title: Non-major bleeding with apixaban versus warfarin in patients with atrial fibrillation.
abstract: We describe the incidence, location and management of non-major bleeding, and assess the association between non-major bleeding and clinical outcomes in patients with atrial fibrillation (AF) receiving anticoagulation therapy enrolled in Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE).
  
  
  
  We included patients who received ≥1 dose of study drug (n=18 140). Non-major bleeding was defined as the first bleeding event considered to be clinically relevant non-major (CRNM) or minor bleeding, and not preceded by a major bleeding event.
  
  
  
  Non-major bleeding was three times more common than major bleeding (12.1% vs 3.8%). Like major bleeding, non-major bleeding was less frequent with apixaban (6.4 per 100 patient-years) than warfarin (9.4 per 100 patient-years) (adjusted HR 0.69, 95% CI 0.63 to 0.75). The most frequent sites of non-major bleeding were haematuria (16.4%), epistaxis (14.8%), gastrointestinal (13.3%), haematoma (11.5%) and bruising/ecchymosis (10.1%). Medical or surgical intervention was similar among patients with non-major bleeding on warfarin versus apixaban (24.7% vs 24.5%). A change in antithrombotic therapy (58.6% vs 50.0%) and permanent study drug discontinuation (5.1% (61) vs 3.6% (30), p=0.10) was numerically higher with warfarin than apixaban. CRNM bleeding was independently associated with an increased risk of overall death (adjusted HR 1.70, 95% CI 1.32 to 2.18) and subsequent major bleeding (adjusted HR 2.18, 95% CI 1.56 to 3.04).
  
  
  
  In ARISTOTLE, non-major bleeding was common and substantially less frequent with apixaban than with warfarin. CRNM bleeding was independently associated with a higher risk of death and subsequent major bleeding. Our results highlight the importance of any severity of bleeding in patients with AF treated with anticoagulation therapy and suggest that non-major bleeding, including minor bleeding, might not be minor.
  
  
  
  NCT00412984; post-results.
authors: INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina.
authors: M Cecilia
authors: MC
authors: Bahit
authors: Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors: Renato D
authors: RD
authors: Lopes
authors: Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors: Daniel M
authors: DM
authors: Wojdyla
authors: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors: Claes
authors: C
authors: Held
authors: Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors: Michael
authors: M
authors: Hanna
authors: University of Medicine and Pharmacy Carol Davila, Bucharest, Romania.
authors: Dragos
authors: D
authors: Vinereanu
authors: Boston University Medical Center, Boston, Massachusetts, USA.
authors: Elaine M
authors: EM
authors: Hylek
authors: Heartcenter, Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, Netherlands.
authors: Freek
authors: F
authors: Verheugt
authors: Tokai University School of Medicine, Isehara, Japan.
authors: Shinya
authors: S
authors: Goto
authors: Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors: John H
authors: JH
authors: Alexander
authors: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors: Lars
authors: L
authors: Wallentin
authors: Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors: Christopher B
authors: CB
authors: Granger
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects*; D001208:Asia; D001281:Atrial Fibrillation / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D057915:Drug Substitution; D005060:Europe; D065427:Factor Xa Inhibitors / Q000009:adverse effects*; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced* / Q000401:mortality / Q000628:therapy; D006801:Humans; D015994:Incidence; D007843:Latin America; D008297:Male; D008875:Middle Aged; D009656:North America; D061214:Patient Safety; D011720:Pyrazoles / Q000009:adverse effects*; D011728:Pyridones / Q000009:adverse effects*; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000175:diagnosis / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D013923:Thromboembolism / Q000175:diagnosis / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin