About this item:

72 Views | 57 Downloads

Author Notes:

Correspondence: Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, 75 Francis Street, Boston, MA 02115. Email: dlbhattmd@post.harvard.edu

Editorial assistance under the direction of the authors, and limited to collation of author comments and formatting, was provided by Joy Bronson, MA, an employee of Amarin Pharma, Inc. The first draft of the article was written by Dr Bhatt.

The authors thank the following Amarin employees who contributed to the success of the trial and the current analyses: Katelyn Diffin, MBA, and Angela Granger, BA for clinical operations support; and Ramakrishna Bhavanthula, MS; Richard H. Iroudayassamy, BS; James Jin, PhD; Dmitry Klevak, MS; Gang Liu, PhD; Hardik Panchal, MS; Jimmy Shi, MS; Robert Wang, PhD; and Shin-Ru Wang, MS; for data management and statistical support.

The analyses were validated by the following employees of the Baim Institute for Clinical Research with funding from Amarin: Qi Gao, MS; Jane J. Lee, PhD; and Xiaohua Chen, MS.

The authors also thank the investigators, the study coordinators, and the patients who participated in the REDUCE-IT trial, including the clinical site personnel and patients in the United States across more than 200 institutions in more than 40 states.

Disclosures: Dr Bhatt had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to the conception and design of the study, data analysis/interpretation, and revision of the article for intellectual content and provided final approval of the article.

Dr Bhatt discloses the following relationships: advisory board: Cardax, Cereno Scientific, Elsevier PracticeUpdate 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; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), 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), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national coleader, 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, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, PLX Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site coinvestigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; trustee: American College of Cardiology; unfunded research: FlowCo, Merck, Novo Nordisk, Takeda. Dr Miller reports receiving consulting fees from Amarin and Akcea. Dr Brinton reports receiving fees as a speaker from Amarin, Amgen, Kowa, Regeneron, and Sanofi-Aventis, and consulting fees from Akcea, Amarin, Amgen, Esperion, Kowa, Medicure, PTS Diagnostics, Regeneron, and Sanofi-Aventis.

Dr Jacobson reports receiving consulting fees from Amgen, Esperion, Novartis, Regeneron, and Sanofi. Dr Steg reports receiving research grant funding from Amarin, Bayer, Merck, Sanofi, and Servier; and 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 Ketchum, R.T. Doyle, Dr Juliano, Dr Jiao, and Dr Granowitz report being employed by and being stock shareholders of Amarin Pharma.

Dr Tardif reports 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 (US 9,909,178 B2) on Dalcetrapib for Therapeutic Use. Dr Olshansky reports serving as Amarin DSMB, Boehringer Ingelheim GLORIA AF US co-coordinator, Sanofi consultant, Lundbeck speaker and consultant, and Respitonics consultant.

Dr Chung served on the Amarin DSMB but has no relevant financial disclosures.

Dr Gibson reports research grant support and consulting fees from Amarin.

Dr Giugliano reports that his institution received research grant support from Amgen, Bristol-Myers Squibb, Merck, and The Medicines Company for clinical trials in lipid therapies, and honoraria for CME programs and/or consulting from Akcea, Amarin, Agmen, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Merck, and Pfizer.

Dr Budoff has received grant support and is on the speaker’s bureau for Amarin Pharmaceuticals.

Dr Ballantyne reports receiving consulting fees from Arrowhead, 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.


Research Funding:

The study was funded by Amarin Pharma, Inc., which was involved in the study design; collection, analysis, and interpretation of data; and development and review of this article. The decision to submit the article for publication was made by the authors.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Cardiac & Cardiovascular Systems
  • Peripheral Vascular Disease
  • Cardiovascular System & Cardiology
  • eicosapentaenoic acid ethyl ester
  • fatty acids, omega-3
  • lipids
  • prevention and control
  • triglycerides
  • United States
  • Icosapent ethyl
  • Clinical trial
  • Heart failure
  • Cardiovascular risk
  • Events
  • Outcomes
  • Triglycerides
  • Clopidogrel
  • Prevalence
  • Ticagrelor

REDUCE-IT USA Results From the 3146 Patients Randomized in the United States

Show all authors Show less authors


Journal Title:



Volume 141, Number 5


, Pages 367-375

Type of Work:

Article | Final Publisher PDF


Background: Some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. This prespecified REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial) subgroup analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States. Methods: REDUCE-IT randomized 8179 statin-treated patients with qualifying triglycerides ≥135 and <500 mg/dL and low-density lipoprotein cholesterol >40 and ≤100 mg/dL and a history of atherosclerosis or diabetes mellitus to icosapent ethyl 4 g/d or placebo. The primary composite end point was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary composite end point was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. A hierarchy was prespecified for examination of individual and composite end points. Results: A total of 3146 US patients (38.5% of the trial) were randomized and followed for a median of 4.9 years; 32.3% were women and 9.7% were Hispanic. The primary composite end point occurred in 24.7% of placebo-treated patients versus 18.2% of icosapent ethyl-treated patients (hazard ratio [HR], 0.69 [95% CI, 0.59-0.80]; P=0.000001); the key secondary composite end point occurred in 16.6% versus 12.1% (HR, 0.69 [95% CI, 0.57-0.83]; P=0.00008). All prespecified hierarchical end points were meaningfully and significantly reduced, including cardiovascular death (6.7% to 4.7%; HR, 0.66 [95% CI, 0.49-0.90]; P=0.007), myocardial infarction (8.8% to 6.7%; HR, 0.72 [95% CI, 0.56-0.93]; P=0.01), stroke (4.1% to 2.6%; HR, 0.63 [95% CI, 0.43-0.93]; P=0.02), and all-cause mortality (9.8% to 7.2%; HR, 0.70 [95% CI, 0.55-0.90]; P=0.004); for all-cause mortality in the US versus non-US patients, Pinteraction=0.02. Safety and tolerability findings were consistent with the full study cohort. Conclusions: Whereas the non-US subgroup showed significant reductions in the primary and key secondary end points, the US subgroup demonstrated particularly robust risk reductions across a variety of individual and composite end points, including all-cause mortality.

Copyright information:

© 2019 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Export to EndNote