Introduction
Atrial fibrillation (AF)-related stroke accounts for 20%-30% of all ischemic strokes and is associated with a high risk of recurrent ischemic events, particularly in the early phase following acute ischemic stroke (AIS) [1]. Long-term oral anticoagulation (OAC) is the cornerstone of secondary prevention. However, determining the optimal timing for initiating OAC in the acute stroke setting remains a clinical dilemma, as early initiation may prevent recurrent ischemic stroke or systemic embolism but increase the risk of hemorrhagic transformation (HT) or intracranial hemorrhage (ICH) [2].
For decades, heparin and vitamin K antagonists (VKAs) were used in this setting. The International Stroke Trial (IST) failed to demonstrate a net clinical benefit of subcutaneous heparin, largely due to an increased hemorrhagic stroke risk [3]. Despite the lack of clinical trial evidence, VKAs have long been used as OACs in AIS. The advent of non-vitamin K antagonist oral anticoagulants (NOACs) changed this landscape. However, the initial pivotal NOACs trials excluded patients with AIS [4-7], practice guidelines were largely based on expert consensus rather than high-quality evidence [8,9].
Over the past decade, observational studies have compared NOACs with VKAs and early versus late NOAC initiation in patients with AF and AIS, and since 2022, several randomized clinical trials (RCTs)—Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation (TIMING) [10], Early versus Late initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial fibrillation (ELAN) [11], Optimal Timing of Anticoagulation After Acute Ischaemic Stroke with Atrial Fibrillation (OPTIMAS) [12], and Optimal Delay Time to Initiate Anticoagulation after Ischemic Stroke in Atrial Fibrillation (START) [13]—have been published. More recently, a collaborative individual patient data meta-analysis (IPDMA) incorporating all available RCTs (TIMING, ELAN, OPTIMAS, and START) has further refined the evidence base on early NOAC initiation in AF patient with AIS [14].
This narrative review integrates these updated randomized data and synthesizes the evolving evidence of early NOAC use in AIS with AF to support healthcare providers in making informed decisions in clinical practice. This review also addresses remaining uncertainties and future directions for clinical research.
Early anticoagulation with heparin or VKA in AIS
The IST randomized 19,435 patients with suspected AIS to receive aspirin, subcutaneous heparin, an aspirin/heparin combination, or placebo. Among them, 3,169 patients had AF. In the AF subgroup, the rate of recurrent ischemic stroke at 14 days was 2.8% in patients receiving heparin and 4.9% in those not receiving heparin. However, the hemorrhagic stroke rates were 2.1% with heparin and 0.4% without heparin. Therefore, the benefit was offset by the risk [3].
The European Atrial Fibrillation Trial (EAFT) was the only large, randomized trial that evaluated VKA in patients with AF who had a transient ischemic attack (TIA) or minor stroke within 3 months and demonstrated the long-term efficacy of VKA. Of the 1,007 enrolled patients, approximately 44% were randomized within 2 weeks from onset. However, the efficacy and safety data for these patients have not been separately reported [15]. Therefore, there are no robust RCT data on the efficacy and safety of early VKA use in AF-related AIS.
The Early Recurrence and Cerebral Bleeding in Patients with Acute Ischemic Stroke and Atrial Fibrillation (RAF) study was an international prospective multicenter study enrolling 1,037 consecutive patients with AIS and AF from 29 European and Asian centers between January 2012 and March 2014. It evaluated the 90-day risk of composite ischemic events, major bleeding associated with individual anticoagulation strategies, and their initiation timing. Compared to no anticoagulation, bridging therapy, or low-molecular-weight heparin alone, OAC alone was associated with the lowest risk of the composite outcome. The 90-day composite outcome rate was approximately 7% with OAC alone, 12%-13% with bridging therapy or no anticoagulation, and approximately 17% with low-molecular-weight heparin alone.
Initiating anticoagulation between 4 and 14 days from onset compared to initiating before 4 or after 14 days was associated with a significantly lower risk of the composite outcome (hazard ratio [HR]: 0.53; 95% confidence interval [CI] 0.30 to 0.93) and ischemic events (HR: 0.43; 95% CI 0.19 to 0.97), as well as a non-significantly lower risk of intracranial bleeding (HR: 0.39; 95% CI 0.12 to 1.19). Considering both the type and timing of anticoagulant therapy, initiating OAC between 4 and 14 days after stroke onset appears to be the optimal strategy [16]. During the study period, VKA remained the predominant oral anticoagulant. Among patients treated with oral anticoagulants alone, 75% received VKA and 25% received NOACs. The RAF study did not perform a comparative analysis between VKA and NOACs.
