Effects of Alirocumab on Cardiovascular Events After Coronary Bypass Surgery

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Effects of Alirocumab on Cardiovascular Events After Coronary Bypass Surgery

Shaun G. Goodman, MD, MSC,âPhilip E. Aylward, MD,^bMichael Szarek, PHD,^cVakhtang Chumburidze, MD,^d Deepak L. Bhatt, MD, MPH,êVera A. Bittner, MD, MSPH,^fRafael Diaz, MD,^gJay M. Edelberg, MD, PHD,^h Corinne Hanotin, MD,ⁱRobert A. Harrington, MD,^jJ. Wouter Jukema, MD, PHD,^kSasko Kedev, MD,^l Alexia Letierce, PHD,ⁱAngele Moryusef, MD,^hRobert Pordy, MD,^mGabriel Arturo Ramos López, MD,ⁿ Matthew T. Roe, MD, MHS,ô,pMargus Viigimaa, MD,^qHarvey D. White, DSC,^rAndreas M. Zeiher, MD,^s

Ph. Gabriel Steg, MD,^t,uGregory G. Schwartz, MD, PHD,^vfor the ODYSSEY OUTCOMES Committees and Investigators*

ABSTRACT

BACKGROUNDPatients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death.

OBJECTIVESThis study sought to determine the clinical beneﬁt of adding alirocumab to statins in ACS patients with prior CABG in a pre-speciﬁed analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab).

METHODSPatients (n¼ 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high- intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks. Median follow-up was 2.8 years. The primary composite endpoint of major adverse cardiovascular events (MACE) comprised coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Patients were categorized by CABG status: no CABG (n¼ 16,896); index CABG after qualifying ACS, but before randomization (n¼ 1,025); or CABG before the qualifying ACS (n ¼ 1,003).

RESULTSIn each CABG category, hazard ratios (95% conﬁdence intervals) for MACE (no CABG 0.86 [0.78 to 0.95], index CABG 0.85 [0.54 to 1.35], prior CABG 0.77 [0.61 to 0.98]) and death (0.88 [0.75 to 1.03], 0.85 [0.46 to 1.59], 0.67 [0.44 to 1.01], respectively) were consistent with the overall trial results (0.85 [0.78 to 0.93] and 0.85 [0.73 to 0.98], respectively). Absolute risk reductions (95% conﬁdence intervals) differed across CABG categories for MACE (no CABG 1.3% [0.5% to 2.2%], index CABG 0.9% [2.3% to 4.0%], prior CABG 6.4% [0.9% to 12.0%]) and for death (0.4% [0.1% to 1.0%], 0.5% [1.9% to 2.9%], and 3.6% [0.0% to 7.2%]).

CONCLUSIONSAmong patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with large absolute reductions in MACE and death in those with CABG preceding the ACS event. (ODYSSEY OUTCOMES: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab;NCT01663402) (J Am Coll Cardiol 2019;74:1177–86) © 2019 by the American College of Cardiology Foundation.

From theâCanadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada and St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada;^bSouth Australian Health and Medical Research Institute, Flinders University and Medical Centre, Adelaide, South Australia, Australia;^cState University of New York, Downstate School of Public Health, Brooklyn, New York;^dChapidze Emergency Cardiology Center, Tbilisi, Georgia;êBrigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts;^fDivision of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama;^gEstudios Cardiológicos Latinoamérica, Instituto Cardiovascular de Rosario, Rosario, Argentina;^hSanofi, Bridgewater, New Jersey;ⁱSanofi, Chilly-Mazarin, France;^jStanford Center for Clinical Research, Department of Medicine, Stan- ford University, Stanford, California;^kDepartment of Cardiology, Leiden University Medical Center, Leiden, the Netherlands;

lUniversity Clinic of Cardiology, Skopje, Macedonia;^mRegeneron Pharmaceuticals Inc., Tarrytown, New York;ⁿMedical Ofﬁce, Guadalajara, Jalisco, Mexico;^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;^qSA Põhja-Eesti Regionaalhaigla, Tallinn, Estonia; ^rGreen Lane Cardiovascular Services Auckland City Hospital, Auckland, New Zealand;

sDepartment of Medicine III, Goethe University, Frankfurt am Main, Germany;^tAssistance Publique-Hôpitaux de Paris, Hôpital

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.07.015

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

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P

atients with prior coronary artery bypass graft surgery (CABG) have extensive native coronary and bypass graft atherosclerosis(1–3)and are at high risk for cardiovascular events and death(2,4–12). Residual atherosclerotic cardiovascular event risk among patients with prior CABG (3,13,14) may be mitigated by lowering of atherogenic lipoproteins (e.g., low-density lipoprotein-cholesterol [LDL-C]) with statins (8,15,16)and ezetimibe(12); however, overall cardiovascular risk remains high and no beneﬁcial effect on death with lipid- lowering therapy has been observed to date in randomized trials in this group(12,15,16).

