Objective  To evaluate the efficacy and safety of early use of new oral anticoagulants (≤3 days) in patients with acute ischemic stroke(AIS) due to atrial fibrillation (AF).

Method  After systematic retrieval of CNKI, WanFang Data, VIP, PubMed, The Cochrane Library and Embase database, clinical studies on early anticoagulation therapy for AF-related AIS patients were screened. The search was conducted from the time of database construction to November 4, 2022, while the references were searched manually. Literature screening, data extraction and quality assessment were performed independently by 2 investigators. Meta-analysis was performed using RevMan 5.4 software, and the combined dichotomous effect sizes were expressed as relative risk (RR) and 95% confidence interval (CI).

Result  A total of 2 randomized controlled trials and 5 non-randomized controlled trials including 2 226 patients were included, and the analysis suggested that early anticoagulation treatment  (≤3 days)  was similar to delayed anticoagulation (> 3 days) in terms of total ischemic events [RR=1.04, 95%CI(0.67, 1.61), P=0.88], recurrent ischemic strokes or transient ischemic attack [RR=0.88, 95%CI(0.58, 1.34), P=0.56], major bleeding [RR=1.24, 95%CI(0.59, 2.62), P=0.56], and symptomatic intracerebral haemorrhage [RR=0.98, 95%CI(0.44, 2.17), P=0.96]. In terms of total cerebral hemorrhages, the incidence was lower than in the delayed anticoagulation group.

Conclusion  Anticoagulation started early after the occurrence of atrial fibrillation related ischemic stroke is similar to delayed anticoagulation in terms of effectiveness, and does not increase the risk of bleeding in patients.

1.Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-thoracic Surgery (EACTS): The task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC[J]. Eur Heart J, 2021, 42(5): 373-498. DOI: 10.1093/eurheartj/ehaa612.

2.Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2015 update: a report from the American Heart Association[J]. Circulation, 2015, 131(4): e29-e322. DOI: 10.1161/CIR.0000000000000152.

3.Norrving B, Barrick J, Davalos A, et al. Action plan for stroke in europe 2018-2030[J]. Eur Stroke J, 2018, 3(4): 309-336. DOI: 10.1177/2396987318808719.

4.Henninger N, Goddeau RJ, Karmarkar A, et al. Atrial fibrillation is associated with a worse 90-day outcome than other cardioembolic stroke subtypes[J]. Stroke, 2016, 47(6): 1486-1492. DOI: 10.1161/STROKEAHA.116.012865.

5.Arboix A, Garcia-Eroles L, Oliveres M, et al. Clinical predictors of early embolic recurrence in presumed cardioembolic stroke[J]. Cerebrovasc Dis, 1998, 8(6): 345-353. DOI: 10.1159/000015878.

6.January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the heart rhythm society in collaboration with the society of thoracic surgeons[J]. Circulation, 2019, 140(2): e125-e151. DOI: 10.1161/CIR.0000000000000665.

7.Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association[J]. Stroke, 2021, 52(7): e364-e467. DOI: 10.1161/STR. 0000000000000375.

8.Klijn CJ, Paciaroni M, Berge E, et al. 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[J]. Eur Stroke J, 2019, 4(3): 198-223. DOI: 10.1177/2396987319841187.

9.Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a Meta-analysis of randomised trials[J]. Lancet, 2014, 383(9921): 955-962. DOI: 10.1016/S0140-6736(13)62343-0.

10.Umashankar K, Mammi M, Badawoud E, et al. Efficacy and safety of direct oral anticoagulants (DOACs) versus warfarin in atrial fibrillation patients with prior stroke: a systematic review and Meta-analysis[J]. Cardiovasc Drugs Ther, 2023, 37(6):1225-1237. DOI: 10.1007/s10557-022-07336-w.

11.Paciaroni M, Agnelli G, Falocci N, et al. Early recurrence and cerebral bleeding in patients with acute ischemic stroke and atrial fibrillation: effect of anticoagulation and its timing: the RAF study[J]. Stroke, 2015, 46(8): 2175-2182. DOI: 10.1161/STROKEAHA.115.008891.