However, a sub-study of Clinical Relevance of Microbleeds in Stroke-2 (CROMIS-2) showed a similar event rate between the early (0-4 days from onset) and late (≥5 days or no anticoagulation) initiation of OACs [17]. CROMIS-2 was a multicenter, prospective observational study designed to investigate whether cerebral microbleeds are independently associated with an increased risk of symptomatic ICH in patients with AF and recent AIS or TIA and treated with OAC [18]. In this sub-study involving 1,355 patients, the rate of the primary outcome (composite of TIA, stroke [ischemic or hemorrhagic], or death at 90 days) was lower in the early group (2%) than in the late group (5%). However, after adjusting for confounders, the difference was not statistically significant (adjusted odds ratio [OR] for late OAC initiation: 1.17; 95% CI 0.48 to 2.84). Recurrent ischemic stroke and TIA rates were similar (adjusted OR: 1.25; 95% CI 0.36 to 4.41). The incidence of symptomatic ICH was too low to adequately analyze (0% in early vs. 0.2% in late) [17]. Among patients who received OAC, 63% were treated with VKA and 37% with NOACs.
NOAC versus VKA for early anticoagulation in AIS
Pivotal NOAC trials (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY] [19], Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE] [20], Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET AF] [21], and Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 [ENGAGE AF-TIMI 48] [22]) demonstrated the long-term efficacy and safety of NOACs. However, those trials excluded patients with recent AIS (within 7-30 days of randomization), and therefore did not provide data on their effects in the acute phase of ischemic stroke [4-7]. Despite the lack of RCT data, the use of NOACs in this population steadily increased, underscoring the need to redefine the existing anticoagulation paradigm.
For early anticoagulation in AIS, NOACs have several advantages over VKA due to their rapid onset of action, lack of transient hypercoagulability, and anticipated lower intracranial bleeding risk. To date, several observational studies and one surrogate marker trial have compared NOACs and VKA in AIS; however, no large RCTs have evaluated their comparative clinical efficacy and safety outcomes in this setting.
The Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-Nonvalvular Atrial Fibrillation (SAMURAI-NVAF) registry in Japan was one of the earliest prospective, multicenter investigations that compared NOACs and VKA in AF-related AIS or TIA [23]. Of 1,137 patients included in this study, 455 received NOACs and 662 received VKA. The median time from stroke onset to OAC initiation was 4 days for NOAC users and 3 days for VKA users. NOAC users had milder stroke than VKA users (admission median National Institutes of Health Stroke Scale [NIHSS] score, 4 [1-13] vs. 11 [4-20]) and had less disability at discharge. At acute hospital discharge, 466 and 650 patients received NOACs and VKA, respectively. The 90-day rate of stroke or systemic embolism was similar: 2.8% with NOACs and 3.1% with VKA (adjusted HR: 0.96; 95% CI 0.44 to 2.04). NOACs showed better safety profiles than VKAs in terms of major bleeding (1.1% vs. 2.6%) and ICH (0.23% vs. 1.10%). At 2 years, the rate of stroke or systemic embolism was similar as 8.4% with NOACs and 10.5% with VKA (adjusted HR: 1.15; 95% CI 0.70 to 1.87). NOACs showed better safety profiles than warfarin in terms of major bleeding (2.6% with NOACs vs. 5.7% with VKA) and ICH (1.0% vs. 2.8%, respectively). However, the differences in safety profiles were not statistically significant, largely because of the small number of events [24].
Acute Stroke With Xarelto to Reduce Intracranial Hemorrhage, Recurrent Embolic Stroke, and Hospital Stay (Triple AXEL) was an open-label trial with a blinded endpoint evaluation utilizing imaging as a surrogate marker [25]. The trial randomized 195 patients with AF-related mild AIS within 5 days of stroke onset to receive either rivaroxaban or VKA. The median interval from stroke onset to randomization was 2 days, and the median NIHSS score at baseline was 2. The rate of the primary endpoint, defined as the occurrence of new ischemic or hemorrhagic lesions on 4-week follow-up magnetic resonance imaging (MRI), was comparable between the rivaroxaban and VKA groups (49.5% vs. 54.5%; relative risk: 0.91; 95% CI 0.69 to 1.20). There were no significant differences in the individual components of new ischemic (29.5% in the rivaroxaban group vs. 35.6% in the VKA group) or new hemorrhagic lesions (31.6% vs. 28.7 %) between the groups. Although the incidence of new lesions was high, most patients were asymptomatic. Only one patient in each group had a clinically recurrent ischemic stroke, and there was no symptomatic ICH. These findings reinforce the notion that NOACs may be at least as safe as VKA in the acute phase, even when initiated relatively early after a mild stroke.
