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Figure 1.  Patients’ Disposition in the Study
Patients’ Disposition in the Study
Figure 2.  Relative Risk (Hazard Ratios [HRs], Unadjusted and Adjusted) for Study Outcomes in Patients With Newly Diagnosed Atrial Fibrillation Treated With Oral Anticoagulants (OAC) Plus Antiplatelet Drugs (AP) or OAC Alone (Reference) Over 12 Months (Intent-to-Treat Analyses)
Relative Risk (Hazard Ratios [HRs], Unadjusted and Adjusted) for Study Outcomes in Patients With Newly Diagnosed Atrial Fibrillation Treated With Oral Anticoagulants (OAC) Plus Antiplatelet Drugs (AP) or OAC Alone (Reference) Over 12 Months (Intent-to-Treat Analyses)

Hazard ratios were adjusted for 40 covariates as shown in eTable 1 in the Supplement. AP indicates antiplatelet drugs; and OAC, oral anticoagulants. ACS indicates acute coronary syndromes; MI, myocardial infarction; NMCR, nonmajor, clinically relevant; and SE, systemic embolism.

Figure 3.  Relative Risk (Hazard Ratios [HRs], Unadjusted and Adjusted) for Study Outcomes in Patients With Newly Diagnosed Atrial Fibrillation Treated With Oral Anticoagulants (OAC) Plus Antiplatelet Drugs (AP) or OAC Alone (Reference) Over 3 Months (Intent-to-Treat Analyses)
Relative Risk (Hazard Ratios [HRs], Unadjusted and Adjusted) for Study Outcomes in Patients With Newly Diagnosed Atrial Fibrillation Treated With Oral Anticoagulants (OAC) Plus Antiplatelet Drugs (AP) or OAC Alone (Reference) Over 3 Months (Intent-to-Treat Analyses)

Hazard ratios were adjusted for 40 covariates as shown in eTable 1 in the Supplement. ACS indicates acute coronary syndromes; MI, myocardial infarction; NMCR, nonmajor, clinically relevant; and SE, systemic embolism.

