Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT

Abstract

Background: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE.

Objectives: The purpose of this study was to determine the effects of IPE on investigator-reported events.

Methods: Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance.

Results: There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints.

Conclusions: IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).

Keywords: central adjudication; clinical trials; icosapent ethyl; investigator-reported endpoints.

Conflict of interest statement

Funding Support and Author Disclosures Dr Bhatt has served as the Chair and International Principal Investigator for REDUCE-IT, with research funding from Amarin to Brigham and Women’s Hospital; has served on the Advisory Board of Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Regado Biosciences; has served on the Board of Directors of Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; has served as Inaugural Chair of the American Heart Association Quality Oversight Committee; has served on Data Monitoring Committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), and the Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), 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; has served as Chair of the NCDR-ACTION Registry Steering Committee and VA CART Research and Publications Committee; has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company, and 89Bio; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, St Jude Medical (now Abbott), and Svelte; was a Trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, Merck, and Takeda. Dr Giugliano’s institution has received research grant support from Amgen, Bristol Myers Squibb, Merck, and The Medicines Company for clinical trials in lipid therapies; and has received honoraria for CME programs and/or consulting from Akcea, Amarin, Agmen, Bristol Myers Squibb, CVS Caremark, Daiichi-Sankyo, GlaxoSmithKline, Merck, and Pfizer. Dr Steg has received research grant funding from Amarin, Bayer, Merck, Sanofi, and Servier; and has received speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol Myers Squibb, Idorsia, Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, and Servier. Dr Miller has received consulting fees from Amarin and Akcea. Dr Brinton has received fees as a speaker from Amarin, Amgen, Kowa, Regeneron, and Sanofi; and has received consulting fees from Akcea, Amarin, Amgen, Esperion, Kowa, Medicure, PTS Diagnostics, Regeneron, and Sanofi. Dr Jacobson reports receiving consulting fees from Amgen, Esperion, Novartis, Regeneron, and Sanofi. Drs Ketchum, Juliano, Jiao, and Granowitz, and Mr Doyle are employed by and stock shareholders of Amarin Pharma. Dr Tardif has received grant support from AstraZeneca, Esperion, and Ionis; has received grant support and consulting fees from DalCor and Servier; has received grant support and fees for serving as co-chairman of an executive committee from Pfizer; has received grant support and fees for serving on an executive committee from Sanofi; and holds a minor equity interest in DalCor and a patent (US 9,909,178 B2) on dalcetrapib for therapeutic use. Dr Ballantyne has received consulting fees from Arrowhead, AstraZeneca, Eli Lilly, Matinas BioPharma, Merck, Boehringer Ingelheim, Novo Nordisk, Denka Seiken, and Gilead; and has received grant support (paid to his institution) and consulting fees from Amarin, Amgen, Esperion, Novartis, Regeneron, Sanofi-Synthelabo, and Akcea. Dr Pinto has received consulting fees from Abbott Vascular, Abiomed, Boston Scientific, Medtronic, and Teleflex; and has received consulting fees and stock options from NuPulseCV. Dr Budoff has received grant support and is on the speaker’s bureau for Amarin Pharmaceuticals. Dr Gibson has received research grant support and consulting fees from Amarin. Dr Gaba has reported that she has no relationships relevant to the contents of this paper to disclose.

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