A collaborative initiative of seven prospective cohort studies—CROMIS-2, RAF, RAF-NOAC, SAMURAI-NVAF, the Novel Oral Anticoagulants in Ischemic Stroke Patients (NOACISP)—LONG-TERM, and the Erlangen and Verona registries—also supported the use of NOACs over VKA in AIS. This pooled individual patient data analysis included 4,912 patients with AF and recent ischemic stroke or TIA (within 3 months). The median time from onset to the initiation of OAC therapy was 5 days in both NOAC and VKA users, with a median baseline NIHSS score of 4 in NOAC users and 6 in VKA users. NOAC treatment compared to VKA treatment was associated with a lower rate of composite endpoint (recurrent ischemic stroke, ICH, and mortality); 11.0%/year vs. 15.1%/year (HR: 0.82; 95% CI 0.67 to 1.00; P=0.05). The reduced risk was largely attributed to the lower ICH risk; 0.9%/year vs. 1.6%/year (HR: 0.42; 95% CI 0.24 to 0.71; P<0.01). There were no differences in the rates of recurrent ischemic stroke (4.4%/year vs. 4.2%/year) and mortality (6.3%/year vs. 10.8%/year) between the NOAC and VKA users [26]. Although observational in nature and subject to potential confounding, the findings consistently favored NOACs over VKAs, or at minimum, demonstrated non-inferiority of NOACs to VKA in terms of both efficacy and safety, even when initiated in the acute phase of ischemic stroke.
The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) was a prospective, multicenter, observational, post-authorization safety study [27]. It recruited 10,039 patients with AF with a recent AIS or TIA within 7 days and reported two studies. The first study compared early (within 7 days, n=1,642) and late (>7 days, n=274) initiation of dabigatran with VKA initiated at any time (n=1,396). The primary endpoint was major bleeding within 3 months. Although the number of events was low, limiting statistical power, the use of dabigatran was associated with fewer major bleeding events compared to VKA; as referenced to VKA, adjusted HR (95% CI) 0.68 (0.32 to 1.47) for early dabigatran; 0.10 (0.01 to 0.68) for late dabigatran. The effect was greater for the ICH endpoint; 0.47 (0.10 to 2.21) for early dabigatran and 0.09 (0.00 to 13.11) for late dabigatran. A second study by Diener et al. [28] compared major bleeding during hospitalization between FXa inhibitors and VKA. The rate of major bleeding per 10,000 treatment days was 14.7 with Factor Xa inhibitors and 20.7 with VKA; adjusted HR 0.70 (0.37 to 1.32). Rates of ischemic stroke or systemic embolism were similar (18.9 vs. 22.0; adjusted HR: 0.96; 95% CI 0.53 to 1.74), and the composite endpoint of stroke, systemic embolism, life-threatening bleeding, or death was nearly identical (46.3 vs. 50.6; adjusted HR: 0.99; 95% CI 0.65 to 1.41). Therefore, these large real-world studies showed that early NOACs appeared to be safer than VKA.
Early versus late NOAC initiation
The 2021 European Heart Rhythm Association (EHRA) practical guide introduced the “1-3-6-12 day rule,” recommending the initiation of NOACs on day 1 after a TIA, day 3 after a minor stroke, day 6 after a moderate stroke, and day 12 after a severe stroke [8]. However, since these recommendations were based on expert opinion, it remains uncertain whether this represents the optimal timing or whether NOACs could be initiated earlier. Observational studies were therefore conducted, and RCTs have generated higher-quality evidence to support early NOAC use.
Observational studies
An observational dataset suggested that early NOAC initiation might be safe and possibly more effective than delayed therapy in reducing recurrent ischemic stroke. In the SAMURAI-NVAF timing analysis, the early NOAC group (<4 days; median 2 [1-3]) compared to the late NOAC group (≥4 days; median 6 [5-9]) showed comparable annual rates of stroke or systemic embolism (4.9% vs. 5.9%), and major bleeding (1.5% vs. 1.2%) [29]. These findings support starting anticoagulation therapy without unnecessary delay especially in non-severe stroke with high risk of recurrent embolism. The data suggest not that “we should wait,” but rather that “we don’t have to wait.”
