Commentary

Is ezetimibe/simvastatin no better than simvastatin alone? Lessons learned and clinical implications

Interpreting the ENHANCE trial

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The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial 1 was probably the most widely publicized clinical study of the past decade. How did a 720-patient imaging trial with a neutral result in patients with severe hypercholesterolemia rise to a level warranting massive media attention, a congressional investigation, and a recommendation to curtail the use of a drug widely used to reduce levels of low-density-lipoprotein cholesterol (LDL-C)?

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The reaction to the ENHANCE trial reveals more about the political climate and the relationship between the pharmaceutical industry and the American public than it does about the effects of ezetimibe (available combined with simvastatin as Vytorin and by itself as Zetia) on the progression of atherosclerosis.

SOME SELF-DISCLOSURE

Before I discuss the clinical implications of the ENHANCE trial, I must describe both my financial conflicts and intellectual biases. I am a paid consultant, speaker, and researcher on behalf of Merck/Schering-Plough, the sponsor of the ENHANCE trial. I was a principal investigator in the first phase II trial of ezetimibe and have conducted more than 10 clinical trials of either ezetimibe or ezetimibe/simvastatin. I also have been a strong advocate for imaging trials to assist in the clinical development of novel therapeutic agents and to support regulatory approval.

Therefore, I believe that the thickness of the intima and media layers of the carotid arteries is a useful surrogate to evaluate the potential antiatherosclerotic effects of drugs (more on this topic below). Also, I believe that the LDL-C-lowering hypothesis has been proven: ie, that all drugs that lower LDL-C safely, without off-target adverse effects, should reduce cardiovascular events. I support the goal levels of LDL-C and non-high-density-lipoprotein cholesterol set by the National Cholesterol Education Program’s third Adult Treatment Panel (ATP III) guidelines, 2,3 which specify LDL-C targets rather than the use of specific drugs. In spite of these conflicts and potential biases, I believe I have always served the best interests of patient care.

HISTORY OF THE ENHANCE TRIAL

The ENHANCE trial was designed in early 2000 by John J. Kastelein, MD, PhD, one of the most prominent clinical trialists in lipidology, 4 and the protocol was finalized in April 2002. The trial was designed to evaluate the effects of two regimens: ezetimibe 10 mg plus simvastatin 80 mg vs simvastatin 80 mg (Zocor) in 720 patients with familial hypercholesterolemia and an LDL-C level of at least 210 mg/dL after stopping all lipid therapies. In fact, after the placebo run-in period, the mean total cholesterol value was 400 mg/dL, and the mean LDL-C value was about 318 mg/dL.

The end point defined as the mean of six measurements

The primary end point was the change in the thickness of the intima and media layers of the carotid arteries over a 2-year period, measured by ultrasonography. A composite measure was used: the mean of the thicknesses in the far walls of the right and left common carotid arteries, the right and left carotid bulbs, and the right and left internal carotid arteries. Secondary end points included the change in the mean maximal carotid artery intima-media thickness (ie, the thickest of the six baseline measurements), the proportion of participants who developed new carotid artery plaque (defined arbitrarily as an intima-media thickness > 1.3 mm), and changes in the mean of the intima-media thickness of the six carotid sites plus the common femoral arteries.

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