title: 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.
authors.affiliation: Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Deepak L
authors.identifier: http://orcid.org/0000-0002-1278-6245
authors.initials: DL
authors.lastname: Bhatt
authors.affiliation: FACT (French Alliance for Cardiovascular Trials), an F-CRIN network, Département Hospitalo-Universitaire FIRE, AP-HP, Hôpital Bichat, Université Paris-Diderot, INSERM U-1148, Paris, France.|NHLI, Imperial College, Royal Brompton Hospital, London, United Kingdom.
authors.forename: Ph Gabriel
authors.initials: PG
authors.lastname: Steg
authors.affiliation: Utah Foundation for Biomedical Research, and Utah Lipid Center, Salt Lake City.
authors.forename: Eliot A
authors.initials: EA
authors.lastname: Brinton
authors.affiliation: Office of Health Promotion and Disease Prevention, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Terry A
authors.initials: TA
authors.lastname: Jacobson
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore.
authors.forename: Michael
authors.initials: M
authors.lastname: Miller
authors.affiliation: Montreal Heart Institute, Université de Montréal, Québec, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: Amarin Pharma Inc., Bedminster, New Jersey.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Ketchum
authors.affiliation: Amarin Pharma Inc., Bedminster, New Jersey.
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Doyle
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: Amarin Pharma Inc., Bedminster, New Jersey.|Albireo Pharma, Boston, Massachusetts.
authors.forename: Paresh N
authors.initials: PN
authors.lastname: Soni
authors.affiliation: Amarin Pharma Inc., Bedminster, New Jersey.|KemPharm, Inc., Celebration, Florida.
authors.forename: Rene A
authors.initials: RA
authors.lastname: Braeckman
authors.affiliation: Amarin Pharma Inc., Bedminster, New Jersey.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Juliano
authors.affiliation: Department of Medicine, Baylor College of Medicine, and Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, Texas.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
mesh_terms: D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005260:Female; D005500:Follow-Up Studies; D005602:France / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D011446:Prospective Studies; D011792:Quebec / Q000453:epidemiology; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom / Q000453:epidemiology; D014481:United States / Q000453:epidemiology
chemical_list: D010975:Platelet Aggregation Inhibitors; C035276:eicosapentaenoic acid ethyl ester; D015118:Eicosapentaenoic Acid
keywords: Clinical trials; General clinical cardiology/adult; Lipidology