Direct, non-Vitamin K antagonist oral anticoagulants compared with warfarin for stroke with atrial fibrillation and cerebral small vessel disease

Lipeng Cai; Honglian Duan; Sara Saymuah; Ruiqiang Xin; Xiaokun Geng; Yuchuan Ding

doi:10.4103/ed.ed_9_21

ORIGINAL ARTICLE

Year : 2021 | Volume : 6 | Issue : 2 | Page : 52-57

Direct, non-Vitamin K antagonist oral anticoagulants compared with warfarin for stroke with atrial fibrillation and cerebral small vessel disease

Lipeng Cai¹, Honglian Duan¹, Sara Saymuah², Ruiqiang Xin³, Xiaokun Geng⁴, Yuchuan Ding²
¹ Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
² Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
³ Department of Medical Imaging, Luhe Hospital, Capital Medical University, Beijing, China
⁴ Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China, 2Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA

Date of Submission	27-May-2021
Date of Decision	01-Jun-2021
Date of Acceptance	10-Jun-2021
Date of Web Publication	06-Jul-2021

Correspondence Address:
Prof. Xiaokun Geng
Department of Neurology, Stroke Center, Beijing Luhe Hospital, Capital Medical University, No. 82 Xinhua South Road, Tongzhou District, Beijing 101149

Prof. Yuchuan Ding
Department of Neurosurgery, Wayne State University School of Medicine, 550 E Canfield, Detroit, MI 48201
USA

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ed.ed_9_21

Abstract

Background: Cerebral small vessel disease (CSVD) is not only associated with an increased risk of intracranial hemorrhage (ICH) in patients on oral anticoagulation, but also associated with an increased risk of ischemic stroke. Limited data support the benefits of direct, non-Vitamin K antagonist oral anticoagulants (direct oral anticoagulants [DOACs]) in acute ischemic stroke (AIS) or transient ischemic attack (TIA) patients with nonvalvular atrial fibrillation (AF) and CSVD. We aimed to evaluate the effectiveness and safety of DOACs in AIS or TIA with AF and CSVD.
Patients and Methods: We conducted a retrospective study with consecutive patients who experienced AIS or TIA with AF and CSVD from January 1, 2017 to December 31, 2019 in the Stroke Center at Beijing Luhe Hospital, Capital Medical University. Patients are followed for 12 months by outpatient visits or telephone interviews. The safety endpoint of this study was symptomatic ICH (sICH), while the efficacy endpoint was recurrent ischemic events (AIS or TIA). Patients in the DOACs group were compared with patients in the warfarin group using Chi-square tests or the continuity correction Chi-square tests. The safety and efficacy endpoint was progression-free survival assessed by the log-rank test.
Results: A total of 542 patients were finally included in this study (353 in the DOACs group and 189 in the warfarin group). There were no significant differences in vascular risk factors, NIH Stroke Scale score at baseline, and CHA2DS2-VASc score between the two groups. There were no significant differences in recurrent events between the two groups (P = 0.68). Patients in the DOACs group showed lower risks of sICH (P = 0.03) and a shorter hospital stay (P = 0.03) compared to patients in the warfarin group followed over 12 months.
Conclusion: DOACs were associated with lower risks of sICH and similar risks of the recurrent ischemic event as compared to the warfarin group with AF and CSVD. Patients in the DOACs group had shorter hospital stay when compared to patients in the warfarin group. DOACs may be a better option than warfarin for AIS or TIA patients with AF and CSVD for secondary prevention.

Keywords: Anticoagulants, atrial fibrillation, cerebral small vessel disease, secondary prevention, stroke

How to cite this article:
Cai L, Duan H, Saymuah S, Xin R, Geng X, Ding Y. Direct, non-Vitamin K antagonist oral anticoagulants compared with warfarin for stroke with atrial fibrillation and cerebral small vessel disease. Environ Dis 2021;6:52-7

How to cite this URL:
Cai L, Duan H, Saymuah S, Xin R, Geng X, Ding Y. Direct, non-Vitamin K antagonist oral anticoagulants compared with warfarin for stroke with atrial fibrillation and cerebral small vessel disease. Environ Dis [serial online] 2021 [cited 2023 Jun 5];6:52-7. Available from: http://www.environmentmed.org/text.asp?2021/6/2/52/320790

Introduction

Due to its high rate of mortality and morbidity, ischemic stroke is a devastating public health concern that results in a high socioeconomic burden,^[1],[2] Approximately 25% of ischemic strokes are caused by cardioembolism, particularly due to nonvalvular atrial fibrillation (AF).^[3] The most effective treatment for secondary prevention after acute ischemic stroke (AIS) or transient ischemic attack (TIA) in patients with AF is oral anticoagulation (OAC). OAC can reduce the risk of recurrence stroke for AF patients by two-thirds, along with a lower risk of intracranial hemorrhage (ICH).^[4] However, ICH, especially symptomatic ICH (sICH), is the most common complication of OAC and has caused 42% of in-hospital mortality along with substantial patient disability.^[5] OAC is a double-edged sword: although it can significantly reduce the risk of recurrence stroke, it should be noted that OAC can simultaneously increase the risk of bleeding with adverse consequences.