Table.  Clinical Characteristics of Patients With Atrial Fibrillation Treated With OAC Plus AP or OAC Alone for Stroke Prophylaxis
Clinical Characteristics of Patients With Atrial Fibrillation Treated With OAC Plus AP or OAC Alone for Stroke Prophylaxis
1.
Kirchhof  P, Benussi  S, Kotecha  D,  et al; ESC Scientific Document Group.  2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.  Eur Heart J. 2016;37(38):2893-2962. doi:10.1093/eurheartj/ehw210PubMedGoogle ScholarCrossref
2.
January  CT, Wann  LS, Calkins  H,  et al.  2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.  J Am Coll Cardiol. 2019;74(1):104-132. doi:10.1016/j.jacc.2019.01.011PubMedGoogle ScholarCrossref
3.
Lip  GY, Nieuwlaat  R, Pisters  R, Lane  DA, Crijns  HJ.  Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation.  Chest. 2010;137(2):263-272. doi:10.1378/chest.09-1584PubMedGoogle ScholarCrossref
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Lane  DA, Lip  GY.  Use of the CHA(2)DS(2)-VASc and HAS-BLED scores to aid decision making for thromboprophylaxis in nonvalvular atrial fibrillation.  Circulation. 2012;126(7):860-865. doi:10.1161/CIRCULATIONAHA.111.060061PubMedGoogle ScholarCrossref
5.
Kakkar  AK, Mueller  I, Bassand  JP,  et al; GARFIELD Registry Investigators.  Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry.  PLoS One. 2013;8(5):e63479. doi:10.1371/journal.pone.0063479PubMedGoogle Scholar
6.
Steinberg  BA, Kim  S, Piccini  JP,  et al; ORBIT-AF Investigators and Patients.  Use and associated risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation: insights from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry.  Circulation. 2013;128(7):721-728. doi:10.1161/CIRCULATIONAHA.113.002927PubMedGoogle ScholarCrossref
7.
Verheugt  FWA, Gao  H, Al Mahmeed  W,  et al; GARFIELD-AF Investigators.  Characteristics of patients with atrial fibrillation prescribed antiplatelet monotherapy compared with those on anticoagulants: insights from the GARFIELD-AF registry.  Eur Heart J. 2018;39(6):464-473. doi:10.1093/eurheartj/ehx730PubMedGoogle ScholarCrossref
8.
Verheugt  FWA, Ambrosio  G, Atar  D,  et al; GARFIELD-AF Investigators.  Outcomes in newly diagnosed atrial fibrillation and history of acute coronary syndromes: insights from GARFIELD-AF.  Am J Med. 2019;132(12):1431-1440.e7. doi:10.1016/j.amjmed.2019.06.008PubMedGoogle ScholarCrossref
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Lip  GY, Lim  HS.  Atrial fibrillation and stroke prevention.  Lancet Neurol. 2007;6(11):981-993. doi:10.1016/S1474-4422(07)70264-8PubMedGoogle ScholarCrossref
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Lip  GY.  The role of aspirin for stroke prevention in atrial fibrillation.  Nat Rev Cardiol. 2011;8(10):602-606. doi:10.1038/nrcardio.2011.112PubMedGoogle ScholarCrossref
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Steffel  J, Verhamme  P, Potpara  TS,  et al; ESC Scientific Document Group.  The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.  Eur Heart J. 2018;39(16):1330-1393. doi:10.1093/eurheartj/ehy136PubMedGoogle ScholarCrossref
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Neumann  FJ, Sousa-Uva  M, Ahlsson  A,  et al; ESC Scientific Document Group.  2018 ESC/EACTS guidelines on myocardial revascularization.  Eur Heart J. 2019;40(2):87-165. doi:10.1093/eurheartj/ehy394PubMedGoogle ScholarCrossref
13.
Kakkar  AK, Mueller  I, Bassand  JP,  et al.  International longitudinal registry of patients with atrial fibrillation at risk of stroke: Global Anticoagulant Registry in the FIELD (GARFIELD).  Am Heart J. 2012;163(1):13-19.e1. doi:10.1016/j.ahj.2011.09.011PubMedGoogle ScholarCrossref
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World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053.Google ScholarCrossref
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Fox  KAA, Gersh  BJ, Traore  S,  et al; GARFIELD-AF Investigators.  Evolving quality standards for large-scale registries: the GARFIELD-AF experience.  Eur Heart J Qual Care Clin Outcomes. 2017;3(2):114-122.PubMedGoogle Scholar
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American Diabetes Association.  Economic costs of diabetes in the U.S. in 2017.  Diabetes Care. 2018;41(5):917-928. doi:10.2337/dci18-0007PubMedGoogle ScholarCrossref
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Buse  JB, Ginsberg  HN, Bakris  GL,  et al; American Heart Association; American Diabetes Association.  Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association.  Diabetes Care. 2007;30(1):162-172. doi:10.2337/dc07-9917PubMedGoogle ScholarCrossref
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Bassand  J-P, Virdone  S, Goldhaber  SZ,  et al; GARFIELD-AF Investigators.  Early risks of death, stroke/systemic embolism, and major bleeding in patients with newly diagnosed atrial fibrillation.  Circulation. 2019;139(6):787-798. doi:10.1161/CIRCULATIONAHA.118.035012PubMedGoogle ScholarCrossref
19.
You  JJ, Singer  DE, Howard  PA,  et al.  Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.  Chest. 2012;141(2)(suppl):e531S-e575S. doi:10.1378/chest.11-2304PubMedGoogle ScholarCrossref
20.
John Camm  A.  Managing anticoagulation for atrial fibrillation: current issues and future strategies.  J Intern Med. 2013;273(1):31-41. doi:10.1111/joim.12001PubMedGoogle ScholarCrossref
21.
van Walraven  C, Hart  RG, Singer  DE,  et al.  Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis.  JAMA. 2002;288(19):2441-2448. doi:10.1001/jama.288.19.2441PubMedGoogle ScholarCrossref
22.
Saxena  R, Koudstaal  P.  Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attack.  Cochrane Database Syst Rev. 2004;18(4):CD000187. doi:10.1002/14651858.CD000187.pub2PubMedGoogle Scholar
23.
Connolly  S, Pogue  J, Hart  R,  et al; ACTIVE Writing Group of the ACTIVE Investigators.  Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE W): a randomised controlled trial.  Lancet. 2006;367(9526):1903-1912. doi:10.1016/S0140-6736(06)68845-4PubMedGoogle ScholarCrossref
24.
Hart  RG, Pearce  LA, Aguilar  MI.  Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.  Ann Intern Med. 2007;146(12):857-867. doi:10.7326/0003-4819-146-12-200706190-00007PubMedGoogle ScholarCrossref
25.
Aguilar  MI, Hart  R, Pearce  LA.  Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks.  Cochrane Database Syst Rev. 2007;3(3):CD006186. doi:10.1002/14651858.CD006186.pub2PubMedGoogle Scholar
26.
Mant  J, Hobbs  FD, Fletcher  K,  et al; BAFTA investigators; Midland Research Practices Network (MidReC).  Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.  Lancet. 2007;370(9586):493-503. doi:10.1016/S0140-6736(07)61233-1PubMedGoogle ScholarCrossref
27.
Andersen  LV, Vestergaard  P, Deichgraeber  P, Lindholt  JS, Mortensen  LS, Frost  L.  Warfarin for the prevention of systemic embolism in patients with non-valvular atrial fibrillation: a meta-analysis.  Heart. 2008;94(12):1607-1613. doi:10.1136/hrt.2007.135657PubMedGoogle ScholarCrossref
28.
Rietbrock  S, Plumb  JM, Gallagher  AM, van Staa  TP.  How effective are dose-adjusted warfarin and aspirin for the prevention of stroke in patients with chronic atrial fibrillation? an analysis of the UK General Practice Research Database.  Thromb Haemost. 2009;101(3):527-534. doi:10.1160/TH08-08-0499PubMedGoogle ScholarCrossref
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Roskell  NS, Lip  GY, Noack  H, Clemens  A, Plumb  JM.  Treatments for stroke prevention in atrial fibrillation: a network meta-analysis and indirect comparisons versus dabigatran etexilate.  Thromb Haemost. 2010;104(6):1106-1115.PubMedGoogle Scholar
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Kumar  S, Danik  SB, Altman  RK,  et al.  Non-vitamin K antagonist oral anticoagulants and antiplatelet therapy for stroke prevention in patients with atrial fibrillation: a meta-analysis of randomized controlled trials.  Cardiol Rev. 2016;24(5):218-223. doi:10.1097/CRD.0000000000000088PubMedGoogle ScholarCrossref
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Hansen  ML, Sørensen  R, Clausen  MT,  et al.  Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation.  Arch Intern Med. 2010;170(16):1433-1441. doi:10.1001/archinternmed.2010.271PubMedGoogle ScholarCrossref
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Lamberts  M, Olesen  JB, Ruwald  MH,  et al.  Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study.  Circulation. 2012;126(10):1185-1193. doi:10.1161/CIRCULATIONAHA.112.114967PubMedGoogle ScholarCrossref
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Lamberts  M, Gislason  GH, Olesen  JB,  et al.  Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention.  J Am Coll Cardiol. 2013;62(11):981-989. doi:10.1016/j.jacc.2013.05.029PubMedGoogle ScholarCrossref
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Lamberts  M, Gislason  GH, Lip  GY,  et al.  Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant: a nationwide cohort study.  Circulation. 2014;129(15):1577-1585. doi:10.1161/CIRCULATIONAHA.113.004834PubMedGoogle ScholarCrossref
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Alexander  JH, Lopes  RD, Thomas  L,  et al.  Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial.  Eur Heart J. 2014;35(4):224-232. doi:10.1093/eurheartj/eht445PubMedGoogle ScholarCrossref
38.
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    1 Comment for this article
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    RE: Outcomes associated with oral anticoagulants plus antiplatelets in patients with newly diagnosed atrial fibrillation
    Tomoyuki Kawada, MD | Nippon Medical School
    Fox et al. conducted a prospective study to investigate outcomes of patients, aged 18 years and older with recently diagnosed nonvalvular atrial fibrillation (AF) and at least 1 risk factor for stroke (1). Patients were prescribed oral anticoagulants (OAC) plus antiplatelet (AP) therapy vs OAC alone. By follow-up of one year, adjusted hazard ratio (aHRs) (95% confidence intervals [CIs]) of patients treated with OAC plus AP against those treated with OAC alone for stroke and any bleeding event were 1.49 (1.01-2.20) and 1.41 (1.17-1.70), respectively. In addition, there were no significant differences of all-cause mortality and incident acute coronary syndrome between two groups. Furthermore, patients treated with OAC plus AP presented higher rates of all clinical outcomes than those treated with OAC alone over 3 months follow-up. I have two concerns.

