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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.

Background: The optimal antiplatelet regimen after percutaneous coronary intervention (PCI) in patients with peripheral artery disease (PAD) is still debated. This analysis aimed to compare the effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients with PAD undergoing PCI., Methods: In the TWILIGHT trial, patients at high ischemic or bleeding risk that underwent PCI were randomized after 3 months of dual antiplatelet therapy (DAPT) to aspirin or matching placebo in addition to open-label ticagrelor for 12 additional months. In this post-hoc analysis, patient cohorts were examined according to the presence or absence of PAD. The primary endpoint was Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding. The key secondary endpoint was a composite of all-cause death, myocardial infarction (MI), or stroke. Endpoints were assessed at 12 months after randomization., Results: Among 7,119 patients, 489 (7%) had PAD and were older, more likely to have comorbidities, and multivessel disease. PAD patients had more bleeding or ischemic complications than no-PAD patients. Ticagrelor monotherapy compared to ticagrelor plus aspirin was associated with less BARC 2, 3, or 5 bleeding in PAD (4.6% vs 8.7%; HR 0.52; 95%CI 0.25-1.07) and no-PAD patients (4.0% vs 7.0%; HR 0.56; 95%CI 0.45-0.69; interaction P-value .830) and a similar risk of death, MI, or stroke in these 2 groups (interaction P-value .446)., Conclusions: Despite their higher ischemic and bleeding risk, patients with PAD undergoing PCI derived a consistent benefit from ticagrelor monotherapy after 3 months of DAPT in terms of bleeding reduction without any relevant increase in ischemic events. CLINICAL TRIAL REGISTRY INFORMATION:: https://www., Clinicaltrials: gov/study/NCT02270242., Competing Interests: Conflict of interest Dr Spirito received a research grant from the Swiss National Science Foundation (SNSF). Dr Baber has received honoraria from AstraZeneca and Boston Scientific. Dr. Angiolillo declares that he has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi and Vectura; D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, and the Scott R. MacKenzie Foundation. Dr Cohen has received grant support, paid to his institution, and consulting fees from AstraZeneca, Medtronic, and Abbott Vascular; and has received grant support, paid to his institution, from Boston Scientific. Dr Dangas has received consulting fees and advisory board fees from AstraZeneca; has received consulting fees from Biosensors; and previously held stock in Medtronic. Dr Escaned has received consulting and lecture fees from Abbott, Philips, Boston Scientific, and Medtronic; and has received lecture fees from Abiomed, Terumo, and Biosensors. Dr. Gibson has received grant support and consulting fees from Angel Medical, Bayer, CSL Behring, Janssen. Pharmaceuticals, Johnson & Johnson, and Portola Pharmaceuticals; has received consulting fees from The Medicines Company, Eli Lilly, Gilead Sciences, Novo Nordisk, WebMD, UpToDate Cardiovascular Medicine, Amarin Pharma, Amgen, Boehringer Ingelheim, Chiesi, Merck, PharmaMar, Sanofi, Somahlution, Verreseon, Boston Scientific, Impact Bio, MedImmume, Medtelligence, MicroPort, the PERT Consortium, and GE Healthcare; holds equity in Inference; serves as chief executive officer of the Baim Institute; and has received grant support, paid to the Baim Institute, from Bristol Myers Squibb and Astra Zeneca. Dr Huber has received lecture fees from AstraZeneca and Bayer. Dr. Kastrati is an inventor in a patent application related to drug-eluting stent technology; he also serves in the Data and Safety Monitoring Board of the TARGET IV trial sponsored by the Cardiovascular Research Foundation in New York, USA. Dr Mehta has received grant support from and has served on an executive committee and as site investigator for AstraZeneca. Dr Steg received research grant from Amarin, Bayer, Sanofi and Servier; speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Bristol Myers Squibb, Idorsia, Myokardia, Novartis, Novo Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, and Servier. Dr. Mehran reports institutional research payments from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Arena, AstraZeneca, Atricure, Bayer, Biosensors, Biotronik, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, Pi-Cardia, PLx Pharma, RenalPro, RM Global, Shockwave, Vivasure, Zoll; personal fees from Cine-Med Research, Novartis, WebMD; Equity <1% in Applied Therapeutics, Elixir Medical, Stel, ControlRad (spouse); Scientific Advisory Board for AMA, ACC (BOT Member), SCAI (Women in Innovations Committee Member), JAMA Associate Editor; Faculty CRF (no fee). The remaining authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Body mass index (BMI) affects drug levels of nonvitamin K antagonist oral anticoagulants. We sought to assess whether BMI affected outcomes in the RE-DUAL PCI trial., Methods: RE-DUAL PCI (NCT02164864) evaluated the safety and efficacy of a dual-antithrombotic-therapy regimen using dabigatran (110 mg or 150 mg twice daily and a P2Y 12 platelet antagonist) in comparison with triple therapy of warfarin, aspirin, and a P2Y 12 platelet inhibitor in 2725 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI). We compared the risk of first International Society on Thrombosis and Haemostasis (ISTH)-defined major or clinically relevant nonmajor bleeding events (primary endpoint) and the composite of death, myocardial infarction, stroke, systemic embolism, or unplanned revascularization (main efficacy endpoint) in relation to baseline BMI., Results: Median (range) BMI was 28.1 (14-66) kg/m 2 . Dabigatran dual therapy versus warfarin triple therapy had relevantly and similarly lower rates of bleeding at both 110 mg and 150 mg twice-daily doses, irrespective of BMI. Thromboembolic event rates appeared consistent across categories of BMI, including those <25 and ≥35 kg/m 2 (P for interaction: 0.806 and 0.279, respectively)., Conclusions: The reduction in bleeding with dabigatran dual therapy compared with warfarin triple therapy in patients here evaluated appears consistent across BMI categories., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Antiplatelet therapy for patients with coronary artery disease has evolved dramatically over the last decade. P2Y12 inhibitors offering more potent and consistent platelet inhibition than clopidogrel are now widely available, dual antiplatelet therapy (DAPT) duration can be tailored to individual ischemic and bleeding risks, and strategies to personalize antiplatelet therapy have been developed when concomitant oral anticoagulation (OAC) is indicated. Scientific societies from Canada, the United States, and Europe have all published updated recommendations addressing antiplatelet therapy in the recent years. The purpose of this review is to put the Canadian guidelines into perspective vis-à-vis international recommendations by highlighting similarities and critically analyzing differences. We focus on 3 major topics relevant for clinical practice: DAPT duration following drug-eluting stent implantation, DAPT following percutaneous coronary intervention in patients with concomitant indications for OAC, and DAPT management for noncardiac surgery following drug-eluting stent implantation. Although guidelines broadly agree on the majority of recommendations, the justifications for major differences were contrasted in the manuscript. Unanswered questions remain, including the place of aspirin in secondary prevention of coronary artery disease in the contemporary era, aspirin-free strategies early after percutaneous coronary intervention, and the safe minimal duration of DAPT with newer generation stents., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: P2Y 12 inhibitor monotherapy with ticagrelor after a brief period of dual antiplatelet therapy can reduce bleeding without increasing ischemic harm after percutaneous coronary intervention (PCI). The impact of this approach among patients with diabetes mellitus (DM) remains unknown., Objectives: The purpose of this study was to examine the effect of ticagrelor monotherapy versus ticagrelor plus aspirin among patients with DM undergoing PCI., Methods: This was a pre-specified analysis of the DM cohort in the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial. After 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The primary endpoint was Bleeding Academic Research Consortium 2, 3, or 5 bleeding. The composite ischemic endpoint was all-cause death, myocardial infarction, or stroke., Results: Patients with DM comprised 37% (n = 2,620) of the randomized cohort and were characterized by more frequent comorbidities and a higher prevalence of multivessel disease. The incidence of Bleeding Academic Research Consortium 2, 3, or 5 bleeding was 4.5% and 6.7% among patients with DM randomized to ticagrelor plus placebo versus ticagrelor plus aspirin (hazard ratio: 0.65; 95% confidence interval: 0.47 to 0.91; p = 0.012). Ticagrelor monotherapy was not associated with an increase in ischemic events compared with ticagrelor plus aspirin (4.6% vs. 5.9%; hazard ratio: 0.77; 95% confidence interval: 0.55 to 1.09; p = 0.14). In the overall trial population, there was no significant interaction between DM status and treatment group for the primary bleeding or ischemic endpoints., Conclusions: Compared with ticagrelor plus aspirin, the effect of ticagrelor monotherapy in reducing the risk of clinically relevant bleeding without any increase in ischemic events was consistent among patients with or without DM undergoing PCI. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242)., (Copyright © 2020 American College of Cardiology Foundation. 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: Monotherapy with a P2Y 12 inhibitor after a minimum period of dual antiplatelet therapy is an emerging approach to reduce the risk of bleeding after percutaneous coronary intervention (PCI)., Methods: In a double-blind trial, we examined the effect of ticagrelor alone as compared with ticagrelor plus aspirin with regard to clinically relevant bleeding among patients who were at high risk for bleeding or an ischemic event and had undergone PCI. After 3 months of treatment with ticagrelor plus aspirin, patients who had not had a major bleeding event or ischemic event continued to take ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. We also evaluated the composite end point of death from any cause, nonfatal myocardial infarction, or nonfatal stroke, using a noninferiority hypothesis with an absolute margin of 1.6 percentage points., Results: We enrolled 9006 patients, and 7119 underwent randomization after 3 months. Between randomization and 1 year, the incidence of the primary end point was 4.0% among patients randomly assigned to receive ticagrelor plus placebo and 7.1% among patients assigned to receive ticagrelor plus aspirin (hazard ratio, 0.56; 95% confidence interval [CI], 0.45 to 0.68; P<0.001). The difference in risk between the groups was similar for BARC type 3 or 5 bleeding (incidence, 1.0% among patients receiving ticagrelor plus placebo and 2.0% among patients receiving ticagrelor plus aspirin; hazard ratio, 0.49; 95% CI, 0.33 to 0.74). The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (difference, -0.06 percentage points; 95% CI, -0.97 to 0.84; hazard ratio, 0.99; 95% CI, 0.78 to 1.25; P<0.001 for noninferiority)., Conclusions: Among high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy, ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of death, myocardial infarction, or stroke. (Funded by AstraZeneca; TWILIGHT ClinicalTrials.gov number, NCT02270242.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear., Methods: In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria., Results: A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02)., Conclusions: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor., Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population)., Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8-3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74-0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, p interaction =0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78-1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75-1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48-2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36-3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74-1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75-0·95, p=0·005, in contrast to patients without PCI where it did not, p interaction =0·012. Benefit was present irrespective of time from most recent PCI., Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk., Funding: AstraZeneca., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients ≥50 years with type 2 diabetes receiving anti-diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of ≥50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Background: Monitoring anticoagulation with activated clotting time (ACT) has been proposed to reduce ischemic or bleeding events. However, the value of using ACT to improve outcomes is uncertain. This study sought to determine the relationship between ACT and outcomes during percutaneous coronary intervention in patients with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) treated by unfractionated heparin with GPIs (glycoprotein IIb/IIIa inhibitors)., Methods and Results: From the randomized TAO trial (Treatment of Acute Coronary Syndromes With Otamixaban), we analyzed the value of ACT to predict ischemic and bleeding outcomes in the 3275 patients receiving unfractionated heparin plus eptifibatide. Ischemic and safety outcomes were analyzed according to ACT to determine the best threshold. Median peak ACT was 225 s. There was no correlation ( r =-0.02; P =0.24) between the unfractionated heparin dose received and the ACT value before percutaneous coronary intervention. There was no evidence of a nonlinear association between ACT and either ischemic or bleeding events ( P =0.66; P =0.07). No threshold was found to predict ischemic complications. Conversely, increased bleeding was observed with ACT >230 s with an optimal threshold of ACTs ≥250 s (4.53% versus 6.17%; odds ratio, 1.46; 95% confidence interval, 1.04-2.06; P =0.028). This optimal threshold varied according to access site: ≥250 s (6.86% versus 10.18%; odds ratio, 1.57; 95% confidence interval, 1.00-2.45; P =0.047) by femoral approach and ≥290 s (2.86% versus 5.43%; odds ratio, 2.24; 95% confidence interval, 1.05-4.44; P =0.027) by radial approach., Conclusions: In the TAO trial, peak procedural ACT ≥250 s was associated with increased bleeding risk in non-ST-segment-elevation acute coronary syndrome patients treated with unfractionated heparin plus GPIs. This threshold was increased to 290 s when performing radial approach., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01076764., (© 2018 American Heart Association, Inc.)

