ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: the CAPTIVATE randomized trial.

Abstract

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.

• Authors: Marijn C Meuwese, Eric de Groot, Raphaël Duivenvoorden, Mieke D Trip, Leiv Ose, Frans J Maritz, Dick C G Basart, John J P Kastelein, Rafik Habib, Michael H Davidson, Aeilko H Zwinderman, Lee R Schwocho, Evan A Stein, CAPTIVATE Investigators
• Journal: JAMA (JAMA) Vol. 301 Issue 11 Pg. 1131-9 (Mar 18 2009) ISSN: 1538-3598 [Electronic] United States
• PMID: 19293413 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Enzyme Inhibitors
• Hypolipidemic Agents
• Indoleacetic Acids
• pactimibe
• Sterol O-Acyltransferase

Topics

• Biomarkers (blood)
• Carotid Artery Diseases (blood, diagnostic imaging, prevention & control)
• Disease Progression
• Double-Blind Method
• Enzyme Inhibitors (therapeutic use)
• Female
• Humans
• Hyperlipoproteinemia Type II (blood, drug therapy)
• Hypolipidemic Agents (therapeutic use)
• Indoleacetic Acids (therapeutic use)
• Male
• Middle Aged
• Prospective Studies
• Sterol O-Acyltransferase (antagonists & inhibitors)
• Ultrasonography