Inhibitors of proprotein convertase subtilisinkexin type 9 (PCSK9) produce

substantial reductions of LDL-C levels when admin- istered with or without concurrent statin(17–19). The addition of a PCSK9 monoclonal antibody to statin treatment reduces major adverse cardiovascular events (MACE) in patients with stable atherosclerotic cardiovascular disease (17,18) and was associated with reduced MACE and fewer deaths in patients with a recent acute coronary syndrome (ACS) (19). How- ever, it is uncertain to what extent the addition of a PCSK9 inhibitor to statin therapy reduces MACE and death in patients with a prior CABG. Here, we report a pre-speciﬁed analysis of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial (NCT01663402)(19,20) of patients with a recent ACS and elevated atherogenic lipoproteins despite high-intensity (or maximally tolerated) statin therapy, comparing the relative and absolute effects of the PCSK9 inhibitor alirocumab with

Bichat, Paris, France;^uNational Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, United Kingdom;

and the^vDivision of Cardiology, University of Colorado School of Medicine, Aurora, Colorado. *A complete list of the ODYSSEY OUTCOMES Committee members, investigators, and contributors is provided in theOnline Appendix. The trial was funded by Sanofi and Regeneron Pharmaceuticals, Inc. Dr. Goodman has received research grants from Daiichi-Sankyo, Luitpold Pharma- ceuticals, 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/on the Advisory Board for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Pfizer, Servier, Tenax Therapeutics, Sanofi, Amgen, and Bayer.

Dr. Aylward has received grants and personal fees from Sanoﬁ, AstraZeneca, and Bayer; has received personal fees from Amgen, Boehringer Ingelheim, and Novartis; and has received grants from CSL. Dr. Szarek has served as a consultant to/on the Advisory Board for CiVi, Resverlogix, Baxter, and Regeneron Pharmaceuticals. Dr. Bhatt has served on an Advisory Board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; Board of Directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; Chair of American Heart Association Quality Oversight Committee;

Data Monitoring Committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the POR- TICO 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; 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 USA national co- leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); other for Clinical Cardiology (Deputy Editor), NCDR- ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Labora- tories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site co- investigator for Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; trustee for American College of Cardiol- ogy; and unfunded research for FlowCo, Fractyl, 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 American College of Cardiology, American Heart Association, and National Lipid Association; and has served as consultant to/on the Advisory Board for Sanofi. Dr. Diaz has received research grants from Sanofi, Amgen, Bayer, Dalcor, PHRI, and DCRI; and has received honoraria from Sanofi. Dr. Edelberg is an employee of Sanofi. Dr. Hanotin is an employee of Sanofi. Dr. Harrington has received research grants from Apple, CSL, Sanofi, Astra, Portola, Janssen, BMS, Novartis, and The Medicines Company; has served as a consultant to/on the Advisory Board for Amgen, Bayer, Gilead, MyoKardia, and WebMD; and has served on the board of directors (unpaid) for AHA and Stanford HealthCare. Dr. Jukema has received research grants from the Netherlands Heart Foundation, the Interuni- versity 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.

SEE PAGE 1187 A B B R E V I A T I O N S

A N D A C R O N Y M S

ACS= acute coronary syndrome

CABG= coronary artery bypass graft surgery

CHD= coronary heart disease CI= conﬁdence interval HDL-C= high-density lipoprotein cholesterol HR= hazard ratio LDL-C= low-density lipoprotein cholesterol MACE= major adverse cardiovascular events NNT= number needed to treat PCSK9= proprotein convertase subtilisinLkexin type 9

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placebo on MACE and death in patients with and without prior CABG.

METHODS

STUDY DESIGN AND PATIENT POPULATION.ODYS- SEY OUTCOMES(19,20)was a multinational, double- blind, placebo-controlled trial of 18,924 patients age $40 years hospitalized 1 to 12 months before randomization with an ACS, who had LDL-C levels$70 mg/dl (1.81 mmol/l), nonhigh-density lipoprotein cholesterol (nonHDL-C) levels $100 mg/dl (2.59 mmol/l), or apolipoprotein B levels$80 mg/dl after$2 weeks of stable treatment with atorvastatin 40 to 80 mg daily, rosuvastatin 20 to 40 mg daily, or the maximum tolerated dose of 1 of these statins (including no statin in case of documented intoler- ance). After a pre-randomization run-in phase, patients were randomly assigned to alirocumab 75 mg or matching placebo given by subcutaneous injection every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL-C level of 25 to 50 mg/dl (0.65 to 1.29 mmol/l), including an in- crease in dose to 150 mg if LDL-C was 50 mg/dl (1.29 mmol/l) or greater on the 75-mg dose, or substi- tution of placebo for alirocumab if LDL-C<15 mg/dl (0.39 mmol/l) on 2 consecutive measurements on the 75-mg dose. Key exclusion criteria were coronary revascularization procedure #2 weeks before randomization or planned after randomization, New York Heart Association functional class III to IV heart failure persisting despite treatment, or left ventricular ejection fraction<25% if measured, history of hem- orrhagic stroke, fasting triglycerides >400 mg/dl (4.52 mmol/l) at qualifying laboratory visit, and estimated glomerularﬁltration rate <30 ml/min/1.73 m².

The present pre-speciﬁed subgroup analysis assessed the consistency of the alirocumab treatment

effect on endpoints according to three categories of CABG status: no CABG; CABG performed after the index ACS but before randomization (index CABG); and CABG performed prior to the index ACS (prior CABG).

