Abstract
The optimal initiation timing of oral anticoagulants (OACs) remains controversial in patients with atrial fibrillation (AF)-related acute ischemic stroke (AIS). The aim of this study is to compare the efficacy and safety of early OACs initiation with that of the delayed initiation for AIS and AF.We searched systematically the following mainstream databases: PubMed, Embase, and Web of Science from the inception to July 2023 for studies that compared the early initiation with the delayed initiation of OACs for AF-related AIS patients. Outcome measures were the incidence of hemorrhagic events, ischemic events, and combined outcomes, as well as all-cause mortality.There were 12 eligible articles included (10 cohort studies and 2 RCT), involving 11421 patients (5690 patients in the early-initiation group and 5731 in the delayed-initiation group). Meta-analysis revealed that patients receiving OACs at the early stage of stroke had a lower incidence of ischemic events (OR: 0.68; 95% CI: 0.55,0.84; p = 0.0003) and combined outcomes (OR=0.74, 95% CI (0.57,0.95), p=0.02). No significant differences were identified in the incidence of hemorrhagic events (p = 0.26) and all-cause mortality ( p = 0.20) between the groups.Early initiation of anticoagulation therapy would be preferable in lowering the incidence of ischemic events and combined outcomes in AIS patients with AF. It is safe compared to the delayed-initiation strategy. However, the conclusion of this study needs to be further validated by more well-designed RCTs.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
For patients suffering from acute ischemic stroke (AIS), concomitance with atrial fibrillation (AF) could typically increase the risk for recurrent ischemic stroke, especially in the early stage after the initial episode [1]. Statistical data have shown that the risk of recurrent stroke ranges from 0.5 to 1.3% per day in the first 14 days after the initial episode in patients receiving no anticoagulation therapies [2]. Previous studies conducted in multiple regions recommended vitamin-K antagonists (VKAs) as a first-line intervention for the prevention of recurrent stroke. Since 2010, 4 direct oral anticoagulants (DOACs) have been approved for medication in patients with non-valvular atrial fibrillation, including apixaban, dabigatran, edoxaban, and rivaroxaban [3], while the most preferable timing for the initiation of these agents after cardioembolic ischemic stroke remains controversial.
Warfarin is the most commonly-used anticoagulative agent in clinical practice. However, several randomized controlled trials (RCTs) have demonstrated that DOACs would be of similar efficacy compared to warfarin while of a lower risk for intracranial hemorrhage in patients with non-valvular AF (NVAF) [4]. The increasing application of DOACs could probably promote the change in the initiation timing of anticoagulation therapy.
There are many concerns and controversies over the initiation timing of OACs. Some studies suggest that the risk of recurrent ischemic stroke and intracranial hemorrhage is highest in the first few days after acute ischemic stroke [5]. The administration in the first few days after stroke could indeed reduce the incidence of recurrent stroke, whereas it might increase the incidence of hemorrhagic events such as symptomatic intracranial hemorrhage (ICH) and hemorrhagic transformation [6]. A study by Mizoguchi et al. has found no differences in the incidence of adverse events (recurrent stroke, systemic embolism, bleeding, and death) between early and delayed use of DOACs after AF-related ischemic stroke or transient ischemic stroke [4]. However, Baker et al. have reported that the incidence of ICH would be higher in patients receiving anticoagulation therapy early after stroke, compared with those who have delayed the initiation, while there were no significant differences in the incidence of other outcomes [7]. Another study by Matos Ribeiro showed that early anticoagulation therapy was associated with a lower recurrence rate of ischemic stroke and more favored functional outcomes at 3 months [8].
Therefore, to address the controversy over the initiation timing of anticoagulation therapy, we have conducted this systematic review and meta-analysis to critically compare the efficacy and safety of early initiation with delayed initiation of OACs (including VKA and DOACs) in patients with AIS and AF.
Materials and methods
This study is conducted and reported strictly following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement, and the study protocol has been pre-registered on PROSPERO (registration No. CRD42023391978). The PRISMA checklist [9] is presented in Online Resource 1.
