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Meta-Analysis
. 2024 Dec 2;7(12):e2449017.
doi: 10.1001/jamanetworkopen.2024.49017.

Risk of Intracranial Hemorrhage Associated With Direct Oral Anticoagulation vs Antiplatelet Therapy: A Systematic Review and Meta-Analysis

Mark Coyle  1   2 , Amy Lynch  1   2 , Meave Higgins  1   2 , Maria Costello  1   2 , Conor Judge  1   2 , Martin O'Donnell  1   2 , Catriona Reddin  1   2   3
Affiliations
Meta-Analysis

Risk of Intracranial Hemorrhage Associated With Direct Oral Anticoagulation vs Antiplatelet Therapy: A Systematic Review and Meta-Analysis

Mark Coyle et al. JAMA Netw Open. .

Abstract

Importance: For patients with atrial fibrillation, clinicians often prescribe antiplatelet therapy rather than oral anticoagulation, which may be related to a concern that direct oral anticoagulants (DOACs) are associated with a higher risk of intracranial bleeding, despite being less effective for stroke prevention.

Objective: To determine whether DOAC therapy, compared with single-agent antiplatelet therapy, was associated with an increased risk of intracranial and major hemorrhage.

Data sources: A systematic search of PubMed and Embase databases from inception to February 7, 2024, was performed.

Study selection: Randomized clinical trials that compared DOAC therapy with single-agent antiplatelet therapies were included. Trials with active follow-up of less than 30 days or a sample size less than 200 were excluded.

Data extraction and synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Data were extracted independently by 2 researchers. A random-effects meta-analysis model was used to report pooled treatment effects and 95% CIs.

Main outcomes and measures: The primary outcome was occurrence of intracranial hemorrhage.

Results: A total of 9 randomized clinical trials were included (45 494 participants). DOAC therapy was not associated with significantly higher odds of intracranial hemorrhage compared with antiplatelet therapy (0.55% vs 0.48% over a mean trial follow-up of 17.1 months; odds ratio [OR], 1.15; 95% CI, 0.71-1.88), but there was heterogeneity among trials (I2 = 53.7%). In an analysis by DOAC agent, the respective estimates for intracranial hemorrhage risk were as follows: rivaroxaban, OR, 2.09 (95% CI, 1.20-3.64); dabigatran, OR, 1.00 (95% CI, 0.61-1.64); and apixaban, OR, 0.72 (95% CI, 0.44-1.17). Overall, DOAC therapy was associated with higher odds of major hemorrhage compared with antiplatelet therapy (2.41% vs 1.76% over a mean trial follow-up of 15.5 months; OR, 1.39; 95% CI, 1.07-1.80), with the following estimates by agent: rivaroxaban, OR, 1.91 (95% CI, 1.22-3.00); dabigatran; OR, 1.21 (95% CI, 0.86-1.69); and apixaban, OR, 1.09 (95% CI, 0.73-1.63).

Conclusions and relevance: In this systematic review and meta-analysis, DOAC therapy was not associated with a significantly higher risk of intracranial hemorrhage compared with antiplatelet therapy, but was associated with a higher risk of major hemorrhage. These findings support the safety of DOAC compared with antiplatelet therapy with respect to risk of ICH and reinforce adherence with current atrial fibrillation guidelines.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Coyle reported receiving personal fees, educational grants, and honoraria from Bayer Pharmaceuticals outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Association of Direct Oral Anticoagulation (DOAC) vs Antiplatelet Therapy With Symptomatic Intracranial Hemorrhage
Forest plot shows the association of DOAC vs antiplatelet therapy with symptomatic intracranial hemorrhage. The squares and horizontal lines represent the mean values and 95% CIs of the effect sizes, and the area of the squares reflects the weight of the studies. The combined effect estimates appear as diamonds, and the vertical dashed line represents the line of no effect. OR indicates odds ratio; and RE, random effects.
Figure 2.
Figure 2.. Association of Direct Oral Anticoagulation (DOAC) vs Antiplatelet Therapy and Major Hemorrhage
Forest plot shows the association of DOAC therapy vs antiplatelet therapy with major hemorrhage events. The squares and horizontal lines represent the mean values and 95% CIs of the effect sizes, and the area of the squares reflects the weight of the studies. The combined effect estimates appear as diamonds, and the vertical dashed line represents the line of no effect. OR indicates odds ratio; and RE, random effects.
Figure 3.
Figure 3.. Association of Direct Oral Anticoagulation (DOAC) vs Antiplatelet Therapy With Hemorrhage Outcomes
Forest plot shows the association of DOAC therapy vs antiplatelet therapy with outcome events. The squares and horizontal lines represent the mean values and 95% CIs of the effect sizes, and the area of the squares reflects the weight of the studies. The vertical dashed line represents the line of no effect. CV indicates cardiovascular; GI, gastrointestinal; and OR, odds ratio.
Figure 4.
Figure 4.. Association of Direct Oral Anticoagulation (DOAC) vs Antiplatelet Therapy and Fatal Hemorrhage
Forest plot shows the association of DOAC therapy vs antiplatelet therapy with fatal hemorrhage. The squares and horizontal lines represent the mean values and 95% CIs of the effect sizes, and the area of the squares reflects the weight of the studies. The combined effect estimates appear as diamonds, and the vertical dashed line represents the line of no effect. OR indicates odds ratio; and RE, random effects.
See this image and copyright information in PMC

References

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