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Importance: The optimal duration of dual antiplatelet therapy (DAPT) in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) remains under debate., Objectives: To analyze the efficacy and safety of DAPT strategies in patients with ACS using a bayesian network meta-analysis., Data Sources: MEDLINE, Embase, Cochrane, and LILACS databases were searched from inception to April 8, 2024., Study Selection: Randomized clinical trials (RCTs) comparing DAPT duration strategies in patients with ACS undergoing PCI were selected. Short-term strategies (1 month of DAPT followed by P2Y12 inhibitors, 3 months of DAPT followed by P2Y12 inhibitors, 3 months of DAPT followed by aspirin, and 6 months of DAPT followed by aspirin) were compared with conventional 12 months of DAPT., Data Extraction and Synthesis: This systematic review and network meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The risk ratio (RR) with a 95% credible interval (CrI) was calculated within a bayesian random-effects network meta-analysis. Treatments were ranked using surface under the cumulative ranking (SUCRA)., Main Outcomes and Measures: The primary efficacy end point was major adverse cardiac and cerebrovascular events (MACCE); the primary safety end point was major bleeding., Results: A total of 15 RCTs randomizing 35 326 patients (mean [SD] age, 63.1 [11.1] years; 26 954 male [76.3%]; 11 339 STEMI [32.1%]) with ACS were included. A total of 24 797 patients (70.2%) received potent P2Y12 inhibitors (ticagrelor or prasugrel). Compared with 12 months of DAPT, 1 month of DAPT followed by P2Y12 inhibitors reduced major bleeding (RR, 0.47; 95% CrI, 0.26-0.74) with no difference in MACCE (RR, 1.00; 95% CrI, 0.70-1.41). No significant differences were observed in MACCE incidence between strategies, although CrIs were wide. SUCRA ranked 1 month of DAPT followed by P2Y12 inhibitors as the best for reducing major bleeding and 3 months of DAPT followed by P2Y12 inhibitors as optimal for reducing MACCE (RR, 0.85; 95% CrI, 0.56-1.21)., Conclusion and Relevance: Results of this systematic review and network meta-analysis reveal that, in patients with ACS undergoing PCI with DES, 1 month of DAPT followed by potent P2Y12 inhibitor monotherapy was associated with a reduction in major bleeding without increasing MACCE when compared with 12 months of DAPT. However, an increased risk of MACCE cannot be excluded, and 3 months of DAPT followed by potent P2Y12 inhibitor monotherapy was ranked as the best option to reduce MACCE. Because most patients receiving P2Y12 inhibitor monotherapy were taking ticagrelor, the safety of stopping aspirin in those taking clopidogrel remains unclear.

Objective: We aimed to evaluate the safety and efficacy of antithrombotic strategies by age in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention in AUGUSTUS., Methods: Patients were stratified into 3 age groups: <65, 65-74, and ≥75 years. Outcomes of interest were major or clinically relevant non-major bleeding, major bleeding, death or rehospitalization, and ischemic events. Treatment effects of apixaban vs. vitamin K antagonist (VKA) and aspirin vs. placebo were assessed across age groups using Cox models., Results: Of 4614 patients, 1267 (27.5%) were <65, 1802 (39.0%) were 65-74, and 1545 (33.5%) were ≥75 years. Apixaban was associated with lower rates of major or clinically relevant non-major bleeding than VKA (<65: HR 0.69 [0.47-1.00]; 65-74: HR 0.57 [0.43-0.75]; ≥75: HR 0.81 [0.63-1.04]). Death or hospitalization occurred less often with apixaban, regardless of age. No differences were observed in rates of ischemic events between apixaban and VKA according to age. Aspirin was associated with higher rates of bleeding than placebo (<65: HR 1.67 [1.15-2.43]; 65-74: HR 2.32 [1.73-3.10]; ≥75: HR 1.69 [1.31-2.19]). Rates of death or rehospitalization and ischemic events were similar among patients receiving aspirin or placebo across age groups., Conclusions: Apixaban was associated with greater absolute reduction in bleeding than VKA in older age groups, reflecting their higher hemorrhagic risk. Aspirin increased bleeding in all age groups vs. placebo. Our findings support the use of apixaban plus a purinergic receptor P2Y 12 (P2Y 12 ) inhibitor without aspirin in patients with atrial fibrillation and recent acute coronary syndrome/percutaneous coronary intervention, regardless of age., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The optimal antithrombotic regimen for patients with atrial fibrillation (AF) who had an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is not known., Objectives: The authors sought to determine which antithrombotic regimen best balances safety and efficacy., Methods: AUGUSTUS, a multicenter 2 × 2 factorial design randomized trial compared apixaban with vitamin K antagonist (VKA) and aspirin with placebo in patients with AF with recent ACS and/or PCI treated with a P2Y 12 inhibitor. We conducted a 4-way analysis comparing safety and efficacy outcomes in the 4 randomized groups. The primary outcome was a composite of all-cause death, major or clinically relevant nonmajor bleeding, or hospitalization for cardiovascular causes over 6-month follow-up. Secondary outcomes included individual components of the primary endpoint., Results: A total of 4,614 patients were enrolled. All patients were treated with a P2Y 12 inhibitor. The primary endpoint occurred in 21.9% of patients randomized to apixaban plus placebo, 27.3% randomized to apixaban plus aspirin, 28.0% randomized to VKA plus placebo, and 33.3% randomized to VKA plus aspirin. Rates of major or clinically relevant nonmajor bleeding and hospitalization for cardiovascular causes were lower with apixaban and placebo compared with the other 3 antithrombotic strategies. There was no difference between the 4 randomized groups with respect to all-cause death., Conclusions: In patients with AF and a recent ACS and/or PCI, an antithrombotic regimen that included a P2Y 12 inhibitor and apixaban without aspirin resulted in a lower incidence of the composite of death, bleeding, or cardiovascular hospitalization than regimens including VKA, aspirin, or both. (An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention; NCT02415400)., Competing Interests: Funding Support and Author Disclosures The AUGUSTUS study and this analysis were funded by Bristol Myers Squibb and Pfizer. Dr Berwanger has received research grants from AstraZeneca, Pfizer, Bayer, Amgen, Novartis, Servier, and Boehringer Ingelheim. Dr Fanaroff has received research grants from the American Heart Association and National Institutes of Health; and has received consulting fees from Abbott Laboratories. Dr Granger has received research grants from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Armetheon, AstraZeneca, U.S. Food and Drug Administration, GlaxoSmithKline, The Medicines Company, Medtronic Foundation, Medtronic Inc, and Novartis; and has received consulting fees from Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Abbvie, Armetheon, AstraZeneca, Eli Lilly, Gilead, GlaxoSmithKline, Hoffmann-La Roche, The Medicines Company, National Institutes of Health, Novartis, Sirtex, Verseon, Apple, Medscape, LLC, Merck, Novo Nordisk, Roche Diagnostics, and Rho Pharmaceuticals. Dr Mehran has received institutional research grants from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol Myers Squibb/Sanofi, CSL Behring, Eli Lilly/Daiichi-Sankyo, Medtronic, Novartis, and OrbusNeich; has received consulting fees from Boston Scientific, Abbott Vascular, Medscape, Siemens Medical Solutions, Roivant Sciences Inc, and Sanofi; has consulted (no fees) for Regeneron Pharmaceuticals Inc; has received institutional consulting fees from Abbott Vascular, Spectranetics/Phillips/Volcano Corporation, Bristol Myers Squibb, Novartis, and Watermark Research; is an executive committee member for Janssen Pharmaceuticals and Bristol Myers Squibb; and has <1% equity in Claret Medical and Elixir Medical. Dr Aronson is an employee of Bristol Myers Squibb. Dr Windecker has received institutional research and educational grants from Abbott, Amgen, Bayer, Bristol Myers Squibb, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, and Sinomed. Dr Goodman has received research grant support and/or speaker/consulting honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, Eli Lilly, Esperion, Fenix Group International, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, Janssen/Johnson and Johnson, Luitpold Pharmaceuticals, Matrizyme, Merck, Novartis, Novo Nordisk A/C, Pfizer, Regeneron, Sanofi, Servier, Tenax Therapeutics, Heart and Stroke Foundation of Ontario/University of Toronto, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Duke Clinical Research Institute, and PERFUSE. Dr Alexander has received research grants from Bristol Myers Squibb, Boehringer Ingelheim, AstraZeneca, CryoLife, CSL Behring, U.S. Food and Drug Administration, National Institutes of Health, Sanofi, and VoluMetrix; and has received consulting fees from Pfizer, Bristol Myers Squibb, AbbVie Pharmaceuticals, CSL Behring, Novo Nordisk, Portola Pharmaceuticals, Quantum Genomics, Teikoku Pharmaceuticals, VA Cooperative Studies, and Zafgen. Dr Lopes has received research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; has received funding for educational activities or lectures from Pfizer, Daiichi-Sankyo, and Novo Nordisk; and has received funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

