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Blood. 2017 Jun 1;129(22):2980-2987. doi: 10.1182/blood-2016-08-731638. Epub 2017 Mar 29.

Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy.

Author information

Duke Clinical Research Institute, Duke Health, Durham, NC.
Department of Neurology, Wake Forest School of Medicine, Winston Salem, NC.
Bristol-Myers Squibb, Princeton, NJ.
University of California San Francisco, San Francisco, CA.
Uppsala Clinical Research Center and.
Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
Brazilian Clinical Research Institute, Sao Paulo, Brazil; and.
Department of Neurology and Headache Center, University of Duisburg-Essen, Essen, Germany.


We investigated the frequency and characteristics of intracranial hemorrhage (ICH), the factors associated with the risk of ICH, and outcomes post-ICH overall and by randomized treatment. We identified patients with ICH from the overall trial population enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial who received ≥1 dose of the study drug (n = 18 140). ICH was adjudicated by a central committee. Cox regression models were used to identify factors associated with ICH. ICH occurred in 174 patients; most ICH events were spontaneous (71.7%) versus traumatic (28.3%). Apixaban resulted in significantly less ICH (0.33% per year), regardless of type and location, than warfarin (0.80% per year). Independent factors associated with increased risk of ICH were enrollment in Asia or Latin America, older age, prior stroke/transient ischemic attack, and aspirin use at baseline. Among warfarin-treated patients, the median (25th, 75th percentiles) time from most recent international normalized ratio (INR) to ICH was 13 days (6, 21 days). Median INR prior to ICH was 2.6 (2.1, 3.0); 78.5% of patients had a pre-ICH INR <3.0. After ICH, the modified Rankin scale score at discharge was ≥4 in 55.7% of patients, and the overall mortality rate at 30 days was 43.3% with no difference between apixaban- and warfarin-treated patients. ICH occurred at a rate of 0.80% per year with warfarin regardless of INR control and at a rate of 0.33% per year with apixaban and was associated with high short-term morbidity and mortality. This highlights the clinical relevance of reducing ICH by using apixaban rather than warfarin and avoiding concomitant aspirin, especially in patients of older age. This trial was registered at as #NCT00412984.

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