ENDPOINTS. The primary endpoint (MACE) was the composite of death from coronary heart disease (CHD), nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. Secondary endpoints for the current analysis by CABG subgroup included: individual components of the primary endpoint, coronary revascularization, cardiovascular death (including deaths of indeterminate cause), and all-cause death.

STATISTICAL ANALYSIS. Baseline characteristics are presented by CABG status as frequencies and per- centages for categorical variables and as medians (25th, 75th percentiles) for continuous variables.

Comparisons of baseline characteristics between CABG status groups and randomized treatment were performed by chi-square tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.

Endpoints among CABG status groups were compared with multivariable Cox proportional hazards models accounting for differences in baseline characteristics (age, sex, geographic region, diabetes status, smoking status, baseline LDL-C, baseline HDL-C, baseline body mass index, renal function [estimated glomerular filtration rate <60 vs. $60 ml/min/1.73 m²], history of myocardial infarction, history of stroke, history of chronic obstructive pulmonary disease, history of peripheral artery disease, percutaneous coronary intervention for index event). Treatment hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox models, stratified by geographic region.

Endpoint rates were based on the observed number of patients having the event of interest. The number- needed-to-treat (NNT) to prevent 1 primary or

Letierce is an employee of Sanoﬁ. Dr. Moryusef is an employee of Sanoﬁ. Dr. Pordy is an employee of Regeneron Pharmaceuticals.

Dr. Ramos López has received personal fees and nonfinancial support from Sanofi. Dr. Roe has received research grant funding from Sanofi, Janssen, AstraZeneca, Patient-Centered Outcomes Research Institute, Ferring Pharmaceuticals, MyoKardia, American College of Cardiology, American Heart Association, and Familial Hypercholesterolemia Foundation; and has received consulting fees or honoraria from AstraZeneca, Amgen, Eli Lilly, Roche-Genentech, Janssen, Regeneron Pharmaceuticals, Ardea Biosciences, Novo Nordisk, Flatiron, Merck, Pfizer, Sanofi, Signal Path, and Elsevier. Dr. Viigimaa has received research grants and personal fees from Amgen; and has received personal fees from Sanofi, Menarini, and NovoNordisk. Dr. White has received grant support (paid to institution) and fees for serving on a Steering Committee from Sanofi and Regeneron Pharmaceuticals (for the ODYSSEY OUTCOMES trial), Eli Lilly (for the ACCELERATE trial), Omthera Pharmaceuticals (for the STRENGTH trial), Pfizer (for the SPIRE trial), American Regent (for the HEART-FID trial), Eisai (for the CAMELLIA-TIMI trial), DalCor (for the dal-GenE trial), CSL Behring (for the AEGIS-II trial), Sanofi (for the SCORED and SOLOIST trials), and Esperion Therapeutics (for the CLEAR Outcomes trial). Dr. Steg has received research grants from Bayer, Merck, Sanofi, and Servier; and has received speaking or consulting fees from Amarin, Amgen, Astra- Zeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck, Novartis, Novo-Nordisk, Pfizer, Regeneron Phar- maceuticals, Inc., Sanofi, and Servier. Dr. Schwartz is co-inventor of pending U.S. patent 14/657192 assigned in full to the University of Colorado; and has received research grants to his institution from Resverlogix, Sanofi, Roche, and The Medicines Company.

Manuscript received April 4, 2019; revised manuscript received June 17, 2019, accepted July 2, 2019.

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secondary endpoint over the median 2.8 years of follow-up (NNT2.8 years) was calculated by 1/absolute risk reduction, where the absolute risk reduction was determined by absolute differences in endpoint rates.

Tests of interaction of alirocumab treatment effects by CABG status was assessed by Cox models with interaction terms for relative risk reduction and Gail-Simon tests for absolute risk reduction.

All analyses were conducted according to intention-to-treat, including all patients and events from randomization to common study end date (11 November 2017). Testing was 2-sided with no adjustment for multiple comparisons. Analyses were performed in SAS 9.4 and Sþ 8.2.

RESULTS

A total of 18,924 patients (83% with a recent myocardial infarction, 17% with high-risk unstable angina) were randomized at 1,315 sites in 57 countries at a median 2.6 months (25th, 75th percentiles: 1.7, 4.3 months) from the qualifying ACS. The median follow-up was 2.8 years (interquartile range: 2.3 to 3.4 years). Ascertainment for vital status was complete in 99.8% of potential patient-years of follow-up.