While divorced or living alone, patients with stable cardiovascular disease are at increased risk for adverse cardiovascular events. The importance of marital status following a myocardial infarction (MI) is less clear. We hypothesized that marital status may affect cardiovascular outcomes following MI. We analyzed outcomes among patients with MI who underwent percutaneous coronary intervention from the Canadian Observational Antiplatelet Study (COAPT). Marital status was categorized into 3 groups: married/common-law patients living together; never married; and divorced, separated, or widowed patients. Patients were followed for 15 months and our primary outcome was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite of mortality, repeat acute MI, stroke, or urgent coronary revascularization. Multivariable logistic regression models were performed, with married/common-law patients living together considered the reference group. Among 2100 patients included in analyses, 1519 (72.3%) were married/common-law patients living together, 358 (17.1%) were separated/divorced/widowed, and 223 (10.6%) patients were never married. Dual antiplatelet therapy use after 15 months was similar across groups (75.4%, 77.8%, and 73.6%, respectively). The risk of MACE after 15 months was similar among married patients living together (12.7%; referent) compared with patients who were never married (13.9%; adjusted odds ratio: 1.09, 95% confidence interval: 0.58-2.07, P = 0.79) and patients separated/divorced/widowed (14.3%; adjusted odds ratio: 0.71, 95% confidence interval: 0.40-1.25, P = 0.23). Similarly, the risk of individual endpoints, including mortality, was similar across the 3 groups. Among patients stabilized following an MI, we found no association between marital status and 15-month outcomes., (© 2018 Wiley Periodicals, Inc.)

