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Eur Heart J. 2015 May 21;36(20):1264-72. doi: 10.1093/eurheartj/ehu463. Epub 2014 Dec 12.

Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial.

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Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, Uppsala 751 85, Sweden
Boston University Medical Center, Boston, MA, USA.
Duke University, Medical Center, Durham, NC, USA.
Bristol-Myers Squibb, Princeton, NJ, USA.
Working Group on Cardiovascular Research the Netherlands, Utrecht, Netherlands.
Department of Pharmacology, Division of Clinical Research and Training, St John's Medical College and Research Institute, Bangalore, India.
Hofstra-North Shore/LIJ School of Medicine, New York, NY, USA.
Department of Medicine, Tokai University, School of Medicine, Isehara, Japan.
Institute of Cardiology, Warsaw, Poland.
Karolinska Institutet, Department of Clinical Sciences, Danderyd University Hospital, Stockholm, Sweden.
Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands.
Fuwai Hospital, Beijing, China.
Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, Uppsala 751 85, Sweden.



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.


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.


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. Identifier: NCT00412984.


Atrial fibrillation; Bleeding; Factor Xa inhibitor

[Indexed for MEDLINE]

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