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Canadian Journal of Cardiology

Alirocumab and Cardiovascular Outcomes in Patients With Previous Myocardial Infarction: Prespecified Subanalysis From ODYSSEY OUTCOMES∗

Open AccessPublished:May 26, 2022DOI:https://doi.org/10.1016/j.cjca.2022.05.021

      Abstract

      Background

      After acute coronary syndrome (ACS), patients with a previous myocardial infarction (MI) may be at particularly high risk for major adverse cardiovascular events (MACE) and death. We studied the effects of the PCSK9 inhibitor alirocumab in patients with recent ACS according to previous history of MI.

      Methods

      The ODYSSEY OUTCOMES trial compared alirocumab with placebo, beginning 1 to 12 months after ACS with median 2.8-year follow-up. The primary MACE outcome comprised death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, and hospitalization for unstable angina. Of 18,924 patients, 3633 (19.2%) had previous MI.

      Results

      Patients with previous MI were older, more likely male, with more cardiovascular risk factors and previous events. With placebo, 4-year risks of MACE and death were higher among those with vs without previous MI (20.5% vs 8.9%, P < 0.001; 7.4% vs 3.4%, P < 0.001, respectively). Alirocumab reduced the risk of events regardless of the presence or absence of a history of MI (MACE, adjusted hazard ratio [aHR] 0.90, 95% confidence interval [CI], 0.78-1.05 vs 0.82, 0.73-0.92; Pinteraction = 0.34; death, aHR 0.84; 95% CI, 0.64-1.08 vs 0.87, 0.72-1.05; Pinteraction = 0.81). Estimated absolute risk reductions with alirocumab were numerically greater with vs without previous MI (MACE, 1.91% vs 1.42%; death, 1.35% vs 0.41%).

      Conclusions

      A previous history of MI places patients with recent ACS at high risk for recurrent MACE and death. Alirocumab reduced the relative risks of these events consistently in patients with or without previous MI but with numerically greater absolute benefit in the former subgroup. (ODYSSEY OUTCOMES: NCT01663402)

      Résumé

      Contexte

      Après un syndrome coronarien aigu (SCA), les patients ayant déjà subi un infarctus du myocarde (IM) peuvent présenter un risque particulièrement élevé d’événements cardiovasculaires indésirables majeurs (ECIM) et de décès. Nous avons évalué les effets de l’alirocumab, un inhibiteur de la proprotéine convertase subtilisine/kexine de type 9 (PCSK9), chez les patients ayant récemment subi un SCA et présentant des antécédents d’IM.

      Méthodologie

      Lors de l’essai ODYSSEY OUTCOMES, le traitement par l’alirocumab, comparé à un placebo, a été instauré de 1 à 12 mois après un SCA, avec un suivi médian de 2,8 ans. Le principal paramètre d’évaluation des ECIM comprenait le décès lié à la coronaropathie, l’IM non fatal, l’accident vasculaire cérébral ischémique fatal ou non fatal et l’hospitalisation pour angine instable. Sur les 18 924 patients de l’étude, 3 633 (19,2 %) avaient déjà eu un IM.

      Résultats

      Les patients ayant des antécédents d’IM étaient plus âgés, étaient plus souvent de sexe masculin, et présentaient davantage de facteurs de risque cardiovasculaire et d’antécédents d’événements cardiovasculaires. Dans le groupe sous placebo, les risques d’ECIM et de décès à 4 ans étaient plus élevés chez les patients présentant des antécédents d’IM que chez ceux n’en présentant pas (20,5 % vs 8,9 %, p < 0,001; 7,4 % vs 3,4 %, p < 0,001, respectivement). L’alirocumab a réduit le risque de survenue d’événements, peu importe la présence ou l’absence d’antécédents d’IM (ECIM : rapport des risques instantanés corrigé [RRIc] de 0,90; intervalle de confiance [IC] à 95 % : de 0,78 à 1,05 vs RRIc de 0,82; IC à 95 % : de 0,73 à 0,92; pinteraction = 0,34; décès : RRIc de 0,84; IC à 95 % : de 0,64 à 1,08 vs RRIc de 0,87; IC à 95 % : de 0,72 à 1,05; pinteraction = 0,81). Les réductions estimées du risque absolu avec l’alirocumab étaient numériquement supérieures chez les patients ayant des antécédents d’IM que chez ceux sans antécédents d’IM (ECIM : 1,91 % vs 1,42 %; décès : 1,35 % vs 0,41 %).

