• Vascular Specialist Newspaper
• Volume 5 - 2009
• Number 9 online
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• Volume 4 - 2008
• Number 6
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• Volume 2 - 2006
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• Volume 1 - 2005
• Number 2
• Number 1

After a year-long review of data from the ENHANCE trial showed no statistically significant difference in the changes in carotid artery thickness between patients treated with ezetimibe and simvastatin and simvastatin alone, the Food and Drug Administration nonetheless concluded that patients should not stop taking ezetimibe/simvastatin or any cholesterol-lowering medications.

This recommendation is largely owing to the results of ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) showing statistically significant reductions in LDL-cholesterol levels of patients who took the combo (Vytorin), compared with those who took simvastatin alone (Zocor) (www.fda.gov/cder/drug/early_comm/ezetimibe_simvastatin200901.htm).

The FDA's conclusion supports the Merck and Schering-Plough assertion that ezetimibe/simvastatin is effective, but there are other questions not addressed in the agency's updated safety review.

The randomized, placebo-controlled SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study (N. Engl. J. Med. 2008;359:1343-56), found that the therapy did not reduce major cardiovascular events and that it was linked to an increase in cancer deaths among asymptomatic patients with aortic stenosis. That study was sponsored by Merck and Schering-Plough. An independent analysis of cancer incidence and mortality among 20,000 patients treated so far in two other ongoing Vytorin trials, SHARP (the Study of Heart and Renal Protection) and IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial), found no increased risk.

The FDA said in its posting that IMPROVE-IT should address questions about cardiovascular events. It is scheduled to be completed in 2012. And, the FDA noted that in ENHANCE, ezetimibe/simvastatin had reduced LDL cholesterol by 56%, compared to a 39% reduction with simvastatin. Thus, concluded the agency, "the results from ENHANCE do not change FDA's position that an elevated LDL cholesterol is a risk factor for cardiovascular disease and that lowering LDL cholesterol reduces the risk for cardiovascular disease."

The FDA said there were several explanations as to why the larger decrease in cholesterol did not lead to a much more significant improvement in carotid artery intimal thickness (cIMT), including that the 2-year study may have been too short to highlight any significant effects and that "there may be unknown properties of ezetimibe that may negate the beneficial effects of LDL lowering on cIMT."

At least 35 states attorney generals and the U.S. Department of Justice are looking into whether Vytorin was illegally promoted. And the U.S. House Energy and Commerce Committee began investigating in 2008 whether the companies purposefully delayed release of the ENHANCE results.