JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 74, NO. 9, 2019 ª 2019 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/). ORIGINAL INVESTIGATIONS Alirocumab in Patients With Polyvascular Disease and Recent Acute Coronary Syndrome ODYSSEY OUTCOMES Trial J. Wouter Jukema, MD, PHD,a,* Michael Szarek, PHD,b,* Laurien E. Zijlstra, MD,a H. Asita de Silva, MBBS, DPHIL,c Deepak L. Bhatt, MD, MPH,d Vera A. Bittner, MD, MSPH,e Rafael Diaz, MD,f Jay M. Edelberg, MD, PHD,g Shaun G. Goodman, MD, MSC,h,i Corinne Hanotin, MD,j Robert A. Harrington, MD,k Yuri Karpov, MD,l Angèle Moryusef, MD,g Robert Pordy, MD,m Juan C. Prieto, MD,n Matthew T. Roe, MD, MHS,o,p Harvey D. White, DSC,q Andreas M. Zeiher, MD,r Gregory G. Schwartz, MD, PHD,s,y P. Gabriel Steg, MD,t,u,y for the ODYSSEY OUTCOMES Committees and Investigatorsz ABSTRACT 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 cate- gories was 10.0%, 22.2%, and 39.7%. With alirocumab, the corresponding absolute risk reduction was 1.4% (95% confi- dence 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 po- tential benefit for these patients. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Listen to this manuscript’s Treatment With Alirocumab [ODYSSEY OUTCOMES]: NCT01663402) (J Am Coll Cardiol 2019;74:1167–76) audio summary by © 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. Editor-in-Chief Dr. Valentin Fuster on This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). JACC.org. From the 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, d Kelaniya, Sri Lanka; Brigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, ISSN 0735-1097 https://doi.org/10.1016/j.jacc.2019.03.013 1168 Jukema et al. JACC VOL. 74, NO. 9, 2019 Alirocumab and Polyvascular Disease in ODYSSEY OUTCOMES SEPTEMBER 3, 2019:1167–76 P ABBREVIATIONS atients with peripheral artery disease warranting more intensive approaches to secondary AND ACRONYMS (PAD) or cerebrovascular disease prevention (5,6). (CeVD) have an elevated risk of ma- SEE PAGE 1187 ACS = acute coronary syndrome jor adverse cardiovascular events (MACEs) and death compared with patients without Lowering of atherogenic lipoproteins, reflected in ARR = absolute risk reduction these conditions, irrespective of a concur- part by reduction of low-density lipoprotein choles- CAD = coronary artery disease rent history of coronary artery disease terol (LDL-C), favorably modifies the risks of MACEs CeVD = cerebrovascular disease (CAD) (1–3). The risk of future MACEs and and death (7). Accordingly, statin treatment is death also remains high among patients broadly recommended for patients with coronary CI = confidence interval with an acute coronary syndrome (ACS), atherosclerosis, PAD, or CeVD in the guidelines of the LDL-C = low-density lipoprotein cholesterol despite application of evidence-based sec- American College of Cardiology and American Heart MACE = major adverse ondary prevention measures including sta- Association, the American College of Cardiology and cardiovascular event tins and dual antiplatelet therapy (4). American Stroke Association, and the European So- PAD = peripheral artery When PAD or CeVD is concurrent with ACS, ciety of Cardiology and European Atherosclerosis disease risk may be particularly elevated, Society (8–11). Massachusetts; eDivision of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama; fLatinoamer- ican 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; m Regeneron Pharma- ceuticals, 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 Zea- land; rDepartment of Medicine III, Goethe University, Frankfurt am Main, Germany; sDivision of Cardiology, University of Col- orado 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; and the uNational Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, United Kingdom. *Drs. Jukema and Szarek are joint first authors and contributed equally to this work. yDrs. Schwartz and Steg are joint senior authors and contributed equally to this work. zA complete list of the ODYSSEY OUTCOMES Committee members, investigators, and contributors is provided in the Online Appendix. 