For almost two decades, 12-month dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) has been the only class I recommendation on DAPT in American and European guidelines, which has resulted in 12-month durations of DAPT therapy being the most frequently implemented in ACS patients undergoing percutaneous coronary intervention (PCI) across the globe. Twelve-month DAPT was initially grounded in the results of the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, which, by design, studied DAPT versus no DAPT rather than the optimal DAPT duration. The average DAPT duration in this study was 9 months, not 12 months. Subsequent ACS studies, which were not designed to assess DAPT duration, rather its composition (aspirin with prasugrel or ticagrelor compared with clopidogrel) were further interpreted as supportive evidence for 12-month DAPT duration. In these studies, the median DAPT duration was 9 or 15 months for ticagrelor and prasugrel, respectively. Several subsequent studies questioned the 12-month regimen and suggested that DAPT duration should either be fewer than 12 months in patients at high bleeding risk or more than 12 months in patients at high ischemic risk who can safely tolerate the treatment. Bleeding, rather than ischemic risk assessment, has emerged as a treatment modifier for maximizing the net clinical benefit of DAPT, due to excessive bleeding and no clear benefit of prolonged treatment regimens in high bleeding risk patients. Multiple DAPT de-escalation treatment strategies, including switching from prasugrel or ticagrelor to clopidogrel, reducing the dose of prasugrel or ticagrelor, and shortening DAPT duration while maintaining monotherapy with ticagrelor, have been consistently shown to reduce bleeding without increasing fatal or nonfatal cardiovascular or cerebral ischemic risks compared with 12-month DAPT. However, 12-month DAPT remains the only class-I DAPT recommendation for patients with ACS despite the lack of prospectively established evidence, leading to unnecessary and potentially harmful overtreatment in many patients. It is time for clinical practice and guideline recommendations to be updated to reflect the totality of the evidence regarding the optimal DAPT duration in ACS., Competing Interests: M.V. reports grants/personal fees from Abbott, Alvimedica/CID, AstraZeneca, Bayer, Biotronik, Bristol Myers Squibb/Jansen, Chiesi, CoreFLOW, Daiichi-Sankyo, Department Klinische Forschung of Universität Basel, Health Life, Idorsia Pharmaceuticals, Medscape, Miracor, Novartis, Radcliffe, Terumo, and Vesalio, outside the submitted work. D.J.A. reports consulting fees/honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Daiichi Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura, outside the present work; as well as disclosing that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Janssen, Matsutani Chemical Industry, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and Scott R. MacKenzie Foundation. U.B. reports honoraria/consulting fees from Amgen, AstraZeneca, Boston Scientific, and Abbott. D.L.B. discloses the following relationships: Advisory Board member for Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; Board of Directors positions for American Heart Association New York City, Angiowave (stock options), Bristol-Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); consulting for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; Data Monitoring Committee member for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial [PorticoTM Re-sheathable Transcatheter Aortic Valve System US IDE Trial], funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial [Pulmonary Embolism Thrombolysis]), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (ENVISAGE trial [Edoxaban Versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation–Atrial Fibrillation], funded by Daiichi Sankyo; ABILITY-DM trial [Abluminus DES+ Sirolimus-Eluting Stent vs. Everolimus-Eluting DES for Percutaneous Coronary Intervention in Patients With Diabetes Mellitus], funded by Concept Medical; ALLAY-HF [A pivotal Trial of the Alleviant System for No-Implant Shunt Creation in Heart Failure Patients], funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded MINT Trial [Myocardial Ischemia and Transfusion]); honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News; Chair, American College of Cardiology Accreditation Oversight Committee), Arnold and Porter law firm (related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research ([formerly Harvard Clinical Research Institute] RE-DUAL PCI clinical trial [Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention] steering committee funded by Boehringer Ingelheim; AEGIS-II [ApoA-I Event Reducing in Ischemic Syndromes 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), CSL Behring (American Heart Association lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including the PRONOUNCE trial [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease], 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 (Continuing Medical Education [CME] steering committees), MJH Life Sciences, Oakstone CME; Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] Operations Committee, Publications Committee, Steering Committee, and USA National Co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); Deputy Editor for Clinical Cardiology; is named on a patent for sotagliflozin (assigned to Brigham and Women’s Hospital who assigned to Lexicon); research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, 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, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties from Elsevier (Editor, Braunwald’s Heart Disease); site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; and trustee of American College of Cardiology. D.L.B. also reports unfunded research for FlowCo. M.P.B. is the Executive Director of CPC, a nonprofit academic research organization affiliated with the University of Colorado, which receives or has received research grant/consulting funding between August 2021 and present from: Abbott Laboratories, Agios Pharmaceuticals, Alexion Pharma, Alnylam Pharmaceuticals, Amgen, Angionetics, Anthos Therapeutics, ARCA Biopharma, Array BioPharma, AstraZeneca and Affiliates, Atentiv, Audentes Therapeutics, Bayer and Affiliates, Beth Israel Deaconess Medical Center, Better Therapeutics, Boston Clinical Research Institute, Bristol-Meyers Squibb Company, Cambrian Biopharma, Cardiol Therapeutics CellResearch, Cleerly, Cook Regentec, CSL Behring, Eidos Therapeutics, EP Trading, EPG Communication Holdings, Epizon Pharma, Esperion Therapeutics, Everly Well, Exicon Consulting, Faraday Pharmaceuticals, Foresee Pharmaceuticals, Fortress Biotech, HDL Therapeutics, HeartFlow, Hummingbird Bioscience, Insmed, Ionis Pharmaceuticals, IQVIA, Janssen and Affiliates, Kowa Research Institute, Kyushu University, Lexicon Pharmaceuticals, Medimmune, Medpace, Merck & Affiliates, Nectero Medical, Novartis Pharmaceuticals, Novo Nordisk, Osiris Therapeutics, Pfizer, PhaseBio Pharmaceuticals, Pharmaceutical Product Development LP, Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc, Regio Biosciences, Saint Luke’s Hospital of Kansas City, Sanifit Therapeutics S.A., Sanofi-Aventis Groupe, Silence Therapeutics, Smith & Nephew, Stanford Center for Clinical Research, Stealth BioTherapeutics, State of Colorado Cancer, Cardiovascular. and Pulmonary Disease Grant, Brigham & Women’s Hospital, Feinstein Institutes for Medical Research, Thrombosis Research Institute, University of Colorado, University of Pittsburgh, VarmX, Virta Health Corporation, Worldwide Clinical Trials, WraSer, and Yale Cardiovascular Research Group. D.C. reports consulting and speaking fees from Abbott Vascular, Medtronic, Novo Nordisk, Sanofi Aventis, and Terumo, outside the present work. D.J.C. reports institutional research grant support from Edwards Lifesciences, Abbott, Boston Scientific, Philips, CathWorks, Corvia, Zoll Medical, and I-Rhythm; and consulting income from Edwards Lifesciences, Abbott, Medtronic, Elixir Medical, and HeartBeam. C.M.G. reports research grant support from Johnson & Johnson, Bristol Myers Squibb, and Daiichi Sankyo. S.J. reports institutional grants from AstraZeneca, Jansen, Amgen, Novartis, Novo Nordisk outside the submitted work. R.D.L. reports research grants/contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis (outside the submitted work); funding for educational activities or lectures from Pfizer, Daiichi Sankyo, and Novo Nordisk; and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novo Nordisk. G.M. reports institutional research funds or fees from Abbott, Amgen, AstraZeneca, Ascendia, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, Celecor, CSL Behring, Idorsia, Lilly, Novartis, Novo, Opalia, Pfizer, Quantum Genomics, Sanofi, and Terumo, outside the submitted work. G.W.S. has received speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, Amgen, Boehringer Ingelheim; has served as a consultant to Abbott, Daiichi Sankyo, Ablative Solutions, CorFlow, Cardiomech, Robocath, Miracor, Vectorious, Apollo Therapeutics, Elucid Bio, Valfix, TherOx, HeartFlow, Neovasc, Ancora, Occlutech, Impulse Dynamics, Adona Medical, Millennia Biopharma, Oxitope, Cardiac Success, HighLife, Elixir, Remote Cardiac Enablement, and Aria; and has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. G.W.S.’s employer, Mount Sinai Hospital, receives research grants from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense-Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave. D.S. has received speaker fees and fees for advisory board activities from Bayer, Sanofi, and Daiichi-Sankyo. R.F.S. reports institutional research grants/support from AstraZeneca and Cytosorbents; personal fees from Alfasigma, AstraZeneca, Chiesi, Cytosorbents, Daiichi-Sankyo, Idorsia, Novartis, Novo Nordisk, Pfizer, PhaseBio, and Tabuk; all outside the submitted work. P.V. reports personal fees from Bayer, Daiichi-Sankyo, and CLS Behring, outside the submitted work. S.W. reports research and educational grants to their institution from Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi-Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave. S.W. serves as unpaid Advisory Board Member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Boston Scientific, Biotronik, Bristol-Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave, and Xeltis, but has not received personal payments by pharmaceutical companies or device manufacturers. He is also member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. R.M. reports institutional research grants from Abbott, Abiomed, Applied Therapeutics, Arena, AstraZeneca, Bayer, Biosensors, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CellAegis, Cardiovascular European Research Center, Chiesi, Concept Medical, CSL Behring, Daiichi Sankyo, Insel Gruppe AG, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Philips, Transverse Medical, and Zoll; personal fees from American College of Cardiology, Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen, WebMD, and Society for Cardiovascular Angiography and Interventions; consulting fees paid to the institution from Abbott, Abiomed, AM-Pharma, Alleviant Medical, Bayer, Beth Israel Deaconess, CardiaWave, CeloNova, Chiesi, Concept Medical, Daiichi-Sankyo, Duke University, Idorsia Pharmaceuticals, Medtronic, Novartis, and Philips; equity, 1% in Applied Therapeutics, Elixir Medical, Stel, and Controlrad (spouse); Scientific Advisory Board for American Medical Association and Biosensors (spouse), all outside the submitted work. The other authors report no conflicts.

Importance: Clinical outcomes after acute coronary syndromes (ACS) or percutaneous coronary interventions (PCIs) in people living with HIV have not been characterized in sufficient detail, and extant data have not been synthesized adequately., Objective: To better characterize clinical outcomes and postdischarge treatment of patients living with HIV after ACS or PCIs compared with patients in an HIV-negative control group., Data Sources: Ovid MEDLINE, Embase, and Web of Science were searched for all available longitudinal studies of patients living with HIV after ACS or PCIs from inception until August 2023., Study Selection: Included studies met the following criteria: patients living with HIV and HIV-negative comparator group included, patients presenting with ACS or undergoing PCI included, and longitudinal follow-up data collected after the initial event., Data Extraction and Synthesis: Data extraction was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Clinical outcome data were pooled using a random-effects model meta-analysis., Main Outcome and Measures: The following clinical outcomes were studied: all-cause mortality, major adverse cardiovascular events, cardiovascular death, recurrent ACS, stroke, new heart failure, total lesion revascularization, and total vessel revascularization. The maximally adjusted relative risk (RR) of clinical outcomes on follow-up comparing patients living with HIV with patients in control groups was taken as the main outcome measure., Results: A total of 15 studies including 9499 patients living with HIV (pooled proportion [range], 76.4% [64.3%-100%] male; pooled mean [range] age, 56.2 [47.0-63.0] years) and 1 531 117 patients without HIV in a control group (pooled proportion [range], 61.7% [59.7%-100%] male; pooled mean [range] age, 67.7 [42.0-69.4] years) were included; both populations were predominantly male, but patients living with HIV were younger by approximately 11 years. Patients living with HIV were also significantly more likely to be current smokers (pooled proportion [range], 59.1% [24.0%-75.0%] smokers vs 42.8% [26.0%-64.1%] smokers) and engage in illicit drug use (pooled proportion [range], 31.2% [2.0%-33.7%] drug use vs 6.8% [0%-11.5%] drug use) and had higher triglyceride (pooled mean [range], 233 [167-268] vs 171 [148-220] mg/dL) and lower high-density lipoprotein-cholesterol (pooled mean [range], 40 [26-43] vs 46 [29-46] mg/dL) levels. Populations with and without HIV were followed up for a pooled mean (range) of 16.2 (3.0-60.8) months and 11.9 (3.0-60.8) months, respectively. On postdischarge follow-up, patients living with HIV had lower prevalence of statin (pooled proportion [range], 53.3% [45.8%-96.1%] vs 59.9% [58.4%-99.0%]) and β-blocker (pooled proportion [range], 54.0% [51.3%-90.0%] vs 60.6% [59.6%-93.6%]) prescriptions compared with those in the control group, but these differences were not statistically significant. There was a significantly increased risk among patients living with HIV vs those without HIV for all-cause mortality (RR, 1.64; 95% CI, 1.32-2.04), major adverse cardiovascular events (RR, 1.11; 95% CI, 1.01-1.22), recurrent ACS (RR, 1.83; 95% CI, 1.12-2.97), and admissions for new heart failure (RR, 3.39; 95% CI, 1.73-6.62)., Conclusions and Relevance: These findings suggest the need for attention toward secondary prevention strategies to address poor outcomes of cardiovascular disease among patients living with HIV.