      Conclusions

      Des antécédents d’IM exposent les patients ayant récemment subi un SCA à un risque plus élevé de récidive d’ECIM et de décès. L’alirocumab réduit le risque relatif de survenue de ces événements chez les patients avec ou sans antécédents d’IM, mais le bénéfice absolu est numériquement plus élevé chez les patients ayant des antécédents. (ODYSSEY OUTCOMES : NCT01663402)
      Among patients hospitalized with acute coronary syndrome (ACS), the event is not the first for 18% to 22%.
      • Cannon C.P.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      Patients with previous myocardial infarction (MI) have higher subsequent events than those with stable coronary disease or patients with multiple risk factors.
      • Bhatt D.L.
      • Eagle K.A.
      • Ohman E.M.
      • et al.
      Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis.
      The risk of recurrent events in patients who have experienced previous MI continues for several years without evidence of decreasing risk.
      • Bonaca M.P.
      • Storey R.F.
      • Theroux P.
      • et al.
      Efficacy and safety of ticagrelor over time in patients with prior MI in PEGASUS-TIMI 54.
      The heightened risk of recurrent events is largely attributable to frequent coexistence of nonobstructive lesion with high-risk characteristics.
      • Stone G.W.
      • Maehara A.
      • Lansky A.J.
      • et al.
      A prospective natural-history study of coronary atherosclerosis.
      Therefore, management of patients with recurrent ACS after previous MI presents a particular challenge for clinicians: What additional medical therapies may help to prevent these recurrent events?
      Lipid lowering with high-intensity statin therapy is a cornerstone of management in ACS.
      • Cannon C.P.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      ,
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, added to statins, have the potential to lower atherogenic lipoproteins below levels achievable with statins and have been shown to improve clinical outcomes after ACS in patients with low-density lipoprotein cholesterol (LDL-C) above goal on optimized statin therapy.
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      In this prespecified analysis of the ODYSSEY OUTCOMES trial, we investigated the relative and absolute benefits of treatment with the PCSK9 inhibitor alirocumab in patients with ACS who had or did not have previous MI.

      Material and Methods

      Study population

      ODYSSEY Outcomes (ClinicalTrials.gov: NCT01663402) was a randomized double-blind placebo-controlled trial that enrolled 18,924 patients ≥ 40 years of age who had been hospitalized with ACS (acute MI or unstable angina) 1 to 12 months before randomization.
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      ,
      • Schwartz G.G.
      • Bessac L.
      • Berdan L.G.
      • et al.
      Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial.
      The study conformed to the principles of the Declaration of Helsinki and was approved by the institutional review board at each site. All patients gave written informed consent to participate.
      To be eligible, patients had to have LDL-C values ≥ 70 mg/dL (1.81 mmol/L) or non–high-density lipoprotein cholesterol (HDL-C) value ≥ 100 mg/dL (2.59 mmol/L), or apolipoprotein B value ≥ 80 mg/dL, measured after a minimum of 2 weeks on stable treatment with intensive LDL-C–lowering drugs (atorvastatin 40 to 80 mg daily, rosuvastatin 20 to 40 mg daily, or the maximum-tolerated dose of either statin, including no statin in the case of documented unacceptable side effects). Full inclusion and exclusion criteria have been published.
      • Schwartz G.G.
      • Bessac L.
      • Berdan L.G.
      • et al.
      Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial.
      Patients were randomly assigned (in a 1:1 ratio), stratified by country, to receive treatment with alirocumab 75 mg subcutaneously every 2 weeks or matching placebo. In the event of a persistent LDL-C value ≥ 50 mg/dL, the alirocumab dose was uptitrated to 150 mg. In patients who had 2 consecutive measurements of LDL-C < 25 mg/dL, the alirocumab dose was reduced to 75 mg (for measurements made on the 150-mg dose), and safety was monitored by an independent physician blinded to treatment allocation. In the case of 2 consecutive measurements of LDL-C < 15 mg/dL on alirocumab 75 mg, alirocumab was discontinued, with blinded substitution of placebo for the remainder of the trial. Occurrence of MI before the index ACS was a prespecified subgroup of interest, with the data collected at enrollment.
      • Schwartz G.G.
      • Bessac L.
      • Berdan L.G.
      • et al.
      Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial.

