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Background: It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations., Objectives: This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial., Methods: Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations., Results: Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82)., Conclusions: Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)., Competing Interests: Funding Support and Author Disclosures This analysis was funded by Regeneron Pharmaceuticals, Inc. The ODYSSEY OUTCOMES trial was funded by Regeneron Pharmaceuticals, Inc, and Sanofi. The trial was designed by an academic steering committee in conjunction with the sponsors. The sponsors were involved in the collection verification, and analysis of the data provided in the manuscript. All authors participated in the interpretation of the data. Dr Zahger has served as national coordinator for the ODYSSEY OUTCOMES trial and the SCORED trial, both funded by Sanofi; and has served as consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Sanofi. Dr Schwartz has received research support to the University of Colorado from AstraZeneca, Sanofi, Silence Therapeutics, and The Medicines Company; and is a coinventor of pending U.S. patent 62/806,313 (“Methods for Reducing Cardiovascular Risk”) assigned in full to the University of Colorado. Drs Du, Manvelian, Pordy, Fazio, and Geba are all employees of and shareholders in Regeneron Pharmaceuticals, Inc. Dr Szarek has received salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, Everly Health, Faraday, Fortress Biotech, HDL Therapeutics, HeartFlow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, MedPace, Medtronic, Moderna, Novate Medical, Novo Nordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Biosciences, Regeneron Pharmaceuticals, Inc, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, University of Pittsburgh, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group; has received fees for performing analyses, steering committee fees, and travel support from Sanofi and Regeneron Pharmaceuticals, Inc; has received consulting fees from CiVi, Lexicon, Amarin, and Esperion Therapeutics; has received Data Safety and Monitoring Board membership fees from Resverlogix and Janssen; and is a member of the Journal of the American College of Cardiology Editorial Board. Dr Bhatt has served on the advisory board for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on the Board of Directors for Angiowave (with stock options), Boston VA Research Institute, Bristol Myers Squibb (with stock), DRS.LINQ (with stock options), High Enroll (with stock), Society of Cardiovascular Patient Care, and TobeSoft; has served as the Inaugural Chair of the American Heart Association Quality Oversight Committee; has served as a consultant for Broadview Ventures and Hims; has served on the Data Monitoring Committee for Acesion Pharma, Assistance Publique–Hôpitaux de Paris, the Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), the Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, the Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded MINT trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, the Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and U.S. national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); has served as the Deputy Editor of Clinical Cardiology; has served as the Chair of the NCDR-ACTION Registry Steering Committee and the VA CART Research and Publications Committee; holds a patent for sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither Dr Bhatt nor Brigham and Women's Hospital receives any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly and Company, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron Pharmaceuticals, Inc, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a trustee of the American College of Cardiology; and conducted unfunded research for FlowCo and Takeda. Dr Bittner has received grant support from Sanofi, AstraZeneca, DalCor, Esperion, Bayer, Novartis, and Amgen, all paid direct to her institution; and has received personal fees from Sanofi and Pfizer. Dr Budaj has received personal fees and nonfinancial support from Sanofi, Bristol Myers Squibb/Pfizer, Bayer, and AstraZeneca; and has received personal fee from Novartis, Amgen, and Novo Nordisk. Dr Diaz has received research grants from Sanofi, DalCor Pharmaceuticals, the Population Health Research Institute, Duke Clinical Research Institute, the TIMI group, Amgen, Cirius, the Montreal Health Innovations Coordinating Center, and Lepetit; and has received 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, Daiichi-Sankyo/American Regent, Eli Lilly and Comapny, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, and Sanofi; has received honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly and Company, Esperion Therapeutics, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, JAMP Pharma, Janssen/Johnson & Johnson, Merck, Novartis, Novo Nordisk A/C, Pendopharm, Pfizer, Regeneron Pharmaceuticals, Inc, Sanofi, Servier, Valeo Pharma, the Canadian Heart Research Centre and MD Primer, the Canadian VIGOUR Centre, the Cleveland Clinic Coordinating Centre for Clinical Research, the Duke Clinical Research Institute, the New York University Clinical Coordinating Centre, the PERFUSE Research Institute, and the TIMI Study Group (Brigham Health); and has served as a consultant or on the advisory board (or both) for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Janssen/Johnson & Johnson, Merck, Novartis, Pendopharm, Pfizer, Regeneron Pharmaceuticals, Inc, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma. 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 has received research support from Amgen, Astellas, AstraZeneca, Daiichi-Sankyo, Eli Lilly and Company, Merck-Schering-Plough, Pfizer, Roche, and Sanofi. Dr Harrington has received research grants (all data safety and monitoring board related) from AstraZeneca, Janssen, and Bristol Myers Squibb; has served on the advisory board for Gilead (uncompensated) and WebMD; and has served on the board of directors (unpaid) for the American Heart Association and Stanford HealthCare. Dr Moriarty has received research grants to his institution for the participation in the ODYSSEY OUTCOMES trial; has received financial fees for serving as a medical monitor for the trial and associated support for travel related to trial meetings from Sanofi; has received consulting and speaking fees from Regeneron Pharmaceuticals, Inc, and Amgen; has received consulting fees from Esperion, Kaneka, and Stage II innovations; has received speaker fees from Amarin; has received advisor fees from Novartis for serving on their advisory committee; and has received research grants to his institution from Ionis, FH Foundation, GB Life Sciences, Aegerion, Amgen, Kowa, Novartis, and Regeneron Pharmaceuticals, Inc. Dr Scemama is an employee of Sanofi and may hold shares and/or stock options in the company. Dr White has received grant support paid to his institution for serving on a Steering Committee for the ODYSSEY OUTCOMES trial from Sanofi and Regeneron Pharmaceuticals, Inc, for the ACCELERATE study from Eli Lilly and Company, for the STRENGTH trial from Omthera Pharmaceuticals, for the CAMELLIA-TIMI study from Eisai, for the HEART-FID study from American Regent, and for the ISCHEMIA Trial and the MINT Trial from the National Institutes of Health; has received grants to his institution and personal fees as Steering Committee member for the dal-GenE study from DalCor Pharma UK Inc, for the AEGIS-II study from CSL Behring, for the SCORED trial and the SOLOIST-WHF trial from Sanofi Australia Pty Ltd, and for the CLEAR Outcomes Study from Esperion Therapeutics Inc; and has served on the advisory board for CSL Behring and Genentech (an affiliate of F. Hoffmann-La Roche Ltd, “Roche”; Lytics Post-PCI Advisory Board at European Society of Cardiology). Dr Zeiher has received fees for serving on a steering committee for the ODYSSEY OUTCOMES trial from Sanofi; and has received advisory board and speaker fees from Sanofi, Amgen, Boehringer Ingelheim, Bayer, Novartis, Pfizer, AstraZeneca, and Vifor. Dr Steg has received grants and nonfinancial support (co-Chair of the ODYSSEY OUTCOMES trial; as such, he received no personal fees, but his institution has received funding for the time he has devoted to trial coordination, and he has received support for travel related to trial meetings) from Sanofi; has received research grants and personal fees from Bayer (Steering Committee MARINER, grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (co-Chair of the ODYSSEY OUTCOMES trial; co-Chair of the SCORED trial; consulting; speaking), Servier (Chair of the CLARIFY registry; grant for epidemiological research), and Amarin (executive steering committee for the REDUCE-IT trial [Disease Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial]; consulting); has received personal fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Idorsia, MyoKardia, Novo Nordisk, Novartis, Regeneron Pharmaceuticals, Inc, and AstraZeneca; and has a European application number/patent number, issued on October 26, 2016 (no. 15712241.7), for a method for reducing cardiovascular risk, with all royalties assigned to Sanofi. Dr Kiss has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS)., Objective: We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level., Methods: This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment., Results: Women were older, had higher baseline low-density lipoprotein cholesterol (LDL-C) levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (p interaction =0.08). Medication adherence and adverse event rates were similar in both sexes., Conclusions: Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a)., Competing Interests: Declaration of competing interest Vera A. Bittner reports grant support from Sanofi, Regeneron Pharmaceuticals, Amgen, Astra Zeneca, DalCor, Esperion, and Novartis; consulting fees from Pfizer; honoraria from Medscape; and fees for participating on Data Safety Monitoring Boards for the National Institutes of Health and for Verve Therapeutics. Gregory G. Schwartz reports research support (all paid to institution) from Sanofi; grants or contracts from AstraZeneca, Resverlogix, Silence Therapeutics, and The Medicines Company/Novartis (all paid to institution); support for attending meetings from University of Oxford, American Society of Preventive Cardiology, and Cardiovascular Clinical Trialists; and receipt of medical writing support from Novartis. Deepak L. Bhatt discloses the following relationships - Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. Terrance Chua reports research grants from Sanofi. Asita De Silva reports no disclosures. Rafael Diaz reports 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. Genevieve Garon is an employee of Sanofi and may hold shares and/or stock options in the company. Shaun G. Goodman reports research grant support (e.g., steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (e.g., advisory boards) from: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, JAMP Pharma, Janssen/Johnson & Johnson, Merck, Novartis, Novo Nordisk A/C, Pendopharm, Pfizer, Regeneron, Sanofi, Servier, Valeo Pharma; and salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Research center and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating center for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating center, and PERFUSE Research Institute. Robert A. Harrington reports research grants from the Patient-Centered Outcomes Research Institute, National Institutes of Health, CSL and Janssen; consulting for Atropos Health, Bitterroot Bio, Bridge Bio, Bristol Myers Squibb, Foresight, Element science; and serving on the boards of directors for the American Heart Association (unpaid) and Cytokinetics. J. Wouter Jukema reports 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. Jennifer McGinniss is an employee of Regeneron Pharmaceuticals, Inc. and holds share options in the company. Robert Pordy is an employee of Regeneron Pharmaceuticals, Inc., and may hold shares and/or stock options in the company. Michel Scemama is an employee of Sanofi may hold shares and/or stock options in the company. Harvey D. White reports grant support paid to the institution for serving on a Steering Committee for the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) from Sanofi-Aventis and Regeneron Pharmaceuticals, for the ACCELERATE study (A Study of Evacetrapib in High-Risk Vascular Disease) from Eli Lilly and Company, for the STRENGTH trial (Outcomes Study to Assess Statin Residual Risk Reduction With EpaNova in High CV Risk Patients With Hypertriglyceridemia) from Omthera Pharmaceuticals, for the CAMELLIA-TIMI study (A Study to Evaluate the Effect of Long-term Treatment With BELVIQ [Lorcaserin HC] on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects With Cardiovascular Disease or Multiple Cardiovascular Risk Factors) from Eisai Inc, for the HEART-FID study (Randomized Placebo-Controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency) from American Regent, and for the ISCHEMIA Trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) and the MINT Trial (Myocardial Ischemia and Transfusion) from the National Institutes of Health USA. He also received grants to the institution and personal fees as Steering Committee member for the dal-GenE study (Effect of Dalcetrapib vs Placebo on CV Risk in a Genetically Defined Population With a Recent ACS) from DalCor Pharma UK Inc, for the AEGIS-II study (The Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Human ApoA-I, After Acute Myocardial Infarction: The ApoA-I Event reducinG in Ischemic Syndromes I) from CSL Behring, for the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and the SOLOIST-WHF trial (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type2 Diabetes Post Worsening Heart Failure) from Sanofi-Aventis Australia Pty Ltd, and for the CLEAR Outcomes Study (Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid [ETC-1002] or Placebo) from Esperion Therapeutics Inc. Dr White was on the Advisory Boards for CSL Behring and Genentech, Inc. (an affiliate of F. Hoffmann-La Roche Ltd, “Roche”; Lytics Post-PCI Advisory Board at European Society of Cardiology. Ph. Gabriel Steg reports grants, personal fees, and non-financial support from Sanofi; grants and personal fees from Amarin, Servier and Bayer; personal fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Idorsia, Pfizer, and Novartis. In addition, Dr Steg has a patent use of alirocumab to reduce risk after ACS (royalties to Sanofi) pending. Michael Szarek reports serving as a consultant or on advisory boards (or both) for CiVi, Resverlogix, Baxter, Esperion, Sanofi, and Regeneron Pharmaceuticals, Inc., (Copyright © 2024. Published by Elsevier Inc.)

