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Clinical Effectiveness of Direct Oral Anticoagulants vs Warfarin in Older Patients With Atrial Fibrillation and Ischemic StrokeFindings From the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) Study

Educational Objective
To determine whether direct oral anticoagulant therapy is a better option than warfarin for secondary prevention in older survivors of ischemic stroke with atrial fibrillation.
1 Credit CME
Key Points

Question  Is direct oral anticoagulant a better option than warfarin for secondary prevention in older survivors of ischemic stroke who have atrial fibrillation?

Findings  In this observational study of 11 662 patients with atrial fibrillation who had had an ischemic stroke and were anticoagulation naive, patients discharged while receiving direct oral anticoagulants had more days at home postdischarge and were less likely to experience major adverse cardiovascular events, all-cause mortality, all-cause readmissions, cardiovascular readmissions, or hemorrhagic strokes, despite a small but significant increase in gastrointestinal bleeding.

Meaning  Direct oral anticoagulants appear to be an effective and safe treatment option compared with warfarin for patients with atrial fibrillation who have ischemic stroke.

Abstract

Importance  Current guidelines recommend direct oral anticoagulants (DOACs) over warfarin for stroke prevention in patients with atrial fibrillation (AF) who are at high risk. Despite demonstrated efficacy in clinical trials, real-world data of DOACs vs warfarin for secondary prevention in patients with ischemic stroke are largely based on administrative claims or have not focused on patient-centered outcomes.

Objective  To examine the clinical effectiveness of DOACs (dabigatran, rivaroxaban, or apixaban) vs warfarin after ischemic stroke in patients with AF.

Design, Setting, and Participants  This cohort study included patients who were 65 years or older, had AF, were anticoagulation naive, and were discharged from 1041 Get With The Guidelines–Stroke–associated hospitals for acute ischemic stroke between October 2011 and December 2014. Data were linked to Medicare claims for long-term outcomes (up to December 2015). Analyses were completed in July 2018.

Exposures  DOACs vs warfarin prescription at discharge.

Main Outcomes and Measures  The primary outcomes were home time, a patient-centered measure defined as the total number of days free from death and institutional care after discharge, and major adverse cardiovascular events. A propensity score–overlap weighting method was used to account for differences in observed characteristics between groups.

Results  Of 11 662 survivors of acute ischemic stroke (median [interquartile range] age, 80 [74-86] years), 4041 (34.7%) were discharged with DOACs and 7621 with warfarin. Except for National Institutes of Health Stroke Scale scores (median [interquartile range], 4 [1-9] vs 5 [2-11]), baseline characteristics were similar between groups. Patients discharged with DOACs (vs warfarin) had more days at home (mean [SD], 287.2 [114.7] vs 263.0 [127.3] days; adjusted difference, 15.6 [99% CI, 9.0-22.1] days) during the first year postdischarge and were less likely to experience major adverse cardiovascular events (adjusted hazard ratio [aHR], 0.89 [99% CI, 0.83-0.96]). Also, in patients receiving DOACs, there were fewer deaths (aHR, 0.88 [95% CI, 0.82-0.95]; P < .001), all-cause readmissions (aHR, 0.93 [95% CI, 0.88-0.97]; P = .003), cardiovascular readmissions (aHR, 0.92 [95% CI, 0.86-0.99]; P = .02), hemorrhagic strokes (aHR, 0.69 [95% CI, 0.50-0.95]; P = .02), and hospitalizations with bleeding (aHR, 0.89 [95% CI, 0.81-0.97]; P = .009) but a higher risk of gastrointestinal bleeding (aHR, 1.14 [95% CI, 1.01-1.30]; P = .03).

Conclusions and Relevance  In patients with acute ischemic stroke and AF, DOAC use at discharge was associated with better long-term outcomes relative to warfarin.

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Article Information

Accepted for Publication: May 3, 2019.

Corresponding Author: Ying Xian, MD, PhD, Duke Clinical Research Institute, 2400 Pratt St, Durham, NC 27705 (ying.xian@duke.edu).

Published Online: July 22, 2019. doi:10.1001/jamaneurol.2019.2099

Author Contributions: Dr Xian 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: Xian, Xu, O'Brien, Fonarow, Hernandez, Olson, Bhatt.

Acquisition, analysis, or interpretation of data: Xian, Xu, O'Brien, Shah, Thomas, Pencina, Fonarow, Hernandez, Olson, Schwamm, Bhatt, Smith, Hannah, Maisch, Lytle, Peterson.

Drafting of the manuscript: Xian, O'Brien.

Critical revision of the manuscript for important intellectual content: Xian, Xu, O'Brien, Shah, Thomas, Pencina, Fonarow, Hernandez, Olson, Schwamm, Bhatt, Smith, Hannah, Maisch, Lytle, Peterson.

Statistical analysis: Xian, Xu, Thomas.

Obtained funding: Xian, O'Brien, Fonarow, Hernandez.

