Author + information
- Received February 8, 2019
- Revision received March 7, 2019
- Accepted March 8, 2019
- Published online July 22, 2019.
- J. Wouter Jukema, MD, PhDa,∗∗ (, )@gabrielsteg,
- Michael Szarek, PhDb,∗,
- Laurien E. Zijlstra, MDa,
- H. Asita de Silva, MBBS, DPhilc,
- Deepak L. Bhatt, MD, MPHd,
- Vera A. Bittner, MD, MSPHe,
- Rafael Diaz, MDf,
- Jay M. Edelberg, MD, PhDg,
- Shaun G. Goodman, MD, MSch,i,
- Corinne Hanotin, MDj,
- Robert A. Harrington, MDk,
- Yuri Karpov, MDl,
- Angèle Moryusef, MDg,
- Robert Pordy, MDm,
- Juan C. Prieto, MDn,
- Matthew T. Roe, MD, MHSo,p,
- Harvey D. White, DScq,
- Andreas M. Zeiher, MDr,
- Gregory G. Schwartz, MD, PhDs,†,
- P. Gabriel Steg, MDt,u,†,
- 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, 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
- fLatinoamerican Cardiological Studies, Cardiovascular Institute of Rosario, Rosario, Argentina
- gSanofi, Bridgewater, New Jersey
- hCanadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada
- iSt. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
- jSanofi, Paris, France
- kStanford Center for Clinical Research, Department of Medicine, Stanford University, Stanford, California
- lRussian Cardiological Scientific-Productive Complex, Moscow, Russian Federation
- mRegeneron Pharmaceuticals, Inc., Tarrytown, New York
- nUniversity of Chile Clinical Hospital, Santiago, Chile
- oDuke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
- pDivision of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- qGreen Lane Cardiovascular Services Auckland City Hospital, Auckland, New Zealand
- rDepartment of Medicine III, Goethe University, Frankfurt am Main, Germany
- sDivision of Cardiology, University of Colorado School of Medicine, Aurora, Colorado
- tAssistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris and Paris Diderot University, Sorbonne Paris Cité, FACT (French Alliance for Cardiovascular Trials), INSERM U1148, Paris, France
- uNational Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, United Kingdom
- ↵∗Address for correspondence:
Dr. J. Wouter Jukema, Department of Cardiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Background Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACEs) and death. The impact of lipid lowering by proprotein convertase subtilisin–kexin type 9 inhibition in such patients is undetermined.
Objectives This pre-specified analysis from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) determined whether polyvascular disease influenced risks of MACEs 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 to 12 months after ACS. The primary MACEs endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, fatal or 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 polyvascular disease in 2 beds (coronary and peripheral artery or cerebrovascular), and 149 had polyvascular disease in 3 beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACEs by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, the corresponding absolute risk reduction was 1.4% (95% confidence interval [CI]: 0.6 to 2.3), 1.9% (95% CI: −2.4% to 6.2%), and 13.0% (95% CI: −2.0 to 28.0). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; the absolute risk reduction with alirocumab was 0.4% (95% CI: −0.1 to 1.0), 1.3% (95% CI: −1.8% to 4.3%), and 16.2% (95% CI: 5.5 to 26.8).
Conclusions In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyvascular disease is associated with high risks of MACEs and death. The large absolute reductions in those risks with alirocumab are a potential benefit for these patients. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]: NCT01663402)
- acute coronary syndrome
- cerebrovascular disease
- major adverse cardiac events
- peripheral artery disease
↵∗ Drs. Jukema and Szarek are joint first authors and contributed equally to this work.
↵† Drs. Schwartz and Steg are joint senior authors and contributed equally to this work.