BASELINE CHARACTERISTICS BY PRIOR CABG STATUS. Patients were categorized by prior CABG status at the time of randomization: no CABG

TABLE 1 Baseline Characteristics by Prior CABG Status

No CABG (n¼ 16,896)

Index CABG (n¼ 1,025)

Prior CABG

(n¼ 1,003) p Value

Age, yrs 58 (51, 65) 60 (53, 65) 63 (57, 70) <0.0001

Age category <0.0001

<65 yrs 12,563 (74.4) 726 (70.8) 551 (54.9)

65 to<75 yrs 3,479 (20.6) 255 (24.9) 343 (34.2)

$75 yrs 854 (5.0) 44 (4.3) 109 (10.9)

Female 4,354 (25.8) 211 (20.6) 197 (19.6) <0.0001

Race <0.0001

White 13,327 (78.9) 832 (81.2) 865 (86.2)

Asian 2,371 (14.0) 65 (6.3) 62 (6.2)

Black 405 (2.4) 40 (3.9) 28 (2.8)

Other 793 (4.7) 88 (8.6) 48 (4.8)

Body mass index, kg/m² 28 (25, 31) 28 (25, 31) 29 (26, 32) <0.0001

Region <0.0001

Western Europe 3,767 (22.3) 230 (22.4) 178 (17.7)

Eastern Europe 5,049 (29.9) 180 (17.6) 208 (20.7)

North America 2,273 (13.5) 247 (24.1) 351 (35.0)

South America 2,293 (13.6) 180 (17.6) 115 (11.5)

Asia 2,196 (13.0) 56 (5.5) 41 (4.1)

Rest of world 1,318 (7.8) 132 (12.9) 110 (11.0)

Index event <0.0001

NSTEMI 7,913 (46.9) 612 (59.8) 650 (64.9)

STEMI 6,156 (36.5) 214 (20.9) 166 (16.6)

Unstable angina 2,798 (16.6) 198 (19.3) 186 (18.6)

Time from index event to randomization, months 2.6 (1.7, 4.2) 3.8 (2.7, 6.8) 2.5 (1.7, 4.1) <0.0001

Lipid-lowering therapy at randomization <0.0001

High-dose atorvastatin or rosuvastatin 15,077 (89.2) 900 (87.8) 834 (83.2)

Other lipid-lowering therapy 1,690 (10.0) 107 (10.4) 138 (13.8)

No lipid-lowering therapy 129 (0.8) 18 (1.8) 31 (3.1)

Laboratory measurements

LDL-C, mg/dl 86 (73, 103) 87 (74, 107) 94 (78, 116) <0.0001

LDL-C$100 mg/dl 4,878 (28.9) 333 (32.5) 418 (41.7) <0.0001

HDL-C, mg/dl 42 (36, 50) 42 (36, 50) 42 (35, 50) 0.0166

NonHDL-C, mg/dl 114 (99, 136) 117 (102, 140) 126 (107, 153) <0.0001

Triglycerides, mg/dl 128 (94, 181) 137 (98, 192) 139 (102, 195) <0.0001

Apolipoprotein B, mg/dl 79 (69, 92) 82 (70, 96) 85 (75, 103) <0.0001

Lipoprotein(a), mg/dl 20.3 (6.6, 58.1) 27.8 (7.5, 69.0) 33.2 (8.1, 79.9) <0.0001

C-reactive protein, mg/dl 0.16 (0.08, 0.38) 0.19 (0.09, 0.47) 0.18 (0.08, 0.41) <0.0001

Hemoglobin A1c, % 5.8 (5.5, 6.3) 5.9 (5.5, 6.4) 6.0 (5.6, 6.7) <0.0001

Continued on the next page

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(n¼ 16,896); CABG after the index ACS but before randomization, including 44 patients who had also undergone prior CABG before the index ACS (index CABG; n ¼ 1,025); and CABG before the index ACS (prior CABG; n¼ 1,003) (Table 1). Compared with patients with no prior CABG or index CABG, those with prior CABG were older, less frequently female, and more frequently had prior myocardial infarction, stroke, peripheral artery disease, diabetes, and hypertension. Further, those with prior CABG more frequently had a nonST-segment elevation myocardial infarction as their index ACS, were more likely to be receiving a reninangiotensin system inhibitor and less likely to receive a beta-blocker.

Prior CABG patients were less frequently receiving high-dose statin and more frequently receiving other lipid-lowering therapy (including ezetimibe) with higher baseline LDL-C, nonHDL-C, apolipoprotein B, and lipoprotein(a) values. Within each CABG category, there were few signiﬁcant differences in baseline characteristics between those assigned to alirocumab or to placebo treatment (Online Table 1).

ENDPOINTS BY PRIOR CABG STATUS. The rate of MACE was signiﬁcantly higher among patients with prior CABG (27.7%) than among patients who under- went CABG during the index ACS hospitalization (7.1%) or those without CABG (9.5%) (Table 2, Central Illustration). Patients with prior CABG also had higher rates of the individual components of the primary endpoint, and of the secondary endpoints indicated inTable 2, which persisted on adjustment of multiple baseline features.

Alirocumab reduced MACE in the overall study population (HR: 0.85; 95% CI: 0.78 to 0.93) with a consistent relative risk reduction in each CABG category (Table 3, Central Illustration). Absolute risk reduction of MACE with alirocumab was most pro- nounced among patients with prior CABG (6.4%;

95% CI: 0.9 to 12.0; NNT2.8 years: 16) compared with index CABG (0.9%; 95% CI:2.3 to 4.0; NNT2.8 years: 111) and no prior CABG patients (1.3%; 95% CI: 0.5 to 2.2; NNT2.8 years:¼ 77), respectively (Table 3, Figure 1).

Findings were similar for secondary endpoints.

