Results from the REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) study show anacetrapib, an investigational cholesteryl ester transfer protein (CETP) inhibitor, lowers the risk of myocardial infarction and related cardiovascular complications in patients intensively treated with a statin.
Presented in a hotline session by Dr Martin Landray (University of Oxford), the trial’s co-principal investigator, and simultaneously published in the New England Journal of Medicine (https://doi.org/10.1056/NEJMoa1706444), this large-scale, placebo-controlled study was carried out on 30,449 patients with cardiovascular disease, who were all receiving lipid-lowering treatment with atorvastatin. Those patients also receiving anacetrapib (100 mg once daily) showed a significant reduction in the primary outcome, the risk of major coronary events (coronary death, myocardial infarction or coronary re-vascularisation) by 9% relative to those patients randomised to placebo (10.8% vs. 11.8%, respectively; p=0.004). The safety of anacetrapib was generally consistent with data from earlier studies.
The mean baseline low-density lipoprotein (LDL) cholesterol level among all patients at the start of the study was 61 mg/dL (1.58 mmol/L), non-high-density lipoprotein (HDL) cholesterol was 92 mg/dL (2.38 mmol/L), and HDL cholesterol was 40 mg/dL (1.03 mg/dL). Compared with placebo, the addition of anacetrapib further reduced the mean level of non-HDL cholesterol by 18% (17 mg/dL [0.44 mmol/L]) and increased HDL cholesterol levels by 104% (43 mg/dL [1.12 mmol/L]) at the study midpoint. During median follow-up of 4.1 years, a 9 % relative reduction in the risk major coronary events was observed among those receiving anacetrapib compared to placebo (1,640 events [10.8%] vs. 1,803 events [11.8%], respectively, rate ratio 0.91, 95% confidence interval [CI] 0.85–0.97, p=0.004). The benefit was similar across multiple pre-specified subgroups.
The difference in the key secondary composite outcome of major atherosclerotic events (myocardial infarction, coronary death or presumed ischemic stroke) did not reach statistical significance (rate ratio 0.93, 95% CI, 0.86–1.00, p=0.052), possibly due to a lack of observed benefit of anacetrapib on presumed ischaemic stroke. There were no statistically significant differences in cause-specific mortality, cancer, or other serious adverse events.
Anacetrapib produced small increases in systolic and diastolic blood pressures of 0.7 mmHg and 0.3 mmHg, respectively; there was no statistically significant increase of serious adverse events attributed to hypertension.
REVEAL was designed and independently conducted by investigators at the Clinical Trial Service Unit (CTSU) at the University of Oxford, the study’s regulatory sponsor, in collaboration with the TIMI Study Group based at Brigham and Women’s Hospital in Boston and MSD who provided funding for REVEAL.
Dr Landray said the findings from REVEAL were “in marked contrast to the disappointing results of previous trials of other CETP inhibitors which were stopped after about two years due to unexpected hazards or an apparent lack of efficacy”.
General Practitioner, Dr Terry McCormack (Spring Vale Medical Centre, Whitby, Yorkshire) commented: “We now potentially have a fourth effective and generally well tolerated drug which is proven to benefit patients by improving their lipid profile. This may be especially important for patients who cannot take statins and further research in that group is needed. It is very interesting that yet again the length of time treated is a major factor in demonstrating benefit.”
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