Oral Anticoagulants For Stroke Prevention Research Articles

Efficacy and safety of different oral anticoagulants for stroke prevention in older patients with atrial fibrillation: A network meta-analysis.

Various oral anticoagulants have been used for stroke prevention in older patients with atrial fibrillation (AF). However, the optimal anticoagulants for stroke prevention has not yet been developed. We performed a systematic review and network meta-analysis to determine the optimal instructions. We searched for randomized controlled trials (RCTs) from PubMed, Embase, and the Cochrane Library without restriction for publication date or language at January 2024. Any RCTs that compared the effectiveness of a direct oral anticoagulant and a vitamin K antagonist (VKA) for stroke prevention in older patients with AF were included in this network meta-analysis. The Bayesian network meta-analysis used a random effects model and surface under the cumulative ranking curve analysis to rank results. All analyses were done using R software with gemtc package, with statistical significance set at P < .05. We included 7 RCTs (79,003 patients) comparing 8 different instructions including Apixaban 5 mg, Dabigatran 110 mg, Dabigatran 150 mg, Edoxaban 30 mg, Edoxaban 60 mg, Rivaroxaban 15 mg, Rivaroxaban 20 mg, and VKA. Apixaban 5 mg, Dabigatran 110 mg, and Dabigatran 150 mg was more effective than the VKA for reducing stroke or systemic embolism risks, and the difference was statistically significant (P < .05). Apixaban 5 mg, Dabigatran 110 mg, Dabigatran 150 mg, Edoxaban 30 mg, and Edoxaban 60 mg was associated with a reduction of the intracranial hemorrhage rate than the VKA (P < .05). The surface under the cumulative ranking curve shows that Dabigatran 110 mg ranked first for reducing stroke or systemic embolism risks. Edoxaban 60 mg ranked first for major bleeding. Dabigatran 110 mg ranked first for intracranial hemorrhage. Apixaban 5 mg ranked first for all bleeding events. Direct oral anticoagulants were found to have lower rates of thromboembolic events compared to VKAs in older patients with AF. Apixaban 5 mg, Dabigatran 110 mg, Dabigatran 150 mg, Edoxaban 30 mg, and Edoxaban 60 mg were also associated with a reduction of intracranial hemorrhage than VKA.

Cost-Effectiveness of Rivaroxaban Compared with Other Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation in Public Sector of Malaysia

Despite the amount of research performed, the cost-effectiveness of direct oral anticoagulants (DOACs) in subpopulations with different risk factors for stroke has been very little studied. This study aims to explore the cost-effectiveness of the DOACs available in Malaysia in preventing stroke in different subpopulations from a government perspective. An existing Markov model was adapted to assess the cost-effectiveness of the DOACs that are available in Malaysia namely, apixaban (AP), dabigatran (DA) and rivaroxaban (RV). Each was compared with vitamin K antagonists (VKA) in stroke prevention in different patient subpopulations including chronic kidney disease (CKD), high-age, diabetes (DM), and prolonged hospital stay. Cost-effectiveness was assessed by the incremental cost-effectiveness ratio (ICER) benchmarked against the local threshold for cost-effectiveness. The total cost of VKA, AP, DA and RV was Malaysian Ringit (RM) RM9,811 (1USD=RM4.76), RM16,858, RM18,318 and RM20,161 respectively. The quality adjusted life-years (QALYs) gained compared with VKA were 6.11, 6.09 and 6.15 respectively. The ICER when compared with VKA at base case was 57,539, -90,682 and 68,156 respectively. AP had the most favourable ICER at base case. RV had the best ICER compared to AP and DA in patients with CKD and DM at a willingness-to-pay threshold of 1-GDP. Probabilistic sensitivity analysis showed that RV was consistently the most favourable DOAC under a threshold of 2-GDP for all subpopulations. These findings suggested that rivaroxaban has the most favourable ICER in the CKD and DM patient subgroups for stroke prevention among the DOACs available in Malaysia at a threshold of 2-GDP.

Risk of gastrointestinal bleeding in Asian patients receiving oral anticoagulants for stroke prevention in atrial fibrillation.

Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used for stroke prevention in atrial fibrillation. At the Asia Pacific Advancing Patient care with EdoXaban 2023 meeting, experts shared insights on gastrointestinal bleeding with NOACs for stroke prevention in atrial fibrillation in Asian clinical practice, where NOACs have gained widespread acceptance due to their favourable profiles. Gastrointestinal bleeding risk varies amongst NOACs, emphasizing the importance of diligent patient assessment, dosage selection and vigilant monitoring. Edoxaban emerged as a viable option with a low gastrointestinal bleeding risk profile in Asian compared with non-Asian patients, supporting its continued clinical utilization for appropriate patients.

