European Heart Journal (2019) 40, 2801–2809 CLINICAL RESEARCH doi:10.1093/eurheartj/ehz299 Lipids Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial Harvey D. White1*, Ph. Gabriel Steg 2,3, Michael Szarek 4, Deepak L. Bhatt 5, Vera A. Bittner 6, Rafael Diaz7, Jay M. Edelberg8, Andrejs Erglis9, Shaun G. Goodman 10,11, Corinne Hanotin12, Robert A. Harrington13, J. Wouter Jukema14, Renato D. Lopes15, Kenneth W. Mahaffey16, Angele Moryusef8, Robert Pordy 17, Matthew T. Roe15, Piyamitr Sritara18, Pierluigi Tricoci19, Andreas M. Zeiher20, and Gregory G. Schwartz 21; for the ODYSSEY OUTCOMES Investigators† 1 Green Lane Cardiovascular Services, Auckland City Hospital, 5 Park Road, Grafton, Auckland 1142, New Zealand; 2FACT (French Alliance for Cardiovascular Trials), an F-CRIN net- work, Département Hospitalo-Universitaire FIRE, AP-HP, Hôpital Bichat, Université Paris-Diderot, Sorbonne Paris-Cité, INSERM U-1148, 46 rue Henri Huchard, 75018 Paris, France; 3 National Heart and Lung Institute, Imperial College, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK; 4Department of Epidemiology and Biostatistics, SUNY Downstate Medical Center School of Public Health, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; 5Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; 6Division of Cardiovascular Disease, University of Alabama at Birmingham, 701 19th Street South - LHRB 310, Birmingham, AL 35294, USA; 7Estudios Cardiológicos Latinoamérica, Instituto Cardiovascular de Rosario, Paraguay 160, Rosario, Santa Fe, Argentina; 8Sanofi, 55 Corporate Drive, Bridgewater, 08807 NJ, USA; 9Latvian Centre of Cardiology, Pauls Stradins Clinical University Hospital, University of Latvia, Pilsonu Street 13, LV1002, Riga, Latvia; 10Canadian VIGOUR Centre, 2-132 Li Ka Shing Centre for Health Research Innovation University of Alberta, Edmonton, Alberta, Canada T6G 2E1; 11St. Michael’s Hospital, 30 Bond Street, University of Toronto, Toronto, ON M5B 1W8, Canada; 12Sanofi, 54-56 Rue la Boétie, 75008 Paris, France; 13Stanford Center for Clinical Research, Department of Medicine, 300 Pasteur Drive, S-102, Stanford, CA 94305, USA; 14Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; 15Duke Clinical Research Institute, 200 Morris Street, Durham, NC 27710, USA; 16Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Grant S-102, Stanford, CA 94305, USA; 17Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA; 18Department of Medicine, Faculty of Medicine, Ramathibodi Hospital/Mahidol University, Rama VI Road 10400, Thailand; 19CSL Behring, 1100 N Miami Blvd Ste 613, Durham, NC 27703, USA; 20Department of Medicine III, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; and 21 Division of Cardiology, University of Colorado School of Medicine, 1700 N. Wheeling Street, Aurora 80045, CO, USA Received 8 February 2019; revised 1 March 2019; editorial decision 19 April 2019; accepted 24 April 2019; online publish-ahead-of-print 23 May 2019 See page 2810 for the editorial comment on this article (doi: 10.1093/eurheartj/ehz451) Aims The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spon- taneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac bio- markers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin– kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coron- ary syndrome (ACS) and elevated LDL-C (>_1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. ................................................................................................................................................................................................... Methods Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 and results total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence inter- val (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. ................................................................................................................................................................................................... * Corresponding author. Tel: þ64 9 630 9992, Fax: þ64 9 630 9915, Email: harveyw@adhb.govt.nz † The ODYSSEY OUTCOMES Committee members, investigators, and contributors are listed in Supplementary material online. C The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 2802 H.D. White et al. Conclusion After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indi- cate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types. 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 Keywords Alirocumab • Prevention • MI types • Mortality .. adjudicated by a central clinical events committee blinded to the treat- Introduction .. .. ment assignment and lipid levels. Biomarker measurements were not Lowering of low-density lipoprotein cholesterol (LDL-C) with statins .. mandated after PCI or CABG. The definitions of Type 1 and Type 2 MIs .. are detailed in Supplementary material online, Tables S1 and S2. by 1 mmol/L (39 mg/L) is associated with an approximate 20% reduc- .. tion in the rate of myocardial infarction (MI).1 The proprotein con- .. Predictors of Type 1 and Type 2 MI and total mortality after MI were .. assessed. Silent MIs were not included. vertase subtilisin–kexin Type 9 (PCSK9) inhibitors evolocumab and .. alirocumab reduce LDL-C by >1 mmol/L below statin-treated levels .. .. Statistical analysis and further reduce the risk of MI among patients treated with .. .. Continuous variables are expressed as median (quartile 1–quartile 3) and statins.2,3 .. categorical variables as count (percentage). Comparisons of baseline In 2007, the Universal Definition of MI Task Force introduced a .. .. characteristics grouped by type of first MI during follow-up (none, Type classification of five types of MI based on presumptive mechanisms, .. 