Association of Intracranial Hemorrhage Risk With Non-Vitamin K Antagonist Oral Anticoagulant Use vs Aspirin Use: A Systematic Review and Meta-analysis

JAMA Neurol. 2018 Dec 1;75(12):1511-1518. doi: 10.1001/jamaneurol.2018.2215.


Importance: Non-vitamin K antagonist oral anticoagulants (NOACs) might be an attractive choice for stroke prevention in people without atrial fibrillation who may harbor a potential source of cardiac emboli, but not if certain individual NOACs carry risks of intracranial hemorrhage that are heightened relative to aspirin.

Objective: To conduct a systematic review and meta-analysis of randomized clinical trials to assess the risk of intracranial hemorrhage with individual NOACs vs aspirin across all indications.

Data sources: We searched PubMed, Embase, CENTRAL, and from inception to May 28, 2018, with the terms novel oral anticoagulants, non-vitamin K antagonist oral anticoagulants, direct oral anticoagulants, dabigatran, rivaroxaban, apixaban, edoxaban, warfarin, Coumadin, vitamin K antagonist, aspirin, acetylsalicylic acid, or ASA, and major bleeding, fatal bleeding, or intracranial hemorrhage. We restricted our search to clinical trials on humans. There were no language restrictions.

Study selection: Randomized clinical trials of 3 months or longer that included a comparison of the outcomes of NOAC use vs use of aspirin.

Data extraction and synthesis: Two investigators independently abstracted data from eligible studies. We computed a fixed-effect estimate based on the Mantel-Haenszel method.

Main outcomes and measures: Odds ratios (ORs) with 95% CI were used as a measure of the association of individual NOAC vs aspirin with the risk of intracranial hemorrhage. The hypothesis that intracranial hemorrhage risk would be higher with NOACs than aspirin was formulated during data collection.

Results: Our principal analysis included 5 randomized clinical trials comparing 1 or more NOACs with aspirin, with 39 398 individuals enrolled. Pooling the results from the fixed-effects model showed that a dose of 15 to 20 mg of rivaroxaban once daily was associated with an increased risk of intracranial hemorrhage (2 trials; OR, 3.31 [95% CI, 1.42 to 7.72]) compared with aspirin, while a 10-mg dose of rivaroxaban once daily or a 5-mg dose twice daily (3 trials; OR, 1.43 [95% CI, 0.93 to 2.21]) and a 5-mg dose of apixaban twice daily (1 trial; OR, 0.84 [95% CI, 0.38 to 1.88]) were not.

Conclusions and relevance: A 15-mg to 20-mg dose of rivaroxaban once daily is associated with substantially increased risks of intracranial hemorrhage, while smaller daily doses of rivaroxaban and apixaban were not, implying that risk increase is dose dependent. It may be worthwhile to conduct randomized clinical trials comparing specific NOACs in specific doses (eg, apixaban, 5 mg twice daily) and aspirin in patients without atrial fibrillation, but with potential sources of cardiac emboli that could cause stroke.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Anticoagulants / administration & dosage
  • Anticoagulants / adverse effects*
  • Aspirin / administration & dosage
  • Aspirin / adverse effects*
  • Dose-Response Relationship, Drug*
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / adverse effects*
  • Humans
  • Intracranial Hemorrhages / chemically induced*
  • Pyrazoles / administration & dosage
  • Pyrazoles / adverse effects*
  • Pyridones / administration & dosage
  • Pyridones / adverse effects*
  • Rivaroxaban / administration & dosage
  • Rivaroxaban / adverse effects*


  • Anticoagulants
  • Fibrinolytic Agents
  • Pyrazoles
  • Pyridones
  • apixaban
  • Rivaroxaban
  • Aspirin