title: Bleeding risk in patients with atrial fibrillation: the AMADEUS study.
abstract: OBJECTIVE
  This study aimed to assess the impact of combination antithrombotic therapy on stroke and bleeding risk compared with anticoagulation therapy only in patients with atrial fibrillation (AF).
  
  
  METHODS
  Post hoc analysis of 4,576 patients with AF (mean ± SD age, 70.1 ± 9.1 years; men, 66.5%) enrolled in the Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation (AMADEUS) trial were randomized to receive either subcutaneous idraparinux (2.5 mg weekly) (n = 2,283) or dose-adjusted vitamin K antagonists (VKAs) (international normalized ratio, 2.0-3.0) (n = 2,293). Of these patients, 848 (18.5%) received antiplatelet therapy (aspirin, clopidogrel, ticlopidine, etc) in addition to anticoagulation treatment (combination antithrombotic therapy).
  
  
  RESULTS
  A total of 572 (15.3% per year) clinically relevant bleeding and 103 (2.6% per year) major bleeding events occurred. Patients receiving combination antithrombotic therapy had a 2.3- to 2.5-fold increased risk of clinically relevant bleeding events and major bleeding events, respectively, compared with those receiving anticoagulation therapy only. Multivariate analyses (hazard ratio, 95% CI) revealed that the risk of clinically relevant bleeding was significantly increased by age 65 to 74 years (1.44, 1.14-1.82) and ≥ 75 years (1.59, 1.24-2.04, P = .001) and by combination antithrombotic therapy (2.47, 2.07-2.96, P < .0001). The same held true for major bleeding events, with analogous figures for age 65 to 74 years (2.26, 1.08-4.71) and ≥ 75 years (4.19, 1.98-8.87, P = .0004) and for combination antithrombotic therapy (2.23, 1.49-3.34, P < .0001). Combination antithrombotic therapy was not associated with a decrease in ischemic stroke risk compared with anticoagulation therapy only (11 [1.4% per year] vs 22 [0.7% per year]; adjusted hazard ratio, 2.01; 95% CI, 0.94-4.30; P = .07).
  
  
  CONCLUSIONS
  Combination antithrombotic therapy increases the risk of clinically relevant bleeding and major bleeding in patients with AF and does not appear to reduce the risk of stroke.
authors.affiliation: University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, England. Electronic address: deirdrelane@nhs.net.
authors.forename: Deirdre A
authors.initials: DA
authors.lastname: Lane
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Pieter W
authors.initials: PW
authors.lastname: Kamphuisen
authors.affiliation: Sanofi-Aventis Research and Development, Biostatistics and Programming, Chilly-Mazarin, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Minini
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Büller
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Gregory Y H
authors.initials: GYH
authors.lastname: Lip
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004739:England / Q000453:epidemiology; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D007279:Injections, Subcutaneous; D008297:Male; D009844:Oligosaccharides / Q000008:administration & dosage / Q000009:adverse effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011379:Prognosis; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D020521:Stroke / Q000209:etiology / Q000517:prevention & control*; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D009844:Oligosaccharides; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin; C479958:idraparinux