1, or Type 2) were by the Wilcoxon rank-sum tests for continuous varia- including Type 1 due to spontaneous plaque rupture or fissuring with .. bles and the v2 and Fisher’s exact tests (where possible) for categorical .. thrombus, Type 2 due to myocardial supply and/or demand imbal- .. variables. For all analyses, P-values <0.05, two-tailed, were considered ance, Type 3 with cardiac death suggestive of MI without biomarker .. statistically significant, with no adjustment for multiple testing. .. elevation, Type 4 related to percutaneous coronary intervention .. The treatment effect on time to first MI of any type and time to first (PCI), and Type 5 related to coronary artery bypass grafting .. Type 1, 2, or 4 MI was initially assessed in Cox proportional hazard .. (CABG).4 In the FOURIER trial,5 which randomized stable patients .. models, with stratification by geographic region; competing risk analyses with a history of MI, stroke, or peripheral vascular disease, evolocu- .. with all-cause death as the competing event were performed as sensitiv- .. mab reduced the number of MIs vs. placebo. Evolocumab reduced .. ity analyses.8 Multivariable Cox regression models of baseline demo- the number of Type 1 and Type 4 MIs, but not Type 2 MIs. .. graphics and clinical characteristics (candidate variables are listed in .. Supplementary material online, Tables S3 and S4) to predict Type 1 or In this pre-specified analysis from the ODYSSEY OUTCOMES .. trial, we studied the occurrence and outcomes of the different types .. Type 2 MI were then determined by stepwise selection, with P-value .. <0.05 for model entry or exit. Models to estimate the associations of MIs in patients with recent acute coronary syndrome (ACS) and .. .. between all-cause and cause-specific (cardiovascular or non- elevated LDL-C despite intensive statin therapy who were random- .. cardiovascular) death and incident Type 1 or Type 2 MI as a time- ized to receive alirocumab or placebo and followed for cardiovascu- .. .. varying covariate were determined, with adjustment for treatment as- lar outcomes. .. signment and baseline covariates previously determined to be prognos- .. tic for survival.9 The effects of treatment assignment on death before or .. .. after a Type 1 or Type 2 MI were determined in separate Cox regres- Methods .. sion models for each MI type by interactions between incident MI as a .. .. time-varying covariate and treatment, with stratification by geographical The study design6 and primary results3 have been published. Qualifying .. region. For a given patient, an MI that occurred on the same day as death patients were >_40 years, provided written informed consent, had been .. was excluded from the analysis. Sensitivity analyses of time to MI hospitalized with ACS (acute MI or unstable angina) 1–12 months before .. .. included events on the same day as death. randomization, and had an LDL-C level >_1.81 mmol/L (70 mg/dL), non- .. All analyses were conducted according to intention-to-treat, including high-density lipoprotein cholesterol (non-HDL-C) >_2.59 mmol/L .. .. all patients and events from randomization to common study end date (100 mg/dL), or apolipoprotein B >_2.07 mmol/L (80 mg/dL), measured .. (11 November 2017). Unless otherwise indicated, analyses were pre- after >_2 weeks of stable treatment with atorvastatin 40–80 mg daily, .. rosuvastatin 20–40 mg daily, or the maximum-tolerated dose of either .. specified before unblinding of the study database. Analyses were per- .. formed in SAS 9.4 and S þ 8.2. statin (including no statin in case of documented intolerance). .. Randomization (1:1) to treatment with alirocumab 75 mg or matching .. .. placebo, stratified by country, was performed, with 18 924 patients meet- .. Results ing the entry criteria. Study medication was given by subcutaneous injec- .. tion every 2 weeks. The dose of alirocumab was adjusted under blinded .. .. A total of 18 924 patients were randomized at 1315 sites in 57 coun- conditions to target an LDL-C level of 0.6–1.3 mmol/L (details on the .. dosing strategy are provided in Supplementary material online, Text S1). .. tries, with 9462 patients assigned to alirocumab and 9462 patients to .. placebo. Median follow-up was 2.8 (2.3–3.4) years. A total of 1860 The primary composite endpoint was death due to coronary heart .. disease, non-fatal MI, fatal and non-fatal ischaemic stroke, or unstable an- .. post-randomization MIs occurred in 1383 (7.3%) patients. Of these, .. 