ABSTRACT
Background
The optimal timing for initiating oral anticoagulation in patients with atrial fibrillation after acute ischemic stroke remains uncertain. This systematic review and meta‐analysis aims to compare early versus later initiation of oral anticoagulants in this patient population.
Methods
We systematically searched multiple databases, including MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov, up to January 2026. We included randomized controlled trials (RCTs) comparing early (≤ 4 days, post‐stroke) versus later (> 5 days) direct oral anticoagulation (DOAC) initiation in patients with atrial fibrillation and acute ischemic stroke. Our main outcomes were a primary composite outcome of ischemic stroke, sICH, or unclassified stroke and the primary composite outcome, or all‐cause mortality.
Results
Four RCTs were included with a total of 6722 patients. Our meta‐analysis revealed no significant difference between early and later DOAC initiation for the primary composite outcome (RR: 0.84, 95% CI: 0.64–1.10), primary composite outcome or mortality (RR: 0.99; 95% CI: 0.82–1.19), ischemic stroke (RR: 0.78, 95% CI: 0.54–1.12), symptomatic intracranial hemorrhage (RR: 1.00, 95% CI: 0.48–2.06), all‐cause mortality (RR: 0.96, 95% CI: 0.80–1.14), or major bleeding (RR: 0.72, 95% CI: 0.33–1.60).
Conclusion
Early initiation of anticoagulants appears to be comparable to later initiation in terms of stroke recurrence, bleeding risks, and mortality in patients with atrial fibrillation. These findings support a more individualized approach to anticoagulation timing, balancing ischemic and hemorrhagic risks based on patient characteristics. Further high‐quality trials are needed to refine clinical guidelines and optimize anticoagulation strategies in this population.
Trial Registration
CRD42024629570 [PROSPERO]
Keywords: atrial fibrillation, DOAC, early initiation, ischemic stroke, oral anticoagulation
In patients with atrial fibrillation and acute ischemic stroke, early (≤ 4 days) initiation of direct oral anticoagulation was comparable to later (> 5 days) initiation for composite stroke outcomes and mortality. Stroke recurrence, bleeding risk, and survival did not significantly differ between strategies, supporting individualized timing decisions.
1. Introduction
Acute ischemic stroke is a significant global health issue with an estimated 17 million cases occurring worldwide each year [1]. Atrial fibrillation (AF) is identified in at least 20% of patients with ischemic stroke and is likely a contributing factor to the event in these cases [2]. It accounts for approximately one‐third of all stroke occurrences and is linked to a fivefold increase in stroke risk [3, 4, 5]. Anticoagulation therapy using direct oral anticoagulants (DOACs) lowers the risk of ischemic stroke and systemic embolism in individuals with AF [6]. However, the optimal timing for initiating DOAC therapy following an acute ischemic stroke remains uncertain. Starting treatment early may elevate the risk of intracranial hemorrhage, while delayed initiation could increase the likelihood of early stroke recurrence [7, 8].
Preventing early recurrence poses a significant clinical challenge in managing acute ischemic stroke linked to AF. The recurrence risk within the first 7 to 14 days ranges from 0.4% to 1.3% daily [9, 10]. Symptomatic intracranial hemorrhage (sICH) is associated with increased mortality and morbidity rates and has been documented in 2%–20% of patients [11]. Ischemic strokes related to AF are associated with a higher likelihood of disability or mortality compared to other stroke types [3, 4, 5]. Consequently, mitigating this risk and preventing early recurrence is essential to improving patient outcomes. However, major organizations such as the American Heart Association (AHA), American Stroke Association (ASA), European Society of Cardiology (ESC), and European Association for Cardiothoracic Surgery (EACTS) lack clear guidelines on the optimal timing for initiating anticoagulation therapy [12, 13].
Recent randomized controlled trials (RCTs) have produced conflicting findings regarding the timing of anticoagulation initiation. The TIMING and OPTIMAS trials suggest that starting DOACs early is non‐inferior to a delayed approach in patients with acute ischemic stroke, while, in contrast, the ELAN trial reports that early initiation of DOACs significantly reduces the risk of a composite outcome of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, sICH, or vascular death compared to delayed initiation over 90 days [14, 15, 16]. In addition, while previous systematic reviews have explored the optimal timing for initiating oral anticoagulation [13, 17, 18], no review has incorporated all the available RCTs, including a recently published large trial with 3621 patients [19]. Moreover, including observational studies alongside RCTs in many prior analyses may compromise their validity and introduce potential confounding biases [13, 17, 18]. As a result, clinicians face uncertainty about the best timing for initiating oral anticoagulation and often withhold DOAC treatment after admission [17, 18]. In light of the conflicting evidence and the absence of clear guidelines, this systematic review and meta‐analysis, focusing exclusively on RCTs, aims to provide a robust evaluation of early versus late initiation of DOACs in acute ischemic stroke patients with AF.