Relative risk reduction with alirocumab was without

TABLE 1 Continued

No CABG (n¼ 16,896)

Prior CABG

(n¼ 1,003) p Value

Estimated GFR<60 ml/min/1.73 m² 2,138 (12.7) 141 (13.8) 260 (25.9) <0.0001

Diabetes status <0.0001

Diabetes 4,691 (27.8) 346 (33.8) 407 (40.6)

Pre-diabetes 7,482 (44.3) 382 (37.3) 382 (38.1)

Normoglycemia 4,723 (28.0) 297 (29.0) 214 (21.3)

Smoking status <0.0001

Current 4,258 (25.2) 136 (13.3) 166 (16.6)

Former 6,795 (40.2) 526 (51.3) 490 (48.9)

Never 5,842 (34.6) 363 (35.4) 347 (34.6)

Medical history before index event

Hypertension 10,672 (63.2) 703 (68.6) 874 (87.1) <0.0001

Myocardial infarction 2,748 (16.3) 194 (18.9) 697 (69.5) <0.0001

Stroke 501 (3.0) 40 (3.9) 70 (7.0) <0.0001

Malignant disease 450 (2.7) 30 (2.9) 52 (5.2) <0.0001

COPD 621 (3.7) 51 (5.0) 74 (7.4) <0.0001

CABG 0 (0.0) 44 (4.3) 1,003 (100.0)

Peripheral artery disease 577 (3.4) 58 (5.7) 124 (12.4) <0.0001

Cerebrovascular disease 735 (4.4) 74 (7.2) 135 (13.5) <0.0001

Revascularization for index event 12,070 (71.4) 1,025 (100.0) 582 (58.0) <0.0001

PCI 12,070 (71.4) 117 (11.4) 582 (58.0) <0.0001

Medications

Aspirin 16,160 (95.6) 978 (95.4) 948 (94.5) NS

P2Y12antagonist 15,280 (90.4) 410 (40.0) 851 (84.8) <0.0001

ACE inhibitor/angiotensin receptor blocker 13,245 (78.4) 656 (64.0) 815 (81.3) <0.0001

Beta-blocker 14,227 (88.0) 895 (87.3) 868 (86.5) 0.0045

Ezetimibe 425 (2.5) 40 (3.9) 89 (8.9) <0.0001

Values are median (25th, 75th percentiles) or n (%). NS: p> 0.05.

ACE¼ angiotensin-converting enzyme; CABG ¼ coronary artery bypass graft surgery; COPD ¼ chronic obstructive pulmonary disease; GFR ¼ glomerular ﬁltration rate;

HDL-C¼ high-density lipoprotein cholesterol; LDL-C ¼ low-density lipoprotein cholesterol; NS ¼ not signiﬁcant; NSTEMI ¼ nonST-segment elevation myocardial infarction;

PCI¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction.

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heterogeneity according to CABG category, except for ischemia-driven coronary revascularization where the HRs ranged from 0.47 (95% CI: 0.27 to 0.82) in patients undergoing index CABG to 0.92 (95% CI: 0.82 to 1.02) in no prior CABG patients (Table 3). Absolute reductions in the risk of secondary endpoints were numerically greater among patients with prior CABG, compared with the other 2 CABG categories, including CHD death (3.0% vs. 0.5% and 0.0%), nonfatal myocardial infarction (2.2% vs. 1.2% and 0.9%), ischemic stroke (2.2% vs.0.3% and 0.4%), coronary revascularization (4.6% vs. 3.7% and 0.7%), cardiovascular death (3.6% vs. 1.0% and 0.1%), and all-cause death (3.6% vs. 0.5% and 0.4%). Among patients with prior CABG, the NNT2.8 yearsto prevent 1 death was 28. Absolute reductions were statistically signiﬁcantly lower with alirocumab versus placebo in prior CABG patients for the primary composite endpoint, nonfatal myocardial infarction, coronary revascularization, and cardiovascular death (Table 3).

For each secondary endpoint except CHD death, there was a signiﬁcant interaction of treatment and CABG category on absolute risk reduction (Table 3, Figure 1).

DISCUSSION

This pre-speciﬁed subgroup analysis of the ODYSSEY OUTCOMES trial by prior CABG status conﬁrms, in a contemporary ischemic heart disease population, that patients with prior CABG who develop an ACS have a markedly elevated risk of recurrent MACE and death (w28% and w9%, respectively, at a median 2.8 years) even on maximally tolerated statin therapy. We further demonstrate that, among patients with prior CABG, recent ACS, and elevated atherogenic

lipoproteins despite intensive statin therapy, the addition of the PCSK9 inhibitor alirocumab is associated with large absolute reductions in MACE and death. Although the relative beneﬁt of alirocumab versus placebo is consistent regardless of prior CABG status, those with prior CABG achieve substantially greater absolute risk reduction and consequently lower NNT.