Background: Some data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors reduce LDL-C below levels achieved with statins alone. We determined whether the incidence of cataracts was influenced by treatment with the PCSK9 inhibitor alirocumab versus placebo, and whether that incidence was affected by achieved LDL-C levels., Methods: The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving high-intensity or maximum-tolerated statin. Incident cataracts were pre-specified events of interest. In multivariable analysis using propensity score-matching on characteristics including cataract risk factors, incident cataracts were compared in the alirocumab and placebo groups according to LDL-C levels achieved with alirocumab., Results: Over median follow-up of 2.8 years (interquartile range 2.3 - 3.4), the incidence of cataracts was similar with alirocumab (127/9462 [1.3%]) versus placebo (134/9462 [1.4%]); hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74 - 1.20). In patients treated with alirocumab with ≥ 2 LDL-C values < 25 mg/dL (0.65 mmol/L), the incidence of cataracts was 71/4305 (1.6%), versus 60/4305 (1.4%) in propensity score-matched patients from the placebo group (HR 1.10, CI 95% 0.78 - 1.55). In patients treated with alirocumab with ≥ 2 LDL-C values < 15 mg/dL (0.39 mmol/L), the incidence of cataracts was 13/782 (1.7%), versus 36/2346 (1.5%) in matched patients from the placebo group (HR 1.03, CI 95% 0.54 - 1.94)., Conclusion: Treatment with alirocumab versus placebo, added to statin, did not influence the incidence of cataracts, even when achieved LDL-C levels on alirocumab were very low. Longer follow-up studies might be necessary to exclude the long-term effects on the incidence or progression of cataracts., Trial Registration: ClinicalTrials.gov Identifier: NCT01663402 ., (© 2023. The Author(s).)

Aims: European guidelines set low-density lipoprotein cholesterol (LDL-C) treatment goals &lt;1.4 mmol/L after acute coronary syndrome (ACS), and &lt;1.0 mmol/L for patients with recurrent cardiovascular events ≤2 years. Many ACS patients do not achieve these goals on statin alone. We examined actual goal achievement with alirocumab and projected achievement with ezetimibe, either added to optimized statin therapy., Methods and Results: The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18 924 patients with recent ACS and hyperlipidaemia despite high-intensity or maximum-tolerated statin therapy. This subanalysis comprised 17 589 patients with LDL-C ≥1.4 mmol/L at baseline who did not receive ezetimibe treatment. High-intensity statin treatment was used in 88.8%. Median (interquartile range) baseline LDL-C was 2.3 (1.9-2.7) mmol/L. With alirocumab, 94.6% of patients achieved LDL-C &lt;1.4 mmol/L at ≥1 post-baseline measurement vs. 17.3% with placebo. Among 2236 patients with a previous cardiovascular event within 2 years (before the qualifying ACS), 85.2% vs. 3.5%, respectively, achieved LDL-C &lt;1.0 mmol/L. Among patients not treated with ezetimibe, we projected that its use would have achieved LDL-C &lt;1.4 and &lt;1.0 mmol/L in 10.6 and 0%, respectively, at baseline (assuming 18 ± 3% reduction of LDL-C)., Conclusion: Among patients with recent ACS and LDL-C ≥1.4 mmol/L despite optimized statin therapy, the addition of alirocumab allowed 94.6% to achieve the 2019 European guideline LDL-C goal &lt;1.4 mmol/L, and 85.2% of those with recurrent cardiovascular events to achieve &lt;1.0 mmol/L. In contrast, the addition of ezetimibe to optimized statin therapy was projected to achieve LDL-C &lt;1.4 mmol/L in only 10.6% of patients at baseline., Competing Interests: Conflict of interest: U.L. reports grants and personal fees from Bayer, Novartis, and Amgen and personal fees from Sanofi, Abbott, Astra Zeneca, Boehringer Ingelheim. J.M. is an employee of Regeneron Pharmaceuticals; P.G.S. reports grants, personal fees, and non-financial support from Sanofi; grants and personal fees from Amarin, Servier, and Bayer; personal fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Idorsia, Pfizer, and Novartis. In addition, P.G.S. has a patent use of alirocumab to reduce risk after ACS (royalties to Sanofi) pending. D.L.B. discloses the following relationships—Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company, 89Bio; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Philips, Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Takeda. V.A.B. reports grant support from Sanofi, Regeneron Pharmaceuticals, Astra Zeneca, DalCor, Esperion, and Novartis; consulting fees from Pfizer; honoraria from Medscape; and fees for participating on a Data Safety Monitoring Board or Advisory Board from the National Institutes of Health. R.D. reports 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. M.D. reports uncompensated; National Coordinator and Principal Investigator in EORP surveys EUROSPIRE IV and EUROASPIRE V, serving as National Coordinator for Bosnia & Herzegovina CVD Prevention, serving as National Coordinator for Bosnia & Herzegovina version of HeartScore Programme, serving on Board of Bosnia & Herzegovina Association of Cardiology, serving as Editor-in-Chief of Medical Journal CCUS; reports research grant from Sanofi, and lectures fees from Bayer, Sanofi, Boehringer Ingelheim, Novartis, Pfizer, GlaxoSmithKline, Bosnalijek, Berlin-Chemie Menarini, Abbott, Krka, and report fee for Chair of PhD Study on Medical Faculty University of Sarajevo. S.G.G. reports research grant support (e.g. steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (e.g. advisory boards) from: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, JAMP Pharma, Janssen/Johnson & Johnson, Merck, Novartis, Novo Nordisk A/C, Pendopharm, Pfizer, Regeneron, Sanofi, Servier, Valeo Pharma; and 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 Centre, and PERFUSE Research Institute. J.W.J. reports 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. M.L. is an employee of Sanofi. I.P. reports receiving honoraria for lectures from Novartis, Amgen, Sanofi and Sandoz. R.P. is an employee of Regeneron Pharmaceuticals, Inc. S.H.P. reports participating in an Advisory Board meeting arranged by Sanofi. M.S. reports serving as a consultant or on advisory boards (or both) for CiVi, Resverlogix, Baxter, Esperion, Sanofi, and Regeneron Pharmaceuticals, Inc. H.D.W. reports receiving grant support paid to the institution and fees for serving on a steering committee for the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) from Sanofi-Aventis and Regeneron Pharmaceuticals, for the ACCELERATE study (A Study of Evacetrapib in High-Risk Vascular Disease) from Eli Lilly, for the STRENGTH trial (Outcomes Study to Assess Statin Residual Risk Reduction With EpaNova in High CV Risk Patients With Hypertriglyceridemia) from Omthera Pharmaceuticals, for the SPIRE trial (The Evaluation of Bococizumab [PF-04950615; RN 316] in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects) from Pfizer USA, for the HEART-FID study (Randomized Placebo-Controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency) from American Regent; for the CAMELLIA-TIMI study (A Study to Evaluate the Effect of Long-term Treatment With BELVIQ [Lorcaserin HC] on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects With Cardiovascular Disease or Multiple Cardiovascular Risk Factors) from Eisai Inc, for the dal-GenE study (Effect of Dalcetrapib vs. Placebo on CV Risk in a Genetically Defined Population With a Recent ACS) from DalCor Pharma UK Inc, for the AEGIS-II study from CSL Behring, for the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and the SOLOIST-WHF trial (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type2 Diabetes Post-Worsening Heart Failure) from Sanofi-Aventis Australia Pty Ltd, and for the CLEAR Outcomes Study (Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid [ETC-1002] or Placebo) from Esperion Therapeutics Inc. H.D.W. was on the Advisory Boards for Acetelion, Sirtex and Genentech, Inc. (an affiliate of F. Hoffmann-La Roche Ltd, ‘Roche’; Lytics Post-PCI Advisory Board at European Society of Cardiology), and received lecture fees from AstraZeneca. G.G.S. reports research grants to the University of Colorado from Resverlogix, Sanofi, The Medicines Company, and Roche; and is coinventor of pending US patent 62/806 313 (‘Methods for Reducing Cardiovascular Risk’) assigned in full to the University of Colorado., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Statins are pivotal to the secondary prevention of major adverse cardiovascular events, but some patients are statin-intolerant. We examined the effects of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab on the risk of major adverse cardiovascular events according to the intensity of background statin treatment., Methods and Results: The ODYSSEY OUTCOMES trial compared alirocumab with placebo in 18,924 patients with acute coronary syndrome and dyslipidaemia despite intensive or maximum-tolerated statin treatment (including no statin if intolerance was documented). The primary outcome (major adverse cardiovascular events) comprised coronary heart disease death, non-fatal myocardial infarction, ischaemic stroke, or unstable angina. Median follow-up was 2.8 years. Baseline statin treatment was high-intensity (88.8%), low/moderate-intensity (8.7%) or none (2.4%). Median baseline low-density lipoprotein cholesterol was 86, 89 and 139 mg/dL (P < 0.001) in these statin treatment categories, respectively. Alirocumab produced similar relative reductions in low-density lipoprotein cholesterol from baseline across statin treatment subgroups, but the mean absolute reductions differed (52.9, 56.7 and 86.1 mg/dL, respectively; P < 0.001). With placebo, the incidence of major adverse cardiovascular events was highest in the no statin subgroup (10.8%, 10.7% and 26.0% respectively). Alirocumab reduced major adverse cardiovascular events in each statin subgroup (hazard ratio 0.88, 95% confidence interval (CI) 0.80-0.96; 0.68, 0.49-0.94; and 0.65, 0.44-0.97, respectively; Pinteraction = 0.14) with a gradient of absolute risk reduction: 1.25%, 95% CI 0.34-2.16; 3.16%, 0.38-5.94; 7.97%, 0.42-15.51; Pinteraction = 0.106)., Conclusions: PCSK9 inhibition with alirocumab reduces the relative risk of major adverse cardiovascular events after acute coronary syndrome irrespective of background statin treatment. However, patients on no statin are at high absolute risk for recurrent major adverse cardiovascular events; alirocumab substantially reduces that risk. PCSK9 inhibition may be an important therapeutic strategy for statin-intolerant patients with acute coronary syndrome., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Few data are available on procedural complications of percutaneous coronary intervention (PCI) in the setting of acute coronary syndrome in the contemporary era., Aim: We sought to describe the prevalence of procedural complications of PCI in a non-ST-segment elevation acute coronary syndrome (NSTE ACS) cohort, and to identify their clinical characteristics and association with clinical outcomes., Methods: Patients randomized in TAO (Treatment of Acute coronary syndrome with Otamixaban), an international randomized controlled trial (ClinicalTrials.gov Identifier: NCT01076764) that compared otamixaban with unfractionated heparin plus eptifibatide in patients with NSTE ACS who underwent PCI, were included in the analysis. Procedural complications were collected prospectively, categorized and adjudicated by a blinded Clinical Events Committee, with review of angiograms. A multivariable model was constructed to identify independent clinical characteristics associated with procedural complications., Results: A total of 8656 patients with NSTE ACS who were enrolled in the TAO trial underwent PCI, and 451 (5.2%) experienced at least one complication. The most frequent complications were no/slow reflow (1.5%) and dissection with decreased flow (1.2%). Procedural complications were associated with the 7-day ischaemic outcome of death, myocardial infarction or stroke (24.2% vs. 6.0%, odds ratio 5.01, 95% confidence interval 3.96-6.33; P<0.0001) and with Thrombolysis In Myocardial Infarction major and minor bleeding (6.2% vs. 2.3%, odds ratio 2.79, 95% confidence interval 1.86-4.2; P<0.0001). Except for previous coronary artery bypass grafting, multivariable analysis did not identify preprocedural clinical predictors of complications., Conclusions: In a contemporary NSTE ACS population, procedural complications with PCI remain frequent, are difficult to predict based on clinical characteristics, and are associated with worse ischaemic and haemorrhagic outcomes., (Copyright © 2021. Published by Elsevier Masson SAS.)

