Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, 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, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: 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. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Cox regression survival models.

<p>Abbreviations: CVD cardiovascular disease.</p><p>*Covariates: age, sex, study site, participation in the WENBIT study, smoking, family history of coronary heart disease, medical history (hypertension, diabetes, acute myocardial infarction, percutaneous intervention, coronary artery bypass surgery, peripheral vascular disease, cerebrovascular disease, cured cancer, active cancer (not in the cardiovascular mortality analyses due to failure of the model to converge), deep vein thrombosis or vein surgery, pulmonary disease, atrial fibrillation, dyspnea grade 0–4), measured parameters at baseline (body mass index, ECG rhythm, left ventricular ejection fraction, number of coronary vessels with >50% stenosis), laboratory values (estimated glomerular filtration rate, uric acid, hemoglobin, potassium, sodium, C-reactive protein, glycated hemoglobin, low density lipoprotein, troponin T), medication (aspirin, adenosine diphosphate receptor inhibitor, warfarin, angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker, beta-blocker, digoxin, spironolactone, thiazide, calcium antagonist, nitrate, statin, insulin, metformin, sulfonylurea, treatment for chronic obstructive pulmonary disease, non-steroid anti-inflammatory drug, corticosteroid, antidepressant, antipsychotic), and baseline revascularization.</p><p>Cox regression survival models.</p

Baseline characteristics after matching.

<p>Continuous variables are shown as means (standard deviation) and medians (interquartile range) and categorical variables as numbers (percentage). Abbreviations: WENBIT = WEstern Norway B-vitamin Trial; CAD = coronary artery disease; PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft; PVD = peripheral vascular disease; DVT = deep venous thrombosis; NYHA = New York Heart Association; BP = blood pressure; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; WBC = white blood cell count; ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; COPD = chronic obstructive pulmonary disease; NSAID = non-steroid anti-inflammatory drug.</p><p>Baseline characteristics after matching.</p