      Trial outcomes

      The primary composite outcome was a composite of major adverse cardiovascular events (MACE: death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization). Secondary outcomes included all-cause death.
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      All primary and secondary outcomes were adjudicated by physicians who were unaware of the trial-group assignments.

      Statistical analyses

      Categorical variables were compared with χ2 tests and continuous variables by Student’s t-test. A Cox proportional hazards model was used to determine hazard ratios (HRs) and 95% confidence intervals (CIs) for MACE and death in patients with and without previous MI in the placebo group, adjusted for the following baseline variables: age (≥ 65 years vs < 65 years), sex, race, geographic region, diabetes mellitus, smoking; history of heart failure, ischemic stroke, and peripheral artery disease; intensive statin treatment; LDL-C and lipoprotein(a) concentrations; and systolic blood pressure. A Cox proportional hazards model was used to compare the treatment effect in the subgroups of patients with and without previous MI. Heterogeneity between patients with and without a previous MI was analyzed with a test for treatment-by-subgroup interaction. The Gail-Simon test was used to analyze the quantitative interaction for absolute risk reduction.
      • Gail M.
      • Simon R.
      Testing for qualitative interactions between treatment effects and patient subsets.
      The cumulative incidence rates of MACE and death were estimated by the Kaplan-Meier method. P values were estimated by a log rank test over the previous MI status subgroups. The analysis was performed in SAS version 9.4 (IBM, Armonk, NY).

      Results

      Patient characteristics

      Among 18,924 patients in the trial, 3633 (19.2%) had histories of MI before the qualifying ACS. The baseline characteristics of the patients are shown in Table 1. Compared with patients without previous MI, those with a previous MI were older; more likely to be male, white; and to have more underlying cardiovascular conditions, previous cardiovascular events and procedures including stroke, peripheral artery disease, heart failure, impaired renal function, percutaneous coronary intervention, and coronary artery bypass graft surgery. In patients with previous MI, the qualifying ACS was more often non-ST elevation MI, and they had higher baseline levels of LDL-C, non–HDL-C, triglycerides, apolipoprotein B, lipoprotein(a), and hemoglobin A1c, but lower HDL-C. Other baseline characteristics are shown in Supplemental Table S1. Findings were similar when patients with and without previous MI were compared in each randomization arm (alirocumab or placebo) (Supplemental Table S2).
      Table 1Baseline characteristics stratified by MI status at baseline
      CharacteristicsPrevious MI (n = 3633)No previous MI (n = 15,291)P value
      Age, y59.8 (9.3)58.3 (9.3)< 0.001
      Female sex756 (20.8)4006 (26.2)< 0.001
      Medical history before index ACS
       Hypertension2884 (79.4)9365 (61.3)< 0.001
       Diabetes1167 (32.1)3478 (22.8)< 0.001
       Current tobacco smoker849 (23.4)3711 (24.3)0.25
       Family history of premature coronary artery disease1543 (42.5)5230 (34.2)< 0.001
       PCI2,399 (66.0)842 (5.5)< 0.001
       CABG727 (20.0)320 (2.1)< 0.001
       Stroke180 (5.0)431 (2.8)< 0.001
       Peripheral artery disease265 (7.3)494 (3.2)< 0.001
       Heart failure970 (26.7)1844 (12.1)< 0.001
      Body mass index, kg/m229.2 (4.9)28.3 (4.9)< 0.001
      Renal function
       EGFR, mL/min per 1.73 m277.4 (19.7)80.2 (19.1)< 0.001
       EGFR < 60 mL/min per 1.73 m2635 (17.5)1905 (12.5)< 0.001
      Index ACS
       ST-segment elevation MI866 (23.8)5670 (37.1)< 0.001
       Non−ST-segment elevation MI2064 (56.8)7111 (46.5)< 0.001
       Unstable angina695 (19.1)2484 (16.2)< 0.001
      PCI or CABG for index ACS2308 (63.5)11,368 (74.3)< 0.001
      Median time from index ACS to randomization, months2.6 (1.7-4.2)2.6 (1.7-4.4)0.27
      LDL-C, mg/dL90.0 (75.7-110.4)85.7 (72.6-102.7)< 0.001
      LDL-C ≥ 100 mg/dL1305 (35.9)4324 (28.3)< 0.001
      HDL-C, mg/dL42.0 (35.9−49.8)42.9 (36.7−50.2)0.004
      Non−HDL-C, mg/dL121.2 (103.9−145.0)113.5 (98.5−135.0)< 0.001
      Triglycerides, mg/dL137.0 (98.0−193.0)127.4 (92.9−179.6)< 0.001
      Lipoprotein(a), mg/dL41.8 (45.4)38.3 (42.8)< 0.001
      Apolipoprotein B, mg/dL)83.0 (72.0−98.0)78.0 (68.0−92.0)< 0.001
      Apolipoprotein A, mg/dL131.0 (118.0-147.0)132.00 (118.0-147.0)0.64
      C-reactive protein, mg/dL0.2 (0.1-0.4)0.2 (0.1-0.4)0.12
      Hemoglobin A1c, %5.9 (5.6-6.6)5.8 (5.5-6.3)< 0.001
      Values are number (percentage), mean (standard deviation [SD]) or median (quartile 1 to quartile 3).
      ACS, acute coronary syndrome; CABG, coronary artery bypass graft; EGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein-cholesterol; MI, myocardial infarction; PCI, percutaneous coronary intervention; SD, standard deviation.