12.England TJ, Bath PM, Sare GM, et al. Asymptomatic hemorrhagic transformation of infarction and its relationship with functional outcome and stroke subtype: assessment from the Tinzaparin in Acute Ischaemic Stroke Trial[J]. Stroke, 2010, 41(12): 2834-2839. DOI: 10.1161/STROKEAHA.109.573063.

13.Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association[J]. Stroke, 2019, 50(12): e344-e418. DOI: 10.1161/STR.0000000000000211.

14.Kimura S, Toyoda K, Yoshimura S, et al. Practical "1-2-3-4-day" rule for starting direct oral anticoagulants after ischemic stroke with atrial fibrillation: combined hospital-based cohort study[J]. Stroke, 2022, 53(5): 1540-1549. DOI: 10.1161/STROKEAHA.121.036695.

15.Koge J, Yamagami H, Toyoda K, et al. Early initiation of rivaroxaban after reperfusion therapy for stroke patients with nonvalvular atrial fibrillation[J]. PLoS One, 2022, 17(4): e264760. DOI: 10.1371/journal.pone.0264760.

16.Oldgren J, Asberg S, Hijazi Z, et al. 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[J]. Circulation, 2022, 146(14): 1056-1066. DOI: 10.1161/CIRCULATIONAHA.122.060666.

17.Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane collaboration's tool for assessing risk of bias in randomised trials[J]. BMJ, 2011, 343: d5928. DOI: 10.1136/bmj.d5928.

18.Slim K, Nini E, Forestier D, et al. Methodological index for non-randomized studies (minors): development and validation of a new instrument[J]. ANZ J Surg, 2003, 73(9): 712-716. DOI: 10.1046/j.1445-2197.2003.02748.x.

19.罗德惠, 万翔, 刘际明, 等. 如何实现从样本量、中位数、极值或四分位数到均数与标准差的转换[J]. 中国循证医学杂志, 2017, 17(11): 1350-1356. [Luo DH, Wan X, Liu JM, et al. How to estimate the sample mean and standard deviation from the sample size, median, extremes or quartiles[J]. Chinese Journal of Evidence-Based Medicine, 2017, 17(11): 1350-1356.] DOI: 10.7507/1672-2531.201706060.

20.陈俊华, 张淳, 张存新, 等. 急性缺血性脑卒中合并非瓣膜性心房颤动患者启用利伐沙班抗凝治疗时机的探讨[J]. 中华老年心脑血管病杂志, 2019, 21(6): 605-608. [Chen JH, Zhang C, Zhang CX, et al. Optimal timing for anticoagulant rivaroxaban therapy in acute ischemic stroke patients with nonvalvular AF[J]. Chinese Journal of Geriatric Heart Brain and Vessel Diseases, 2019, 21(6): 605-608.] DOI: 10.3969/j.issn.1009-0126.2019.06.012.

21.俞芃, 弥娜, 王涵, 等. 口服利伐沙班在脑梗死合并心房颤动患者中抗凝时机的研究[J]. 中国医院用药评价与分析, 2022, 22(7): 796-798. [Yu P, Mi N, Wang H, et al. Anticoagulant timing of oral rivaroxaban in patients with cerebral infarction complicated with atrial fibrillation[J]. Evaluation and Analysis of Drug-Use in Hospitals of China, 2022, 22(7): 796-798.] DOI: 10.14009/j.issn. 1672-2124.2022.07.008.

22.Mizoguchi T, Tanaka K, Toyoda K, et al. Early initiation of direct oral anticoagulants after onset of stroke and short- and long-term outcomes of patients with nonvalvular atrial fibrillation[J]. Stroke, 2020, 51(3): 883-891. DOI: 10.1161/STROKEAHA.119.028118.

23.Yasaka M, Minematsu K, Toyoda K, et al. Rivaroxaban administration after acute ischemic stroke: the RELAXED study[J]. PLoS One, 2019, 14(2): e212354. DOI: 10.1371/journal.pone.0212354.

24.Cappellari M, Carletti M, Danese A, et al. Early introduction of direct oral anticoagulants in cardioembolic stroke patients with non-valvular atrial fibrillation[J]. J Thromb Thrombolysis, 2016, 42(3): 393-398. DOI: 10.1007/s11239-016-1393-9.

