- Coyle M et al. Risk of Intracranial Hemorrhage Associated With Direct Oral Anticoagulation vs Antiplatelet Therapy: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2024;7(12):e2449017.
The meta-analysis (DOI:10.1001/jamanetworkopen.2024.49017) found no significant difference between direct oral anticoagulants (DOAC) and acetylsalicylic acid (ASA) in terms of the risk of intracranial haemorrhages. Over an average observation period of approximately 17 months, the incidence in both treatment groups was less than 1% (DOAC: 0.55% vs. ASA: 0.48%). The odds ratio of 1.15 (95% CI: 0.71–1.88) shows no statistically significant difference between the two treatment options. These results suggest that DOACs are no more dangerous than ASA in terms of the risk of cerebral haemorrhage.
However, there was moderate heterogeneity in the study results, suggesting different effects of the individual DOAC active ingredients: Rivaroxaban was the only anticoagulant with a significantly increased risk of intracranial haemorrhage compared to ASA (OR ≈ 2.1). In contrast, dabigatran (OR ≈ 1.0) and apixaban (OR ≈ 0.7) showed no increase in risk.
Although these data indicate substance-specific differences, they should be interpreted with caution. The studies analysed differ in terms of populations, study design and dosage. There are no direct head-to-head comparisons of DOAC, so it is not possible to draw definitive conclusions about the superiority of individual active substances.
While the risk of cerebral haemorrhage was generally not increased with DOACs, the overall picture was different for severe bleeding. Clinically relevant, major bleeding – such as gastrointestinal or retroperitoneal bleeding – was considered ‘major bleeding’.
For major bleeding, there was a statistically significant difference in favour of ASA over an average observation period of 15.5 months. Major bleeding events occurred significantly more frequently under DOAC therapy than under ASA treatment (2.41% vs. 1.76%). The pooled odds ratio of 1.39 (95% CI: 1.07–1.80) demonstrates a moderate but statistically significant increase in the risk of bleeding under DOAC. In absolute terms, this means that while approximately one in 56 patients suffered severe bleeding under ASA therapy, the figure was approximately one in 40 patients under DOAC.
Here, too, there was study heterogeneity and possible evidence of differences between the DOACs:
Despite the increased risk of severe bleeding, the clinical benefit of DOAC remains undisputed: they significantly reduced the risk of ischemic stroke more than ASA (2.43% vs. 3.26% over an average of 15.5 months).
The study results provide an important reassurance: DOAC therapy does not increase the risk of cerebral haemorrhage compared to ASA. Apixaban in particular appears to be a suitable alternative to ASA for patients with an increased risk of bleeding – based on convincing safety data and proven efficacy in stroke prevention. These results, combined with the known superiority of DOACs over ASA in the prevention of ischaemic strokes, reinforce the current guideline recommendations to treat patients with atrial fibrillation primarily with DOACs.
At the same time, the increased risk of severe (non-intracranial) bleeding must be taken into account. Careful patient selection and close monitoring remain crucial. Overall, however, the clinical benefits outweigh the risks: in the absence of specific contraindications, there is no reason to forego effective anticoagulation with DOAC in favour of ASA.