Simvastatin and Ezetimibe in Aortic Stenosis - SEAS

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 moderate AS patients is associated with improved cardiovascular outcomes, compared with placebo.

Hypothesis:

The use of aggressive lipid lowering with ezetimibe/simvastatin will be associated with a reduction in the need for aortic valve replacement and the risk of cardiovascular mortality and morbidity in patients with asymptomatic moderate AS, compared with placebo.

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%

Patient Populations:

  • 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

Primary Endpoints:

Composite of cardiovascular death, aortic valve replacement surgery, nonfatal myocardial infarction (MI), congestive heart failure (CHD) from AS progression, 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

Drug/Procedures Used:

After a 4-week diet/placebo run-in period, patients were randomized to either ezetimibe/simvastatin 10/40 mg daily (n = 944) or matching placebo (n = 929).

Concomitant Medications:

Angiotensin-converting enzyme inhibitors (15%), beta-blockers (27%), calcium channel blockers (17%), diuretics (24%), and aspirin (26%)

Principal Findings:

A total of 1,873 patients from 173 centers in 7 European countries were randomized. Approximately 51% of patients had hypertension, 19% were smokers, and 28% had a family history of coronary artery disease. Concomitant aortic regurgitation (grade 2 or 3) was noted in 15% 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). This was determined by less coronary artery bypass grafting (CABG) in the ezetimibe/simvastatin arm (7.3% vs. 10.8%, p = 0.02).

Incident cancer was noted more frequently in the ezetimibe/simvastatin arm, as compared with placebo (11.1% vs. 7.5%, p = 0.01). Cancer deaths were also more frequent in the ezetimibe/simvastatin arm (4.1% vs. 2.5%, p = 0.05). 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, driven by a reduction in the need for CABG. Although the higher incidence of cancer and cancer-related deaths in the ezetimibe/simvastatin arm may represent a safety concern, combined analysis of the IMPROVE-IT and SHARP trials does not support this association.

References:

Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;Sep 2:[Epub ahead of print].

Detailed Results From the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) Trial. Presented by Dr. Terje Pedersen at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.

Press conference, Dr. Terje Pedersen on behalf of the SEAS investigators, July 21, 2008, London. Press release.

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Valvular Heart Disease, Congenital Heart Disease, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Diet, Hypertension, Mitral Regurgitation

Keywords: Heart Defects, Congenital, Cholesterol, LDL, Mitral Valve Insufficiency, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Calcinosis, Simvastatin, Cholesterol, Azetidines, Cholesterol, HDL, Confidence Intervals, Diet, Triglycerides, Hypertension


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