991 patients had a total of 1223 Type 1 MIs, 287 patients had 386 gina requiring hospitalization. The incidence of MI was defined as the .. time to first occurrence of MI. In a pre-specified analysis, the types of MI .. Type 2 MIs, 225 patients had 244 Type 4 MIs, and a remaining 7 were defined according to the Third Universal Definition7 and were .. patients had Type 3 or Type 5 MIs. The baseline characteristics of the Reduction of Type 1 and 2 MIs with alirocumab 2803 Table 1 Selected baseline characteristics of patients with Type 1 and 2 myocardial infarctions (A) No event (B) First (C) First P-value for (A) vs. P-value for (N 5 17 719) event 5 Type 1 event 5 Type 2 (B) vs. (C)a (B) vs. (C)b (N 5 963) (N 5 242) .................................................................................................................................................................................................................... Age (years) 58 (52–65) 59 (52–66) 65 (59–72) <0.0001 <0.0001 Women 4416 (24.9) 267 (27.7) 79 (32.6) 0.004 NS Race <0.0001 NS White 14 039 (79.2) 788 (81.8) 197 (81.4) Asian 2390 (13.5) 86 (8.9) 22 (9.1) Black 411 (2.3) 44 (4.6) 18 (7.4) Other 879 (5.0) 45 (4.7) 5 (2.1) Region of enrolment <0.0001 0.029 Western Europe 3894 (22.0) 232 (24.1) 49 (20.2) Eastern Europe 5185 (29.3) 199 (20.7) 53 (21.9) North America 2555 (14.4) 234 (24.3) 82 (33.9) South America 2469 (13.9) 103 (10.7) 16 (6.6) Asia 2194 (12.4) 80 (8.3) 19 (7.9) Rest of world 1422 (8.0) 115 (11.9) 23 (9.5) Medical history before index ACS Hypertension 11 277 (63.6) 758 (78.1) 214 (88.4) <0.0001 0.0005 Diabetes 4924 (27.8) 404 (42.0) 116 (47.9) <0.0001 NS Current smoker 4261 (24.0) 252 (26.2) 47 (19.4) NS 0.0305 MI 3174 (17.9) 373 (38.7) 92 (38.0) <0.0001 NS PCI 2805 (15.8) 347 (36.0) 89 (36.8) <0.0001 NS CABG 844 (4.8) 162 (16.8) 41 (16.9) <0.0001 NS Stroke 541 (3.1) 55 (5.7) 15 (6.2) <0.0001 NS Malignant disease 475 (2.7) 36 (3.7) 21 (8.7) <0.0001 0.0033 COPD 637 (3.6) 68 (7.1) 41 (16.9) <0.0001 <0.0001 Peripheral artery disease 628 (3.5) 89 (9.2) 42 (17.4) <0.0001 0.0007 Heart failure 2542 (14.3) 195 (20.2) 78 (32.2) <0.0001 0.0001 Index ACS <0.0001 NS NSTEMI 8443 (47.7) 587 (61.0) 145 (59.9) STEMI 6209 (35.1) 259 (26.9) 68 (28.1) Unstable angina 3037 (17.2) 116 (12.1) 29 (12.0) PCI or CABG for index ACS 12 886 (72.7) 630 (65.4) 161 (66.5) <0.0001 NS GFR (mL/min/1.73 m2) 79 (68–90) 76 (63–88) 67 (54–84) <0.0001 <0.0001 GFR <60 mL/min/1.73 m2 2256 (12.7) 199 (20.7) 84 (34.7) <0.0001 <0.0001 Time from index ACS to randomization (months) 2.6 (1.7–4.4) 2.5 (1.7–3.9) 2.5 (1.7–4.2) 0.037 NS Body mass index (kg/m2) 28 (25–31) 29 (26–32) 29 (26–33) <0.0001 NS LDL-C (mg/dL) 86 (73–103) 91 (76–113) 91 (75–109) <0.0001 NS LDL-C >_100 mg/dL 5177 (29.2) 365 (37.9) 87 (36.0) <0.0001 NS Triglycerides (mg/dL) 128 (94–181) 138 (100–201) 130 (90–178) <0.0001 0.012 Lipoprotein(a) (mg/dL) 20.8 (6.6–59.0) 25.4 (7.3–70.0) 34.9 (9.3–76.8) <0.0001 NS Randomized to placebo 8808 (49.7) 512 (53.2) 142 (58.7) 0.003 NS Data are represented as median (quartile 1–quartile 3) or n (%). Additional information on baseline characteristics is presented in Supplementary material online, Table S5. a Rank-based tests, comparing A vs. B vs. C. b Rank-based test, comparing B vs. C. ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NS, not significant; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction. patients without an MI, and with Type 1 or Type 2 MI, are detailed in .. post-randomization event of Type 1 MI, patients with a first post- .. Table 1 and Supplementary material online, Table S5. Compared to .. randomization event of Type 2 MI were older, more likely to be from patients without an MI, those with an MI were older and the propor- .. North America, to have a lower glomerular filtration rate, and were .. tion of women was greater. Compared to patients with a first . more likely to have a history of hypertension, heart failure, chronic 2804 H.D. White et al. Table 2 Types of myocardial infarctions and effects of alirocumab Alirocumab Placebo Treatment P-valuea ............................................. ............................................. HR (95% CI)a Patients Total MIs Patients Total MIs with MI,a n (%) with MI,a n (%) .................................................................................................................................................................................................................... Any MI 639 (6.8) 866 744 (7.9) 994 0.85 (0.77–0.95) 0.003 Universal classification Type 1b 463 (4.9) 560 528 (5.6) 663 0.87 (0.77–0.99) 0.032 Type 2c 125 (1.3) 180 162 (1.7) 206 0.77 (0.61–0.97) 0.025 Type 3d 2 (<0.1) 2 0 0 – – Type 4Ae 22 (0.2) 23 28 (0.3) 29 0.94 (0.72–1.22)f 0.62 Type 4Bg 50 (0.5) 55 46 (0.5) 49 Type 4Ch 37 (0.4) 44 42 (0.4) 44 Type 5i 2 (<0.1) 2 3 (<0.1) 3 – – ECG classification NSTEMI 437 (4.6) 576 529 (5.6) 692 0.82 (0.72–0.93) 0.002 STEMI 92 (0.5) 96 109 (1.2) 116 0.84 (0.64–1.11) 0.22 ECG not interpretable or not available 161 (1.7) 194 162 (1.7) 186 1.01 (0.81–1.25) 0.96 Q-wave classification Q-wave 52 (0.5) 52 71 (0.9) 73 0.73 (0.51–1.04) 0.08 Non-Q-wave 483 (5.1) 634 560 (5.9) 725 0.86 (0.76–0.97) 0.013 ECG not interpretable or available 146 (1.5) 180 165 (1.7) 196 0.88 (0.71–1.10) 0.27 a Analysis of time to first Type 1, Type 