Background: Prior Studies have suggested better outcomes in smokers compared with nonsmokers receiving clopidogrel ("smoker's paradox"). The impact of a more intensive clopidogrel regimen on ischemic and bleeding risks in smokers with acute coronary syndromes requiring percutaneous coronary interventions remains unclear., Methods and Results: We analyzed 17 263 acute coronary syndrome patients undergoing percutaneous coronary intervention from the CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organization to Assess Strategies in Ischemic Symptoms) trial, which compared double-dose (600 mg day 1;150 mg days 2-7; then 75 mg daily) versus standard-dose (300 mg day 1; then 75 mg daily) clopidogrel in acute coronary syndrome patients. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Interactions between treatment allocation and smoking status (current smokers versus nonsmokers) were evaluated. Overall, 6394 patients (37.0%) were current smokers. For the comparison of double- versus standard-dose clopidogrel, there were significant interactions in smokers and nonsmokers for the primary outcome ( P =0.031) and major bleeding ( P =0.002). Double- versus standard-dose clopidogrel reduced the primary outcome among smokers by 34% (hazard ratio [HR] 0.66, 95% confidence interval [CI], 0.50-0.87, P =0.003), whereas in nonsmokers, there was no apparent benefit (HR 0.96, 95% CI, 0.80-1.14, P =0.61). For major bleeding, there was no difference between the groups in smokers (HR 0.77, 95% CI, 0.48-1.24, P =0.28), whereas in nonsmokers, the double-dose clopidogrel regimen increased bleeding (HR 1.89, 95% CI, 1.37-2.60, P <0.0001). Double-dose clopidogrel reduced the incidence of definite stent thrombosis in smokers (HR 0.41, 95% CI, 0.24-0.71) and nonsmokers (HR 0.63, 95% CI, 0.42-0.93; P for interaction=0.19)., Conclusions: In smokers, a double-dose clopidogrel regimen reduced major cardiovascular events and stent thrombosis after percutaneous coronary intervention, with no increase in major bleeding. This suggests that clopidogrel dosing in patients with acute coronary syndromes should be personalized, taking into consideration both ischemic and bleeding risk., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00335452., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Aims: There is a paucity of real-world, contemporary data of practice patterns and clinical outcomes following dual-antiplatelet therapy (DAPT) in acute myocardial infarction (AMI) patients treated with percutaneous coronary intervention (PCI)., Methods and Results: The Canadian Observational Antiplatelet Study was a prospective, multicentre, cohort study examining adenosine diphosphate receptor antagonist use following PCI for AMI. We compared practice patterns, patient characteristics, and clinical outcomes in relation to DAPT duration (<6 weeks, 6 weeks to <6 months, 6 to <12, and ≥12 months). The primary outcome was the composite of non-fatal AMI, unplanned coronary revascularization, stent thrombosis, new or worsening heart failure, cardiogenic shock, or stroke. We identified 2034 patients with AMI treated with PCI. DAPT duration was <6 weeks in 5.2% of patients; 6 weeks to <6 months in 7.0%; 6 to <12 months in 12.6%; and ≥12 months in 75.3%. Patients who discontinued DAPT early had higher GRACE risk scores. Overall, mortality rate at 15 months was 2.5%. Compared with a duration of DAPT of ≥12 months, discontinuation of DAPT <6 weeks (P < 0.0001) and 6 weeks to <6 months (P = 0.02), but not 6 months to <12 months (P = 0.06), were independently associated with a higher incidence of the primary outcome among survivors., Conclusion: One-in-four patients with AMI treated with PCI discontinued DAPT prior to the guideline-recommended 12-month duration. Patients in whom DAPT was discontinued early were at higher baseline risk and had higher rates of non-fatal ischaemic events during follow up., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.)

Purpose of Review: Platelet P2Y12 receptor inhibitors are routinely prescribed for patients after acute coronary syndromes and percutaneous coronary interventions. Patients may have underresponsiveness (or resistance) to these drugs and in particular to clopidogrel, the most often used type. This review aims to focus on the concept of P2Y12 receptor inhibitor resistance and discuss incidence, mechanisms, novel diagnostic techniques and past and future clinical trials on the topic., Recent Findings: Patients treated with P2Y12 receptor inhibitors may develop high on-treatment platelet reactivity (HPR), a phenomenon of impaired response toward the drug, which has been associated with ischemic complications. Although potent P2Y12 inhibitors provide better ischemic protection, this must be balanced with increased bleeding risk. Several clinical factors, including common genetic variants such as Cytochrome P450 2C19 loss-of-function alleles, have been shown to predispose to HPR among patients on clopidogrel. Platelet function tests and genotyping platforms have enabled identification of patients at-risk for HPR. Past studies using platelet testing and tailoring therapy among patients with HPR have failed to provide conclusive data to support its routine use., Summary: Ongoing studies using genotyping and novel antiplatelet regimens may identify potential strategies to minimize ischemic and bleeding risks concurrently. Until definitive studies demonstrate clear benefit of a personalized approach to P2Y12 inhibitor prescription, the choice of P2Y12 inhibitors should continue to be based on best evidence from previous large clinical trials.

Background: After myocardial infarction (MI) treated with percutaneous coronary intervention (PCI), guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and an ADP receptor inhibitor (ADPri) for at least 1year. However, whether real-world Canadian practice patterns reflect this recommendation is unknown., Methods: We studied 2175 MI patients treated with PCI and discharged from 26 Canadian hospitals between 12/2011 and 05/2013 in the Canadian Observational Antiplatelet sTudy (COAPT). Hierarchical Cox proportional hazard regression modeling was used to determine baseline demographic and clinical factors associated with duration of ADPri therapy post-discharge., Results: At index-hospitalization discharge, 1597 (73%) patients were treated with clopidogrel, 220 (10%) with prasugrel, and 358 (17%) with ticagrelor. ADPri was discontinued prior to 1year in 474 (21.8%) patients; discontinuation rates were lowest for patients discharged on prasugrel (17.7%), compared with clopidogrel (22.5%) or ticagrelor (21.0%), (log rank test, p=0.03). In addition to regional variability, factors associated with shorter ADPri duration included older age, low body weight, Killip III/IV heart failure, atrial fibrillation, ticagrelor on discharge, and bare metal stent use, while longer ADPri duration was associated with history of prior MI., Conclusions: One in five PCI-treated MI patients did not complete Canadian guideline-recommended 1-year course of ADPri treatment. Premature ADPri discontinuation was most strongly associated with factors that increase the risk of bleeding. Further study is required to assess the clinical implications of premature ADPri discontinuation on patient outcomes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Since the introduction of newer, more potent P2Y12 receptor inhibitors (P2Y12ris), practice patterns and associated clinical outcomes in patients with myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI) and also requiring oral anticoagulation (OAC) have not been fully characterized., Methods: The Canadian Observational Antiplatelet Study was a prospective, multicenter, longitudinal, observational study (26 hospitals, December 2011 to May 2013) describing P2Y12ri treatment patterns and outcomes in patients with ST-elevation and non-ST-elevation MI undergoing PCI. We describe the clinical characteristics, treatment patterns, bleeding, and ischemic outcomes over the 15-month follow-up within and between the subgroups of patients discharged on either dual-antiplatelet therapy (DAPT) (acetyl salicylic acid [ASA]+P2Y12ri) or triple therapy (ASA+P2Y12ri+OAC)., Results: Of the 2,034 patients at discharge, 86% (n = 1,757) were on DAPT, whereas 14% (n = 277) were on triple therapy (50% warfarin, 50% non-vitamin K OAC [NOAC]). The frequency of newer P2Y12ri use (prasugrel or ticagrelor) was similar in the DAPT and triple therapy groups (28% vs 26%, respectively). In the triple therapy group, NOAC use was higher in those receiving a new P2Y12ri compared to those receiving clopidogrel (75% vs 41%, respectively, P < .0001). The unadjusted and adjusted events of major cardiovascular event (MACE) and bleeding were higher in the triple therapy group. For patients on triple therapy, the bleeding or MACE events were not significantly different between those on clopidogrel versus those on ticagrelor or prasugrel., Conclusion: In this observational study of MI patients requiring PCI, 1 in 8 were discharged on triple antithrombotic therapy, of whom 26% were on newer P2Y12ris. Patients on triple therapy had higher risk at baseline, with higher unadjusted and adjusted MACE and bleeding events compared to those on DAPT alone. Among triple therapy-treated patients, there was no difference in the MACE and bleeding events regardless of the P2Y12ri used., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: We assessed the effectiveness of dual antiplatelet therapy (DAPT) post elective or urgent (i.e., post acute coronary syndrome [ACS]) coronary artery bypass graft surgery (CABG)., Methods: We systematically searched MEDLINE, EMBASE, and the Cochrane Registry from inception to August 2015. Randomized controlled trials (RCTs) in adults undergoing CABG comparing either dual vs. single antiplatelet therapy or higher- vs. lower-intensity DAPT were identified., Results: Nine RCTs (n = 4,887) with up to 1y follow-up were included. Five RCTs enrolled patients post-elective CABG (n = 986). Two multi-centre RCTs enrolled ACS patients who subsequently underwent CABG (n = 2,155). These 7 RCTs compared clopidogrel plus aspirin to aspirin alone. Two other multi-centre RCTs reported on ACS patients who subsequently underwent CABG comparing higher intensity DAPT with either ticagrelor (n = 1,261) or prasugrel (n = 485) plus aspirin to clopidogrel plus aspirin. Post-operative anti-platelet therapy was started when chest tube bleeding was no longer significant, typically within 24-48 h. There were no differences in all-cause mortality in clopidogrel plus aspirin vs. aspirin RCTs; conversely, all-cause mortality was significantly lower in ticagrelor and prasugrel vs. clopidogrel RCTs (risk ratio[RR] 0.49, 95% confidence interval[CI] 0.33-0.71, p = 0.0002; 2 RCTs, n = 1695; I(2)  = 0%; interaction p < 0.01 compared to clopidogrel plus aspirin vs aspirin RCTs). There were no differences in myocardial infarctions, strokes, or composite outcomes. Overall, major bleeding was not significantly increased (RR 1.31, 95% CI 0.81-2.10, p = 0.27; 7 RCTs, n = 4500). There was heterogeneity (I(2)   = 42%) due almost entirely to higher bleeding reported for the prasugrel RCT which included mainly CABG-related major bleeding (RR 3.15, 95% CI 1.45-6.87, p = 0.004; 1 RCT, n = 437)., Conclusions: Most RCT data for DAPT post CABG is derived from subgroups of ACS patients in DAPT RCTs requiring CABG who resume DAPT post-operatively. Limited RCT data with heterogeneous trial designs suggest that higher intensity (prasugrel or ticagrelor) but not lower intensity (clopidogrel) DAPT is associated with an approximate 50% lower mortality in ACS patients who underwent CABG based on post-randomization subsets from single RCTs. Large prospective RCTs evaluating the use of DAPT post-CABG are warranted to provide more definitive guidance for clinicians.