2. Methods
This meta‐analysis was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the identifier CRD42024629570. The review was conducted according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions and reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) statement [20, 21].
2.1. Eligibility Criteria
The inclusion criteria were as follows: (1) study design: RCTs; (2) population: adult patients with acute ischemic stroke and atrial fibrillation; (3) intervention: early anticoagulation as defined by the study or started within 4 days after stroke; and (4) comparator: later coagulation as defined by the study or started at 5 days or more after stroke.
The exclusion criteria were as follows: (1) all study designs other than RCTs; (2) studies not reporting any outcome of interest; and (3) studies conducted on animals.
2.2. Information Sources
We searched the following electronic databases and international trial registers from inception to February 2025 (updated January 2026) with no language restrictions: the Cochrane Central Register of Controlled Trials (CENTRAL, via The Cochrane Library), MEDLINE (via PubMed), Embase (via Ovid), and ClinicalTrials.gov. We also searched gray literature sources, such as ProQuest Dissertations and Theses Global (PQDT) and Google Scholar. We used a search strategy consisting of relevant keywords and Medical Subject Headings (MeSH) related to terms such as “stroke,” “atrial fibrillation,” “anticoagulants,” “early,” and “late.” The detailed search strategies for each database are presented in Table S1. The reference lists of included articles and relevant reviews were also evaluated.
2.3. Selection Process
We imported the articles retrieved through the online search into Zotero and removed duplicates. Two reviewers independently completed the title and abstract screening, followed by full‐text screening. A third reviewer settled any disagreements.
2.4. Data Collection Process and Data Items
Two reviewers independently extracted the following data into a structured prepiloted Excel spreadsheet to ensure consistency of data extraction: study characteristics including study/trial name, location, year of publication, number of patients included, and time of follow up; participant characteristics including age, gender, history of prior stroke hemorrhage, baseline NIHSS score; intervention and comparator details, such as time of therapy initiation.
Our main outcomes were a primary composite outcome of ischemic stroke, sICH, or unclassified stroke and the primary composite outcome or all‐cause mortality. The secondary outcomes were the incidence of ischemic stroke, sICH, all‐cause mortality, and major bleeding.
2.5. Risk of Bias Assessment
To assess the risk of bias in the included studies, two authors independently applied the revised Cochrane “Risk of bias” tool for randomized trials (RoB 2.0). RoB 2.0 addresses five specific domains: (1) bias arising from the randomization process; (2) bias due to deviations from intended interventions; (3) bias due to missing outcome data; (4) bias in the measurement of the outcome; and (5) bias in the selection of the reported result. The studies were assigned a rating of low risk of bias, some concerns, and a high risk of bias. Any disagreements were resolved by discussion to reach a consensus between the two review authors or by the final judgment of a third review author.
2.6. Data Synthesis
The meta‐analyses were conducted using Review Manager (RevMan 5.4, Version 5.4; The Cochrane Collaboration, Copenhagen, Denmark) under a random effects model, utilizing risk ratio (RR) and mean difference (MD), with corresponding 95% confidence intervals (CIs) as the effect measures. We used the I 2 statistic to quantify heterogeneity.
3. Results
3.1. Study Selection and Characteristics of Included Studies
After screening, a total of 4 studies were included in the systematic review (Figure 1) [16, 19, 22, 23]. One study [16] was multinational, while the rest were conducted in a single country each. All trials had a 90‐day follow‐up period. Patient demographics were comparable across the studies. A higher proportion of participants were male, with the median age ranging from 75 to 78 years. The baseline stroke severity (National Institutes of Health Stroke Scale [NIHSS] score) of the patients included in the trials varied, with medians ranging from 5 to 7 across the trials. The detailed characteristics of the studies are shown in Table 1.
FIGURE 1.
PRISMA 2020 flowchart.
TABLE 1.