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 Bio- sciences; 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 (Secre- tary/Treasurer), WebMD (CME steering committees), Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Com- mittee (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 JACC VOL. 74, NO. 9, 2019 Jukema et al. 1169 SEPTEMBER 3, 2019:1167–76 Alirocumab and Polyvascular Disease in ODYSSEY OUTCOMES The advent of inhibitors of proprotein convertase METHODS subtilisin–kexin type 9 (PCSK9) provided an op- portunity to lower LDL-C to levels not previously Details of the study design (13) and primary efficacy achievable with statins or ezetimibe. The FOURIER and safety results have been published (14). In brief, (Further Cardiovascular Outcomes Research With ODYSSEY OUTCOMES was a multicenter, double- PCSK9 Inhibition in Subjects With Elevated Risk) blind, placebo-controlled trial in 18,924 patients at trial compared the PCSK9 inhibitor evolocumab least 40 years of age who provided written informed with placebo in patients with established, stable consent and had been hospitalized with an ACS atherosclerotic cardiovascular disease, including (defined as myocardial infarction or unstable angina) CAD, PAD, or CeVD. Evolocumab reduced MACEs, 1 to 12 months before randomization. Qualifying pa- but not death. Benefits were particularly pro- tients had a level of LDL-C of at least 70 mg/dl nounced among patients with PAD at entry into the (1.81 mmol/l), non–high-density lipoprotein choles- trial (12). terol at least 100 mg/dl (2.59 mmol/l), or apolipopro- The ODYSSEY OUTCOMES (Evaluation of Cardio- tein B at least 80 mg/dl, measured after a minimum of vascular Outcomes After an Acute Coronary Syn- 2 weeks of stable treatment with atorvastatin 40 to drome During Treatment With Alirocumab) trial 80 mg daily, rosuvastatin 20 to 40 mg daily, or the showed that MACEs were reduced with the PCSK9 maximum tolerated dose of either statin (including inhibitor alirocumab compared with placebo in 18,924 no statin in case of documented intolerance). Patients patients with recent ACS and elevated atherogenic were randomly assigned in a 1:1 ratio stratified by lipoproteins despite intensive statin therapy. In country to receive treatment with alirocumab 75 mg addition, fewer deaths occurred among patients subcutaneously every 2 weeks or matching placebo. treated with alirocumab. The aims of this pre- CATEGORIES OF POLYVASCULAR DISEASE. In this specified analysis of the ODYSSEY OUTCOMES trial analysis, 3 subgroups of patients with recent ACS were to determine whether the benefits of alirocumab were defined on the basis of the distribution of other on MACE and death were influenced by the presence evident vascular disease: 1) monovascular disease of polyvascular disease, defined as concomitant PAD, (CAD without known PAD or CeVD); 2) polyvascular CeVD, or both, and thus to identify preferred candi- disease in 2 vascular beds (CAD and either PAD or dates for alirocumab treatment. CeVD); and 3) polyvascular disease in 3 vascular beds 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 Thera- peutics, 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 Mor- yusef 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 & Dohme, Bayer, Novartis, and GlaxoSmithKline; and has served as a speaker for Merck. Dr. Roe has received research grant funding from Sanofi, Janssen Pharmaceuticals, AstraZeneca, Patient Centered Outcomes Research Insti- tute, Ferring Pharmaceuticals, Myokardia, American College of Cardiology, American Heart Association, Familial Hypercholes- terolemia 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. 