Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)

Abstract

Background: IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) showed that adding the nonstatin ezetimibe to statin therapy further reduced cardiovascular events in patients after an acute coronary syndrome. In a prespecified analysis, we explore results stratified by sex.

Methods and results: In IMPROVE-IT, patients with acute coronary syndrome and low-density lipoprotein cholesterol of 50 to 125 mg/dL were randomized to placebo/simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg. They were followed up for a median of 6 years for the primary composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, coronary revascularization ≥30 days, and stroke. Among 18 144 patients in IMPROVE-IT, 4416 (24%) were women. At 12 months, the addition of ezetimibe to simvastatin significantly reduced low-density lipoprotein cholesterol from baseline compared with simvastatin monotherapy in men and women equally (absolute reduction, 16.7 mg/dL in men and 16.4 mg/dL in women). Women receiving ezetimibe/simvastatin had a 12% risk reduction over those receiving placebo/simvastatin for the primary composite end point (hazard ratio, 0.88; 95% confidence interval, 0.79-0.99) compared with a 5% reduction for men (hazard ratio, 0.95; 95% confidence interval, 0.90-1.01; P=0.26 for interaction). When the total number of primary events was considered, women had an 18% reduction with the addition of ezetimibe (relative risk, 95% confidence interval, 0.81; 0.71-0.94) and men had a 6% reduction (relative risk, 0.94; 95% confidence interval, 0.87-1.02; P=0.08 for interaction). The addition of ezetimibe did not increase the rates of safety events in either women or men.

Conclusions: IMPROVE-IT demonstrated that the benefit of adding ezetimibe to statin is present in both women and men, with a good safety profile supporting the use of intensive, combination, lipid-lowering therapy to optimize cardiovascular outcomes.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00202878.

Keywords: cholesterol; chronic ischemic heart disease; coronary artery disease; ezetimibe; lipids and lipoprotein metabolism; secondary prevention; sex; women.

Figure 1

Seven year Kaplan‐Meier estimate curves of primary end point by sex. The treatment effects were similar between women and men for the primary end point of cardiovascular death, major coronary event (nonfatal myocardial infarction, rehospitalization for unstable angina, or coronary revascularization event occurring at least 30 days after randomization), or nonfatal stroke (P=0.26 for interaction). The Kaplan‐Meier rates at 7 years were 34.0% with placebo/simvastatin and 31.0% with ezetimibe/simvastatin in women and 34.9% with placebo/simvastatin and 33.3% with ezetimibe/simvastatin in men. EZE indicated ezetimibe; HR, hazard ratio; PBO, placebo; Simva, Simvastatin.

Figure 2

Efficacy outcomes by sex. Women had a significant 22% reduction of myocardial infarction and a 12% reduction of major adverse cardiac events (composite of cardiovascular death, myocardial infarction, and stroke) with ezetimibe compared with placebo. There were no significant treatment interactions by sex for any of the end points. CHD indicates coronary heart disease; CI, confidence interval; Eze, ezetimibe; HR, hazard ratio; KM, Kaplan‐Meier; PBO, placebo; P _int, P value for interaction; Simva, simvastatin.

Figure 3

Total primary end point by sex. Adding ezetimibe to simvastatin reduced the total number of primary end points in both men and women (P=0.08 for interaction). RR indicates relative reduction.

Figure 4

Risk stratification by sex. Approximately half of the men were categorized as low risk, and fewer men were at high risk compared with women.

Figure 5

Cumulative incidence of cardiovascular death, myocardial infarction, and ischemic stroke by risk stratification and treatment group in women and men. Each risk indicator (ie, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke, prior coronary artery bypass grafting, peripheral arterial disease, estimated glomerular filtration rate <60 ml/min/1.73 m², and current smoking) is assigned 1 point. Low risk, 0 or 1 risk indicator; intermediate risk, 2 risk indicators; and high risk, ≧3 risk indicators. Women categorized as high risk benefitted the most from adding ezetimibe to simvastatin, whereas no benefit was observed in women who were categorized as low risk. Eze indicates ezetimibe; HR, hazard ratio; PBO, placebo; Simva, simvastatin.