Abstract
The optimal timing for initiating direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) following acute ischemic stroke (AIS) remains a critical clinical question. This review evaluates findings from three pivotal randomized controlled trials—TIMING, ELAN, and OPTIMAS—comparing early versus delayed DOAC initiation in AF patients with AIS. Collectively, these trials provide strong evidence supporting the safety and efficacy of early initiation of DOACs in patients with AIS and AF. The TIMING trial demonstrated the non-inferiority of early DOAC initiation (≤4 days) compared to delayed initiation (5-10 days), with numerically lower rates of ischemic stroke and no cases of symptomatic ICH. The ELAN trial further corroborated these findings, showing no significant difference in the composite outcome of recurrent ischemic stroke, systemic embolism, or major hemorrhage between early initiation (≤48 h for minor/moderate strokes; days 6-7 for major strokes) and later initiation (days 3-4 to 12-14). OPTIMAS, the largest trial to date, confirmed the non-inferiority of early initiation (≤4 days) versus delayed initiation (7-14 days), without an increased risk of symptomatic ICH and with comparable rates of recurrent ischemic events.
Introduction
Atrial fibrillation (AF) is a significant risk factor for ischemic stroke, and direct oral anticoagulants (DOACs) are increasingly used to prevent stroke in these patients.1‐6 Although DOACs have demonstrated efficacy in reducing stroke risk, the optimal timing for their initiation after an acute ischemic stroke (AIS) in AF patients remains debated. Current guidelines do not provide clear recommendations, reflecting the variability in clinical practice. Initiating oral anticoagulants (OACs) involves balancing the risk of early stroke recurrence with the potential for hemorrhagic complications, particularly intracerebral hemorrhage (ICH).
DOACs, such as apixaban, dabigatran, edoxaban, and rivaroxaban, are at least as effective as warfarin for stroke prevention in AF, with comparable or lower risks of major bleeding. However, pivotal trials excluding patients with recent strokes (within 7-30 days) limit the evidence for initiating DOACs in the acute phase post-AIS. The TIMING (Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation), 7 ELAN (Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischemic Stroke Patients With Atrial Fibrillation), 8 and OPTIMAS (Optimal Timing of Anticoagulation After Acute Ischemic Stroke with Atrial Fibrillation) 9 trials were designed to address this knowledge gap by comparing early versus delayed initiation of DOACs in AIS patients with AF. Therefore, we conducted a narrative review of the TIMING, ELAN, and OPTIMAS Trials to assess the efficacy and safety outcomes of early versus delayed DOAC initiation in AF patients with AIS.
Study Selection
We performed a systematic search of the PubMed database up to December 2024 to identify relevant articles. Our inclusion criteria were: (i) Randomized controlled trials (RCTs) reporting on the efficacy and safety outcomes of DOACs in adult patients with AF; (ii) Studies randomizing patients to early or delayed DOAC initiation; (iii) The DOACs were dabigatran, rivaroxaban, apixaban, and edoxaban; (iv) The primary outcome was a composite of recurrent ischemic stroke, symptomatic ICH, or mortality, with secondary outcomes including individual components of the primary outcome and major bleeding events. Finally, three RCTs7‐9—TIMING, ELAN, and OPTIMAS—that evaluated the timing of DOAC initiation in patients with AIS and AF were identified. Since fewer than five studies met our inclusion criteria, we opted for a narrative review.
