Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia
John J.P. Kastelein, M.D., Ph.D., Fatima Akdim, M.D., Erik S.G. Stroes, M.D., Ph.D., Aeilko H. Zwinderman, Ph.D., Michiel L. Bots, M.D., Ph.D., Anton F.H. Stalenhoef, M.D., Ph.D., F.R.C.P., Frank L.J. Visseren, M.D., Ph.D., Eric J.G. Sijbrands, M.D., Ph.D., Mieke D. Trip, M.D., Ph.D., Evan A. Stein, M.D., Ph.D., Daniel Gaudet, M.D., Ph.D., Raphael Duivenvoorden, M.D., Enrico P. Veltri, M.D., A. David Marais, M.D., Ph.D., Eric de Groot, M.D., Ph.D., for the ENHANCE Investigators
Background Ezetimibe, a cholesterol-absorption inhibitor, reduceslevels of low-density lipoprotein (LDL) cholesterol when addedto statin treatment. However, the effect of ezetimibe on theprogression of atherosclerosis remains unknown.
Methods We conducted a double-blind, randomized, 24-month trialcomparing the effects of daily therapy with 80 mg of simvastatineither with placebo or with 10 mg of ezetimibe in 720 patientswith familial hypercholesterolemia. Patients underwent B-modeultrasonography to assess the intima–media thickness ofthe walls of the carotid and femoral arteries. The primary outcomemeasure was the change in the mean carotid-artery intima–mediathickness, which was defined as the average of the means ofthe far-wall intima–media thickness of the right and leftcommon carotid arteries, carotid bulbs, and internal carotidarteries.
Results The primary outcome, the mean (±SE) change inthe carotid-artery intima–media thickness, was 0.0058±0.0037mm in the simvastatin-only group and 0.0111±0.0038 mmin the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29).Secondary outcomes (consisting of other variables regardingthe intima–media thickness of the carotid and femoralarteries) did not differ significantly between the two groups.At the end of the study, the mean (±SD) LDL cholesterollevel was 192.7±60.3 mg per deciliter (4.98±1.56mmol per liter) in the simvastatin group and 141.3±52.6mg per deciliter (3.65±1.36 mmol per liter) in the combined-therapygroup (a between-group difference of 16.5%, P<0.01). Thedifferences between the two groups in reductions in levels oftriglycerides and C-reactive protein were 6.6% and 25.7%, respectively,with greater reductions in the combined-therapy group (P<0.01for both comparisons). Side-effect and safety profiles weresimilar in the two groups.
Conclusions In patients with familial hypercholesterolemia,combined therapy with ezetimibe and simvastatin did not resultin a significant difference in changes in intima–mediathickness, as compared with simvastatin alone, despite decreasesin levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.govnumber, NCT00552097
[ClinicalTrials.gov]
.)
Source Information
From the Academic Medical Center, Amsterdam (J.J.P.K., F.A., E.S.G.S., A.H.Z., M.D.T., R.D., E.G.); the University Medical Center, Utrecht (M.L.B., F.L.J.V.); Radboud University Nijmegen Medical Center, Nijmegen (A.F.H.S.); and Erasmus Medical Center, Rotterdam (E.J.G.S.) — all in the Netherlands; the Metabolic and Atherosclerosis Research Center, Cincinnati (E.A.S.); Department of Medicine, Montreal University, Montreal (D.G.); Schering-Plough Research Institute, Kenilworth, NJ (E.P.V.); and Cape Heart Center, Cape Town, South Africa (A.D.M.). This article (10.1056/NEJMoa0800742) was published at www.nejm.org on March 30, 2008.
Address reprint requests to Dr. Kastelein at the Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, P.O. Box 22660, 1100 DD Amsterdam, the Netherlands, or at j.j.kastelein{at}amc.uva.nl.
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