Administrative, technical, or material support: Xian, Shah, Hannah, Hernandez, Maisch, Lytle, Peterson.

Supervision: Xian, Fonarow, Hernandez.

Conflict of Interest Disclosures: Dr Xian reports research funding to Duke Clinical Research Institute from the American Heart Association, Daiichi Sankyo, Janssen Pharmaceuticals, and Genentech during the conduct of this study. Dr O’Brien reports research funding to Duke Clinical Research Institute from Novartis, Bristol-Myers Squibb, Glaxo Smith Kline, and the Patient-Centered Outcomes Research Institute (PCORI). Dr Pencina reports grants from Regeneron/Sanofi, PCORI, and Amgen and personal fees from Knobbe, Merck, and Boehringer Ingelheim, outside the submitted work. Dr Fonarow reports grant support from PCORI, serving as a consultant to Bayer and Janssen, being of a member of the Get With the Guidelines–Stroke Steering Committee, and being an employee of the University of California Regents, who hold a patent on an endovascular device. Dr Schwamm reports grant support from the PCORI and the National Institute of Neurological Disorders and Stroke and serving as chair of the American Heart Association/American Stroke Association Get With the Guidelines–Stroke Systems of Care Work Group and Quality Oversight Committee, as a stroke systems consultant to the Massachusetts Department of Public Health, and as a scientific consultant regarding trial design and conduct to Medtronic for stroke prevention in atrial fibrillation (including acting as co-principal investigator of the Stroke AF trial). Dr Bhatt reports serving on the advisory boards of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; the board of directors of Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; the data safety monitoring committees of the Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; and as a chair of the American Heart Association Quality Oversight Committee. Dr Bhatt has also received honoraria from the American College of Cardiology (as senior associate editor of clinical trials and news on ACC.org and vicechair of the Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, as part of the RE-DUAL PCI clinical trial steering committee, funded by Boehringer Ingelheim), Belvoir Publications (as editor in chief of Harvard Heart Letter), Duke Clinical Research Institute (for participation in clinical trial steering committees), HMP Global (as editor in chief of Journal of Invasive Cardiology), Journal of the American College of Cardiology (as a guest editor and associate editor), Medtelligence/ReachMD (as a continuing medical education steering committee member), Population Health Research Institute (for membership on the COMPASS operations committee, publications committee, and steering committee and as a USA national coleader; funded by Bayer), Slack Publications (as chief medical editor of Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (as secretary/treasurer), WebMD (as a member of continuing medical education steering committees), Clinical Cardiology (as deputy editor), the National Cardiovascular Data Registry–ACTION Registry Steering Committee (as a chair), the VA CART Research and Publications Committee (as a chair), and the American College of Cardiology (as a trustee); and receiving research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company and royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease). Dr Bhatt also reports serving as site coinvestigator for studies funded by Biotronik, Boston Scientific, St Jude Medical (now Abbott), and Svelte, as well as completing unfunded research for FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr Smith reports serving as an unpaid member of the Get With the Guidelines Steering Committee and reports consulting fees from Portola and Alnylam Pharmaceuticals. Dr Peterson reports research support from Janssen and Bayer, consulting fees from Janssen, Bayer, and AstraZeneca, and grants from AstraZeneca, Genentech, the American Heart Association, and Get With the Guidelines–Stroke Analysis Center at the Duke Clinical Research Institute. Dr Hernandez reports research grants from AstraZeneca, Bristol Myers Squibb, Daiichi, Genentech, Janssen, Merck, Novartis, Portola Pharmaceuticals, and Verily and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, and Sanofi. Dr Hannah reports grants from PCORI during the conduct of the study. Dr Lytle reports grants from PCORI during the conduct of the study. Mrs. Maisch reports grants from PCORI during the conduct of the study. Dr Olson reports serving as the editor of Journal of Neuroscience Nursing. Dr Shah reports personal fees from the Ischemic Stroke Lab, American Heart Association, and INC research, outside the submitted work. Dr Thomas reports personal fees from Pfizer, outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by an award (CE-1304-7073) from the Patient-Centered Outcomes Research Institute. The Get With The Guidelines–Stroke program is provided by the American Heart Association/American Stroke Association, sponsored in part by Medtronic, and has been funded in the past through support from Boeringher-Ingelheim, Merck, Bristol-Myers Squib/Sanofi Pharmaceutical Partnership, Janssen Pharmaceutical Companies of Johnson & Johnson, and the American Heart Association Pharmaceutical Roundtable.

Role of the Funder/Sponsor: The funders 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.

Additional Contributions: The authors thank Brianna Lindholm, BA, Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research Study, for her contributions to the identification of the research topic, and Erin Campbell, MS, Duke Clinical Research Institute, for her editorial contributions to the manuscript. Ms Campbell did not receive compensation, except for her employment at the institute where this study was conducted. Ms Lindholm was compensated via the study funder for her work as a patient coinvestigator.

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