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Stormy SEAS

Unexpected findings from a trial of simvastatin plus ezetimibe raise questions about the effects of aggressive LDL-cholesterol reduction.

High blood levels of LDL have been associated with increased risk for many cardiovascular diseases, including aortic stenosis. To find out whether aggressive lowering of LDL levels would slow or halt disease progression in patients with mild-to-moderate aortic stenosis, investigators for the manufacturer-sponsored, international, Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study randomized 1873 patients to receive either a combination of simvastatin (40 mg daily) and ezetimibe (10 mg daily) or matching placebo.

After a median of 52.2 months of follow-up, LDL levels in the combined-therapy group were reduced by 53.8%, compared with 3.8% in the placebo group, but no between-group difference was observed in the primary endpoint, a composite of events resulting from aortic valve disease, atherosclerotic disease, or both. The number of events attributable to atherosclerotic disease were lower in the combination group than in the placebo group by 22% (P=0.02), although the difference in bypass surgery between the two groups accounted for much of the difference. Unexpectedly, the incidence of cancer was significantly higher in the combined-therapy group than in the placebo group (105 [11.1%] vs. 70 [7.5%]; P=0.01), and a 67% increase was seen in the rate of cancer deaths (39 [4.1%] vs. 23 [2.5%]; P=0.05). No specific cancer at any particular site accounted for this excess.

Comment: The main finding from this trial, the failure of ezetimibe and simvastatin to retard the progression of aortic stenosis, has been overshadowed by the surprising finding of an increased risk for cancer. Whether this increased risk was a result of chance or represents a true adverse effect cannot be determined from these results. The authors state that "higher incidence of cancer in the simvastatin–ezetimibe group requires further exploration in ongoing and future trials." For now, clinicians and their patients should know that trials to address the efficacy and safety of ezetimibe are in progress, although the results are unlikely to be available for several years.

— Harlan M. Krumholz, MD, SM

Published in Journal Watch Cardiology September 2, 2008

Citation(s):

Rossebø AB et al. for the SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008 Sep 2; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa0804602)