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What is the most appropriate antithrombotic regimen to manage atrial fibrillation and coronary artery disease, in particular with acute coronary syndrome and/or percutaneous coronary intervention, while balancing ischemic and bleeding risk in an understudied high-risk patient population?
In this network meta-analysis, simultaneous comparisons of multiple antithrombotic strategies were performed for safety and efficacy outcomes in a study involving more than 10 000 participants. The study demonstrated that vitamin K antagonist plus dual antiplatelet therapy should be avoided, whereas the use of a non–vitamin K antagonist oral anticoagulant plus P2Y12 inhibitor, without aspirin, should be the preferred treatment.
Meaningful information about antithrombotic regimens may help physicians in their decision making when treating this high-risk group of patients.
The antithrombotic treatment of patients with atrial fibrillation (AF) and coronary artery disease, in particular with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), poses a significant treatment dilemma in clinical practice.
To study the safety and efficacy of different antithrombotic regimens using a network meta-analysis of randomized controlled trials in this population.
PubMed, EMBASE, EBSCO, and Cochrane databases were searched to identify randomized controlled trials comparing antithrombotic regimens.
Four randomized studies were included (n = 10 026; WOEST, PIONEER AF-PCI, RE-DUAL PCI, and AUGUSTUS).
Data Extraction and Synthesis
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used in this systematic review and network meta-analysis between 4 regimens using a Bayesian random-effects model. A pre hoc statistical analysis plan was written, and the review protocol was registered at PROSPERO. Data were analyzed between November 2018 and February 2019.
Main Outcomes and Measures
The primary safety outcome was Thrombolysis in Myocardial Infarction (TIMI) major bleeding; secondary safety outcomes were combined TIMI major and minor bleeding, trial-defined primary bleeding events, intracranial hemorrhage, and hospitalization. The primary efficacy outcome was trial-defined major adverse cardiovascular events (MACE); secondary efficacy outcomes were individual components of MACE.
The overall prevalence of ACS varied from 28% to 61%. The mean age ranged from 70 to 72 years; 20% to 29% of the trial population were women; and most patients were at high risk for thromboembolic and bleeding events. Compared with a regimen of vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT; P2Y12 inhibitor plus aspirin), the odds ratios (ORs) for TIMI major bleeding were 0.58 (95% CI, 0.31-1.08) for VKA plus P2Y12 inhibitor, 0.49 (95% CI, 0.30-0.82) for non-VKA oral anticoagulant (NOAC) plus P2Y12 inhibitor, and 0.70 (95% CI, 0.38-1.23) for NOAC plus DAPT. Compared with VKA plus DAPT, the ORs for MACE were 0.96 (95% CI, 0.60-1.46) for VKA plus P2Y12 inhibitor, 1.02 (95% CI, 0.71-1.47) for NOAC plus P2Y12 inhibitor, and 0.94 (95% CI, 0.60-1.45) for NOAC plus DAPT.
Conclusions and Relevance
A regimen of NOACs plus P2Y12 inhibitor was associated with less bleeding compared with VKAs plus DAPT. Strategies omitting aspirin caused less bleeding, including intracranial bleeding, without significant difference in MACE, compared with strategies including aspirin. Our results support the use of NOAC plus P2Y12 inhibitor as the preferred regimen post–percutaneous coronary intervention for these high-risk patients with AF. A regimen of VKA plus DAPT should generally be avoided.
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Corresponding Author: Renato D. Lopes, MD, PhD, Division of Cardiology, Duke Clinical Research Institute, Duke Health, 200 Morris St, Durham, NC 27701 (firstname.lastname@example.org).
Accepted for Publication: May 2, 2019.
Published Online: June 19, 2019. doi:10.1001/jamacardio.2019.1880
Author Contributions: Dr Lopes had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Lopes, Hong, Harskamp, Bhatt, Cannon, Granger, Verheugt, Alexander.
Acquisition, analysis, or interpretation of data: Lopes, Hong, Harskamp, Bhatt, Mehran, Cannon, Li, ten Berg, Sarafoff, Gibson, Alexander.
Drafting of the manuscript: Lopes, Hong, Harskamp, Mehran.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Hong, Mehran, Li, Gibson.
Obtained funding: Lopes.
