Author + information
- J. Wouter Jukema, MD, PhDa,∗∗ (, )@gabrielsteg,
- Michael Szarek, PhDb,∗,
- Laurien E. Zijlstra, MDa,
- H. Asita de Silva, DPhilc,
- Deepak L. Bhatt, MD, MPHd,
- Vera A. Bittner, MD, MSPHe,
- Rafael Diaz, MDf,
- Jay M. Edelberg, MD, PhDg,
- Shaun G. Goodman, MD, MSch,
- Corinne Hanotin, MDi,
- Robert A. Harrington, MDj,
- Yuri Karpov, PhDk,
- Angèle Moryusef, MDg,
- Robert Pordy, MDl,
- Juan C. Prieto, MDm,
- Matthew T. Roe, MD, MHSn,o,
- Harvey D. White, DScp,
- Andreas M. Zeiher, MDq,
- Gregory G. Schwartz, MD, PhDr,∗,
- Ph. Gabriel Steg, MDs,t,∗,
- for the ODYSSEY OUTCOMES Committees and Investigators†
- aDepartment of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
- bState University of New York, Downstate School of Public Health, Brooklyn, New York
- cClinical Trials Unit, Faculty of Medicine, University of Kelaniya, Sri Lanka
- dBrigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts
- eDivision of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama
- fEstudios Cardiológicos Latinoamérica, Instituto Cardiovascular de Rosario, Rosario, Argentina
- gSanofi, Bridgewater, New Jersey
- hCanadian VIGOUR Centre, University of Alberta, Canada and St. Michael’s Hospital, University of Toronto, Edmonton, Alberta, Toronto, Ontario, Canada
- iSanofi, Paris, France
- jStanford Center for Clinical Research, Department of Medicine, Stanford University, Stanford, California
- kRussian Cardiological Scientific-Productive Complex, Moscow, Russian Federation
- lRegeneron Pharmaceuticals Inc., Tarrytown, New York
- mHospital Clinico Universidad De Chile, Santiago, Chile
- nDuke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
- oDivision of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- pGreen Lane Cardiovascular Services Auckland City Hospital, Auckland, New Zealand
- qDepartment of Medicine III, Goethe University, Frankfurt am Main, Germany
- rDivision of Cardiology, University of Colorado School of Medicine, Aurora, Colorado
- sAssistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris and Paris Diderot University, Sorbonne Paris Cité, FACT (French Alliance for Cardiovascular Trials, an F-CRIN Network), INSERM U1148, Paris, France
- tNational Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, UK
- ↵∗Corresponding author: J. Wouter Jukema, MD, PhD Professor of Cardiology, Department of Cardiology Leiden University Medical Center PO Box 9600, 2300 RC Leiden The Netherlands Telephone: +31 71 5262020 Fax: +31 71 5266809.
Background Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACE) and death. The impact of lipid-lowering by proprotein convertase subtilisin−kexin type 9 (PCSK9) inhibition in such patients is undetermined.
Objectives This pre-specified analysis from ODYSSEY OUTCOMES determined whether polyvascular disease (polyVD) influenced risks of MACE and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy.
Methods Patients were randomized to alirocumab or placebo 1−12 months after ACS. The primary MACE endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint.
Results Median follow-up was 2.8 years. Of 18,924 patients, 17,370 had monovascular (coronary) disease, 1,405 had polyVD in two beds (coronary and peripheral artery or cerebrovascular), and 149 had polyVD in three beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACE by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, corresponding absolute risk reduction (ARR [95% confidence interval]) was 1.4% (0.6, 2.3), 1.9% (−2.4%, 6.2%), and 13.0% (−2.0, 28.0). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; ARR with alirocumab was 0.4% (−0.1, 1.0), 1.3% (−1.8%, 4.3%), and 16.2% (5.5, 26.8).
Conclusions In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyVD is associated with high risks of MACE and death. The large absolute reductions in those risks with alirocumab are a potential benefit for this population.
- Acute coronary syndrome
- Cerebrovascular disease
- Major adverse cardiac events
- Peripheral artery disease
↵∗ Drs. Jukema, Szarek, Schwartz, and Steg contributed equally to this work.
↵† A complete list of the ODYSSEY OUTCOMES Committee members, investigators, and contributors is provided in the Online Appendix.
Tweet: Patients with recent acute coronary syndrome and polyvascular disease derive large absolute benefit from alirocumab: The ODYSSEY OUTCOMES trial.
FUNDING: This study was supported by Sanofi, Regeneron Pharmaceuticals, Inc., and Fondation Assistance Publique-Hôpitaux de Paris.
DISCLOSURES: 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. Szarek has served as a consultant and/or on the advisory board for CiVi, Resverlogix, Baxter, Esperion, and Regeneron Pharmaceuticals, Inc.
Dr. Zijlstra has no disclosures.
Dr. de Silva has no disclosures.
Dr. Bhatt discloses the following relationships - 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 (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. 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. Diaz reports grants, personal fees and non-financial support from SANOFI, during the conduct of the study; grants from DALCOR, PHRI, DCRI, TIMI GROUP, MHICC, non-financial support from LEPETIT, personal fees from ASTRA, Eli Lilly, grants and AMGEN, outside the submitted work.
Drs. Edelberg, Hanotin and Moryusef are employees 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. 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. Karpov reports grants and personal fees from Sanofi, during the conduct of the study, grants and personal fees as a speaker from Servier, AstraZeneca, Pfizer, Amgen, Berlin-Chemie, Bayer, Recordati, Novo Nordick, Sandoz.
Dr. Pordy is an employee of and shareholder in Regeneron Pharmaceuticals, Inc.
Dr. Prieto has received research grants from Astra Zeneca, Merck Sharp & Dome, Bayer, Novartis, Glaxo Smith Kline, and has served as speaker for Merck.
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. 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. 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. Schwartz has received research support to his institution from Resverlogix, Sanofi, and Roche; is a co-inventor of US patent application 14/657192 (“Methods for Reducing Cardiovascular Risk”) assigned in full to the University of Colorado.
Dr. Steg reports grants and non-financial support from Sanofi, during the conduct of the study; grants and personal fees from Bayer, grants and personal fees from Merck, grants and personal fees from Sanofi, grants and personal fees from Servier, grants and personal fees from Amarin, personal fees from Amgen, personal fees from Bristol-Myers Squibb, personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from Novartis, personal fees from Regeneron, personal fees from Lilly, personal fees from AstraZeneca, outside the submitted work; In addition, Dr. Steg has a patent Method for reducing cardiovascular risk issued.
- Received February 8, 2019.
- Revision received March 7, 2019.
- Accepted March 8, 2019.
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