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Macrovascular Residual Risk Studies

16 October 2017
REVEAL: modest benefit on major coronary events with anacetrapib
In the REVEAL (Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification) trial, the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib reduced major coronary events by 9% against a background of well-controlled low-density lipoprotein cholesterol (LDL-C) levels with intensive statin therapy. However, this modest benefit was only observed after 2 years on treatment.
HPS3/TIMI55-REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017; doi: 10.1056/NEJMoa1706444. [Epub ahead of print]
Objective: To investigate the clinical efficacy and safety of anacetrapib (100 mg once daily) in patients with pre-existing atherosclerotic vascular disease treated with effective statin therapy.
Study design: Randomized, double-blind, placebo-controlled trial. Patients who had a total cholesterol of ≤155 mg/dl (4.0 mmol/L) at the end of a pre-randomization run-in phase were randomly allocated to anacetrapib or placebo. 
Study population: 30,449 adults (mean age 67 years, 88% with coronary heart disease and 37% with diabetes) with a history of myocardial infarction, cerebrovascular atherosclerotic disease, peripheral artery disease, or diabetes with symptomatic coronary heart with well controlled LDL-C levels (61 mg/dl or 1.58 mmol/l) at baseline, were randomized at 431 sites in Europe, North America, and China.
Efficacy variables: The primary outcome was the time to first major coronary event, a composite of coronary death, myocardial infarction [MI], or coronary revascularization.
Secondary outcomes were major atherosclerotic events (a composite of coronary death, MI, or presumed ischaemic stroke), presumed ischemic stroke, and major vascular events (a composite of major coronary events or presumed ischaemic stroke).
Methods: The trial assumed an annual rate of major coronary events of 1.8% in the placebo group and that a sample size of 30,000 patients with a median follow-up of 4 years would provide the trial with a power of 88% at a two-tailed p-value of <0.01 (and 96% power at p<0.05) to detect a 15% lower risk of major coronary events with anacetrapib versus placebo. The primary analysis was an intention-to-treat analysis using the log-rank method of the time to the first primary outcome.  If the between-group difference for this outcome was significant at a two-tailed p-value of <0.05, the secondary outcome of major atherosclerotic events was evaluated.
Main results:

The median duration of follow-up was 4.1 years (mean, 3.8). Over this time, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval [CI], 0.85 to 0.97; P=0.004). The effect of anacetrapib on components of the primary outcome are summarized in Table 1.

Table 1. Effect of anacetrapib on components of the primary outcome






Rate ratio

(95% CI)


No. (%) with event




Primary outcome

1803 (11.8)

1640 (10.8)

0.91 (0.85–0.97)


Coronary death

420 (2.8)

388 (2.5)

0.92 (0.80–1.06)



769 (5.1)

669 (4.4)

0.87 (0.78–0.96)


Coronary death or MI

1048 (6.9)

934 (6.1)

0.89 (0.81–0.97)


Coronary revascularization

1201 (7.9)

1081 (7.1)

0.90 (0.83–0.97)


Presumed ischaemic stroke

489 (3.2)

485 (3.2)

0.90 (0.87-1.12)

Not available

At the trial midpoint, anacetrapib treatment increased high-density lipoprotein cholesterol (HDL-C) by 104% (absolute increase 43 mg/dl or 1.12 mmol/l), reduced non-HDL-C by 18% (absolute decrease 17 mg/dl or 0.44 mmol/l), and reduced LDL-C by 41% (absolute decrease 26 mg/dl or 0.68 mmol/l, measured using direct methods). When LDL-C was measured by ultracentrifugation with apolipoprotein (apo) B-containing particle precipitation in 2000 post-therapy samples, the LDL-C reduction was 17%.

Treatment with anacetrapib was not associated with significant effects on mortality due to cardiovascular causes (3.4% with anacetrapib vs. 3.7% with placebo, p=0.17), non-cardiovascular causes (4.0% vs. 3.9%, p=0.77), or all causes combined (7.4% vs. 7.6%, p=0.46). There was no significant effect on the incidence of fatal or nonfatal cancer (6.4% vs. 6.3%, p=0.71). The incidence of adverse events by category did not differ significantly between anacetrapib or placebo.

There was reduction in the incidence of new-onset diabetes in the anacetrapib group compared with placebo (5.3% vs. 6.0%; rate ratio, 0.89; 95% CI, 0.79 to 1.00; p=0.0496). Anacetrapib was also associated with slightly higher blood-pressure levels compared with placebo (by 0.7 mmHg for systolic blood pressure and 0.3 mmHg for diastolic blood pressure) at the final visit, although there was no significant difference in the rates of serious adverse events attributed to hypertension (1.0% in the anacetrapib group vs. 0.9% in the placebo group).
Authors’ conclusion: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo.


The results of the REVEAL trial indicate a modest benefit with anacetrapib against a background of well controlled LDL-C levels in secondary prevention patients. Treatment was well tolerated, albeit there was still a signal for elevated blood pressure, as seen with other CETP inhibitors (torcetrapib and evacetrapib), although no increase in serious adverse events related to hypertension compared with placebo (statin alone) was observed.

There are two key questions. First, why was REVEAL significant, unlike ACCELERATE with evacetrapib, with a similar profile of lipid changes?1 REVEAL was much larger than other CETP-inhibitor trials (30,449 patients versus 12,092 in the ACCELERATE trial) and the duration of the trial was much longer than ACCELERATE (4.1 versus 2.2 years). Moreover, the benefit in REVEAL became apparent only after 2 years of treatment. Thus, with the larger number of events over an extended duration it is more likely that the benefit of treatment would have been significant, from a statistical perspective, in REVEAL.

Second, was the benefit explained by the change in LDL-C – or were other lipid changes also relevant? In their discussion of the trial, the authors suggest that LDL-C reduction may be the prime mediator of the outcome of REVEAL. However, the CETP inhibitors were originally developed to target HDL-C; indeed, the mechanism of this class of drug involves inhibition of the heteroexchange of cholesteryl ester from HDL to very low-density lipoproteins (VLDL) or LDL. Given that patients had well controlled LDL-C levels at baseline, the benefit could also be attributed to reduction in the cholesterol load of VLDL and their remnants, as suggested by this month’s FOCUS article.2

Does anacetrapib represent a therapeutic option for management of lipid-related residual cardiovascular risk? Given that there were only 163 fewer primary events with anacetrapib during more than 4 years of follow in REVEAL, and that anacetrapib has been shown to accumulate in adipose tissue with prolonged use,3 suggests that this is unlikely. It is clear that we need other approaches focusing on non-LDL-related residual cardiovascular risk.


1. Lincoff AM, Nicholls SJ, Riesmeyer JS et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med 2017;376:1933-1942.

2. Lawler PR, Akinkuolie AO, Chu AY et al. Atherogenic lipoprotein determinants of cardiovascular disease and residual risk among individuals with low low-density lipoprotein cholesterol. J Am Heart Assoc;6(7). pii: e005549. doi: 10.1161/JAHA.117.005549.

3. Krishna R, Gheyas F, Liu Y et al. Chronic administration of anacetrapib is associated with accumulation in adipose and slow elimination. Clin Pharmacol Ther 2017. doi: 10.1002/cpt.700. [Epub ahead of print]

Key words anacetrapib; cholesteryl ester transfer protein inhibitor; outcomes study; residual cardiovascular risk; REVEAL