Literature search
The following mainstream electronic English databases were searched from the inception of the databases to July 2023: PubMed, Embase, and Web of Science, the detailed search strategy for each database was presented in Online Resource 2. Furthermore, the reference lists of retrieved articles were searched manually to avoid missing eligible studies. All the identified studies were independently screened by two review authors and any disagreement would be resolved through discussion.
Identification of eligible studies
The following inclusion criteria were defined for study inclusion:
-
(1)
Study design: randomized controlled trial (RCT), cohort study, or case control study.
-
(2)
Types of participants: patients with AIS and AF.
-
(3)
Intervention: anticoagulation therapy initiated at an early or late stage of stroke.
-
(4)
Reporting on more than one of the following outcome measures: ischemia recurrence rate, incidence of hemorrhagic events, and all-cause mortality.
-
(5)
Providing sufficient data for calculating the weighted mean difference (WMD) and pooled odd ratio (OR).
Literature reviews, letters, case-report, comments, conference summaries, studies with full texts unavailable, and studies reported and published in non-English were excluded.
Data extraction
The data were extracted by two review authors independently, and the disagreements were settled by discussing with a third review author to make a consensus. The extracted contents were: name of the first author, date of publication, study period, nationality, study-design, number of recruited patients, follow-up duration, characteristics of the participants (age, gender, CHADS2 score, CHADS2-VASc score, HASBLED score, NHISS Score, etc.), and outcome measures (hemorrhagic events, ischemic events, combined outcomes, and all-cause mortality).
For continuous data reported in the original studies as median (range interquartile), the mean with the standard deviation (MD) would be calculated via a validated mathematical method [9, 10].
Quality assessment
Newcastle–Ottawa Scale (NOS) was adopted for assessing the quality of observational studies [11], and studies scored 7–9 were regarded as “high quality” [12]. As for RCTs, the Cochrane risk-of-bias tool was used [13]. Two review authors independently completed the process of quality assessment, with the disagreements settled through discussion.
Statistical analysis
Review Manager (RevMan) 5.4 software (Cochrane Collaboration, Oxford, UK) was adopted for data synthesis and meta-analysis. WMD and OR were applied as pooled statistics for continuous data and dichotomous data, respectively. The 95% confidential interval (95%CI) of each variable was provided. Chi-squared (χ2) test and I2 statistic were adopted for testing the heterogeneity among the studies [14]. A p value < 0.05 in χ2 test with an I2 > 50% indicated that evident heterogeneity existed, and thus a random-effect model was used for meta-analysis. Otherwise (p value > 0.05 in χ2 test with an I2 < 50%), a fixed-effect model was applied. One-way sensitivity analysis was also conducted to detect the effect of each included study on the pooled results. A funnel plot was produced to reveal the existence of publication bias.
Results
Study selection and characteristics
The PRISMA flow diagram of the literature searching and screening process is provided in Fig. 1.
The searches in PubMed(n = 4874), Embase (n = 1231), and Web of Science (n = 1217) retrieved 7322 articles. Following the process of duplicate-checking, the titles and abstracts of 5719 articles were browsed. A total of 12 studies meeting the inclusion criteria were included [4, 5, 7, 8, 15,16,17,18,19,20,21,22], involving 11,421 patients who had administered OACs after being diagnosed with AF-related IS. Among the included studies, 10 were cohort-design [4, 7, 8, 15,16,17,18, 20,21,22], and 2 was RCTs-design.[5, 19]. Characteristics and the score of quality assessment of the studies are presented in Table 1.
The included RCTs were graded as “low risk” in all the domains, and the 10 cohort studies were graded as “high quality”, with a median score of 8 (7–8) [4, 7, 8, 15,16,17,18, 20,21,22]. Detailed results of the quality assessment are presented in Online Resource 3 and 4.
Demographic characteristics
Between the two groups, no evident differences were identified in age (WMD:0.00; 95% CI: -0.78, 0.78; p = 1.00), gender (female/total, OR: 0.97; 95% CI: 0.89, 1.05; p = 0.40), CHADS2 Score(WMD:0.35; 95% CI: -0.07,0.78; p = 0.1), and CHADS2-VASc Score (WMD: 0.26; 95%CI: -0.02,0.54; p = 0.07).
