Author + information
- Received September 25, 2018
- Revision received October 25, 2018
- Accepted October 25, 2018
- Published online November 14, 2018.
- Michael Szarek, PhDa,∗,† (, )@gabrielsteg@DLBHATTMD,
- Harvey D. White, DScb,†,
- Gregory G. Schwartz, MD, PhDc,†,
- Marco Alings, MD, PhDd,
- Deepak L. Bhatt, MD, MPHe,
- Vera A. Bittner, MD, MSPHf,
- Chern-En Chiang, MD, PhDg,
- Rafael Diaz, MDh,
- Jay M. Edelberg, MD, PhDi,
- Shaun G. Goodman, MD, MSck,
- Corinne Hanotin, MDj,
- Robert A. Harrington, MDl,
- J. Wouter Jukema, MD, PhDm,
- Takeshi Kimura, MDn,
- Robert Gabor Kiss, MD, PhDo,
- Guillaume Lecorps, MScj,
- Kenneth W. Mahaffey, MDl,
- Angèle Moryusef, MDi,
- Robert Pordy, MDp,
- Matthew T. Roe, MD, MHSq,r,
- Pierluigi Tricoci, MD, PhDr,
- Denis Xavier, MD, MScs,
- Andreas M. Zeiher, MDt,
- Ph. Gabriel Steg, MDu,v,†,
- for the ODYSSEY OUTCOMES Committees and Investigators∗
- aState University of New York, Downstate School of Public Health, Brooklyn, NY
- bUniversity of Auckland and Green Lane Cardiovascular Services Auckland City Hospital, Auckland, New Zealand
- cDivision of Cardiology, University of Colorado School of Medicine, Aurora, CO
- dAmphia Ziekenhuis Molengracht, Breda, The Netherlands
- eBrigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA
- fDivision of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL
- gGeneral Clinical Research Center, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan
- hEstudios Cardiológicos Latinoamérica, Instituto Cardiovascular de Rosario, Rosario, Argentina
- iSanofi, Bridgewater
- jSanofi, Paris, France
- kCanadian VIGOUR Centre, University of Alberta, Canada and St. Michael’s Hospital, University of Toronto, Edmonton, Alberta, Toronto, Ontario, Canada
- lStanford Center for Clinical Research, Department of Medicine, Stanford University, Stanford, CA
- mDepartment of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
- nKyoto University Graduate School of Medicine, Kyoto-shi, Kyoto, Japan
- oMagyar Honvédség Egészségügyi Központ, Budapest, Hungary
- pRegeneron Pharmaceuticals Inc., Tarrytown, NY
- qDivision of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC
- rDuke Clinical Research Institute, Duke University Medical Center, Durham, NC
- sDepartment of Pharmacology and Division of Clinical Research, St John's Medical College and Research Institute, Bangalore, India
- tDepartment of Medicine III, Goethe University, Frankfurt am Main, Germany
- uAssistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris and Paris Diderot University, Sorbonne Paris Cité, FACT (French Alliance for Cardiovascular Trials), INSERM U1148, Paris, France
- vNational Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, UK
- ↵∗Address for correspondence: Michael Szarek, PhD 450 Clarkson Avenue, MS 43 Brooklyn NY 11203 Telephone: 646-696-8447 Fax: 718-270-2533.
Background The ODYSSEY OUTCOMES trial compared alirocumab with placebo, added to high-intensity or maximum tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths.
Objectives This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES.
Methods Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death.
Results With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio 0.87, 95% confidence interval 0.82 to 0.93) and death (hazard ratio 0.83, 95% confidence interval 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk.
Conclusions In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.
↵∗ A complete list of the ODYSSEY OUTCOMES Committee members, investigators, and contributors, and their institutional affiliations, is provided in the Online Appendix.
↵† Drs. Szarek, White, Schwartz, and Steg contributed equally to this manuscript.
Funding. Supported by Sanofi and Regeneron Pharmaceuticals, Inc.
Michael Szarek: consultant/advisory board for CiVi, Resverlogix, Baxter, Esperion, and Regeneron Pharmaceuticals, Inc.
Harvey D. White: research grants from Eli Lilly and Company, National Institute of Health. Other: AstraZeneca, Omthera Pharmaceuticals, Pfizer, Eisai Inc, Eli Lilly and Company, DalCor Pharma UK Inc, Sirtex, Acetelion, CSL Behring LLC, Luitpold Pharmaceuticals Ltd, Sanofi Aventis.