      Risks of mace and death in the placebo group stratified by previous MI status at baseline

      In the placebo group, the incidence of MACE (20.5% vs 8.9%; adjusted HR [aHR], 1.85; 95% CI, 1.62-2.11; P < 0.001), all-cause death (7.4% vs 3.4%; aHR, 1.56, 95% CI, 1.25-1.95; P < 0.001), and other outcomes were higher among those with previous MI (Table 2). Exceptions were ischemic stroke and hospitalization for unstable angina, which were directionally congruent.
      Table 2Event rates and HR of outcomes stratified by MI status at baseline: placebo arm
      Previous MI n (%)No previous MI n (%)Unadjusted HR (95% CI)P valueAdjusted HR (95% CI)P value
      Primary composite outcome
      Death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring revascularization.
      378 (20.5)674 (8.9)2.41 (2.12-2.73)< 0.0011.85 (1.62-2.11)< 0.001
      Any coronary heart disease event
      Death from coronary heart disease, nonfatal MI, unstable angina requiring hospitalization, or ischemia-driven coronary revascularization.
      440 (23.9)909 (11.9)2.08 (1.86-2.34)< 0.0011.67 (1.48-1.88)< 0.001
      Major coronary heart disease event
      Death from coronary heart disease or nonfatal MI.
      336 (18.2)563 (7.4)2.56 (2.23-2.93)< 0.0011.97 (1.71-2.28)< 0.001
      Any cardiovascular event
      Death from cardiovascular cause, nonfatal MI, unstable angina requiring hospitalization, ischemia-driven coronary revascularization procedure, or nonfatal ischemic stroke.
      477 (25.9)997 (13.1)2.07 (1.85-2.30)< 0.0011.63 (1.45-1.83)< 0.001
      Composite of death from any cause, nonfatal MI, or nonfatal ischemic stroke398 (21.6)728 (9.6)2.35 (2.08-2.66)< 0.0011.81 (1.59-2.06)< 0.001
      Death from coronary heart disease87 (4.7)135 (1.8)2.62 (2.00-3.43)< 0.0011.87 (1.40-2.50)< 0.001
      Death from cardiovascular causes102 (5.5)169 (2.2)2.45 (1.92-3.13)< 0.0011.70 (1.31-2.21)< 0.001
      Death from any cause136 (7.4)256 (3.4)2.15 (1.75-2.65)< 0.0011.56 (1.25-1.95)< 0.001
      Nonfatal MI273 (14.8)449 (5.9)2.61 (2.24-3.03)< 0.0012.03 (1.73-2.38)< 0.001
      Fatal or nonfatal ischemic stroke50 (2.7)102 (1.3)2.01 (1.44-2.83)< 0.0011.33 (0.92-1.92)0.13
      Unstable angina requiring hospitalization20 (1.1)40 (0.5)2.05 (1.20-3.51)0.0091.73 (0.99-3.04)0.06
      Ischemia-driven coronary revascularization procedure260 (14.1)568 (7.5)1.93 (1.67-2.24)< 0.0011.62 (1.38-1.90)< 0.001
      Hospitalization for congestive heart failure73 (4.9)106 (1.4)2.85 (2.11-3.83)< 0.0011.66 (1.21-2.28)0.002
      CI, confidence interval; HR, hazard ratio; MI, myocardial infarction.
      Death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring revascularization.
      Death from coronary heart disease, nonfatal MI, unstable angina requiring hospitalization, or ischemia-driven coronary revascularization.
      Death from coronary heart disease or nonfatal MI.
      § Death from cardiovascular cause, nonfatal MI, unstable angina requiring hospitalization, ischemia-driven coronary revascularization procedure, or nonfatal ischemic stroke.