There were evident differences in the HASBLED Score (WMD: -0.27; 95% CI: -0.45,-0.09;p = 0.003) and NHISS Score (WMD: -4.01; 95% CI:-6.65,-1.36;p = 0.003) between the groups (Table 2).
Hemorrhagic events
There were 10 studies reporting the incidence of hemorrhagic events [4, 5, 7, 8, 16,17,18, 20,21,22], involving 7903 participants (3840 in the early-initiation group and 4063 in the delayed-initiation group). The pooled results indicated no evident difference in the incidence of hemorrhagic events between the two groups (OR:0.72; 95% CI: 0.41, 1.27; p = 0.26). Significant heterogeneity existed among the studies (I2 = 66%, p = 0.003) (Fig. 2). The funnel plot showed the presence of slight publication bias (Fig. 3A).
Ischemic events
There were 9 studies that reported ischemic events [4, 5, 7, 8, 16, 17, 20,21,22], with a total of 7830 patients (3799 in the early-initiation group and 4031 in the delayed-initiation group). The pooled results indicated that patients in the early-initiation group had an evidently lower incidence of recurrent ischemia (OR: 0.68; 95% CI: 0.55,0.84; p = 0.0003)(Fig. 4). No evident heterogeneity (I2 = 0%, p = 0.44) and publication bias was confirmed among the studies(Fig. 3B).
Combined outcomes
There were 5 studies that provided data on combined outcomes [15, 19, 20,21,22], with 6492 patients (3255 in the early-initiation group and 3237 in the delayed-initiation group). Meta-analysis revealed that patients receiving OACs at the early stage of stroke had an evidently lower incidence of combined outcomes (OR: 0.74; 95% CI:0.57,0.95; p = 0.02)(Fig. 5). No evident heterogeneity (I2 = 46%, p = 0.12) and publication bias was confirmed among the studies (Fig. 3C).
Mortality
There were 5 studies reporting the all-cause mortality of the patients [4, 5, 16, 19, 21], involving 6418 patients (2784 in the early-initiation group and 3634 in the delayed-initiation group). No evident difference was identified in all-cause mortality between the two groups (OR: 0.74; 95% CI:0.47,1.17; p = 0.20). Significant heterogeneity existed (I2 = 54%, p = 0.07) (Fig. 6), and no evidence of publication bias was confirmed through the funnel plot (Fig. 3D).
Sensitivity analysis
A one-way sensitivity analysis was performed for the incidence of hemorrhagic events (Fig. 7) and all-cause mortality (Fig. 8), so as to detect the effect of each study on the pooled results. After the one-by-one removal of the studies reporting hemorrhagic events, the pooled OR failed to be reversed.However, the exclusion of the study by Wilson et al. [21] resulted in decreased heterogeneity for the mortality (I2 = 14%, p = 0.32), suggesting that this study would be a source of heterogeneity.
Discussion
Episode of cardioembolic stroke in the setting of atrial fibrillation (AF) is of a significantly high risk of mortality. Those patients also have high morbidity of recurrent stroke in the first 90 days after the preliminary attack [23].
Direct oral anti-coagulants (DOACs) and Vitamin-K antagonists (VKAs) have been recommended for secondary prevention in patients with non-valvular AF [3].
Recent international guidelines provide no specific recommendations on the initiation timing of OACs after AF-related AIF due to the controversies over the benefits of early initiation and delayed initiation of OACs. According to the guideline released by the American Heart Association, OACs are recommended within 4 to 14 days after the episode of cardioembolic stroke [24]. However, such a recommendation is typically based on the results of observational studies that fail to consider several circumstances that might affect the clinical decision on the initiation of OACs after the episode of stroke [3, 21, 25, 26]. Guideline released by the European Stroke Organization (ESO) [27] recommends a delayed OACs administration, for patients with disabling ischemic stroke to at least 14 days after the episode of stroke, and the specific timing could be decided by clinicians. For non-disabling ischemic stroke, OCAs administration should be initiated no more than 14 days after the stroke. As for patients with TIA, anti-coagulation therapy is typically initiated immediately. Guideline released by the European Society of Cardiology guidelines [28] recommends that initiation of OACs is based on the infarct size at 1, 3, 6, or 12 days, which could be assessed by experts.