Background It is unclear whether HIV infection affects the long-term prognosis after an acute coronary syndrome (ACS). The objective of the current study was to compare rates of major adverse cardiac and cerebrovascular events after a first ACS between people living with HIV (PLHIV) and HIV-uninfected (HIV-) patients, and to identify determinants of cardiovascular prognosis. Methods and Results Consecutive PLHIV and matched HIV- patients with a first episode of ACS were enrolled in 23 coronary intensive care units in France. Patients were matched for age, sex, and ACS type. The primary end point was major adverse cardiac and cerebrovascular events (cardiac death, recurrent ACS, recurrent coronary revascularization, and stroke) at 36-month follow-up. A total of 103 PLHIV and 195 HIV- patients (mean age, 49 years [SD, 9 years]; 94.0% men) were included. After a mean of 36.6 months (SD, 6.1 months) of follow-up, the risk of major adverse cardiac and cerebrovascular events was not statistically significant between PLHIV and HIV- patients (17.8% and 15.1%, P =0.22; multivariable hazard ratio [HR], 1.60; 95% CI, 0.67-3.82 [ P =0.29]). Recurrence of ACS was more frequent among PLHIV (multivariable HR, 6.31; 95% CI, 1.32-30.21 [ P =0.02]). Stratified multivariable Cox models showed that HIV infection was the only independent predictor for ACS recurrence. PLHIV were less likely to stop smoking (47% versus 75%; P =0.01) and had smaller total cholesterol decreases (-22.3 versus -35.0 mg/dL; P =0.04). Conclusions Although the overall risk of major adverse cardiac and cerebrovascular events was not statistically significant between PLHIV and HIV- individuals, PLHIV had a higher rate of recurrent ACS. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00139958.

Aims: Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular risk irrespective of age, but the evidence is less strong for older patients., Methods and Results: This prespecified analysis from ODYSSEY OUTCOMES compared the effect of alirocumab vs. placebo in 18 924 patients with recent acute coronary syndrome (ACS) according to age. We examined the effect of assigned treatment on occurrence of the primary study outcome, a composite of coronary heart disease death, myocardial infarction, ischaemic stroke, or unstable angina requiring hospitalization [major adverse cardiovascular event (MACE)] and all-cause death. Relative risk reductions were consistent for patients ≥65 vs. <65 years for MACE [hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.68-0.91 vs. 0.89, 0.80-1.00; Pinteraction = 0.19] and all-cause death [HR 0.77, 0.62-0.95 vs. 0.94, 0.77-1.15; Pinteraction = 0.46], and consistent for MACE when dichotomizing at age 75 years (HR 0.85, 0.64-1.13 in ≥75 vs. 0.85, 0.78-0.93 in <75, Pinteraction = 0.19). When considering age as a continuous variable in regression models, advancing age increased risk of MACE, as well as the absolute reduction in MACE with alirocumab, with numbers-needed-to-treat for MACE at 3 years of 43 (25-186) at age 45 years, 26 (15-97) at age 75 years, and 12 (6-81) for those at age 85 years. Although adverse events were more frequent in older patients, there were no differences between alirocumab and placebo., Conclusion: In patients with recent ACS, alirocumab improves outcomes irrespective of age. Increasing absolute benefit but not harm with advancing age suggests that LDL-C lowering is an important preventive intervention for older patients after ACS., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C)., Objectives: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE)., Methods: One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina., Results: Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081)., Conclusions: Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The 2018 US cholesterol management guidelines recommend additional lipid-lowering therapies for secondary prevention in patients with low-density lipoprotein cholesterol ≥70 mg/dL or non-high-density lipoprotein cholesterol ≥100 mg/dL despite maximum tolerated statin therapy. Such patients are considered at very high risk (VHR) based on a history of >1 major atherosclerotic cardiovascular disease (ASCVD) event or a single ASCVD event and multiple high-risk conditions. We investigated the association of US guideline-defined risk categories with the occurrence of ischemic events after acute coronary syndrome and reduction of those events by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor., Methods: In the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), patients with recent acute coronary syndrome and residual dyslipidemia despite optimal statin therapy were randomly assigned to alirocumab or placebo. The primary trial outcome (major adverse cardiovascular events, ie, coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) was examined according to American College of Cardiology/American Heart Association risk category., Results: Of 18 924 participants followed for a median of 2.8 years, 11 935 (63.1%) were classified as VHR: 4450 (37.3%) had multiple prior ASCVD events and 7485 (62.7%) had 1 major ASCVD event and multiple high-risk conditions. Major adverse cardiovascular events occurred in 14.4% of placebo-treated patients at VHR versus 5.6% of those not at VHR. In the VHR category, major adverse cardiovascular events occurred in 20.4% with multiple prior ASCVD events versus 10.7% with 1 ASCVD event and multiple high-risk conditions. Alirocumab was associated with consistent relative risk reductions in both risk categories (hazard ratio=0.84 for VHR; hazard ratio=0.86 for not VHR; P interaction =0.820) and by stratification within the VHR group (hazard ratio=0.86 for multiple prior ASCVD events; hazard ratio=0.82 for 1 major ASCVD event and multiple high-risk conditions; P interaction =0.672). The absolute risk reduction for major adverse cardiovascular events with alirocumab was numerically greater (but not statistically different) in the VHR group versus those not at VHR (2.1% versus 0.8%; P interaction =0.095) and among patients at VHR with multiple prior ASCVD events versus a single prior ASCVD event (2.4% versus 1.8%; P interaction =0.661)., Conclusions: The US guideline criteria identify patients with recent acute coronary syndrome and dyslipidemia who are at VHR for recurrent ischemic events and who may derive a larger absolute benefit from treatment with alirocumab., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.

Background: In ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab was compared with placebo, added to high-intensity or maximum tolerated statin treatment after acute coronary syndrome in 18 924 patients. Alirocumab reduced first occurrence of the primary composite end point-coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or hospitalization for unstable angina-as well as total nonfatal cardiovascular events and all-cause deaths. The present analysis determined whether alirocumab reduced total (first and subsequent) hospitalizations and death and increased days alive and out of hospital (DAOH) and percent DAOH in ODYSSEY OUTCOMES., Methods and Results: In prespecified analyses, hazard functions for total hospitalizations and death were jointly estimated by a semiparametric model, while in post hoc analyses, DAOH and percent DAOH were compared between treatment groups with Poisson regression and one-inflated beta regression, respectively. With 16 629 total hospitalizations and 726 deaths, 331 fewer hospitalizations, and 58 fewer deaths were observed with alirocumab compared with placebo, translating to 15.6 total hospitalizations or deaths avoided with alirocumab per 1000 patient-years of assigned treatment. Alirocumab reduced total hospitalizations (hazard ratio, 0.96 [95% CI, 0.92-1.00]; P =0.04) and increased DAOH relative to placebo (rate ratio, 1.003 [95% CI, 1.000-1.007]; P =0.05), primarily through a reduction in days dead (rate ratio, 0.847 [95% CI, 0.728-0.986]; P =0.03). Patients randomized to alirocumab were also more likely to survive to the end of the study without hospitalization (odds ratio, 1.06 [95% CI, 1.00-1.13]; P =0.03)., Conclusions: Alirocumab reduced total hospitalizations with corresponding small increases in DAOH and percent DAOH. These outcomes provide alternative patient-centered metrics to capture the totality of alirocumab clinical efficacy after acute coronary syndrome., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01663402.