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. Manuscript received February 8, 2019; revised manuscript received March 7, 2019, accepted March 8, 2019. 1170 Jukema et al. JACC VOL. 74, NO. 9, 2019 Alirocumab and Polyvascular Disease in ODYSSEY OUTCOMES SEPTEMBER 3, 2019:1167–76 T A B L E 1 Baseline Characteristics by History of PAD or CeVD Category Monovascular Disease Disease in 2 Vascular Beds Disease in 3 Vascular Beds CAD Without PAD or CeVD CAD and PAD CAD and CeVD CAD, PAD, and CeVD (n ¼ 17,370) (n ¼ 610) (n ¼ 795) (n ¼ 149) p Value Age, yrs 58 (51, 65) 62 (56, 68) 62 (56, 69) 66 (60, 71) <0.0001 Age category <0.0001 <65 yrs 12,956 (74.6) 368 (60.3) 456 (57.4) 60 (40.3) 65 to <75 yrs 3,575 (20.6) 178 (29.2) 252 (31.7) 72 (48.3) $75 yrs 839 (4.8) 64 (10.5) 87 (10.9) 17 (11.4) Female 4,298 (24.7) 163 (26.7) 264 (33.2) 37 (24.8) <0.0001 Region <0.0001 Western Europe 3,852 (22.2) 152 (24.9) 142 (17.9) 29 (19.5) Eastern Europe 4,993 (28.7) 189 (31.0) 215 (27.0) 40 (26.8) North America 2,513 (14.5) 134 (22.0) 170 (21.4) 54 (36.2) South America 2,413 (13.9) 64 (10.5) 101 (12.7) 10 (6.7) Asia 2,170 (12.5) 22 (3.6) 92 (11.6) 9 (6.0) Rest of world 1,429 (8.2) 49 (8.0) 75 (9.4) 7 (4.7) Index event <0.0001 NSTEMI 8,300 (47.9) 342 (56.3) 439 (55.4) 94 (63.1) STEMI 6,080 (35.1) 195 (31.1) 227 (28.6) 34 (22.8) Unstable angina 2,963 (17.1) 71 (11.7) 127 (16.0) 21 (14.1) Time from index event to 2.6 (1.7, 4.3) 3.0 (1.8, 5.4) 2.7 (1.7, 4.8) 3.0 (2.1, 3.9) 0.0003 randomization, months Lipid-lowering therapy at randomization <0.0001 High-dose atorvastatin or rosuvastatin 15,486 (89.2) 525 (86.1) 679 (85.4) 121 (81.2) Other LLT 1,734 (10.0) 75 (12.3) 102 (12.8) 24 (16.1) No LLT 150 (0.9) 10 (1.6) 14 (1.8) 4 (2.7) LDL-C, mg/dl 86 (73, 103) 91 (76, 108) 90 (75, 109) 95 (80, 115) <0.0001 LDL-C $100 mg/dl 5,060 (29.1) 218 (35.7) 290 (36.5) 61 (40.9) <0.0001 HDL-C, mg/dl 42 (36, 50) 42 (36, 50) 43 (36, 51) 43 (37, 51) NS Non–HDL-C, mg/dl 114 (99, 136) 121 (105, 143) 120 (103, 144) 124 (108, 143) <0.0001 Triglycerides, mg/dl 128 (94, 181) 134 (99, 187) 136 (98, 190) 135 (94, 182) 0.002 Apolipoprotein B, mg/dl 79 (69, 93) 83 (72, 96) 83 (71, 96) 82 (75, 95) <0.0001 Lipoprotein(a), mg/dl 20.8 (6.6, 59.4) 25.5 (7.5, 68.1) 23.0 (7.1, 61.7) 29.4 (9.4, 74.5) 0.004 C-reactive protein, mg/dl 0.16 (0.08, 3.73) 0.26 (0.11, 0.55) 0.22 (0.10, 0.48) 0.21 (0.11, 0.49) <0.0001 Body mass index, kg/m2 27.9 (25.2, 31.1) 27.7 (24.9, 31.0) 28.1 (25.4, 31.5) 27.7 (24.5, 30.7) NS Hemoglobin A1c, % 5.8 (5.5, 6.3) 6.0 (5.6, 6.7) 6.1 (5.7, 7.0) 6.0 (5.7, 6.7) <0.0001 eGFR, ml/min/1.73 m2 78.5 (68.1, 90.4) 74.1 (61.6, 86.7) 72.9 (59.5, 85.8) 67.0 (52.2, 84.4) <0.0001 eGFR <60 ml/min/1.73 m2 2,139 (12.3) 135 (22.1) 206 (25.9) 59 (39.6) <0.0001 Diabetes status <0.0001 Diabetes 4,805 (27.7) 225 (36.9) 349 (43.9) 65 (43.6) Pre-diabetes 7,630 (43.9) 260 (42.6) 299 (37.6) 57 (38.3) Normoglycemia 4,935 (28.4) 125 (20.5) 147 (18.5) 27 (18.1) Smoking status <0.0001 Current 4,181 (24.1) 189 (31.0) 147 (18.5) 43 (28.9) Former 7,095 (40.8) 302 (49.5) 335 (42.1) 79 (53.0) Never 6,093 (35.1) 119 (19.5) 313 (39.4) 27 (18.1) Medical history prior to index event Hypertension 10,930 (62.9) 489 (80.2) 694 (87.3) 136 (91.3) <0.0001 Myocardial infarction 3,147 (18.1) 204 (33.4) 226 (28.4) 62 (41.6) <0.0001 Stroke 0 (0.0) 0 (0.0) 526 (66.2) 85 (57.0) <0.0001 Malignant disease 458 (2.6) 28 (4.6) 34 (4.3) 12 (8.1) <0.0001 COPD 613 (3.5) 64 (10.5) 46 (5.8) 23 (15.4) <0.0001 CABG 826 (4.8) 82 (13.4) 91 (11.4) 48 (32.2) <0.0001 PAD 0 (0.0) 610 (100.0) 0 (0.0) 149 (100.0) <0.0001 CeVD 0 (0.0) 0 (0.0) 795 (100.0) 149 (100.0) <0.0001 Continued on the next page JACC