Baseline Clinical Characteristics of the TIMING, ELAN, and OPTIMAS Trials
Table 1 shows the baseline clinical characteristics of patients in the TIMING, ELAN, and OPTIMAS trials. In the TIMING trial, the average age was around 72 years, with a predominance of male participants. The majority of patients had a history of hypertension and diabetes, with a moderate incidence of prior ischemic stroke. The ELAN trial enrolled a similar cohort with a median age of 73 years, and the baseline characteristics included a high prevalence of comorbidities such as hypertension, diabetes, and coronary artery disease. The OPTIMAS trial had a median age of 68 years, and it also included a similar proportion of patients with hypertension and diabetes. All three trials included patients with mild to moderate stroke severity, with the National Institutes of Health Stroke Scale (NIHSS) scores reflecting mild deficits overall. Key differences in baseline characteristics among the trials were the varying inclusion criteria for stroke severity, with TIMING and ELAN focusing on a broader range of AIS severities, while OPTIMAS had more stringent criteria regarding stroke severity. The use of antiplatelet therapy was similar across the trials, with the majority of patients receiving aspirin or clopidogrel.
Clinical Characteristics of the TIMING, ELAN, and OPTIMAS Trials.
AF = atrial fibrillation; AIS = acute ischemic stroke; DOAC = direct oral anticoagulant; RCT = randomized controlled trial; TIMING = Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation; ELAN = Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischemic Stroke Patients With Atrial Fibrillation; OPTIMAS = Optimal Timing of Anticoagulation After Acute Ischemic Stroke with Atrial Fibrillation; NIHSS = National Institutes of Health Stroke Scale.
Outcomes in the TIMING, ELAN, and OPTIMAS Trials
The prior observational studies and meta-analyses suggest that early initiation of OACs in AIS patients with AF is associated with reduced rates of ischemic stroke recurrence compared to later initiation, while maintaining a similar safety profile in terms of ICH and major bleeding events.10‐18 These studies highlight the potential benefits of early OAC initiation in terms of secondary stroke prevention without significantly increasing the risk of adverse bleeding outcomes. However, the observational data have several limitations that highlight the need for RCTs (the TIMING, ELAN, and OPTIMAS trials) to provide more definitive evidence.
Efficacy and Safety Outcomes in the TIMING Trial
The TIMING trial by Oldgren et al investigated the optimal timing for initiating DOACs in patients with AIS and AF. Through a registry-based randomized controlled noninferiority trial, this study compared early (≤4 days post-stroke) versus delayed (5-10 days post-stroke) DOAC initiation in 888 patients. The primary composite outcome—recurrent ischemic stroke, symptomatic ICH, or all-cause mortality at 90 days—occurred in 6.89% of the early group and 8.68% of the delayed group, demonstrating noninferiority (absolute risk difference: −1.79%; 95% CI: −5.31% to 1.74%; Pnoninferiority = 0.004). Notably, no symptomatic ICH was observed, and ischemic stroke and mortality rates were numerically lower with early initiation, supporting its safety. The study's pragmatic design, leveraging the Swedish Stroke Register, enhances generalizability, though the smaller-than-planned sample size (due to recruitment challenges and the COVID-19 pandemic) and lack of imaging data are limitations. These findings suggest that early DOAC initiation is a viable strategy for secondary stroke prevention.
Efficacy and Safety Outcomes in the ELAN Trial
The ELAN trial, an international, multicenter, randomized study, investigated the optimal timing of DOAC initiation in patients with AF following AIS. The trial compared early anticoagulation (within 48 h for minor/moderate strokes or days 6-7 for major strokes) versus later initiation (days 3-4, 6-7, or 12-14, stratified by stroke severity) in 2013 participants. The primary composite outcome—encompassing recurrent ischemic stroke, systemic embolism, major bleeding, symptomatic ICH, or vascular death at 30 days—occurred in 2.9% of the early-treatment group versus 4.1% in the later-treatment group (risk difference: −1.18%; 95% CI: −2.84 to 0.47), suggesting a non-significant trend favoring early intervention without increased hemorrhagic risk. Notably, recurrent ischemic stroke rates were numerically lower with early treatment (1.4% vs 2.5%), while symptomatic ICH remained rare (0.2% in both groups). The trial's imaging-based stratification and pragmatic design strengthen its clinical relevance, though limitations include exclusion of high-risk hemorrhage patients and predominantly European cohort.