Background: Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death., Objectives: This 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)., Methods: Patients (n = 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 (n = 16,896); index CABG after qualifying ACS, but before randomization (n = 1,025); or CABG before the qualifying ACS (n = 1,003)., Results: In 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%])., Conclusions: Among 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)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Pulse pressure is a readily available vital sign that has been shown to independently predict outcomes in several cardiovascular disease states. We investigated the prognostic significance of pulse pressure (PP) and systolic blood pressure (SBP) among patients with acute coronary syndromes (ACS)., Methods: A total of 14,514 patients with ACS in the prospective, multicentre Global Registry of Acute Coronary Events (GRACE), expanded GRACE (GRACE-2) and Canadian Registry of Acute Coronary Events (CANRACE) were stratified by initial PP on presentation. Patient characteristics and in-hospital outcomes were compared by PP quartiles and the independent prognostic significance of PP for in-hospital mortality was quantified. We compared the discriminative ability (c-statistic) of models incorporating either PP or SBP., Results: Patients with higher PPs were older, more frequently female and had higher prevalence rates of conventional cardiovascular risk factors (all p  < 0.01). Lower PP was associated with ST-segment elevation myocardial infarction presentation, higher GRACE risk scores and higher rates of adverse in-hospital outcomes ( p  < 0.001). PP was strongly correlated with SBP (Pearson's correlation coefficient = 0.79, p  < 0.001). After adjustment for other GRACE risk model predictors, lower PP was independently associated with in-hospital mortality (first vs. fourth quartile [reference]: adjusted odds ratio 2.57, 95% confidence interval 1.80-3.67). The c-statistic was slightly higher for the multivariable model incorporating SBP as compared to the model with PP (0.868 vs. 0.864, respectively, p  = 0.028) for in-hospital mortality., Conclusion: Higher presenting PP is associated with increased age and more prevalent cardiovascular risk factors, whereas patients with lower PP present with worse clinical characteristics and in-hospital outcomes. Lower PP is an independent adverse prognosticator in ACS. However, PP did not improve the discriminatory performance of the GRACE risk score compared with SBP.

Background: The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths., Objectives: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES., Methods: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death., Results: With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk., Conclusions: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is a frequent complication of acute coronary syndromes (ACS) and is associated with an increased risk of in-hospital and long-term mortality. Our objective was to determine whether patients with previous AF and those who presented with or developed AF during their ACS hospitalization (new onset) have an associated increased risk of short- and mid-term cardiovascular events, death, or a composite. We included 7,228 patients from the Global Registry of Acute Coronary Events electrocardiogram core laboratory substudy, who presented with an ACS. Associated multivariable-adjusted risk of death and major adverse cardiovascular events (MACE) of death, re-infarction, or stroke in-hospital and at 6 months were estimated. New-onset AF and previous AF patients had higher rates of in-hospital mortality (14.9% and 10.9%, respectively) compared with patients without AF (3.8%; both p < 0.001). New-onset AF and previous AF patients had higher rates of 6-month mortality (22.3% and 21.3%, respectively) compared with patients without AF (7.0%; both p <0.001). After adjustment for clinical prognosticators, including those in the Global Registry of Acute Coronary Events risk model, new-onset AF was associated with higher mortality in-hospital (OR adj 1.87, 95% CI 1.30 to 2.70) and at 6 months (OR adj 1.75, 95% CI 1.29 to 2.39) as well as MACE at 6 months (OR adj 1.43, 95% CI 1.12 to 1.81) compared with patients without AF, but were at similar risk compared to those with previous AF (all p > 0.40). In conclusion, the risk of death and MACE after ACS in patients with new-onset and previous AF appears similar and significantly increased compared with patients without AF., (Copyright © 2018. Published by Elsevier Inc.)

Aims: The purpose of this study was to test whether different results between Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON (CHAMPION) PCI/PLATFORM and PHOENIX trials are due in part to different definitions of percutaneous coronary intervention (PCI)-related myocardial infarction (MI)., Methods and Results: In patients with acute coronary syndrome (ACS), the definition of MI was identical in CHAMPION PCI and PLATFORM and did not require an assessment of baseline cardiac biomarker status, while in PHOENIX specific MI criteria were associated with different patient presentations. The same MI criteria were used in PCI, PLATFORM, and PHOENIX for patients with stable angina. Logistic regression assessed the effect of cangrelor on MI (PCI- and non-PCI related) in the combined PCI/PLATFORM population and in PHOENIX. Consistency of cangrelor's effect in PCI/PLATFORM and in PHOENIX in patients with stable angina and in those with an ACS (with or without ST elevation) was evaluated. Overall, the incidence of PCI-related MI at 48 h was 6.3% in PCI/PLATFORM and 4.0% in PHOENIX. In patients with ACS, MI incidence was 6.4% in PCI/PLATFORM and 1.7% in PHOENIX, and 6.3% and 5.6%, respectively in stable angina patients. Cangrelor's effect on PCI-related MI differed between PCI/PLATFORM (odds ratio (OR) 1.03, 95% confidence interval (CI) 0.90-1.17) and PHOENIX (OR 0.80, 95% CI 0.66-0.98) with p INT =0.04. This difference was mostly evident in patients with ACS ( p INT = 0.06) while the effect was consistent in patients with stable angina ( p INT =0.81). Results were similar when all MIs were analyzed., Conclusions: The definition of PCI-related MI has important implications for event rates, treatment effect, and study results. This illustrates the importance of a rigorous assessment of PCI-related MI in clinical trials of patients with an ACS.

Background: Nine oral antithrombotic medications currently available in the United States and Europe have been studied in clinical trials for secondary prevention of cardiac events following acute coronary syndrome (ACS). Few combinations of these medications have been directly compared, and studies have used multiple different comparator regimens., Methods: We performed a systematic review and network meta-analysis of randomized controlled trials evaluating one or more available oral antithrombotic therapies in patients with ACS or prior myocardial infarction (MI). Co-primary outcomes were all-cause and cardiovascular mortality compared with imputed placebo and aspirin monotherapy., Results: Forty-seven studies (196,057 subjects) met inclusion criteria and were included in the systematic review. Almost all studies tested either aspirin monotherapy compared with placebo or a combination of antithrombotic agents that included aspirin. Nearly all regimens reduced all-cause and cardiovascular mortality compared with imputed placebo. However, compared with imputed aspirin monotherapy, only combination therapy with aspirin plus ticagrelor was associated with lower cardiovascular mortality (OR 0.80, 95% CI 0.68-0.93), and triple therapy with aspirin, clopidogrel, and very low dose rivaroxaban was associated with lower all-cause mortality (OR 0.67, 95% CI 0.49-0.90). Major bleeding was increased 45-95% with dual antithrombotic therapy, and 2-6-fold with triple therapy., Conclusion: Few combinations of antithrombotic therapy were associated with a reduction in mortality compared with aspirin monotherapy, highlighting the difficulty in clinical interpretation of composite ischemic endpoints. Future studies may need to focus on limiting the number of antithrombotic therapies tested in combination to best balance ischemic event reduction and bleeding., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To assess the relationship between the evolution of T wave inversion (TWI) on the 24-48 h postadmission ECG and the patient characteristics, management and clinical outcomes among those with non-ST elevation acute coronary syndrome (NSTE-ACS)., Methods: We evaluated admission and 24-48 h follow-up ECGs of 7201 patients with NSTE-ACS from the prospective, multicentre Global Registry of Acute Coronary Events (GRACE) and Canadian ACS Registry I. We performed multivariable analyses to determine the association between new TWI (on follow-up ECG only), resolved TWI (on admission ECG only) and persistent TWI (on both admission and follow-up ECG) and inhospital and cumulative 6-month all-cause mortality., Results: Patients with TWI were older, more likely to have cardiovascular risk factors, higher Killip class and GRACE risk scores. After adjustment for known prognostic factors, compared with patients presenting without TWI, new TWI was associated with significantly lower inhospital mortality (OR=0.60, 95% CI 0.38 to 0.95, p=0.029), whereas resolved (OR=1.06, 95% CI 0.65 to 1.75, p=0.81) and persistent (OR=0.73, 95% CI 0.48 to 1.11, p=0.14) TWI did not predict inhospital mortality. No TWI pattern independently predicted inhospital adverse cardiovascular events or cumulative 6-month mortality. In contrast, ST depression on the admission and follow-up ECG were independent predictors of inhospital and 6-month mortality., Conclusions: Across the spectrum of NSTE-ACS, TWI within 48 h of presentation was associated with high-risk clinical features, but its presence or dynamic change did not provide additional prognostic value beyond other established clinical predictors., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Ticagrelor reduced cardiovascular events compared with clopidogrel in PLATO without increasing overall major bleeding. We evaluated whether the use of glycoprotein IIb/IIIa inhibitor (GPI) impacts the relative efficacy and safety of ticagrelor compared with clopidogrel., Methods: PLATO randomized 18,624 subjects with acute coronary syndrome to ticagrelor versus clopidogrel. The primary efficacy end point was cardiovascular death/myocardial infarction/stroke, and the primary safety end point was major bleeding. The use of GPI was at the physician's discretion and open-label. We evaluated outcomes at 30 days stratified by GPI use in the subgroup of 9,983 patients who underwent percutaneous coronary intervention (PCI) within 72 hours., Results: A total of 4,020 (40%) received a GPI. Those receiving a GPI were more likely to be younger, be male, and undergo multivessel PCI. There was no interaction between treatment and GPI use for the primary efficacy and safety end points. Patients treated without GPI had a lower rate of definite stent thrombosis and higher rate of minor/major bleeding with ticagrelor compared with clopidogrel (P < .05), whereas there was no such difference with GPI (P interaction < .05)., Conclusions: In patients with acute coronary syndrome undergoing early PCI, the efficacy and safety of ticagrelor as compared with clopidogrel were not modified by GPI use according to the primary efficacy and safety end point of the trial, although there were indications of greater benefit on definite stent thrombosis and more major or minor bleeding with ticagrelor in patients without (vs with) GPI treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: The prognostic significance of prior heart failure in acute coronary syndromes has not been well studied. Accordingly, we evaluated the baseline characteristics, management patterns and clinical outcomes in patients with acute coronary syndromes who had prior heart failure., Methods and Results: The study population consisted of acute coronary syndrome patients in the Global Registry of Acute Coronary Events, expanded Global Registry of Acute Coronary Events and Canadian Registry of Acute Coronary Events between 1999 and 2008. Of the 13,937 eligible patients (mean age 66±13 years, 33% female and 28.3% with ST-elevation myocardial infarction), 1498 (10.7%) patients had a history of heart failure. Those with prior heart failure tended to be older, female and had lower systolic blood pressure, higher Killip class and creatinine on presentation. Prior heart failure was also associated with significantly worse left ventricular systolic function and lower rates of cardiac catheterization and coronary revascularization. The group with previous heart failure had significantly higher rates of acute decompensated heart failure, cardiogenic shock, myocardial (re)infarction and mortality in hospital. In multivariable analysis, prior heart failure remained an independent predictor of in-hospital mortality (odds ratio 1.48, 95% confidence interval 1.08-2.03, p=0.015)., Conclusions: Prior heart failure was associated with high risk features on presentation and adverse outcomes including higher adjusted in-hospital mortality in acute coronary syndrome patients. However, acute coronary syndrome patients with prior heart failure were less likely to receive evidence-based therapies, suggesting potential opportunities to target more intensive treatment to improve their outcome., (© The European Society of Cardiology 2015.)