Gregory G. Schwartz: research support to institution from Resverlogix, Sanofi, and Roche.
Marco Alings: research support from Sanofi and Regeneron Pharmaceuticals; honoraria from Pfizer. Consultant/advisory board for Bayer, BMS, Boehringer Ingelheim, and Daiichi Sankyo.
Deepak L. Bhatt: advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, 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, 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, Merck, Novo Nordisk, PLx Pharma, Takeda.
Vera A. Bittner: research grants from Amgen, DalCor, Esperion, Sanofi, AstraZeneca, Bayer Healthcare. Honoraria from American College of Cardiology, American Heart Association, National Lipid Association. Consultant/advisory board for Sanofi.
Chern-En Chiang: Honoraria from Pfizer, Sanofi, Novartis, MSD, AstraZeneca, Daiichi-Sankyo, Bayer, and Boehringer-Ingelheim.
Rafael Diaz: honoraria from Sanofi, AstraZeneca, Bayer, and Dalcor..
Jay M. Edelberg: employee of Sanofi.
Shaun G. Goodman: research grants from Daiichi-Sankyo, Luitpold Pharmaceuticals, Merck, Novartis, Servier, Regeneron Pharmaceuticals Inc., Sanofi, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Eli Lilly, Pfizer, Tenax Therapeutics. Honoraria from Bristol-Myers Squibb, Eli Lilly, Fenix Group International, Ferring Pharmaceuticals, Merck, Novartis, Pfizer, Servier, Regeneron Pharmaceuticals Inc., Sanofi, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim. Consultant/advisory board for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Pfizer, Servier, Tenax Therapeutics, Sanofi, Amgen, Bayer.
Corinne Hanotin: employee of Sanofi.
Robert A. Harrington: research grants from Apple, CSL, Sanofi, Astra, Portola, Janssen, BMS, Novartis, The Medicines Company. Consultant/advisory board for Amgen, Bayer, Gilead, MyoKardia, WebMD. Other: Board of directors (unpaid) for AHA and Stanford HealthCare.
J. Wouter Jukema: research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, the European Community Framework KP7 Program. Other research support from Amgen, Astellas, AstraZeneca, Daiichi Sankyo, Lilly, Merck-Schering-Plough, Pfizer, Roche, and Sanofi-Aventis.
Takeshi Kimura: research grants from Pfizer, Sanofi, MSD, and Bayer. Honoraria from Kowa, Sanofi, Pfizer, Asteras-Amgen-Biopharma, MSD, Bayer and AstraZeneca.
Robert Gabor Kiss: none.
Guillaume Lecorps: employee of and shareholder in Sanofi.
Kenneth W. Mahaffey: research grants from Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc., Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, Novartis, Sanofi, St. Jude, Tenax. Ownership interest in BioPrint Fitness. Consultant/advisory board for Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiometabolic Health Congress, Elsevier, GlaxoSmithKline, Johnson & Johnson, Medergy, Medscape, Merck, Mitsubishi, Myokardia, Novartis, Oculeve, Portola, Radiometer, Springer Publishing, Theravance, UCSF, WebMd.
Angèle Moryusef: employee of Sanofi.
Robert Pordy: employee of and shareholder in Regeneron Pharmaceuticals, Inc.
Matthew T. Roe: research grants from American College of Cardiology, American Heart Association, Familial Hypercholesterolemia Foundation, Ferring Pharmaceuticals, Myokardia, Patient Centered Outcomes Research Institute, Sanofi-Aventis. Consultant/advisory board for Amgen, Ardea Biosciences, AstraZeneca, Eli Lilly, and Merck. Other: Flatiron, Janssen Pharmaceuticals, Novartis, Novo Nordisk, Regeneron Pharmaceuticals, and Roche-Genentech.
Pierluigi Tricoci: research grant from Merck. Consultant/advisory board for Merck.
Denis Xavier: research grants and/or meeting support from NHLBI (NIH), UK MRC, Wellcome Trust, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cadila, Pfizer, Sanofi, Indian Council for Medical Research, Population Health Research Institute, Duke Clinical Research Institute. Advisory board Pfizer.
Andreas M. Zeiher: none.
Ph. Gabriel Steg: research grants from Bayer, Merck, Sanofi, and Servier; speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer-Ingelheim, Bristol Myers-Squibb, Lilly, Merck, Novartis, Novo-Nordisk, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, and Servier.
- Received September 25, 2018.
- Revision received October 25, 2018.
- Accepted October 25, 2018.
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