Thefinding that patients with prior CABG, specif- ically those with CABG before ACS, are at high risk for recurrent cardiovascular events is consistent with previous randomized clinical trial main (14,15) and subgroup(5–8,10–12,16)results. This observation may be due in part to a clustering of multiple prognostic factors including older age, diabetes, hypertension, chronic kidney disease, advanced atherosclerosis (e.g., prior myocardial infarction, cerebrovascular disease, peripheral artery disease), and higher levels of atherogenic lipoproteins. The present and prior findings (12) confirm the independent association between prior CABG, worse cardiovascular outcomes, and higher mortality, even after adjusting for these prognostic characteristics. The current analysis re- inforces the concept that the benefits from effective secondary prevention therapies in atherosclerosis are greatest among those at high residual athero- thrombotic risk. In the ODYSSEY OUTCOMES trial, patients with prior CABG were at very high risk for recurrent cardiovascular events (as noted inTable 1), and would therefore be expected to realize greater absolute benefits of lipid-lowering therapy. Analo- gously, prior studies in ACS have found large absolute benefits of intensive statin or ezetimibe therapy (8,12), antiplatelet therapy (5,6,11), and an early invasive versus a conservative strategy (7) among

TABLE 2 Primary and Secondary Endpoints by Prior CABG Status

No CABG (n¼ 16,896)

Prior CABG (n¼ 1,003)

Index vs.

No CABG*

Prior vs.

No CABG*

Primary endpoint 1,604 (9.5) 73 (7.1) 278 (27.7) 0.56 (0.44–0.72) 1.46 (1.27–1.69)

CHD death 347 (2.1) 17 (1.7) 63 (6.3) 0.54 (0.33–0.89) 1.34 (1.00–1.81)

Nonfatal myocardial infarction 1,083 (6.4) 50 (4.9) 215 (21.4) 0.59 (0.44–0.79) 1.62 (1.38–1.91) Fatal and nonfatal ischemic stroke 219 (1.3) 11 (1.1) 33 (3.3) 0.69 (0.37–1.29) 1.14 (0.76–1.71)

Unstable angina 79 (0.5) 5 (0.5) 13 (1.3) 0.80 (0.31–2.05) 1.64 (0.85–3.17)

Secondary endpoints

Ischemia-driven coronary revascularization procedure 1,311 (7.8) 57 (5.6) 191 (19.0) 0.65 (0.49–0.85) 1.57 (1.33–1.86)

Cardiovascular death 415 (2.5) 22 (2.1) 74 (7.4) 0.60 (0.39–0.93) 1.33 (1.01–1.75)

All-cause death 592 (3.5) 40 (3.9) 94 (9.4) 0.81 (0.58–1.13) 1.24 (0.98–1.58)

Values are n (%) or hazard ratio (95% confidence interval). Endpoint data are for the aggregate of the alirocumab and placebo groups in each CABG category. *Reflects adjustment for age, sex, geographic region, diabetes status, smoking status, baseline low-density lipoprotein cholesterol, baseline high-density lipoprotein cholesterol, baseline body mass index, renal function (estimated glomerularfiltration rate <60 vs. $60 ml/min/1.73 m²), history of myocardial infarction, history of stroke, history of chronic obstructive pulmonary disease, history of peripheral artery disease, percutaneous coronary intervention for index event.

CABG¼ coronary artery bypass graft; CHD ¼ coronary heart disease.

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patients with prior CABG. Further, in stable patients with prior CABG, more-intensive LDL-C lowering compared with less-intensive LDL-C lowering(15,16) has been shown to reduce MACE.

Although prior studies in patients with stable coronary heart disease and prior CABG showed lower vascular and all-cause death rates with more- versus less-intensive statin regimens (15,16), prior studies in patients with ACS and prior CABG have not shown mortality differences with ezetimibe versus placebo (added to simvastatin) (12) or with higher versus lower intensity statin therapy (8). In contrast, the present analysis of patients with ACS and prior CABG indicates that use of alirocumab to lower LDL-C to levels substantially below those achieved with statin alone is

associated with fewer CHD, cardiovascular, and total deaths.

Prior CABG is only one of several characteristics associated with a higher absolute risk of MACE and death and therefore shows greater absolute beneﬁt of alirocumab treatment. To date, other characteristics that have been determined to associate with greater absolute risk and absolute beneﬁt of alirocumab treatment in this population include high baseline LDL-C (19,21) or lipoprotein(a) and the presence of diabetes. In many respects, prior CABG status may be a surrogate for chronicity and severity of coronary and systemic atherosclerosis, limited options for further percutaneous or surgical coronary revascularization, or reduced left ventricular function, all of which may affect prognosis. ODYSSEY OUTCOMES CENTRAL ILLUSTRATION Prior Coronary Artery Bypass Graft Status and Alirocumab Versus Placebo: Primary Endpoint

Prior

None

Index

MACE (%)

40

30

20

10

0 0

Number at Risk None Index

16,896 1,025 1,003

15,790 985 877

14,815 947 783

6,354 348 343

1,142 64 76 Prior

1 2

Years Since Randomization

3 4

Placebo Alirocumab

Goodman, S.G. et al. J Am Coll Cardiol. 2019;74(9):1177–86.

*Index CABG is CABG between the index ACS event and randomization (including 44 patients with prior CABG).†Prior CABG is CABG before the index ACS event. ACS¼ acute coronary syndrome; CABG ¼ coronary artery bypass graft; MACE ¼ major adverse cardiovascular event.

