Physicians' Academy for Cardiovascular Education

Lower absolute rates of ICH with dabigatran

Literature - Hart RG, et al.Stroke 2012 April

Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With Warfarin or Dabigatran

Hart RG, Diener H-C, et al.
Stroke 2012 April doi: 10.1161/STROKEAHA.112.650614

Among older patients with AF with well-controlled blood pressure, similar frequencies of spontaneous hemorrhages were observed in patients given warfarin or dabigatran. However, with dabigatran lower absolute rates were observed at all sites and of both fatal and traumatic intracranial hemorrhages.


Among participants in the RE-LY trial [1](Randomized Evaluation of Long-term anticoagulant therapy), intracranial hemorrhages occurring during anticoagulation were analyzed.


Data were analyzed from 18.113 patients with AF from 951 sites in 44 countries in the RE-LY trial who were assigned to either adjusted-dose warfarin (target INR 2-3) or dabigatran 110 mg or 150 mg bid.

Main results

  • 154 ICHs occurred in 153 patients; overall 30-day mortality 36%
  • Intracerebral hemorrhages: 46% (49% mortality), subdural hematomas: 45% (24% mortality), subarachnoid hemorrhages: 8% (31% mortality)
  • Rate of ICH: 0.76% in warfarin group, 0.31% in dabigatran 150 mg and 0.23% in dabigatran 110 mg group (P<0.001 for each dabigatran dose vs warfarin); mortality due to ICH similar between arms
  • Intracerebral hemorrhages were lower in both dabigatran groups than in the warfarin treatment group (P<0.001)
  • Concomitant aspirin use was a risk factor for ICH

The results during a mean of 2.0 years of follow-up

Rates of overall ICH and intracerebral hemorrhage by treatment assignment.
Dabigatran 150 mg vs Warfarin
Dabigatran 110 mg vs Warfarin
Dabigatran 150 mg vs 110 mg
N/Rate (%/y)
Dabigatran 150 mg
N/Rate (%/y)
Dabigatran 100 mg
N/Rate (%/y)
RR (95% CI)
P value
RR (95% CI)
P value
RR (95% CI)
P value
All intracranial (n=154)
0.40 (0.27-0.59)
0.30 (0.19-0.45)
1.4 (0.83-2.2)
Intracerebral (n=71)
0.23 (0.12-0.45)
0.30 (0.16-0.54)
0.78 (0.35-1.7)
RR indicates relative risk; NS, not statistically significant (P>0.05).


The clinical spectrum of intracranial hemorrhages was similar for warfarin and dabigatran in older AF patients with well-controlled blood pressure. Dabigatran showed substantially lower absolute rates of all sites of ICH and of traumatic ICH; fatal ICHs were substantially less frequent with dabigatran. Aspirin use was the most important independent risk factor for ICH, as shown in previous studies as well [2-5].


1. Connolly SJ, Ezekowitz MD, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139 –1151.
2. Hansen ML, Sorensen R, Clausen MT, Fog-Petersen ML, Raunso J, Gadsboll N, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010;170:1433–1441.
3. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke. 2005;36:1588 –1593.
4. Hart RG, Benavente O, Pearce LA. Increased risk of intracranial hemorrhage when aspirin is combined with warfarin: a meta-analysis and hypothesis. Cerebrovasc Dis. 1999;9:215–217.
5. Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke. 2004;35:2362–2367.


Background and Purpose—Intracranial hemorrhage is the most devastating complication of anticoagulation. Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined.
Methods—Analysis of 18 113 participants with atrial fibrillation in the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial assigned to adjusted-dose warfarin (target international normalized ratio, 2–3) or dabigatran (150 mg or 110 mg, both twice daily).
Results—During a mean of 2.0 years of follow-up, 154 intracranial hemorrhages occurred in 153 participants: 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of intracranial hemorrhage were 0.76%, 0.31%, and 0.23% per year among those assigned to warfarin, dabigatran 150 mg, and dabigatran 110 mg, respectively (P<0.001 for either dabigatran dose versus warfarin). Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg (n=13 and n=11, respectively) versus warfarin (n=32; P<0.01 for both). Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran (11 patients with each dose) compared with warfarin (24 patients; P<0.05 for both dabigatran doses versus warfarin). Independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk, 2.9; P<0.001), aspirin use (relative risk, 1.6; P=0.01), age (relative risk, 1.1 per year; P<0.001), and previous stroke/transient ischemic attack (relative risk, 1.8; P=0.001).
Conclusions—The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran. Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin. Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage.

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