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The CAPTIVATE Randomized Trial

Marijn C. Meuwese, MD; Eric de Groot, MD, PhD; Raphaël Duivenvoorden, MD; Mieke D. Trip, MD, PhD; Leiv Ose, MD, PhD; Frans J. Maritz, MD; Dick C. G. Basart, MD; John J. P. Kastelein, MD, PhD; Rafik Habib, MD; Michael H. Davidson, MD; Aeilko H. Zwinderman, PhD; Lee R. Schwocho, PhD; Evan A. Stein, MD, PhD; for the CAPTIVATE Investigators

JAMA. 2009;301(11):1131-1139.

Context  Inhibition of acyl coenzyme A:cholesterol acyltransferase (ACAT), an intracellular enzyme involved in cholesterol accumulation, with pactimibe was developed to assist in the prevention of cardiovascular disease.

Objective  To evaluate the efficacy and safety of pactimibe in inhibition of atherosclerosis.

Design, Setting, and Patients  A prospective, randomized, stratified, double-blind, placebo-controlled study (Carotid Atherosclerosis Progression Trial Investigating Vascular ACAT Inhibition Treatment Effects [CAPTIVATE]) of 892 patients heterozygous for familial hypercholesterolemia conducted at 40 lipid clinics in the United States, Canada, Europe, South Africa, and Israel between February 1, 2004, and December 31, 2005. Study was terminated on October 26, 2005.

Intervention  Participants received either 100 mg/d of pactimibe (n = 443) or matching placebo (n = 438), in addition to standard lipid-lowering therapy.

Main Outcome Measures  Carotid atherosclerosis, assessed by ultrasound carotid intima-media thickness (CIMT), at baseline, 12, 18, and 24 months. Maximum CIMT was the primary end point and mean CIMT the secondary end point.

Results  Because pactimibe failed to show efficacy in the intravascular coronary ultrasound ACTIVATE study, the CAPTIVATE study was terminated prematurely after a follow-up of 15 months. After 6 months of treatment with pactimibe, low-density lipoprotein cholesterol increased by 7.3% (SD, 23%) compared with 1.4% (SD, 28%) in the placebo group (P = .001). The carotid ultrasonographic scans of the 716 patients with at least 2 scans and obtained at least 40 weeks apart were analyzed. Maximum CIMT measurements did not show a pactimibe treatment effect (difference, 0.004 mm; 95% confidence interval [CI], –0.023 to 0.015 mm; P = .64); however, the less variable mean CIMT measurement revealed an increase of 0.014 mm (95% CI, –0.027 to 0.000 mm; P = .04) in patients administered pactimibe vs placebo. Major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) occurred more often in patients administered pactimibe vs placebo (10/443 [2.3%] vs 1/438 [0.2%]; P = .01).

Conclusions  In patients with familial hypercholesterolemia, pactimibe had no effect on atherosclerosis as assessed by changes in maximum CIMT compared with placebo but was associated with an increase in mean CIMT as well as increased incidence of major cardiovascular events.

Trial Registration  clinicaltrials.gov Identifier: NCT00151788

Author Affiliations: Departments of Vascular Medicine (Drs Meuwese, de Groot, Duivenvoorden, Trip, and Kastelein) and Clinical Epidemiology and Biostatistics (Dr Zwinderman), Academic Medical Center, Amsterdam, the Netherlands; Lipid Clinic, Rikshospitalet, Oslo, Norway (Dr Ose); Department of Internal Medicine, Karl Bremer Hospital, Bellville, South Africa (Dr Maritz); Department of Cardiology, Westfries Gasthuis, Hoorn, the Netherlands (Dr Basart); Cardiovascular Center of Laval, Laval, Quebec, Canada (Dr Habib); Pritzker School of Medicine, University of Chicago, Chicago, Illinois (Dr Davidson); Daiichi Sankyo Pharma Development, Edison, New Jersey (Dr Schwocho); and Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio (Dr Stein).
Deceased.

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