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

HPS3/TIMI55-REVEAL Collaborative Group, Writing Committee, E Sammons, J C Hopewell, F Chen, W Stevens, K Wallendszus, E Valdes-Marquez, R Dayanandan, C Knott, K Murphy, E Wincott, A Baxter, R Goodenough, M Lay, M Hill, S Macdonnell, G Fabbri, D Lucci, M Fajardo-Moser, S Brenner, D Hao, H Zhang, J Liu, B Wuhan, S Mosegaard, W Herrington, C Wanner, C Angermann, G Ertl, A Maggioni, P Barter, B Mihaylova, Y Mitchel, R Blaustein, S Goto, J Tobert, P DeLucca, Y Chen, Z Chen, A Gray, R Haynes, J Armitage, C Baigent, S Wiviott, C Cannon, E Braunwald, R Collins, L Bowman, M Landray, REVEAL Collaborative Group, HPS3/TIMI55-REVEAL Collaborative Group, Writing Committee, E Sammons, J C Hopewell, F Chen, W Stevens, K Wallendszus, E Valdes-Marquez, R Dayanandan, C Knott, K Murphy, E Wincott, A Baxter, R Goodenough, M Lay, M Hill, S Macdonnell, G Fabbri, D Lucci, M Fajardo-Moser, S Brenner, D Hao, H Zhang, J Liu, B Wuhan, S Mosegaard, W Herrington, C Wanner, C Angermann, G Ertl, A Maggioni, P Barter, B Mihaylova, Y Mitchel, R Blaustein, S Goto, J Tobert, P DeLucca, Y Chen, Z Chen, A Gray, R Haynes, J Armitage, C Baigent, S Wiviott, C Cannon, E Braunwald, R Collins, L Bowman, M Landray, REVEAL Collaborative Group

Abstract

Aims: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period.

Methods and results: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants.

Conclusion: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms.

Trial registration: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Keywords: CETP inhibitor therapy; Randomized trial.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Structured Graphical Abstract
Structured Graphical Abstract
Figure 1
Figure 1
Consort diagram for randomized in-trial and post-trial cohorts. PTFU, post-trial follow-up.
Figure 2
Figure 2
Effects of anacetrapib on first major coronary event by year during the in-trial, post-trial, and overall follow-up periods. Rate ratios are shown for the first major coronary event among patients in the anacetrapib group vs. those in the placebo group according to period of follow-up. The numbers at risk decline with each year of follow-up because of censoring, and the percentages are the number of events as a proportion of the number at risk. For each year of follow-up, rate ratios are plotted as squares (with the size of each square proportional to the amount of statistical information) and their 95% confidence intervals are represented as horizontal lines. For pre-specified composite periods of follow-up (indicated in bold text), the rate ratios and their corresponding 95% confidence intervals are represented by diamonds, and P-values are shown. Squares or diamonds to the left of the vertical line indicate benefit with anacetrapib, and the comparison is significant (P < 0.05) if the horizontal line or diamond does not overlap the solid vertical line. CI, confidence interval.
Figure 3
Figure 3
(A) Effects of anacetrapib on first major coronary event during the in-trial, post-trial, and overall follow-up periods. (B) Effect of anacetrapib on major coronary events by year of follow-up. Figure legend as for Figure 2. P-value for trend across rate ratios by year of first event = 0.01. CI, confidence interval.
Figure 4
Figure 4
Effect of anacetrapib on other pre-specified vascular outcomes during the in-trial, post-trial, and overall follow-up periods. Figure legend as for Figure 2. The primary outcome was major coronary event (composite of coronary death, myocardial infarction, or coronary revascularization). Secondary outcomes were presumed ischaemic stroke (i.e. not known to be haemorrhagic), major atherosclerotic event (coronary death, myocardial infarction, or presumed ischaemic stroke), and major vascular event (major coronary event or presumed ischaemic stroke). The composite of coronary death or myocardial infarction was a pre-specified tertiary outcome. A single patient may have had multiple events and so may contribute information to more than one row. CI, confidence interval; MI, myocardial infarction.

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Source: PubMed

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