Adding ezetimibe to statins in ACS may improve cardiovascular outcomes

Combined with statin therapy, ezetimibe appears to lower the risk of cardiovascular events more than simvastatin alone, according to a new study.

During the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), 18,144 patients who were recently hospitalized with an acute coronary syndrome were randomly assigned to 10 mg of simvastatin per day plus 40 mg of ezetimibe or to 10 mg of simvastatin plus placebo. The study, which was supported by a drug manufacturer, was published online on June 3 by the New England Journal of Medicine.

At baseline, patients had an LDL cholesterol level of 50 mg/dL or higher. The maximum LDL to participate was 125 mg/dL for patients already on lipid therapy and 100 mg/dL for those not on therapy. If LDL cholesterol was greater than 79 mg/dL on 2 measurements after treatment initiation, as occurred in 6% of the combination group and 27% of the monotherapy group, simvastatin was increased to 80 mg.

After 1 year, the mean LDL cholesterol level was 53.2 mg/dL in the simvastatin/ezetimibe group versus 69.9 mg/dL in the simvastatin-only group. The primary end point was a composite of cardiovascular death, major coronary event, or nonfatal stroke. After 7 years, the rate of the primary end point was 2% lower in the combined group than in the monotherapy group (32.7% vs. 34.7%, P=0.016). There were no significant differences in rates of adverse events between the 2 study groups, although the benefits appeared to be greater in patients with diabetes mellitus and in patients 75 years of age and older.

The study noted several limitations, such as how the study population was very specific, how ezetimibe was not individually tested, and how about a quarter of patients in the monotherapy group were taking high-dose simvastatin, which the FDA no longer recommends. Still, the study authors concluded that ezetimibe lowered LDL cholesterol and improved cardiovascular outcomes and that this LDL lowering provided benefit to patients whose levels already were already within guideline recommendations.

The IMPROVE-IT study “offers important new evidence in favor of the LDL hypothesis,” which asserts that LDL cholesterol is a causal factor in developing atherosclerotic vascular disease and that reducing LDL levels, regardless of the means, should produce a corresponding reduction in cardiovascular events, according to an accompanying editorial.

Aside from being the first clinical trial to show a benefit of adding a nonstatin lipid-modifying agent to statin therapy, IMPROVE-IT also reinforces previous research, the editorialists wrote. This study shows almost exactly the same hazard ratio for clinical benefit per millimole of LDL cholesterol reduction with ezetimibe (0.80) as compared with 0.78 observed with statins in a past analysis “which suggests that reduction of LDL cholesterol levels per se explains the effect of statins on coronary heart disease,” the editorial states. “Perhaps the LDL hypothesis should now be considered the ‘LDL principle.’”