    First, the authors described poor clinical outcomes and increased risk of bleeding by the combination of OAC plus AP against OAC alone. I think that appropriate explanation for continuing OAC plus AP treatment is needed, although they did not conduct a randomized study. If there is an advantage of OAC plus AP treatment for ischemic diseases, the effect size should be presented.

    Second, Lamberts et al. investigate the risk of thrombosis and bleeding according to multiple antithrombotic treatment regimens in patients with AF after myocardial infarction (MI) or percutaneous coronary intervention (PCI) (2). Triple therapy (OAC plus aspirin plus clopidogrel) was set as control. Within 1 year, HR (95% CI) of OAC plus clopidogrel for recurrent coronary events was 0.69 (0.48 to 1.00). In addition, HR (95% CI) of aspirin plus clopidogrel for ischemic stroke was 1.50 (1.03 to 2.20). Furthermore, HR (95% CI) of OAC plus aspirin and aspirin plus clopidogrel for all-cause mortality were 1.52 (1.17-1.99) and 1.60 (1.25-2.05), respectively, and bleeding risk was significantly lower. They concluded that OAC and clopidogrel was recommended with benefit and safety outcomes against triple therapy. Although they did not set patients with treatment of OAC alone, different types of AP had different combination effects with OAC. I understand that patients with AF after MI or PCI has an elevated risk of recurrence and treatment of OAC alone might not be recommended with benefit and safety outcomes. Risk assessment for events and safety with OAC and different types of AP might be needed in patients with newly diagnosed AF.


    References

    1. Fox KAA, Velentgas P, Camm AJ, et al. Outcomes associated with oral anticoagulants plus antiplatelets in patients with newly diagnosed atrial fibrillation. JAMA Netw Open. 2020;3(2):e200107. doi: 10.1001/jamanetworkopen.2020.0107

    2. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol. 2013;62(11):981-9. doi: 10.1016/j.jacc.2013.05.029
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    Cardiology
    February 26, 2020

    Resultados asociados con anticoagulantes orales más antiplaquetarios en pacientes con fibrilación auricular recién diagnosticada