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did not systematically acquire data to describe such characteristics; nonetheless, prior CABG status may be a simple and practical identiﬁer of patients who are likely to accrue substantial beneﬁt from PCSK9 inhibition after ACS.

STUDY LIMITATIONS AND STRENGTHS. Our study has limitations. This was a highly selected randomized trial cohort, which raises some uncertainty around the generalizability to a broader patient

population. Patients with prior CABG who also un- derwent CABG during the index ACS were arbitrarily included in the latter group. Information regarding when the prior CABG was done and details regarding the surgery (e.g., number of grafts, arterial vs.

venous conduits) was not available. Our study also has a number of strengths, including that this pre- speciﬁed subgroup analysis was undertaken in a reasonably large cohort, intensively treated with

TABLE 3 Primary and Secondary Endpoints by Randomized Treatment and According to Prior CABG Status

Alirocumab Placebo HR (95% CI)

HR Interaction

p Value ARR (95% CI)

ARR Interaction p Value Primary composite endpoint

No CABG 747/8,466 (8.8) 857/8,430 (10.2) 0.86 (0.78 to 0.95) 0.71 1.3 (0.5 to 2.2) 0.0007

Index CABG 33/494 (6.7) 40/531 (7.5) 0.85 (0.54 to 1.35) 0.9 (2.3 to 4.0)

Prior CABG 123/502 (24.5) 155/501 (30.9) 0.77 (0.61 to 0.98) 6.4 (0.9 to 12.0)

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)

CHD death

No CABG 174/8,466 (2.1) 173/8,430 (2.1) 1.00 (0.81 to 1.23) 0.20 0 (0.4 to 0.4) 0.09

Index CABG 7/494 (1.4) 10/531 (1.9) 0.73 (0.28 to 1.91) 0.5 (1.1 to 2.0)

Prior CABG 24/502 (4.8) 39/501 (7.8) 0.62 (0.37 to 1.03) 3.0 (0 to 6.0)

All patients 205/9,462 (2.2) 222/9,462 (2.3) 0.92 (0.76 to 1.11) 0.2 (0.2 to 0.6)

Nonfatal myocardial infarction

No CABG 503/8,466 (5.9) 580/8,430 (6.9) 0.86 (0.76 to 0.97) 0.87 0.9 (0.2 to 1.7) 0.0161

Index CABG 21/494 (4.3) 29/531 (5.5) 0.74 (0.42 to 1.30) 1.2 (1.4 to 3.8)

Prior CABG 102/502 (20.3) 113/501 (22.6) 0.88 (0.67 to 1.15) 2.2 (2.8 to 7.3)

All patients 626/9,462 (6.6) 722 (7.6) 0.86 (0.77 to 0.96) 1.0 (0.3 to 1.8)

Fatal and nonfatal ischemic stroke

No CABG 94/8,466 (1.1) 125 (1.5) 0.75 (0.57 to 0.98) 0.37 0.4 (0 to 0.7) 0.0118

Index CABG 6/494 (1.2) 5/531 (0.9) 1.24 (0.38 to 4.05) 0.3 (1.5 to 1.0)

Prior CABG 11/502 (2.2) 22/501 (4.4) 0.49 (0.24 to 1.01) 2.2 (0 to 4.4)

Unstable angina requiring hospitalization

No CABG 29/8,466 (0.3) 50/8,430 (0.6) 0.57 (0.36 to 0.91) 0.81 0.3 (0 to 0.5) 0.0397

Index CABG 2/494 (0.4) 3/531 (0.6) 0.69 (0.12 to 4.10) 0.2 (0.7 to 1.0)

Prior CABG 6/502 (1.2) 7/501 (1.4) 0.85 (0.28 to 2.52) 0.2 (1.2 to 1.6)

Coronary revascularization

No CABG 629/8,466 (7.4) 682/8,430 (8.1) 0.92 (0.82 to 1.02) 0.0319 0.7 (0.2 to 1.5) 0.0013

Index CABG 18/494 (3.6) 39/531 (7.3) 0.47 (0.27 to 0.82) 3.7 (0.9 to 6.5)

Prior CABG 84/502 (16.7) 107/501 (21.4) 0.74 (0.55 to 0.98) 4.6 (0.2 to 9.5)

Cardiovascular death

No CABG 204/8,466 (2.4) 211/8,430 (2.5) 0.96 (0.79 to 1.16) 0.14 0.1 (0.4 to 0.6) 0.0341

Index CABG 8/494 (1.6) 14/531 (2.6) 0.59 (0.25 to 1.42) 1.0 (0.7 to 2.8)

Prior CABG 28/502 (5.6) 46/501 (9.2) 0.61 (0.38 to 0.97) 3.6 (0.4 to 6.8)

All-cause death

No CABG 278/8,466 (3.3) 314/8,430 (3.7) 0.88 (0.75 to 1.03) 0.48 0.4 (0.1 to 1.0) 0.0304

Index CABG 18/494 (3.6) 22/531 (4.1) 0.85 (0.46 to 1.59) 0.5 (1.9 to 2.9)

Prior CABG 38/502 (7.6) 56/501 (11.2) 0.67 (0.44 to 1.01) 3.6 (0 to 7.2)

Values are n/N (%) unless otherwise indicated. HR and HR interaction p value reﬂect stratiﬁcation by geographic region.

