title: Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial.
abstract: OBJECTIVE
  In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced the risk of stroke, major bleed, and death in patients with atrial fibrillation. In this ancillary study, we evaluated clinical consequences of major bleeds, as well as management and treatment effects of warfarin vs. apixaban.
  
  
  RESULTS
  Major International Society on Thrombosis and Haemostasis bleeding was defined as overt bleeding accompanied by a decrease in haemoglobin (Hb) of ≥2 g/dL or transfusion of ≥2 units of packed red cells, occurring at a critical site or resulting in death. Time to event [death, ischaemic stroke, or myocardial infarction (MI)] was evaluated by Cox regression models. The excess risk associated with bleeding was evaluated by separate time-dependent indicators for intracranial (ICH) and non-intracranial haemorrhage. Major bleeding occurred in 848 individuals (4.7%), of whom 126 (14.9%) died within 30 days. Of 176 patients with an ICH, 76 (43.2%) died, and of the 695 patients with major non-ICH, 64 (9.2%) died within 30 days of the bleeding. The risk of death, ischaemic stroke, or MI was increased roughly 12-fold after a major non-ICH bleeding event within 30 days. Corresponding risk of death following an ICH was markedly increased, with HR 121.5 (95% CI 91.3-161.8) as was stroke or MI with HR 21.95 (95% CI 9.88-48.81), respectively. Among patients with major bleeds, 20.8% received vitamin K and/or related medications (fresh frozen plasma, coagulation factors, factor VIIa) to stop bleeding within 3 days, and 37% received blood transfusion. There was no interaction between apixaban and warfarin and major bleeding on the risk of death, stroke, or MI.
  
  
  CONCLUSIONS
  Major bleeding was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following ICH, and this risk was similarly elevated regardless of treatment with apixaban or warfarin. These results underscore the importance of preventing bleeding in anti-coagulated patients. ClinicalTrials.gov Identifier: NCT00412984.
authors.affiliation: Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, Uppsala 751 85, Sweden claes.held@ucr.uu.se.
authors.forename: Claes
authors.initials: C
authors.lastname: Held
authors.affiliation: Boston University Medical Center, Boston, MA, USA.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Hylek
authors.affiliation: Duke University, Medical Center, Durham, NC, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Alexander
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hanna
authors.affiliation: Duke University, Medical Center, Durham, NC, USA.
authors.forename: Renato D
authors.initials: RD
authors.lastname: Lopes
authors.affiliation: Duke University, Medical Center, Durham, NC, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Wojdyla
authors.affiliation: Duke University, Medical Center, Durham, NC, USA.
authors.forename: Laine
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Duke University, Medical Center, Durham, NC, USA.
authors.forename: Hussein
authors.initials: H
authors.lastname: Al-Khalidi
authors.affiliation: Working Group on Cardiovascular Research the Netherlands, Utrecht, Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Alings
authors.affiliation: Department of Pharmacology, Division of Clinical Research and Training, St John's Medical College and Research Institute, Bangalore, India.
authors.forename: Dennis
authors.initials: D
authors.lastname: Xavier
authors.affiliation: Hofstra-North Shore/LIJ School of Medicine, New York, NY, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Ansell
authors.affiliation: Department of Medicine, Tokai University, School of Medicine, Isehara, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Goto
authors.affiliation: Institute of Cardiology, Warsaw, Poland.
authors.forename: Witold
authors.initials: W
authors.lastname: Ruzyllo
authors.affiliation: Karolinska Institutet, Department of Clinical Sciences, Danderyd University Hospital, Stockholm, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Rosenqvist
authors.affiliation: Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands.
authors.forename: Freek W A
authors.initials: FW
authors.lastname: Verheugt
authors.affiliation: Fuwai Hospital, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Duke University, Medical Center, Durham, NC, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
authors.affiliation: Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, Uppsala 751 85, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
mesh_terms: D001281:Atrial Fibrillation / Q000150:complications* / Q000401:mortality; D065427:Factor Xa Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced* / Q000401:mortality; D006801:Humans; D020300:Intracranial Hemorrhages / Q000139:chemically induced / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000401:mortality; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects; D020521:Stroke / Q000401:mortality / Q000517:prevention & control*; D013923:Thromboembolism / Q000401:mortality / Q000517:prevention & control*; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin
keywords: Atrial fibrillation; Bleeding; Factor Xa inhibitor