A pooled analysis of two large Japanese registries—SAMURAI-NVAF and Recurrent Embolism Lessened by rivaroxaban and Anti-Xa agent, of Early Dosing for Acute Ischemic Stroke and Transient Ischemic Attack With Atrial Fibrillation (RELAXED)—investigated the optimal timing of NOAC initiation according to stroke severity, with external validation using six European prospective registries [30]. When analyzing data from the derivation cohort (n=1,797), the median time to NOAC initiation in real world practice in Japan was 2 days for TIA, 3 days for mild stroke, 4 days for moderate stroke, and 5 days for severe stroke. Based on this observation, patients were classified into early and late groups based on whether NOACs were initiated before or after the median time for each severity level. The early group (n=785) compared to the late group had lower 90-day rates of stroke/systemic embolism (1.9% vs. 3.9%; adjusted HR: 0.50; 95% CI 0.27 to 0.89) and ischemic stroke (1.7% vs. 3.2%; adjusted HR: 0.54; 95% CI 0.27 to 0.99) without an increased risk of major bleeding (0.8% vs. 1.0%) or ICH (0.3% vs. 0.4%). Using the same classification as that used in the derivation cohort, the early and late groups in the European external validation cohort (n=2,036) showed similarly low rates of recurrent ischemic stroke (2.4% vs. 2.2%) and ICH (0.2% vs. 0.6%). These findings support a severity-based 1-2-3-4-day rule, reflecting earlier NOAC initiation than the 2021 EHRA recommendation, as a potentially safe and effective strategy for reducing recurrent ischemic events without increasing the risk of major bleeding.
Randomized controlled trials and collaborative IPDMA
The TIMING trial was a registry-based, randomized, open-label, non-inferiority study conducted in Sweden. It randomized 888 patients with AF-related AIS or TIA within 72 hours from stroke onset to early (≤4 days) or delayed (5-10 days) NOAC initiation [10]. It was a non-inferiority trial with 3% margin. The planned sample size was 3,000; however, the trial was terminated early owing to the COVID-19 pandemic. Characteristics of the TIMING and non-TIMING populations in the Swedish Stroke Register were generally comparable, supporting the representativeness of Swedish patients with AF-related AIS. The primary composite endpoint—recurrent ischemic stroke, symptomatic ICH, or all-cause mortality at 90 days—occurred in 6.9% of the early group and 8.7% of the delayed group (absolute risk difference: -1.8%; 95% CI -5.3 to 1.7), meeting the criteria for non-inferiority. Recurrent ischemic stroke occurred in 3.1% and 4.6% of the patients and mortality occurred in 4.5% and 5.1% of the patients, respectively. Symptomatic ICH did not occur in either group during the study period. The trial demonstrated that early initiation did not increase bleeding risk and had similar efficacy as delayed therapy. While the differences were not statistically significant, the incidence of both the composite event and recurrent ischemic stroke was lower in the early group. The Kaplan-Meier curves for the primary outcome and recurrent ischemic stroke showed early separation and remained parallel thereafter, indicating that the effect was largely driven by the early initiation of anticoagulation.
A pilot randomized study involving Asian patients evaluated an early NOAC initiation strategy (≤48 h from symptom onset) after AF-related AIS [31]. In this multicenter, open-label trial conducted in Korea, patients with AF-related AIS with mild-to-moderate severity were assigned to conventional (standard-dose edoxaban on day 3 [mild] or day 6 [moderate]) versus early (half-dose edoxaban from onset until day 3 or 6, followed by standard-dose thereafter) strategy. The primary endpoint, defined as new infarcts on follow-up diffusion-weighted imaging at days 10-14, occurred in 33.3% in early group versus 19.4% in conventional group (relative: 1.72; 95% CI 0.72 to 4.15; P=0.21), all asymptomatic [31].