Background: Heart failure (HF) may complicate acute coronary syndrome (ACS) and is associated with a high burden of short- and long-term morbidity and mortality. Only limited data regarding future ischemic events and rehospitalization are available for patients who suffer HF before or during ACS., Methods: A secondary analysis of 4 large ACS trials (PLATO, APPRAISE-2, TRACER, and TRILOGY ACS) using Cox proportional hazards models was performed to investigate the association of HF status (no HF, chronic HF, de novo HF) at presentation for ACS with all-cause and cardiovascular death, major adverse cardiovascular event (MACE ), myocardial infarction, stroke, and hospitalization for heart failure (HHF) by 1 year. Cumulative incidence plots are presented at 30 days and 1 year., Results: A total of 11.1% of the 47,474 patients presenting with ACS presented with evidence of acute HF, 55.0% of whom presented with de novo HF. Patients with chronic HF presented with evidence of acute HF at a higher rate than those with no previous HF (40.3% vs 6.9%). Compared to those without HF, those with chronic and de novo HF had higher rates of all-cause mortality (adjusted hazard ratio [aHR] 2.01, 95% confidence interval [CI] 1.72-2.34 and aHR 1.47, 95% CI1.15-1.88, respectively), MACE (aHR 1.47, 95% CI1.31-1-.66 and aHR 1.38, 95% CI1.12-1.69), and HHF (aHR 2.29, 95% CI2.02-2.61 and aHR 1.48, 95% CI 1.20-1.82) at 1 year., Conclusion: In this large cohort of patients with ACS, both prior and de novo HF complicating ACS were associated with significantly higher risk-adjusted rates of death, ischemic events and HHF at 30 days and 1 year. Further studies examining the association between HF and outcomes in this high-risk population are warranted, especially given the advent of more contemporary HF therapies., Competing Interests: Disclosures JAU reports speaker/consulting honoraria from Amgen, Boehringer Ingelheim, Janssen, Merck, Novartis, and Sanofi; grant support to his institutions: AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Novartis, Sanofi; and is supported by an Ontario Ministry of Colleges and Universities Early Researcher Award (ER15-11-037); University of Toronto Department of Medicine Merit Award; Women's College Research Institute and Department of Medicine, Women's College Hospital; and the Peter Munk Cardiac Centre, Toronto General Hospital. JB is a consultant to Abbott, Adrenomed, American Regent, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Medtronic, Merck, Novartis, Novo Nordisk, Roche, and Vifor. JLJ is a trustee of the American College of Cardiology and a Board member of Imbria Pharmaceuticals, has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics and consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda, and is supported in part by the Hutter Family Professorship. PBP has served on the Advisory Board for AstraZeneca Pharmaceuticals and as a consultant for Medtronic. SJ reports research grants from Uppsala Clinical Research Center, Astra Zeneca, Novartis, and Jansen Pharmaceuticals. JHA reports research grants through Duke University from Bayer, Bristol-Myers Squibb, CryoLife, CSL Behring, Ferring, the US Food and Drug Administration, Glaxosmithkline, Humacyte, the US National Institutes of Health, and XaTek and consultant/honoraria payments from AbbVie, Akros, Atricure, Bristol-Myers Squibb, CryoLife, Ferring, Glaxosmithkline, Janssen, Pfizer, Portola, and the US Veterans Administration. AFH reports research grants from American Regent, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, and Verily and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, and Novartis. WSJ reports research grants from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Doris Duke Charitable Foundation, National Institutes of Health, and Patient-Centered Outcomes Research Institute and honoraria/other from Bayer, Bristol-Myers Squibb and Janssen Pharmaceuticals. All other authors report no disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Dual antiplatelet therapy (DAPT) is currently the standard of care after percutaneous coronary intervention (PCI). Recent studies suggest that reducing DAPT to 1-3 months followed by an aspirin-free single antiplatelet therapy (SAPT) strategy with a potent P2Y 12 inhibitor is safe and associated with less bleeding. However, to date, no randomised trial has tested the impact of initiating SAPT immediately after PCI, particularly in patients with acute coronary syndromes (ACS). NEOMINDSET is a multicentre, randomised, open-label trial with a blinded outcome assessment designed to compare SAPT versus DAPT in 3,400 ACS patients undergoing PCI with the latest-generation drug-eluting stents (DES). After successful PCI and up to 4 days following hospital admission, patients are randomised to receive SAPT with a potent P2Y 12 inhibitor (ticagrelor or prasugrel) or DAPT (aspirin plus a potent P2Y 12 inhibitor) for 12 months. Aspirin is discontinued immediately after randomisation in the SAPT group. The choice between ticagrelor and prasugrel is at the investigator's discretion. The primary hypothesis is that SAPT will be non-inferior to DAPT with respect to the composite endpoint of all-cause mortality, stroke, myocardial infarction or urgent target vessel revascularisation, but superior to DAPT on rates of bleeding defined by Bleeding Academic Research Consortium 2, 3 or 5 criteria. NEOMINDSET is the first study that is specifically designed to test SAPT versus DAPT immediately following PCI with DES in ACS patients. This trial will provide important insights on the efficacy and safety of withdrawing aspirin in the early phase of ACS. (ClinicalTrials.gov: NCT04360720).

Background: Few data exist regarding the implementation of high-sensitivity cardiac troponin (hs-cTn) assays in the United States since their approval., Objectives: This study sought to explore trends in hs-cTn assay implementation over time and assess the association of their use with in-hospital cardiac testing and outcomes., Methods: The study examined trends in implementation of hs-cTn assays among participating hospitals in the National Cardiovascular Data Registry Chest Pain-MI [Myocardial Infarction] Registry from January 1, 2019 through September 30, 2021. Associations among hs-cTn use, use of in-hospital diagnostic imaging, and patient outcomes were assessed using generalized estimating equation models with logistic or gamma distributions., Results: Among 550 participating hospitals (N = 251,000), implementation of hs-cTn assays increased from 3.3% in the first quarter of 2019 to 32.6% in the third quarter of 2021 (P trend  < 0.001). Use of hs-cTn was associated with more echocardiography among persons with non-ST-segment elevation acute coronary syndrome (NSTE-ACS; 82.4% vs 75.0%; adjusted odds ratio: 1.43; 95% CI: 1.19-1.73) but not among low-risk chest pain individuals. Use of hs-cTn was associated with less invasive coronary angiography among low-risk patients (3.7% vs 4.5%; adjusted odds ratio: 0.73; 95% CI: 0.58-0.92) but similar use for patients with NSTE-ACS. There was no association between hs-cTn use and noninvasive stress testing or coronary computed tomography angiography testing. Among individuals with NSTE-ACS, hs-cTn use was not associated with revascularization or in-hospital mortality. Use of hs-cTn was associated with a shorter length of stay (median 47.6 hours vs 48.0 hours; ratio: 0.94; 95% CI: 0.90-0.98)., Conclusions: Implementation of hs-cTn among U.S. hospitals is increasing, but most U.S. hospitals continue to use less sensitive assays. The use of hs-cTn was associated with modestly shorter length of stay, greater use of echocardiography for NSTE-ACS, and less use of invasive angiography among low-risk patients., Competing Interests: Funding Support and Author Disclosures This research was supported by the American College of Cardiology’s National Cardiovascular Data Registry (NCDR). The views expressed in this manuscript represent those of the author(s) and do not necessarily represent the official views of the NCDR or its associated professional societies identified at CVQuality.ACC.org/NCDR. Dr McCarthy has received support from the National Heart, Lung, and Blood Institute (NHLBI) T32 postdoctoral training grant (5T32HL094301-12); and has received consulting income from Abbott Laboratories. Dr Wang has received research grants to the Duke Clinical Research Institute from Abbott, AstraZeneca, Bristol Myers Squibb, Boston Scientific, Cryolife, Chiesi, Merck, Portola, and Regeneron; and has received consulting honoraria from AstraZeneca, Bristol Myers Squibb, Cryolife, and Novartis. Dr Sandoval has served on advisory boards for Roche Diagnostics and Abbott Diagnostics without personal financial compensation; and has also been a speaker without personal financial compensation for Abbott Diagnostics. Dr Smilowitz has received partial support from a Career Development Award from NHLBI (K23HL150315); and has received consulting honoraria from Abbott Vascular. Dr Wasfy has received support from the American Heart Association (18 CDA 34110215). Dr de Lemos has received grant support from Abbott Diagnostics and Roche Diagnostics; and has received consulting income from Ortho Clinical Diagnostics, Quidel, Beckman Coulter, and Siemens’s Health Care Diagnostics. Dr Kontos has served as chair of the Chest Pain-MI Steering committee. Dr Apple has served as an Associate Editor of Clinical Chemistry; has participated in the advisory boards of Werfen, Siemens Healthineers, and Qorvo Biotechnology; has received consulting income from AWE Medical and Hytest; and has received cardiac biomarker grant support (nonsalaried) through his institutional research institute from Abbott Diagnostics, Abbott POC, Siemens Healthcare, Ortho-Clinical Diagnostics, Roche Diagnostics, Beckman Coulter, BD, and Quidel. Dr Daniels has received consulting income from Quidel, Roche, and Siemens; and has participated in clinical endpoint committees or data safety monitoring boards for Abbott, Applied Therapeutics, and Quidel. Dr Newby has received research grant support from Roche Diagnostics and BioKier; and has received consulting honoraria from Beckman-Coulter, CSL, and Medtronic. Dr Jaffe has served as a consultant for Abbott, Beckman-Coulter, Siemens, Roche, Ortho Diagnostics, Radiometer, ET Healthcare, Sphingotec, Astellas, RCE Technologies, Amgen, and Novartis. Dr Januzzi has served as a Trustee of the American College of Cardiology; has received grant support from Abbott, Applied Therapeutics, HeartFlow Inc, Innolife, and Roche Diagnostics; has received consulting income from Abbott, Janssen, Novartis, Merck, and Roche Diagnostics; and has participated in clinical endpoint committees or data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Pfizer, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Levels of growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, have been associated with multiple types of cardiovascular (CV) events. However, its comparative prognostic performance across different presentations of atherosclerotic cardiovascular disease (ASCVD) remains unknown., Methods and Results: An individual patient meta-analysis was performed using data pooled from eight trials including 53 486 patients. Baseline GDF-15 concentration was analyzed as a continuous variable and using established cutpoints (<1200 ng/L, 1200-1800 ng/L, > 1800 ng/L) to evaluate its prognostic performance for CV death/hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE), and their components using Cox models adjusted for clinical variables and established CV biomarkers. Analyses were further stratified on ASCVD status: acute coronary syndrome (ACS), stabilized after recent ACS, and stable ASCVD. Overall, higher GDF-15 concentration was significantly and independently associated with an increased rate of CV death/HHF and MACE (P < 0.001 for each). However, while GDF-15 showed a robust and consistent independent association with CV death and HHF across all presentations of ASCVD, its prognostic association with future myocardial infarction (MI) and stroke only remained significant in patients stabilized after recent ACS or with stable ASCVD [hazard ratio (HR): 1.24, 95% confidence interval (CI): 1.17-1.31 and HR: 1.16, 95% CI: 1.05-1.28 for MI and stroke, respectively] and not in ACS (HR: 0.98, 95% CI: 0.90-1.06 and HR: 0.87, 95% CI: 0.39-1.92, respectively)., Conclusion: Growth differentiation factor 15 consistently adds prognostic information for CV death and HHF across the spectrum of ASCVD. GDF-15 also adds prognostic information for MI and stroke beyond clinical risk factors and cardiac biomarkers but not in the setting of ACS., Competing Interests: Conflict of interest: E.T.K. reports receiving lecture fees from Astellas, Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly Japan KK, Daiichi-Sankyo, Menarini, Ono Pharmaceutical, Ootsuka Pharmaceutical, MSD KK, Takeda Pharmaceutical, Tanabe-Mitsubishi, Bayer, Pfizer; consultant fee from Boehringer Ingelheim and Daiichi-Sankyo; research fund from Abbott, Ono Pharmaceutical, and Tanabe-Mitsubishi; D.M. reports grants to the Brigham and Women’s Hospital from Abbott Laboratories, Amgen, Anthos Therapeutics, AstraZeneca, Eisai, Medicines Co., Merck, Novartis, Pfizer, Roche Diagnostics, and Siemens; and consultant fees from InCardia, Inflammatix, Merck & Co, Novartis, and Roche Diagnostics. D.M. is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences; J.G. is a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s from Abbott Laboratories, Amgen; AstraZeneca; Critical Diagnostics, Daiichi-Sankyo; Eisai; Genzyme; Gilead; GlaxoSmithKline; Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Poxel; Roche Diagnostics; and Takeda; D.D.B. is supported by Harvard Catalyst KL2/CMeRIT (NIH/NCATS grant UL 1TR002541). He has received research grant support to his institution from AstraZeneca and Pfizer; consulting fees from AstraZeneca; and participates on a clinical endpoint committee for a study sponsored by Kowa Pharmaceuticals. M.B. has no conflict of interest; E.A.B. is a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Roche, Siemens Healthcare Diagnostics, Inc., The Medicines Company, Zora Biosciences. E.A.B. has received personal fees from Servier, Kowa, Medscape, Novo Nordisk, Amgen, PriMed and Merck; M.P.B. is the Executive Director of CPC, a non-profit 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, EverlyWell, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, Medtronic, Moderna, Novate Medical, NovoNordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Ciosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, Worldwide Clinical Trials, Wraser, Yale Cardiovascular Research Group. M.P.B. also reports stock in Medtronic and Pfizer and consulting fees from Audent; C.P.C. reports research grants from: Amgen, Better Therapeutics, Boehringer-Ingelheim (BI), Bristol-Myers Squibb (BMS), Daiichi Sankyo, Janssen, Merck, Novo Nordisk, Pfizer, Consulting fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, and Sanofi. C.P.C. serve on Data and Safety Monitoring Boards for the Veteran’s Administration, Applied Therapeutics and NovoNordisk; J.A.d.L reports grant support from Roche Diagnostics and Abbott Diagnostics, consulting fees from Ortho Clinical Diagnostics, Siemen’s Health Care Diagnostics, Beckman Coulter, and Quidel; R.P.G. reports clinical trials/research support from Amgen, Anthos Therapeutics, Daiichi Sankyo, honoraria for Lectures/CME Programs for Amgen, Centrix, Daiichi Sankyo, Dr. Reddy’s Laboratories, Medical Education Resources (MER), Medscape, Menarini, Merck, Pfizer, SAJA Pharmaceuticals, Servier, Shanghai Medical Telescope, Voxmedia, Consultant fee from Amarin, Amgen, Boston Scientific, CryoLife, CSL Behring, CVS Caremark, Daiichi Sankyo, Esperion, Gilead, Hengrui, Inari, Janssen, Novartis, Pfizer, PhaseBio Pharmaceuticals, St. Lukes, Samsung; P.J. reports research support from Abbott Laboratories, Amgen, Inc., AstraZeneca, LP, Daiichi-Sankyo, Inc., GlaxoSmithKline, Merck & Co., Inc., Regeneron, Roche Diagnostics Corporation, and Siemens Healthineers; T.K. has been a paid consultant for and/or received honoraria payments from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Edwards, Novartis, Pharmacosmos, and Vifor and has received research support from Vifor; K.N. reports research funding through Duke University from Roche Diagnostics; Consulting honoraria from Beckman-Coulter; M.O’. reports Grants via Brigham and Women’s Hospital from Amgen, Novartis, AstraZeneca, Janssen, Intarcia, Merck, Pfizer. Honararia from Novartis, AstraZeneca, Amgen, Janssen; M.A.P. reports Research Grant Support from Novartis; consultant to AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, DalCor, GlaxoSmithKline, Lexicon, NHLBI CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge and Sanofi; and has equity in DalCor; N.R. has no conflic of interest; S.D.W. reports research grants from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Janssen, and Merck. He reports consulting fees from AstraZeneca, Boston Clinical Research Institute, ICON Clinical, Novo Nordisk. Spouse, Dr. Caroline Fox is an employee of Merck. S.D.W. is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from: Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences; S.D.W. has been a paid consultant for and has received research support from Boehringer Ingelheim, and has received honoraria payments from Roche Diagnostics. T.K. and S.D.W. hold patents (EP 2047275 B1 and US 8951742) and have a licensing contract with Roche Diagnostics related to GDF-15; E.B. reports research grants through his institution from Astra Zeneca, Daiichi Sankyo, Merck and Novartis, and consultancies with Amgen, Boehringer-Ingelheim/Lilly, Bristol Myers Squibb, Cardurion, Novo Nordisk, and Verve; M.S. report research grant support through Brigham and Women’s Hospital from Amgen; Anthos Therapeutics; AstraZeneca; Bayer; Daiichi-Sankyo; Eisai; Intarcia; Ionis; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Quark Pharmaceuticals. Consulting for: Althera; Amgen; Anthos Therapeutics; AstraZeneca; Beren Therapeutics; Bristol-Myers Squibb; DalCor; Dr. Reddy’s Laboratories; Fibrogen; Intarcia; Merck; Moderna; Novo Nordisk; Silence Therapeutics. Additionally, M.S. is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, ARCA Biopharma, Inc., Janssen Research and Development, LLC, Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, Regeneron, Roche, and Zora Biosciences., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Importance: Studies have demonstrated an association between single measures of high-sensitivity troponin (hsTn) and future cardiovascular events in patients with chronic coronary syndromes. However, limited data exist regarding the association between changes in serial values of hsTn and subsequent cardiovascular events in this patient population., Objective: To evaluate the association between changes in high-sensitivity troponin T (hsTnT) and subsequent cardiovascular events in patients stabilized after acute coronary syndrome (ACS)., Design, Setting, and Participants: This is a secondary analysis from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), a randomized clinical trial of ezetimibe vs placebo on a background of simvastatin in 18 144 patients hospitalized for an ACS across 1147 sites in 39 countries. The current biomarker substudy includes the 6035 participants consenting to the biomarker substudy with available hsTnT at months 1 and 4. Data were collected from October 26, 2005, through July 8, 2010, with the database locked October 21, 2014. Data were analyzed from February 28, 2021, through August 14, 2022., Main Outcomes and Measures: The outcomes of interest were cardiovascular death, myocardial infarction (MI), stroke, or hospitalization for heart failure (HHF). Associations of absolute and relative changes in hsTnT between month 1 and month 4 as a function of the starting month 1 hsTnT and the composite outcome were examined using landmark analyses., Results: Of 6035 patients in this analysis (median [IQR] age, 64 [57-71]), 1486 (24.6%) were female; 361 (6.0%) were Asian; 121 were (2.0%) Black; 252 (4.2%) were Spanish descent; 4959 were (82.2%) White; and 342 (5.7%) reported another race (consolidated owing to small numbers), declined to respond, or were not asked to report race owing to regulatory prohibitions. Most patients (4114 [68.2%]) had stable hsTnT values (change <3 ng/L), with 1158 (19.2%) and 763 (12.6%) having changes of 3 to less than 7 ng/L and 7 ng/L or more, respectively. After adjustment for clinical risk factors and stratification by the starting month 1 hsTnT level, an absolute increase in hsTnT of 7 ng/L or more was associated with a more than 3-fold greater risk of the composite outcome (adjusted hazard ratio [aHR], 3.33; 95% CI, 1.99-5.57; P < .001), whereas decreases of 7 ng/L or more were associated with similar to lower risk (aHR, 0.51; 95% CI, 0.26-1.03; P = .06) compared with stable values. There was a stepwise association moving from larger absolute decreases (aHR, 0.51; 95% CI, 0.26-1.03) to larger absolute increases (aHR, 3.33; 95% CI, 1.99-5.57) in hsTnT with future risk of the composite outcome (P trend <.001). A similar association was observed when analyzed on the basis of relative percent and continuous change., Conclusions and Relevance: Among stable patients post-ACS, changes in hsTnT were associated with a gradient of risk of subsequent cardiovascular events across the range of starting hsTnT values. Serial assessment of hsTnT may refine risk stratification with the potential to guide therapy decisions in this patient population., Trial Registration: ClinicalTrials.gov Identifier: NCT00202878.