    Author Affiliations
    • 1Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
    • 2Aetion Inc, New York, New York
    • 3Cardiology Clinical Academic Group Molecular & Clinical Sciences Research Institute, St George's University of London, London, United Kingdom
    • 4Thrombosis Research Institute, London, United Kingdom
    • 5University of Besançon, Besançon, France
    • 6University of Warwick Medical School, Coventry, United Kingdom
    • 7Mayo Clinic College of Medicine, Rochester, Minnesota
    • 8Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
    • 9Tokai University, Isehara, Japan
    • 10Formerly Department of Medicine, Technical University of Munich, Munich, Germany
    • 11Bayer HealthCare Pharmaceuticals, Berlin, Germany
    • 12Duke University, Durham, North Carolina
    • 13McMaster University, Hamilton, Ontario, Canada
    • 14Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, the Netherlands
    • 15University College London, London, United Kingdom
    JAMA Netw Open. 2020;3(2):e200107. doi:10.1001/jamanetworkopen.2020.0107
    Puntos claveEnglish 中文 (chinese)

    Pregunta  ¿Qué resultados se asocian con la terapia combinada con anticoagulantes orales (OAC) más fármacos antiplaquetarios en pacientes con fibrilación auricular recién diagnosticada?

    Conclusiones  Este estudio de cohortes de 24 436 pacientes con fibrilación auricular de novo encontró que, después de ajustar las características basales y las comedicaciones, los pacientes tratados con OAC más fármacos antiplaquetarios tuvieron tasas de incidencia de accidente cerebrovascular y hemorragia significativamente mayores que aquellos que solamente recibieron OAC. El uso de OAC más fármacos antiplaquetarios no se asoció con un menor riesgo de experimentar síndromes coronarios agudos.

    Significado  Estas conclusiones sugieren que los pacientes con fibrilación auricular tratados con OAC más fármacos antiplaquetarios pueden tener un riesgo significativamente mayor de accidente cerebrovascular y hemorragia en comparación con aquellos que reciben solamente OAC.

    Abstract

    Importance  Patients with nonvalvular atrial fibrillation at risk of stroke should receive oral anticoagulants (OAC). However, approximately 1 in 8 patients in the Global Anticoagulant Registry in the Field (GARFIELD-AF) registry are treated with antiplatelet (AP) drugs in addition to OAC, with or without documented vascular disease or other indications for AP therapy.

    Objective  To investigate baseline characteristics and outcomes of patients who were prescribed OAC plus AP therapy vs OAC alone.

    Design, Setting, and Participants  Prospective cohort study of the GARFIELD-AF registry, an international, multicenter, observational study of adults aged 18 years and older with recently diagnosed nonvalvular atrial fibrillation and at least 1 risk factor for stroke enrolled between March 2010 and August 2016. Data were extracted for analysis in October 2017 and analyzed from April 2018 to June 2019.

    Exposure  Participants received either OAC plus AP or OAC alone.

    Main Outcomes and Measures  Clinical outcomes were measured over 3 and 12 months. Outcomes were adjusted for 40 covariates, including baseline conditions and medications.

    Results  A total of 24 436 patients (13 438 [55.0%] male; median [interquartile range] age, 71 [64-78] years) were analyzed. Among eligible patients, those receiving OAC plus AP therapy had a greater prevalence of cardiovascular indications for AP, including acute coronary syndromes (22.0% vs 4.3%), coronary artery disease (39.1% vs 9.8%), and carotid occlusive disease (4.8% vs 2.0%). Over 1 year, patients treated with OAC plus AP had significantly higher incidence rates of stroke (adjusted hazard ratio [aHR], 1.49; 95% CI, 1.01-2.20) and any bleeding event (aHR, 1.41; 95% CI, 1.17-1.70) than those treated with OAC alone. These patients did not show evidence of reduced all-cause mortality (aHR, 1.22; 95% CI, 0.98-1.51). Risk of acute coronary syndrome was not reduced in patients taking OAC plus AP compared with OAC alone (aHR, 1.16; 95% CI, 0.70-1.94). Patients treated with OAC plus AP also had higher rates of all clinical outcomes than those treated with OAC alone over the short term (3 months).

    Conclusions and Relevance  This study challenges the practice of coprescribing OAC plus AP unless there is a clear indication for adding AP to OAC therapy in newly diagnosed atrial fibrillation.

    Introduction

    Atrial fibrillation (AF) occurs when structural remodeling and/or electrophysiological abnormalities (eg, myocarditis or fibrosis) caused by diverse pathophysiological mechanisms (eg, hypertension or heart failure) alter atrial tissue to promote abnormal pulse wave generation and/or propagation, leading to atrial tachyarrhythmias.1,2 Both AF and the underlying abnormal atrial tissue predispose affected individuals to thrombus formation in the left atrium or left atrial appendage, and this can embolize to the brain and other sites. Guidelines1,2 recommend that patients with nonvalvular AF and CHA2DS2-VASc (cardiac failure, hypertension, age >75 years [2 points], diabetes, stroke, transient ischemic attack, or thromboembolism [2 points]–vascular disease, age >60 years, sex category female)3,4 risk stratification score of 2 or greater (not counting sex) should receive oral anticoagulation (OAC; vitamin K antagonist [VKA] or non-VKA OACs [NOACs]) as stroke prophylaxis regardless of symptoms; in patients with CHA2DS2-VASc score of 1, OAC may be considered. Although antiplatelet (AP) agents are not advocated for stroke prophylaxis in AF, it is known that some patients are coprescribed these drugs with OAC.5-8

