Original Investigation
Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events: The ODYSSEY OUTCOMES Trial

https://doi.org/10.1016/j.jacc.2018.10.039Get rights and content
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Abstract

Background

The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) 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.

Key Words

acute coronary syndrome
alirocumab
total events

Abbreviations and Acronyms

ACS
acute coronary syndrome
CI
confidence interval
HR
hazard ratio
LDL-C
low-density lipoprotein cholesterol

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Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

Drs. Szarek, White, Schwartz, and Steg contributed equally to this work.

A complete list of the ODYSSEY OUTCOMES Committee members, investigators, and contributors, and their institutional affiliations, is provided in the Online Appendix. This study was supported by Sanofi, Regeneron Pharmaceuticals, Inc., and Fondation Assistance Publique−Hôpitaux de Paris. Dr. Szarek has served as a consultant and/or on the advisory board for CiVi, Resverlogix, Baxter, Esperion, and Regeneron Pharmaceuticals, Inc. Dr. White has received research grants from Sanofi, Eli Lilly, National Institute of Health, George Institute, Omthera Pharmaceuticals, Pfizer New Zealand, Intarcia Therapeutics Inc., Elsai Inc., Dalcor Pharma UK Inc., CSL Behring LLC, and Luitpold Pharmaceuticals Inc.; has received honoraria and nonfinancial support from AstraZeneca; and has served on the advisory boards of Sirtex and Acetilion. Dr. Schwartz has received research support to his institution from Resverlogix, Sanofi, and Roche; and is a co-inventor of pending U.S. patent application 14/657192 (“Methods for Reducing Cardiovascular Risk”) that has been assigned to the University of Colorado. Dr. Alings has received research support from Sanofi and Regeneron Pharmaceuticals; has received honoraria from Pfizer; and has served as a consultant and/or on the advisory board for Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Milestone, Pfizer, and Daiichi-Sankyo. Dr. Bhatt has served on the advisory board of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, 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 Chair of the American Heart Association Quality Oversight Committee, NCDR-ACTION Registry Steering Committee, and VA CART Research and Publications 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, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), and Population Health Research Institute; has received honoraria from 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 U.S. national co-leader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), and Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (CME steering committees); has served as deputy editor of Clinical Cardiology; has received research funding from 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, Synaptic, 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, St. Jude Medical (now Abbott), and Svelte; is a trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr. Bittner has received research grants from Amgen, DalCor, Esperion, Sanofi, AstraZeneca, and Bayer Healthcare; has received honoraria from the American College of Cardiology, American Heart Association, and National Lipid Association; and has served as a consultant and on the advisory board for Sanofi. Dr. Chiang has received honoraria from Pfizer, Sanofi, Novartis, Merck Sharp and Dohme, AstraZeneca, Daiichi-Sankyo, Bayer, and Boehringer Ingelheim. Dr. Diaz has received honoraria from Sanofi, AstraZeneca, Bayer, and Dalcor. Dr. Edelberg is an employee of Sanofi. Dr. Goodman has received 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, and Tenax Therapeutics; has received honoraria from Bristol-Myers Squibb, Eli Lilly, Fenix Group International, Ferring Pharmaceuticals, Merck, Novartis, Pfizer, Servier, Regeneron Pharmaceuticals Inc., Sanofi, Amgen, AstraZeneca, Bayer, and Boehringer Ingelheim; and has served as a consultant and/or on the advisory board for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Pfizer, Servier, Tenax Therapeutics, Sanofi, Amgen, and Bayer. Dr. Hanotin is an employee of Sanofi. Dr. Harrington has received research grants from Apple, CSL, Sanofi, AstraZeneca, Portola, Janssen, Bristol-Myers Squibb, Novartis, and The Medicines Company; has served as a consultant and/or on the advisory board for Amgen, Bayer, Gilead, MyoKardia, and WebMD; and has served on the Board of Directors (unpaid) for the American Heart Association and Stanford HealthCare. Dr. Jukema has received research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Community Framework KP7 Program; and has received other research support from Amgen, Astellas, AstraZeneca, Daiichi-Sankyo, Lilly, Merck-Schering-Plough, Pfizer, Roche, and Sanofi. Dr. Kimura has received research grants from Pfizer, Sanofi, Merck Sharp and Dohme, and Bayer; and has received honoraria from Kowa, Sanofi, Pfizer, Asteras-Amgen-Biopharma, Merck Sharp and Dohme, Bayer, and AstraZeneca. Dr. Lecorps is an employee of and shareholder in Sanofi. Dr. Mahaffey has received research grants from Afferent, Amgen, Apple, AstraZeneca, Cardiva Medical, Inc., Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, Novartis, Sanofi, St. Jude, and Tenax; has ownership interest in BioPrint Fitness; and has served as a consultant and/or on the 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, and WebMD. Dr. Moryusef is an employee of Sanofi. Dr. Pordy is an employee of and shareholder in Regeneron Pharmaceuticals, Inc. Dr. Roe has received research grants from American College of Cardiology, American Heart Association, Familial Hypercholesterolemia Foundation, Ferring Pharmaceuticals, Myokardia, Patient Centered Outcomes Research Institute, and Sanofi; has served as a consultant and/or on the advisory board for Amgen, Ardea Biosciences, AstraZeneca, Eli Lilly, and Merck; and has other relationships with Flatiron, Janssen Pharmaceuticals, Novartis, Novo Nordisk, Regeneron Pharmaceuticals, and Roche-Genentech. Dr. Tricoci has received research grants from Merck, Sanofi, and Refeneron; has served as a consultant and/or on the advisory board for Merck; and is an employee of CSL Behring. Dr. Xavier has received research grants and/or meeting support from the National Heart, Lung, and Blood Institute (National Institutes of Health), UK MRC, Wellcome Trust, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cadila, Pfizer, Sanofi, Indian Council for Medical Research, Population Health Research Institute, and Duke Clinical Research Institute; and has served on the advisory board for Pfizer. Dr. Zeiher has served as a scientific advisor for Sanofi, Amgen, Pfizer, and Boehringer; and has served as a speaker for Bayer, Novartis, and Vifor. Dr. Steg has received research grants 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, Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, and Servier.