VOL. 74, NO. 9, 2019 Jukema et al. 1171 SEPTEMBER 3, 2019:1167–76 Alirocumab and Polyvascular Disease in ODYSSEY OUTCOMES T A B L E 1 Continued Monovascular Disease Disease in 2 Vascular Beds Disease in 3 Vascular Beds CAD Without PAD or CeVD CAD and PAD CAD and CeVD CAD, PAD, and CeVD (n ¼ 17,370) (n ¼ 610) (n ¼ 795) (n ¼ 149) p Value Revascularization for index event 12,596 (72.5) 436 (71.5) 540 (67.9) 105 (70.5) 0.04 Medications Aspirin 16,647 (95.8) 564 (92.5) 737 (92.7) 138 (92.6) <0.0001 P2Y12 antagonist 15,223 (87.6) 525 (86.1) 664 (83.5) 129 (86.6) 0.005 ACE inhibitor/ARB 13,444 (77.4) 494 (81.0) 655 (82.4) 123 (82.6) 0.0008 Beta-blocker 14,687 (84.6) 507 (83.1) 672 (84.5) 124 (83.2) NS Ezetimibe 473 (2.7) 38 (6.2) 30 (3.8) 13 (8.7) <0.0001 Treatment variables among 8,683 302 406 71 alirocumab-treated patients % switched to placebo 691 (8.0) 12 (4.0) 25 (6.2) 2 (2.8) 0.01 Values are median (quartile 1, quartile 3), n (%), or n. The p values reflect the statistical comparison among the 4 vascular disease subgroups (CAD without PAD or CeVD; CAD and PAD; CAD and CeVD; CAD PAD, and CeVD). ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; CABG ¼ coronary artery bypass graft; CAD ¼ coronary artery disease; CeVD ¼ cerebrovascular disease; COPD ¼ chronic obstructive pulmonary disease; eGFR ¼ estimated glomerular filtration rate; HDL-C ¼ high-density lipoprotein cholesterol; LDL-C ¼ low-density lipoprotein cholesterol; LLT ¼ lipid-lowering therapy; NS ¼ not significant (p > 0.05); NSTEMI ¼ non–ST-segment elevation myocardial infarction; PAD ¼ peripheral artery disease; STEMI ¼ ST-segment elevation myocardial infarction. (CAD with both PAD and CeVD). Two additional heterogeneity by categories of polyvascular disease sensitivity analyses were performed. The first was assessed by Cox models with interaction terms considered 2 vascular disease categories: 1) mono- for relative risk reduction and Gail-Simon tests for vascular disease (CAD without known PAD or CeVD); absolute risk reduction (ARR). Analyses were per- and 2) polyvascular disease (CAD with any combina- formed in SAS software version 9.4 (IBM Corp., tion of PAD or CeVD). The second analysis considered Armonk, New York). 4 subgroups of patients with ACS: 1) those with RESULTS monovascular disease, as defined earlier; 2) all pa- tients with PAD, with or without concurrent CeVD; 3) Of 18,924 randomized patients, 9,462 were assigned all patients with CeVD, with or without concurrent to the alirocumab group and 9,462 to the placebo PAD; and 4) patients with disease in all 3 vascular group, with a median (quartile 1, quartile 3) follow-up beds, as defined earlier. PAD included arterial disease of 2.8 years (2.3, 3.4 years). At baseline, 17,370 pa- of the extremities or abdominal aortic aneurysm. tients had monovascular disease (91.8%), 1,405 pa- CeVD was defined as a history of carotid endarterec- tients had polyvascular disease in 2 vascular beds tomy, carotid stenting, prior stroke, or transient (7.4%; 3.2% PAD and 4.2% CeVD), and 149 had poly- ischemic attack. vascular disease in 3 vascular beds (0.8%). ENDPOINTS. The primary MACE endpoint was a BASELINE CHARACTERISTICS. Table 1 summarizes composite of coronary heart disease death, nonfatal the baseline characteristics of patients with mono- myocardial infarction, fatal or nonfatal ischemic vascular (coronary) disease, polyvascular disease in 2 stroke, or unstable angina requiring hospitalization. beds (split by PAD only and CeVD only), and poly- All-cause death was a secondary endpoint. vascular disease in 3 beds. Compared with patients STATISTICAL CONSIDERATIONS. Analyses of clin- with monovascular disease, those with CAD and ical outcomes and LDL-C levels were performed PAD, CAD and CeVD, and polyvascular disease in 3 according to the