Background: In patients with acute coronary syndrome (ACS), there is residual and variable risk of recurrent ischemic events., Objectives: This study aimed to develop biomarker-based prediction models for 1-year risk of cardiovascular (CV) death and myocardial infarction (MI) in patients with ACS undergoing percutaneous coronary intervention., Methods: We included 10,713 patients from the PLATO (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome) trial in the development cohort and externally validated in 3,508 patients from the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial. Variables contributing to risk of CV death/MI were assessed using Cox regression models, and a score was derived using subsets of variables approximating the full model., Results: There were 632 and 190 episodes of CV death/MI in the development and validation cohorts. The most important predictors of CV death/MI were the biomarkers, growth differentiation factor 15, and N-terminal pro-B-type natriuretic peptide, which had greater prognostic value than all candidate variables. The final model included 8 items: age (A), biomarkers (B) (growth differentiation factor 15 and N-terminal pro-B-type natriuretic peptide), and clinical variables (C) (extent of coronary artery disease, previous vascular disease, Killip class, ACS type, P2Y 12 inhibitor). The model, named ABC-ACS ischemia, was well calibrated and showed good discriminatory ability for 1-year risk of CV death/MI with C-indices of 0.71 and 0.72 in the development and validation cohorts, respectively. For CV death, the score performed better, with C-indices of 0.80 and 0.84 in the development and validation cohorts, respectively., Conclusions: An 8-item score for the prediction of CV death/MI was developed and validated for patients with ACS undergoing percutaneous coronary intervention. The ABC-ACS ischemia score showed good calibration and discrimination and might be useful for risk prediction and decision support in patients with ACS. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872; Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER]; NCT00527943)., Competing Interests: Funding Support and Author Disclosures Grants from The Swedish Foundation for Strategic Research (grant number RB13-0197) supported this project. The PLATO trial was funded by AstraZeneca, Cambridge, United Kingdom. The TRACER trial was funded by Merck, Kenilworth, New Jersey, USA. Roche Diagnostics, Rotkreuz, Switzerland, provided GDF-15 assays free of charge. The funding sources had no influence on the work but were given the opportunity to review the final version of the report. Dr Batra has received institutional research grants from Pfizer; has received expert committee and consulting fees to his institution from Bayer; and has received honoraria for lectures and scientific advice from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Pfizer, and Sanofi. Dr Lindbäck has received institutional research grants from GlaxoSmithKline. Dr Becker has participated on a Data Safety Monitoring Board (DSMB) for Ionis and Novartis; serves on the scientific advisory board for Basking; and has received payment for expert testimony from Plunkett and Cooney. Dr Harrington has received institutional research grants from AstraZeneca during the conduct of the study; has received research grants from Janssen; and has received consulting fees from Bristol Myers Squibb. Dr Held has received institutional research grants from GlaxoSmithKline; has received honoraria and research grants from Pfizer; and has received consultant and Advisory Board fees from AstraZeneca, Bayer, Boehringer Ingelheim, and Coala Life. Dr James has received an institutional research grant, honoraria, and consultant/advisory board fee from AstraZeneca; has received an institutional research grant and consultant/advisory board fee from Medtronic; has received institutional research grants and honoraria from The Medicines Company; and has received consultant/advisory board fees from Janssen, Bayer, Novartis, Amgen, and PhaseBio. Dr Kempf has patents related to GDF-15 that have been licensed to Roche Diagnostics. Dr Lopes has received institutional research grants and consulting fees from Bayer, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; and has received consulting fees from Boehringer Ingelheim, Daiichi-Sankyo, Merck, and Portola. Dr Mahaffey has received grants and consulting fees from and participation on a DSMB for AstraZeneca and Johnson & Johnson; has received grants and consulting fees from Amgen, Bayer, Novartis, and Sanofi; has received consulting fees and speaker honoraria from Inova, Intermountain Health, Medscape, and Mount Sinai; has received grants and participation on a DSMB for Ferring, Luitpold, and Sanifit; has received consulting fees and participation on a DSMB for Myokardia and Theravance; has received grants from Afferent, American Heart Association, Apple Inc, Cardiva Medical Inc, Eidos, Gilead, Google (Verily), Medtronic, Merck, and St. Jude; has received consulting fees from Anthos Applied Therapeutics, CSL Behring, Elsevier, Mundi Pharma, Novo Nordisk, Otsuka, Portola, and SmartMedics; and participates on a DSMB for National Health and Medical Research Council and The George Institute for Global Health, Australia. Dr Steg has received grants and speaker/consultancy fees from Amarin, Bayer, Sanofi, and Servier; and has received speaker/consultancy fees from AstraZeneca, Amgen, Amarin, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Idorsia, Janssen, Novartis, Pfizer, and Regeneron. Dr Storey has received institutional research grants and speaker/consultancy fees from AstraZeneca, Cytosorbents, GlyCardial Diagnostics, and Thromboserin; and has received speaker/consultancy fees from Alnylam, Bayer, Bristol Myers Squibb/Pfizer, Chiesi, CSL-Behring, Hengrui, Idorsia, Intas Pharmaceuticals, Medscape, Novartis, PhaseBio, Portola, and Sanofi. Dr Wollert has received patents related to GDF-15 that have been licensed to Roche Diagnostics. Dr Siegbahn has received institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, and Roche Diagnostics; and has received consulting fees from OLINK Proteomics. Dr Wallentin has received institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, Merck & Co, and Roche Diagnostics; has received consulting fees from Abbott; and has patents related to GDF-15 that have been licensed to Roche Diagnostics. Dr Swahn has reported that she has no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without substantially increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI)., Methods: We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6 to 12 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on FXIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo., Results: The median age was 68 years, 23% of participants were women, 51% had ST-segment-elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity, with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian versus placebo: hazard ratio, 0.98 [90% CI, 0.71-1.35]). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian 20 and 50 mg versus placebo: hazard ratio, 1.05 [90% CI, 0.69-1.61])., Conclusions: In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients who experienced acute MI., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04304534; URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2019-003244-79.

