In order to investigate the effect of the combination of simvastatin and ezetimibe on a composite of major cardiovascular events, investigators of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial randomized a total of 1,873 individuals to receive either placebo or a combination of simvastatin 40 mg and ezetimibe 10 mg and followed them for approximately 52 months. Although plasma LDL cholesterol levels were twice as low in the simvastatin plus ezetimibe group, the peak aortic-jet velocity was comparable throughout the study follow-up period in the two groups. Compared to placebo, the simvastatin plus ezetimibe group had the same odds of developing the primary outcomes, which included cardiovascular disease (CVD) mortality, aortic valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Unexpectedly, it was found that cancer occurred more frequently in the simvastatin plus ezetimibe group (105 vs. 70, p=0.01). However, a subanalysis of three ezetimibe trials, including the SEAS trial, which was performed by Sir Richard Peto et al. and published in the same issue of the New England Journal of Medicine revealed that there is no credible evidence that ezetimibe has an adverse effect on rates of cancer. Finally, the authors highlighted the fact that simvastatin and ezetimibe could be beneficial to reduce the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. Dr. Catherine M. Otto was asked to comment on the results of SEAS . She listed the most widely accepted risk factors for aortic stenosis (age, sex, circulating levels of oxidized LDL and lipoprotein(a), smoking, metabolic syndrome, etc.) and highlighted the fact that hypercholesterolemia does not figure among the risk factors for aortic stenosis. She also mentioned that the results of SEAS were somewhat disappointing and that the medical community can no longer be reassured by the idea that lipid-lowering agents will slow disease progression in the valve leaflets. She concluded her editorial by mentioning that the discovery of an effective approach for targeting aortic stenosis will require innovative thinking based on what is known so far about the progression of this disease.
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