A combination of simvastatin and ezetimibe (Vytorin) lowered cholesterol better than simvastatin alone, but it had no effect on arterial plaque in a major clinical trial. As a result, cardiologists are recommending that clinicians use ezetimibe only as a drug of last resort.

The results were presented at the American College of Cardiology’s (ACC) meeting in April, about one year after the study ended. That delay caused considerable controversy.

Known as ENHANCE, the two-year trial enrolled 720 patients with familial hypercholesterolemia. They were randomly and blindly assigned daily therapy of 80 mg of simvastatin (Zocor) with either 10 mg ezetimibe (Zetia) or a placebo. B-mode ultrasonography then measured the intima-media thickness of carotid and femoral artery walls.

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After 24 months, the mean LDL cholesterol level was substantially lower in the combination group: 141.3 mg/dL vs. 192.7 mg/dL in the group that took simvastatin alone. But the mean change in the carotid artery intima-media thickness was 0.0058 mm in the statin-only group and 0.0111 in the combined-therapy group. The difference (0.0053 mm) was not statistically significant (N Engl J Med. 2008; 358: 1431-1443).

The reason for the failure remains unknown, the researchers say. It’s possible that statins have unique properties that produce vascular benefits. Statins work in the liver to lower cholesterol by boosting its clearance. Ezetimibe prevents cholesterol from being absorbed in the digestive tract.

“This study dramatically contradicts our expectations,” write two experts in an accompanying editorial. “ ‘Lower [LDL] is better’ has been the mantra for the past two decades. But the benefits may depend not only on how low you go but also on how you get there,” observe Greg Brown, MD, PhD, University of Washington Medical School, Seattle, and Allen J. Taylor, MD, of the Walter Reed Army Medical Center.

In another editorial, journal editors note that data from this trial “do not directly address the question of whether lowering LDL with ezetimibe is clinically beneficial.” Ongoing trials to address that issue are expected to be completed no sooner than 2011. In the meantime, the editors and the ACC recommend limiting ezetimibe therapy: “Niacin, fibrates, and resins should be considered when diet, exercise, and a statin fail to achieve the target, with ezetimibe reserved for patients who cannot tolerate these agents.”