Background: With the improvement in outcomes for acute coronary syndrome (ACS), the practice of routine admission to cardiac intensive care units (CICUs) is evolving. We aimed to describe the epidemiology of patients with ACS admitted to contemporary CICUs., Methods: Using the CCCTN (Critical Care Cardiology Trials Network) Registry for consecutive medical CICU admissions across 26 advanced CICUs in North America between 2017 and 2020, we identified patients with a primary diagnosis of ACS at CICU admission and compared patient characteristics, resource utilization, and outcomes to patients admitted with a non-ACS diagnosis and across sub-populations of patients with ACS, including by indication for CICU admission., Results: Of 10 118 CICU admissions, 29.4% (n=2978) were for a primary diagnosis of ACS, with significant interhospital variability (range, 13.4%-56.6%). Compared with patients admitted with a diagnosis other than ACS, patients with ACS had fewer comorbidities, lower acute severity of illness with less utilization of advanced CICU therapies (41.3% versus 66.1%, P <0.0001), and lower CICU mortality (5.4% versus 9.9%, P <0.0001). Monitoring alone, without another CICU indication at the time of admission, was the most frequent admission indication in patients with ACS (53.8%); less common indications in patients with ACS included respiratory insufficiency, shock, or the need for vasoactive therapy. Of patients with ACS admitted for monitoring alone, 94.8% did not subsequently require advanced intensive care unit therapies and had a low CICU length of stay (1.5 days [0.9-2.4] versus 2.6 [1.4-5.1], P <0.0001) and CICU mortality (0.6% versus 11.0%, P <0.0001), compared with patients with ACS with an admission indication beyond monitoring., Conclusions: In a registry of tertiary care CICUs, ACS represent ≈1/3 of all admissions with significant variability across hospitals. More than half of the ACS admissions to the CICU were for routine monitoring alone, with a low rate of complications and mortality. This observation highlights an opportunity for prospective studies to refine triage strategies for lower risk patients with ACS.

Importance: Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI)., Objective: Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE)., Design, Setting, and Participants: In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded., Interventions: Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo., Main Outcomes and Measures: Major or clinically relevant nonmajor (CRNM) bleeding., Results: Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant)., Conclusions and Relevance: The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status., Trial Registration: ClinicalTrials.gov Identifier: NCT02415400.

Aims: Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis, we evaluated outcomes in ODYSSEY OUTCOMES in patients with vs. without a history of HF randomized to the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo., Methods and Results: Among 18 924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment, the primary outcome of major adverse cardiovascular events (MACE) was compared in patients with or without a history of HF. The pre-specified secondary outcome of hospitalization for HF was also analysed. Overall, 2815 (14.9%) patients had a history of HF. Alirocumab reduced low-density lipoprotein cholesterol and lipoprotein(a) similarly in patients with or without HF. Overall, alirocumab reduced MACE compared with placebo [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.78-0.93; P = 0.0001]. This effect was observed among patients without a history of HF (HR: 0.78; 95% CI: 0.70-0.86; P < 0.0001), but not in those with a history of HF (HR: 1.17; 95% CI: 0.97-1.40; P = 0.10) (Pinteraction = 0.0001). Alirocumab did not reduce hospitalization for HF, overall or in patients with or without prior HF., Conclusion: Alirocumab reduced MACE in patients without a history of HF but not in patients with a history of HF. Alirocumab did not reduce hospitalizations for HF in either group. Patients with a history of HF are a high-risk group that does not appear to benefit from PCSK9 inhibition after ACS., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Importance: Acute coronary syndromes (ACS) are characterized by a sudden reduction in blood supply to the heart and include ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and unstable angina. Each year, an estimated more than 7 million people in the world are diagnosed with ACS, including more than 1 million patients hospitalized in the US., Observations: Chest discomfort at rest is the most common presenting symptom of ACS and affects approximately 79% of men and 74% of women presenting with ACS, although approximately 40% of men and 48% of women present with nonspecific symptoms, such as dyspnea, either in isolation or, more commonly, in combination with chest pain. For patients presenting with possible ACS, electrocardiography should be performed immediately (within 10 minutes of presentation) and can distinguish between STEMI and non-ST-segment elevation ACS (NSTE-ACS). STEMI is caused by complete coronary artery occlusion and accounts for approximately 30% of ACS. ACS without significant ST-segment elevation on electrocardiography, termed NSTE-ACS, account for approximately 70% of ACS, are caused by partial or intermittent occlusion of the artery and are associated with ST-segment depressions (approximately 31%), T-wave inversions (approximately 12%), ST-segment depressions combined with T-wave inversions (16%), or neither (approximately 41%). When electrocardiography suggests STEMI, rapid reperfusion with primary percutaneous coronary intervention (PCI) within 120 minutes reduces mortality from 9% to 7%. If PCI within 120 minutes is not possible, fibrinolytic therapy with alteplase, reteplase, or tenecteplase at full dose should be administered for patients younger than 75 years without contraindications and at half dose for patients 75 years or older (or streptokinase at full dose if cost is a consideration), followed by transfer to a facility with the goal of PCI within the next 24 hours. High-sensitivity troponin measurements are the preferred test to evaluate for NSTEMI. In high-risk patients with NSTE-ACS and no contraindications, prompt invasive coronary angiography and percutaneous or surgical revascularization within 24 to 48 hours are associated with a reduction in death from 6.5% to 4.9%., Conclusions and Relevance: Each year, an estimated more than 7 million people are diagnosed with ACS worldwide. For patients with STEMI, coronary catheterization and PCI within 2 hours of presentation reduces mortality, with fibrinolytic therapy reserved for patients without access to immediate PCI. For high-risk patients with NSTE-ACS without contraindications, prompt invasive coronary angiography followed by percutaneous or surgical revascularization is associated with lower rates of death.

Background: The use of apixaban instead of vitamin K antagonists (VKA) as well as dropping aspirin results in less bleeding and comparable ischemic events in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention treated with a P2Y 12 inhibitor., Objectives: The authors assessed the safety and efficacy of antithrombotic regimens according to HAS-BLED and CHA 2 DS 2 -VASc scores in AUGUSTUS (The Open-Label, 2 × 2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention)., Methods: In AUGUSTUS, 4,614 patients were randomized in a 2-by-2 factorial design to open-label apixaban or VKA and blinded aspirin or placebo. The primary endpoint was major or clinically relevant nonmajor bleeding over 6 months of follow-up. Cox proportional hazards models were used to assess treatment effects by baseline HAS-BLED (≤2 vs ≥3) and CHA 2 DS 2 -VASc (≤2 vs ≥3) scores., Results: Of 4,386 (95.1%) patients with calculable scores, 66.8% had HAS-BLED ≥3 and 81.7% had CHA 2 DS 2 -VASc ≥3. Bleeding rates were lower with apixaban than VKA irrespective of baseline risk (HR: 0.57; 95% CI: 0.41-0.78 [HAS-BLED ≤2]; HR: 0.72; 95% CI: 0.59-0.88 [HAS-BLED ≥3]; interaction P = 0.23). Aspirin increased bleeding irrespective of baseline risk (HR: 1.86; 95% CI: 1.36-2.56 [HAS-BLED ≤2]; HR: 1.81; 95% CI: 1.47-2.23 [HAS-BLED ≥3]; interaction P = 0.88). Apixaban resulted in a lower risk of death or hospitalization than VKA without a significant interaction with baseline stroke risk (HR: 0.92; 95% CI: 0.67-1.25 [CHA 2 DS 2 -VASc ≤2]; HR: 0.82; 95% CI: 0.73-0.94 [CHA 2 DS 2 -VASc ≥3]; interaction P = 0.53)., Conclusions: Our findings support the use of apixaban and a P2Y 12 inhibitor without aspirin for most patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention, irrespective of a patient's baseline bleeding and stroke risk (NCT02415400)., Competing Interests: Funding Support and Author Disclosures The AUGUSTUS trial and this analysis were supported by Bristol Myers Squibb and Pfizer. Dr Fanaroff has received research grants and consulting fees from the American Heart Association; and has received research grants from Boston Scientific. Dr Lopes has received institutional research grants and consulting fees from Bristol Myers Squibb, Pfizer, GlaxoSmithKline, Medtronic PLC, and Sanofi; and has received consulting fees from Amgen, Bayer, and Boehringer Ingelheim. Dr Goodman has received research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (eg, 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 and Johnson, Merck, Novartis, Novo Nordisk A/C, Pendopharm, Pfizer, Regeneron, Sanofi, Servier, and Valeo Pharma; and has received salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) (Chair), Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, and PERFUSE Research Institute. Dr Thomas has received institutional research grants from Akili Interactive Labs Inc, Amgen Inc, Gilead, and Novartis. Dr Aronson is an employee of Bristol Myers Squibb. Dr Windecker has received Institutional research and educational grants from Abbott, Amgen, Bayer, Bristol Myers Squibb, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, and Sinomed. Dr Mehran has received institutional research grants from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol Myers Squibb/Sanofi, CSL Behring, Eli Lilly/Daiichi-Sankyo, Medtronic, Novartis, and OrbusNeich; has received consulting fees from Boston Scientific, Abbott Vascular, Medscape, Siemens Medical Solutions, Roivant Sciences Inc, and Sanofi; has performed consulting (no fees) for Regeneron Pharmaceuticals; has received institutional consulting fees from Abbott Vascular, Spectranetics/Phillips/Volcano Corporation, Bristol Myers Squibb, Novartis, and Watermark Research; has served as an executive committee member for Janssen Pharmaceuticals and Bristol Myers Squibb; and has <1% equity in Claret Medical and Elixir Medical. Dr Granger has received research grants from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Armetheon, AstraZeneca, the U.S. Food and Drug Administration, GlaxoSmithKline, The Medicines Company, Medtronic Foundation, Medtronic Inc, and Novartis; and has received consulting fees from Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Abbvie, Armetheon, AstraZeneca, Eli Lilly, Gilead, GlaxoSmithKline, Hoffmann-La Roche, The Medicines Company, National Institutes of Health, Novartis, Sirtex, Verseon, Apple, Medscape, LLC, Merck, Novo Nordisk, Roche Diagnostics, and Rho Pharmaceuticals. Dr Alexander has received institutional research grants and consulting fees/honoraria from Bristol Myers Squibb and CSL Behring; has received institutional research grants from AstraZeneca, CryoLife, the U.S. Food and Drug Administration, National Institutes of Health, Sanofi, VoluMetrix, and Boehringer Ingelheim; and has received consulting fees/honoraria from Pfizer, AbbVie Pharmaceuticals, NovoNordisk, Portola Pharmaceuticals, Quantum Genetics, Teikoku Pharmaceuticals, VA Cooperative Studies Program, and Zafgen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL despite maximally tolerated statin., Objectives: The purpose of this study was to evaluate the relationship between baseline LDL-C above and below 70 mg/dL and the benefit of adding ezetimibe to statin in patients post-acute coronary syndrome (ACS)., Methods: IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a double-blind, placebo-controlled, randomized trial of ezetimibe/simvastatin vs placebo/simvastatin in post-ACS patients followed for 6 years (median). A total of 17,999 patients were stratified by LDL-C at qualifying event into 3 groups (50-<70, 70-<100, and 100-125 mg/dL). The primary endpoint was a composite of cardiovascular death, major coronary events, or stroke., Results: Absolute differences in median LDL-C achieved at 4 months between treatment arms were similar (17-20 mg/dL). The effect of ezetimibe/simvastatin vs placebo/simvastatin on primary endpoint was consistent regardless of baseline LDL-C of 50-<70 mg/dL (HR: 0.92 [95% CI: 0.80-1.05]), 70-<100 mg/dL (HR: 0.93 [95% CI: 0.87-1.01]), or 100-125 mg/dL (HR: 0.94 [95% CI: 0.86-1.03]; P interaction = 0.95). Normalized relative risk reductions per 1-mmol/L difference in achieved LDL-C at 4 months between treatment arms were 21% in patients with baseline LDL-C of 50-<70 mg/dL, 16% in those with 70-<100 mg/dL, and 13% in those with 100-125 mg/dL (P interaction = 0.91). No significant treatment interactions by baseline LDL-C were present for safety endpoints., Conclusions: Adding ezetimibe to statin consistently reduced the risk for cardiovascular events in post-ACS patients irrespective of baseline LDL-C values, supporting the use of intensive lipid-lowering therapy with ezetimibe even in patients with baseline LDL-C <70 mg/dL. (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878)., Competing Interests: Funding Support and Author Disclosures The IMPROVE-IT trial was supported by Merck and Co. Dr Oyama has received a grant from JSPS Overseas Research Fellowships. Dr Giugliano has received grants from Amgen and Anthos Therapeutics; has received honoraria from Amgen, Centrix, Daiichi-Sankyo, Dr Reddy's Laboratories, Medical Education Resources, Medscape, Menarini, Pfizer, SAJA Pharmaceuticals, Servier, and Voxmedia; and has received consultant fees from Amarin, Amgen, Bayer, CryoLife, Daiichi-Sankyo, Esperion, Gilead, Hengrui, Inari, Pfizer, PhaseBio Pharmaceuticals, St Lukes, and Sanofi. Dr Blazing has received research support from Merck; has received consulting fees from Espirion (<$10,000); and has received indirect support from Sanofi through Duke Clinical Research Institute. Dr Park has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, Roche, The Medicines Company, and Zora Biosciences. Dr Tershakovec is a former employee of Merck Sharp and Dohme Corp, a subsidiary of Merck and Co, Inc, and may own stock in the company. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, IONIS, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; and has received consulting fees from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol Myers Squibb, CVS Caremark, DalCor, Dr Reddy's Laboratories, Fibrogen, IFM Therapeutics, Intarcia, MedImmune, Merck, Moderna, and Novo Nordisk. Dr Cannon has received grant support and consulting fees from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Pfizer, and Merck; has received grant support from Daiichi-Sankyo; and has received consulting fees from Aegerion, Alnylam, Amarin, Applied Clinical Therapeutics, Ascendia, Corvidia, HLS Therapeutics, Innovent, Kowa, Eli Lilly, and Rhoshan. Dr Braunwald has received research grants through the Brigham and Women’s Hospital from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; has served as a consultant for Amgen, Cardurion, MyoKardia, NovoNordisk, Boehringer Ingelheim/Lilly, IMMEDIATE, and Verve; and has performed uncompensated consultancies and lectures for The Medicines Company., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: The optimal choice of oral P2Y12 receptor inhibitors has the potential to significantly influence outcomes. We seek to compare the safety and efficacy of the three most commonly used oral P2Y12 receptor inhibitors (clopidogrel, prasugrel, and ticagrelor) in acute coronary syndromes (ACS) via a comprehensive systematic review and network meta-analysis., Evidence Acquisition: In line with the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, we performed a comprehensive search for RCTs which compared cardiovascular and hemorrhagic outcomes after use of at least two of the distinct oral P2Y12 receptor inhibitors (i.e. clopidogrel, prasugrel, and ticagrelor). A search strategy has been designed to systematically search multiple databases, including MEDLINE with PubMed interface, The Cochrane Central Register of Controlled Trials, and Embase. In addition, key inclusion criteria will be trial size of at least 100 patients and at least 1 month of follow-up time. Several prespecified subgroups will be explored, including Asian patients, patients presenting with ST-elevation myocardial infarction, patients of advanced age, and others., Evidence Synthesis: Exploratory frequentist pairwise meta-analyses will be based primarily on a random-effects method, relying on relative risks (RR) for short-term outcomes and incidence rate ratios (IRR) for long-term outcomes. Inferential frequentist network meta-analysis will be based primarily on a random-effects method, relying on RR and IRR as specified above. Results will be reported as point summary of effect, 95% CI, and P values for effect, and graphically represented using forest plots., Conclusions: An international collaborative network meta-analysis has begun to comprehensively analyze the safety and efficacy of prasugrel, ticagrelor and clopidogrel, each on a background of aspirin, for management of patients with ACS. It is our hope that the rigor and breadth of the undertaking described herein will provide novel insights that will inform optimal patient care for patients with ACS treated conservatively, or undergoing revascularization.