Objective: We evaluated the efficacy and safety of an early invasive strategy post-fibrinolysis in relation to glycoprotein (GP) IIb/IIIa inhibitor use., Methods: The Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) randomised 1059 ST elevation myocardial infarction patients to an early invasive strategy or standard therapy post-fibrinolysis. The primary end point was the composite of death, reinfarction, recurrent ischaemia, new or worsening heart failure, or cardiogenic shock at 30 days. In this pre-specified analysis, we examined efficacy and safety outcomes of an early invasive strategy after stratification by GPIIb/IIIa inhibitor use, which was permitted during percutaneous coronary intervention (PCI) at the discretion of the treating physician., Results: A total of 695 patients (65.6%) received GPIIb/IIIa inhibitors. There was significant heterogeneity (p<0.001) in the efficacy of an early invasive strategy compared to standard therapy, between the strata with GPIIb/IIIa inhibitor use (primary end point 9.6% vs 22.3% respectively, p<0.001) and without GPIIb/IIIa inhibitor use (primary end point 14.8% vs 10.4% respectively, p=0.21). Patients who received GPIIb/IIIa inhibitors had lower Global Registry of Acute Coronary Events (GRACE) risk scores compared to those without GPIIb/IIIa inhibitor use (median 121 vs 130, p<0.001). After adjusting for the interaction between GRACE risk score and treatment assignment, the heterogeneity in the efficacy of an early invasive strategy with respect to GPIIb/IIIa inhibitor use was no longer significant (p interaction=0.08)., Conclusions: The apparent difference in the efficacy of an early invasive strategy between GPIIb/IIIa inhibitor strata likely reflects an association between GPIIb/IIIa inhibitor use and baseline risk. GPIIb/IIIa inhibitor use during PCI at the discretion of the treating physician does not appear to modulate the efficacy of an early invasive strategy post-fibrinolysis., Clinical Trial Registration: http://www.clinicaltrials.gov/ct2/show/NCT00164190, NCT00164190.

The initial 2010 Canadian Cardiovascular Society (CCS) Guidelines for the Use of Antiplatelet Therapy in the Outpatient Setting were published in May 2011. As part of a planned re-evaluation within 2 years, we conducted an extensive literature search encompassing all topics included in the 2010 CCS Guidelines, and concluded that there were sufficient new data to merit revisiting the guidance on antiplatelet therapy for secondary prevention in the first year after acute coronary syndrome (ACS), percutaneous coronary intervention, or coronary artery bypass grafting, and the interaction between clopidogrel and proton pump inhibitors. In addition, new clinical trials information about the efficacy and safety of combining novel oral anticoagulants with antiplatelet therapy in ACS justified the addition of a new section of recommendations to the Guidelines. In this focused update, we provide recommendations for the use of clopidogrel, ticagrelor, and prasugrel in non-ST elevation ACS, avoidance of prasugrel in patients with previous stroke/transient ischemic attack, higher doses of clopidogrel (j) /day) for the first 6 days after ACS, and the preferential use of prasugrel or ticagrelor after percutaneous coronary intervention in ACS. For non-ACS stented patients, we recommend acetylsalicylic acid/clopidogrel for 1 year, with at least 1 month of therapy for bare-metal stent patients and 3 months for drug-eluting stent patients unable to tolerate year-long double therapy. We also consider therapy for patients with a history of stent thrombosis, the indications for longer-term treatment, discontinuation timing preoperatively, indications for changing agents, the management of antiplatelet therapy before and after bypass surgery, and use/selection of proton pump inhibitors along with antiplatelet agents., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Background: Otamixaban is a synthetic intravenous direct factor Xa inhibitor, with rapid onset/offset, linear kinetics, and no significant renal elimination. A phase II trial in acute coronary syndromes (ACS) showed a marked reduction in the combined end point of death or myocardial infarction (MI) and similar bleeding rates with otamixaban at midrange doses, compared with unfractionated heparin (UFH) and eptifibatide., Design: The TAO trial is a phase III, randomized, double-blind, triple-dummy controlled trial testing the efficacy of otamixaban over UFH plus eptifibatide in patients with non-ST-segment elevation ACS to be treated with dual oral antiplatelet therapy and an invasive strategy. Approximately 13,220 patients in 55 countries will be randomized (1:1:1 ratio) to receive UFH plus downstream eptifibatide (started pre-percutaneous coronary intervention and continued per label) or otamixaban (0.08 mg/kg intravenous bolus at randomization then 0.100 or 0.140 mg/kg per hour intravenous infusion). An interim analysis was performed after ≥1,969 patients per arm completed 7 days of follow-up and the Data Monitoring Committee selected 1 otamixaban dose (blinded to investigators) to be carried forward using a prespecified algorithm. The primary efficacy outcome is the composite of all-cause mortality or new MI through day 7. The primary safety outcome is thrombolysis in MI major or minor bleeding through day 7. Secondary outcomes include all-cause mortality, recurrent ischemia/infarction resulting in prolonged/recurrent hospitalization, periprocedural angiographic complications, and pharmacokinetic data in 6,000 patients., Conclusions: The TAO trial will assess the clinical efficacy and safety of otamixaban in non-ST-segment elevation ACS with planned invasive strategy., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: It has been suggested that clopidogrel may be less effective in reducing the rate of cardiovascular events among persons who are carriers of loss-of-function CYP2C19 alleles that are associated with reduced conversion of clopidogrel to its active metabolite., Methods: We genotyped patients from two large, randomized trials that showed that clopidogrel, as compared with placebo, reduced the rate of cardiovascular events (the primary efficacy outcome) among patients with acute coronary syndromes and among patients with atrial fibrillation. Patients were genotyped for three single-nucleotide polymorphisms (*2, *3, *17) that define the major CYP2C19 alleles., Results: Among 5059 genotyped patients with acute coronary syndromes, clopidogrel as compared with placebo significantly reduced the rate of the primary efficacy outcome, irrespective of the genetically determined metabolizer phenotype (P=0.12 for heterogeneity). The effect of clopidogrel in reducing the rate of the primary efficacy outcome was similar in patients who were heterozygous or homozygous for loss-of-function alleles and in those who were not carriers of the alleles (rate among carriers, 8.0% with clopidogrel vs. 11.6% with placebo; hazard ratio with clopidogrel, 0.69; 95% confidence interval [CI], 0.49 to 0.98; rate among noncarriers, 9.5% vs. 13.0%; hazard ratio, 0.72; 95% CI, 0.59 to 0.87). In contrast, gain-of-function carriers derived more benefit from clopidogrel treatment as compared with placebo than did noncarriers (rate of primary outcome among carriers, 7.7% vs. 13.0%; hazard ratio, 0.55; 95% CI, 0.42 to 0.73; rate among noncarriers, 10.0% vs. 12.2%; hazard ratio, 0.85; 95% CI, 0.68 to 1.05; P=0.02 for interaction). The effect of clopidogrel on bleeding did not vary according to genotypic subgroups. Among 1156 genotyped patients with atrial fibrillation, there was no evidence of an interaction with respect to either efficacy or bleeding between the study treatment and the metabolizer phenotype, loss-of-function carrier status, or gain-of-function carrier status., Conclusions: Among patients with acute coronary syndromes or atrial fibrillation, the effect of clopidogrel as compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00249873.).

