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Abstract

Background

The management of atrial fibrillation (AF) in patients with a history of intracranial hemorrhage (ICH) presents a significant clinical challenge. Although oral anticoagulants (OACs), have been shown to effectively reduce thromboembolic events in AF patients, their use in survivors of ICH raises concerns regarding the risk of recurrent bleeding. In this study, we conduct a systematic review of randomized controlled trials (RCTs) to assess the safety and efficacy of OAC therapy in AF patients following ICH.

Methods

We searched PubMed/Embase for RCTs assessing OACs in AF patients with ICH history. Efficacy outcomes included ischemic stroke, major vascular events, stroke or vascular death, major embolic events, and all-cause mortality.

Results

A total of three RCTs with 623 participants were included. Compared to no anticoagulation or antiplatelet therapy alone, OAC did not significantly reduce the risk of ischemic stroke (HR = 0.27, 95% CI [0.02, 3.92], P = .13), but it significantly reduced the occurrence of major vascular events (HR = 0.65, 95% CI [0.43, 0.98], P = .04). However, OACs significantly increased the risk of recurrent ICH (HR = 4.05, 95% CI [1.62, 10.17], P = .003) and major bleeding events (HR = 3.70, 95% CI [1.64, 8.35], P = .002). No significant effect was observed on stroke or vascular death (HR = 0.74, 95% CI [0.39, 1.41], P = .36).

Conclusions

OACs can reduce the risk of major vascular events, but they significantly increase the risk of bleeding, particularly recurrent ICH. Clinical decision-making should be individualized, carefully evaluating the thromboembolic and bleeding risks for each patient. Further high-quality RCTs are needed to validate these findings.

Keywords

atrial fibrillation intracranial hemorrhage oral anticoagulants randomized controlled trials

Introduction

AF is one of the most common arrhythmias in clinical practice^1,2 with ischemic stroke being its most severe complication.^3,4 OACs can reduce the risk of stroke in AF patients.^5,6 Many authoritative guidelines recommend long-term and continuous anticoagulation therapy for selected patient populations. Currently, OACs are the first-line treatment for preventing stroke and systemic embolism in AF patients.^2,7,8 Adults with a history of spontaneous ICH are at high risk for major cardiovascular events.^9,10 However, anticoagulation therapy, while reducing thromboembolic risk, inevitably carries the risk of bleeding complications, with ICH being the most dangerous and associated with a high mortality rate^11,12 Some studies have shown that despite increasing the risk of brain hemorrhage, anticoagulation therapy may improve functional outcomes.¹³ Therefore, the question of when to restart anticoagulation therapy in AF patients after ICH remains unresolved.^14,15 Contemporary evidence necessitates meticulous, patient-specific risk-benefit stratification for anticoagulation in AF following intracerebral hemorrhage. While current data support direct oral anticoagulant (DOAC) therapy in appropriately selected candidates, the optimal temporal framework for anticoagulant reinitiation remains clinically indeterminate and merits validation through rigorously designed, adequately powered RCTs.

Previous studies have suggested that OACs significantly reduce ischemic cardiovascular events without increasing the risk of recurrent ICH.^16–19 However, this conclusion still requires validation through high-quality RCTs.²⁰ Moreover, the etiology of ICH (eg, hypertensive, cerebral amyloid angiopathy), the location of the hemorrhage (eg, cortical vs deep), and the individual thromboembolic-bleeding risk ratio of the patient (eg, CHA₂DS₂-VASc and HAS-BLED scores) may all influence treatment decisions.^12,21 This decision-making process requires clinicians to precisely assess and balance thromboembolic and bleeding risks, considering the benefits of anticoagulation in preventing stroke and the potential increase in bleeding risk.²² This meta-analysis reviews the latest RCTs evaluating the efficacy and safety of resuming oral anticoagulation therapy in AF patients who have survived ICH.

Methods

Literature Search

This study adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement.²³ From the start of the year until May 2025, we conducted a systematic search in PubMed and Embase. The search strategy combined MeSH terms and free-text terms, focusing on keywords such as “AF,” “ICH/cerebral hemorrhage,” and “OACs.” Boolean operators (“AND”) were used for precise matching. To ensure comprehensive coverage, we also included relevant search terms for RCTs and manually screened the reference lists of retrieved articles. Notably, no language restrictions were applied to ensure the inclusiveness and representativeness of the studies.