Background: Patients with chronic obstructive pulmonary disease (COPD) experiencing acute coronary syndromes (ACS) are at high risk for clinical events. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor versus clopidogrel reduced the primary endpoint of death from vascular causes, myocardial infarction, or stroke after ACS, but increased the incidence of dyspnea, which may lead clinicians to withhold ticagrelor from COPD patients., Methods and Results: In 18 624 patients with ACS randomized to treatment with ticagrelor or clopidogrel, history of COPD was recorded in 1085 (5.8%). At 1 year, the primary endpoint occurred in 17.7% of patients with COPD versus 10.4% in those without COPD (P<0.001). The 1-year event rate for the primary endpoint in COPD patients treated with ticagrelor versus clopidogrel was 14.8% versus 20.6% (hazard ratio [HR]=0.72; 95% confidence interval [CI]: 0.54 to 0.97), for death from any cause 8.4% versus 12.4% (HR=0.70; 95% CI: 0.47 to 1.04), and for PLATO-defined major bleeding rates at 1 year 14.6% versus 16.6% (HR=0.85; 95% CI: 0.61 to 1.17). Dyspnea occurred more frequently with ticagrelor (26.1% vs. 16.3%; HR=1.71; 95% CI: 1.28 to 2.30). There was no differential increase in the relative risk of dyspnea compared to non-COPD patients (HR=1.85). No COPD status-by-treatment interactions were found, showing consistency with the main trial results., Conclusions: In this post-hoc analysis, COPD patients experienced high rates of ischemic events. Ticagrelor versus clopidogrel reduced and substantially decreased the absolute risk of ischemic events (5.8%) in COPD patients, without increasing overall major bleeding events. The benefit-risk profile supports the use of ticagrelor in patients with ACS and concomitant COPD., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Aims: Ticagrelor, a direct-acting P2Y12-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial., Methods and Results: A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1 was associated with levels of ticagrelor (P = 1.1 × 10(-6)) and ARC (P = 4.6 × 10(-13)). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 × 10(-15) and rs56324128, P = 9.7 × 10(-12)) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 × 10(-14)) in UGT2B7. At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea., Conclusion: In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci (SLCO1B1, UGT2B7, and CYP3A4). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment., Clinical Trial Registration: NCT00391872., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Purpose: Short-term outcomes have been well characterized in acute coronary syndromes; however, longer-term follow-up for the entire spectrum of these patients, including ST-segment-elevation myocardial infarction, non-ST-segment-elevation myocardial infarction, and unstable angina, is more limited. Therefore, we describe the longer-term outcomes, procedures, and medication use in Global Registry of Acute Coronary Events (GRACE) hospital survivors undergoing 6-month and 2-year follow-up, and the performance of the discharge GRACE risk score in predicting 2-year mortality., Methods: Between 1999 and 2007, 70,395 patients with a suspected acute coronary syndrome were enrolled. In 2004, 2-year prospective follow-up was undertaken in those with a discharge acute coronary syndrome diagnosis in 57 sites., Results: From 2004 to 2007, 19,122 (87.2%) patients underwent follow-up; by 2 years postdischarge, 14.3% underwent angiography, 8.7% percutaneous coronary intervention, 2.0% coronary bypass surgery, and 24.2% were re-hospitalized. In patients with 2-year follow-up, acetylsalicylic acid (88.7%), beta-blocker (80.4%), renin-angiotensin system inhibitor (69.8%), and statin (80.2%) therapy was used. Heart failure occurred in 6.3%, (re)infarction in 4.4%, and death in 7.1%. Discharge-to-6-month GRACE risk score was highly predictive of all-cause mortality at 2 years (c-statistic 0.80)., Conclusion: In this large multinational cohort of acute coronary syndrome patients, there were important later adverse consequences, including frequent morbidity and mortality. These findings were seen in the context of additional coronary procedures and despite continued use of evidence-based therapies in a high proportion of patients. The discriminative accuracy of the GRACE risk score in hospital survivors for predicting longer-term mortality was maintained., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: While prior work has suggested that a high-grade atrioventricular block (HAVB) in the setting of an acute coronary syndrome (ACS) is associated with in-hospital death, limited information is available on the incidence of, and death associated with, HAVB in ACS patients receiving contemporary management., Methods and Results: The incidence of HAVB was determined within The Global Registry of Acute Coronary Events (GRACE). The clinical characteristics, in-hospital therapies, and outcomes were compared between patients with and without HAVB. Factors associated with death in patients with HAVB were determined. A total of 59 229 patients with ACS between 1999 and 2007 were identified; 2.9% of patients had HAVB at any point during the index hospitalization; 22.7% of whom died in hospital [adjusted odds ratio (OR) = 4.2, 95% confidence interval (CI), 3.6-4.9, P < 0.001]. The association between HAVB and in-hospital death varied with type of ACS [OR: ST-segment elevation myocardial infarction (STEMI) = 3.0; non-STEMI = 6.4; unstable angina = 8.2, P for interaction < 0.001]. High-grade atrioventricular block present at the time of presentation to hospital (vs. occurring in-hospital) and early (<12 h) percutaneous coronary intervention or fibrinolysis (vs.>12 h or no intervention) were associated with improved in-hospital survival, whereas temporary pacemaker insertion was not. Patients with HAVB surviving to discharge had similar adjusted survival at 6 months compared with those without HAVB. A reduction in the rate of, but not in-hospital mortality associated with, HAVB was noted over the study period., Conclusion: Although the incidence of HAVB is low and decreasing, this complication continues to have a high risk of in-hospital death., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Purpose: To examine the prognostic significance of low QRS voltage in a large contemporary cohort of patients with a broad spectrum of acute coronary syndromes (ACS)., Methods: 12409 patients with STEMI or NSTE-ACS from the Global Registry of Acute Coronary Events (GRACE) and Canadian ACS I registries were stratified based on the presence of low QRS voltage (<0.5 mV in all limb leads and <1.0 mV in all precordial leads) on the admission ECG. We performed multivariable logistic regression to assess the independent association between low voltage and in-hospital and 6-month mortality, and tested for its interaction with ST-segment deviation for these outcomes., Results: Patients with low voltage (3.2%) had higher GRACE risk scores, rates of prior myocardial infarction, and pathological Q waves, with less prevalent ST-segment deviation and ST-segment depression. They had worse left ventricular function and higher unadjusted rates of in-hospital and 6-month mortality. After adjustment for established prognosticators in the GRACE risk models in multivariable analysis, low voltage was independently associated with higher in-hospital mortality (adjusted OR 1.77, 95% CI 1.13-2.78, P=0.013) and mortality/re-infarction (adjusted OR 1.42, 95% CI 1.05-1.93, P=0.023), but not 6-month mortality (adjusted OR 1.25, 95% CI 0.85-1.84, P=0.27). There was no significant interaction between low voltage and ST-segment deviation for any endpoint (interaction P>0.10 for all endpoints)., Conclusions: Low QRS voltage was associated with previous myocardial infarction and adverse hemodynamic variables at presentation. After adjusting for other prognosticators, low voltage independently predicted higher in-hospital mortality. This increased risk was not modulated by concomitant ST-segment deviation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: The aim of this study was to assess the relationship between sex and clinical outcomes and treatment-related complications in patients with ST-elevation or non-ST-elevation acute coronary syndromes (ACS) randomized to treatment with ticagrelor or clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial., Methods: The associations between sex subgroup and the primary composite outcomes, secondary outcomes, and major bleeding endpoints as well as interaction of sex subgroup with treatment effects were analysed using Cox proportional-hazards models., Results: Sex was not significantly associated with the probability of the primary composite endpoint [adjusted hazard ratio (HR): 1.02 (0.91-1.16)], or other adverse cardiovascular endpoints. Ticagrelor was similarly more effective than clopidogrel in reducing rates of the primary endpoint in women 11.2 vs. 13.2% [adjusted HR: 0.88 (0.74-1.06)] and men 9.4 vs. 11.1% [adjusted HR: 0.86 (0.76-0.97)] (interaction P-value 0.78), all-cause death in women 5.8 vs. 6.8% [adjusted HR: 0.90 (0.69-1.16)] and men 4.0 vs. 5.7% [adjusted HR: 0.80 (0.67-0.96)] (interaction P-value 0.49), and definite stent thrombosis in women 1.2 vs. 1.4% [adjusted HR: 0.71 (0.36-1.38)] and men 1.4 vs. 2.1% [adjusted HR: 0.63 (0.45-0.89)] (interaction P-value 0.78). The treatments did not differ for PLATO-defined overall major bleeding complications in women [adjusted HR: 1.01 (0.83-1.23)] or men [adjusted HR: 1.10 (0.98-1.24)]. Sex had no significant association with these outcomes (interactions P = 0.43-0.88)., Conclusion: Female sex is not an independent risk factor for adverse clinical outcomes in moderate-to-high risk ACS patients. Ticagrelor has a similar efficacy and safety profile in men and women., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high-sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial., Methods and Results: Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels. Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively. NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS and hs-TnT ≥14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT <14.0 ng/L, there was no difference between ticagrelor and clopidogrel in the noninvasive group, Conclusions: Hs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively. Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed patients, but no apparent benefit was seen at normal hs-TnT., Clinical Trial Registration: URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Background: Hypertension is a well-established risk factor for cardiovascular disease, whereas low systolic blood pressure (SBP) is a powerful adverse prognosticator in acute coronary syndrome. However, it is unclear whether the prognostic significance of low SBP differs in patients with versus without prior history of hypertension. We sought to investigate the relationships between presenting SBP, prior hypertension, antihypertensive medication use, and outcomes in non-ST-segment elevation acute coronary syndrome (NSTEACS)., Methods: Using data from GRACE/GRACE(2) and CANRACE, we stratified 10,337 patients with NSTEACS from 1999 to 2008 into 2 groups: those with and those without prior diagnosis of hypertension. We performed multivariable logistic regression analysis to assess the prognostic significance of prior hypertension on in-hospital mortality and tested for the interactions between prior hypertension, antihypertensive medication use, and presenting SBP., Results: Compared with patients without prior hypertension (n = 3,732), those with prior hypertension (n = 6,605) were older; more likely to be female; and more frequently had diabetes, previous myocardial infarction, heart failure, renal insufficiency, and higher Killip class and GRACE risk scores on presentation. Patients with prior hypertension were more likely to be on antihypertensive medications before admission, to present with higher SBP, and to have heart failure or cardiogenic shock in hospital (6.0% vs 10.1%; P < .001). In-hospital mortality was higher among patients presenting with lower SBP but did not differ between the groups with and without prior hypertension. In multivariable analysis, neither prior hypertension (adjusted odds ratio = 1.15, 95% CI 0.78-1.70, P = .48) nor the number of antihypertensive medications used (P for trend = .84) was independently associated with in-hospital mortality. In contrast, SBP was a strong independent predictor of in-hospital mortality (adjusted odds ratio = 1.21 per 10 mm Hg lower, 1.15-1.27, P < .001). There was no significant interaction between SBP and prior hypertension (P for interaction = .62) or pre-admission antihypertensive medication use (P for interaction = .46) with respect to in-hospital mortality., Conclusion: Low SBP on presentation, but not prior hypertension, was independently associated with in-hospital mortality in NSTEACS. The powerful prognostic value of SBP is similar regardless of a history of hypertension or pre-admission antihypertensive medication use., (© 2013.)