Background: Clopidogrel and aspirin are the most commonly used antiplatelet therapies for percutaneous coronary intervention (PCI). We assessed the effect of various clopidogrel and aspirin regimens in prevention of major cardiovascular events and stent thrombosis in patients undergoing PCI., Methods: The CURRENT-OASIS 7 trial was undertaken in 597 centres in 39 countries. 25,086 individuals with acute coronary syndromes and intended early PCI were randomly assigned to double-dose (600 mg on day 1, 150 mg on days 2-7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clopidogrel, and high-dose (300-325 mg daily) versus low-dose (75-100 mg daily) aspirin. Randomisation was done with a 24 h computerised central automated voice response system. The clopidogrel dose comparison was double-blind and the aspirin dose comparison was open label with blinded assessment of outcomes. This prespecified analysis is of the 17,263 individuals who underwent PCI. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Analyses were by intention to treat, adjusted for propensity to undergo PCI. This trial is registered with ClinicalTrials.gov, number NCT00335452., Findings: 8560 patients were assigned to double-dose and 8703 to standard-dose clopidogrel (8558 and 8702 completed 30-day follow-up, respectively), and 8624 to high-dose and 8639 to low-dose aspirin (8622 and 8638 completed 30-day follow-up, respectively). Compared with the standard dose, double-dose clopidogrel reduced the rate of the primary outcome (330 events [3·9%] vs 392 events [4·5%]; adjusted hazard ratio 0·86, 95% CI 0·74-0·99, p=0·039) and definite stent thrombosis (58 [0·7%] vs 111 [1·3%]; 0·54 [0·39-0·74], p=0·0001). High-dose and low-dose aspirin did not differ for the primary outcome (356 [4·1%] vs 366 [4·2%]; 0·98, 0·84-1·13, p=0·76). Major bleeding was more common with double-dose than with standard-dose clopidogrel (139 [1·6%] vs 99 [1·1%]; 1·41, 1·09-1·83, p=0·009) and did not differ between high-dose and low-dose aspirin (128 [1·5%] vs 110 [1·3%]; 1·18, 0·92-1·53, p=0·20)., Interpretation: In patients undergoing PCI for acute coronary syndromes, a 7-day double-dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose. Efficacy and safety did not differ between high-dose and low-dose aspirin. A double-dose clopidogrel regimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended early PCI., Funding: Sanofi-Aventis and Bristol-Myers Squibb., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Clopidogrel and aspirin are widely used for patients with acute coronary syndromes and those undergoing percutaneous coronary intervention (PCI). However, evidence-based guidelines for dosing have not been established for either agent., Methods: We randomly assigned, in a 2-by-2 factorial design, 25,086 patients with an acute coronary syndrome who were referred for an invasive strategy to either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days., Results: The primary outcome occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (hazard ratio, 0.94; 95% confidence interval [CI], 0.83 to 1.06; P=0.30). Major bleeding occurred in 2.5% of patients in the double-dose group and in 2.0% in the standard-dose group (hazard ratio, 1.24; 95% CI, 1.05 to 1.46; P=0.01). Double-dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis among the 17,263 patients who underwent PCI (1.6% vs. 2.3%; hazard ratio, 0.68; 95% CI, 0.55 to 0.85; P=0.001). There was no significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome (4.2% vs. 4.4%; hazard ratio, 0.97; 95% CI, 0.86 to 1.09; P=0.61) or major bleeding (2.3% vs. 2.3%; hazard ratio, 0.99; 95% CI, 0.84 to 1.17; P=0.90)., Conclusions: In patients with an acute coronary syndrome who were referred for an invasive strategy, there was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, myocardial infarction, or stroke. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00335452.)

Despite its universal use, the optimal dose of aspirin from an efficacy and safety perspective remains unclear. There are wide variations in international practice and a lack of consensus as to the most appropriate dose of aspirin in patients with acute coronary syndromes (ACS), mainly because of the wide range of doses evaluated in early randomized trials of aspirin versus placebo. Comparisons of aspirin dose have been based on observational studies or indirect comparisons from meta-analysis of antiplatelet trials. These studies have suggested that aspirin, in doses>or=300 mg, is similar to aspirin doses 75-100 mg/d for prevention of major vascular events, but that higher doses increase the risk of major bleeding complications. Recently, the CURRENT-OASIS study, a randomized head-to-head comparison of higher-dose (>or=300 mg/d) versus low-dose aspirin (75-81 mg/d) for 1 month in over 25,000 patients with ACS referred for an early invasive strategy demonstrated similar outcomes between higher- and low-dose aspirin for efficacy, with no difference in the risk of major bleeding complications. Results from this mega-trial suggest that low-dose or higher-dose aspirin is a reasonable option in ACS patients undergoing an early invasive strategy.

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

Objectives: This study sought to investigate the efficacy and safety of clopidogrel in women and men., Background: Previous analyses have shown sex-based differences in response to several antiplatelet medications. Little is known about the efficacy and safety of clopidogrel in women and men., Methods: This study performed a meta-analysis of all blinded randomized clinical trials comparing clopidogrel and placebo (CURE [Clopidogrel in Unstable Angina to Prevent Recurrent Events], CREDO [Clopidogrel for the Reduction of Events During Observation], CLARITY-TIMI 28 [Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28], COMMIT [Clopidogrel and Metoprolol in Myocardial Infarction Trial], and CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance] trials), involving a total of 79,613 patients, of whom 30% were women. The relative efficacy and safety of clopidogrel at reducing cardiovascular events (cardiovascular death, myocardial infarction [MI], or stroke) in women and men was estimated using random-effects modeling., Results: Overall, clopidogrel was associated with a highly significant 14% proportional reduction in the risk of cardiovascular events (odds ratio [OR]: 0.86; 95% confidence interval [CI]: 0.80 to 0.93), with no significant differences in treatment effect between women and men. Among the 23,533 women enrolled, there were fewer cardiovascular events in the clopidogrel group compared with the placebo group (11.0% vs. 11.8%; OR: 0.93; 95% CI: 0.86 to 1.01). In women the risk reduction with clopidogrel seemed to be greatest for MI (OR: 0.81; 95% CI: 0.70 to 0.93), with the effects on stroke (OR: 0.91; 95% CI: 0.69 to 1.21) or total death (OR: 0.99; 95% CI: 0.90 to 1.08) not statistically significant. Among the 56,091 men enrolled, there were fewer cardiovascular events in those receiving clopidogrel compared with placebo (7.8% vs. 9.0%; OR: 0.84; 95% CI: 0.78 to 0.91), and the risk reduction was significant for MI (OR: 0.83; 95% CI: 0.76 to 0.92), stroke (OR: 0.83; 95% CI: 0.71 to 0.96), and total death (OR: 0.91; 95% CI: 0.84 to 0.97). Clopidogrel increased the risk of major bleeding in both women (OR: 1.43; 95% CI: 1.15 to 1.79) and men (OR: 1.22; 95% CI: 1.05 to 1.42)., Conclusions: Clopidogrel reduces the risk of cardiovascular events in both women and men.

Objectives: This study sought to evaluate the relative safety and efficacy of fondaparinux and enoxaparin in patients with acute coronary syndromes (ACS) treated with glycoprotein (GP) IIb/IIIa inhibitors or thienopyridines., Background: The OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial showed that fondaparinux reduced major bleeding by 50% compared with enoxaparin while preserving similar efficacy. Whether this benefit is consistent in the presence or absence of concurrent antiplatelet therapy with clopidogrel and GP IIb/IIIa inhibitors is unknown., Methods: Patients with ACS (n = 20,078) were randomized as a part of the OASIS 5 trial to receive either fondaparinux or enoxaparin. The use of GP IIb/IIIa inhibitors or thienopyridines was at the discretion of the treating physician. A Cox proportional hazard model was used to compare outcomes., Results: Of the 20,078 patients randomized, 3,630 patients received GP IIb/IIIa and 13,531 received thienopyridines. There was a 40% reduction in major bleeding with fondaparinux compared with enoxaparin in those treated with GP IIb/IIIa (5.2% vs. 8.3%, hazard ratio [HR]: 0.61, p < 0.001). A similar reduction was found in those treated with thienopyridines (3.4% vs. 5.4%, HR: 0.62, p < 0.001). Ischemic events were similar between the groups, resulting in a superior net clinical outcome (death, myocardial infarction, refractory ischemia, or major bleeding) favoring fondaparinux (GP IIb/IIIa subgroup 14.8% vs. 18.9%, HR: 0.77, p = 0.001 and thienopyridines subgroup 11.0% vs. 13.2%, HR: 0.82, p < 0.001)., Conclusions: In patients receiving GP IIb/IIIa inhibitors or thienopyridines, fondaparinux reduces major bleeding and improves net clinical outcome compared with enoxaparin.

Aims: In the setting of percutaneous coronary intervention (PCI), due to a paucity of data, the optimal dose of aspirin is uncertain. We evaluated the safety of different doses of aspirin after PCI., Methods and Results: In the PCI-CURE study, 2658 patients with acute coronary syndromes undergoing PCI were stratified into three aspirin dose groups >/=200 mg (high, n = 1064), 101-199 mg (moderate, n = 538), and

Background: Antiplatelet therapy with clopidogrel and acetylsalicylic acid (ASA) reduces major cardiovascular events in patients with ST and non-ST-segment-elevation acute coronary syndromes (ACS). Recent mechanistic and clinical data suggest that higher loading and maintenance doses of clopidogrel may achieve a more rapid and greater degree of platelet inhibition that translates into improved clinical outcomes, but this is yet to be formally evaluated in an adequately powered randomized trial., Objectives: To evaluate the efficacy and safety of (1) a higher loading and initial maintenance dose of clopidogrel compared with the standard-dose regimen and (2) high-dose ASA compared with low-dose ASA in patients with ST or non-ST-segment-elevation ACS managed with an early invasive strategy., Design: Multicenter, international, randomized, 2 x 2 factorial design trial evaluating a clopidogrel high-dose regimen (600 mg loading dose on day 1 followed by 150 mg once daily on days 2 to 7, followed by 75 mg once daily on days 8-30) compared with the standard-dose regimen (300 mg loading dose on day 1, followed by 75 mg once daily on days 2-30) and high-dose ASA (300-325 mg daily) versus low-dose ASA (75-100 mg daily) in patients with ST or non-ST-segment-elevation ACS managed with an early invasive strategy. The clopidogrel dose comparison is double-blind and the ASA dose comparison is open-label. The primary outcome is the composite of death from cardiovascular causes, myocardial (re)infarction or stroke up to day 30. The primary safety outcome is major bleeding. The sample size is 18,000 to 20,000 patients., Conclusions: The CURRENT-OASIS 7 trial will help to define optimal dosing regimens for clopidogrel and ASA in patients with ST and non-ST-segment-elevation ACS treated with an early invasive strategy.

Background: Clopidogrel pretreatment before percutaneous coronary intervention (PCI) has been shown to reduce the risk of death and ischemic complications after PCI. However, the need for clopidogrel pretreatment is debated in patients receiving a glycoprotein IIb/IIIa inhibitor (GPI)., Methods: We performed a collaborative meta-analysis of the results of 3 randomized trials of clopidogrel pretreatment: PCI-CURE, CREDO, and PCI-CLARITY. Patients were stratified based on GPI use at the time of PCI (a postrandomization subgroup analysis). Odds ratios (ORs) and 95% CIs for the effect of clopidogrel pretreatment versus placebo pretreatment on the incidence of cardiovascular death, myocardial infarction (MI), or stroke for up to 30 days after PCI were calculated for each trial within each GPI stratum and were combined using a random effects model., Results: Six thousand three hundred twenty-five patients were included, 32.4% of whom received a GPI. There was a consistent benefit of clopidogrel pretreatment in reducing the incidence of cardiovascular death, MI, or stroke after PCI both in patients who did not receive a GPI (OR 0.72, 95% CI 0.53-0.98, P = .03) and in those who did (OR 0.69, 95% CI 0.47-1.00, P = .05). There was no evidence of heterogeneity in the benefit of clopidogrel pretreatment between GPI use strata (P = .85 for heterogeneity). Clopidogrel pretreatment was not associated with a significant excess of TIMI major or minor bleeding, either in those who did not receive a GPI (OR 1.20, 95% CI 0.76-1.92) or in those who did (OR 1.22, 95% CI 0.71-2.09) (P = .97 for heterogeneity)., Conclusion: Clopidogrel pretreatment before PCI is beneficial and safe regardless of whether a GPI is used at the time of PCI.

Background: Cardiovascular diseases account for nearly 20% of all hospitalizations in Canada and consume 12% of the total cost of all illnesses. With increasing trends of cardiovascular disease and increasing costs of care, development of cost-effective strategies is vital. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial demonstrated the effectiveness of clopidogrel plus acetylsalicylic acid (ASA) compared with ASA alone in reducing cardiovascular events in patients with acute coronary syndromes and, in addition, patients undergoing percutaneous coronary intervention in the Percutaneous Coronary Intervention in CURE (PCI-CURE) trial., Objective: To assess the cost-effectiveness of clopidogrel in the Canadian health care system., Methods: Estimates of hospitalization costs were based on the 2003 cost schedules released by the Health Funding and Costing Branch of the Alberta Health and Wellness, as well as on the Case Mix Group classification system. Life expectancy beyond the trial was estimated from the Saskatchewan Health Database. Cost-effectiveness was expressed as the incremental cost-effectiveness ratio, and bootstrap methods were used to estimate the joint distribution of costs and effectiveness., Results: Clopidogrel was shown to be cost-effective, with incremental cost-effectiveness ratios less than $10,000 per event prevented and less than $4,000 per life-year gained. The probability of clopidogrel resulting in cost per life-year gained of less than $20,000 was 0.975 for CURE patients and 0.904 for PCI-CURE patients., Conclusions: The economic analysis demonstrated that clopidogrel combination therapy is not only cost-effective as antiplatelet therapy compared with ASA alone, but it is also cost-effective compared with other commonly used and openly reimbursed cardiovascular therapies in the Canadian health care system.