      Effect of alirocumab on MACE and death stratified by previous MI status at baseline

      Figure 1 shows adjusted risk of outcomes for alirocumab vs placebo stratified according to previous MI status at baseline. In the overall study population, alirocumab reduced MACE by 15.0% (HR, 0.85; 95% CI, 0.78-0.93; P < 0.001).
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      Among patients with previous MI, MACE occurred in 20.5% of patients in the placebo group vs 18.6% in the alirocumab group (aHR, 0.90; 95% CI, 0.78-1.05). Among patients without previous MI, MACE occurred in 8.8% of patients in the placebo group vs 7.4% in the alirocumab group (aHR, 0.82, 95% CI, 0.73-0.92; Pinteraction = 0.34). The estimated 4-year absolute risk reduction in MACE was numerically greater in patients with previous MI (1.91%; 95% CI, −0.67 to 4.49 vs 1.42%; 95% CI, 0.55-2.28; quantitative Pheterogeneity = 0.72). Among patients with previous MI, 7.4% of patients in the placebo group died vs 6.0% in the alirocumab group (aHR 0.84; 95% CI, 0.64-1.08). Among patients without previous MI, 3.4% of patients in the placebo group died vs 2.9% in the alirocumab group (aHR 0.87; 95% CI, 0.72-1.05; Pinteraction = 0.81). Likewise, estimated absolute risk reduction for death was numerically greater in patients with vs without previous MI (1.35%; 95% CI, −0.28 to 2.97% vs 0.41%,; 95% CI, −0.14 to 0.97; quantitative Pheterogeneity = 0.29). The unadjusted risks of outcomes are shown in Supplemental Fig. S1. Cumulative incidence curves are shown in Figure 2.
      Figure thumbnail gr1
      Figure 1Outcomes for alirocumab vs placebo stratified by previous myocardial infarction (MI) status. ∗Adjusted for the following independent variables: age (≥ 65 vs < 65 years), sex, race, diabetes mellitus, geographic region, history of heart failure, baseline low-density lipoprotein-cholesterol (LDL-C), lipoprotein(a), intensive statin use, systolic blood pressure at baseline, smoking status, history of ischemic stroke, and history of peripheral artery disease. CI, confidence interval; HR, hazard ratio.
      Figure thumbnail gr2
      Figure 2Cumulative incidence for alirocumab vs placebo stratified by previous myocardial infarction (MI). (A) Major adverse cardiovascular event (MACE) (composite of death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization). (B) All-cause death. CI, confidence interval; HR, hazard ratio; LDL-C, low-density lipoprotein-cholesterol.

      Effect of alirocumab on outcomes stratified by timing of previous MI

      In patients with previous MI, the median time from the last MI to the index ACS was 4.5 years. The effect of alirocumab vs placebo on MACE in patients with MI that occurred ≤ 2 years before the qualifying ACS (20.5% vs 19.9%; HR, 1.02; 95% CI, 0.78-1.34) did not differ from that in patients with MI that occurred > 2 years before the qualifying ACS (17.8% vs 20.9%; HR, 0.85; 95% CI, 0.71-1.03; Pinteraction = 0.16) (Fig. 3).
      Figure thumbnail gr3
      Figure 3Adjusted risk of major adverse cardiovascular event (MACE) stratified by timing of previous myocardial infarction (MI). ∗Adjusted for the following independent variables: age (≥ 65 vs < 65 years), sex, race, diabetes mellitus, geographic region, history of heart failure, baseline LDL-C, lipoprotein(a), intensive statin use, systolic blood pressure at baseline, smoking, history of ischemic stroke, and history of peripheral artery disease. CI, confidence interval; HR, hazard ratio; LDL-C, low-density lipoprotein-cholesterol.