Eligibility Criteria

We used the PICOS (Population, Intervention, Comparison,²⁴ Outcome, Study Design) framework to define the inclusion and exclusion criteria. The population (P) was adult patients diagnosed with AF and a history of ICH. The intervention (I) consisted of DOACs or vitamin K antagonists (VKAs). The comparison (C) was patients receiving no anticoagulation therapy or antiplatelet therapy. The primary outcome (O) was efficacy (ischemic stroke, major vascular events, stroke or vascular death, major embolic events, and all-cause mortality) and safety (recurrent ICH and major bleeding events)(Supplemental Table 1). Only RCTs were included. Studies were excluded if they were post hoc analyses of RCTs, non-human studies, case reports, reviews, meta-analyses, editorials, conference abstracts, observational studies, or duplicate publications (for duplicate studies, the one with a longer follow-up or larger sample size was prioritized).

Study Selection

The literature screening process was rigorous: Initially, two trained researchers independently screened the titles and abstracts of retrieved studies against the inclusion and exclusion criteria. Full-text articles of potentially eligible studies were then assessed. To ensure objectivity and accuracy, a dual-reviewer process was employed, with disagreements resolved by discussion. If consensus could not be reached, a third senior researcher experienced in systematic reviews was consulted for arbitration.

Data Extraction

Data extracted from each study included: (1) study characteristics—publication year, study design, trial abbreviation, location, sample size, and follow-up duration; (2) participant characteristics—demographic details, CHA₂DS₂-VASc score, HAS-BLED score; (3) intervention details—the type and dosage of OACs; (4) control group details—the type and dosage of antiplatelet therapy or no treatment; and (5) outcomes—incidence of primary and secondary outcomes. Definitions of primary outcomes were extracted according to the original protocols of each trial. Major bleeding criteria were reported in all three trials, while ischemic event definitions were explicitly provided in Apache-AF and PRESTIGE-AF but not in SoSTART. Detailed criteria are summarized in Supplemental Table 2.

Risk of Bias Assessment

The methodological quality of the included studies was evaluated using the Cochrane Collaboration's revised risk-of-bias tool (RoB 2.0),²⁵ assessing bias across five key domains: random sequence generation and allocation concealment (randomization process), adherence to the intervention (deviation from the intended intervention), completeness of outcome data (impact of missing data), outcome measurement (detection bias), and selective reporting (reporting bias). Each domain was assessed using standardized algorithms, and studies were classified as low, moderate, or high risk of bias. Two researchers independently conducted the risk-of-bias assessment, with disagreements resolved through discussion or arbitration by a third senior researcher to ensure objectivity and reliability.

Statistical Analysis

Statistical analysis followed the guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Version 6.2).²⁶ We used Review Manager 5.4 software (2014, Cochrane Collaboration, Nordic Cochrane Centre, Copenhagen, Denmark) for the meta-analysis. Cochran's Q test and I² statistics were used to assess statistical heterogeneity across studies. We calculated the standard errors and natural logarithms for hazard ratios (HRs) from each study and combined the results using a random-effects model with an inverse-variance approach.

Results

Study Selection

As shown in Figure 1, a total of 3411 articles were retrieved using the predefined search strategy. After removing 310 duplicate articles, 3090 publications were excluded based on title and abstract screening. The full text of 11 studies was reviewed, with 8 studies being excluded. After further assessment, three studies—Apache-AF, SoSTART, and PRESTIGE-AF^27–29—were included in the meta-analysis.

Figure 1.

PRISMA Flow Diagram of Study Selection.

Main Features of Included Studies

Table 1 presents the key characteristics of the three included RCTs. A total of 623 participants were enrolled, with 309 participants receiving treatment in the intervention group (including novel OACs or VKAs) and 314 participants in the control group (receiving no anticoagulation therapy or only antiplatelet therapy).

Table 1.

Key Characteristics of Included Studies.

