Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia

Kastelein, John J.P. M.D., Ph.D.
Akdim, Fatima M.D.
Stroes, Erik S.G. M.D., Ph.D.
Zwinderman, Aeilko H. Ph.D.
Bots, Michiel L. M.D., Ph.D.
Stalenhoef, Anton F.H. M.D., Ph.D., F.R.C.P.
Visseren, Frank L.J. M.D., Ph.D.
Sijbrands, Eric J.G. M.D., Ph.D.
Trip, Mieke D. M.D., Ph.D.
Stein, Evan A. M.D., Ph.D.
Gaudet, Daniel M.D., Ph.D.
Duivenvoorden, Raphael M.D.
Veltri, Enrico P. M.D.
David Marais, A. M.D., Ph.D.
de Groot, Eric M.D., Ph.D.

the ENHANCE Investigators
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.); the Quebec Heart Institute, Hôpital Laval Research Centre, Quebec, QC, Canada (D.G.); Schering-Plough Research Institute, Kenilworth, NJ (E.P.V.); and Cape Heart Center, Cape Town, South Africa (A.D.M.). 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 [email protected].
This article (10.1056/NEJMoa0800742) was published at www.nejm.org on March 30, 2008.

Supported by Merck and Schering-Plough.

Dr. Kastelein reports receiving consulting and lecture fees from Pfizer, Roche, AstraZeneca, Merck, and Schering-Plough and grant support from AstraZeneca, Merck, and Schering-Plough; Dr. Stroes, receiving consulting fees from Novartis, Isis Pharmaceuticals, AstraZeneca, and Roche and lecture fees from AstraZeneca, Merck, and Isis Pharmaceuticals; Dr. Bots, receiving consulting fees from Pfizer and AstraZeneca and lecture fees from Pfizer, AstraZeneca, and Organon; Dr. Stalenhoef, receiving grant support from Merck and Pfizer; Dr. Veltri, being an employee of, receiving royalties for coinventions with, and having an equity interest in Schering-Plough; Dr. Marais, receiving consulting and lecture fees from Abbott, AstraZeneca, Pfizer, and Merck; and Dr. de Groot, receiving consulting fees from Wyeth and lecture fees from Merck. No other potential conflict of interest relevant to this article was reported.

We thank the investigators and study nurses who made this trial possible; Drs. Strony, Yang, and Suresh from Schering-Plough Research Institute; and Dr. Gene Bond for his invaluable comments during the course of this trial.

New England Journal of Medicine 358(14):p 1431-1443, April 3, 2008. | DOI: 10.1056/NEJMoa0800742

Background

Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown.

Methods

We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries.

Results

The primary outcome, the mean (±SE) change in the carotid-artery intima-media thickness, was 0.0058±0.0037 mm in the simvastatin-only group and 0.0111±0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (±SD) LDL cholesterol level was 192.7±60.3 mg per deciliter (4.98±1.56 mmol per liter) in the simvastatin group and 141.3±52.6 mg per deciliter (3.65±1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups.

Conclusions

In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097.)