Background: Half the global burden of cardiovascular disease (CVD) is concentrated in the Asia-Pacific (APAC) region., Hypothesis: Suboptimal control of low-density lipoprotein cholesterol (LDL-C) may play a large role in the burden of CVD in APAC and non-Western countries., Methods: The Acute Coronary Syndrome Management (ACOSYM) registry is a multinational, multicenter, prospective observational registry designed to evaluate LDL-C control in patients within 6 months after hospitalization following an acute coronary syndrome (ACS) event across nine countries., Results: Overall, 1581 patients were enrolled, of whom 1567 patients met the eligibility criteria; 80.3% of the eligible patients were men, 46.1% had ST-elevation myocardial infarction, and 39.5% had non-ST-elevation myocardial infarction. Most (1245; 79.5%) patients were discharged on a high-intensity statin. During the follow-up, only 992 (63.3%) patients had at least one LDL-C measurement; of these, 52.9% had persistently elevated LDL-C (>70 mg/dl). The patients not discharged on a high-dose statin were more likely (OR 3.2; 95% CI 2.1-4.8) to have an LDL-C above the 70 mg/dl LDL-C target compared with those who were discharged on a high-dose statin., Conclusion: Our real-world registry found that a third or more of post-ACS patients did not have a repeat LDL-C follow-up measurement. In those with an LDL-C follow-up measurement, more than half (52.9%) were not achieving a <70 mg/dl LDL-C goal, despite a greater uptake of high-intensity statin therapy than has been observed in recent evidence. This demonstrates the opportunity to improve post-ACS lipid management in global community practice., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Aims: Safety and efficacy of antithrombotic regimens in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) may differ based on clinical presentation. We sought to compare double vs. triple antithrombotic therapy (DAT vs. TAT) in AF patients with or without acute coronary syndrome (ACS) undergoing PCI., Methods and Results: A systematic review and meta-analysis was performed using PubMed to search for non-vitamin K antagonist oral anticoagulant (NOAC)-based randomized clinical trials. Data on subgroups of ACS or elective PCI were obtained by published reports or trial investigators. A total of 10 193 patients from four NOAC trials were analysed, of whom 5675 presenting with ACS (DAT = 3063 vs. TAT = 2612) and 4518 with stable coronary artery disease (SCAD; DAT = 2421 vs. TAT = 2097). The primary safety endpoint of ISTH major bleeding or clinically relevant non-major bleeding was reduced with DAT compared with TAT in both ACS (12.2% vs. 19.4%; RR 0.63, 95% CI 0.56-0.71; P < 0.0001; I2 = 0%) and SCAD (14.6% vs. 22.0%; RR 0.68, 95% CI 0.55-0.85; P = 0.0008; I2 = 66%), without interaction (P-int = 0.54). Findings were consistent for secondary bleeding endpoints, including intra-cranial haemorrhage. In both subgroups, there was no difference between DAT and TAT for all-cause death, major adverse cardiovascular events, or stroke. Myocardial infarction and stent thrombosis were numerically higher with DAT vs. TAT consistently in ACS and SCAD (P-int = 0.60 and 0.86, respectively). Findings were confirmed by multiple sensitivity analyses, including a separate analysis on dabigatran regimens and a restriction to PCI population., Conclusions: DAT, compared with TAT, is associated with lower bleeding risks, including intra-cranial haemorrhage, and a small non-significant excess of cardiac ischaemic events in both patients with or without ACS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: In the AUGUSTUS trial (An Open-Label, 2×2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban Versus Vitamin K Antagonist and Aspirin Versus Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention), apixaban resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, and aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention treated with a P2Y 12 inhibitor. We evaluated the risk-benefit balance of antithrombotic therapy according to kidney function., Methods: In 4456 patients, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was used to calculate baseline estimated glomerular filtration rate (eGFR). The effect of apixaban versus vitamin K antagonists and aspirin versus placebo was assessed across kidney function categories by using Cox models. The primary outcome was International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and ischemic events (death, stroke, myocardial infarction, stent thrombosis [definite or probable], or urgent revascularization). Creatinine clearance <30 mL/min was an exclusion criterion in the AUGUSTUS trial., Results: Overall, 30%, 52%, and 19% had an eGFR of >80, >50 to 80, and 30 to 50 mL·min -1 ·1.73 m -2 , respectively. At the 6-month follow-up, a total of 543 primary outcomes of bleeding, 1125 death or hospitalizations, and 282 ischemic events occurred. Compared with vitamin K antagonists, patients assigned apixaban had lower rates for all 3 outcomes across most eGFR categories without significant interaction. The absolute risk reduction with apixaban was most pronounced in those with an eGFR of 30 to 50 mL·min -1 ·1.73 m -2 for bleeding events with rates of 13.1% versus 21.3% (hazard ratio, 0.59; 95% CI, 0.41-0.84). Patients assigned aspirin had a higher risk of bleeding in all eGFR categories with an even greater increase among those with eGFR >80 mL·min -1 ·1.73 m -2 : 16.6% versus 5.6% (hazard ratio, 3.22; 95% CI, 2.19-4.74; P for interaction=0.007). The risk of death or hospitalization and ischemic events were comparable to aspirin and placebo across eGFR categories with hazard ratios ranging from 0.97 (95% CI, 0.76-1.23) to 1.28 (95% CI, 1.02-1.59) and from 0.75 (95% CI, 0.48-1.17) to 1.34 (95% CI, 0.81-2.22), respectively., Conclusions: The safety and efficacy of apixaban was consistent irrespective of kidney function, compared with warfarin, and in accordance with the overall trial results. The risk of bleeding with aspirin was consistently higher across all kidney function categories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02415400.

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.)

Importance: Conducting a clinical trial involves significant risks, time, and resources. The return on investment for these trials, measured by advancing health care and contributions to the scientific literature, is often uncertain., Objective: To assess the long-term effects of major clinical trials of acute coronary syndromes contemporary to the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial, which did not achieve its primary objective., Evidence Review: The Cochrane Central Register of Controlled Trials database was screened for clinical trials of acute coronary syndromes (including unstable angina, ST-elevation myocardial infarction, and non-ST-elevation myocardial infarction) with more than 1000 participants and primary results published between January 1, 2005, and December 31, 2009, in Circulation, European Heart Journal, JAMA, Journal of the American College of Cardiology, The Lancet, and The New England Journal of Medicine. For identified trials, bibliographic information, citations, trial name, registration, inclusion diagnosis, intervention type, sample size, primary outcome result, sponsor information, and academic involvement were extracted. To identify secondary analyses, bibliographic information for citing articles, their citations, and their abstracts were extracted. Clinical practice guideline bibliographies for citations of trial publications were reviewed, and the class and level of evidence of resulting recommendations were extracted., Findings: Of 784 records screened, 30 were primary publications of 25 clinical trials. Through December 31, 2018, these trials were cited a median of 497 times (interquartile range [IQR], 424-931 citations). Trials that did not achieve their primary objective had fewer primary citations (the number of times that each published journal article with the primary [main] results of a trial was cited) (median, 443 [IQR, 396-468] vs 868 [IQR, 645-1774] citations, P = .006). The frequency of secondary analyses peaked within 5 years of the primary trial at 643. Trials that did not achieve the primary objective had fewer secondary analyses (median, 15 [IQR, 5-31] vs 18 [IQR, 10-43] analyses, P = .44) that were not cited significantly less often (median, 484 [IQR, 191-1299] vs 1124 [IQR, 410-4283] citations, P = .16). All trials were cited by at least 1 clinical practice guideline., Conclusions and Relevance: This review found that trials that achieved the primary objective were frequently cited. Secondary research activity did not differ by primary result, and the primary trials and secondary analyses contributed to clinical practice recommendations. These data show the long-term importance of clinical trials regardless of primary outcome result.

Background: Prior randomized controlled trials (RCT) evaluating the optimal antithrombotic therapies for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) have not been powered to evaluate ischemic outcomes. We compared double therapy with oral anticoagulation (OAC) and a P2Y12 inhibitor to triple therapy with an OAC + dual antiplatelet therapy in patients with AF requiring PCI., Methods: Using PRISMA guidelines, we searched for RCTs including patients with AF as an indication for OAC and undergoing PCI or medical management of acute coronary syndrome. The results were pooled using fixed-effects and random-effects models to estimate the overall effect of double therapy versus triple therapy on ischemic and bleeding outcomes., Results: We identified four RCTs, comprising 10,238 patients (5,498 double therapy, 4,740 triple therapy). Trial-reported major adverse cardiovascular events were similar between double therapy and triple therapy (fixed effect model OR 1.09, 95% CI 0.94-1.26). However, stent thrombosis (61/5,496 double therapy vs. 33/4738 triple therapy; fixed effect model OR 1.57, 95% CI 1.02-2.40; number needed to treat with triple therapy = 242) favored triple therapy. Bleeding outcomes were less frequent with double therapy (746/5470 vs. 950/4710; fixed effect model OR 0.59, 95% CI 0.53-0.65; number needed to harm with triple therapy = 16), but with significant heterogeneity (Q = 8.33, p = .04; I 2 = 64%), as were intracranial hemorrhages (19/5470 vs. 30/4710; fixed effect model OR 0.54, 95% CI 0.31-0.96)., Conclusions: Double therapy in patients with AF requiring OAC following PCI or Acute coronary syndrome has a significantly better safety profile than triple therapy but may be associated with a modest increased risk of stent thrombosis., (© 2019 Wiley Periodicals, Inc.)