intention-to-treat principle, beds were older (median ages 58, 62, 62, and 66 including all patients, events, and measurements years; p < 0.0001); patients with CAD and PAD or from randomization to the common study end date CAD and CeVD were more likely to be female (26.7% (November 11, 2017). Hazard ratios and 95% confi- and 33.2%, respectively) than those with mono- dence intervals (CIs) were estimated using a Cox vascular disease (24.7%; p < 0.0001). Of all patients proportional hazards model, stratified by geographic with CeVD, 526 (66.2%) had a history of stroke. Pa- region; p values were determined using stratified tients with polyvascular disease in 3 beds had more log-rank tests. Endpoint rates were based on comorbidities, including a history of hypertension, observed incidences. Alirocumab treatment effect myocardial infarction, and coronary artery bypass 1172 Jukema et al. JACC VOL. 74, NO. 9, 2019 Alirocumab and Polyvascular Disease in ODYSSEY OUTCOMES SEPTEMBER 3, 2019:1167–76 C E N T R A L IL L U ST R A T I O N Alirocumab and Vascular Disease: Primary Major Adverse Cardiovascular Event Endpoint 40 Placebo ARR: 13.0 (95% CI: –2.0 to 28.0) ARR: 1.9 (95% CI: –2.4 to 6.2) ARR: 1.4 (95% CI: 0.6 to 2.3) ARR interaction p = 0.0006 30 3 vascular beds Alirocumab Placebo MACE (%) 20 Alirocumab 2 vascular beds 10 Placebo Alirocumab 1 vascular bed 0 0 1 2 3 Years Since Randomization Jukema, J.W. et al. J Am Coll Cardiol. 2019;74(9):1167–76. Kaplan-Meier curves for primary major adverse cardiovascular event (MACE) endpoint in patients with arterial disease in, respectively, 1 (coronary artery disease [CAD] and no peripheral artery disease [PAD] or cerebrovascular disease [CeVD]), 2 (CAD and PAD or CeVD), or 3 (CAD and PAD and CeVD) vascular beds. ARR ¼ absolute risk reduction; CI ¼ confidence interval. grafting, compared with patients with monovascular disease, 91 mg/dl (76, 108 mg/dl) in CAD and PAD, disease (all p < 0.0001). Furthermore, patients with 90 mg/dl (75, 109 mg/dl) in CAD and CeVD, and polyvascular disease in 3 beds versus patients with 95 mg/dl (80, 115 mg/dl) in polyvascular disease in 3 monovascular disease had a higher prevalence of beds (p < 0.0001). In the placebo group, LDL-C at diabetes (43.6% vs. 27.7%; p < 0.0001) and were 4 months was 87 mg/dl (72, 106 mg/dl) in patients with more likely to be current or former smokers (81.9% monovascular disease, 90 mg/dl (73, 108 mg/dl) in only vs. 64.9%; p < 0.0001). More patients with poly- PAD, 90 mg/dl (73, 115 mg/dl) in CeVD only, and vascular disease in 3 beds versus patients with 93 mg/dl (78, 118 mg/dl) in polyvascular disease in monovascular disease had an estimated glomerular 3 beds. In patients treated with alirocumab, LDL-C at filtration rate of <60 ml/min/1.73 m2 (39.6% vs. 4 months was 30 mg/dl (20, 47 mg/dl), 34 (23, 12.3%) with median estimated glomerular filtration 50 mg/dl), 34 mg/dl (21, 52 mg/dl), and 31 mg/dl (20, rates of 78.5, 74.1, 72.9, and 67.0 ml/min/1.73 m 2 in 42 mg/dl) in the same 4 vascular disease categories. patients with monovascular disease, CAD and PAD, PRIMARY MACE ENDPOINT AND ALL-CAUSE CAD and CeVD, and polyvascular disease in 3 beds, DEATH. Overall in the ODYSSEY OUTCOMES trial, respectively (p < 0.0001). the incidence of MACE in the placebo and alirocumab LDL-C LOWERING. At baseline, median LDL-C groups was 11.1% and 9.5%, respectively, with a cor- (quartile 1, quartile 3) was higher in patients with responding ARR of 1.6% (95% CI: 0.7% to 2.4%; polyvascular disease, with values of 86 mg/dl p ¼ 0.0003) (14). The Central Illustration and Online (73, 103 mg/dl) in patients with monovascular Figure 1 show that this overall efficacy reflects a JACC VOL. 74, NO. 9, 2019 Jukema et al. 1173 SEPTEMBER 3, 2019:1167–76 Alirocumab and Polyvascular Disease in ODYSSEY OUTCOMES