Trials	SoSTART(2021)	APACHE-AF（2021）	PRESTIGE-AF（2025）
Study	Pilot RCT	Phase II RCT	Phase III RCT
Location	67 hospitals in the UK	16 hospitals in the Netherlands	75 hospitals in six European countries
Participants	203	101	319
Follow-Up time	Median 1.2 years	Median 1.9 years	Median 1.4 years
Participant Age	Median 79 years (IQR 74-85)	Median 78 years (IQR 73-83)	Median 79 years (IQR 73-83)
Female (%)	37%	46%	35%
male（%）	63%	54%	65%
CHA2DS2-VASc Score	Median 4 (IQR 3-5)	Median 4 (IQR 3-5)	Median 4 (IQR 3-6)
HAS-BLED Score	Median 2 (IQR 1-2)	Not mentioned	Median 3 (IQR 2-3)
Intervention	DOACs/VKAs	Apixaban	DOACs
Comparator	Antiplatelet/none	No anticoagulation	No anticoagulation
Primary outcome(s)	Recurrent ICH	Non-fatal stroke or vascular death	Ischemic stroke and recurrent ICH
secondary outcomes	Any symptomatic major vascular event, Any stroke, Any stroke or vascular death	Intracerebral haemorrhage, All major haemorrhagic events,Ischaemic stroke, All major occlusive events, All major vascular events according to the protocol^†, All major vascular events (myocardial infarction, stroke, or vascular death)	All-cause mortality，Cardiovascular mortality, Cardiovascular mortality, Any major bleeding, Any intracranial bleeding, All stroke and systemic embolism, Net clinical benefit

Abbreviations: RCT: Randomised Controlled Trial; ICH: Intracranial Haemorrhage; DOACs: Direct Oral Anticoagulants; VKA: Vitamin K Antagonists, CHA2DS2-VASc: Congestive Heart Failure(1), Hypertension, (1)Age ≥75(2), Diabetes(1), Stroke(2), Vascular Disease,(1) Age 65-74(1), Female(1)

HAS-BLED: Hypertension(1), Abnormal Renal/Liver Function(1), Stroke(1), Bleeding(1), Labile INR(1), Age >65 (1), Drugs (1), Alcohol (1).

†

Composite endpoint defined as the first occurrence of any major haemorrhagic event, major occlusive event, or vascular death, according to the study protocol.

Quality Assessment of Included Studies

SoSTART (2021) exhibited a low risk of bias across all domains, indicating a robust and rigorous study design. Although Apache-AF (2021) and PRESTIGE-AF (2025) showed certain limitations in the domain of “deviations from intended interventions” due to their open-label designs, all other methodological domains met the required standards, suggesting an overall high methodological quality (Figures 2 and 3). Heterogeneity analysis demonstrated good consistency across outcomes (I² ≤ 33%), with the exception of ischemic stroke, which showed significant heterogeneity (I² = 84%) (Figure 4).

Figure 2.

Summary of Risk of Bias for Included Studies.

Figure 3.

Risk of Bias Assessment by Domain for Each Included Study.

Figure 4.

Forest Plot from Meta-analysis of Efficacy and Safety Outcomes in Patients with Atrial Fibrillation after Intracranial Hemorrhage.

Results of Meta-Analysis

This meta-analysis included three studies: SoSTART (2021), Apache-AF (2021), and PRESTIGE-AF (2025), involving a total of 623 participants. The primary outcomes varied among the studies, with SoSTART focusing on recurrent ICH, Apache-AF on non-fatal stroke or vascular death, and PRESTIGE-AF on ischemic stroke and recurrent ICH.

Efficacy of OAC Therapy in ICH Patients with AF

OAC therapy did not significantly reduce the incidence of ischemic stroke compared to no anticoagulation or antiplatelet therapy (HR = 0.27, 95% CI [0.02, 3.92], P = .34). However, the results showed high heterogeneity (I² = 84%), suggesting potential methodological or population differences across studies. OAC significantly reduced the risk of any symptomatic major vascular events (HR = 0.65, 95% CI [0.43, 0.98], P = .04), with very low heterogeneity (I² = 0%), supporting the stability of the results. OAC therapy had no significant impact on the composite endpoint of stroke or vascular death (HR = 0.74, 95% CI [0.39, 1.41], P = .36), likely due to the limited evidence from only two studies (Figure 4).

Safety of OAC Therapy in ICH Patients with AF

OAC significantly increased the risk of recurrent ICH (HR = 4.05, 95% CI [1.62, 10.17], P = .003), with low heterogeneity (I² = 3%), suggesting robust results. OAC also significantly increased the risk of all major bleeding events (HR = 3.70, 95% CI [1.64, 8.35], P = .002), with low heterogeneity (I² = 0%) (Figure 4).

