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Aortic stenosis (which involves partial blockage of the aortic valve inthe heart) is a relatively common disease among older people in Westernpopulations. Left untreated, it can progress to death from heart failure orcardiac arrest. Aortic valve replacement for severe symptoms is the secondmost frequent type of heart surgery. Apart from surgery, there is no medicaltherapy known to prevent or heal this condition. Population studies and otherscientific research indicate that a high blood level of LDL-cholesterol (socalled "bad cholesterol) is a risk factor for developing aortic stenosis andmay be involved in the pathological process. Treatment to lowerLDL-cholesterol in many other types of patient has been shown to producesubstantial reductions in the rates of heart attacks, strokes and otheradverse outcomes.
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The SEAS study is the first large-scale randomised trial to assess theeffects of lowering LDL-cholesterol in patients with aortic stenosis. Thestudy was initiated and designed by academic researchers in Scandinavia, andcarried out at 173 clinical centres in Norway, Denmark, Sweden, Finland,Germany, UK and Ireland. It included 1873 patients with mild to moderateaortic stenosis without symptoms who were not considered to have a clearindication for treatment with cholesterol-lowering drugs. Patients wererandomly assigned to receive either intensive cholesterol lowering with thecombination of simvastatin (40 mg daily) and ezetimibe (10 mg daily) ormatching placebo. The first patient was included in 2001. The study wascompleted according to the study plan when the last patient included had beenfollowed for 4 years (March 2008). Vital status at the end of the study wasestablished for all patients. All data have been checked for completeness andthe data file for analysis was closed on 30 June 2008.
The scientific leadership of the study was a Steering Committeeconsisting of 14 academic representatives of centres in each of theparticipating countries and two members (a statistician and a coordinator)representing the funders. The SEAS study is funded by the pharmaceuticalcompanies Merck Sharp & Dohme (MSD) and Schering-Plough who market the drugsbeing tested. All clinical endpoint events were adjudicated by an independentcommittee that was blinded to the study treatment allocation. The study wasmonitored by an independent Data Safety and Monitoring Board. Data collectionwas performed by MSD, and the data were analyzed by statisticians at UllevalUniversity Hospital in Oslo, Norway, and at MSD.
The primary endpoint of the SEAS study was "major cardiovascular events",which is the composite of events associated with aortic valve disease andwith atherosclerotic disease. The secondary endpoints were the two separatecomponents of the primary endpoint: "aortic valve disease events" (surgicalvalve replacement, hospitalization because of heart failure, andcardiovascular death); and "atherosclerotic disease events" (non-fatalmyocardial infarction, coronary artery bypass surgery or percutaneouscoronary intervention, hospitalization because of unstable angina pectoris,non-haemorrhagic stroke and cardiovascular death). Subsidiary outcomesincluded echocardiographic evidence of aortic stenosis progression and safety.
Compared with placebo, the combination of simvastatin and ezetimibereduced LDL-cholesterol by an average of 61%, corresponding to a reduction ofabout 2 mmol/L (76 mg/dl), and this effect was sustained throughout thestudy. 688 patients had one or more primary endpoint events. No significantdifference was observed between the treatment groups for the combined primaryendpoint (333 patients with