      Safety outcomes

      Adverse events and laboratory abnormalities were, in general, similar for alirocumab vs placebo when stratified by previous MI status at baseline (Supplemental Table S3).

      Discussion

      Among patients with recent ACS who did not receive alirocumab, those with vs without previous MI had higher risks of MACE and all-cause death. Alirocumab was associated with consistent relative risk reductions in both patients with and without previous MI, with numerically greater absolute benefit in patients with previous MI.
      On the basis of multiple major atherosclerotic cardiovascular disease events, the subgroup with previous MI would be classified as very high risk according to the US guidelines.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      Approximately 18% to 22% of patients with ACS have histories of previous MI.
      • Cannon C.P.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ,
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      Indeed, the adjusted risks for MACE and all-cause death were higher for patients with vs without previous MI. The management of patients with recurrent ACS presents a particular challenge for clinicians. Alirocumab reduced risk of MACE and all-cause death in patients receiving maximum tolerated (including ∼90% high-intensity) statins with a numerally greater absolute effect in patients with previous MIs, supporting recent guideline recommendations.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Mach F.
      • Baigent C.
      • Catapano A.L.
      • et al.
      2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS).
      • Pearson G.J.
      • Thanassoulis G.
      • Anderson T.J.
      • et al.
      2021 Canadian Cardiovascular Society Guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults.
      The lack of statistical significance of alirocumab on MACE and all-cause death in the subgroup of patients with previous MI is most likely due to a relative small number of patients with previous MI.
      A previous analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial in patients with stable atherosclerotic cardiovascular disease and previous MI found that treatment with the PCSK9 inhibitor evolocumab was effective in reducing MACE in those with recent MI (< 2 years) but not in those with only remote MI (≥ 2 years).
      • Sabatine M.S.
      • De Ferrari G.M.
      • Giugliano R.P.
      • et al.
      Clinical benefit of evolocumab by severity and extent of coronary artery disease: analysis from FOURIER.
      In the current analysis, the efficacy of alirocumab in patients with ACS was consistent with or without previous MI and in those with previous MI irrespective of whether it had occurred ≤ 2 or > 2 years before the qualifying ACS. Therefore, it may be reasonable to consider PCSK9 inhibitor treatment in all patients with ACS and dyslipidemia uncontrolled by statins.
      This analysis from the ODYSSEY OUTCOMES trial indicates that previous MI is a marker of higher risk of MACE and death following ACS and, accordingly, that such patients might derive a larger absolute benefit from alirocumab treatment. Previously, effects of alirocumab in patients at very high-risk vs not, according to the US guidelines,
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      have been reported in the ODYSSEY OUTCOMES trial, showing similar findings that patients at very high risk derived a larger absolute benefit from treatment with alirocumab.
      • Roe M.T.
      • Li Q.H.
      • Bhatt D.L.
      • et al.
      Risk categorization using new American College of Cardiology/American Heart Association guidelines for cholesterol management and its relation to alirocumab treatment following acute coronary syndromes.
      Similarly, analyses from this trial have identified several subgroups of post-ACS patients at high risk for recurrent cardiovascular events who derive a greater absolute benefit from alirocumab treatment, including those with type 2 diabetes,
      • Ray K.K.
      • Colhoun H.M.
      • Szarek M.
      • et al.
      Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial.
      polyvascular disease,
      • Jukema J.W.
      • Szarek M.
      • Zijlstra L.E.
      • et al.
      Alirocumab in patients with polyvascular disease and recent acute coronary syndrome: ODYSSEY OUTCOMES trial.
      previous coronary artery bypass graft surgery,
      • Goodman S.G.
      • Aylward P.E.
      • Szarek M.
      • et al.
      Effects of alirocumab on cardiovascular events after coronary bypass surgery.
      higher lipoprotein(a) concentration,
      • Bittner V.A.
      • Szarek M.
      • Aylward P.E.
      • et al.
      Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome.
      and high genome-wide polygenic risk scores.
      • Damask A.
      • Steg P.G.
      • Schwartz G.G.
      • et al.
      Patients with high genome-wide polygenic risk scores for coronary artery disease may receive greater clinical benefit from alirocumab treatment in the ODYSSEY OUTCOMES trial.
      Although the primary analysis of the current study did not reach statistical significance, the numerically greater benefits in patients with previous MI might suggest a true effect if the sample size could be enlarged.
      The effects of alirocumab on MACE in patients with previous MI seemed to occur earlier, with the MACE curves separated at approximately 1 year after randomization compared with approximately 2 years for patients without previous MI. Similar findings have also been observed in the FOURIER trial in which the MACE curves separated at approximately 180 days in patients with recent MI (≤ 12 months), compared with approximately 540 days in patients with remote MI (> 12 months).
      • Gencer B.
      • Mach F.
      • Murphy S.A.
      • et al.
      Efficacy of evolocumab on cardiovascular outcomes in patients with recent myocardial infarction: a prespecified secondary analysis from the FOURIER trial.
      Although we did not collect systematic angiographic information at baseline, it is likely that patients who have had > 1 ACS event have a greater burden of coronary atherosclerosis. More pronounced atherosclerotic lesions are susceptible to be modified by LDL-C lowering. Therefore, intensive LDL-C lowering with alirocumab has a favourable effect on plaque stabilization.
      • Sugizaki Y.
      • Otake H.
      • Kawamori H.
      • et al.
      Adding alirocumab to rosuvastatin helps reduce the vulnerability of thin-cap fibroatheroma: an ALTAIR trial report.
      More recently, the addition of subcutaneous biweekly alirocumab, compared with placebo, to high-intensity statin therapy in patients with acute MI resulted in significantly greater coronary plaque regression in noninfarct-related arteries after 52 weeks.
      • Räber L.
      • Ueki Y.
      • Otsuka T.
      • et al.
      Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial.
      Whether earlier initiation of treatment (ie, before hospital discharge after ACS) would magnify an early treatment benefit is a hypothesis worthy of testing prospectively.

