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

• Authors: Deepak L. Bhatt, Brigham & Womens Hospital; Ph. Gabriel Steg, University of Paris Diderot; Eliot A. Brinton, Utah Foundation for Biomedical Research; Terry A Jacobson, Emory University; Michael Miller, University of Maryland; Jean-Claude Tardif, University of Montreal; Steven B. Ketchum, Amarin Pharma Inc.; Ralph T. Doyle, Jr., Amarin Pharma Inc.; Sabina A. Murphy, Harvard Medical School; Paresh N. Soni, Albireo Pharma.; Rene A. Braeckman, Amarin Pharma Inc.; Rebecca A. Juliano, Amarin Pharma Inc.; Christie M. Ballantyne, Baylor College of Medicine
• Journal Title: Clinical Cardiology
• Volume: Volume 40, Number 3
• Publisher: Wiley Open Access: Various Creative Commons Licenses | 2017-03-01, Pages 138-148
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1002/clc.22692
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cardiac & Cardiovascular Systems; Cardiovascular System & Cardiology; Clinical trials; General clinical cardiology/adult; Lipidology; CORONARY-HEART-DISEASE; ESTER AMR101 THERAPY; EICOSAPENTAENOIC ACID; HYPERCHOLESTEROLEMIC PATIENTS; STATIN THERAPY; RISK-FACTORS; DOUBLE-BLIND; FATTY-ACIDS; TRIGLYCERIDE; OMEGA-3-FATTY-ACIDS

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.