EWTOPIA 75 Trial: Lowering LDL-Cholesterol with Ezetimibe Prevents Cardiovascular Events in the Elderly

Mandana Chitsazan, M.D.
By Mandana Chitsazan, M.D. on

Individuals older than 75 years treated with ezetimibe had a significantly lower risk of atherosclerotic cardiovascular events over 4 years compared with standard care, according to the results of the EWTOPIA 75 trial recently published in Circulation.

A recent post hoc analysis of the IMPROVE-IT trial has revealed beneficial effects of adding ezetimibe to simvastatin in patients older than 75 years hospitalized for an acute coronary syndrome (ACS). However, evidence regarding the primary prevention of coronary artery disease events by intense low-density lipoprotein cholesterol (LDL-C) lowering therapy in the elderly is limited. The EWTOPIA 75 trial aimed to assess the utility of ezetimibe for the primary prevention of atherosclerotic cardiovascular events in the elderly.

This multicenter, prospective, and blinded RCT was conducted at 363 medical centers in Japan. Patients aged ≥ 75 years, with elevated LDL-C and without any history of coronary artery disease were assigned in a 1:1 ratio to receive a once-daily dose of ezetimibe 10 mg as well as dietary counseling versus dietary counseling alone (control group). The primary outcome was a composite of sudden cardiac death, fatal/nonfatal myocardial infarction, coronary revascularization, or fatal/nonfatal stroke. Some of the secondary outcomes included any components of the primary outcome, all-cause mortality, all-cause hospitalizations, atrial fibrillation, incident malignancy, and adverse effects.

Overall, data from 1716 patients in the ezetimibe group and 1695 patients in the control group were included in the analysis. Median follow-up was 4.1 years. Ezetimibe significantly reduced the incidence of the primary outcome of interest (hazard ratio [HR], 0.66; 95% CI, 0.50–0.86; P = 0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37–0.98; P = 0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18–0.79; P = 0.007) were lower in the ezetimibe group compared with the control group. Two groups were comparable in regard to the risk for stroke, all-cause mortality, or adverse events.

This is the first RCT demonstrating that LDL-C–lowering therapy with ezetimibe prevented cardiovascular events in older individuals aged ≥ 75 years with elevated LDL-C. Moreover, ezetimibe was well tolerated and did not increase the incidence of adverse events as compared with the control group”, the investigators concluded.

The study had some significant limitations. Only outcome assessors were blinded. The investigators did not use a matching placebo in the control group. Moreover, the number of lost to follow up and excluded cases after randomization were quite high. All the patients were Japanese and therefore, the results might not be generalizable to other ethnicities. Lastly, the trial ended up sooner while less than 65% of the desired sample size was recruited.



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