Using real-world evidence to complement evidence from randomized controlled trials on oral anticoagulants for stroke prevention.

Mark J. R. Smeets and Suzanne C. Cannegieter discuss the use of real world data to complement data generated by clinical trials of systemic anticoagulants.

Comparison of oral anticoagulants for stroke prevention in atrial fibrillation using the UK clinical practice research Datalink Aurum: A reference trial (ARISTOTLE) emulation study.

Stroke prevention guidance for patients with atrial fibrillation (AF) uses evidence generated from randomised controlled trials (RCTs). However, applicability to patient groups excluded from trials remains unknown. Real-world patient data provide an opportunity to evaluate outcomes in a trial analogous population of direct oral anticoagulants (DOACs) users and in patients otherwise excluded from RCTs; however, there remains uncertainty on the validity of methods and suitability of the data. Successful reference trial emulation can support the generation of evidence around treatment effects in groups excluded or underrepresented in trials. We used linked United Kingdom primary care data to investigate whether we could emulate the pivotal ARISTOTLE trial (apixaban versus warfarin) and extend the analysis to investigate the impact of warfarin time in therapeutic range (TTR) on results. Patients with AF in the UK Clinical Practice Research Datalink (CPRD Aurum) prescribed apixaban or warfarin from 1 January 2013 to 31 July 2019 were selected. ARISTOTLE eligibility criteria were applied to this population and matched to the RCT apixaban arm on baseline characteristics creating a trial-analogous apixaban cohort; this was propensity-score matched to warfarin users in the CPRD Aurum. ARISTOTLE outcomes were assessed using Cox proportional hazards regression stratified by prior warfarin exposure status during 2.5 years of patient follow-up and results benchmarked against the trial results before treatment effectiveness was further evaluated based on (warfarin) TTR. The dataset comprised 8,734 apixaban users and propensity-score matched 8,734 warfarin users. Results [hazard ratio (95% confidence interval)] confirmed apixaban noninferiority for stroke or systemic embolism (SE) [CPRD 0.98 (0.82,1.19) versus trial 0.79 (0.66,0.95)] and death from any cause [CPRD 1.03 (0.93,1.14) versus trial 0.89 (0.80,0.998)] but did not indicate apixaban superiority. Absolute event rates for stroke/SE were similar for apixaban in CPRD Aurum and ARISTOTLE (1.27%/year), whereas a lower event rate was observed for warfarin (CPRD Aurum 1.29%/year, ARISTOTLE 1.60%/year). Analysis by TTR suggested similar effectiveness of apixaban compared with poorly controlled warfarin (TTR < 0.75) for stroke/SE [0.91 (0.73, 1.14)], all-cause death [0.94 (0.84, 1.06)], and superiority for major bleeding [0.74 (0.63, 0.86)]. However, when compared with well-controlled warfarin (TTR ≥ 0.75), apixaban was associated with an increased hazard for all-cause death [1.20 (1.04, 1.37)], and there was no significant benefit for major bleeding [1.08 (0.90, 1.30)]. The main limitation of the study's methodology are the risk of residual confounding, channelling bias and attrition bias in the warfarin arm, and selection bias and misclassification in the analysis by TTR. Analysis of noninterventional data generated results demonstrating noninferiority of apixaban versus warfarin consistent with prespecified benchmarking criteria. Unlike in ARISTOTLE, superiority of apixaban versus warfarin was not seen, possible due to the lower proportion of Asian patients and higher proportion of patients with well-controlled warfarin compared to ARISTOTLE. This methodological template can be used to investigate treatment effects of oral anticoagulants in patient groups excluded from or underrepresented in trials and provides a framework that can be adapted to investigate treatment effects for other conditions.

Long-term outcomes after echocardiography versus fluoroscopy-guided left atrial appendage closure: Is there still a role for a simplified approach?