T A B L E 2 Primary MACE Endpoint and All-Cause Death by History of PAD or CeVD Category HR Interaction ARR Interaction Alirocumab Placebo HR* (95% CI) p Value* ARR (95% CI) p Value* Primary composite Monovascular disease 740/8,683 (8.5) 866/8,687 (10.0) 0.85 (0.77 to 0.93) 1.4 (0.6 to 2.3) (CAD without PAD or CeVD) Disease in 2 vascular beds CAD and PAD 69/302 (22.8) 73/308 (23.7) 0.93 (0.67 to 1.30) 0.40 0.9 (5.9 to 7.6) 0.0006 CAD and CeVD 75/406 (18.5) 82/389 (21.1) 0.87 (0.63 to 1.19) 2.6 (2.9 to 8.2) Disease in 3 vascular beds 19/71 (26.8) 31/78 (39.7) 0.64 (0.35 to 1.12) 13.0 (2.0 to 28.0) (CAD, PAD, and CeVD) All patients 903/9,462 (9.5) 1,052/9,462 (11.1) 0.85 (0.78 to 0.93) 1.6 (0.7 to 2.4) All-cause death Monovascular disease 268/8,683 (3.1) 305/8,687 (3.5) 0.88 (0.75 to 1.04) 0.4 (0.1 to 1.0) (CAD without PAD or CeVD) Disease in 2 vascular beds CAD and PAD 28/302 (9.3) 27/308 (8.8) 1.03 (0.60 to 1.75) 0.06 0.5 (5.1 to 4.0) 0.002 CAD and CeVD 34/406 (8.4) 43/389 (11.1) 0.68 (0.44 to 1.08) 2.7 (1.4 to 6.8) Disease in 3 vascular beds 4/71 (5.6) 17/78 (21.8) 0.23 (0.08 to 0.68) 16.2 (5.5 to 26.8) (CAD, PAD, and CeVD) All patients 334/9,462 (3.5) 392/9,462 (4.1) 0.85 (0.77 to 0.98) 0.6 (0.1 to 1.2) Values are n/N (%) unless otherwise indicated. *HRs reflect stratification by geographic region in models with interaction between treatment and the 3 disease bed subgroups (monovascular disease, disease in 2 beds, and disease in 3 beds). ARR ¼ absolute risk reduction; CAD ¼ coronary artery disease; CI ¼ confidence interval; HR ¼ hazard ratio; MACE ¼ major adverse cardiovascular event; other abbreviations as in Table 1. gradient of absolute risk and ARR according to the to 6.2%), and 13.0% (95% CI: 2.0% to 28.0%), with an number of diseased vascular beds. For patients in the interaction p ¼ 0.0006. placebo group with 1, 2, or 3 diseased vascular beds, For all-cause death in ODYSSEY OUTCOMES, the the incidence of MACEs was 10.0%, 22.2%, and 39.7%, overall incidence of death in the placebo and alir- respectively. The corresponding ARR with alirocumab ocumab groups was 4.1% and 3.5%, respectively, with a was 1.4% (95% CI: 0.6% to 2.3%), 1.9% (95% CI: 2.4% corresponding ARR of 0.6% (95% CI: 0.2% to 1.2%) (14). T A B L E 3 Safety Endpoints Disease in 3 Vascular Monovascular Disease Disease in 2 Vascular Beds Beds CAD Without PAD or CeVD CAD and PAD CAD and CeVD CAD, PAD, and CeVD Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo (n ¼ 8,672) (n ¼ 8,668) (n ¼ 302) (n ¼ 308) (n ¼ 406) (n ¼ 389) (n ¼ 71) (n ¼ 78) Any adverse event 6,532 (75.3) 6,619 (76.4) 250 (82.8) 262 (85.1) 321 (79.1) 328 (84.3) 62 (87.3) 73 (93.6) Serious adverse event 1,905 (22.0) 2,012 (23.2) 124 (41.1) 142 (46.1) 136 (33.5) 151 (38.8) 37 (52.1) 45 (57.7) Adverse event that led to death 143 (1.6) 175 (2.0) 15 (5.0) 15 (4.9) 22 (5.4) 24 (6.2) 1 (1.4) 8 (10.3) Adverse event that led to treatment 298 (3.4) 285 (3.3) 21 (7.0) 15 (4.9) 19 (4.7) 18 (4.6) 5 (7.0) 6 (7.7) discontinuation Local injection-site reaction 339 (3.9) 185 (2.1) 8 (2.6) 4 (1.3) 9 (2.2) 11 (2.8) 4 (5.6) 3 (3.8) General allergic reaction 670 (7.7) 643 (7.4) 31 (10.3) 38 (12.3) 41 (10.1) 45 (11.6) 6 (8.5) 10 (12.8) Diabetes worsening or diabetic complication 444/2,369 (18.7) 521/2,427 (21.5) 23/99 (2.3) 28/126 (22.2) 29/188 (15.4) 32/161 (19.9) 10/32 (31.3) 2/33 (6.1) in patients with diabetes at baseline New-onset diabetes among patients 595/6,303 (9.4) 617/6,241 (9.9) 26/203 (12.8) 22/182 (12.1) 24/218 (11.0) 32/228 (14.0) 3/39 (7.7) 5/45 (11.1) without diabetes at baseline* Neurocognitive disorder 120 (1.4) 143 (1.6) 6 (2.0) 10 (3.2) 9 (2.2) 10 (2.6) 8 (11.3) 4 (5.1) Hepatic disorder 450 (5.2) 493 (5.7) 19 (6.3) 18 (5.8) 24 (5.9) 21 (5.4) 7 (9.9) 2 (2.6) Cataracts 99 (1.1) 117 (1.3) 8 (2.6) 9 (2.9) 10 (2.5) 5 (1.3) 