Background: ST-segment depression (STD) is predictive of adverse outcomes in non-ST-segment elevation acute coronary syndromes (NSTE-ACS), but there are conflicting data on the incremental prognostic value of T-wave inversions (TWIs) on the admission electrocardiogram., Methods: Admission electrocardiograms of 7,343 patients with NSTE-ACS from the Global Registry of Acute Coronary Events (GRACE) and ACS I registry were independently analyzed at a core laboratory and stratified by TWI and STD status. We performed multivariable analyses to determine the independent prognostic significance of TWI and tested for interaction between TWI and STD for adverse outcomes., Results: Patients with TWI and/or STD had a higher prevalence of cardiovascular risk factors, higher Killip class, and higher GRACE risk scores. Among the 2,708 patients with available angiographic data, rates of 3-vessel or left main disease were similar between patients with TWI and those without TWI/STD. After adjusting for other established prognosticators, TWI did not independently predict in-hospital (adjusted odds ratio 1.03, 95% CI 0.75-1.42, P = .85) or 6-month mortality (adjusted odds ratio 1.02, 95% CI 0.80-1.30, P = .88); STD remained a strong independent predictor. There was no interaction between TWI and STD for these outcomes. No contiguous lead groups or cumulative number of leads with TWI provided independent prognostic information., Conclusions: TWI is associated with other high-risk clinical features but is not an independent predictor of adverse short- and long-term mortality in NSTE-ACS. T-wave inversion does not provide additional prognostication beyond the GRACE risk model, and its concomitant presence does not alter the prognostic value of STD., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objectives: The PLATO (Platelet Inhibition and Patient Outcomes) angiographic substudy sought to compare the efficacy of ticagrelor versus clopidogrel with respect to angiographic outcomes before and after PCI in the setting of acute coronary syndrome., Background: Greater platelet inhibition has been associated with improved angiographic outcomes before and after percutaneous coronary intervention (PCI). Therefore, it was hypothesized that treatment with ticagrelor, which achieves more rapid, higher, and more consistent platelet inhibition, would be associated with improved angiographic outcomes when compared with those of clopidogrel treatment., Methods: The angiographic cohort consists of 2,616 patients drawn from the 18,624-patient PLATO trial. Clopidogrel naïve or pre-treated patients were randomized to 180 mg of ticagrelor or 300 mg of clopidogrel (75 mg for clopidogrel pre-treated patients). PCI patients were administered, as per treatment group: 1) an additional 90 mg of ticagrelor if >24 h following the initial loading dose; or 2) an optional further 300 mg of clopidogrel or placebo (total 600 mg) prior to PCI. The substudy primary endpoint was the incidence of post-PCI TIMI (Thrombolysis In Myocardial Infarction) myocardial perfusion grade 3 (TMPG 3) among patients who received a study drug prior to PCI., Results: In total, 21.3% of patients were pretreated with clopidogrel prior to randomization. There was a short time interval between randomization and PCI (median: 0.68 [interquartile range (IQR): 0.30 to 2.21] h) among all patients. Post-PCI TMPG 3 was similar between the ticagrelor and clopidogrel groups (47.1% vs. 46.9%; p = 0.96). Likewise, the following pre-PCI outcomes were similar in the ticagrelor and clopidogrel groups, respectively: TMPG 3 (30.5% vs. 31.2%), TIMI flow grade 3 (37.1% vs. 39.3%), corrected TIMI frame count (median: 100 vs. 71 frames), TIMI thrombus grade 0 (24.1% vs. 27.6%), minimum lumen diameter (median: 0.3 [IQR: 0.0 to 0.6] vs. 0.3 [IQR: 0.0 to 0.6] mm) and percentage of diameter stenosis (median: 89 [IQR: 78 to 100] vs. 89 [IQR: 77 to 100])., Conclusions: Neither coronary flow nor myocardial perfusion, evaluated on coronary angiograms performed before or following PCI procedures within a few hours after the start of oral antiplatelet treatment in the setting of acute coronary syndromes, demonstrated a difference with ticagrelor versus clopidogrel. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study investigated the differences in specific causes of post-coronary artery bypass graft surgery (CABG) deaths in the PLATO (Platelet Inhibition and Patient Outcomes) trial., Background: In the PLATO trial, patients assigned to ticagrelor compared with clopidogrel and who underwent CABG had significantly lower total and cardiovascular mortality., Methods: In the 1,261 patients with CABG performed within 7 days after stopping study drug, reviewers blinded to treatment assignment classified causes of death into subcategories of vascular and nonvascular, and specifically identified bleeding or infection events that either caused or subsequently contributed to death., Results: Numerically more vascular deaths occurred in the clopidogrel versus the ticagrelor group related to myocardial infarction (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2). Clopidogrel was also associated with an excess of nonvascular deaths related to infection (8 vs. 2). Among factors directly causing or contributing to death, bleeding and infections were more common in the clopidogrel group compared with the ticagrelor group (infections: 16 vs. 6, p < 0.05, and bleeding: 27 vs. 9, p < 0.01, for clopidogrel and ticagrelor, respectively)., Conclusions: The mortality reduction with ticagrelor versus clopidogrel following CABG in the PLATO trial was associated with fewer deaths from cardiovascular, bleeding, and infection complications. (Platelet Inhibition and Patient Outcomes [PLATO]; NCT00391872)., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Ticagrelor, when compared with clopidogrel, reduced the 12-month risk of vascular death/myocardial infarction and stroke in patients with ST-elevation acute coronary syndromes intended to undergo primary percutaneous coronary intervention in the PLATelet inhibition and patient Outcomes (PLATO) trial. This prespecified ECG substudy explored whether ticagrelor's association with vascular death and myocardial infarction within 1 year would be amplified by (1) the extent of baseline ST shift and (2) subsequently associated with fewer residual ST changes at hospital discharge., Methods and Results: ECGs were evaluated centrally in a core laboratory in 3122 ticagrelor- and 3084 clopidogrel-assigned patients having at least 1 mm ST-elevation in 2 contiguous leads as identified by site investigators on the qualifying ECG. Patients with greater ST-segment shift at baseline had higher rates of vascular death/myocardial infarction within 1 year. Among those who also had an ECG at hospital discharge (n=4798), patients with ≥50% ΣST-deviation (ΣST-dev) resolution had higher event-free survival than those with incomplete resolution (6.4% versus 8.8%, adjusted hazard ratio 0.69 (0.54-0.88), P=0.003). The extent of ΣST-dev resolution was similar irrespective of treatment assignment. The benefit of ticagrelor versus clopidogrel on clinical events was consistent irrespective of the extent of baseline ΣST-dev (P(interaction)=0.728). When stratified according to conventional times from symptom onset, ie, ≤3 hours, 3 to 6 hours, >6 hours, the extent of baseline ΣST-dev declined progressively over time. As time from symptom onset increased beyond 3 hours, the benefit of ticagrelor appeared to be more pronounced; however, the interaction between time and treatment was not significant (P=0.175)., Conclusions: Ticagrelor did not modify ΣST-dev resolution at discharge nor was its benefit affected by the extent of baseline ΣST-dev. These hypothesis-generating observations suggest that the main effects of ticagrelor may not relate to the rapidity or the completeness of acute reperfusion, but rather the prevention of recurrent vascular events by more powerful platelet inhibition or other mechanisms., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Background: Higher levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with a higher risk of cardiovascular events and may play a causal role in atherogenesis. Darapladib inhibits Lp-PLA(2) activity in plasma and in arterial plaques and may confer clinical benefit in preventing cardiovascular events., Study Design: The SOLID-TIMI 52 trial is a randomized, double-blind, placebo-controlled, multicenter, event-driven trial. Approximately 13,000 subjects are being randomized to darapladib (160 mg enteric-coated tablet daily) or matching placebo within 30 days of hospitalization with an acute coronary syndrome. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points include major and total coronary events, individual components of the primary end point, and all-cause mortality. The study will continue until approximately 1,500 primary end point events have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be approximately 3 years, with a total study duration of approximately 4.1 years., Conclusions: The SOLID-TIMI 52 trial will determine the clinical benefit of direct inhibition of Lp-PLA(2) activity with darapladib in patients after an acute coronary syndrome., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Aims: To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS)., Methods: In a 26-week, multi-centre, double-blind, randomized, parallel-group study, 1279 patients with recent high-risk non-ST-segment or ST-segment elevation ACS received one of six darexaban regimens: 5 mg b.i.d., 10 mg o.d., 15 mg b.i.d., 30 mg o.d., 30 mg b.i.d., or 60 mg o.d. or placebo, on top of dual antiplatelet treatment. Primary outcome was incidence of major or clinically relevant non-major bleeding events. The main efficacy outcome was a composite of death, stroke, myocardial infarction, systemic thromboembolism, and severe recurrent ischaemia., Results: Bleeding rates were numerically higher in all darexaban arms vs. placebo (pooled HR: 2.275; 95% CI: 1.13-4.60, P = 0.022). Using placebo as reference (bleeding rate 3.1%), there was a dose-response relationship (P = 0.009) for increased bleeding with increasing darexaban dose (6.2, 6.5, and 9.3% for 10, 30, and 60 mg daily, respectively), which was statistically significant for 30 mg b.i.d. (P = 0.002). There was no decrease (indeed a numerical increase in the 30 and 60 mg dose arms) in efficacy event rates with darexaban, but the study was underpowered for efficacy. Darexaban showed good tolerability without signs of liver toxicity., Conclusions: Darexaban when added to dual antiplatelet therapy after ACS produces an expected dose-related two- to four-fold increase in bleeding, with no other safety concerns but no signal of efficacy. Establishing the potential of low-dose darexaban in preventing major cardiac events after ACS requires a large phase III trial. ClinicalTrials.gov Identifier: NCT00994292.