This study was supported by Sanofi, Regeneron Pharmaceuticals, Inc., and Fondation Assistance Publique-Hôpitaux de Paris. 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, Eli Lilly, Merck-Schering-Plough, Pfizer, Roche, and Sanofi. Dr. Szarek has served as a consultant for or on the Advisory Board of CiVi, Resverlogix, Baxter, Esperion, and Regeneron; has received compensation from Sanofi to institution (SUNY Downstate) for publication; and has provided expert testimony regarding a patent case for Sanofi. Dr. Bhatt has served on the Advisory Board of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; is on the Board of Directors of the Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; is Chair of the American Heart Association Quality Oversight Committee; is on The Data Monitoring Committees of the 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), and Population Health Research Institute; has received honoraria from the 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), Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); has received research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Eli 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); is site co-investigator for Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; is Trustee of the American College of Cardiology; and has conducted unfunded research for Flowco, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr. Bittner has received institutional 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 for and on the Advisory Board of Sanofi. Dr. Diaz has received grants, personal fees, and nonfinancial support from Sanofi during the conduct of the study; has received grants from DalCor, Population Health Research Institute, Duke Clinical Research Institute, TIMI Group, and Montreal Health Innovations Coordinating Center has received nonfinancial support from Lepetit; has received personal fees from AstraZeneca and Eli Lilly; and has received grants from Amgen. Dr. Edelberg was previously an employee of Sanofi. Dr. Goodman has received research grants from Daiichi-Sankyo, Luitpold, Merck, Novartis, Servier, Regeneron, Sanofi, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Eli Lilly, Pfizer, HLS Therapeutics, and Tenax Therapeutics; has received speaker or consulting honoraria from Bristol-Myers Squibb, Eli Lilly, Fenix Group International, Ferring, Merck, Novartis, Pfizer, Servier, Regeneron, Sanofi, Amgen, AstraZeneca, Bayer, HLS Therapeutics, and Boehringer Ingelheim; and has served as a consultant for or on the Advisory Board of AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Pfizer, Servier, Tenax Therapeutics, Sanofi, Amgen, and Bayer. Drs. Hanotin and Moryusef are employees 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 for or on the Advisory Board of Amgen, Bayer, Gilead, MyoKardia, and WebMD; and has served on the board of directors (unpaid) of the American Heart Association and Stanford HealthCare. Dr. Karpov has received grants and personal fees from Sanofi during the conduct of the study; and has received grants and personal fees as a Speaker from Servier, AstraZeneca, Pfizer, Amgen, Berlin-Chemie, Bayer, Recordati, Novo Nordisk, and Sandoz. Dr. Pordy is an employee of and shareholder in Regeneron. Dr. Prieto has received research grants from AstraZeneca, Merck Sharp & Dome, Bayer, Novartis, and GlaxoSmithKline; and has served as Speaker for Merck. Dr. Roe has received research grant funding from Sanofi, Janssen Pharmaceuticals, AstraZeneca, Patient Centered Outcomes Research Institute, Ferring Pharmaceuticals, Myokardia, American College of Cardiology, American Heart Association, Familial and the Hypercholesterolemia Foundation; and has received consulting or honoraria from AstraZeneca, Amgen, Eli Lilly, Roche-Genentech, Janssen Pharmaceuticals, Regeneron, Ardea Biosciences, Novo Nordisk, Flatiron, Merck, Pfizer, Sanofi, Signal Path, and Elsevier. Publishers. Dr. White has received research grants from Sanofi, Eli Lilly, National Institutes of Health, George Institute, Omthera, Pfizer New Zealand, Intarcia Therapeutics, Elsai, DalCor Pharma UK, CSL Behring, and Luitpold; has received honoraria and nonfinancial support from AstraZeneca; and has served on the Advisory Boards of Sirtex and Actelion. Dr. Zeiher has served as a Scientific Advisor for Sanofi, Amgen, Pfizer, and Boehringer Ingelheim; and has served as a Speaker for Bayer, Novartis, Boehringer Ingelheim, and Vifor. Dr. Schwartz has received research support to his institution from Resverlogix, Sanofi, The Medicines Company, and Roche; and is a co-inventor of U.S. patent application 14/657192 (“Methods for Reducing Cardiovascular Risk”) assigned in full to the University of Colorado. Dr. Steg has received grants and nonfinancial support from Sanofi; has received grants and personal fees from Bayer, Janssen, Indorsia, Novo Nordisk, Merck, Sanofi, Servier, and Amarin; has received speaker or consulting fees from Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron, Eli Lilly, and AstraZeneca; and has a patent for a method for reducing cardiovascular risk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received February 8, 2019.
- Revision received March 7, 2019.
- Accepted March 8, 2019.
- 2019 The Authors