Characteristics of included studies.
| Study ID | Trial name | Location | No. of patients | Timing of therapy initiation | Age (years) a | Male (%) | Prior ischemic stroke (%) | Prior intracranial hemorrhage (%) | Baseline NIHSS score a | Follow‐up time (days) | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Early | Late | ||||||||||
| Fischer 2023 | ELAN | Europe, the Middle East, and Asia | 2013 (1006 vs. 1007) | Within 48 h for minor stroke, day 6 or 7 for moderate or major stroke | day 3 or 4‐minor, day 6 or 7‐moderate, day 12, 13, or 14‐major | 77 (70–84) versus 78 (71–84) | 12.7 versus 13.9 | NR | 5 (2–12) versus 5 (2–11) | 90 | |
| Oldgren 2022 | TIMING | Sweden | 888 (450 vs. 438) | ≤ 4 days | 5–10 days | 78.3 ± 9.9 (78.4 ± 10.1 vs. 78.3 ± 9.7) | 54 versus 53.7 | 17.6 versus 17.4 | NR | 6.1 ± 5.9 (6.2 ± 5.8 vs. 5.9 ± 5.9) | 90 |
| Warach 2025 | START trial | USA | 200 (107 vs. 93) | ≤ 4 days | 6–14 days | 75 (65–81) | 50 | NR | NR | 7 (4–14) | 30 |
| Werring 2024 | OPTIMAS | UK | 3621 (1814 vs. 1807) | ≤ 4 days | 7–14 days | 78.5 (9.9) versus 78.5 (9.9) | 55.3 versus 54.1 | 16.3 versus 13.4 | 1.9 versus 1.5 | 6 (3–11) versus 5 (3–10) | 90 |
Values are in mean ± SD or median (IQR).
3.2. Risk of Bias of Included Studies
All studies were found to have some concerns of bias (Figure S1). The concerns arose due to deviations from the intended intervention.
3.3. Results of the Meta‐Analysis
3.3.1. Primary Outcomes7
There was no significant difference in the primary composite outcome of ischemic stroke, intracranial hemorrhage, or unclassified stroke (RR: 0.84; 95% CI: 0.64–1.10; I 2 = 0%; Figure 2) and primary composite outcome or mortality (RR: 0.99; 95% CI: 0.82–1.19; I 2 = 5%; Figure 3) between the early and late anticoagulation groups.
FIGURE 2.
Effect of early versus later anticoagulation on the risk of primary composite outcome of ischemic stroke, intracranial hemorrhage, or unclassified stroke.
FIGURE 3.
Effect of early versus later anticoagulation on the risk of primary composite outcome or mortality.
3.3.2. Secondary Outcomes
There was no significant difference in the rate of ischemic stroke (RR: 0.78; 95% CI: 0.54–1.12; I 2 = 22%; Figure S2), symptomatic intracranial hemorrhage (RR: 1.00; 95% CI: 0.48–2.06; I 2 = 0%; Figure S3), all‐cause mortality (RR: 0.96; 95% CI: 0.80–1.14; I 2 = 0%; Figure S4), or major bleeding (RR: 0.72; 95% CI: 0.33–1.60; I 2 = 26%; Figure S5) between the early and late anticoagulation groups.
4. Discussion
Our systematic review and meta‐analysis, which includes four RCTs, shows that there is no statistically significant difference between early and later oral anticoagulation in patients with acute ischemic stroke and AF in the primary composite outcome of ischemic stroke, sICH, or unclassified stroke, and the primary composite outcome or mortality. Similarly, no significant differences were observed for the secondary outcomes of the risk of ischemic stroke, sICH, all‐cause mortality, or major bleeding between the two groups.
These results align with some of the findings of the meta‐analyses by Palaiodimou et al. [24] and Jiang et al. [25], which included RCTs and observational cohort studies, in showing no significant differences between early and later anticoagulation initiation for outcomes such as the risk of intracranial hemorrhage, major bleeding, and all‐cause mortality. Another meta‐analysis [12], including only RCTs, reported similar observations to ours but failed to include the recently published results of the START trial [23]. Conversely, some prior findings contradict our results. Palaiodimou et al. found that early initiation of oral anticoagulants was associated with a lower rate of ischemic stroke [24]. Similarly, Tirumandyam et al. suggested that early initiation of anticoagulation significantly increased the risk of intracranial hemorrhage but also correlated with a reduction in recurrent ischemic strokes [17]. These discrepancies could be attributed to differences in the study designs, wherein we focused only on RCTs and included OPTIMAS, the largest trial published to date, with a total of 3621 patients [19].