This apparent paradox—fewer vascular events but more ICH recurrences—may reflect the tension between systemic anticoagulation and vulnerable cerebral vasculature. While OACs reduce ischemic risk by preventing atrial thrombus formation, they may increase bleeding in fragile cerebral vessels, particularly in the context of cerebral amyloid angiopathy or hypertensive small vessel disease.

Discussion

This study evaluates the efficacy and safety of OACs in AF patients following ICH using a meta-analysis approach. The results suggest that while OACs can reduce the risk of major vascular events, they significantly increase the risk of recurrent ICH and other bleeding events, which indicates that clinical decisions should carefully consider both benefits and risks.

The primary benefit of OAC therapy in AF patients is the prevention of ischemic stroke and systemic embolism. As demonstrated by the included trials, this benefit extends to survivors of ICH. The three trials (SoSTART, Apache-AF, and PRESTIGE-AF) found that OACs reduced the occurrence of major ischemic cardiovascular events. The Apache-AF trial showed that OAC therapy reduced the risk of ischemic stroke. Similarly, the latest PRESTIGE-AF trial showed that, compared to no anticoagulation therapy, DOACs significantly reduced the incidence of first ischemic stroke. Although the individual HRs from these trials suggest that OACs may reduce the risk of ischemic stroke, the combined analysis did not reach statistical significance due to high heterogeneity and wide confidence intervals. This discrepancy may reflect differences in patient populations or intervention methods, and further research with standardized study designs or individual patient data meta-analyses is needed to explore this issue further.

The main concern with resuming OAC therapy in survivors of ICH is the risk of recurrent bleeding, particularly recurrent ICH. Recurrent ICH risk was found to be significantly higher with OAC therapy. Similarly, the risk of major bleeding events was also significantly elevated, which highlights the necessity of carefully selecting patients for anticoagulation therapy, even with the use of DOACs. Apache-AF and SoSTART both reported a higher incidence of recurrent ICH in OAC-treated patients compared to those not receiving anticoagulation, although this difference was not statistically significant. The PRESTIGE-AF trial emphasized this risk, showing that recurrent ICH was significantly higher in the DOAC group. This difference might reflect variations in study design, sample size, and follow-up duration, underscoring the need for larger, more definitive trials to clarify these findings.

The effect of OACs in reducing major vascular events is consistent with previous studies on anticoagulation therapy in AF, supporting the value of OACs in reducing thromboembolic events. OACs did not significantly impact the composite endpoint of stroke or vascular death, which may be attributed to variations in treatment regimens (eg, anticoagulant and control group protocols) across different studies. The effect of OACs on mortality and functional outcomes in survivors of ICH with AF remains uncertain. The OCROACH meta-analysis found no significant difference in all-cause mortality between the OAC and control groups.³⁰ Similarly, the most recent PRESTIGE-AF trial reported comparable results for all-cause mortality. Functional outcomes assessed using the modified Rankin scale (mRS) also showed no significant difference between groups. Therefore, although OACs may reduce ischemic events, their overall impact on survival and functional recovery remains unclear.

Subgroup analyses, especially those focusing on the location of ICH, are critical. Lobar ICH is often associated with cerebral amyloid angiopathy (CAA), which increases the risk of recurrent hemorrhage. The PRESTIGE-AF trial showed no significant heterogeneity in bleeding risk based on the location of ICH. However, due to safety concerns, ongoing trials, such as ENRICH-AF (NCT03950076), have discontinued the use of OACs in the lobar ICH subgroup, highlighting the need for further investigation in this area. These findings underscore the importance of continued studies to identify safe anticoagulation strategies tailored to patients with different ICH characteristics.

The included studies exhibited significant methodological heterogeneity, making direct comparisons challenging. For example, the Apache-AF and SoSTART trials allowed antiplatelet therapy in the control groups (51% and 33%, respectively), which could have influenced the results. In contrast, the PRESTIGE-AF trial excluded antiplatelet therapy from the control group, allowing for a clearer evaluation of OAC effects. Furthermore, the use of DOACs in the OAC regimen (comprising 99% of the COCROACH protocol) differs from earlier trials involving VKAs, which are associated with a higher bleeding risk.