2, or Type 4A, 4B, 4C MI by Cox proportional hazards models, stratified by geographical region. b Spontaneous. c Supply/demand imbalance. d Cardiac death suggestive of MI without increased biomarkers. e Peri-percutaneous coronary intervention. f Correspond to any Type 4 MI. g Stent thrombosis. h Restenosis. i Peri-coronary artery bypass grafting. CI, confidence interval; ECG, electrocardiogram; HR, hazard ratio; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction. obstructive pulmonary disease, peripheral artery disease, or malig- .. observations are supported by post hoc model results: allowing the .. nant disease, and were less likely to be smokers. Baseline LDL-C, lip- .. treatment HR to change for each of the time intervals indicated in oprotein(a), and high-sensitivity C-reactive protein levels were .. Figure 1 fit the data better than a constant HR for Type 1 MI .. higher in patients with than without MI. Baseline LDL-C, lipopro- .. (P = 0.05) but not for Type 2 MI (P = 0.34). tein(a), and high-sensitivity C-reactive protein did not differ between .. Most MIs (82.7%) were non-ST-segment elevation MI (non- .. those with Type 1 or Type 2 MI. Triglyceride levels were higher at .. STEMI) and were significantly reduced with alirocumab (HR 0.82, baseline in patients who had MIs compared with those not having .. 95% CI 0.72–0.93; P = 0.002). There were consistent effects on .. MIs, and patients with Type 2 MIs had lower triglyceride levels than .. STEMIs. Q-wave MIs were identified in a minority (10.5%) of patients .. patients with Type 1 MIs (P = 0.012). .. with interpretable electrocardiograms (ECGs), with consistent Mean LDL-C levels were reduced by 54% with alirocumab vs. pla- .. effects of alirocumab for Q-wave and non-Q-wave MIs (Table 2). .. cebo, from 2.39 mmol/L (92 mg/dL) to 1.24 mmol/L (48 mg/dL), at .. A sensitivity analysis including patients who died on the day of MI 12 months. Alirocumab reduced the occurrence of post- .. (n = 7 alirocumab; n = 11 placebo) showed similar effects of alirocu- .. randomization MI vs. placebo [6.8% vs. 7.9%; hazard ratio (HR) 0.85, .. mab on reducing both Type 1 and Type 2 MIs (Supplementary mater- 95% confidence interval (CI) 0.77–0.95; P = 0.003]. Both Type 1 MIs .. ial online, Table S6). .. (P = 0.032) and Type 2 MIs (P = 0.025) were reduced with alirocumab .. Supplementary material online, Table S7 shows the effect of aliro- (Table 2). There was no apparent effect on Type 3, 4, or 5 MIs. .. cumab on biomarker levels, predominantly cardiac troponin (92%) .. Take home figure shows the Kaplan–Meier curve of the occurrence .. and high-sensitivity troponins (29%), at various cut-points. of Type 1 and Type 2 MIs after randomization by treatment group. A .. Alirocumab treatment was associated with no apparent reduction in .. benefit of alirocumab treatment on Type 1 MI was apparent after .. smaller MIs (with peak biomarker levels <3 times the upper limit of year 1 and increased after year 2, whereas the treatment effect on .. normal) but with large reductions in larger MIs as defined by peak .. Type 2 MI appeared more constant over time (Figure 1). These . biomarker value. Reduction of Type 1 and 2 MIs with alirocumab 2805 Take home figure Kaplan–Meier curves for the first occurrence of Type 1 and Type 2 myocardial infarctions and the effects of alirocumab over time. MI, myocardial infarction. Figure 1 Treatment effect of alirocumab categorized according to the time between randomization and the first occurrence of myocardial infarc- tion. CI, confidence interval; HR, hazard ratio; MI, myocardial infarction. .. Predictors of Type 1 and Type 2 .. Mortality in patients with Type 1 or Type myocardial infarction .. 2 myocardial infarction .. Tables 3 and 4 and Supplementary material online, Figure S1 show the .. During 1.6 (0.8–2.4) and 1.3 (0.5–2.3) years of follow-up following .. independent predictors for Type 1 and Type 2 MIs, respectively. .. Type 1 and Type 2 MI, respectively, mortality following the occur- Most of the factors predicting occurrence of Type 1 or Type 2 MI .. rence of Type 2 MI (n = 73, 25.4%) was more than double that of .. were similar. Of note, baseline LDL-C was an independent predictor .. patients with Type 1 MI (n = 118, 11.9%). In post hoc analyses, rates of of occurrence of Type 1 but not Type 2 MI. Similarly, previous .. death were 10.2% with alirocumab vs. 13.4% with placebo (HR 0.69, .. CABG, revascularization at the time of the index ACS event, current .. 95% CI 0.48–1.00) following Type 1 MI and 24.8% vs. 25.9% (HR smoking, and previous stroke were significant predictors of occur- .. .. 