Efficacy and Safety Outcomes in the OPTIMAS Trial
The OPTIMAS trial represents a pivotal multicentre, randomized controlled study addressing the critical yet unresolved question of optimal timing for initiating DOACs in patients with AIS and AF. Conducted across 100 UK hospitals, this phase 4 trial rigorously compared early (≤4 days post-stroke) versus delayed (7-14 days) DOAC initiation in 3621 participants, employing a blinded-endpoint, non-inferiority-superiority gatekeeper design. The primary composite outcome—encompassing recurrent ischaemic stroke, symptomatic ICH, unclassifiable stroke, or systemic embolism at 90 days—demonstrated non-inferiority of early initiation (adjusted risk difference 0.000, 95% CI −0.011 to 0.012; Pnoninferiority = 0.0003), with no superiority observed (P = 0.96). Notably, ICH rates were low (0.6% early vs 0.7% delayed) and comparable, reinforcing the safety of early DOAC use even in moderate-to-severe strokes (NIHSS >10). These findings challenge current guideline-recommended delays, particularly given the absence of heterogeneity across subgroups, including reperfusion therapy recipients and prior anticoagulant users. The trial's robust methodology—stratified randomization, independent adjudication, and broad eligibility—enhances generalisability, though limitations include exclusion of severe haemorrhagic transformations (eg, parenchymal haematoma type 2) and lack of granularity within the 4-day early window. OPTIMAS significantly advances evidence by demonstrating that early DOAC initiation does not increase haemorrhagic risk while potentially streamlining secondary prevention, urging reconsideration of conservative delay practices.
Collectively, these trials demonstrate consistent safety and noninferiority of early anticoagulation initiation (within 4 days) compared to delayed strategies. Key convergent findings include the absence of increased symptomatic ICH risk with early DOACs, numerically lower recurrent ischemic stroke rates, and applicability across stroke severities. ELAN and OPTIMAS provided granularity through imaging stratification and broad inclusion, respectively, while TIMING's real-world registry design enhanced pragmatic generalizability. All trials challenge existing guidelines that recommend delaying anticoagulation, providing evidence that early initiation optimizes secondary stroke prevention without compromising safety. Future individual participant data meta-analyses (eg, CATALYST) may refine timing precision within the first week post-stroke.
Study Limitations of the TIMING, ELAN, and OPTIMAS Trials
While the TIMING, ELAN, and OPTIMAS trials provide valuable insights into the timing of DOAC initiation in AIS patients with AF, there are several limitations that should be considered. First, the patient populations in these trials were heterogeneous, with differences in stroke severity, comorbid conditions, and time to treatment, which may impact the generalizability of the results. For example, the TIMING trial included a broader range of stroke severities, whereas OPTIMAS focused on patients with milder strokes, potentially limiting the applicability of findings to more severe cases. Second, while bleeding risks were carefully monitored, differences in how bleeding events were defined and categorized could lead to variability in outcomes. Third, all three trials had relatively short follow-up periods, which leaves questions about the long-term safety and efficacy of early anticoagulation unanswered. The effects of early DOAC initiation on long-term stroke recurrence, bleeding complications, and overall survival need further exploration. Additionally, there was variability in how anticoagulation was managed post-randomization across study centers, which may introduce confounding factors that affect the consistency of the results. Finally, the exclusion of patients with severe stroke or high-risk features limits the generalizability of the findings to this important subgroup, and more research is needed to assess the role of early anticoagulation in these higher-risk populations.
Stratifying Patients for Early DOAC Start
Infarct volume and stroke severity, as measured by the NIHSS, are strongly associated with hemorrhagic transformation (HT)—the primary safety concern when initiating early anticoagulation. Large infarcts (eg, those involving major arterial territories) and higher NIHSS scores independently predict both HT risk and poorer functional outcomes in cases where HT occurs.19,20 Historically, professional guidelines recommended delaying oral anticoagulation in moderate to severe strokes (eg, NIHSS ≥8) to mitigate this risk, reflecting concerns that early anticoagulation might exacerbate hemorrhagic complications in vulnerable brain tissue.