ARR¼ absolute risk reduction; CI ¼ conﬁdence interval; HR ¼ hazard ratio; other abbreviations as inTable 2.

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standard of care (although most patients were randomized prior to the results of the IMPROVE-IT [Improved Reduction of Outcomes: Vytorin Efﬁcacy International Trial] (22) being available, such that ezetimibe use at baseline was only 3%), were fol- lowed carefully in a clinical trial setting, and with blinded adjudication of most events. In contrast to the IMPROVE-IT trial analysis of patients with prior CABG and ACS(12), the later enrollment time win- dow ($1 month post-ACS) in the ODYSSEY OUT- COMES trial also allowed those referred to CABG for their index event to be included. Patients undergoing CABG for their index ACS had the lowest event rates, perhaps because they were enrolled in ODYS- SEY OUTCOMES somewhat later than those with prior or no CABG (median: w4 vs. 2.5 months) together with the potential beneﬁt derived from extensive coronary revascularization post-ACS.

Although the median duration of follow-up was shorter in ODYSSEY OUTCOMES (w3 years) compared with other trials such as IMPROVE-IT (w6 years), the relative beneﬁts observed with alirocumab—particularly among those with patients with prior CABG—would be anticipated to continue beyond 3 years’ time(23). The statistical signiﬁcance of the mortality reduction with alirocumab in the

ODYSSEY OUTCOMES trial is considered nominal given the position of all-cause death after endpoints that were not significantly reduced in the pre- specified hierarchy of efficacy endpoints.

CONCLUSION

Among patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with a large absolute reduction in fatal and nonfatal cardiovascular events in those with CABG preceding the ACS.

ACKNOWLEDGMENTS The authors thank the patients, study coordinators, and investigators who participated in this trial. Sophie Rushton-Smith, PhD (MedLink Healthcare Communications, London) provided editorial assistance in the preparation of the manuscript (limited to editing for style, referencing, and ﬁgure and table editing) and was funded by Fondation Assistance PubliqueHôpitaux de Paris, Paris, France.

ADDRESS FOR CORRESPONDENCE: Dr. Shaun G.

Goodman, St. Michael’s Hospital, Room 6-034 Don- nelly Wing, Toronto, Ontario M5B 1W8, Canada.

E-mail:goodmans@smh.ca. Twitter:@gabrielsteg.

FIGURE 1 Primary Endpoint and All-Cause Death According to Prior CABG Status

Primary Endpoint

All-Cause Death

Alirocumab

n (%) HR (95% CI) ARR (95% CI)

No CABG 747 (8.8) 857 (10.2) 0.86 (0.78, 0.95) 1.3% (0.5, 2.2)

0.9% (–2.3, 4.0) 6.4% (0.9, 12.0) 1.6% (0.7, 2.4)

0.4% (–0.1, 1.0) 0.5% (–1.9, 2.9) 3.6% (0.0, 7.2) 0.6% (0.1, 1.2)

Primary endpoint: P = 0.0007 All-cause death: P = 0.03 ARR interaction P values:

Primary endpoint: P = 0.71 All-cause death: P = 0.48 HR interaction P values:

0.33 0.50

Alirocumab Better Placebo Better Alirocumab Better Placebo Better

1.0 2.0 12.0% 6.0% 0%

0.85 (0.54, 1.35) 0.77 (0.61, 0.98) 0.85 (0.78, 0.93) 155 (30.9)

123 (24.5) 903 (9.5) 278 (3.3)

392 (4.1) 56 (11.2) 22 (4.1) 314 (3.7)

0.85 (0.46, 1.59) 0.85 (0.73, 0.98) 0.67 (0.44, 1.01) 0.88 (0.75, 1.03) 18 (3.6)

38 (7.6) 334 (3.5)

1052 (11.1) 33 (6.7) 40 (7.5) All patients

All patients Index CABG*

Prior CABG†

No CABG Index CABG*

Prior CABG†

Placebo n (%)

*Index CABG is CABG between the index ACS event and randomization (including 44 patients with prior CABG).†Prior CABG is CABG before the index ACS event. HRs reflect stratification by geographic region. ACS ¼ acute coronary syndrome; ARR ¼ absolute risk reduction; CABG ¼ coronary artery bypass graft; CI ¼ confidence interval; HR¼ hazard ratio.

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KEY WORDS alirocumab, cholesterol, coronary artery bypass graft, lipids, PCSK9

APPENDIX For a complete list of the ODYSSEY OUTCOMES committee members, investigators, and contributors as well as a supplemental table, please see the online version of this paper.

PERSPECTIVES

COMPETENCY IN PATIENT CARE AND

PROCEDURAL SKILLS:Among patients with a history of CABG surgery or those undergoing CABG during hospitalization for an ACS, treatment with alirocumab is associated with large but similar reductions in cardiovascular events and mortality compared with those without CABG surgery.

TRANSLATIONAL OUTLOOK:Prospective studies are needed to identify additional high-risk patient groups, such as those with ACS and prior CABG surgery, who gain particular beneﬁt from PCSK9 inhibitor therapy.