0.98, 95% CI 0.62–1.56) following Type 2 MI. rence of subsequent Type 1 MI but not Type 2 MI. Conversely, age .. .. (by discrete categories), history of chronic obstructive pulmonary .. disease, and lower baseline HDL-C levels were significant predictors .. .. Discussion of Type 2 but not Type 1 MI. Race, history of diabetes, hypertension, .. and peripheral artery disease were risk factors for both types of MI. .. After an index ACS, there is a substantial incidence of recurrent MI. .. Randomization to alirocumab was associated with lower risk of both .. In the placebo group of the ODYSSEY OUTCOMES trial, this types of MI. .. incidence was 7.9% over a median follow-up of 2.8 years, despite 2806 H.D. White et al. Table 3 Independent predictors of Type 1 myocardial Table 4 Independent predictors of Type 2 myocardial infarction following initial acute coronary syndrome infarction following initial acute coronary syndrome Baseline characteristics HR (95% CI) P-value Baseline characteristics HR (95% CI) P-value ................................................................................................. ................................................................................................. Medical history Medical history Peripheral artery disease 1.61 (1.29–2.00) <0.0001 Peripheral artery disease 2.49 (1.83–3.39) <0.0001 Percutaneous coronary intervention 1.51 (1.27–1.79) <0.0001 Percutaneous coronary intervention 1.48 (1.09–2.01) 0.012 CABG 1.74 (1.45–2.09) <0.0001 COPD 2.26 (1.63–3.15) <0.0001 Diabetes 1.57 (1.38–1.79) <0.0001 Heart failure 2.36 (1.80–3.09) <0.0001 Current smoker 1.23 (1.06–1.42) 0.006 Diabetes 1.76 (1.38–2.25) <0.0001 Hypertension 1.54 (1.31–1.81) <0.0001 Hypertension 2.66 (1.79–3.97) <0.0001 MI 1.46 (1.23–1.74) <0.0001 MI 1.49 (1.11–2.01) 0.009 Heart failure 1.33 (1.12–1.57) 0.001 Region <0.0001 Stroke 1.34 (1.02–1.75) 0.034 Western Europe Reference Region <0.0001 Eastern Europe 0.45 (0.30–0.65) Western Europe Reference North America 1.16 (0.83–1.64) Eastern Europe 0.50 (0.41–0.61) South America 0.44 (0.25–0.76) North America 0.93 (0.77–1.13) Asia 1.23 (0.36–4.21) South America 0.65 (0.51–0.84) Rest of world 1.22 (0.77–1.94) Asia 2.03 (0.97–4.26) HDL-C per 1 mg/dL increment 1.01 (1.00–1.02) 0.017 Rest of world 1.16 (0.92–1.46) GFR <60 mL/min/1.73 m2 2.05 (1.57–2.67) <0.0001 LDL-C per 1 mmol/L increment 1.19 (1.11–1.27) <0.0001 Age category <0.0001 GFR <60 mL/min/1.73 m2 1.37 (1.17–1.60) 0.0001 <65 years Reference Revascularization for index event 0.80 (0.70–0.91) 0.0009 65 to <75 years 1.46 (1.11–1.91) Race 0.009 >_75 years 2.26 (1.58–3.23) White Reference Race 0.021 Asian 0.38 (0.19–0.77) White Reference Black 1.37 (1.01–1.87) Asian 0.76 (0.24–2.36) Other 0.97 (0.70–1.33) Black 1.92 (1.22–3.02) Alirocumab treatment 0.87 (0.77–0.99) 0.029 Other 0.62 (0.27–1.45) Alirocumab treatment 0.77 (0.61–0.97) 0.029 CABG, coronary artery bypass grafting; CI, confidence interval; GFR, glomerular filtration rate; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; MI, CI, confidence interval; COPD, chronic obstructive pulmonary disease; GFR, myocardial infarction. glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; HR, haz- ard ratio; MI, myocardial infarction. high-intensity statin treatment and high use of other evidence-based therapies. The rate of Type 1 MI was more than double that of all .. therefore have had similar effects in ODYSSEY OUTCOMES in pre- .. other types combined. Alirocumab treatment reduced the overall in- .. venting plaque progression or promoting plaque regression, resulting .. cidence of MI, an observation that appears driven by a reduction in .. in greater capacity for myocardial oxygen delivery and consequently both Type 1 and Type 2 MIs. The treatment benefit on Type 1 MI .. a lower risk of Type 2 MI. It is not known whether PCSK9 inhibitors .. increased with time elapsed since randomization, suggesting that .. have favourable effects on coronary endothelial or microvascular treatment benefit may increase with longer treatment duration. The .. function. .. finding that a lipid-lowering treatment could reduce the incidence of .. The incidence of Type 2 MI as a proportion of total MIs has varied Type 2 MI is novel. The benefit of alirocumab on reducing both types .. from around 1.6% to 29.6% in randomized trials and population stud- .. of MI was more pronounced when biomarker elevation, as a measure .. ies.11 Here, the incidence was in the higher portion of that range. In of infarct size, exceeded three times the upper limit of normal. .. this trial, potent lipid-lowering with alirocumab reduced the occur- .. It is unlikely that the reduced occurrence of Type 2 MI with aliro- .. rence of Type 2 MI. To our knowledge, this is the first such observa- cumab treatment resulted from an effect on myocardial oxygen de- .. tion and contrasts with the lack of effect on Type 2 MI seen in the .. mand. However, alirocumab treatment may have improved .. FOURIER trial.5 The reason for this contrast is unknown, but could myocardial oxygen supply. In the GLAGOV trial,10 evolocumab treat- .. be related to differences in patient populations, number of events, .. ment added to statin treatment in patients with coronary artery dis- .. duration of follow-up, definitions, and adjudication processes. ease (CAD) produced substantial further lowering of LDL-C and .. Specifically, the ODYSSEY OUTCOMES trial included high-risk .. reduced the volume of coronary artery plaque within 18 months, .. patients with recent ACS rather than stable patients with a history of compared with placebo. In the current study, alirocumab reduced .. MI, stroke, or peripheral vascular disease, and they were followed for .. LDL-C levels by 54% from baseline to 12 months. Alirocumab may . longer (2.8 vs 2.2 years in the FOURIER trial5). Differences between Reduction of Type 1 and 2 MIs with alirocumab 2807 .. the studies in the effects of treatment with a PSCK9 inhibitor on spe- .. showed that Type 2 MIs were relatively more frequent in North cific types of MI might also be related to differences in prevailing bio- .. America (ratio of Type 2 to Type 1 MI 0.35) than in South America, .. marker assays, and cut-off values. .. Asia, and the rest of the world (ratio of Type 2 to Type 1 MI 0.16, Some reports ascertaining the incidence of Type 2 MI have used .. 