However, recent prospective randomized trials—ELAN, TIMING, and OPTIMAS—have challenged this paradigm by demonstrating that early DOAC initiation can be safe even in selected patients with moderate strokes. These trials employed stratified timing protocols, such as initiating DOACs within 48 h for minor/moderate strokes (NIHSS ≤10) while deferring until day 6–7 for major strokes (NIHSS >10). Notably, these studies reported comparable rates of symptomatic ICH between early and delayed initiation groups, while suggesting a trend toward reduced recurrent ischemic events with earlier treatment. This emerging evidence supports the use of infarct size (assessed via NIHSS and neuroimaging) as a key stratification tool in clinical decision-making for anticoagulation timing.
The CHA2DS2-VASc score remains the most validated predictor of recurrent ischemic stroke in AF, helping identify high-risk patients who stand to benefit most from early anticoagulation. While CHA2DS2-VASc does not directly predict hemorrhage risk, integrating it with bleeding risk assessment tools (eg, HAS-BLED) and neuroimaging markers (eg, presence of microbleeds or severe white matter disease) allows for a more nuanced risk–benefit evaluation. For example: A patient with a small infarct (NIHSS ≤4), low HT risk on imaging, and a high CHA2DS2-VASc score (eg, ≥ 4) may be an optimal candidate for early DOAC initiation, given the substantial thromboembolic risk and minimal hemorrhagic concern. Conversely, a patient with a large infarct (NIHSS ≥16), a low CHA2DS2-VASc score (eg, 1 to 2 points), and a high HAS-BLED score (eg, ≥ 3 points) may still warrant a delayed approach (eg, 7-14 days post-stroke) to minimize bleeding complications. DOACs generally exhibited comparable or lower bleeding risks than warfarin, with specific outcomes influenced by patient age and comorbidities.21,22 Future clinical protocols should incorporate these stratification strategies to optimize the timing of DOAC initiation, balancing ischemic stroke prevention against hemorrhagic risk in a patient-tailored manner.
Conclusion and Further Directions
The TIMING, ELAN, and OPTIMAS trials collectively provide robust evidence supporting the safety and efficacy of early initiation of DOACs in patients with AIS and AF. TIMING demonstrated non-inferiority of early DOAC initiation (≤4 days) compared to delayed initiation (5-10 days), with numerically lower rates of ischemic stroke and no symptomatic ICH. ELAN further reinforced these findings, showing no significant difference in the composite outcome of recurrent ischemic stroke, systemic embolism, or hemorrhage between early (≤48 h for minor/moderate strokes; day 6-7 for major strokes) and later initiation (day 3-4 to day 12-14). OPTIMAS, the largest trial to date, confirmed non-inferiority of early initiation (≤4 days) versus delayed initiation (7-14 days), with no increased risk of symptomatic ICH and comparable rates of recurrent ischemic events.
These trials challenge the conventional practice of delaying anticoagulation, particularly in moderate-to-severe strokes, and suggest that early DOAC initiation is safe across a broad spectrum of stroke severities. The absence of heterogeneity in subgroups, including those receiving reperfusion therapy or prior anticoagulation, further supports the generalizability of these findings.
However, long-term follow-up studies are essential to assess the sustainability of early anticoagulation benefits and to identify potential delayed adverse events, such as late-onset bleeding or cognitive decline. Future trials should also include high-risk populations, such as those with severe strokes or contraindications to anticoagulation, to evaluate the safety and efficacy of early DOAC initiation in these groups. Additionally, real-world data from large, multicenter registries and observational studies will be crucial to validate trial findings and ensure their applicability to diverse clinical settings. By addressing these gaps, future research can provide more nuanced guidance on the timing, safety, and efficacy of anticoagulation therapy, ultimately improving outcomes for AIS patients with AF.
Footnotes
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data and Materials Availability
All relevant data and materials are presented in the paper.