Left atrial appendage closure (LAAC) represents an alternative to oral anticoagulation for stroke prevention in patients with non-valvular atrial fibrillation (AF). While transoesophageal echocardiography is the current standard for guiding LAAC procedures, several centers have employed fluoroscopic guidance alone. However, data on long-term outcomes are lacking. A total of 536 patients with AF undergoing LAAC and with available data on long-term follow-up were included in the retrospective, single-center analysis. Outcomes of patients undergoing fluoroscopy-guided LAAC were compared with those undergoing echocardiography guided LAAC. Time-dependent analysis was performed with the Kaplan-Meier method. A total of 234 (44%) and 302 (56%) patients were treated with echocardiography and fluoroscopy guidance, respectively. Baseline characteristics did not differ between the two groups. Procedural success rates were high in both groups (97% of fluoroscopy vs. 98% of echocardiography guided procedures; p = 0.92) and rates of relevant peri-device leaks (p = 0.50) and device-related thrombus formation (p = 0.22) did not differ between groups. Median clinical follow-up time was 48 (IQR 19-73) months. Rates of all-cause mortality (p = 0.15, HR 0.83, CI 0.64-1.07) and stroke (p = 0.076, HR 2.23, CI 0.90-5.54) were comparable among groups. LAAC with fluoroscopy guidance alone is equally safe and leads to similar clinical outcome compared to LAAC with additional echocardiography guidance.

Direct oral anticoagulants for stroke prevention in patients with device-detected atrial fibrillation: assessing net clinical benefit.

Subclinical, device-detected atrial fibrillation (AF) is frequently recorded by pacemakers and other implanted cardiac rhythm devices. Patients with device-detected AF have an elevated risk of stroke, but a lower risk of stroke than similar patients with clinical AF captured with surface electrocardiogram. Two randomized clinical trials (NOAH-AFNET 6 and ARTESiA) have tested a direct oral anticoagulant (DOAC) against aspirin or placebo. A study-level meta-analysis of the two trials found that treatment with a DOAC resulted in a 32% reduction in ischaemic stroke and a 62% increase in major bleeding; the results of the two trials were consistent. The annualized rate of stroke in the control arms was ∼1%. Several factors point towards overall net benefit from DOAC treatment for patients with device-detected AF. Strokes in ARTESiA were frequently fatal or disabling and bleeds were rarely lethal. The higher absolute rates of major bleeding compared with ischaemic stroke while on treatment with a DOAC in the two trials are consistent with the ratio of bleeds to strokes seen in the pivotal DOAC vs. warfarin trials in patients with clinical AF. Prior research has concluded that patients place a higher emphasis on stroke prevention than on bleeding. Further research is needed to identify the characteristics that will help identify patients with device-detected AF who will receive the greatest benefit from DOAC treatment.

In device-detected AF, DOACs vs. aspirin or placebo reduce ischemic stroke and increase major bleeding.

McIntyre WF, Benz AP, Becher N, et al. Direct oral anticoagulants for stroke prevention in patients with device-detected atrial fibrillation: a study-level meta-analysis of the NOAH-AFNET 6 and ARTESiA trials. Circulation. 2024;149:981-988. 37952187.

Antithrombotic therapy in acute coronary syndrome

Dual antiplatelet therapy (DAPT) is the cornerstone of maintenance medication following acute coronary syndromes (ST elevation myocardial infarction, non-ST elevation myocardial infarction, unstable angina). Over the last decade, P2Y12 inhibition in addition to low-dose acetylsalicylic acid has been intensively debated. In patients with acute coronary syndromes, balancing the reduction in cardiovascular events and increase in major bleeding during treatment with more potent P2Y12 inhibitors such as prasugrel and ticagrelor is still an issue. A special focus is on patients already treated with oral anticoagulants for stroke prevention in atrial fibrillation who require additional platelet inhibition following coronary stenting. This article summarizes the major recommendations given in the most recent Guideline for "Acute Coronary Syndromes" published by the European Society of Cardiology (ESC). The recommendations finally address strategies to reduce an increased bleeding risk based on clinical predictors.

Comparative Safety and Effectiveness of Reduced Doses of Direct Acting Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation

This Nordic observational cohort study aims to assess the effectiveness and safety of reduced-dose direct-acting oral anticoagulants (DOACs) dabigatran, rivaroxaban, and apixaban compared to standard warfarin for stroke prevention in nonvalvular atrial fibrillation. The study, utilizing nationwide administrative databases from Denmark, Sweden, Norway, and Finland, spanned from January 1, 2011 to December 31, 2018 (2017 for Sweden). The cohort included 26,883 patients initiating reduced-dose DOACs and 108,014 comparable warfarin patients. Effectiveness was measured by the composite endpoint of ischemic stroke and systemic embolism, while safety was assessed through intracranial hemorrhage. The meta-analysis across countries revealed similar or lower incidences of ischemic stroke and systemic embolism in patients on reduced-dose DOACs compared to standard warfarin (rivaroxaban: HR 0.93, dabigatran: HR 0.88, apixaban: HR 0.79). Incidences within warfarin groups ranged from 2.16 to 3.71 per 100 person-years, comparable to DOAC recipients. Intracranial hemorrhage rates were generally low, ranging from 0.16 to 1.85 per 100 person-years. In comparison with warfarin patients, meta-analyses yielded HRs for rivaroxaban (1.41), dabigatran (0.35), and apixaban (0.72). In this study, atrial fibrillation patients initiating reduced-dose rivaroxaban and dabigatran exhibited incidences of ischemic stroke and systemic embolism similar to warfarin, and for apixaban, even lower. Rates of intracranial hemorrhage were comparable to or lower for patients on DOACs compared to warfarin.

Left Atrial Appendage Occlusion and Post-procedural Antithrombotic Management

Left atrial appendage occlusion (LAAO) is an established alternative to oral anticoagulation for stroke prevention in atrial fibrillation. Antithrombotic therapy is used in the post-procedural period to prevent device-related thrombosis (DRT). The risk of DRT is considered highest in the first 45–90 days after device implantation, based on animal studies of the device healing process. Clinically applied antithrombotic regimens vary greatly across studies, continents, and centers. This article gives an overview of the evidence behind current antithrombotic regimens, ongoing randomized trials, and future post-procedural management.

Efficacy and Safety of Direct Oral Anticoagulants for Stroke Prevention in Older Patients With Atrial Fibrillation: A Network Meta-Analysis of Randomized Controlled Trials.

Although older patients with atrial fibrillation are at heightened risk of thromboembolic and bleeding events, their optimal treatment choice remains uncertain. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the PubMed, EMBASE, and Cochrane databases for randomized controlled trials that compared thromboembolic or bleeding outcomes between a direct oral anticoagulant (DOAC) and a vitamin K antagonist (VKA) and reported outcomes for patients aged ≥75 years with atrial fibrillation. The efficacy outcome was the composite of stroke and systemic embolism. Safety outcomes included major bleeding, any clinically relevant bleeding, and intracranial hemorrhage. Each DOAC and VKA was compared pairwise in a network meta-analysis. High- and low-dose regimens and factor IIa and Xa inhibitors were also compared. Seven randomized controlled trials were included in the analysis. Stroke and systemic embolism risks did not differ significantly among DOACs. There were no significant differences in major bleeding between each DOAC and VKA. Intracranial hemorrhage risk was significantly lower with dabigatran, apixaban, and edoxaban than with VKA and rivaroxaban, which had similar risks. High-dose regimens led to lower risks of stroke or systemic embolism compared with VKA and low-dose regimens, with both doses having similar bleeding risks. In patients aged ≥75 years with atrial fibrillation, DOACs were associated with fewer thromboembolic events compared with VKA, whereas dabigatran, apixaban, and edoxaban were associated with lower risks of intracranial hemorrhage compared with VKA and rivaroxaban. URL: www.crd.york.ac.uk/prospero/. Unique identifier: CRD42022329557.

Left Atrial Appendage Occlusion versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation-One-Year Survival.

We have conducted an indirect, retrospective comparison between LAAO and NOAC registries. The LAAO registry is a national prospective cohort of 419 AF patients who underwent percutaneous LAAO between January 2008 and October 2015. The NOACs registry is a multicenter prospective cohort of 3138 AF patients treated with NOACs between November 2015 and August 2018. Baseline patient characteristics were retrospectively collected from coded diagnoses of hospitalization and outpatient clinic notes. Follow-up data was sorted from coded diagnoses and the national civil registry. Subjects were matched according to propensity score. Baseline characteristics were compared using Chi-Square and student's t-test. Survival analysis was performed using Kaplan-Meier survival curves, log-rank test, and multivariable Cox regression, adjusting for possible confounding variables. This study included 114 subjects who underwent LAAO implantation and 342 subjects treated with NOACs. The mean age of participants was 77.9 ± 7.44 and 77.1 ± 11.2 years in the LAAO and NOAC groups, respectively (p = 0.4). The LAAO group had 70 (61%) men compared to 202 (59%) men in the NOAC group (p = 0.74). No significant differences were found in baseline comorbidities, renal function, or CHA2DS2-VASc score. One-year mortality was observed in 5 (4%) patients and 32 (9%) patients of the LAAO and NOAC groups, respectively. After adjusting for confounders, LAAO was significantly associated with a lower risk for 1-year mortality (HR 0.38, 95%CI 0.14-0.99). In patients with impaired renal function, this difference was even more prominent (HR 0.21 for creatinine clearance (CrCl) < 60 mL/min). In a pooled analysis of two registries, we found a significantly lower risk for 1-year mortality in patients with AF who were implanted with LAAO than those treated with NOACs. This finding was more prominent in patients with impaired renal function. Future prospective direct studies should further investigate the efficacy and adverse effects of both treatment strategies.

