Author + information
- Received February 10, 2019
- Revision received February 26, 2019
- Accepted February 28, 2019
- Published online March 18, 2019.
- Deepak L. Bhatt, MD, MPHa,∗ (, )@DLBhattMD,
- Ph. Gabriel Steg, MDb,c,
- Michael Miller, MDd,
- Eliot A. Brinton, MDe,
- Terry A. Jacobson, MDf,
- Steven B. Ketchum, PhDg,
- Ralph T. Doyle Jr., BAg,
- Rebecca A. Juliano, PhDg,
- Lixia Jiao, PhDg,
- Craig Granowitz, MD, PhDg,
- Jean-Claude Tardif, MDh,
- John Gregson, PhDi,
- Stuart J. Pocock, PhDi,
- Christie M. Ballantyne, MDj,
- on Behalf of the REDUCE-IT Investigators∗
- aBrigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School (D.L.B.) Boston, Massachusetts
- bFACT (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
- cNHLI, Imperial College, Royal Brompton Hospital, London, United Kingdom
- dDepartment of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
- eUtah Lipid Center, Salt Lake City, Utah
- fOffice of Health Promotion and Disease Prevention, Department of Medicine, Emory University School of Medicine, Atlanta, GA
- gAmarin Pharma, Inc., Bedminster, New Jersey
- hMontreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
- iDepartment of Medical Statistics, London School of Hygiene & Tropical Medicine, London, United Kingdom
- jDepartment of Medicine, Baylor College of Medicine, Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX
- ↵∗Correspondence: Deepak L. Bhatt, MD, MPH Brigham and Women’s Hospital Heart and Vascular Center Harvard Medical School 75 Francis Street Boston, Massachusetts.
Background In time-to-first-event analyses, icosapent ethyl significantly reduced the risk of ischemic events, including cardiovascular death, among patients with elevated triglycerides receiving statins. These patients are at risk for not only first but also subsequent ischemic events.
Objectives Pre-specified analyses determined the extent to which icosapent ethyl reduced total ischemic events.
Methods The Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT) randomized 8,179 statin-treated patients with triglycerides ≥135 and <500 mg/dL (median baseline of 216 mg/dL) and LDL-cholesterol >40 and ≤100 mg/dL (median baseline of 75 mg/dL), and a history of atherosclerosis (71% patients) or diabetes (29% patients) to icosapent ethyl 4g/day or placebo. The main outcomes were total (first and subsequent) primary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) and total key secondary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). As a pre-specified statistical method, we determined differences in total events using negative binomial regression. We also determined differences in total events using other statistical models, including Andersen-Gill, Wei-Lin-Weissfeld (Li and Lagakos modification), both pre-specified, and a post hoc joint-frailty analysis.
Results In 8,179 patients, followed for a median of 4.9 years, 1,606 (55.2%) first primary endpoint events and 1,303 (44.8%) subsequent primary endpoint events occurred (which included 762 second events, and 541 third or more events). Overall, icosapent ethyl reduced total primary endpoint events (61 versus 89 per 1000 patient years for icosapent ethyl versus placebo, respectively; RR 0.70, 95% CI 0.62-0.78, P<0.0001). Icosapent ethyl also reduced each component of the primary composite endpoint, as well as the total key secondary endpoint events (32 versus 44 per 1000 patient years for icosapent ethyl versus placebo, respectively, RR 0.72, 95% CI 0.63-0.82, P<0.0001).
Conclusions Among statin-treated patients with elevated triglycerides and cardiovascular disease or diabetes, multiple statistical models demonstrate that icosapent ethyl substantially reduces the burden of first, subsequent, and total ischemic events.
Short tweet: REDUCE-IT found large, statistically significant reductions in first, recurrent, and total ischemic events with icosapent ethyl versus placebo.
Conflict of Interest: Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: 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), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), 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), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, Takeda; Dr. Steg, receiving research grant funding from Amarin, Bayer, Merck, Sanofi, and Servier; speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer-Ingelheim, Bristol-Myers-Squibb, Idorsia, Lilly, Merck, Novartis, Novo-Nordisk, Pfizer, Regeneron, Sanofi, Servier; Dr. Brinton, receiving fees as a speaker from Akcea, Amarin, Amgen, Boehringer-Ingelheim, Kowa, Merck, Novo-Nordisk, Regeneron, Sanofi-Aventis, and consulting fees from Akcea, Amarin, Amgen, Kowa, Merck, Precision Biosciences, PTS Diagnostics, Regeneron, Sanofi-Aventis; Dr. Miller, receiving consulting fees from Amarin and Akcea; Dr. Jacobson, receiving consulting fees from AstraZeneca, Amarin, Amgen, Esperion, Novartis, Regeneron, and Sanofi; Dr. Ketchum, Mr. Doyle, Dr. Juliano, Dr. Jiao, and Dr. Granowitz, being employed by and being a stock shareholder of Amarin Pharma; Dr. Tardif, receiving grant support from AstraZeneca, Esperion, and Ionis, grant support and consulting fees from DalCor, grant support and fees for serving as co-chairman of an executive committee from Pfizer, grant support and fees for serving on an executive committee from Sanofi, and grant support and consulting fees from Servier and holding a minor equity interest in DalCor and a patent (U.S. 9,909,178 B2) on Dalcetrapib for Therapeutic Use; Dr. Pocock and Dr. Gregson receiving consultancy fees from Amarin Pharma, Inc.; and Dr. Ballantyne, receiving consulting fees from AstraZeneca, Eli Lilly, Matinas BioPharma, Merck, Boehringer Ingelheim, Novo Nordisk, Denka Seiken, and Gilead and grant support (paid to his institution) and consulting fees from Amarin, Amgen, Esperion, Novartis, Regeneron, Sanofi-Synthelabo, and Akcea. No other potential conflict of interest relevant to this article was reported.
Funding/Support: The study was funded by Amarin Pharma was involved in the study design, collection, analysis, and interpretation, and the development and review of this manuscript. The statistical analysis by Drs. Gregson and Pocock was funded by Amarin Pharma, Inc. The decision to submit the manuscript for publication was made by the authors.
Additional Contributions: Editorial assistance under the direction of the authors, and limited to collation of author comments and formatting, was provided by Joy Bronson MA and Sephy Philip RPh PharmD, employees of Amarin Pharma, Inc. The first draft of the manuscript was written by Dr. Bhatt. The authors wish to acknowledge the following Amarin employees who contributed to the success of the trial and the current analyses: Katelyn Diffin MBA and Angela Granger for clinical operations support; Ramakrishna Bhavanthula MS, Richard H Iroudayassamy, James Jin PhD, Dmitry Klevak MS, Hardik Panchal MS, Robert Wang PhD, and Shin-Ru Wang MS for data management and statistical support. We also thank the investigators, the study.
- Received February 10, 2019.
- Revision received February 26, 2019.
- Accepted February 28, 2019.