Preliminary Observations From Preliminary Trial Results

Abstract

Results from the Simvastatin Ezetimibe Aortic Stenosis study (SEAS, registration No. NCT00092677) were prematurely released in a surprise announcement on July 21, 2008. In a carefully scripted media event, including a webcast from the United Kingdom, surprise findings of increased incidence of cancer and cancer death in patients treated with simvastatin-ezetimibe were disclosed and immediately dismissed as “not credible.” To refute the observation of excess cancer events, the SEAS investigators offered a well-intentioned but hastily performed pooled analysis using data derived from 2 prematurely unblinded, ongoing ezetimibe outcomes trials (Study of Heart and Renal Protection [SHARP, registration No. NCT00125593] and IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT, registration No. NCT00202878]). Unrelated to the cancer findings, primary and secondary outcome data were also prematurely disclosed. The purpose of this event was no doubt to dispel cancer concerns for a “blockbuster” drug (ezetimibe) that had already been subjected to considerable criticism and scrutiny.1,2 However, all of this occurred without any peer review of the data, which denied the medical community the opportunity to fully evaluate the benefits and risks of this drug in the usual scientific fashion. SEAS was a 4-year, prospective, randomized trial that compared simvastatin-ezetimibe with placebo in 1873 adults with mild to moderate aortic stenosis. The primary end point of the SEAS study was “major cardiovascular events,” a composite of events associated with aortic valve and atherosclerotic diseases. The secondary end points were the 2 separate components of the primary end point: “aortic valve disease events” (surgical valve replacement, hospitalization because of heart failure, and cardiovascular death), and “atherosclerotic disease events” (nonfatal myocardial infarction, coronary artery bypass surgery or percutaneous coronary intervention, hospitalization for unstable angina pectoris, nonhemorrhagic stroke, and cardiovascular death). In their haste to report these results at a press conference before …