Effectiveness and Safety of Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation Patients With Extreme Obesity

Direct oral anticoagulants (DOACs) are a favored treatment to prevent stroke in patients with atrial fibrillation (AF). There are limited data concerning the efficacy and safety of DOACs in obese. Obesity leads to wide structural and physiological changes that may affect the pharmacokinetics and pharmacodynamics of drugs. The optimal dosing strategies for DOACs in this significant and growing sub-group remain unknown. The study aimed to evaluate on a large scale the safety and efficacy of DOAC treatment in extreme obese patients with AF. In this retrospective cohort study, we included patients with AF treated with DOACs. Patients were divided according to body mass index (BMI). Study outcomes included stroke, major bleeding, and death. Between 2012 and 2017, 5183 patients with AF were included in the analysis (2,688, 2137, and 358 patients had a BMI <30, 30 to 40, and >40 accordingly). There was no significant difference in the prevalence of ischemic events (9.9%, 8.2%, and 7.5% of patients with BMI <30, 30 to 40, and >40, respectively, p=0.088), major bleeding events (13%, 14.1%, and 11.2% of patients with BMI <30, 30 to 40, and >40, respectively, p value = 0.257) or net ischemic and major bleeding events (18.7%, 18.7%, and 15.4% of patients with BMI <30, 30 to 40, and >40 respectively, p=0.297) between the BMI groups. In conclusion, DOACs treatment for prevention of ischemic events in AF is effective and safe through the BMI spectrum, including extreme obesity.

The Budget Impact Analysis of Adopting Direct Oral Anticoagulants for Stroke Prevention in Nonvalvular Atrial Fibrillation Patients in Malawi

ObjectivesThis study aimed to estimate the budget impact of adopting direct oral anticoagulants (DOACs) for stroke prevention in patients with nonvalvular atrial fibrillation in Malawi after the inclusion of DOACs in the World Health Organization’s essential medicine list. MethodsA model was developed in Microsoft Excel. An eligible population of 201 491 was adjusted with 0.05 % incidence rate and mortality rates yearly according to the treatments. The model estimated the implication of supplementing rivaroxaban or apixaban to the standard treatment mix (also the comparator), thus warfarin and aspirin. The current market share of 43% aspirin and 57% warfarin was adjusted proportionally with 10% DOAC uptake in the first year and 5% annually over the subsequent 4 years. Clinical events of stroke and major bleeding from the ROCKET-AF and ARISTOTLE trials were used because health outcome indicators affect resource utilization. The analysis was conducted solely from the Malawi Ministry of Health perspective and it considered direct costs over 5 years. The sensitivity analysis involved varying drug costs, population, and care costs from both public and private sectors. ResultsThe research suggests that despite potential savings of $6 644 141 to $6 930 812 in stroke care because of fewer stroke events, the total Ministry of Health healthcare budget (approximately $260 400 000) may increase by between $42 488 342 to $101 633 644 in 5 years because drug acquisition costs are greater than savings. ConclusionsWith a fixed budget and current DOACs prices, Malawi can consider using DOACs in patients at the highest risk while waiting for cheaper generic versions.

EE340 Integrating Real-World Evidence in Economic Evaluation of Oral Anticoagulants for Stroke Prevention in Non-Valvular Atrial Fibrillation in a Developing Country

EE340 Integrating Real-World Evidence in Economic Evaluation of Oral Anticoagulants for Stroke Prevention in Non-Valvular Atrial Fibrillation in a Developing Country

Economic evaluation in cardiac electrophysiology: Determining the value of emerging technologies.

