Ezetimibe plus statin therapy consistently reduces the risk for cardiovascular events in patients after acute coronary syndrome (ACS), regardless of low-density lipoprotein cholesterol (LDL-C) levels, according to research results published in the Journal of the American College of Cardiology.  

Investigators analyzed data from the IMPROVE-IT Trial (ClinicalTrials.gov Identifier: NCT00202878) to evaluate the relationship between baseline LDL-C levels and the benefit of intensive lipid-lowering therapy with ezetimibe plus statins in patients after ACS.

IMPROVE-IT was a randomized, double-blind, placebo-controlled trial that included 18,144 participants hospitalized with ACS in the preceding 10 days with an LDL-C level of 50 to 100 mg/dL. Patients were randomly assigned to receive either ezetimibe 10 mg plus simvastatin 40 mg or a matching placebo plus simvastatin once daily. Patients were followed-up for a median of 6 years (interquartile range [IQR], 4.3-7.1 years).


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Patients in either treatment group with LDL-C greater than 79 mg/dL on 2 consecutive measurements had their simvastatin dose increased to 80 mg. As a result of the US Food and Drug Administration (FDA) guidance in 2011, those who were receiving simvastatin 80 mg for less than 1 year started receiving a reduced dose of 40 mg, with future uptitration to 80 mg not permitted.

Prespecified trial efficacy endpoints were used in the study. The primary endpoint was a composite of death from cardiovascular disease, a major coronary event (nonfatal myocardial infarction [MI], documented unstable angina requiring hospital admission, or coronary revascularization) or ischemic or hemorrhagic stroke. The 3 secondary efficacy endpoints included a composite of death from any cause, major coronary event, or stroke; a composite of death from coronary heart disease, MI, or urgent coronary revascularization at least 30 days after randomization; and a composite of CV death, MI, hospitalization for unstable angina, all arterial revascularization at least 30 days after randomization, or stroke.

Prespecified safety endpoints included abnormal liver and creatinine kinase level elevations, myopathy, rhabdomyolysis, hepatobiliary events, cancer, and adverse events leading to drug discontinuation.

The cohort for the analysis included 17,999 patients with baseline LDL-C data and a qualifying ACS event. Within this group, 8990 patients were randomly assigned to receive ezetimibe/simvastatin and 9009 to receive placebo/simvastatin.

Patients with lower LDL-C at baseline were older, more likely to be men, and had a greater prevalence of atherosclerotic risk factors and CV diseases, as well as chronic statin therapy prior to admission. Baseline characteristics were similar between treatment arms and within LDL-C groups.

Median baseline LDL-C levels were 62 mg/dL, 86 mg/dL, and 113 mg/dL in the 3 groups stratified by baseline LDL-C (50 to <70, 70 to <100, and 100-125 mg/dL, respectively). A “significant and progressively greater” absolute LDL-C reduction was observed between baseline and month 4 as baseline LDL-C increased in both treatment arms, with similar absolute differences in median LDL-C achieved at 4 months.

Hazard ratio (HR) for the primary endpoint at 7 years with ezetimibe/simvastatin vs placebo/simvastatin was 0.93 (95% CI, 0.89-0.99). Relative risk reductions in the primary endpoint in both groups were consistent among the 3 baseline LDL-C categories.

In the lowest LDL-C group, the primary endpoint occurred in 38.3% vs 42.2% in each treatment group (HR, 0.92; 95% CI, 0.80-1.05), with an absolute risk reduction consistent across baseline LDL-C categories.

Analyzing LDL-C as a continuous variable, the benefit of ezetimibe/simvastatin vs placebo/simvastatin was similar across LDL-C values from 50 to 125 mg/dL. Normalized relative risk reductions in the primary endpoint, per 1 mmol/L difference in LDL-C at 4 months, was 16% overall, 21% in the LDL-C 50 to less than 70 mg/dL group, 16% in the 70 to less than 100 mg/dL group, and 13% in the 100 to 125 mg/dL group.

Intensive lipid-lowering therapy with ezetimibe/simvastatin vs placebo/simvastatin consistently reduced 7-year event rates of each secondary endpoints, regardless of baseline LDL-C.

Rates of discontinuation due to adverse events were similar between the treatment groups across the baseline LDL-C categories (7.2% vs 7.8%, 7.7% vs 7.2%, and 8.6% vs 8.0%, respectively).

Study limitations included the fact that the study design that was not intended to detect differences in treatment effect as a function of baseline LDL-C; post-hoc cutpoints of 70 and 100 mg/dL; the inclusion of only patients hospitalized with recent ACS, and the use of 40 mg simvastatin, which was not representative of a maximally potent statin regimen.

“Adding ezetimibe to statin therapy consistently, and in a generally well-tolerated manner, reduced the risk for [cardiovascular] events in patients post-ACS across a range of baseline LDL-C concentrations,” the researchers concluded. “These data support the use of further intensification of [lipid-lowering therapy] by adding ezetimibe to statin in ACS patients with baseline LDL-C of [less than] 70 mg/dL.”

Disclosure: This clinical trial was supported by Merck and Co. Please see the original reference for a full list of authors’ disclosures.

Reference

Oyama K, Giugliano RP, Blazing MA, et al. Baseline low-density lipoprotein cholesterol and clinical outcomes of combination ezetimibe with statin therapy in IMPROVE-IT. J Am Coll Cardiol. 2021:78(15):1499-1507. doi:10.1016/j.jacc.2021.08.001

This article originally appeared on The Cardiology Advisor