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

LONDON, 27 july 2008-- The SEAS (Simvastatin and Ezetimibe in
Aortic Stenosis) study has investigated the effects of intensive
cholesterol lowering with the combination of simvastatin (40 mg 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.