3 (4.2) 3 (3.8) Hemorrhagic stroke, adjudicated 10 (0.1) 13 (0.1) 1 (0.3) 1 (0.3) 2 (0.5) 3 (0.8) 0 (0.0) 0 (0.0) (fatal and nonfatal) Values are n (%) or n/N (%). *New-onset diabetes was defined according to the presence of 1 or more of the following, with confirmation of the diagnosis by blinded external review by experts in the field of diabetes: an adverse event report, a new prescription for diabetes medication, a glycated hemoglobin level of $6.5% on 2 occasions (and a baseline level of <6.5%), or a fasting serum glucose level of $126 mg/dl (7.0 mmol/l) on 2 occasions (and a baseline level of <126 mg/dl). Abbreviations as in Table 1. 1174 Jukema et al. JACC VOL. 74, NO. 9, 2019 Alirocumab and Polyvascular Disease in ODYSSEY OUTCOMES SEPTEMBER 3, 2019:1167–76 Similar to MACEs, there was a gradient of absolute Stratification of Unstable Angina Patients Suppress risk and ARR with alirocumab. In the placebo group, Adverse Outcomes with Early Implementation of the the incidence of death in patients with 1, 2, or 3 American College of Cardiology/American Heart As- diseased vascular beds was 3.5%, 10.0%, and 21.8%, sociation Guidelines), and the American Heart Asso- respectively. With alirocumab, the corresponding ciation Get With the Guidelines registries (2,5,17), but ARR was 0.4% (95% CI: 0.1% to 1.0%), 1.3% they remain a therapeutic challenge. It is likely that (95% CI: 1.8% to 4.3%), and 16.2% (95% CI: 5.5% to the elevated cardiovascular risk associated with 26.8%), with an interaction p ¼ 0.002. polyvascular disease is the result in part of clustering Details of the primary MACE endpoint and all- of risk factors known to affect prognosis, including cause death are shown in Table 2, including the to- older age and more frequent history of hypertension, tal number of events with corresponding hazard ratio diabetes, prior myocardial infarction, coronary artery and ARR of alirocumab versus placebo for primary bypass surgery, and chronic kidney disease, as was endpoint and all-cause death for patients with mon- observed in the present analysis. Dyslipidemia, ovascular disease, polyvascular disease in 2 or 3 beds, including higher levels of LDL-C and lipoprotein(a), polyvascular disease in 2 beds (split by PAD or CeVD), was also more pronounced in patients with poly- and polyvascular disease in 3 beds. Online Tables 1 vascular disease than in patients with monovascular and 2 show these details for both sensitivity ana- (coronary) disease (Table 1). Studies have shown that lyses (monovascular vs. polyvascular and the 4 high-intensity compared with low- to moderate- overlapping vascular groups on the basis of PAD or intensity statin therapy reduces MACEs and death CeVD). in patients with polyvascular disease, including trials SAFETY OUTCOMES. Overall, there were no differ- with ACS, but also PAD and CeVD (7,18,19). Our ences in the incidence of adverse events or laboratory findings reinforce and extend this concept with abnormalities between alirocumab and placebo reduction of LDL-C to less than levels achievable with groups, with the exception of local injection-site re- statins by using alirocumab. Although alirocumab actions, which occurred more often in the alirocumab produced a similar degree of LDL-C lowering in each group (14). Table 3 shows all safety endpoints for vascular category, a particularly pronounced absolute alirocumab versus placebo for patients with mono- reduction of MACEs and death was observed in pa- vascular disease, polyvascular disease in 2 beds tients with ACS and concurrent disease in other (categorized as PAD or CeVD), and polyvascular dis- vascular beds. Similar conclusions regarding MACEs ease in 3 beds. No major differences were observed were drawn from an analysis of the FOURIER trial, among the groups. using the PCSK9 