The ELAN trial, a large, international, investigator-initiated RCT, randomized 2,013 patients with recent AF-related AIS to early or late NOAC initiation [11]. ELAN did not test for superiority or non-inferiority of early NOAC use, but provided point estimates of key outcomes that are useful in clinical practice. Patients were stratified according to stroke severity (minor, moderate, or major) based on infarct size and distribution. The early group started NOACs within 48 hours for minor or moderate stroke and on days 6-7 for major stroke, while the delayed group started on days 3-4 for minor, 6-7 for moderate, and 12-14 for major stroke, following the “1-3-6-12-day rule.” Of the 2,013 randomized patients, 37% had minor stroke, 40% had moderate stroke, and 23% had major stroke, encompassing a range of stroke severities. The primary composite outcomes of ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic ICH, or vascular death at 30 days occurred in 2.9% of the early group versus 4.1% of the delayed group (risk difference: -1.18%; 95% CI -2.84 to 0.47). Recurrent ischemic stroke was numerically lower in the early group (1.4% vs. 2.5%; risk difference: -1.14; 95% CI -2.41 to 0.13), while symptomatic ICH rates were identical (0.2% each). At 90 days, the early group continued to show a trend toward fewer ischemic events without excess bleeding complications. Subgroup analyses showed consistent treatment effects across the prespecified subgroups, particularly within the clinical and imaging-based stroke severity subgroups.
The OPTIMAS trial randomized 3,648 patients with AF-related AIS (within 4 days of stroke onset) to early (≤4 days) versus delayed (7-14 days) NOAC initiation [12]. It was a non-inferiority trial with a 95% upper margin of 2 percentage points. If noninferiority was met, superiority was tested. Of the enrolled patients, 58% had a minor stroke of NIHSS score of 4 or less, and 42% had moderate or severe strokes. The primary endpoint, a composite of recurrent ischemic stroke, symptomatic ICH, unclassifiable stroke, or systemic embolism at 90 days, occurred in 3.3% of patients in both groups (adjusted risk difference: 0.00%; 95% CI -0.011 to 0.012), meeting the non-inferiority criteria. Symptomatic ICH occurred in 0.6% of the early group versus 0.7% of the delayed group; recurrent ischemic stroke, in 2.4% versus 2.3%; and all-cause mortality, in 8.8% versus 8.9%, respectively. The trial confirmed that early initiation within 4 days was non-inferior to the delayed initiation for composite vascular events at 90 days. Subgroup analyses showed that the treatment effect was consistent across the prespecified subgroups of stroke severity, reperfusion therapy, and previous anticoagulation therapy.
The START trial was a phase 2, response-adaptive randomized study that compared four NOAC initiation times after AF-related AIS: day 3-4 (group 1) (n=75), day 6 (group 2) (n=76), day 10 (group 3) (n=76), and day 14 (group 4) (n=76) [13]. The primary outcome was the 30-day composite of recurrent ischemic stroke or systemic embolism, symptomatic ICH, or major systemic bleeding. The sample size and number of events were too small to draw valid conclusions. Bayesian analysis indicated that the day 3-4 strategy had the highest posterior probability (0.41) of being optimal, although no statistical superiority was achieved.
Individual RCTs showed that early initiation of NOACs was non-inferior to late initiation in preventing early ischemic events without increasing the risk of symptomatic ICH or major bleeding. However, no trials have clearly demonstrated the superiority of early over late NOAC initiation.
Two prior meta-analyses of RCTs and observational studies indicated that early NOAC initiation was safe but did not provide evidence for superior efficacy. Furthermore, data from observational studies are subject to confounding factors [32,33]. To determine the efficacy and safety of early NOAC initiation using a large set of individual patient data from RCTs, the Collaboration on the Optimal Timing of Anticoagulation After Ischemic Stroke and Atrial Fibrillation: Prospective Individual Participant Data Meta-Analysis of Randomised Controlled Trials (CATALYST) was initiated before the results of individual RCTs (TIMING, ELAN, OPTIMAS, and START) came out [14].
This IPDMA assessed whether early initiation of NOACs (within 4 days) is superior to late initiation (5 days or later) in preventing the primary outcomes of composite recurrent ischemic stroke, symptomatic ICH, or unclassified stroke at 30 days, as well as to evaluate individual components and effect heterogeneity among the key subgroups. It included 5,441 patients with a mean age of 77.7 years and 45.4% were females. At admission, 42.8% had minor stroke (NIHSS score 0-4), 32.1% had moderate stroke (NIHSS score 5-10), 11.9% had moderate-to-severe stroke (NIHSS score 11-15), and 12.5% had severe stroke (NIHSS score >15). Of the included patients, 32.5% received reperfusion therapy and 32.7% received pre-stroke anticoagulation therapy. The median time from symptom onset to NOAC initiation was 3.0 days in the early group and 7.2 days in the late group.
