post-trial period (RR 0.82, 95%CI: 0.74-0.91, P<0.001), resulting in an overall risk reduction of 10% (RR 0.90, 95%CI:0.86-0.95, P<0.001).

Recurrent vascular events

  • First and subsequent major coronary events combined were reduced by 14% in patients allocated to anacetrapib (RR 0.86, 95%CI:0.81-0.92, P<0.001).
  • Treatment of 1000 patients with anacetrapib for a median of 4.1 years results in 17.9 (95%CI:9.9-26.0) people avoiding 27.5 (95%CI:18.5-36.5) major coronary events during a median of 6.3 years follow-up.

Mortality, cancer and other serious adverse events

  • During the post-trial follow-up, a benefit of anacetrapib on coronary death was observed (RR 0.78, 95%CI:0.62-0.98), and at the end of the combined follow-up there were fewer coronary deaths in patients randomized to anacetrapib (RR 0.88, 95%CI:0.79-1.00, P=0.04).
  • Also, there were fewer deaths from CV causes in patients who had been randomized to anacetrapib, but there was no effect on death due to non-vascular causes.
  • There was no evidence of adverse effects on cancer, or hypertension-related or other serious adverse events.


Long-term follow-up of patients in the REVEAL trial showed that patients who had been randomized to anacetrapib had reduced risk of major coronary events compared to patients who had been randomized to placebo. No safety signals emerged with longer follow-up.

The authors conclude that these results emphasize the importance of sufficiently long treatment and follow-up in randomized trials of lipid-modifying medication in order to full assess benefits and potential harms.


1. Bowman L, Hopewell JC, Chen F et al.; HPS37TIMI55-REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017;377:1217–1227.

2. Bowman L, Chen F, Sammons E et al.; REVEAL Collaborative Group. Randomized Evaluation of the Effects of Anacetrapib through Lipid modification (REVEAL)—a large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular dis ease: trial design, recruitment, and baseline characteristics. Am Heart J 2017; 187:182–190.

3. Krishna R, Gheyas F, Liu Y et al. Chronic administration of anacetrapib is associ ated with accumulation in adipose and slow elimination. Clin Pharmacol Ther 2017;102:832–840.

4. Gotto AM, Cannon CP, Li XS et al.; DEFINE Investigators. Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Am J Cardiol 2014;113: 76–83.

5. Barter PJ, Waters DD. Variations in time to benefit among clinical trials of cholesterol-lowering drugs. J Clin Lipidol 2018;12:857–862

Find this article online at Eur Heart J

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