inhibitor evolocumab added to statin in patients with stable, established athero- DISCUSSION sclerotic cardiovascular disease (12). In that analysis, evolocumab reduced the risk of cardiovascular- In patients with recent ACS and dyslipidemia despite related events in patients with PAD. Of note, intensive statin therapy and high rates of guideline- because of trial selection criteria, patients with PAD directed medical therapy, polyvascular disease is comprised 13.2% of the FOURIER cohort, compared associated with high risks of MACEs and death. The with 3.2% in ODYSSEY OUTCOMES (12). However, large absolute reductions in both MACEs and death some patients in FOURIER with PAD or CeVD had with alirocumab therapy are a potential benefit for monovascular disease in those territories. this group of patients. Conversely, because qualification for ODYSSEY This analysis of ODYSSEY OUTCOMES defines OUTCOMES required ACS, all patients with PAD or easily identifiable subsets of patients with ACS with CeVD had disease in at least 2 vascular beds. high absolute risk and marked absolute benefit of STUDY LIMITATIONS. A substantial fraction of the PCSK9 inhibition with alirocumab. Identification of patients categorized as having monovascular (coro- patient subsets likely to derive large absolute benefit nary) disease may have had undetected PAD or CeVD, is important (15,16). given that they were not systematically evaluated for Increasing risks of MACEs and death in patients those conditions at baseline. However, the classifi- with an increasing number of affected vascular beds cation used in the present analysis is representative have been described previously in large cohorts such of daily clinical practice and decision making because as the REACH (Reduction of Atherothrombosis for patients with ACS are not routinely screened for Continued Health), CRUSADE (Can Rapid Risk polyvascular disease (20). JACC VOL. 74, NO. 9, 2019 Jukema et al. 1175 SEPTEMBER 3, 2019:1167–76 Alirocumab and Polyvascular Disease in ODYSSEY OUTCOMES CONCLUSIONS Fondation Assistance PubliqueHôpitaux de Paris, Paris, France. The present findings indicate that patients with polyvascular disease comprise an easily identifiable ADDRESS FOR CORRESPONDENCE: Dr. J. Wouter subgroup of patients with recent ACS with a high Jukema, Department of Cardiology, Leiden University absolute risk of MACEs and death. The large absolute Medical Center, PO Box 9600, 2300 RC Leiden, the benefit of PCSK9 inhibition with alirocumab, when Netherlands. E-mail: j.w.jukema@lumc.nl. Twitter: added to high-intensity statin therapy, is a potential @gabrielsteg. benefit for this group of patients. However, further studies are needed to guide the selection of patients PERSPECTIVES with ACS for treatment with a PCSK9 inhibitor in the context of other established and evolving therapies in atherosclerosis, so that efficacy and efficiency are COMPETENCY IN PATIENT CARE AND PROCEDURAL optimized (21–23). SKILLS: Patients with polyvascular disease and ACS gain considerable absolute benefit from PCSK9 inhibition with ACKNOWLEDGMENTS The authors thank the pa- alirocumab. tients, study coordinators, and investigators who participated in this trial. Sophie Rushton-Smith TRANSLATIONAL OUTLOOK: Further studies are needed to (MedLink Healthcare Communications, London) pro- identify other subgroups of patients with atherosclerosis who vided editorial assistance in the preparation of the stand to gain substantial benefit from PCSK9 inhibition. manuscript (limited to editing for style, referencing, and figure and table editing) and was funded by REFERENCES 1. Bhatt DL, Eagle KA, Ohman EM, et al. Compar- peripheral artery disease: executive summary: a 13. Schwartz GG, Bessac L, Berdan LG, et al. 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