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.

Conflict of interest statement

Dr. Bhatt has served on advisory boards for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; has served on the board of directors for Boston VA Research Institute and Society of Cardiovascular Patient Care; has been chair of the American Heart Association Quality Oversight Committee; has served on data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and the Population Health Research Institute; has received honoraria from the American College of Cardiology (senior associate editor, clinical trials and news, for acc.org), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (CME steering committees); has served as deputy editor of Clinical Cardiology, as chair of the NCDR‐ACTION Registry Steering Committee, and as chair of the VA CART Research and Publications Committee; has received research funding from Amarin (for his role as chair of the steering committee and principal investigator of REDUCE‐IT), Amgen, AstraZeneca, Bristol‐Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi‐Aventis, and The Medicines Company; has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); has served as site co‐investigator for Biotronik, Boston Scientific, and St. Jude Medical; has served as a trustee of the American College of Cardiology; and reports unfunded research with FlowCo, PLx Pharma, and Takeda. Dr. Steg has received research grants from Merck, Sanofi, and Servier and has received speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, CSL‐Behring, Daiichi‐Sankyo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and The Medicines Company. Dr. Brinton has received speaking and/or consulting honoraria from Alexion, Amarin, Amgen, Aralez, Arisaph, AstraZeneca, Janssen, Kastle, Kowa, Merck, PTS Diagnostics, Regeneron, and Sanofi‐Aventis and has received research funding from Amarin (for his role as steering committee member of REDUCE‐IT) and Kowa (for his role as steering committee member of PROMINENT). Dr. Jacobson has served as a consultant for Amarin, Amgen, AstraZeneca, Merck, Regeneron, and Sanofi and has done research for Amgen and Regeneron/Sanofi. Dr. Miller has served as a consultant for Amarin, Akcea, Gemphire, and Pfizer. Dr. Tardif has received research grants from Amarin, AstraZeneca, DalCor, Eli Lilly, Esperion, Merck, Pfizer, Sanofi, and Servier; has received honoraria from Amarin, AstraZeneca, DalCor, Sanofi, and Servier; and holds equity (modest position) in DalCor. Drs. Ketchum, Soni, Braeckman, and Juliano, and Mr. Doyle, are current or former Amarin employees and shareholders. Ms. Murphy has served as a consultant for Amarin and received honoraria from Merck. Dr. Ballantyne discloses grant/research support (all paid to the institution, not individual) from Amarin, Amgen, Eli Lilly, Esperion, Ionis, Novartis, Pfizer, Regeneron, Sanofi‐Synthelabo, the National Institutes of Health, the American Heart Association, and the American Diabetes Association, and has served as a consultant for Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, Ionis, Matinas BioPharma Inc, Merck, Novartis, Pfizer, Regeneron, and Sanofi‐Synthelabo.

© 2017 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.

Figures

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.