There have been multiple retrospective and observational studies published recently. These studies explored the early OACs administration in AIS patients, and found that early OACs administration did not increase the incidence of recurrent stroke or mortality [18, 25, 26, 29,30,31,32]. There are 4 ongoing RCTs (ELAN [NCT03148457] [33], OPTIMAS [NCT03759938] [34], TIMING [NCT0291348] [19], START [NCT03021928] [35]) that aim to evaluate the safety and efficacy of early OAC administration for ischemic stroke. The TIMING and ELAN studies have been recently completed, and the details will be elaborated on and discussed in the following part.
In view of the above situations, we conducted this study that included 12 comparative studies with a total of 11,421 participants,the conclusions are intended to provide a direction of clinical practice. The results showed that AIS patients receiving OACs in the early stage had a lower recurrence rate of ischemic events. However, this study did not consider the fact that patients receiving anti-coagulation therapy at the early stage often had lower HASBLED score and NHISS score, so selective bias would exist. Because of the limitations of the study, patients’ characteristics varied to some extent between the early-OAC initiation group and the delayed-OAC initiation group. In most of the included studies, the condition of patients receiving OACs at the early stage was milder while those receiving OACs more than 1 week after the stroke were more severe. There are still 2 studies that had no significant differences in HASBLED score and NHISS score between the two groups after using some statistical methods. In the study by Kimura et al., the occurrence of systemic embolism and stroke was less common in the early-initiation group (n = 785) (defined as initiating DOACs within 1–4 days), compared with the delayed-initiation group (n = 1012) [(1.9% versus 3.9%), HR = 0.50, 95%CI (0.27, 0.89)], as well as the incidence of ischemic stroke [(1.7% versus 3.2%), HR = 0.54, 95%CI (0.27, 0.999)] [16]. The study by Oldgren et al. also showed that the early-initiation group had a lower incidence of ischemic stroke than the delayed-initiation group (3.11% versus 4.57%, risk difference=-1.46% [95% CI, -3.98–1.07%]) [19]. These studies firmly supported that the early administration of anticoagulants could effectively prevent the recurrence of ischemia.
On the other hand, analyses of the safety outcomes in the two groups found no significant difference in the incidence of hemorrhagic events and mortality, which was inconsistent with the previous studies that early administration of anticoagulants would be of higher risk for hemorrhagic events. However, the reason for these findings might be attributed to the increasing use of DOACs, but previous conclusions were largely based on studies of warfarin. Our meta-analysis combined VKA and DOAC studies, which provided stronger supporting evidence. Due to the small sample size, there are DOAC-only and OAC studies included. The results might be reversed if all included studies used DOACs. Different HASBLED score and NHISS scores also affect the accuracy of safety results. Similarly, we analyzed the 2 studies that had no significant differences in HASBLED score and NHISS score. In the study by Kimura et al., the incidence of major bleeding presented to be similar between the groups (0.8% versus 1.0%), as well as that of intracranial hemorrhage (0.2% in the early-initiation group and 0.6% in the delayed-initiation group) [16]. In the study conducted by Oldgren et al., the all-cause mortality of the patients was 4.67% in the early-initiation group and 5.71% in the delayed-initiation group [RD=-1.04%, (95% CI (-3.96, 1.88)]. There was no report regarding the occurrence of symptomatic intracerebral hemorrhage in the patients [19]. Therefore, early initiation of OACs would not be unsafer than the delayed initiation for AIS patients with AF.
Third, a pooled analysis of combined outcomes evaluated showed that the early group had less incidence rate of efficacy and safety outcomes. The present result contradicted the report of Palaiodimou et al [36], a similar meta-analysis published in recent years, which showed that OACs initiation within the first week after stroke might be of comparable efficacy and safety compared to the initiation within two weeks after stroke, while DOACs presented to be more effective in reducing the incidence of recurrent stroke and improving the survival of the patients, compared with VKAs. Our study included more newly-published studies, with a larger sample size, which would make a difference.