Administrative, technical, or material support: Lopes, Harskamp, Cannon, Verheugt, Sarafoff, Alexander.
Supervision: Lopes, Hong, Mehran, Cannon, Alexander.
Conflict of Interest Disclosures: Dr Lopes reported grants and personal fees from Bristol-Myers Squibb and Pfizer and personal fees from Boehringer Ingelheim and Bayer AG during the conduct of the study and grants from Amgen Inc, GlaxoSmithKline, Medtronic PLC, and Sanofi Aventis outside the submitted work. Dr Harskamp reported grants from Netherlands Organization for Scientific Research (NWO Rubicon) during the conduct of the study. Dr Bhatt reported personal fees from Harvard Clinical Research Institute (now Baim Institute for Clinical Research) and personal fees and other support from Boehringer Ingelheim during the conduct of the study; grants from Idorsia, Synaptic, Abbott, Regeneron, Amgen, Lilly, Chiesi, Ironwood, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Roche, and The Medicines Company; other support from Novo Nordisk, Fractyl, Svelte, Merck, St Jude Medical (now Abbott), Biotronik, Cardax, Boston Scientific, Veterans Affairs, Clinical Cardiology, FlowCo, PLx Pharma, Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, and Takeda; personal fees from Medtelligence/ReachMD, Bayer, TobeSoft, Cleveland Clinic, Mount Sinai School of Medicine, Journal of the American College of Cardiology, Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, HMP Global, Harvard Clinical Research Institute (now Baim Institute for Clinical Research), and Elsevier; personal fees, nonfinancial support, and other support from American College of Cardiology; personal fees and nonfinancial support from Society of Cardiovascular Patient Care; nonfinancial support from American Heart Association; and grants and other support from PhaseBio outside the submitted work. Dr Mehran reported grants from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol Myers Squibb/Sanofi, CSL Behring, DSI, Medtronic, Novartis Pharmaceuticals, and OrbusNeich; personal fees from Boston Scientific, Medscape, Siemens Medical Solutions, Regeneron Pharmaceuticals, Roivant Sciences, and Sanofi; grants and personal fees from Abbott Vascular; other support from Abbott Laboratories, Spectranetics/Philips/Volcano, Janssen, BMS, Watermark Research, Medtelligence/Janssen, Claret Medical, and Elixir Medical; and personal fees and other support from PLx Opco/PLx Pharma outside the submitted work. Dr Cannon reported grants from Boehringer-Ingelheim, Daiichi Sankyo, and Janssen and personal fees from Boehringer-Ingelheim and Janssen during the conduct of the study and personal fees from Aegerion, Alnylam, Amarin, Amgen, BMS, Corvidia, Eisai, Innovent, Kowa, Merck, Pfizer, Regeneron, Sanofi and grants from Amgen, Bristol-Myers Squibb, and Merck outside the submitted work. Dr Granger reported grants and personal fees from Pfizer, Bristol-Myers Squibb, Daiichi Sankyo, Boehringer-Ingelheim, Janssen, and Bayer during the conduct of the study. Dr Verhuegt reported personal fees from Bayer HealthCare, Bristol-Myers Squibb/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo during the conduct of the study. Dr Sarafoff reported travel grants from Bayer Healthcare, and Bristol-Myers Squibb/Pfizer. Dr Gibson reported grants and personal fees from Portola, Bayer, Janssen, and Johnson and Johnson; and grants from Bristol-Myers Squibb during the conduct of the study; grants and personal fees from Portola, Bayer, Janssen, and Johnson and Johnson, and grants from Bristol-Myers Squibb outside the submitted work. Dr Alexander reported grants and personal fees from Bristol-Myers Squibb, CSL Behring; personal fees from Pfizer, AbbVie Pharmaceuticals, Novo Nordisk, Portola Pharmaceuticals, Quantum Genomics, Teikoku Pharmaceuticals, VA Cooperative Studies Program, Zafgen, and Boehringer-Ingelheim; and grants from AstraZeneca, CryoLife, the US Food and Drug Administration, the National Institutes of Health, Sanofi, and VoluMetrix. No other disclosures were reported.
Funding/Support: Support for this study was provided by Duke Clinical Research Institute. Salary support for Dr Harskamp was provided by a Rubicon fellowship provided by the Netherlands Organisation for Scientific Research.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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