Background: Patients with acute coronary syndrome are at risk for peripheral artery disease (PAD) events and venous thromboembolism (VTE). PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C) levels. Our objective was to ascertain whether PCSK9 inhibition reduces the risk of PAD events or VTE after acute coronary syndrome, and if such effects are related to levels of lipoprotein(a) or LDL-C., Methods: This was a prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome), which was conducted in 18 924 patients with recent acute coronary syndrome on intensive or maximum-tolerated statin treatment who were randomized to the PCSK9 inhibitor alirocumab or placebo. In a prespecified analysis, PAD events (critical limb ischemia, limb revascularization, or amputation for ischemia) and VTE (deep vein thrombosis or pulmonary embolism) were assessed. LDL-C was corrected (LDL-C corrected ) for cholesterol content in lipoprotein(a)., Results: At baseline, median lipoprotein(a) and LDL-C corrected were 21 and 75 mg/dL, respectively; with alirocumab, median relative reductions were 23.5% and 70.6%, respectively. PAD events and VTE occurred in 246 and 92 patients, respectively. In the placebo group, risk of PAD events was related to baseline quartile of lipoprotein(a) ( P trend =0.0021), and tended to associate with baseline quartile of LDL-C corrected ( P trend =0.06); VTE tended to associate with baseline quartile of lipoprotein(a) ( P trend =0.06), but not LDL-C corrected ( P trend =0.85). Alirocumab reduced risk of PAD events (hazard ratio [HR], 0.69 [95% CI, 0.54-0.89]; P =0.004), with nonsignificantly fewer VTE events (HR, 0.67 [95% CI, 0.44-1.01]; P =0.06). Reduction in PAD events with alirocumab was associated with baseline quartile of lipoprotein(a) ( P trend =0.03), but not LDL-C corrected ( P trend =0.50). With alirocumab, the change from baseline to Month 4 in lipoprotein(a), but not LDL-C corrected , was associated with the risk of VTE and the composite of VTE and PAD events., Conclusions: In statin-treated patients with recent acute coronary syndrome, risk of PAD events is related to lipoprotein(a) level and is reduced by alirocumab, particularly among those with high lipoprotein(a). Further study is required to confirm whether risk of VTE is related to lipoprotein(a) level and its reduction with alirocumab. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Background: In AUGUSTUS (Open-Label, 2×2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs Vitamin K Antagonist and Aspirin vs Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention), patients with atrial fibrillation and a recent acute coronary syndrome and those undergoing percutaneous coronary intervention had less bleeding with apixaban than vitamin K antagonist (VKA) and with placebo than aspirin. However, the number of ischemic events was numerically higher with placebo. The aim of this analysis is to assess the tradeoff of risk (bleeding) and benefit (ischemic events) over time with apixaban versus VKA and aspirin versus placebo., Methods: In AUGUSTUS, 4614 patients with atrial fibrillation and recent acute coronary syndrome or percutaneous coronary intervention on a P2Y 12 inhibitor were randomized to blinded aspirin or placebo and to open-label apixaban or VKA for 6 months. In a post hoc analysis, we compared the risk of 3 composite bleeding outcomes and 3 composite ischemic outcomes from randomization through 30 days and from 30 days to 6 months with apixaban and VKA and with aspirin and placebo., Results: Compared with VKA, apixaban had either a lower or a similar risk of bleeding and ischemic outcomes from randomization to 30 days and from 30 days to 6 months. From randomization to 30 days, aspirin caused more severe bleeding (absolute risk difference, 0.97% [95% CI, 0.23-1.70]) and fewer severe ischemic events (absolute risk difference, -0.91% [95% CI, -1.74 to -0.08]) than placebo. From 30 days to 6 months, the risk of severe bleeding was higher with aspirin than placebo (absolute risk difference, 1.25% [95% CI, 0.23-2.27]), whereas the risk of severe ischemic events was similar (absolute risk difference, -0.17% [95% CI, -1.33 to 0.98])., Conclusions: In patients with atrial fibrillation and recent acute coronary syndrome or percutaneous coronary intervention receiving a P2Y 12 inhibitor, apixaban is preferred over VKA. Use of aspirin immediately and for up to 30 days results in an equal tradeoff between an increase in severe bleeding and a reduction in severe ischemic events. After 30 days, aspirin continues to increase bleeding without significantly reducing ischemic events. These results inform shared, patient-centric decision making on the ideal duration of the use of aspirin after an acute coronary syndrome or percutaneous coronary intervention in patients with atrial fibrillation receiving oral anticoagulation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02415400.

Background: Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain., Objectives: This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy., Methods: A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non-high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were <15 mg/dl. Incremental cost per quality-adjusted life-year (QALY) was determined with the addition of alirocumab versus placebo and, based on clinical efficacy findings from the trial, was stratified by baseline LDL-C levels ≥100 mg/dl and <100 mg/dl., Results: Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C <100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C ≥100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses., Conclusions: In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C <100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: High bleeding risk (HBR) patients undergoing percutaneous coronary intervention have been widely excluded from randomized device registration trials. The LF study (LEADERS FREE) reported superior outcomes of HBR patients receiving 30-day dual antiplatelet therapy after percutaneous coronary intervention with a polymer-free drug-coated stent (DCS). LFII was designed to assess the reproducibility and generalizability of the benefits of DCS observed in LF to inform the US Food and Drug Administration in a device registration decision., Methods: LFII was a single-arm study using HBR inclusion/exclusion criteria and 30-day dual antiplatelet therapy after percutaneous coronary intervention with DCS, identical to LF. The 365-day rates of the primary effectiveness (clinically indicated target lesion revascularization) and safety (composite cardiac death and myocardial infarction) end points were reported using a propensity-stratified analysis compared with the LF bare metal stent arm patients as controls., Results: A total of 1203 LFII patients were enrolled with an average 1.7 HBR criteria per patient, including 60.7% >75 years of age, 34.1% on anticoagulants, and 14.7% with renal failure. Propensity-adjusted 365-day clinically indicated target lesion revascularization was significantly lower with DCS (7.2% versus 9.2%; hazard ratio, 0.72 [95% CI, 0.52-0.98]; P =0.0338 for superiority), as was the primary safety (cardiac death and myocardial infarction) composite (9.3% versus 12.4%; hazard ratio, 0.72 [95% CI, 0.55-0.94]; P =0.0150 for superiority). Stent thrombosis rates were 2.0% DCS and 2.2% bare metal stent. Major bleeding at 1 year occurred in 7.2% DCS patients and 7.2% bare metal stent., Conclusions: LFII reproduces the results of the DCS arm of LF in an independent, predominantly North American cohort of HBR patients.

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.)

Traditional statistical models allow population based inferences and comparisons. Machine learning (ML) explores datasets to develop algorithms that do not assume linear relationships between variables and outcomes and that may account for higher order interactions to make individualized outcome predictions. To evaluate the performance of machine learning models compared to traditional risk stratification methods for the prediction of major adverse cardiovascular events (MACE) and bleeding in patients with acute coronary syndrome (ACS) that are treated with antithrombotic therapy. Data on 24,178 ACS patients were pooled from four randomized controlled trials. The super learner ensemble algorithm selected weights for 23 machine learning models and was compared to traditional models. The efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. The safety endpoint was a composite of TIMI major and minor bleeding or bleeding requiring medical attention. For the MACE outcome, the super learner model produced a higher c-statistic (0.734) than logistic regression (0.714), the TIMI risk score (0.489), and a new cardiovascular risk score developed in the dataset (0.644). For the bleeding outcome, the super learner demonstrated a similar c-statistic as the logistic regression model (0.670 vs. 0.671). The machine learning risk estimates were highly calibrated with observed efficacy and bleeding outcomes (Hosmer-Lemeshow p value = 0.692 and 0.970, respectively). The super learner algorithm was highly calibrated on both efficacy and safety outcomes and produced the highest c-statistic for prediction of MACE compared to traditional risk stratification methods. This analysis demonstrates a contemporary application of machine learning to guide patient-level antithrombotic therapy treatment decisions.Clinical Trial Registration ATLAS ACS-2 TIMI 46: https://clinicaltrials.gov/ct2/show/NCT00402597. Unique Identifier: NCT00402597. ATLAS ACS-2 TIMI 51: https://clinicaltrials.gov/ct2/show/NCT00809965. Unique Identifier: NCT00809965. GEMINI ACS-1: https://clinicaltrials.gov/ct2/show/NCT02293395. Unique Identifier: NCT02293395. PIONEER-AF PCI: https://clinicaltrials.gov/ct2/show/NCT01830543. Unique Identifier: NCT01830543.

Background: The safety and efficacy of antithrombotic regimens may differ between patients with atrial fibrillation who have acute coronary syndromes (ACS), treated medically or with percutaneous coronary intervention (PCI), and those undergoing elective PCI., Methods: Using a 2×2 factorial design, we compared apixaban with vitamin K antagonists and aspirin with placebo in patients with atrial fibrillation who had ACS or were undergoing PCI and were receiving a P2Y 12 inhibitor. We explored bleeding, death and hospitalization, as well as death and ischemic events, by antithrombotic strategy in 3 prespecified subgroups: patients with ACS treated medically, patients with ACS treated with PCI, and those undergoing elective PCI., Results: Of 4614 patients enrolled, 1097 (23.9%) had ACS treated medically, 1714 (37.3%) had ACS treated with PCI, and 1784 (38.8%) had elective PCI. Apixaban compared with vitamin K antagonist reduced International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding in patients with ACS treated medically (hazard ratio [HR], 0.44 [95% CI, 0.28-0.68]), patients with ACS treated with PCI (HR, 0.68 [95% CI, 0.52-0.89]), and patients undergoing elective PCI (HR, 0.82 [95% CI, 0.64-1.04]; P interaction =0.052) and reduced death or hospitalization in the ACS treated medically (HR, 0.71 [95% CI, 0.54-0.92]), ACS treated with PCI (HR, 0.88 [95% CI, 0.74-1.06]), and elective PCI (HR, 0.87 [95% CI, 0.72-1.04]; P interaction =0.345) groups. Compared with vitamin K antagonists, apixaban resulted in a similar effect on death and ischemic events in the ACS treated medically, ACS treated with PCI, and elective PCI groups ( P interaction =0.356). Aspirin had a higher rate of bleeding than did placebo in patients with ACS treated medically (HR, 1.49 [95% CI, 0.98-2.26]), those with ACS treated with PCI (HR, 2.02 [95% CI, 1.53-2.67]), and those undergoing elective PCI (HR, 1.91 [95% CI, 1.48-2.47]; P interaction =0.479). For the same comparison, there was no difference in outcomes among the 3 groups for the composite of death or hospitalization ( P interaction =0.787) and death and ischemic events ( P interaction =0.710)., Conclusions: An antithrombotic regimen consisting of apixaban and a P2Y 12 inhibitor without aspirin provides superior safety and similar efficacy in patients with atrial fibrillation who have ACS, whether managed medically or with PCI, and those undergoing elective PCI compared with regimens that include vitamin K antagonists, aspirin, or both., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02415400.