Our study is the latest and largest meta-analysis that compares directly the efficacy and safety of OACs administration at different timing in AIS patients with AF. However, there is no doubt that several limitations exist. Firstly, our meta-analysis included just 2 RCTs (16.7%), whereas the other studies were retrospective or prospective cohort-design, without appropriate processing of confounding factors. As for the incidence of hemorrhagic events and all-cause mortality, evident heterogeneity was observed. Though sensitivity analysis was conducted to assess the robustness of the results, the sources of heterogeneity could not be identified. Given the potential confounding factors, the results of this study ought to be interpreted prudently. Finally, we failed to perform a more comprehensive assessment to specify the timing of early OACs administration in that the definition of the initiation timing varied among the studies.
Despite the limitations mentioned above, our study is the latest and largest meta-analysis regarding optimal initiation timing of OACs in AIS patients with AF. Most of the included studies were published between 2019 and 2022, especially 2 influential RCTs [5, 19] were published in 2022 and 2023, which makes the evidence more reliable. The evidence produced by our study further supported the superiority of early initiation of OACs for preventing the recurrence of stroke in AIS patients with AF, which has been reported in previous study. Meanwhile, we found that early initiation of OACs did not cause more hemorrhagic events. More well-designed and large-scale RCTs with a long follow-up duration are expected to further identify the optimal initiation timing of OACs.
Conclusion
The present meta-analysis indicates that early initiation of OACs could be more effective in preventing the recurrence of ischemic events and reducing the incidence of combined outcomes in AF-related AIS patients. And early-initiation of OACs would be of similar safety (hemorrhagic events and mortality) to the delayed initiation. These findings require further validation by more RCTs.
Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Group SRiAFW (2007) Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology 69(6):546–554. https://doi.org/10.1212/01.wnl.0000267275.68538.8d
Hart RG, Coull BM, Hart D (1983) Early recurrent embolism associated with nonvalvular atrial fibrillation: a retrospective study. Stroke 14(5):688–693. https://doi.org/10.1161/01.str.14.5.688
Seiffge DJ, Werring DJ, Paciaroni M, Dawson J, Warach S, Milling TJ, Engelter ST et al (2019) Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. Lancet Neurol 18(1):117–126. https://doi.org/10.1016/s1474-4422(18)30356-9
Mizoguchi T, Tanaka K, Toyoda K, Yoshimura S, Itabashi R, Takagi M, Todo K et al (2020) Early initiation of direct oral Anticoagulants after Onset of Stroke and short- and long-term outcomes of patients with Nonvalvular Atrial Fibrillation. Stroke 51(3):883–891. https://doi.org/10.1161/strokeaha.119.028118
Fischer U, Koga M, Strbian D, Branca M, Abend S, Trelle S, Paciaroni M et al (2023) Early versus later anticoagulation for stroke with Atrial Fibrillation. N Engl J Med 388(26):2411–2421. https://doi.org/10.1056/NEJMoa2303048
Paciaroni M, Agnelli G, Corea F, Ageno W, Alberti A, Lanari A, Caso V et al (2008) Early hemorrhagic transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results of a prospective multicenter study. Stroke 39(8):2249–2256. https://doi.org/10.1161/strokeaha.107.510321
Al Bakr AI, AlOmar RS, Nada MAF, Ishaque N, Aljaafari D, Hadhiah K, Al Khmais FA et al (2020) Timing to start anticoagulants after acute ischemic stroke with non-valvular atrial fibrillation. J Neurol Sci 409:116582. https://doi.org/10.1016/j.jns.2019.116582
Matos-Ribeiro J, Castro-Chaves P, Oliveira-Ferreira M, Fonseca L, Pintalhao M (2022) Early anticoagulation in atrial fibrillation-related acute ischaemic stroke: efficacy and safety profile. J Neurol 269(4):2099–2112. https://doi.org/10.1007/s00415-021-10788-z
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71. https://doi.org/10.1136/bmj.n71
Luo D, Wan X, Liu J, Tong T (2018) Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 27(6):1785–1805. https://doi.org/10.1177/0962280216669183
Wells G, Shea B, O’Connell D, Peterson j, Welch V, Losos M, Tugwell P (2000) The Newcastle–Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies in Meta-Analysis.