Objective: To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy., Design: Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial., Setting: 862 centres in 43 countries., Participants: 5216 (28%) of 18,624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management., Interventions: Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615)., Main Outcome Measurements: Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year., Results: 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel., Conclusions: In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy., Trial Registration: Clinical trials NCT00391872.

Objectives: The aim of this study was to determine whether ticagrelor increased the risk of ventricular pauses compared with clopidogrel and whether these pauses were associated with any clinical bradycardic events in patients presenting with acute coronary syndromes., Background: Ticagrelor, an oral reversibly binding P2Y(12) inhibitor, provides more potent and consistent inhibition of platelet aggregation than clopidogrel but in a phase II study was associated with increased risk for ventricular pauses. A prospective continuous electrocardiographic (cECG) assessment was therefore performed within the PLATO (Platelet Inhibition and Patient Outcomes) study comparing ticagrelor and clopidogrel in patients hospitalized with acute coronary syndromes., Methods: Patients in the cECG assessment had planned 7-day cECG recording initiated at the time of randomization (week 1), which was within 24 h of symptom onset, and then repeated at 1 month after randomization during the convalescent phase. The principal safety endpoint was the incidence of ventricular pauses lasting at least 3 s. Investigators also reported symptomatic bradycardic adverse events during the entire study duration (median 277 days)., Results: A total of 2,908 patients were included in the cECG assessment, of whom 2,866 (98.5%) had week 1 recordings, 1,991 (68.4%) had 1-month recordings, and 1,949 (67.0%) had both. During the first week after randomization, ventricular pauses ≥3 s occurred more frequently in patients receiving ticagrelor than clopidogrel (84 [5.8%] vs. 51 [3.6%]; relative risk: 1.61; p = 0.006). At 1 month, pauses ≥3 s occurred overall less frequently and were similar between treatments (2.1% vs. 1.7%). Most were ventricular pauses, and the greatest excess associated with ticagrelor were asymptomatic, sinoatrial nodal in origin (66%), and nocturnal. There were no differences between ticagrelor and clopidogrel in the incidence of clinically reported bradycardic adverse events, including syncope, pacemaker placement, and cardiac arrest., Conclusions: In the PLATO cECG assessment, more patients treated with ticagrelor compared with clopidogrel had ventricular pauses, which were predominantly asymptomatic, sinoatrial nodal in origin, and nocturnal and occurred most frequently in the acute phase of acute coronary syndromes. There were no apparent clinical consequences related to the excess in ventricular pauses in patients assigned to ticagrelor. (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Left ventricular hypertrophy (LVH) is frequently associated with ST depression (STD) on the electrocardiogram (ECG), a so-called strain pattern. Although STD is a well-established adverse prognosticator in non-ST-elevation acute coronary syndrome (NSTE-ACS), the relative prognostic importance of LVH and associated STD has not been elucidated., Methods: A total of 7,761 patients with NSTE-ACS in the Global Registry of Acute Coronary Events (GRACE) and ACS-I registries had admission ECGs analyzed at a core laboratory. Left ventricular hypertrophy (determined by Sokolow-Lyon and/or Casale criteria) was observed in 296 (3.8%) patients. We examined the independent association between LVH (determined by the admission ECG) and outcomes in relation to STD., Results: Patients with LVH were older, had more comorbidities and STD, and presented with a higher Killip class. They were less likely to undergo cardiac catheterization (43.1% vs 51.2%, P = .006) and percutaneous coronary intervention (18.3% vs 24.6%, P = .014). Patients with LVH had higher unadjusted mortality at 6 months (10.5% vs 7.1%, P = .038), but similar rates of in-hospital mortality (4.1% vs 3.4%, P = .54) and reinfarction (7.1% vs 7.6%, P = .75). Patients with LVH were more likely to have heart failure in-hospital (21.8% vs 11.8%, P < .001). Among LVH patients, degree of quantitative STD did not predict higher short- or long-term mortality, but was associated with in-hospital heart failure. Multivariable analysis adjusting for other clinical prognosticators of the GRACE risk models revealed that LVH was not a significant independent predictor of in-hospital mortality (adjusted odds ratio = 0.75, 95% CI 0.40-1.41, P = .37) or 6-month mortality (adjusted odds ratio = 0.83, 95% CI 0.52-1.35, P = .44). In contrast, STD remained a strong independent predictor of adverse outcomes. There was no significant interaction between STD and LVH., Conclusions: Across the broad spectrum of NSTE-ACS, LVH is associated with adverse prognostic factors including STD. Electrocardiographic-determined LVH provides no significant additional prognostic utility beyond comprehensive risk assessment using the GRACE risk score. The adverse prognosis associated with LVH in NSTE-ACS may be attributable to other prognosticators such as STD., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Aims: The aim of the present study was to examine the impact of the transradial approach (TRA), in comparison to the transfemoral approach (TFA), on PCI-related bleeding and patient outcomes in acute coronary syndrome patients who underwent PCI in the OASIS-5 trial., Methods and Results: The primary outcome (death, myocardial infarction, refractory ischaemia) at nine days was similar in both groups (7.1% in 872 TRA and 7.7% in 7,013 TFA). Major bleeding was significantly lower in patients who underwent PCI with TRA by comparison to TFA (1.6% vs 3.5%, p<0.003, respectively). No difference between patients treated by fondaparinux or enoxaparin was noted for ischaemic events at nine days according to the access site. The rate of major bleeding at nine days was markedly reduced with fondaparinux when compared to enoxaparin for both access sites (from 4.8% to 2.3%, HR 0.48 [0.37-0.62], p< 0.0001 for TFA and from 2.4 to 0.9%, HR 0.36 [0.11- 1.16], p<0.08 for TRA)., Conclusions: TRA is associated with substantial decrease of PCI-related bleeding in current contemporary pharmacological environment in comparison to TFA. Even in the context of low access site complication rate provided by TRA, fondaparinux was effective in reducing major bleeding.

Background: Smoking induces CYP1A2, thereby enhancing clopidogrel conversion to its active metabolite. We sought to determine the association between clopidogrel use and clinical outcomes in smokers versus nonsmokers with a broad spectrum of acute coronary syndrome (ACS)., Methods: We examined the association between early clopidogrel use in-hospital and 6-month outcomes among 44,426 patients with ACS in relation to smoking status in the Global Registry of Acute Coronary Events. We tested for heterogeneity of clopidogrel effect among smokers versus nonsmokers in separate multivariable models that adjusted for (1) established prognosticators in the Global Registry of Acute Coronary Events risk score and (2) independent predictors of major bleeding., Results: Rates of in-hospital mortality, death/myocardial infarction, and major bleeding were 4.3%, 5.9%, and 2.5%, respectively. Current smokers (n = 12,149) were more likely to be younger men without documented vascular disease; had lower rates of hypertension, hyperlipidemia, and diabetes; and more frequently presented with ST elevation (all P < .0001). Early clopidogrel use (55%) was associated with a reduction in the composite endpoint of mortality and myocardial infarction both in-hospital and at 6 months among current smokers and nonsmokers. There was no interaction between current smoking and clopidogrel use for ischemic endpoints. Major bleeding associated with early clopidogrel use was actually lower among current smokers compared with nonsmokers., Conclusions: Despite prior observations of smoking-enhanced clopidogrel effects, early clopidogrel use among smokers presenting with ACS compared with nonsmokers was not independently associated with a greater reduction in cardiovascular events. In contrast with nonsmokers, clopidogrel use among smokers was not associated with excess bleeding, perhaps because of unmeasured confounders., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Aims: To determine whether changes in practice, over time, are associated with altered rates of major bleeding in acute coronary syndromes (ACS)., Methods and Results: Patients from the Global Registry of Acute Coronary Events were enrolled between 2000 and 2007. The main outcome measures were frequency of major bleeding, including haemorrhagic stroke, over time, after adjustment for patient characteristics, and impact of major bleeding on death and myocardial infarction. Of the 50 947 patients, 2.3% sustained a major bleed; almost half of these presented with ST-elevation ACS (44%, 513). Despite changes in antithrombotic therapy (increasing use of low molecular weight heparin, P < 0.0001), thienopyridines (P < 0.0001), and percutaneous coronary interventions (P < 0.0001), frequency of major bleeding for all ACS patients decreased (2.6 to 1.8%; P < 0.0001). Most decline was seen in ST-elevation ACS (2.9 to 2.1%, P = 0.02). The overall decline remained after adjustment for patient characteristics and treatments (P = 0.002, hazard ratio 0.94 per year, 95% confidence interval 0.91-0.98). Hospital characteristics were an independent predictor of bleeding (P < 0.0001). Patients who experienced major bleeding were at increased risk of death within 30 days from admission, even after adjustment for baseline variables., Conclusion: Despite increasing use of more intensive therapies, there was a decline in the rate of major bleeding associated with changes in clinical practice. However, individual hospital characteristics remain an important determinant of the frequency of major bleeding.