Objectives: We explored the anatomical, plaque, and hemodynamic characteristics of high-risk non-obstructive coronary lesions that caused acute coronary syndrome (ACS)., Methods: From the EMERALD study which included ACS patients with available coronary CT angiography (CCTA) before the ACS, non-obstructive lesions (percent diameter stenosis < 50%) were selected. CCTA images were analyzed for lesion characteristics by independent CCTA and computational fluid dynamics core laboratories. The relative importance of each characteristic was assessed by information gain., Results: Of the 132 lesions, 24 were the culprit for ACS. The culprit lesions showed a larger change in FFR CT across the lesion (ΔFFR CT ) than non-culprit lesions (0.08 ± 0.07 vs 0.05 ± 0.05, p = 0.012). ΔFFR CT showed the highest information gain (0.051, 95% confidence interval [CI] 0.050-0.052), followed by low-attenuation plaque (0.028, 95% CI 0.027-0.029) and plaque volume (0.023, 95% CI 0.022-0.024). Lesions with higher ΔFFR CT or low-attenuation plaque showed an increased risk of ACS (hazard ratio [HR] 3.25, 95% CI 1.31-8.04, p = 0.010 for ΔFFR CT ; HR 2.60, 95% CI 1.36-4.95, p = 0.004 for low-attenuation plaque). The prediction model including ΔFFR CT , low-attenuation plaque and plaque volume showed the highest ability in ACS prediction (AUC 0.725, 95% CI 0.724-0.727)., Conclusion: Non-obstructive lesions with higher ΔFFR CT or low-attenuation plaque showed a higher risk of ACS. The integration of anatomical, plaque, and hemodynamic characteristics can improve the noninvasive prediction of ACS risk in non-obstructive lesions., Key Points: • Change in FFR CT across the lesion (ΔFFR CT ) was the most important predictor of ACS risk in non-obstructive lesions. • Non-obstructive lesions with higher ΔFFR CT or low-attenuation plaque were associated with a higher risk of ACS. • The integration of anatomical, plaque, and hemodynamic characteristics can improve the noninvasive prediction of ACS risk.

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.

Diabetes mellitus (DM) and abnormal glucose metabolism are associated with cardiovascular (CV) disease. We investigated the prevalence and prognostic importance of dysglycaemia in patients with acute coronary syndromes (ACS) in the PLATelet inhibition and patient Outcomes (PLATO) trial. Diabetes was defined as known diabetes or HbA1c ≥ 6.5% or non-fasting glucose ≥ 11.1 mmol/L on admission, prediabetes as HbA1c ≥ 5.7% but < 6.5%, and no diabetes as HbA1c < 5.7%. The primary endpoint was the composite of CV death, spontaneous myocardial infarction type 1 (sMI) or stroke at 12 months. Multivariable Cox regression models, adjusting for baseline characteristics, and biomarkers NT-proBNP and troponin I, were used to explore the association between glycaemia and outcome. On admission, 16,007 (86.1%) patients had HbA1c and/or glucose levels available and were subdivided into DM 38.5% (6160) (1501 patients had no previous DM diagnosis), prediabetes 38.8% (6210), and no DM 22.7% (3637). Kaplan Meier event rates at 12 months for CV death, sMI or stroke per subgroups were 14.5% (832), 9.0% (522), and 8.5% (293), respectively with multivariable adjusted HRs, versus no diabetes, for diabetes: 1.71 (1.50-1.95) and for prediabetes 1.03 (0.90-1.19). Corresponding event rates for CV death were 6.9% (391), 3.4% (195) and 3.0% (102), respectively, with adjusted HRs for patients with DM of: 1.92 (1.42-2.60) and for prediabetes 1.02 (0.79-1.32). Abnormal glucose metabolism is common in ACS patients, but only patients with definite DM have an increased CV risk, indicating that prediabetes is not immediately associated with worse CV outcomes.

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: Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACEs) and death. The impact of lipid lowering by proprotein convertase subtilisin-kexin type 9 inhibition in such patients is undetermined., Objectives: This pre-specified analysis from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) determined whether polyvascular disease influenced risks of MACEs and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy., Methods: Patients were randomized to alirocumab or placebo 1 to 12 months after ACS. The primary MACEs endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint., Results: Median follow-up was 2.8 years. Of 18,924 patients, 17,370 had monovascular (coronary) disease, 1,405 had polyvascular disease in 2 beds (coronary and peripheral artery or cerebrovascular), and 149 had polyvascular disease in 3 beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACEs by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, the corresponding absolute risk reduction was 1.4% (95% confidence interval [CI]: 0.6% to 2.3%), 1.9% (95% CI: -2.4% to 6.2%), and 13.0% (95% CI: -2.0% to 28.0%). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; the absolute risk reduction with alirocumab was 0.4% (95% CI: -0.1% to 1.0%), 1.3% (95% CI: -1.8% to 4.3%), and 16.2% (95% CI: 5.5% to 26.8%)., Conclusions: In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyvascular disease is associated with high risks of MACEs and death. The large absolute reductions in those risks with alirocumab are a potential benefit for these patients. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]: NCT01663402)., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome., Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death., Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths ( P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events ( P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; P interaction =0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend)., Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01663402.

Background: Heart failure (HF) following acute coronary syndromes (ACS) is associated with worse prognosis; however, the efficacy and safety of ticagrelor in patients with HF and if ticagrelor influences the risk of new-onset HF are unknown., Methods: We examined the efficacy and safety of ticagrelor compared to clopidogrel in patients with ACS in the randomized PLATelet inhibition and patient Outcomes (PLATO) trial subdivided by strata: (1) previous HF and/or clinical signs of HF on admission or (2) no HF on admission. The primary outcome was the combination of cardiovascular death, myocardial infarction, or stroke evaluated by multivariable Cox regression models. The safety outcome was major bleeding. New-onset HF was defined as an HF event after discharge in patients without previous HF., Results: Data were available in 18,556 patients, whom 2,862 (15.4%) patients had HF, including 1,584 (8.5%) patients with previous HF. Patients randomized to ticagrelor had lower risk of the composite end point regardless of HF status: hazard ratio (HR) 0.87 (95% CI: 0.73-1.03) in patients with HF and HR 0.84 (95% CI: 0.75-0.93) in patients with no HF (P = .76). Corresponding HR for major bleeding were HR 1.08 (95% CI: 0.87-1.34) and HR 1.03 (95% CI: 0.94-1.14) (P = .71). There was no difference in new-onset HF at 12 months between patients randomized to ticagrelor (4.1%, n = 278) or clopidogrel (4.0%, n = 276)., Conclusions: In patients with ACS, ticagrelor is more efficacious in protecting against new ischemic events and mortality than clopidogrel irrespective of the presence of HF. There is no difference between ticagrelor or clopidogrel treatment in new-onset HF post-ACS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

There has been a tremendous growth quantity of high-quality imaging evidence in the area of acute and stable ischemic heart disease (SIHD). A number of recent comparative effectiveness trials have spurned significant controversies in the field of cardiovascular imaging. The result of this evidence is that many health care policies and national guidelines have undergone significant revisions. With all of this evidence, many challenges remain and the optimal evaluation strategy for evaluation of patients presenting with chest pain remains ill-defined. This paper enlisted the guidance of numerous experts in the field of cardiovascular imaging to garner their perspective on available imaging research in chest pain syndromes. Each of these vignettes represent editorial perspectives and diverse opinions as to which, if any, should be the primary test in the evaluation of stable chest pain. These perspectives are not meant to be all inclusive but to highlight many of the commonly discussed controversies in the evaluation of chest pain symptoms. These perspectives are presented as a pre-amble to an upcoming American College of Cardiology/American Heart Association clinical practice guideline that is undergoing revision from the previous report published in 2012. The evidence has changed considerably since the 2012 SIHD guideline, and the current perspectives represent the diversity of available evidence as to the optimal imaging strategy for evaluation of the symptomatic patient., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Physician behavior in response to knowledge of a patient's CYP2C19 clopidogrel metabolizer status is unknown., Objective: To investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial., Design, Setting, and Participants: The GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019., Interventions: Investigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization., Main Outcomes and Measures: Reasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected., Results: Of 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated., Conclusions and Relevance: Physicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach., Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02293395.

Objectives: The authors investigated the utility of noninvasive hemodynamic assessment in the identification of high-risk plaques that caused subsequent acute coronary syndrome (ACS)., Background: ACS is a critical event that impacts the prognosis of patients with coronary artery disease. However, the role of hemodynamic factors in the development of ACS is not well-known., Methods: Seventy-two patients with clearly documented ACS and available coronary computed tomographic angiography (CTA) acquired between 1 month and 2 years before the development of ACS were included. In 66 culprit and 150 nonculprit lesions as a case-control design, the presence of adverse plaque characteristics (APC) was assessed and hemodynamic parameters (fractional flow reserve derived by coronary computed tomographic angiography [FFR CT ], change in FFR CT across the lesion [△FFR CT ], wall shear stress [WSS], and axial plaque stress) were analyzed using computational fluid dynamics. The best cut-off values for FFR CT , △FFR CT , WSS, and axial plaque stress were used to define the presence of adverse hemodynamic characteristics (AHC). The incremental discriminant and reclassification abilities for ACS prediction were compared among 3 models (model 1: percent diameter stenosis [%DS] and lesion length, model 2: model 1 + APC, and model 3: model 2 + AHC)., Results: The culprit lesions showed higher %DS (55.5 ± 15.4% vs. 43.1 ± 15.0%; p < 0.001) and higher prevalence of APC (80.3% vs. 42.0%; p < 0.001) than nonculprit lesions. Regarding hemodynamic parameters, culprit lesions showed lower FFR CT and higher △FFR CT , WSS, and axial plaque stress than nonculprit lesions (all p values <0.01). Among the 3 models, model 3, which included hemodynamic parameters, showed the highest c-index, and better discrimination (concordance statistic [c-index] 0.789 vs. 0.747; p = 0.014) and reclassification abilities (category-free net reclassification index 0.287; p = 0.047; relative integrated discrimination improvement 0.368; p < 0.001) than model 2. Lesions with both APC and AHC showed significantly higher risk of the culprit for subsequent ACS than those with no APC/AHC (hazard ratio: 11.75; 95% confidence interval: 2.85 to 48.51; p = 0.001) and with either APC or AHC (hazard ratio: 3.22; 95% confidence interval: 1.86 to 5.55; p < 0.001)., Conclusions: Noninvasive hemodynamic assessment enhanced the identification of high-risk plaques that subsequently caused ACS. The integration of noninvasive hemodynamic assessments may improve the identification of culprit lesions for future ACS. (Exploring the Mechanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary CT Angiography and Computational Fluid Dynamic [EMERALD]; NCT02374775)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Prior observational studies suggest that quality of care improvement (QCI) initiatives can improve the clinical outcomes of acute coronary syndrome (ACS). To our knowledge, this has never been demonstrated in a well-powered randomized clinical trial., Objective: To determine whether a clinical pathway-based, multifaceted QCI intervention could improve clinical outcomes among patients with ACS in resource-constrained hospitals in China., Design, Setting, Participants: This large, stepped-wedge cluster randomized clinical trial was conducted in nonpercutaneous coronary intervention hospitals across China and included all patients older than 18 years and with a final diagnosis of ACS who were recruited consecutively between October 2011 and December 2014. We excluded patients who died before or within 10 minutes of hospital arrival. We recruited 5768 and 0 eligible patients for the control and intervention groups, respectively, in step 1, 4326 and 1365 in step 2, 3278 and 3059 in step 3, 1419 and 4468 in step 4, and 0 and 5645 in step 5., Interventions: The intervention included establishing a QCI team, training clinical staff, implementing ACS clinical pathways, sequential site performance assessment and feedback, online technical support, and patient education. The usual care was the control that was compared., Main Outcomes and Measures: The primary outcome was the incidence of in-hospital major adverse cardiovascular events (MACE), comprising all-cause mortality, reinfarction/myocardial infarction, and nonfatal stroke. Secondary outcomes included 16 key performance indicators (KPIs) and the composite score developed from these KPIs., Results: Of 29 346 patients (17 639 men [61%]; mean [SD] age for control, 64.1 [11.6] years; mean [SD] age for intervention, 63.9 [11.7] years) who were recruited from 101 hospitals, 14 809 (50.5%) were in the control period and 14 537 (49.5%) were in the intervention period. There was no significant difference in the incidence of in-hospital MACE between the intervention and control periods after adjusting for cluster and time effects (3.9% vs 4.4%; odds ratio, 0.93; 95% CI, 0.75-1.15; P = .52). The intervention showed a significant improvement in the composite KPI score (mean [SD], 0.69 [0.22] vs 0.61 [0.23]; P < .01) and in 7 individual KPIs, including the early use of antiplatelet therapy and the use of appropriate secondary prevention medicines at discharge. No unexpected adverse events were reported., Conclusions and Relevance: Among resource-constrained Chinese hospitals, introducing a multifaceted QCI intervention had no significant effect on in-hospital MACE, although it improved a few of the care process indicators of evidence-based ACS management., Trial Registration: ClinicalTrials.gov identifier: NCT01398228.