0.24, and 0.20, respectively). These findings could reflect regional dif- .. specific defined oxygen supply/demand mismatch criteria,11,12 where- .. ferences in patient baseline characteristics or prevailing practice pat- as others have used more liberal criteria.13 The ischaemic thresholds .. terns influencing the ascertainment of electrocardiographic, biomarker .. for myocardial oxygen supply/demand imbalance vary markedly in re- .. or echocardiographic data to support MI diagnosis. spect to the magnitude of the stressor and the amount of underlying .. The prevalent use of therapies well-established to reduce the risk .. CAD.14 Most studies have shown a higher frequency of Type 2 MI in .. of recurrent MI were examined according to type of MI. Beta-blocker patients with comorbid conditions. Similarly, we found that patients .. use at randomization was high and similar in patients who subse- .. with Type 2 MI were more likely than patients with Type 1 MI to .. quently had Type 1 or Type 2 MI (86.5% vs. 85.1%, respectively). have comorbidities including hypertension, heart failure, chronic ob- .. Large majorities of the patients with either Type 1 or Type 2 MI were .. structive pulmonary disease, diabetes, or malignancy. The rate of .. treated with aspirin (94.5% and 89.3%, respectively). STEMI was relatively high in patients with Type 2 MI, but was similar .. .. to patients with Type 1 MI (28.1% vs. 26.9%). Reported rates of .. Limitations STEMI in patients with Type 2 MI have ranged from 3.4% to 9.7%.11,13 .. We did not specify study-specific adjudication algorithms to distin- .. Some of the patients in the present study with STEMI and Type 2 MI .. guish Type 1 and 2 MI. The trial did not mandate routine biomarker may have had plaque rupture with thrombus formation or emboliza- .. measurements following PCI or CABG to detect Type 4 and Type 5 .. tion of thrombus, which may have been missed on angiography be- .. MIs, and consequently there may have been under ascertainment of cause of the low sensitivity for detecting thrombus, including beyond .. .. those events. The absence of any alirocumab treatment effect on the the plaque rupture in the proximal epicardial coronary vessel. Also, .. occurrence of Type 4 MI could represent Type 2 error, due to the .. some of these patients may have had coronary artery spasm causing .. relatively small number of these events. Classification of MI according transmural ischaemia and STEMI. .. to the development of Q-waves may have been limited because the .. The short- and long-term mortality rates for patients with Type 2 .. protocol did not specify ECGs at fixed times in the study and there MI are generally higher than for Type 1 MI patients in most studies, .. was no core ECG laboratory. We had no protocol-specified meas- .. due to an increased prevalence of comorbid conditions.11–13,15–20 .. urement of left ventricular function to ascertain the size of the MIs in However, adjusted mortality may be similar.13 Here, we found all- .. addition to biomarker assessment. Finally, as pre-specified, we .. cause death to be more than twice as high after Type 2 than Type 1 .. focused on first MI after randomization rather than analysing total MI MI. .. events.9 .. The presence of significant CAD is a common finding in patients .. with Type 2 MI selected to undergo coronary angiography. The inci- .. .. dence of CAD depends on the population and how intensively they .. Conclusion are studied. The presence of CAD in Type 2 MI ranges from 55% to .. .. In patients with ACS, alirocumab added to intensive statin therapy 68%.13,21,22 In general, patients with Type 2 MI and CAD have a .. worse prognosis than those without CAD.18,20,22 As patients in the .. during 2.8 years of follow-up reduced the occurrence of both Type 1 .. and Type 2 MI. For Type 1 MIs, treatment benefit appeared to in- present study all had a recent ACS (within the past 1–12 months), it .. is likely that most had significant CAD and many would have bene- .. crease over time. The data indicate for the first time that a lipid- .. lowering therapy can attenuate the risk of Type 2 MI. Therefore, fited from lipid-lowering therapy through a decrease in plaque lipid .. content, and inflammatory cells perhaps leading to improved plaque .. LDL-C lowering with alirocumab below levels achieved with statins .. may be an important preventive treatment for both Type 1 and Type stability and decreased progression of atherosclerosis. There are no .. data that statins or PCSK9 inhibitors modulate the risk associated .. 