Cardiac electrophysiology is a constantly evolving speciality that has benefited from technological innovation and refinements over the past several decades. Despite the potential of these technologies to reshape patient care, their upfront costs pose a challenge to health policymakers who are responsible for the assessment of the novel technology in the context of increasingly limited resources. In this context, it is critical for new therapies or technologies to demonstrate that the measured improvement in patients' outcomes for the cost of achieving that improvement is within conventional benchmarks for acceptable health care value. The field of Health Economics, specifically economic evaluation methods, facilitates this assessment of value in health care. In this review, we provide an overview of the basic principles of economic evaluation and provide historical applications within the field of cardiac electrophysiology. Specifically, the cost-effectiveness of catheter ablation for both atrial fibrillation (AF) and ventricular tachycardia, novel oral anticoagulants for stroke prevention in AF, left atrial appendage occlusion devices, implantable cardioverter defibrillators, and cardiac resynchronization therapy will be reviewed.

Barriers and enablers to healthcare system uptake of direct oral anticoagulants for stroke prevention in atrial fibrillation: a qualitative interview study with healthcare professionals and policy makers in England

ObjectiveTo better understand the factors influencing the uptake of direct oral anticoagulants (DOACs) across different health economies in National Health Service England from the perspective of health professionals and other...

Post-operative atrial fibrillation after cardiac surgery: Challenges throughout the patient journey.

Atrial fibrillation (AF) is the most common complication of cardiac surgery, occurring in up to half of patients. Post-operative AF (POAF) refers to new-onset AF in a patient without a history of AF that occurs within the first 4 weeks after cardiac surgery. POAF is associated with short-term mortality and morbidity, but its long-term significance is unclear. This article reviews existing evidence and research challenges for the management of POAF in patients who have had cardiac surgery. Specific challenges are discussed in four phases of care. Pre-operatively, clinicians need to be able to identify high-risk patients, and initiate prophylaxis to prevent POAF. In hospital, when POAF is detected, clinicians need to manage symptoms, stabilize hemodynamics and prevent increases in length of stay. In the month after discharge, the focus is on minimizing symptoms and preventing readmission. Some patients require short term oral anticoagulation for stroke prevention. Over the long term (2-3 months after surgery and beyond), clinicians need to identify which patients with POAF have paroxysmal or persistent AF and can benefit from evidence-based therapies for AF, including long-term oral anticoagulation.

Evaluation of the timing of using direct oral anticoagulants after ischemic stroke for patients with atrial fibrillation

Background and objectivePatients with atrial fibrillation (AF) are prescribed oral anticoagulants for stroke prevention; however, no evidence indicates that the use of direct oral anticoagulants (DOACs) in the first few days after ischemic stroke (IS) would result in favorable outcomes. This study evaluated the association between the timing of using DOACs after IS and their effectiveness and safety to determine the optimal timing. MethodsIn this retrospective cohort study, we reviewed the electronic medical records of Taipei Veterans General Hospital. The 1-year outcomes of patients after DOAC initiation were evaluated. Different initiation time windows were compared (initiation time ≤3 days and >3 days in primary analysis). The primary composite outcome was stroke, transient ischemic attack, systemic embolism, or death due to IS. The primary safety outcome was major bleeding or clinically relevant nonmajor bleeding. The secondary composite outcome was all-cause mortality, thromboembolic event, or acute myocardial infarction/hemorrhagic events. ResultsThis study included 570 patients. The median initiation time of DOACs after IS in the patients with AF was 14 days. Compared the patients in whom DOACs were initiated after >3 days with those DOACs were initiated after ≤3 days, the adjusted hazard ratios (aHRs) of the primary composite outcome was 0.73 (95% confidence interval [CI]: 0.23–1.79), the aHR of primary safety outcome was 0.87 (95% CI: 0.34–1.90), and the aHR of secondary composite outcome was 0.65 (95% CI: 0.32–1.19). All the results were not statistically significant. In secondary analysis, we tested multiple time points of initiating DOACs. Compared with DOAC initiation after >14 days, the primary composite outcomes in the patients in whom DOACs were initiated ≤3, 4–7, and 8–14 days after IS were the same as the findings of the main analysis. After separating patients into different stroke severity groups, the results were similar to those in the main analysis. ConclusionNo significant association was observed between the timing of using DOACs and ischemic or hemorrhagic outcomes. The findings did not differ among different time points. Although we do not recommend avoiding the initiation of DOACs in the first few days after IS, we should consider that the early initiation of DOACs (≤3 days) would be appropriate only for patients who tend to experience thromboembolic events and have a low risk of bleeding. The optimal timing of initiation still must be confirmed by randomized controlled trials.