    Patients with new-onset AF may have comorbid cardiovascular disease (CVD) requiring therapy with OAC in combination with AP.8 Potential benefits of AP drugs in patients with CVD may be due to their favorable effects on inhibiting arterial thrombosis.9,10 Antiplatelet drugs may be given in combination with OAC in patients with AF after percutaneous coronary intervention, to prevent stent thrombosis, or after acute coronary syndromes (ACS).1,2 In patients with AF who require stenting, guidelines recommend concurrent AP plus OAC for up to 1 year and, in those at risk for stroke, OAC alone thereafter.11,12

    In the large observational Global Anticoagulant Registry in the Field–Atrial Fibrillation (GARFIELD-AF) study,5 approximately 1 in 8 patients with AF at risk for stroke received AP therapy concomitantly with OAC, irrespective of whether they had a confirmed indication for AP. Because the balance of risk vs benefit with combination therapy using OAC plus AP is not well defined, the present study investigated baseline characteristics and outcomes of patients who were newly prescribed OAC plus AP therapy at the time of diagnosis of AF, using data from GARFIELD-AF.

    Methods
    Study Design and Participants

    The GARFIELD-AF study design and main findings have been reported previously.5,13 The registry is a prospective, multicenter, observational study of adults aged 18 years and older with recently diagnosed nonvalvular AF and at least 1 risk factor for stroke. Patients were recruited from a range of representative care settings in each country between December 2009 and October 2017. No specific treatments, tests, or procedures were mandated by the study protocol. Decisions to initiate, continue, or change treatment were solely at the discretion of treating physicians. Patients with a transient reversible cause of AF and those for whom follow-up was not envisaged or possible were excluded.2

    Independent ethics committee and hospital-based institutional review board approvals were obtained for the GARFIELD-AF study, including all subsequent analyses of the data. The registry was conducted in accordance with the principles of the Declaration of Helsinki,14 local regulatory requirements, and the International Conference on Harmonisation–Good Pharmacoepidemiological and Clinical Practice guidelines. Written informed consent was obtained from all study participants. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    Data Capture

    In this prospective observational study, outcomes were captured by electronic case report forms. Submitted data were examined for completeness and accuracy by the coordinating center (Thrombosis Research Institute, London, United Kingdom), and data queries were sent to study sites. An audit and quality control program was implemented that included source documentation (20% of all electronic case report forms were monitored against source records).15

    Baseline characteristics collected at study entry included medical history, care setting, type of AF, date and method of diagnosis of AF, symptoms, antithrombotic treatment (VKAs, NOACs, and AP), as well as all cardiovascular drugs. Race was classified by the investigator in agreement with the patient.13 Vascular disease included coronary artery disease (CAD) with a history of ACS and/or peripheral artery disease. Chronic kidney disease was classified according to National Kidney Foundation guidelines into moderate to severe (stages 3-5), mild (stages 1 and 2), or none. Data on components of the CHA2DS2-VASc risk stratification scheme were collected and calculated retrospectively since patients’ inclusion in the registry was decided by physicians’ clinical judgment. Collection of follow-up data occurred at 4-month intervals up to 24 months. Data for the present investigation were extracted from the study database in October 2017 and analyzed from April 2018 to June 2019.

    In the present analysis, clinical outcomes and bleeding risk were investigated and compared in patients with de novo AF who received either OAC plus AP or OAC alone over 3 and 12 months.

    Statistical Analysis

    Patients who were prescribed AP drugs, defined as aspirin or P2Y12-type ADP receptor inhibitors in combination with OAC were compared with those who did not receive concomitant AP therapy. To reduce risk of bias due to patient selection, patients who had previously taken OACs or AP drugs were excluded from this analysis, as were those prescribed VKA and a NOAC. Subgroup analyses were performed in patients classified as having low and high risk for AF-related stroke (defined as CHA2DS2-VASc score <2 and ≥2, respectively).

    An intent-to-treat analysis was calculated using Cox proportional hazards regression to estimate multivariate adjusted hazard ratios (aHR) and 95% confidence intervals for the study end points of all-cause mortality, myocardial infarction (MI) or ACS, stroke, stroke or systemic embolism, any bleeding, major bleeding, major bleeding and hemorrhagic stroke, and major or nonmajor clinically relevant bleeding (see study design article13 for definitions of these events). Models were adjusted for 40 covariates (eTable 1 in the Supplement) reflecting demographic and clinical characteristics, medical history, and concomitant medication at registry entry. The covariates included all documented vascular indications for AP therapy. As a falsification analysis, the same approach was used to investigate the influence of supplemental AP therapy on an implausible end point such as death unrelated to cardiovascular disease. For each adverse outcome analyzed, patients were censored on first occurrence of that event, loss to follow-up, death, or reaching 90 days of follow-up for 3-month analyses and 365 days for 12-month analyses. Additionally, a propensity score model including the same set of covariates was developed and patients treated with AP drugs were matched 1:1 to patients not treated with AP drugs to create balanced cohorts, in which Cox regression was used to estimate HRs and 95% confidence intervals. Patients with missing values were included in the analysis.

