Abstract
BackgroundPatients with prior vascular disease remain at high risk for cardiovascular events despite intensive statin–based treatment. Inhibition of cholesteryl ester transfer protein by anacetrapib reduces low-density lipoprotein (LDL) cholesterol by around 25% to 40% and more than doubles high-density lipoprotein (HDL) cholesterol. However, it is not known if these apparently favorable lipid changes translate into reductions in cardiovascular events.MethodsThe REVEAL study is a randomized, double-blind, placebo-controlled clinical trial that is assessing the efficacy and safety of adding anacetrapib to effective LDL-lowering treatment with atorvastatin for an average of at least 4 years among patients with preexisting atherosclerotic vascular disease. The primary assessment is an intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib on major coronary events (defined as the occurrence of coronary death, myocardial infarction, or coronary revascularization).ResultsBetween August 2011 and October 2013, 30,449 individuals in Europe, North America, and China were randomized to receive anacetrapib 100 mg daily or matching placebo. Mean (SD) age was 67 (8) years, 84% were male, 88% had a history of coronary heart disease, 22% had cerebrovascular disease, and 37% had diabetes mellitus. At the randomization visit (after at least 8 weeks on a protocol-defined atorvastatin regimen), mean plasma LDL cholesterol was 61 (15) mg/dL and HDL cholesterol was 40 (10) mg/dL.InterpretationThe REVEAL trial will provide a robust evaluation of the clinical efficacy and safety of adding anacetrapib to an effective statin regimen. Results are anticipated in 2017.
Highlights
Patients with prior vascular disease remain at high risk for cardiovascular events despite intensive statin–based treatment
Large-scale randomized trials have shown that lowering low-density lipoprotein (LDL) cholesterol concentration by about 40 mg/dL (1 mmol/L) for 4 to 5 years reduces the risk of coronary events and stroke by about one-fifth,[1] and that lowering LDL cholesterol more produces further reductions in risk.[2,3]
Study organization The study was designed by the independent investigators at the Clinical Trial Service Unit at the University of Oxford in collaboration with the TIMI Study Group based at Brigham and Women's Hospital, Boston, and Merck & Co, Inc (Merck), which manufactures anacetrapib and provides funding for the study
Summary
Patients with prior vascular disease remain at high risk for cardiovascular events despite intensive statin–based treatment. Genetic variants that lead to lower CETP activity are associated with higher HDL cholesterol levels and lower risk of coronary heart disease[9,10] (by contrast with other genetic variants that impact HDL cholesterol levels).[11] Pharmacological CETP inhibition produces increases in HDL cholesterol and apolipoprotein A1, along with reductions in LDL cholesterol and apolipoprotein B.12. The magnitude of these effects varies between different CETP inhibitors. Torcetrapib was found to increase systolic blood pressure by about 5 mm Hg as well as causing increases in blood sodium, bicarbonate, and aldosterone concentrations. 13-15
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