ENHANCE Findings Question the Role of Ezetimibe in Hypercholesterolemia

4 april - Researchers said that their attempt to improve changes in blood vessel thickness with a combination of simvastatin-ezetimibe failed to show any improvement beyond that achieved with simvastatin alone. The findings, from the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study, were presented here of the American College of Cardiology (ACC) 57th Annual Scientific Session. The difference in mean carotid intima-media thickness after 2 years of treatment increased a mean of 0.0058 mm for the 342 patients assigned to the cholesterol-lowering drug simvastatin compared with a mean increase of 0.0111 mm with the combination of simvastatin and ezetimibe, a difference that was not statistically significant ([P = .29), said the study's principal investigator of John Kastelein, MD, PhD, Professor of Paediatrics, Academic Medical Centre, Amsterdam, the Netherlands.
"The addition of ezetimibe to simvastatin did lead to expected changes in low-density lipoprotein [LDL] cholesterol and in C-reactive protein, but did not reduce any carotid intima-media thickness," Dr. Kastelein said on March 30 at the opening plenary session."The reasons for this discrepancy currently remain unknown," he added.Dr. Kastelein said the ENHANCE experiment among patients with familial hypercholesterolaemia might have failed because measurement of the minute changes in carotid intima-media thickness might have been flawed, because the patient population was improper for the design of the study, or because there is a problem with the drug combination.Ongoing studies that will report the drug's impact on hard clinical outcomes -- rather than a surrogate marker such as changes in the carotid arteries -- are underway.The results of the study prompted a response from Harlan Krumholz, MD, the Harold H. Hines, Jr. Professor of Medicine and Epidemiology and Public Health (Cardiology), Yale University, New Haven, Connecticut, speaking for an expert panel. Dr. Krumholz said the failure of ezetimibe to show benefit raises the question of whether the drug may be causing harm to patients.He called for doctors to "turn back to statins" for treating patients with high cholesterol, reserving ezetimibe for patients who cannot tolerate statins or other cholesterol-lowering medications or who have reached the limits of cholesterol lowering achievable with statins.In his presentation and in a press briefing following the session, Dr. Kastelein said his study found no signs that would alert doctors of any problems with ezetimibe. He did note that the addition of ezetimibe reduced C-reactive protein by 26% compared with simvastatin alone (P < .01) and reduced LDL cholesterol by 16.5% compared with simvastatin alone.Robert Bonow, MD, Chief, Division of Cardiology, Northwestern Medical Hospital, and Professor of Medicine, Northwestern University School of Medicine, Chicago, Illinois, a spokesperson for the American Heart Association who did not participate in the study, commented that while statin use should be the mainstay of treatment for high cholesterol, the reduction of LDL by ezetimibe would tend to indicate that the drug remains useful in treatment of patients who need additional help to reach cholesterol-lowering goals.Funding for the ENHANCE study was provided by Merck and Schering-Plough. The study is being published simultaneously online by The New England Journal of Medicine, accompanied by two editorials and a second article.