    A supplementary as-treated analysis was performed for all study end points using Cox proportional hazard regression to estimate multivariate adjusted HRs and 95% confidence intervals in the full analysis population and in the propensity score–matched cohorts that we have described. Patients were censored on occurrence of any outcome, loss to follow-up, death, discontinuation of therapy, or interruption of index therapy plus a 7-day risk window, addition or change of the index AP regimen, or reaching 365 days of follow-up.

    An α of .05 (2-tailed) was used for statistical significance. All analyses were conducted using Aetion Evidence Platform version 3.13 (Aetion Inc).

    Results
    Baseline Patient Characteristics

    In total, 57 276 patients were enrolled in GARFIELD-AF between December 2009 and October 2017. After all inclusion and exclusion criteria were applied, the final number of eligible patients newly treated with OAC plus AP or OAC alone at registry entry was 24 436 (13 438 [55.0%] male; median [interquartile range] age, 71 [64-78] years) (Figure 1). Of these, 3059 patients (12.5%) composed the OAC plus AP group, and 21 377 (87.2%) composed the OAC alone group. Both patients who received OAC plus AP and those who received OAC alone had a median age of 71 years. The majority of patients (84.4%) had a moderate to high risk of stroke (CHA2DS2-VASc score ≥2); in the overall population, the median (interquartile range) CHA2DS2-VASc score was 3 (2-4) (Table).

    Compared with patients receiving OAC alone, those who received OAC plus AP therapy had a greater prevalence of cardiovascular indications for AP, including ACS (22.0% vs 4.3%), CAD (39.1% vs 9.8%), and carotid occlusive disease (4.8% vs 2.0%). These patients also had a higher prevalence of cardiovascular conditions such as congestive heart failure (25.2% vs 16.8%), history of hypertension (80.7% vs 76.2%), history of hypercholesterolemia (49.1% vs 36.4%), and history of bleeding (2.7% vs 1.6%) as well as severe renal disease (13.3% vs 9.8%) and diabetes (30.2% vs 19.9%). A higher proportion of patients receiving OAC plus AP were male (Table).

    Among 20 687 patients at high risk of stroke (CHA2DS2-VASc score ≥2), 2735 (13.2%) received OAC plus AP therapy. This subpopulation had a higher prevalence of indications for AP, cardiovascular conditions (except congestive heart failure), severe renal disease, and diabetes and higher likelihood of receiving cardiovascular medications than their counterparts receiving OAC alone. Within this high-risk subpopulation, median (interquartile range) CHA2DS2-VASc score for those prescribed OAC plus AP and OAC alone was 4 (3-4) and 3 (2-4), respectively (eTable 2 in the Supplement).

    Clinical Outcomes at 12 Months

    Unadjusted and adjusted HRs for outcome events over 12 months are displayed in Figure 2. After adjustment for 40 covariates, including baseline medications, patients treated with OAC plus AP had significantly higher incidence rates of stroke (aHR, 1.49; 95% CI, 1.01-2.20) and any bleeding event (aHR, 1.41; 95% CI, 1.17-1.70) as well as composite end points death or stroke (aHR, 1.27; 95% CI, 1.05-1.55) and death, stroke, or major bleeding (aHR, 1.32; 95% CI, 1.10-1.59) than those treated with OAC alone. Moreover, patients prescribed OAC plus AP did not show evidence of reduced all-cause mortality (aHR, 1.22; 95% CI, 0.98-1.51), stroke and/or systemic embolism (aHR, 1.32; 95% CI, 0.90-1.93), and major bleeding events including hemorrhagic stroke (aHR, 1.40; 95% CI, 0.93-2.11). Risk of ACS was not reduced in patients taking OAC plus AP compared with OAC alone (aHR, 1.16; 95% CI, 0.70-1.94). Hazard ratios generated from the propensity score model were similar for each outcome, although precision was slightly reduced owing to smaller sample size after matching 1:1 (results not shown).

    Within the subpopulation of patients at high risk for stroke, the aHRs and HRs generated from the propensity score model were similar to those seen in the overall population for all outcomes (eg, stroke: aHR 1.55; 95% CI, 1.04-2.30; any bleeding event: aHR, 1.42; 95% CI, 1.17-1.72; major and nonmajor clinically relevant bleeding: aHR, 1.50; 95% CI, 1.13-1.99; death or stroke: aHR, 1.27; 95% CI, 1.04-1.56; death, stroke, or major bleeding: aHR, 1.33; 95% CI, 1.10-1.60). No reductions in risk of other clinical outcomes with OAC plus AP vs OAC alone were noted, including ACS (eFigure 1 in the Supplement).

    Clinical Outcomes at 3 Months

    Patients treated with OAC plus AP at registry entry had numerically higher rates of all clinical outcomes than those treated with OAC alone over 3 months (Figure 3). However, only any bleeding (aHR, 1.54; 95% CI, 1.15-2.07), major and nonmajor clinically relevant bleeding (aHR, 1.86; 95% CI, 1.20-2.88), and death, stroke, or major bleeding (aHR, 1.48; 95% CI, 1.07-2.06) exhibited statistically significant increases. Similar patterns were seen among the subgroup of patients at high risk for stroke at 3 months of follow-up (eFigure 2 in the Supplement).