Background: There are limited contemporary data on the early use of clopidogrel or glycoprotein (Gp) IIb/IIIa inhibitors, alone versus combination therapies, in non-ST-elevation acute coronary syndrome (NSTE-ACS)., Methods: This study included 5,806 Canadian NSTE-ACS patients with elevated cardiac biomarker and/or ST deviation on presentation in the prospective GRACE between 2003-2007. We stratified the study population according to the management strategy (non-invasive vs invasive) and into low-(GRACE risk score or=141)., Results: Overall, 3,893 patients (67.1%) received early (

Background: Clinical trials of antithrombotic agents for the treatment of ACS routinely assess bleeding as a safety endpoint, but variation in bleeding definitions makes comparison of the relative safety of these agents difficult., Methods: The ABC Multidisciplinary Working Group, an informal working group comprising clinical researchers and representatives from the US Food and Drug Administration, the National Institutes of Health, and the pharmaceutical industry, sought to develop a consensus approach to measuring the incidence and severity of bleeding complications during clinical trials of acute coronary syndromes (ACS). A meeting of the ABC was convened in April 2008 in Washington, DC, with the goal of developing a consensus approach to measuring the incidence and severity of hemorrhagic complications during clinical trials of ACS. Relevant literature on bleeding was reviewed through a series of short lectures and intensive group discussion., Results: Using existing evidence on bleeding and outcomes as well as clinical judgment, criteria for the assessment of bleeding were developed through expert consensus. This consensus statement divides bleeding-related data elements into three categories: essential, recommended, and optional., Conclusions: The ABC Group recommendations for collection and reporting of bleeding complications provide a framework for consistency in the collection of information on hemorrhagic complications in trials of ACS. Widespread adoption of the statement recommendations will facilitate understanding of the mechanisms of adverse outcomes after bleeding and comparisons of the relative safety of antithrombotic agents, as well as the interpretation of safety results from future studies.

Aims: In acute coronary syndromes (ACS), the optimal revascularization strategy for unprotected left main coronary disease (ULMCD) has been little studied. The objectives of the present study were to describe the practice of ULMCD revascularization in ACS patients and its evolution over an 8-year period, analyse the prognosis of this population and determine the effect of revascularization on outcome., Methods and Results: Of 43 018 patients enrolled in the Global Registry of Acute Coronary Events (GRACE) between 2000 and 2007, 1799 had significant ULMCD and underwent percutaneous coronary intervention (PCI) alone (n = 514), coronary artery bypass graft (CABG) alone (n = 612), or no revascularization (n = 673). Mortality was 7.7% in hospital and 14% at 6 months. Over the 8-year study, the GRACE risk score remained constant, but there was a steady shift to more PCI than CABG over time. Patients undergoing PCI presented more frequently with ST-segment elevation myocardial infarction (STEMI), after cardiac arrest, or in cardiogenic shock; 48% of PCI patients underwent revascularization on the day of admission vs. 5.1% in the CABG group. After adjustment, revascularization was associated with an early hazard of hospital death vs. no revascularization, significant for PCI (hazard ratio (HR) 2.60, 95% confidence interval (CI) 1.62-4.18) but not for CABG (1.26, 0.72-2.22). From discharge to 6 months, both PCI (HR 0.45, 95% CI 0.23-0.85) and CABG (0.11, 0.04-0.28) were significantly associated with improved survival in comparison with an initial strategy of no revascularization. Coronary artery bypass graft revascularization was associated with a five-fold increase in stroke compared with the other two groups., Conclusion: Unprotected left main coronary disease in ACS is associated with high mortality, especially in patients with STEMI and/or haemodynamic or arrhythmic instability. Percutaneous coronary intervention is now the most common revascularization strategy and preferred in higher risk patients. Coronary artery bypass graft is often delayed and performed in lower risk patients, leading to good 6-month survival. The two approaches therefore appear complementary.

Duration of delay in seeking medical care in persons with symptoms of evolving acute myocardial infarction (AMI) is of current interest given the time-dependent benefits associated with early use of coronary reperfusion approaches. The objectives of this multinational study were to describe geographic variation in the extent of and factors associated with prehospital delay in patients enrolled in the GRACE study. Data were collected from 44,695 patients hospitalized with an acute coronary syndrome in 14 countries from 2000 to 2006. The regions under study included Argentina and Brazil (n = 8,203), United States/Canada (n = 12,810), Europe (n = 19,354), and Australia/New Zealand (n = 4,328). Patients with ST-segment elevation AMI, non-ST-segment elevation AMI, and unstable angina comprised the study population. There were marked geographic differences in extent of prehospital delay in patients with ST-segment elevation AMI and those with non-ST-segment elevation AMI/unstable angina. In patients with ST-segment elevation AMI, the shortest duration of prehospital delay was observed in patients from Australia/New Zealand (median 2.2 hours), whereas patients from Argentina and Brazil delayed the longest (median 4.0 hours). Median duration of prehospital delay was shortest (2.5 hours) in patients with ST-segment elevation AMI, whereas patients with non-ST-segment elevation AMI/unstable angina showed considerably longer prehospital delay (3.1 hours). Several demographic and clinical characteristics were associated with prolonged delay overall and in the different geographic locations under study. In conclusion, results of this large multinational registry provided insights into contemporary patterns of care-seeking behavior in patients with acute coronary disease.

The incidence of thrombocytopenia after hospital admission, patient and treatment characteristics, and outcomes in patients enrolled in the prospective multinational GRACE were examined. Heparin (unfractionated or low molecular weight) and glycoprotein IIb/IIIa-inhibition can be associated with immune-mediated thrombocytopenia of clinical importance. The prevalence of thrombocytopenia in patients with acute coronary syndromes (ACSs) in general and specifically related to these therapies and associated outcomes have been studied little outside of clinical trials. Patients with an ACS were stratified into 4 groups of those with heparin-induced thrombocytopenia (HIT), those with glycoprotein IIb/IIIa-associated thrombocytopenia (GAT), those with other thrombocytopenia (not diagnosed as HIT or associated with glycoprotein inhibitors), and those with no thrombocytopenia. From June 2000 to September 2007, a total of 52,647 patients with an ACS and information for platelet count were enrolled in GRACE. Of these, 152 (0.3%) were reported to develop HIT, 324 (0.6%) developed GAT, and 368 (0.7%) developed other thrombocytopenia. Patients with HIT, GAT, or other thrombocytopenia were significantly more likely to die in the hospital versus those without these diseases (adjusted odds ratio [OR] 1.94, 95% confidence interval [CI] 1.07 to 3.53; adjusted OR 3.45, 95% CI 2.35 to 5.05; and adjusted OR 2.83, 95% CI 1.97 to 4.06, respectively). They were also more likely to experience major bleeding, (re)infarction, or stroke. In conclusion, in this large multinational registry, 1.6% of patients with ACS were reported to develop thrombocytopenia, with only 0.3% being HIT. Regardless of whether patients had clinically recognized HIT, GAT, or other thrombocytopenia, all 3 groups had significantly higher rates of major bleeding, recurrent infarction, stroke, and death.

This aim of this study was to assess the clinical utility of quantitative ST-segment depression (STD) for refining the risk stratification of non-ST elevation acute coronary syndromes in the prospective, multinational Global Registry of Acute Coronary Events (GRACE). Quantitative measurements of STD on admission electrocardiograms were evaluated independently by a core laboratory, and their predictive value for in-hospital and cumulative 6-month mortality was examined. Although more severe STD is a marker of increased short- and long-term mortality, it is also associated with higher risk clinical features and biomarkers. Thus, after adjustment for these clinically important predictors, quantitative STD does not provide incremental prognostic value beyond simple dichotomous evaluation for the presence of STD. Furthermore, adopting quantitative instead of the prognostically proven qualitative evaluation of STD does not improve risk discrimination afforded by the validated GRACE risk models. In conclusion, the findings do not support the quantification of STD in routine clinical practice beyond simple evaluation for the presence of STD as an integral part of comprehensive risk stratification using the GRACE risk score.

AimsLipoprotein(a) concentration is associated with first cardiovascular events in clinical trials. It is unknown if this relationship holds for total (first and subsequent) events. In the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab reduced lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), and cardiovascular events compared with placebo. This post hoc analysis determined whether baseline levels and alirocumab-induced changes in lipoprotein(a) and LDL-C [corrected for lipoprotein(a) cholesterol] independently predicted total cardiovascular events.Methods and resultsCardiovascular events included cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina or heart failure, ischaemia-driven coronary revascularization, peripheral artery disease events, and venous thromboembolism. Proportional hazards models estimated relationships between baseline lipoprotein(a) and total cardiovascular events in the placebo group, effects of alirocumab treatment on total cardiovascular events by baseline lipoprotein(a), and relationships between lipoprotein(a) reduction with alirocumab and subsequent risk of total cardiovascular events. Baseline lipoprotein(a) predicted total cardiovascular events with placebo, while higher baseline lipoprotein(a) levels were associated with greater reduction in total cardiovascular events with alirocumab (hazard ratio Ptrend = 0.045). Alirocumab-induced reductions in lipoprotein(a) (median -5.0 [-13.6, 0] mg/dL) and corrected LDL-C (median -51.3 [-67.1, -34.0] mg/dL) independently predicted lower risk of total cardiovascular events. Each 5-mg/dL reduction in lipoprotein(a) predicted a 2.5% relative reduction in cardiovascular events.ConclusionBaseline lipoprotein(a) predicted the risk of total cardiovascular events and risk reduction by alirocumab. Lipoprotein(a) lowering contributed independently to cardiovascular event reduction, supporting the concept of lipoprotein(a) as a treatment target after ACS.