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Navigating Uncharted Waters

In contrast to a recent trial’s findings, an analysis of pooled data from two trials of ezetimibe plus simvastatin finds no increase in cancer risk, but the voyage has just begun.

The surprise finding of an increased cancer risk associated with the combination of ezetimibe and simvastatin in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (JW Cardiol Sep 2 2008) has raised concerns. Investigators with the Clinical Trial Service Unit at Oxford University and the Duke Clinical Research Institute, which are conducting two ongoing studies of the combination of ezetimibe and simvastatin, performed an early, unplanned analysis of pooled data to explore the association of this combination with cancer. All three trials are sponsored by the manufacturer.

In SEAS, 10 mg of ezetimibe plus 40 mg of simvastatin was compared with placebo in patients with aortic stenosis. In the Study of Heart and Renal Protection (SHARP), 10 mg of ezetimibe plus 20 mg of simvastatin is compared with placebo in patients with chronic renal disease. In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), 10 mg of ezetimibe plus 40 mg of simvastatin is compared with 40 mg of simvastatin in patients with an acute coronary syndrome. Mean follow-up times were 4.1 years in SEAS, 2.7 years in SHARP, and 1 year in IMPROVE-IT. There were 1873 patients in SEAS, 9264 in SHARP, and 11,353 in IMPROVE-IT.

In the combined SHARP/IMPROVE-IT analysis, no significant increase in the diagnosis of cancer was found (313 in the active-treatment group vs. 326 in the control group; relative risk, 0.96; 95% confidence interval, 0.82–1.12). No excess of any particular type of cancer was seen, and the analysis did not show an increase in cancer incidence with longer follow-up. However, more cancer deaths occurred in the combination-therapy groups than in the control groups (97 vs. 72; P=0.07).

Comment: This examination of data from SHARP and IMPROVE-IT does not support the increased cancer risk found with ezetimibe plus simvastatin in SEAS, but it is insufficient to exclude the possibility. The follow-up time for IMPROVE-IT, in particular, was relatively short. Moreover, no trial to date has demonstrated that ezetimibe reduces cardiovascular risk. We need more information to make a clear determination of the risk profile of ezetimibe. For now, clinicians and their patients who use this drug should be aware that some uncertainty remains about the effects of the drug on patient outcomes, at least until the results of large trials become available.

— Harlan M. Krumholz, MD, SM

Published in Journal Watch Cardiology September 2, 2008

Citation(s):

Peto R et al. Hypothesis-testing analysis of cancer data from three ezetimibe trials. N Engl J Med 2008 Sep 2; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMsa0806603)