    As-Treated Analyses

    As-treated analyses, in which patients were censored at the time of discontinuation or change of initial treatment, resulted in similar findings to the primary intent-to-treat analyses (data not shown).

    Falsification Analysis

    Among 2541 patients treated with OAC plus AP and 17 673 patients treated with OAC alone who died from causes unrelated to cardiovascular disease over the first 12 months, risk per 1000 patients was estimated to be 9.45 and 11.32, respectively (aHR for event, 0.76; 95% CI, 0.48-1.22) (eTable 3 in the Supplement).

    Discussion

    In this prospective registry of patients with newly diagnosed AF receiving anticoagulant therapy, the majority (87.2%) was treated with OAC alone, whereas 1 in 8 individuals (12.5%) received OAC plus AP. Patients prescribed OAC plus AP had a higher burden of cardiovascular indications for AP therapy such as ACS, CAD, and carotid occlusive disease, as well as a range of cardiovascular conditions that AP drugs are not known to ameliorate, including hypertension, diabetes (an independent risk factor for MI and stroke16,17), and history of bleeding. During the observation period, patients treated with OAC plus AP experienced a higher incidence of adverse outcomes such as stroke, bleeding, and death than those treated with OAC alone over the longer term (12 months) and shorter term (3 months), both before and after adjusting for baseline conditions and comedications. Moreover, patients receiving OAC plus AP did not achieve lower risk of ACS vs patients who were prescribed OAC alone. Reducing early risk is challenging because it is known that the rate of cardiovascular mortality is highest during the first 1 month after diagnosis of AF.18

    Patients presenting with AF and moderate to high risk for AF-related stroke (CHA2DS2-VASc score ≥2)19,20 are usually offered anticoagulant therapy. In low-risk patients (CHA2DS2-VASc ≤1), neither OAC nor AP is recommended because the potential for causing bleeding as an adverse effect could exceed the beneficial effects of preventing stroke. Conversely, in higher-risk patients, preventing stroke is a treatment priority, albeit at a cost of some increase in risk of bleeding. Antiplatelet drugs such as aspirin and clopidogrel, either alone or in combination (dual AP therapy), have been demonstrated to be less efficacious than OACs at preventing stroke in patients with AF and can cause similar or higher rates of bleeding.21-31 Therefore, AP drugs are not routinely recommended for stroke prophylaxis in patients with AF.

    Combining antithrombotic drugs increases their potential to cause bleeding. In a Danish registry study of 82 854 patients with AF with follow-up of more than 3 years, drug-induced nonfatal or fatal bleeding was seen in 11.4%; the risk was lowest in patients who took aspirin or warfarin monotherapy, slightly higher for clopidogrel, and markedly higher (more than 3-fold compared with warfarin alone) for dual warfarin plus clopidogrel and triple therapy using warfarin, aspirin, and clopidogrel.32 These findings were confirmed in patients with AF receiving multiple antithrombotic drugs, including triple therapy, following MI or percutaneous coronary intervention.33,34 The same researchers retrospectively studied patients with AF with coexisting stable CAD and found that risk of recurrent coronary events or thromboembolism was the same for VKA plus aspirin or clopidogrel as for VKA alone, whereas the risk for bleeding increased when either AP drug was given concurrently with VKA.35

    Hsu et al36 analyzed 200 000 outpatients with AF at risk for stroke enrolled in the American College of Cardiology’s Practice Innovation and Clinical Excellence (PINNACLE) registry and identified factors associated with prescribing aspirin alone over OAC that included hypertension, dyslipidemia, CAD, prior MI, angina, recent coronary artery bypass graft, and peripheral artery disease. Patients prescribed OAC, on the other hand, were more often male or had higher body mass index, prior stroke or transient ischemic attack, or heart failure.

    Steinberg and colleagues6 looked at patterns of use and associated risks of coprescribing antithrombotic drugs in a cohort of 10 000 patients enrolled in the US-based Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) study. Patients receiving aspirin plus OAC were more likely to be male (66% vs 53%; P < .0001) and had more comorbid illness, although 39% did not have atherosclerotic disease. Major bleeding and bleeding hospitalizations were significantly greater (by approximately 50%) in patients receiving aspirin plus OAC than in those receiving OAC alone. Overall rates of ischemic events were low. These researchers suggested that adding aspirin therapy to OAC may not be worth the risk in AF, in particular in patients who do not have a convincing indication for aspirin, such as manifest atherosclerosis.

    Several clinical trials37-39 have investigated the efficacy and safety of add-on AP therapy in patients with AF receiving OACs. In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study37 conducted in more than 18 000 patients with AF at risk of stroke, apixaban exerted comparable favorable effects on preventing stroke, systemic embolism, and mortality and caused less major bleeding than warfarin irrespective of whether aspirin was concomitantly used, including in subgroups of patients with arterial disease. Comparable findings were reported for the pivotal Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE-AF) study38 of edoxaban vs warfarin and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial39 of rivaroxaban vs warfarin in AF.

