Level 2: Mid-level evidence
Ezetimibe/simvastatin (Vytorin) was associated with an increased incidence of cancer, based on a secondary analysis of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) randomized trial (N Engl J Med. 2008;359:1343-1356). Patients who had asymptomatic aortic stenosis (N=1,873; mean age 68 years) were randomized to ezetimibe 10 mg/simvastatin 40 mg vs. placebo once daily. Median follow-up was 52.2 months.

Compared with the control group, patients taking ezetimibe/simvastatin had higher rates of fatal cancer (4.1% vs. 2.5%, P =.05, NNH 63) and incident cancer (11.1% vs. 7.5%, P =.01, NNH 27). The FDA is investigating a potential association between ezetimibe/simvastatin and cancer based on this trial (FDA MedWatch 2008 Aug 21).

In response, two ongoing trials of ezetimibe/simvastatin released interim analyses (N Engl J Med. 2008;359:1357-1366). The Study of Heart and Renal Protection (SHARP) trial is evaluating 9,264 patients aged 40 years and older with chronic kidney disease randomized to ezetimibe 10 mg/simvastatin 20 mg vs. placebo, with mean follow-up 2.7 years. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is evaluating 11,353 patients aged 50 years and older with acute coronary syndrome randomized to ezetimibe 10 mg/simvastatin 40 mg vs. simvastatin 40 mg, mean follow-up one year. Data were not reported for each trial individually. After excluding patients with cancer prior to randomization, incidence of cancer was 3% in combined ezetimibe/simvastatin groups vs. 3.2% in combined control groups (not statistically significant).

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Although a meta-analysis was reported for all three trials, combination of these trials was considered inappropriate for meta-analysis because of differences in patient populations, drug doses, comparison groups, and study durations. Based on other randomized trials, cancer risk appears to increase with statins in the elderly (J Clin Oncol. 2006;24:4808-4817).