25.Macha K, Volbers B, Bobinger T, et al. Early initiation of anticoagulation with direct oral anticoagulants in patients after transient ischemic attack or ischemic stroke[J]. J Stroke Cerebrovasc Dis, 2016, 25(9): 2317-2321. DOI: 10.1016/j.jstrokecerebrovasdis.2016.06.031.

26.赵宗权, 吴贻红, 张豪, 等. 急性缺血性脑卒中合并非瓣膜性心房颤动应用利伐沙班时机选择及血栓发生的因素分析[J]. 中华老年心脑血管病杂志, 2022, 24(9): 936-939. [Zhao ZQ, Wu YH, Zhang H, et al. Treatment timing of anticoagulant rivaroxaban in patients with AIS and NVAF and influencing factors of thrombotic events[J]. Chinese Journal of Geriatric Heart Brain and Vessel Diseases, 2022, 24(9): 936-939.] https://kns.cnki.net/kcms/detail/detail.aspx?FileName=LNXG202209011&DbName=CJFQ2022.

27.Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients[J]. J Thromb Haemost, 2005, 3(4): 692-694. DOI: 10.1111/j.1538-7836.2005.01204.x.

28.Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association[J]. Circulation, 2019, 139(10): e56-e528. DOI: 10.1161/CIR.0000000000000659.

29.Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 study[J]. Circulation, 2014, 129(8): 837-847. DOI: 10.1161/CIRCULATIONAHA.113.005119.

30.Colilla S, Crow A, Petkun W, et al. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population[J]. Am J Cardiol, 2013, 112(8): 1142-1147. DOI: 10.1016/j.amjcard.2013.05.063.

31.Krijthe BP, Kunst A, Benjamin EJ, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060[J]. Eur Heart J, 2013, 34(35): 2746-2751. DOI: 10.1093/eurheartj/eht280.

32.Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary[J]. Eur Heart J, 2013, 34(27): 2094-2106. DOI: 10.1093/eurheartj/eht134.

33.Powers WJ, Rabinstein AA, Ackerson T, et al. 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[J]. Stroke, 2018, 49(3): e46-e110. DOI: 10.1161/STR.0000000000000158.

34.Intercollegiate Stroke Working Party. National clinical guideline for stroke[J/OL]. 2016. https://www.strokeaudit.org/SupportFiles/Documents/Guidelines/2016-National-Clinical-Guideline-for-Stroke-5t-(1).aspx.

35.Paciaroni M, Agnelli G, Corea F, et al. Early hemorrhagic transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results of a prospective multicenter study[J]. Stroke, 2008, 39(8): 2249-2256. DOI: 10.1161/STROKEAHA.107.510321.

36.Kablau M, Kreisel SH, Sauer T, et al. Predictors and early outcome of hemorrhagic transformation after acute ischemic stroke[J]. Cerebrovasc Dis, 2011, 32(4): 334-341. DOI: 10.1159/000331702.

37.Munn D, Abdul-Rahim AH, Fischer U, et al. A survey of opinion: When to start oral anticoagulants in patients with acute ischaemic stroke and atrial fibrillation?[J]. Eur Stroke J, 2018, 3(4): 355-360. DOI: 10.1177/2396987318787124.

38.Palaiodimou L, Stefanou MI, Katsanos AH, et al. Early anticoagulation in patients with acute ischemic stroke due to atrial fibrillation: a systematic review and Meta-analysis[J]. J Clin Med, 2022, 11(17): 4981. DOI: 10.3390/jcm11174981.

39.De Marchis GM, Seiffge DJ, Schaedelin S, et al. 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]. J Neurol Neurosurg Psychiatry, 2022, 93(2): 119-125. DOI: 10.1136/jnnp-2021-327236.

40.Wankowicz P, Staszewski J, Debiec A, et al. Ischemic stroke risk factors in patients with atrial fibrillation treated with new oral anticoagulants[J]. J Clin Med, 2021, 10(6): 1223. DOI: 10.3390/jcm10061223.

41.Choi SY, Kim MH, Lee KM, et al. Anticoagulant therapy in initially low-risk patients with nonvalvular atrial fibrillation who develop risk factors[J]. J Am Heart Assoc, 2020, 9(16): e16271. DOI: 10.1161/JAHA.120.016271.