Limitations

Despite the valuable insights provided by these studies, several limitations should be acknowledged. First,the relatively small pooled sample size (n = 623) limited statistical power, particularly for outcomes like ischemic stroke, where wide confidence intervals may have obscured clinically meaningful differences. Second, the open-label design of these trials may introduce performance and detection bias. Third, the inclusion of antiplatelet therapy in the control groups complicates the interpretation of OAC effects. Fourth, our analysis could not evaluate potential differences in bleeding risk among specific types or doses of DOACs due to limited trial-level data. This heterogeneity warrants investigation in future studies. Fifth, despite notable heterogeneity in trial methodologies, the paucity of available studies precluded meaningful subgroup analyses based on ICH topography or the temporal parameters of anticoagulation resumption. The deliberate exclusion of patients with lobar ICH from anticoagulation in the PRESTIGE-AF trial accentuates the imperative for targeted investigations within this high-risk cohort. Future prospective trials should be designed to rigorously address these clinically consequential stratifications. Finally, the relatively short follow-up periods may underestimate the long-term risks and benefits of OAC therapy in this patient population.

Conclusions

In conclusion, while OACs can reduce ischemic events in AF patients with a history of ICH, they also present the uncertain risk of recurrent bleeding, particularly ICH. OAC therapy did not demonstrate a statistically significant reduction in the risk of ischemic stroke; however, this finding should be interpreted with caution, as it may be attributable to limited statistical power resulting from the small sample size and study heterogeneity, rather than indicating a true lack of treatment effect.Current evidence supports the cautious use of DOACs in carefully selected patients, but further research is needed to identify the optimal patient subgroups and refine the risk-benefit profile of anticoagulation therapy in this high-risk population. Clinicians should remain vigilant and prioritize shared decision-making to optimize outcomes for these patients.

Supplemental Material

sj-docx-1-cat-10.1177_10760296251368889 - Supplemental material for Oral Anticoagulant Therapy in Patients with Atrial Fibrillation After Intracranial Hemorrhage: A Meta-Analysis of Randomized Controlled Trials

Supplemental material, sj-docx-1-cat-10.1177_10760296251368889 for Oral Anticoagulant Therapy in Patients with Atrial Fibrillation After Intracranial Hemorrhage: A Meta-Analysis of Randomized Controlled Trials by Guangjing Zhang, Yipeng Wu, Luxia Gao, Zhiqiang Xiao and Xi Chen in Clinical and Applied Thrombosis/Hemostasis

Supplemental Material

sj-docx-2-cat-10.1177_10760296251368889 - Supplemental material for Oral Anticoagulant Therapy in Patients with Atrial Fibrillation After Intracranial Hemorrhage: A Meta-Analysis of Randomized Controlled Trials

Supplemental material, sj-docx-2-cat-10.1177_10760296251368889 for Oral Anticoagulant Therapy in Patients with Atrial Fibrillation After Intracranial Hemorrhage: A Meta-Analysis of Randomized Controlled Trials by Guangjing Zhang, Yipeng Wu, Luxia Gao, Zhiqiang Xiao and Xi Chen in Clinical and Applied Thrombosis/Hemostasis

Supplemental Material

sj-docx-3-cat-10.1177_10760296251368889 - Supplemental material for Oral Anticoagulant Therapy in Patients with Atrial Fibrillation After Intracranial Hemorrhage: A Meta-Analysis of Randomized Controlled Trials

Supplemental material, sj-docx-3-cat-10.1177_10760296251368889 for Oral Anticoagulant Therapy in Patients with Atrial Fibrillation After Intracranial Hemorrhage: A Meta-Analysis of Randomized Controlled Trials by Guangjing Zhang, Yipeng Wu, Luxia Gao, Zhiqiang Xiao and Xi Chen in Clinical and Applied Thrombosis/Hemostasis

Footnotes

Author Contributions

Zhang G: Conceptualization, Data curation, Writing – original draft preparation.

Wu Y: Formal analysis, Visualization, Methodology.

Gao L: Validation, Investigation, Writing – review & editing.

Xiao Z: Resources, Supervision, Project administration.

Chen X: Supervision, Final approval of the manuscript, Funding acquisition.

Availability of Data and Materials

All relevant data and materials are provided within the manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Natural Science Foundation of Fujian Province, (grant number 2024J011485 ).

ORCID iD

Zhiqiang Xiao

Supplemental Material

Supplemental material for this article is available online.

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