      Limitations

      First, analyses in subgroups are limited by sample size and power, and the confidence interval of the relative risk reduction in patients with previous MI crossed the line of unity. Second, number of MIs was not recorded, and details on previous MI were based on medical history rather than systematic review of laboratory data and electrocardiographic tracings. Third, we did not investigate the impact of previous atherosclerotic cardiovascular disease events other than MI, such as stroke or peripheral artery disease events, on the clinical efficacy of alirocumab.

      Conclusions

      Patients with recent ACS and previous MI were at higher risk for MACE and death than those without previous MI. Alirocumab reduced the relative risks of these events consistently in patients with or without previous MI but with numerically greater absolute benefit in the former subgroup.

      Acknowledgements

      The authors thank the patients, study coordinators and investigators who participated in this trial. Sophie Rushton-Smith (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 Sanofi.

      Funding Sources

      The trial was funded by Sanofi and Regeneron Pharmaceuticals, Inc . The sponsors participated in the selection of the trial sites, the monitoring of the trial, and the supervision of data collection.

      Disclosures

      Dr Chiang has received honoraria from Sanofi, Pfizer, Novartis, Merck Sharp Dohme, AstraZeneca, Daiichi Sankyo, Bayer, and Boehringer Ingelheim. Dr Schwartz has received grants to his institution (University of Colorado) from Sanofi, AstraZeneca, Resverlogix, Roche, and The Medicines Company. Dr Elbez has received research grants from Sanofi and Bristol-Myers Squibb. Dr Szarek has received grants from Sanofi and Regeneron Pharmaceuticals; personal fees from CiVi and Esperion; and grants from Lexicon, Resverlogix, Baxter, and Janssen. Dr Bhatt has served on advisory boards for Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, and Regado Biosciences and has served on the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft. He has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company and has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); served as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte and has served as Trustee for American College of Cardiology and has participated in unfunded research for FlowCo, Merck, and Takeda. Dr Bittner has received grant support from Sanofi, Astra Zeneca, DalCor, Esperion, Bayer, The Medicines Company, and Amgen, all paid direct to her institution, and she has received personal fees from Sanofi. Dr Diaz has received research grants from Sanofi, DalCor Pharmaceuticals, Population Health Research Institute, Duke Clinical Research Institute, the TIMI group, Amgen, Cirius, Montreal Health Innovations Coordinating Center, and Lepetit and personal fees as a member of the Executive Steering Committee from Amgen and Cirius. Dr Goodman has received research grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Eli Lilly, Merck, Novartis, Pfizer, Regeneron, and Sanofi; honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, Janssen/Johnson & Johnson, Merck, Novartis, Novo Nordisk A/C, Pendopharm, Pfizer, Regeneron, Sanofi, Servier, and Valeo Pharma and has served as a consultant or on advisory boards (or both) for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Eli Lilly, Ferring Pharmaceuticals, HLS Therapeutics, Janssen/Johnson & Johnson, Merck, Novartis, Pendopharm, Pfizer, Regeneron, Sanofi, and Servier. He has received salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Center, and PERFUSE Research Institute. Dr Hagström has received research grants from the Swedish Heart and Lung Foundation, Sweden; Uppsala University, Sweden; EMPIR European Union Horizon 2020; research support from Amgen and Sanofi and has served as a consultant or on advisory for Amgen, Sanofi, Bayer, NovoNordisk, and Boehringer Ingelheim. Dr Harrington has received research grants (all DSMB related) from AstraZeneca, Janssen, and Bristol-Myers Squibb; served on advisory boards for Gilead (uncompensated) and WebMD; and has served on the boards of directors (unpaid) for the American Heart Association and Stanford HealthCare. Dr Jukema has received research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Commission Seventh Framework Programme and research support from Amgen, Astellas, AstraZeneca, Daiichi- Sankyo, Lilly, Merck-Schering-Plough, Pfizer, Roche, and Sanofi. Dr Liberopoulos has received personal fees from Amgen and Sanofi and grants, personal fees, and nonfinancial support from AstraZeneca. He has received personal fees from Novo Nordisk, MSD, Lilly, Servier, Boehringer-Ingelheim, and Novartis and personal fees and nonfinancial support from Bayer and Viatris. Ms Loy is an employee of Sanofi and may hold shares and/or stock options in the company. Dr Pordy is an employee of Regeneron Pharmaceuticals. Dr White has received grant support paid to the institution and fees from Sanofi-Aventis and Regeneron Pharmaceuticals, Eli Lilly, Omthera Pharmaceuticals, Pfizer USA, Eisai Inc, DalCor Pharma UK Inc, Sanofi-Aventis Australia Pty Ltd, and Esperion Therapeutics Inc. Dr White was on the advisory boards for Genentech, Inc. (an affiliate of F. Hoffmann-La Roche Ltd, “Roche,” Lytics Post-PCI Advisory Board at European Society of Cardiology) and has received lecture fees from AstraZeneca. Dr Zeiher has been a scientific advisor for Sanofi, Amgen, Pfizer, and Boehringer and speaker for Bayer, Novartis, and Vifor. Dr Simon has received grants from Programme de Recherche Medico Economique and from Instituto de Salud Carlos III, Grant number PI15/01543; personal fees from Astra Zeneca, Novartis, Sanofi, Astellas, and MSD; and grants from Astra Zeneca, Bayer, Boehringer, Daiichi-Sankyo, Eli Lilly, GSK, Novartis, and Sanofi. Dr Steg has received grants and personal fees from Sanofi and Regeneron Pharmaceuticals (as co-chair of the ODYSSEY OUTCOMES trial); grants and personal fees from Amarin (executive steering committee REDUCE IT, consulting, speaking), Bayer (speaking), Servier (Chair CLARIFY registry, DMC); personal fees from Amgen, Bristol Myers Squibb (Steering Committee NAXOS and PAROS studies, speaking), Boehringer Ingelheim (executive steering committee, REDUAL PCI trial), Idorsia (Steering Committee SOS AMI trial), Novartis (consulting, executive steering committee PARADISE MI trial, speaking), Novo Nordisk (consulting, speaking), Pfizer (Critical Event Committee), Sanofi/Lexicon (executive steering committee, SCORED and SOLOIST trials), and Myokardia; personal fees and nonfinancial support from AstraZeneca (co-chair THEMIS trial; consulting, speaking); in addition, Dr Steg has a patent assigned to Sanofi issued. Dr Erglis has no conflicts of interest to disclose. For detailed author disclosure please see the Declaration of Interest Form (Supplemental Appendix S2).

      Supplementary Material

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