Results From the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) Study


    LONDON, July 21 /CNW/ - The SEAS (Simvastatin and Ezetimibe in Aortic
Stenosis) study has investigated the effects of intensive cholesterol lowering
with the combination of simvastatin (40 dmg daily) and ezetimibe (10 mg daily)
in patients with aortic stenosis.
    Aortic stenosis (which involves partial blockage of the aortic valve in
the heart) is a relatively common disease among older people in Western
populations. Left untreated, it can progress to death from heart failure or
cardiac arrest. Aortic valve replacement for severe symptoms is the second
most frequent type of heart surgery. Apart from surgery, there is no medical
therapy known to prevent or heal this condition. Population studies and other
scientific research indicate that a high blood level of LDL-cholesterol (so
called "bad cholesterol) is a risk factor for developing aortic stenosis and
may be involved in the pathological process. Treatment to lower
LDL-cholesterol in many other types of patient has been shown to produce
substantial reductions in the rates of heart attacks, strokes and other
adverse outcomes.
    The SEAS study is the first large-scale randomised trial to assess the
effects of lowering LDL-cholesterol in patients with aortic stenosis. The
study was initiated and designed by academic researchers in Scandinavia, and
carried out at 173 clinical centres in Norway, Denmark, Sweden, Finland,
Germany, UK and Ireland. It included 1873 patients with mild to moderate
aortic stenosis without symptoms who were not considered to have a clear
indication for treatment with cholesterol-lowering drugs. Patients were
randomly assigned to receive either intensive cholesterol lowering with the
combination of simvastatin (40 mg daily) and ezetimibe (10 mg daily) or
matching placebo. The first patient was included in 2001. The study was
completed according to the study plan when the last patient included had been
followed for 4 years (March 2008). Vital status at the end of the study was
established for all patients. All data have been checked for completeness and
the data file for analysis was closed on 30 June 2008.
    The scientific leadership of the study was a Steering Committee
consisting of 14 academic representatives of centres in each of the
participating countries and two members (a statistician and a coordinator)
representing the funders. The SEAS study is funded by the pharmaceutical
companies Merck Sharp & Dohme (MSD) and Schering-Plough who market the drugs
being tested. All clinical endpoint events were adjudicated by an independent
committee that was blinded to the study treatment allocation. The study was
monitored by an independent Data Safety and Monitoring Board. Data collection
was performed by MSD, and the data were analyzed by statisticians at Ulleval
University 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 and with
atherosclerotic disease. The secondary endpoints were the two separate
components of the primary endpoint: "aortic valve disease events" (surgical
valve replacement, hospitalization because of heart failure, and
cardiovascular death); and "atherosclerotic disease events" (non-fatal
myocardial infarction, coronary artery bypass surgery or percutaneous coronary
intervention, hospitalization because of unstable angina pectoris,
non-haemorrhagic stroke and cardiovascular death). Subsidiary outcomes
included echocardiographic evidence of aortic stenosis progression and safety.
    Compared with placebo, the combination of simvastatin and ezetimibe
reduced LDL-cholesterol by an average of 61%, corresponding to a reduction of
about 2 mmol/L (76 mg/dl), and this effect was sustained throughout the study.
688 patients had one or more primary endpoint events. No significant
difference was observed between the treatment groups for the combined primary
endpoint (333 patients with an event on LDL-lowering treatment versus 355 on
placebo; hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.83 to 1.12).
Nor was there a significant difference for the secondary endpoint of aortic
valve disease events alone (308 versus 326; HR 0.97; 95% CI 0.83 to 1.14). The
combination of simvastatin and ezetimibe did, however, produce a statistically
significant 22% (95% CI 3% to 37%; p=0.02) proportional reduction in the
secondary endpoint of atherosclerotic events alone: 148 (15.7%) in the
simvastatin plus ezetimibe group versus 187 (20.1%) in the placebo group.
    The study therapy was generally well tolerated, with no significant
differences between the treatment groups in the proportions of patients who
stopped taking study treatment (irrespective of whether it was active or
placebo). In the subsidiary safety analyses, a total of 158 patients were
recorded with a serious adverse event attributed to cancer. More of these
events were observed among patients assigned the combination of simvastatin
and ezetimibe than among those assigned placebo (93 (9.9%) versus 65 (7.0%);
unadjusted p=0.03), and there were also slightly more cancer deaths (39 (4.1%)
versus 23 (2.5%); unadjusted p=0.05). These apparent differences were not
related to any particular type of cancer and did not become significantly
larger with more prolonged treatment.
    The observed differences in cancer in the SEAS study are based on small
numbers and could have occurred as a result of chance. In order to assess
their relevance, the SEAS data have been provided to an independent academic
group for combined analysis with data on cancer from the two other large
trials of simvastatin and ezetimibe, which are still in progress. The SHARP
(Study of Heart and Renal Protection) study is a randomized placebo-controlled
trial of simvastatin and ezetimibe in 9400 patients with chronic kidney
disease. The IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy
International Trial) study is a randomized double-blind trial of simvastatin
and ezetimibe compared to simvastatin alone which has recruited 12,000 of a
planned 18,000 patients with acute coronary disease.
    In combination, the SHARP and IMPROVE-IT studies involve about 4 times as
many cancers as in the SEAS study. The analysis of SHARP and IMPROVE-IT does
not support the suggestion of an increase in cancer that was raised by the
subsidiary analyses of the relatively small numbers of cancers in the SEAS
study. Independent analysis of these data was initiated and has been conducted
and interpreted by the Clinical Trial Service Unit (CTSU) at the University of
Oxford, UK. The CTSU also designed and is conducting the SHARP trial, which is
funded by a research grant to the University of Oxford from MSD and
Schering-Plough academic. Both the SHARP study and the analyses of cancer data
have been conducted by the CTSU independently of the pharmaceutical companies.
Please, refer to the press release issued by the CTSU today.
    In conclusion, the SEAS study has found that intensive LDL-cholesterol
lowering with the combination of simvastatin and ezetimibe in patients with
mild to moderate aortic stenosis does appear to reduce the risk of coronary
artery disease events (as has been shown for many other types of patient in
previous trials) but not the rate of progression of aortic valve disease. The
use of simvastatin and ezetimibe in such patients was generally well tolerated
and safe.




For further information: Terje R. Pedersen, MD, Professor of Medicine,
Head of the Centre for Preventive Medicine, and Chairman of the SEAS trial
Steering Committee, Ulleval University Hospital, Oslo, Norway, mobile
telephone: +47-91-78-71-26, e-mail: t.r.pedersen@medisin.uio.no