Compared to late initiation, early NOAC initiation significantly reduced the primary outcome (2.12% vs. 3.02%; OR: 0.70; 95% CI 0.50 to 0.98). The number needed to treat to prevent one primary outcome was 108. The Kaplan-Meier curves for the primary outcome diverged early to approximately 7-9 days and remained parallel thereafter, suggesting that the observed difference was likely attributable to the early anticoagulation effect. The treatment effect was consistent across clinically important subgroups of stroke severity, reperfusion treatment, previous anticoagulation therapy, sex, and age. Early NOAC also reduced the risk of recurrent ischemic stroke (1.68% vs. 2.55%; OR: 0.66; 95% CI 0.45 to 0.96), and the risk of symptomatic ICH rates were almost identical (0.37% vs. 0.36%; OR: 1.02; 95% CI 0.43 to 2.46). At 90 days, the benefit was attenuated, although there was a numerical reduction in favor of early NOAC initiation.
Remaining uncertainties and future directions
The safety and efficacy of early NOAC initiation in patients with severe stroke remain unclear. The RCTs, TIMING, ELAN, OPTIMAS, and START, and the CATALYST meta-analyses showed that the treatment effect of early initiation of NOACs as compared to late initiation was consistent across stroke severities. However, patients with very severe stroke (NIHSS scores >15) at admission were underrepresented: 8.9% in TIMING, no data in ELAN (major stroke according to infarct size: 23%), 12.6% in OPTIMAS, and 12.5% in the CATALYST meta-analysis. Moreover, due to the effects of reperfusion therapy or spontaneous improvement, there was a tendency for NIHSS scores to decrease by the time of randomization, as observed in the ELAN and OPTIMAS studies; NIHSS scores improved by approximately 2 points in both trials. Therefore, by the time NOAC treatment was initiated, the number of patients with very severe stroke was likely further reduced.
There are still insufficient data to support the idea that early NOAC initiation is effective without increasing the risk in patients with HT. A post hoc analysis of the ELAN trial showed no evidence of safety concerns with early NOAC initiation compared to late initiation in patients with HT, with no symptomatic cases observed in either group. The effect of treatment on the primary outcome was consistent regardless of the presence of HT. However, only 247 patients (12.5% of the study population) had HT in the ELAN trial, and 46.2% of those with HT had hemorrhagic infarct type 1 [34]. Additional data on patients with HT are expected from planned analyses of the OPTIMAS and CATALYST data.
It is well known that Asian patients have a higher risk of bleeding compared to Western populations. Among the 6,722 patients included in the four RCTs, only 355 (5.3%) were Asian [10-14]. Therefore, it remains uncertain whether the results of these RCTs can be directly applied to Asian populations. Among the trials, the ELAN trial had the highest proportion of Asian participants, with 247 (12.3%) patients [11]. Analyses of these patients are pending. In two small surrogate marker-based RCTs (Triple AXEL [25] and Kim [31]) conducted exclusively in Korean patients with mild-to-moderate stroke severity, no cases of symptomatic ICH were observed with early NOAC initiation despite a high frequency of HT on follow-up MRI, whether occurring spontaneously, attributable to NOACs, or a combination. These findings suggest that early initiation of NOACs may be clinically safe, even in Asian populations. Conducting RCTs to establish the efficacy and safety of early NOAC initiation in these populations is expected to be challenging. Alternatively, there is a need to conduct systematic, large-scale, prospective registry studies to provide evidence, even at the observational level. Asian countries should undertake collaborative, harmonized international registries to assess whether the results of RCTs are applicable to their populations. For effective harmonization, standardized definitions of “early” and “late” initiation, as well as patient stratification frameworks that integrate clinical and neuroimaging features, are essential.
Conclusions
The paradigm of anticoagulation therapy for AF-related AIS is shifting. Accumulating evidence from large-scale observational studies and recent RCTs supports the early initiation of NOACs, especially in patients with mild to moderate stroke. Early initiation of NOACs appears to reduce the risk of recurrent ischemic events without increasing the risk of symptomatic ICH or major bleeding. However, several important gaps remain, particularly regarding patients with very severe stroke, those with HT, and Asian populations who may have higher bleeding risks and are underrepresented in RCTs. The decision to initiate NOACs early should be individualized based on stroke severity, imaging findings, bleeding risk, and overall patient profile, guided by the best available evidence and clinical judgment.
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