Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis

N Engl J Med. 2008 Sep 25;359(13):1343-56. doi: 10.1056/NEJMoa0804602. Epub 2008 Sep 2.

Abstract

Background: Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results.

Methods: We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events.

Results: During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin-ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97). Fewer patients had ischemic cardiovascular events in the simvastatin-ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs. 70, P=0.01).

Conclusions: Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic-valve events and ischemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. (ClinicalTrials.gov number, NCT00092677.)

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alanine Transaminase / blood
  • Anticholesteremic Agents / adverse effects
  • Anticholesteremic Agents / therapeutic use*
  • Aortic Valve Stenosis / drug therapy*
  • Aortic Valve Stenosis / surgery
  • Aspartate Aminotransferases / blood
  • Azetidines / adverse effects
  • Azetidines / therapeutic use*
  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / mortality
  • Cardiovascular Diseases / prevention & control
  • Cholesterol, LDL / blood
  • Coronary Artery Bypass
  • Disease Progression
  • Double-Blind Method
  • Drug Therapy, Combination
  • Ezetimibe
  • Female
  • Follow-Up Studies
  • Heart Valve Prosthesis Implantation / statistics & numerical data
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Neoplasms / chemically induced
  • Simvastatin / adverse effects
  • Simvastatin / therapeutic use*
  • Treatment Outcome

Substances

  • Anticholesteremic Agents
  • Azetidines
  • Cholesterol, LDL
  • Simvastatin
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Ezetimibe

Associated data

  • ClinicalTrials.gov/NCT00092677