Title: Simvastatin and Ezetimibe in Aortic Stenosis (SEAS)
Trial Sponsor: MSP Singapore Company, LLC, Singapore, a partnership between Merck & Co., Inc., and the Schering-Plough Corporation
Year Presented: 2008
Topic(s): General Cardiology, Noninvasive Cardiology, Prevention/Vascular
Summary Posted: 7/21/2008 2:00:00 PM
Writer: Dharam J Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., F.A.C.C.
Author Disclosure: Research Grants: Eisai, Significant (>= $10,000); Research Grants: Sanofi Aventis, Significant (>= $10,000); Research Grants: Bristol Myers Squibb, Significant (>= $10,000); Research Grants: Ethicon, Significant (>= $10,000); Research Grants: The Medicines Company, Significant (>= $10,000); Research Grants: Heartscape, Significant (>= $10,000)

Description
Some preliminary data suggest that statin therapy may have a beneficial effect on calcific aortic stenosis (AS). Accordingly, the goal of SEAS, a double-blind, randomized controlled trial, was to investigate whether aggressive lipid lowering with ezetimibe/simvastatin 10/40 mg daily in asymptomatic AS patients is associated with improved cardiovascular outcomes, compared with placebo.
Hypothesis
The use of aggressive lipid lowering with ezetimibe/simvastatin is associated with a reduction in the need for aortic valve replacement and the risk of cardiovascular mortality and morbidity in patients with asymptomatic AS, compared with placebo.
Drugs/Procedures Used
After a 4-week diet/placebo run-in period, patients were randomized to either ezetimibe/simvastatin 10/40 mg daily or matching placebo.
Concomitant Medications
Angiotensin-converting enzyme inhibitor (15.1%), beta-blockers (26.9%), calcium channel blockers (16.7%), diuretics (23.0%), and aspirin (25.8%)
Principal Findings
A total of 1,873 patients from 173 centers in 7 European countries were randomized. About 51% of patients had hypertension, 19.2% were smokers, and 27.9% had a family history of coronary artery disease. Concomitant aortic regurgitation (grade 2 or 3) was noted in 15.3% of patients, whereas mitral regurgitation was noted in 1.9% of the patients. The mean aortic valve area was 1.28 ± 0.47 cm2, with a peak and mean gradient of 39/23 mm Hg. The mean ejection fraction was 66%; about 16% had ejection fractions lower than 50%. The mean baseline total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were 222 ± 39, 139 ± 36, 58 ± 17, and 126 ± 61 mg/dl, respectively.

Compared with placebo, there was a 76 mg/dl reduction in LDL cholesterol (61%) noted in the ezetimibe/simvastatin arm. There was no difference in the incidence of the composite primary endpoint between the ezetimibe/simvastatin arm and placebo (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.83-1.12). There was also no difference between the two arms in the incidence of aortic valve disease endpoints (HR 0.97, 95% CI 0.83-1.14). There was a significant reduction in the incidence of atherosclerotic adverse events in the ezetimibe/simvastatin arm compared with placebo (15.7% vs. 20.1%, p = 0.02).

An adverse event attributable to cancer was noted more frequently in the ezetimibe/simvastatin arm, as compared with placebo (9.9% vs. 7.0%, p = 0.03). Cancer deaths were also more frequent in the ezetimibe/simvastatin arm (4.1% vs. 2.5%, p = 0.05). On further scrutiny, these differences did not seem to be related to any particular type of cancer and did not become significantly larger with more prolonged treatment.
Interpretation
The results of the large randomized SEAS trial demonstrate that ezetimibe/simvastatin 10/40 mg daily is not associated with a reduction in the progression of AS in asymptomatic AS patients with mild to moderate AS. There is, however, a significant reduction in atherosclerotic events in patients who receive ezetimibe/simvastatin compared with placebo, which has been demonstrated in other trials of statins as well. While the higher incidence of cancer and cancer-related deaths in the ezetimibe/simvastatin arm may represent a safety concern, it is unknown if this represents a cause-effect relationship or a chance association. Ongoing large clinical trials with ezetimibe/simvastatin such as SHARP (Study of Heart and Renal Protection) and IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) will shed further light on this topic, although interim analysis does not suggest such an effect.
Conditions
• Valvular heart disease
• Prevention/Secondary

Therapies
• Lipid-lowering agent/ezetimibe
• Lipid-lowering agent / HMG CoA Reductase Inhibitor / Simvastatin

Study Design
Placebo controlled. Randomized. Blinded. Parallel.

Patients Enrolled: 1,873
Mean Follow-Up: 4 years
Mean Patient Age: 68 years
% Female: 39

Mean Ejection Fraction: 66%

Primary Endpoints
Composite of cardiovascular death, aortic valve replacement surgery, nonfatal myocardial infarction (MI), congestive heart failure (CHF) from AS progression, coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), hospitalized unstable angina, and nonhemorrhagic stroke
Secondary Endpoints

Aortic valve disease:
Aortic valve replacement
CHF from AS progression
Cardiovascular death
Atherosclerotic disease events
Nonfatal MI
CABG
PCI
Hospitalization for unstable angina
Nonhemorrhagic stroke
Cardiovascular death
Echocardiographic progression of AS
Safety of ezetimibe/simvastatin
Patient Population

Age 45-85 years
Asymptomatic AS, with aortic flow velocity =2.5 and =4.0 m/sec (mild to moderate AS)
Exclusions:

Other significant valvular heart disease, including rheumatic AS, supra- or sub-valvular AS
Systolic heart failure
Established coronary, cerebral, and/or peripheral vascular disease
Diabetes mellitus
Planned aortic valve replacement or coronary revascularization
Serum creatinine >1.8 mg/dl
Uncontrolled metabolic, endocrine, or active liver disease
Previously on lipid-lowering therapy
LDL cholesterol >232 mg/dl, or if local guidelines required lipid-lowering therapy
References: Press conference, Dr. Terje Pederson on behalf of the SEAS investigators, July 21, 2008, London. Press release.

Source
Content provided by the American College of Cardiology Foundation