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(Circulation. 2004;110:3372-3377.)
© 2004 American Heart Association, Inc.

Vascular Medicine

Effects of the Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor Avasimibe on Human Atherosclerotic Lesions

Jean-Claude Tardif, MD; Jean Grégoire, MD; Philippe L. L’Allier, MD; Todd J. Anderson, MD; Olivier Bertrand, MD; Francois Reeves, MD; Lawrence M. Title, MD; Fernando Alfonso, MD; Erick Schampaert, MD; Alita Hassan, MPH; Richard McLain, MSc; Milton L. Pressler, MD; Reda Ibrahim, MD; Jacques Lespérance, MD; John Blue, PharmD; Therese Heinonen, DVM; Josep Rodés-Cabau, MD, for the Avasimibe and Progression of Lesions on UltraSound (A-PLUS) Investigators

From the Montreal Heart Institute, Montreal, Quebec, Canada.

Correspondence to Jean-Claude Tardif, MD, Montreal Heart Institute, 5000 Belanger St, Montreal, H1T 1C8, Canada. E-mail jean-claude.tardif{at}icm-mhi.org

Received June 25, 2004; revision received August 11, 2004; accepted August 18, 2004.

Background— Inhibition of the acyl coenzyme A:cholesterol acyltransferase (ACAT) enzyme may prevent excess accumulation of cholesteryl esters in macrophages. The ACAT inhibitor avasimibe was shown to reduce experimental atherosclerosis. This study was designed to investigate the effects of avasimibe on human coronary atherosclerosis.

Methods and Results— This randomized, double-blind, placebo-controlled trial assessed the effects of avasimibe at dosages of 50, 250, and 750 mg QD on the progression of coronary atherosclerosis as assessed by intravascular ultrasound (IVUS). All patients received background lipid-lowering therapy if necessary to reach a target baseline LDL level <125 mg/dL (3.2 mmol/L). IVUS and coronary angiography were performed at baseline and repeated after up to 24 months of treatment. Approximately equal percentages of patients across groups received concurrent statin therapy (87% to 89%). The mean total plaque volume at baseline was 200 mm³, and the least squares mean change at end of treatment was 0.7 mm³ for placebo and 7.7, 4.1, and 4.8 mm³ for the avasimibe 50, 250, and 750 mg groups, respectively (adjusted P=0.17 [unadjusted P=0.057], 0.37, and 0.37, respectively). Percent atheroma volume increased by 0.4% with placebo and by 0.7%, 0.8%, and 1.0% in the respective avasimibe groups (P=NS). LDL cholesterol increased during the study by 1.7% with placebo but by 7.8%, 9.1%, and 10.9% in the respective avasimibe groups (P<0.05 in all groups).

Conclusions— Avasimibe did not favorably alter coronary atherosclerosis as assessed by IVUS. This ACAT inhibitor also caused a mild increase in LDL cholesterol.

Key Words: atherosclerosis • ultrasonics • enzymes

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