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

London (ots/PRNewswire) - 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
Ullevål 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.

ots Originaltext: Prof Terje Pedersen, SEAS Study Principal Investigator & Head of Steering Committee
Im Internet recherchierbar: http://www.presseportal.de

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