Introduction: Patients with renal dysfunction are more prone to bleeding when receiving antithrombotic drugs. The aim of the study was to assess the impact of clopidogrel on safety and efficacy in patients with renal dysfunction in non-ST elevation acute coronary syndromes., Methods and Results: Patients in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial were analysed to assess the relationship of chronic kidney disease to cardiovascular outcomes. Renal function was estimated by the glomerular filtration rate computed from the baseline serum creatinine measurements in 12 253 (97.5%) patients enrolled in the trial. Patients were grouped into tertiles of glomerular filtration rate. The primary outcome (cardiovascular death, myocardial infarction, stroke combined) occurred more frequently in the lowest glomerular filtration rate tertile. The bleeding risk was also significantly increased in patients in this tertile, compared with the other two. The beneficial effect of adding clopidogrel to standard treatment in non-ST elevation acute coronary syndrome was observed in all three tertiles of renal function {(lower third relative risk (RR)=0.89 [95% confidence interval (CI) 0.76-1.05]; medium third RR=0.68 (95% CI 0.56-0.84); upper third RR=0.74 (95% CI 0.60-0.93) (P for heterogeneity=0.11)}. Clopidogrel treatment significantly increased the risk of minor bleeding in all tertiles of renal function. The risk of major or life-threatening bleeding increased moderately with the addition of clopidogrel to standard treatment [lower third RR=1.12 (95% CI 0.83-1.51); medium third RR=1.4 (95% CI 0.97-2.02); upper third RR=1.83 (95% CI 1.23-2.73)], but this did not appear to be greatest in those with the lowest renal function., Conclusions: Even mild chronic kidney disease worsens the prognosis in patients with non-ST elevation acute coronary syndromes. Clopidogrel was beneficial and safe in patients with and without chronic kidney disease.

The pathogenesis of ST-elevation myocardial infarction (STEMI) involves plaque disruption, platelet aggregation and intracoronary artery thrombus formation. Aspirin is the cornerstone of antiplatelet therapy in patients with STEMI, reducing the risk of recurrent myocardial infarction or death during the acute phase and long term by about one-quarter. Recent large randomized trials have demonstrated that the addition of clopidogrel to aspirin reduces the risk of major ischemic events by up to a further one-third in patients with STEMI treated with fibrinolytic therapy and undergoing percutaneous coronary intervention, with no significant increase in bleeding. Thus, dual antiplatelet therapy with the combination of clopidogrel and aspirin is becoming the new standard of care for the management of patients with STEMI.

Background: The CURE study demonstrated the benefit of clopidogrel in patients with non-ST elevation (NSTE) acute coronary syndromes (ACSs), including those undergoing percutaneous coronary intervention (PCI). It did not report the relation between clopidogrel and timing of PCI or, more specifically, the role of clopidogrel in patients managed with an early interventional strategy, the current preferred treatment option for patients with NSTE ACSs. In the present study, we examined the relation between clopidogrel therapy, timing of PCI, and cardiovascular (CV) events in patients participating in the CURE study., Methods: A total of 12562 patients with NSTE ACSs was randomized in double-blind fashion to clopidogrel or placebo (300 mg loading dose, then 75 mg/d) in addition to aspirin for up to 1 year. We analyzed the data of the 2658 CURE patients undergoing PCI and related the incidence of outcome events (CV death/myocardial infarction [MI]) to timing of PCI after randomization: early (< 48 hours, median 1.0 day, n = 370), intermediate (> or = 48 hours to initial hospital discharge, median 6.8 days, n = 1360), and late (after initial hospital discharge, median 47.6 days, n = 928)., Results: Clopidogrel showed consistent treatment benefit over the 12-month (mean 9 months) follow-up period irrespective of timing of PCI (relative risk [RR] 0.53 for the early group, RR 0.72 for the intermediate group, RR 0.70 for the late group). After adjustment for propensity to undergo PCI, the greatest treatment benefit of clopidogrel was observed in patients undergoing PCI < 48 hours after randomization (RR 0.45, 95% CI 0.21-0.96, P = .038), although with overlap between groups. The lowest absolute event rate (6.7% CV death/MI) was observed in patients treated with clopidogrel and undergoing PCI within 48 hours. There was no increased risk of major bleeding in the early PCI group., Conclusions: The benefit of therapy with clopidogrel in addition to aspirin in patients presenting with NSTE ACSs was significant irrespective of the timing of PCI. The combination of clopidogrel and an early (< 48 hours) interventional strategy was associated with low absolute event rates for CV death/nonfatal MI.

Concern about possible hemorrhagic complications arising from use of oral antiplatelet agents in immediate proximity to coronary artery bypass graft (CABG) surgery leads many clinicians to avoid or discontinue these agents preoperatively. Recent evidence suggests that aspirin and clopidogrel can be used with relative safety in the preoperative period; dual antiplatelet therapy in the 5 days immediately preceding CABG surgery results in a moderate and variable increase in the risk of procedural bleeding. This modest hemorrhagic risk may be acceptable, given the clinical benefits of sustained antiplatelet therapy in preventing graft occlusion and ischemic complications pre- and post-CABG. Because the bleeding risk with aspirin is dose dependent, use of a low dose is preferred post-CABG.

Background: Antiplatelet therapy and antithrombin therapy have been demonstrated to reduce the risk of cardiac events in patients presenting with acute coronary syndrome, yet all effective therapies also increase the risk of bleeding., Methods and Results: In the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial, 12 562 patients were randomized to clopidogrel or placebo in addition to aspirin, and the primary outcome was cardiovascular (CV) death, myocardial infarction (MI), or stroke. The benefits were consistent among those undergoing percutaneous coronary intervention (PCI) [9.6% for clopidogrel, 13.2% for placebo; relative risk (RR), 0.72; 95% CI, 0.57 to 0.90], coronary artery bypass grafting (CABG) surgery (14.5% for clopidogrel 16.2% for placebo; RR, 0.89; 95% CI, 0.71 to 1.11), and medical therapy only (8.1% for clopidogrel, 10.0% for placebo; RR, 0.80; 95% CI, 0.69 to 0.92; test for interaction among strata, 0.53). For CABG during the initial hospitalization (530 for placebo, 485 for clopidogrel), the frequency of CV death, MI or stroke before CABG was 4.7% for placebo and 2.9% for clopidogrel (RR, 0.56; 95% CI, 0.29 to 1.08). For the entire study, there was a 1% excess of major bleeding but no significant excess of life-threatening bleeding. Among patients undergoing CABG, the rates of life-threatening bleeding were 5.6% for clopidogrel and 4.2% for placebo (RR, 1.30; 95% CI, 0.91 to 1.95; both nonsignificant)., Conclusions: The benefits versus risks of early and long-term clopidogrel therapy (freedom from CV death, MI, stroke, or life-threatening bleeding) are similar in those undergoing revascularization (CABG or PCI) and in the study population as a whole. Overall, the benefits of starting clopidogrel on admission appear to outweigh the risks, even among those who proceed to CABG during the initial hospitalization.

Background: We studied the benefits and risks of adding clopidogrel to different doses of aspirin in the treatment of patients with acute coronary syndrome (ACS)., Methods and Results: In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, 12 562 patients with ACS using aspirin, 75 to 325 mg daily, were randomized to clopidogrel or placebo for up to 1 year. In this analysis, patients were divided into the following 3 aspirin dose groups: < or =100 mg, 101 through 199 mg, and > or =200 mg. The combined incidence of cardiovascular death, myocardial infarction, or stroke was reduced by clopidogrel regardless of aspirin dose, as follows: < or =100 mg, 10.5% versus 8.6% (relative risk [RR], 0.81 [95% CI, 0.68 to 0.97]); 101 to 199 mg, 9.8% versus 9.5% (RR, 0.97 [95% CI 0.77 to 1.22]); and > or =200 mg, 13.6% versus 9.8% (RR, 0.71 [95% CI, 0.59 to 0.85]). The incidence of major bleeding increased with increasing aspirin dose both in the placebo group (1.9%, 2.8%, and 3.7%, respectively; P=0.0001) and the clopidogrel group (3.0%, 3.4%, and 4.9%, respectively; P=0.0009); thus, the excess risk with clopidogrel was 1.1%, 1.2%, and 1.2%, respectively. The adjusted hazard ratio for major bleeding for the highest versus the lowest dose of aspirin was 1.9 (95% CI 1.29 to 2.72) in the placebo group, 1.6 (95% CI 1.19 to 2.23) in the clopidogrel group, and 1.7 (95% CI 1.36 to 2.20) in the combined group., Conclusions: In patients with ACS, adding clopidogrel to aspirin is beneficial regardless of aspirin dose. Bleeding risks increase with increasing aspirin dose, with or without clopidogrel, without any increase in efficacy. Our findings suggest that the optimal daily dose of aspirin may be between 75 and 100 mg, with or without clopidogrel.