2 MI following ACS. .. with erosions. It is possible that Alirocumab by reducing LDL-C could .. .. improve coronary endothelial function.23 .. Supplementary material In the FOURIER trial, evolocumab reduced Type 4 MI (n = 194).5 .. .. However, in this trial we found no effect of alirocumab on reducing .. Supplementary material is available at European Heart Journal online. Type 4 MI despite a similar number of events (n = 225) as in the .. .. Acknowledgements FOURIER trial. Several small trials have suggested that statin loading .. before PCI may reduce the occurrence of Type 4 MI.24 However, the .. The authors thank the patients, study coordinators, and investigators .. recent large randomized SECURE-PCI trial showed that two loading .. who participated in this trial. Sophie K. Rushton-Smith (MedLink doses of 80 mg atorvastatin before and 24 h after a planned PCI had .. Healthcare Communications, London, UK) and Michelle D’Souza .. no effect on a composite of death, MI, stroke, or unplanned coronary .. (Green Lane Cardiovascular Research Unit, Auckland, New Zealand) revascularization.25 Our observations are consistent with the latter .. provided editorial and secretarial assistance in the preparation of the .. trial with no apparent effect of alirocumab on reducing Type 4a, 4b, .. manuscript (limited to formatting, editing for style, referencing, and or 4c MI, with 109 events occurring with alirocumab and 116 with .. figure and table editing and submission) and were funded by .. placebo. .. Fondation Assistance Publique – Hôpitaux de Paris, Paris, France and We pre-specified five geographic regions for the 57 participating .. The Green Lane Research and Educational Fund, Auckland City .. countries (Supplementary material online, Table S8). Regional analysis . Hospital, Auckland, New Zealand, respectively. 2808 H.D. White et al. .. Funding .. Trustee: American College of Cardiology; Unfunded Research: FlowCo, Supported by Sanofi and Regeneron Pharmaceuticals. .. Fractyl, Merck, Novo Nordisk, PLx Pharma, Takeda. V.A.B.: serving on a .. steering committee for Eli Lilly, serving as the national coordinator of the Conflict of interest: H.D.W.: receiving grant support paid to the insti- .. .. STRENGTH trial and the site principal investigator for the Artemis trial tution and fees for serving on a steering committee for the ODYSSEY .. for AstraZeneca, serving as national coordinator of the Dalgene trial for Trial from Sanofi-Aventis and Regeneron Pharmaceutical, for the .. .. DalCor, serving as national coordinator of the CLEAR trial for Esperion, ACCELERATE study from Eli Lilly, for the STRENGTH Trial from .. serving as a site principal investigator for the COMPASS trial for Bayer, Omthera Pharmaceuticals, for the SPIRE Trial from Pfizer USA, for the .. serving as an investigator for Amgen, and receiving advisory board fees HEART-FID Study from American Regent; for the CAMELIA Study from .. .. from Sanofi. R.D.: receiving grant support from DalCor and TIMI Group, Eisai Inc., for the DalGenE Study from DalCor Pharma UK Inc. for the .. provision of antihypertensive therapy by LEPETIT, fees for serving as a AEGIS-II study from CSL Behring, for the SCORED and SOLOIST Trials .. .. former committee member from ASTRA and Eli Lilly, and receiving grant from Sanofi-Aventis Australia Pty Ltd, and for the CLEAROUT Study .. support and fees for serving as a former committee member from from Esperion Therapeutics Inc. P.G.S.: receiving grant support and fees .. Amgen. J.M.E. (former employee), C.H., and A.M.: employees of Sanofi. .. for serving on a steering committee from Bayer, grant support and lec- .. A.E: consulting fees and honoraria from Abbott Vascular, Biosensors, ture fees from Merck, grant support, fees for serving as co-chair of the .. Biotronik, Boston Scientific, and Johnson & Johnson/Cordis. S.G.G.: receiv- ODYSSEY OUTCOMES trial and the SCORED trial, consulting fees, and .. .. ing grant support, lecture fees, consulting fees, and advisory board fees lecture fees from Sanofi, grant support and fees for serving as chair of the .. from Sanofi, honoraria from Regeneron, grant support, fees for serving CLARIFY registry from Servier, grant support, consulting fees, and fees .. on a steering committee, lecture fees, consulting fees, and advisory board .. for serving on an executive steering committee from Amarin, consulting .. fees from Amgen and Lilly, grant support, lecture fees, consulting fees, fees and lecture fees from Amgen, consulting fees, lecture fees, and fees .. and advisory board fees from Merck, Pfizer, and AstraZeneca, and fees for critical-event committee work from Bristol-Myers Squibb, fees for .. .. for serving on a steering committee and for serving as the Canadian na- serving on an executive steering committee from Boehringer Ingelheim, .. tional leader for a trial from Esperion. R.A.H.: receiving grant support, fees for critical-event committee work from Pfizer, consulting fees and .. paid to his institution, from CSL, Apple, Portola, Janssen, and Novartis, .. fees for serving on an executive steering committee from Novartis, con- .. grant support, paid to his institution, from and serving on a data and sulting fees from Regeneron