Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial

Abstract

Residual cardiovascular risk persists despite statins, yet outcome studies of lipid-targeted therapies beyond low-density lipoprotein cholesterol (LDL-C) have not demonstrated added benefit. Triglyceride elevation is an independent risk factor for cardiovascular events. High-dose eicosapentaenoic acid (EPA) reduces triglyceride-rich lipoproteins without raising LDL-C. Omega-3s have postulated pleiotropic cardioprotective benefits beyond triglyceride-lowering. To date, no large, multinational, randomized clinical trial has proved that lowering triglycerides on top of statin therapy improves cardiovascular outcomes. The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT; NCT01492361) is a phase 3b randomized, double-blinded, placebo-controlled trial of icosapent ethyl, a highly purified ethyl ester of EPA, vs placebo. The main objective is to evaluate whether treatment with icosapent ethyl reduces ischemic events in statin-treated patients with high triglycerides at elevated cardiovascular risk. REDUCE-IT enrolled men or women age ≥45 years with established cardiovascular disease or age ≥50 years with diabetes mellitus and 1 additional risk factor. Randomization required fasting triglycerides ≥150 mg/dL and <500 mg/dL and LDL-C >40 mg/dL and ≤100 mg/dL with stable statin (± ezetimibe) ≥4 weeks prior to qualifying measurements. The primary endpoint is a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Several secondary, tertiary, and exploratory endpoints will be assessed. Approximately 8000 patients have been randomized at approximately 470 centers worldwide. Follow-up will continue in this event-driven trial until approximately 1612 adjudicated primary-efficacy endpoint events have occurred.

Keywords: Clinical trials; General clinical cardiology/adult; Lipidology.

Figure 1

Study design for REDUCE‐IT. During the screening period, patients were evaluated for inclusion/exclusion criteria. If patients met the inclusion criteria at Visit 1, they were asked to return for the randomization visit (Visit 2) and entered the treatment/follow‐up period. Patients who were not eligible at Visit 1 but who became eligible in the next 28 days (such as patients whose statin dose changed at Visit 1 and/or needed to wash out prohibited medications) may have returned for an optional second screening visit (Visit 1.1). Such patients entered a statin stabilization/medication washout period of ≥28 days prior to rescreening. Patients who were eligible following screening/rescreening entered the treatment/follow‐up period, with follow‐up visits occurring at 4 months, 12 months, and annually thereafter. *A study amendment (May 2013) was made, increasing the lower end of the fasting TG level from ≥150 mg/dL to ≥200 mg/dL to increase enrollment of patients with TG ≥200 mg/dL; it is anticipated that mean and median qualifying TG levels will be >200 mg/dL. †Final values to be known at study unblinding. Event‐driven design: approximately 1612 primary efficacy events will be required during the study; study duration will vary accordingly. Abbreviations: CV, cardiovascular; CVD, cardiovascular disease; LDL‐C, low‐density lipoprotein cholesterol; MI, myocardial infarction; REDUCE‐IT, Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial; T2DM, type 2 diabetes mellitus; TG, triglycerides.