Background: The risk of ischemic events is high, both early and late after acute coronary syndromes (ACS). We examine the benefits and risks associated with the use of adding clopidogrel to aspirin within the first 30 days and later (31 days to 12 months) in 12 562 patients with ACS., Methods and Results: A total of 12 562 ACS patients were randomized to receive clopidogrel (300 mg initially followed by 75 mg/d) or placebo for 3 to 12 months. The proportion of patients experiencing cardiovascular death, myocardial infarction, or strokes (primary outcome) at 30 days was 5.4% in the placebo group and 4.3% in the active group (relative risk 0.79, 95% CI 0.67 to 0.92). Beyond 30 days, the corresponding rates were 6.3% versus 5.2% (relative risk 0.82, 95% CI 0.70 to 0.95). There was no significant excess in life-threatening bleeds in each period (0.97% versus 1.28%, relative risk 1.32, 95% CI 0.95 to 1.84 for 0 to 30 days; 0.83% versus 0.91%, relative risk 1.09, 95% CI 0.75 to 1.59 for 31 days to 12 months). Further subdivision of the early data indicates benefits within 24 hours with consistently lower rates of the primary outcome in combination with refractory or severe ischemia., Conclusions: Clopidogrel reduces the risk of ischemic vascular events, with the benefits emerging within 24 hours of initiation of treatment and continuing throughout the 12 months (mean 9 months) of the study.

Platelets play a central role in both the short- and long-term manifestations of atherothrombosis. In acute coronary syndrome (ACS), there is a steep rise in cardiovascular events early, followed by an incremental rise in cardiovascular events over the long term. This long-term event rate is related to persistent platelet activation and thrombin generation. There is therefore a need to optimize both short- and long-term oral antiplatelet and antithrombotic strategies. The benefits of aspirin therapy, when administered early and continued over the long term, were demonstrated in several early randomized trials. The Antithrombotic Trialists' Collaboration found a 46% reduction in vascular events with antiplatelet therapy (mostly aspirin). However, despite treatment with aspirin and proven therapies, recurrent events remain high. The adenosine diphosphate receptor antagonists, ticlopidine and clopidogrel, inhibit the early steps of platelet activation, degranulation, and release of prothrombotic and inflammatory mediators, while also preventing activation of the glycoprotein IIb/IIIa receptor. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial demonstrated the benefits of aspirin plus clopidogrel in reducing major cardiovascular events (cardiovascular death, myocardial infarction [MI], and stroke reduced by 20%, p = 0.00009) in a broad range of patients with ACS when administered early and continued over the long term. The benefits emerge very rapidly after a 300 mg loading dose. For the large number of patients undergoing percutaneous coronary intervention in the CURE trial, there was a substantial risk reduction with clopidogrel pretreatment followed by long-term therapy (p < 0.002). This benefit was present, regardless of whether intervention was performed early or late. The significant benefits of aspirin and clopidogrel persist for the combined efficacy-safety end point of cardiovascular death, MI, stroke, or life-threatening bleeding when clopidogrel is started early, combined with aspirin and other standard therapies, and continued for up to one year.

Thrombosis is the most important pathological mechanism of acute coronary syndromes (ACS). In addition to standard antithrombotic treatment with aspirin and heparin, clopidogrel, glycoprotein IIb/IIIa inhibitors, and low-molecular-weight have a therapeutic benefit in ACS patients. Updated American College of Cardiology/American Heart Association guidelines for the management of ACS patients were published in mid-2002, and this article summarizes the rationale for the recommendations outlined in these guidelines for the use of antithrombotic and antiplatelet therapies.

Background: The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial demonstrated that clopidogrel, given early and continued long term, was superior to placebo in patients with non-ST-elevation acute coronary syndromes receiving aspirin. The purpose of the present analysis was to estimate the treatment effect Zof clopidogrel in patients who were stratified according to their risk of future cardiovascular events., Methods and Results: Patients (n=12 562) who presented within 24 hours after the onset of symptoms were randomized to receive clopidogrel (300 mg followed by 75 mg daily) or placebo in addition to aspirin for 3 to 12 months. Treatment effect was analyzed in various risk groups according to the Thrombolysis in Myocardial Infarction (TIMI) risk score. The TIMI risk model was validated in the CURE population (C statistic, 0.634). The primary composite outcome of cardiovascular death, myocardial infarction, or stroke increased proportionally with increasing risk according to the TIMI risk score. The impact of clopidogrel versus placebo on the rate of the primary outcome was as follows: low-risk group (TIMI score 0 to 2), 4.1% versus 5.7% (relative risk [RR], 0.71; 95% confidence interval [CI], 0.52 to 0.97; P< 0.04), intermediate-risk group (TIMI score 3 to 4), 9.8% versus 11.4% (RR, 0.85; 95% CI, 0.74 to 0.98; P<0.03), and high-risk group (TIMI score 5 to 7), 15.9% versus 20.7% (RR, 0.73; 95% CI, 0.60 to 0.90; P<0.004). There was no evidence of statistical heterogeneity among the groups., Conclusions: The benefit of clopidogrel demonstrated in the CURE trial is consistent in low-, intermediate-, and high-risk patients with acute coronary syndromes (as stratified by TIMI risk score), thus supporting its use in all patients with documented non-ST elevation acute coronary syndromes.

Chronic kidney disease (CKD) increases the risk of adverse outcomes in acute coronary syndrome (ACS). The optimal regimen of dual antiplatelet therapy (DAPT) post-percutaneous coronary intervention (PCI) in CKD poses a challenge due to the increased bleeding and clotting tendencies, particularly since patients with CKD were underrepresented in randomized controlled trials. We examined the practice patterns of DAPT prescription stratified by the presence of CKD. The multicentre prospective Canadian Observational Antiplatelet Study (COAPT) enrolled patients with ACS between December 2011 and May 2013. The present study is a subgroup analysis comparing type and duration of DAPT and associated outcomes among patients with and without CKD (eGFR < 60 ml/min/1.73 m2, calculated by CKD-EPI). Patients with CKD (275/1921, 14.3%) were prescribed prasugrel/ticagrelor less (18.5% vs 25.8%, p = 0.01) and had a shorter duration of DAPT therapy versus patients without CKD (median 382 vs 402 days, p = 0.003). CKD was associated with major adverse cardiovascular events (MACE) at 12 months (p < 0.001) but not bleeding when compared to patients without CKD. CKD was associated with MACE in both patients on prasugrel/ticagrelor (p = 0.017) and those on clopidogrel (p < 0.001) (p for heterogeneity = 0.70). CKD was associated with increased bleeding only among patients receiving prasugrel/ticagrelor (p = 0.007), but not among those receiving clopidogrel (p = 0.64) (p for heterogeneity = 0.036). Patients with CKD had a shorter DAPT duration and were less frequently prescribed potent P2Y12 inhibitors than patients without CKD. Overall, compared with patients without CKD, patients with CKD had higher rates of MACE and similar bleeding rates. However, among those prescribed more potent P2Y12 inhibitors, CKD was associated with more bleeding than those without CKD. Further studies are needed to better define the benefit/risk evaluation, and establish a more tailored and evidence-based DAPT regimen for this high-risk patient group. [ABSTRACT FROM AUTHOR]