Kim SR, Kim K, Lee SA, Kwon SO, Lee JK, Keum N, Park SM (2019) Effect of Red, processed, and White Meat Consumption on the risk of gastric Cancer: an overall and Dose–Response Meta-Analysis. Nutrients 11(4). https://doi.org/10.3390/nu11040826
Mcpheeters ML, Kripalani S, Peterson NB, Idowu RT, Jerome RN, Potter SA, Andrews JC (2012) Cochrane Risk of Bias Tool. Cochrane Risk of Bias Tool
Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558. https://doi.org/10.1002/sim.1186
De Marchis GM, Seiffge DJ, Schaedelin S, Wilson D, Caso V, Acciarresi M, Tsivgoulis G et al (2022) Early versus late start of direct oral anticoagulants after acute ischaemic stroke linked to atrial fibrillation: an observational study and individual patient data pooled analysis. J Neurol Neurosurg Psychiatry 93(2):119–125. https://doi.org/10.1136/jnnp-2021-327236
Kimura S, Toyoda K, Yoshimura S, Minematsu K, Yasaka M, Paciaroni M, Werring DJ et al (2022) Practical “1-2-3-4-Day” rule for starting direct oral Anticoagulants after ischemic stroke with Atrial Fibrillation: Combined Hospital-Based Cohort Study. Stroke 53(5):1540–1549. https://doi.org/10.1161/strokeaha.121.036695
Kimura T, Tucker A, Nakagaki A, Sugimura T, Fukuda S, Katsuno M, Fujita T et al (2021) Anticoagulation Protocol for secondary Prevention of Acute Ischemic Stroke Associated with Nonvalvular Atrial Fibrillation. J Stroke Cerebrovasc Dis 30(8):105893. https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.105893
Macha K, Volbers B, Bobinger T, Kurka N, Breuer L, Huttner HB, Schwab S et al (2016) Early initiation of anticoagulation with direct oral anticoagulants in patients after transient ischemic attack or ischemic stroke. J Stroke Cerebrovasc Dis 25(9):2317–2321. https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.06.031
Oldgren J, Åsberg S, Hijazi Z, Wester P, Bertilsson M, Norrving B (2022) Early Versus delayed Non-Vitamin K antagonist oral anticoagulant therapy after Acute ischemic stroke in Atrial Fibrillation (TIMING): a Registry-Based Randomized Controlled Noninferiority Study. Circulation 146(14):1056–1066. https://doi.org/10.1161/circulationaha.122.060666
Paciaroni M, Agnelli G, Giustozzi M, Tsivgoulis G, Yaghi S, Grory BM, Furie KL et al (2020) Timing of initiation of oral anticoagulants in patients with acute ischemic stroke and atrial fibrillation comparing posterior and anterior circulation strokes. Eur Stroke J 5(4):374–383. https://doi.org/10.1177/2396987320937116
Wilson D, Ambler G, Banerjee G, Shakeshaft C, Cohen H, Yousry TA, Al-Shahi Salman R et al (2019) Early versus late anticoagulation for ischaemic stroke associated with atrial fibrillation: multicentre cohort study. J Neurol Neurosurg Psychiatry 90(3):320–325. https://doi.org/10.1136/jnnp-2018-318890
Yaghi S, Trivedi T, Henninger N, Giles J, Liu A, Nagy M, Kaushal A et al (2020) Anticoagulation timing in Cardioembolic Stroke and recurrent event risk. Ann Neurol 88(4):807–816. https://doi.org/10.1002/ana.25844
Kamel H, Healey JS (2017) Cardioembolic stroke. Circ Res 120(3):514–526. https://doi.org/10.1161/circresaha.116.308407
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J et al (2018) 2018 guidelines for the early management of patients with Acute ischemic stroke: a Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke 49(3):e46–e110. https://doi.org/10.1161/str.0000000000000158
Paciaroni M, Agnelli G, Falocci N, Caso V, Becattini C, Marcheselli S, Rueckert C et al (2015) Early recurrence and cerebral bleeding in patients with Acute Ischemic Stroke and Atrial Fibrillation: Effect of Anticoagulation and its timing: the RAF Study. Stroke 46(8):2175–2182. https://doi.org/10.1161/strokeaha.115.008891
Seiffge DJ, Traenka C, Polymeris A, Hert L, Peters N, Lyrer P, Engelter ST et al (2016) Early start of DOAC after ischemic stroke: risk of intracranial hemorrhage and recurrent events. Neurology 87(18):1856–1862. https://doi.org/10.1212/wnl.0000000000003283