The OPTIMAS trial demonstrated that starting anticoagulation within 4 days of an acute ischemic stroke in patients with AF is non‐inferior to starting it after 7–14 days in terms of systemic embolism or recurrent strokes [19]. There was also no significant increase in the risk of major bleeding events. This trial has a robust study design as a multicentre, randomized trial, ensuring high‐quality evidence with minimal bias. A diverse patient population was included across multiple centers, which increases the generalizability of the results. Our findings, consistent with the OPTIMAS trial, indicate the reliability and robustness of our analyses.
The stroke risk in patients with non‐valvular AF is significantly increased, with research suggesting that the annual incidence of stroke may reach 5% to 6% in untreated individuals [26, 27]. This risk is exacerbated by characteristics including age, hypertension, and other comorbidities, which can further elevate the probability of thromboembolic events. AF constitutes roughly 15% of all ischemic strokes, increasing to 30% in individuals over 80 years old [27, 28]. While subgroup analyses from the ELAN and TIMING trials revealed no significant differences in treatment effects based on age, stroke severity, or infarct size, observational data suggest that patients with large infarctions are more likely to develop ICH, implying that delayed initiation may benefit high‐risk individuals [16, 22].
The biggest strength of our meta‐analysis is that the evidence is synthesized solely from RCTs. In addition, this is the largest aggregate of data from RCTs, as we included more RCTs and patients than prior analyses. However, some limitations need to be acknowledged. Differences in patient populations, baseline stroke severity, and anticoagulation regimens could be a source of undetected heterogeneity in our analyses. In addition, the number of included studies, being only four, leaves us with low statistical power. Moreover, most trials focused primarily on DOACs, excluding other anticoagulants such as vitamin K antagonists, limiting the application of the findings to other anticoagulation methods. Furthermore, the trials did not assess longer‐term outcomes beyond 90 days, which can be critical for thoroughly understanding the impact of early versus late anticoagulant therapy. Finally, publication bias could not be evaluated due to the low number of included trials. Underreported studies with negative or null results may skew the meta‐analysis findings.
The lack of a notable difference in clinical outcomes between early and delayed anticoagulation regimens indicates that the timing of initiation should be tailored to individual patient characteristics, including stroke severity, bleeding risk, and comorbidities. For patients with a low risk of hemorrhage, early anticoagulation may be a viable strategy to mitigate the risk of repeated ischemic episodes. Conversely, for patients at elevated risk of hemorrhage, postponing the beginning of anticoagulation may be more prudent.
Further research is necessary to confirm these findings through large, well‐conducted RCTs with diverse patient populations and well‐defined anticoagulation protocols. Trials may focus on high‐risk populations, including those with severe strokes, large infarcts, or a high likelihood of hemorrhagic transformation, to gain a more comprehensive understanding of the risks and benefits of early anticoagulation in these subpopulations. Expanding studies to include alternative anticoagulants, such as vitamin K antagonists, can provide a more complete picture of therapy choices. Furthermore, investigating the combination of anticoagulation with reperfusion therapy, such as thrombolysis and thrombectomy, could yield important insights, especially in patients with moderate to severe strokes. Such studies could help refine recommendations on the optimal timing of anticoagulation in acute ischemic stroke patients with AF and provide greater clarity on the balance between efficacy and safety.
5. Conclusions
Our meta‐analysis found no significant difference between early and later oral anticoagulation in patients with acute ischemic stroke and AF in the primary composite outcome of ischemic stroke, sICH, or unclassified stroke, primary composite outcome, or mortality and major bleeding. These findings underline the significance of tailoring treatment to individual patient characteristics, including stroke severity, bleeding risk, and comorbidities. Further large, well‐conducted RCTs with diverse patient populations and well‐defined anticoagulation protocols are needed to build upon these findings.
Funding
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: Search strategy for online databases.
Figure S1: Quality assessment of included trials.
Figure S2: Effect of early versus later anticoagulation on the risk of ischemic stroke.
Figure S3: Effect of early versus later anticoagulation on the risk of symptomatic intracranial hemorrhage.
Figure S4: Effect of early versus later anticoagulation on the risk of all‐cause mortality.
Figure S5: Effect of early versus later anticoagulation on the risk of major bleeding.
Acknowledgments
The authors have nothing to report.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Search strategy for online databases.
Figure S1: Quality assessment of included trials.
Figure S2: Effect of early versus later anticoagulation on the risk of ischemic stroke.
Figure S3: Effect of early versus later anticoagulation on the risk of symptomatic intracranial hemorrhage.
Figure S4: Effect of early versus later anticoagulation on the risk of all‐cause mortality.
Figure S5: Effect of early versus later anticoagulation on the risk of major bleeding.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.