    Strengths and Limitations

    To our knowledge, GARFIELD-AF is the largest international prospective registry in AF with extensive quality control measures providing reassurance for accuracy of results.5,13,15 Although the data were adjusted for an extensive range of clinical and medical history variables known to influence outcomes, differences between patients treated with either OAC plus AP or OAC alone may be subject to unmeasured confounders related to treatment selection by physicians. Indeed, although we were able to analyze clinical scenarios significantly associated with likelihood of receiving comedication with OAC plus AP, treating physicians’ actual reasons for adopting this strategy in individual patients were not recorded. On the other hand, our falsification analysis suggests lack of appreciable bias in this research. Patients included in the present analysis had not received prior OAC or AP therapy.

    Conclusions

    This study suggests that patients with AF at risk for stroke who receive OAC do not require supplemental AP therapy unless there are clear indications for these medications, such as intercurrent ACS or as adjunct to percutaneous coronary intervention. However, this study shows that approximately 1 in 8 patients who are not in this category do receive OAC plus AP. In this study, patients receiving add-on AP therapy had more cardiovascular complications than those given OAC alone, even after adjusting for all baseline risk factors and medications. These findings challenge the clinical practice of combining OAC and AP therapy for stroke prevention in patients with de novo AF.

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    Article Information

    Accepted for Publication: January 5, 2020.

    Published: February 26, 2020. doi:10.1001/jamanetworkopen.2020.0107

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Fox KAA et al. JAMA Network Open.

    Corresponding Author: Keith A. A. Fox, MBChB, BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom (k.a.a.fox@ed.ac.uk).

    Author Contributions: Dr Fox 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: Fox, Camm, Fitzmaurice, Goldhaber, Haas, Misselwitz, Pieper, Verheugt, Kakkar.

    Acquisition, analysis, or interpretation of data: Fox, Velentgas, Camm, Bassand, Gersh, Goto, Pieper, Turpie, Dabrowski, Luo, Gibbs.

    Drafting of the manuscript: Fox, Velentgas, Camm, Dabrowski.

    Critical revision of the manuscript for important intellectual content: Fox, Velentgas, Camm, Bassand, Fitzmaurice, Gersh, Goldhaber, Goto, Haas, Misselwitz, Pieper, Turpie, Verheugt, Luo, Gibbs, Kakkar.

    Statistical analysis: Velentgas, Dabrowski, Luo, Gibbs.

    Obtained funding: Misselwitz, Kakkar.

    Administrative, technical, or material support: Bassand, Fitzmaurice, Pieper.

    Supervision: Fox, Goto, Haas, Verheugt.

    Conflict of Interest Disclosures: Dr Fox reported receiving grants and personal fees from Bayer during the conduct of the study and grants from AstraZeneca, personal fees from Sanofi/Regeneron, and personal fees from Verseon outside the submitted work. Dr Velentgas reported receiving grants from Bayer during the conduct of the study. Dr Camm reported receiving grants and personal fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer BMS Alliance outside the submitted work. Dr Fitzmaurice reported receiving grants from the University of Warwick during the conduct of the study. Dr Goldhaber reported receiving grants from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Boston Scientific’s BTG EKOS, Daiichi Sankyo, Janssen, and the National Heart, Lung, and Blood Institute and consulting fees from Bayer and Boehringer Ingelheim outside the submitted work. Dr Goto reported receiving personal fees from the Thrombosis Research Institute during the conduct of the study. Dr Haas reported receiving personal fees from Aspen, Bayer, Daiichi Sankyo, Bristol-Myers Squibb/Pfizer, and Portola outside the submitted work. Dr Turpie reported receiving personal fees from the Thrombosis Research Institute during the conduct of the study and personal fees from Janssen and Portola outside the submitted work. Dr Verheugt reported receiving personal fees from Bayer, Daiichi Sankyo, Boehringer Ingelheim, and Bristol-Meyers Squibb/Pfizer during the conduct of the study. Ms Dabrowski reported receiving personal fees from Aetion, Inc during the conduct of the study. Ms Luo reported receiving personal fees from Aetion, Inc during the conduct of the study. Ms Gibbs reported receiving personal fees from Aetion, Inc during the conduct of the study. Dr Kakkar reported receiving grants and personal fees from Bayer AG during the conduct of the study and personal fees from Bayer AG, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Sanofi, and Verseon outside the submitted work. No other disclosures were reported.

    Funding/Support: The GARFIELD-AF Registry is an independent academic research initiative sponsored by the Thrombosis Research Institute (TRI; London, United Kingdom) and supported by an unrestricted research grant from Bayer Pharma AG (Berlin, Germany).

    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.

    Group Information: See the eAppendix in the Supplement.

    Additional Contributions: We thank the physicians, nurses, and patients involved in the GARFIELD-AF registry. Martin van Eickels, MD (Bayer HealthCare Pharmaceuticals, Berlin, Germany), contributed to the study design. Medical writing support was provided by Alex Kahney, BSc (Thrombosis Research Institute, London, United Kingdom). Neither were compensated beyond their regular salaries.

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