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The addition of the cholesterol-absorption inhibitor ezetimibe to simvastatin does not enhance the statin's effect on carotid artery intima-media wall thickness, investigators with the ENHANCE trial announced.

by Martha Kerr

The addition of the cholesterol-absorption inhibitor ezetimibe (Zetia, Schering-Plough) to simvastatin (Zocor, Merck and Co.) does not enhance the statin's effect on carotid artery intima-media wall thickness, investigators with the ENHANCE trial (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherogenesis Regression) announced here at the opening session of the 57th annual meeting of the American College of Cardiology.

The ENHANCE results were reported by principal investigator Dr. John J. Kastelein of the Academic Medical Center in Amsterdam, the Netherlands.

The 24-month, double-blind, randomized trial involved 363 patients with familial hypercholesterolemia assigned to simvastatin monotherapy, 80 mg daily, and 357 patients assigned to simvastatin 80 mg plus ezetimibe 10 mg (Vytorin) daily or placebo. Average patient age was 46 years.

The primary outcome was the change in wall thickness in the common carotid, the carotid bulb and the internal carotid artery -- as a measure of atherosclerosis progression.

The mean change in the carotid artery intima-media thickness was 0.0058 mm in the simvastatin-only group and 0.0111 mm (p = 0.29) in the simvastatin-plus-ezetimibe group.

"There were no differences in intima-media thickness values across any subgroups...There was not a single statistically significant 'p' value in primary or secondary endpoints in any of the arteries," Dr. Kastelein told the audience. "Longitudinally, there was no difference in intima-media values across subgroups."

Dr. Kastelein said three explanations for the negative findings have been proposed: the technology is inadequate to evaluate wall thickness change; the compound itself doesn't affect wall thickness; or, over the last ten years during which statin therapy has been used, the whole paradigm has shifted to one of already-inhibited growth of the intima-media wall.

The Dutch investigator said none of these explanations adequately explains the negative result. "How LDL cholesterol is lowered may matter more than how much it is lowered," he said.

The study is published in the April 3 issue of The New England Journal of Medicine, available online now. The embargo was lifted early to coincide with Dr. Kastelein's presentation.

In an accompanying editorial, Dr. B. Greg Brown of the University of Washington in Seattle and Dr. Allen J. Taylor of the Uniformed Services University in Bethesda, Maryland, ask whether the study's findings rule out the role of combination therapy in lowering LDL cholesterol. "For now, the study's findings are a red flag but not a black box," they caution.

A similar but longer trial may show benefit, particularly in patients who have not previously undergone lipid-lowering therapy, the editorialists comment. More than 80 per cent of patients in both arms of treatment were on statins at enrollment.

These facts, plus future evidence, "could confirm that the benefits of lowering LDL cholesterol may depend not only on 'how low you go' but also on 'how you get there'," Drs. Brown and Taylor write.

Also reported at the meeting was a study by ENHANCE investigators showing markedly different patterns of prescribing between the Canada and the United States. US physicians prescribe combination therapy at five times the rate of their Canadian colleagues, but "the effect on clinical outcomes is uncertain." (A full, separate report is included in today's Reuters Health news.)


Source: Reuters