and Lilly, consulting fees and fees for serving .. safety monitoring board for AstraZeneca and Bristol-Myers Squibb, and as cochair of the THEMIS trial, and holding a patent (14/657192) on a .. .. receiving consulting fees from Amgen, Bayer, Gilead, MyoKardia, and method for reducing cardiovascular risk. M.S.: receiving consulting fees .. WebMD, and grant support, paid to his institution, and consulting fees from CiVi and Esperion, and grant support, consulting fees, and fees for .. from the Medicine Company. J.W.J.: receiving research grants from the .. serving on a data and safety monitoring board from Resverlogix and .. Netherlands Heart Foundation, the Interuniversity Cardiology Institute Baxter. D.L.B.: discloses the following relationships—Advisory Board: .. of the Netherlands, the European Community Framework KP7 Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, .. .. Program; and other research support from Amgen, Astellas, Regado Biosciences; Board of Directors: Boston VA Research Institute, .. AstraZeneca, Daiichi Sankyo, Lilly, Merck-Schering-Plough, Pfizer, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart .. Roche, and Sanofi-Aventis. R.D.L: receiving research support from .. Association Quality Oversight Committee; Data Monitoring Committees: .. Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer; consulting Baim Institute for Clinical Research (formerly Harvard Clinical Research .. fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Institute, for the PORTICO trial, funded by St. Jude Medical, now .. .. Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, and Portola. Abbott), Cleveland Clinic (including for the ExCEED trial, funded by .. K.W.M.: receiving consulting fees from Ablynx, Baim Institute, Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai .. Boehringer Ingelheim, Bristol-Myers Squibb, Cardiometabolic Health .. School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), .. Congress, Elsevier, GlaxoSmithKline, Medergy, Medscape, Mitsubishi, Population Health Research Institute; Honoraria: American College of .. Myokardia, Oculeve, Portola, Radiometer, Springer Publishing, Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; .. .. Theravance, and WebMD; grant support and consulting fees from Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical .. AstraZeneca, Johnson & Johnson, Merck, and Novartis, equity in Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI .. BioPrint Fitness, and grant support from Afferent, Amgen, Apple, .. clinical trial steering committee funded by Boehringer Ingelheim), Belvoir .. Cardiva Medical, Daiichi, Ferring, Google (Verily), Luitpold, Medtronic, Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical .. and Tenax. R.P.: employee of and shareholder in Regeneron Research Institute (clinical trial steering committees), HMP Global (Editor .. .. Pharmaceuticals, Inc. M.T.R.: receiving grant support, paid to his institu- in Chief, Journal of Invasive Cardiology), Journal of the American College .. tion, from Sanofi Aventis, Ferring Pharmaceuticals, and Myokardia, con- of Cardiology (Guest Editor; Associate Editor), Population Health .. sulting fees from Janssen Pharmaceuticals, AstraZeneca, Amgen, Ardea .. Research Institute (for the COMPASS operations committee, publications .. Biosciences, and Flatiron, consulting fees and fees for serving on a data committee, steering committee, and USA national co-leader, funded by .. and safety monitoring board from Regeneron Pharmaceuticals, fees for Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s .. .. serving on a data and safety monitoring board from Roche-Genentech, Intervention), Society of Cardiovascular Patient Care (Secretary/ .. fees for clinical events adjudication from Eli Lilly, and fees for serving as Treasurer), WebMD (CME steering committees); Other: Clinical .. chairman of the clinical event adjudication committee from Novo .. Cardiology (Deputy Editor), NCDR-ACTION Registry Steering .. Nordisk. P.S.: none declared. P.T.: being employed by and receiving Committee (Chair), VA CART Research and Publications Committee .. grant support from CSL Behring and grant support from Merck. (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, .. .. A.M.Z.: receiving lecture fees from Sanofi, Amgen, Boehringer Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest .. Ingelheim, and Bayer Healthcare, and advisory board fees and lecture Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, .. fees from Novartis and Pfizer. G.G.S.: research grants to University of .. Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines .. Colorado from Resverlogix, Sanofi, and Roche. Co-inventor of pending Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A .. US patent application 14/657192 ‘Methods of Reducing Cardiovascular Companion to Braunwald’s Heart Disease); Site Co-Investigator: .. .. Risk’ assigned in full to University of Colorado. No other potential Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; . conflict of interest relevant to this article was reported. Reduction of Type 1 and 2 MIs with alirocumab 2809 References .. 11. 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