Klijn CJ, Paciaroni M, Berge E, Korompoki E, Kõrv J, Lal A, Putaala J et al (2019) Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation: a european Stroke Organisation guideline. Eur Stroke J 4(3):198–223. https://doi.org/10.1177/2396987319841187
Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M et al (2016) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 37(38):2893–2962. https://doi.org/10.1093/eurheartj/ehw210
Abdul-Rahim AH, Fulton RL, Frank B, Tatlisumak T, Paciaroni M, Caso V, Diener HC et al (2015) Association of improved outcome in acute ischaemic stroke patients with atrial fibrillation who receive early antithrombotic therapy: analysis from VISTA. Eur J Neurol 22(7):1048–1055. https://doi.org/10.1111/ene.12577
Arihiro S, Todo K, Koga M, Furui E, Kinoshita N, Kimura K, Yamagami H et al (2016) Three-month risk-benefit profile of anticoagulation after stroke with atrial fibrillation: the SAMURAI-Nonvalvular Atrial Fibrillation (NVAF) study. Int J Stroke 11(5):565–574. https://doi.org/10.1177/1747493016632239
Canavero I, Cavallini A, Sacchi L, Quaglini S, Arnò N, Perrone P, DeLodovici ML et al (2017) Safely addressing patients with Atrial Fibrillation to Early Anticoagulation after Acute Stroke. J Stroke Cerebrovasc Dis 26(1):7–18. https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.08.022
Gioia LC, Kate M, Sivakumar L, Hussain D, Kalashyan H, Buck B, Bussiere M et al (2016) Early Rivaroxaban Use after Cardioembolic Stroke May not result in Hemorrhagic Transformation: a prospective magnetic resonance imaging study. Stroke 47(7):1917–1919. https://doi.org/10.1161/strokeaha.116.013491
Fischer U, Trelle S, Branca M, Salanti G, Paciaroni M, Ferrari C, Abend S et al (2022) Early versus late initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial fibrillatioN (ELAN): protocol for an international, multicentre, randomised-controlled, two-arm, open, assessor-blinded trial. Eur Stroke J 7(4):487–495. https://doi.org/10.1177/23969873221106043
Best JG, Arram L, Ahmed N, Balogun M, Bennett K, Bordea E, Campos MG et al (2022) Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): protocol for a randomized controlled trial. Int J Stroke 17(5):583–589. https://doi.org/10.1177/17474930211057722
King BT, Lawrence PD, Milling TJ, Warach SJ (2019) Optimal delay time to initiate anticoagulation after ischemic stroke in atrial fibrillation (START): methodology of a pragmatic, response-adaptive, prospective randomized clinical trial. Int J Stroke 14(9):977–982. https://doi.org/10.1177/1747493019870651
Palaiodimou L, Stefanou MI, Katsanos AH, Paciaroni M, Sacco S, De Marchis GM, Shoamanesh A et al (2022) Early Anticoagulation in patients with Acute Ischemic Stroke due to Atrial Fibrillation: a systematic review and Meta-analysis. J Clin Med 11(17). https://doi.org/10.3390/jcm11174981
Acknowledgements
We would like to thank the researchers and study participants for their contributions.
Funding
The authors did not receive support from any organization for the submitted work.
Author information
Authors and Affiliations
Contributions
Conceptualization: Mengjin Jiang; Methodology: Mengjin Jiang, Yaodong Zhang, Congyao Wang; Formal analysis and investigation: Yaodong Zhang, Congyao Wang; Writing - original draft preparation: Mengjin Jiang, Congyao Wang; Writing - review and editing: Mengjin Jiang, Yaodong Zhang. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing interest.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Jiang, M., Wang, C. & Zhang, Y. Comparison of early and delayed anticoagulation therapy after ischemic stroke in patients with atrial fibrillation: a systematic review and meta-analysis. J Thromb Thrombolysis 56, 603–613 (2023). https://doi.org/10.1007/s11239-023-02872-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11239-023-02872-0