Vitamin K antagonists (warfarin) are still recommended as first-line therapy in patients with AF worldwide. Since 2010, four large, multicenter, double-blind, randomized controlled trials (RCT) regarding direct oral anticoagulants (DOACs) including apixaban,^[6] dabigatran,^[7] edoxaban,^[8] and rivaroxaban,^[9] demonstrated that DOACs have similar efficacy to warfarin in primary and secondary prevention of stroke but are associated with about half the frequency of ICH. American stroke association/American heart association guidelines for the management of AIS with AF recommend DOACs or warfarin for patients with nonvalvular AF with high-risk stroke risk factors. However, there are still some issues that need further clarification. The four RCT clinical trials comparing DOACs and warfarin excluded patients with AIS associated with AF, and there remains a lack of large randomized controlled clinical trials addressing the optimal timing of DOACs for cardiogenic embolism in AIS or TIA, presumably due to concerns regarding the risk of hemorrhagic transformation of ischemic brain tissue or because of concerns for additional intracranial hemorrhage.^[10] A growing body of research shows that cerebral small vessel disease (CSVD), as an independent condition, causes adverse effects during anticoagulantion therapy in AIS patients with cardiogenic embolism. A recent study^[11] suggests that the presence of cerebral microbleeds (CMBs) is not only associated with an increased risk of ICH in patients on OAC, but also associated with an increased risk of ischemic stroke during follow-up. Moreover, another study^[12] showed that higher composite CSVD score is associated with increasing risk of ischemic stroke. Studies further revealed that CSVD is associated with an unfavorable outcome in stroke patients on OAC.^[13] Criteria to select anticoagulants (DOACs or warfarin) for AIS or TIA patients with AF and CSVD needs to be further clarified.

Therefore, in this retrospective study, we aimed to compare DOACs with warfarin in with regard to reduction of stroke recurrence and the risk of ICH for AIS or TIA patients with AF and CSVD.

Patients and Methods

Study design and patient population

We conducted a retrospective study with consecutive patients who underwent AIS or TIA with AF and CSVD from January 1, 2017 to December 31, 2019 in the Stroke Center, Beijing Luhe Hospital, Capital Medical University.

Inclusion and exclusion criteria

Patients with AF aged ≥18 years, had an AIS or TIA and had been prescribed OACs at discharge were included in this study. AIS is defined as a focal neurological deficit with acute onset and presence of a corresponding lesion on diffusion weighted imaging (DWI). TIA is defined as a transient, acute-onset focal neurological deficit of presumed ischemic origin.^[13] AF defined as nonvalvular AF, either preexisting or in-hospital. CSVD is a term used for different pathological processes that affect the small vessels of the brain, including small arteries, arterioles, capillaries, and small veins.^[14],[15] CSVD was evaluated by neuroimaging markers, including white matter hyperintensity or cerebral CMBs in this study.^[16] OAC with DOACs or warfarin was continued (for those already on anticoagulation), started, or restarted within 1 month after the index event. Patients with mechanical heart valves were excluded.

Using of oral anticoagulation

The selection of anticoagulant drugs (warfarin vs. DOACs) is based on the specific conditions of the patient (the size of the brain infarct, the presence of hemorrhagic transformation, relevant comorbidities such as renal failure, patient age), indications of anticoagulant drugs, characteristics of the drugs, economic capacity of the patient and other factors. Final anticoagulation was decided by an attending physician and in conjunction with patient preference. DOACs are dabigatran (110 mg bid or 150 mg bid) or rivaroxaban (15–20 mg qd). Warfarin is required with an INR goal of 2–3. Warfarin was initially used in combination with low molecular weight heparin within 3–5 days for rapid anticoagulant action.

Magnetic resonance imaging image

All patients received magnetic resonance imaging (MRI) with a sequence including axial DWI and apparent diffusion coefficient, T1-weighted imaging (T1WI), T2WI, and axial T2-weighted fluid-attenuated inversion recovery imaging with Susceptibility-weighted imaging using Siemens 3.0 T magnetic resonance scan after AIS or TIA within 7 days.

Follow-up

Patients are followed up using a standardized form at 1, 6, and 12 months via an outpatient visit or telephone interviews. We collected basic information along with date of ICH, recurrent events, and death. Functional outcome was assessed using the modified Rankin scale. The basic information included age, sex, previous medical history (hypertension, diabetes, hypercholesteremia, smoking, stroke, coronary heart disease), NIH Stroke Scale (NIHSS) score, CHA2DS2-VASc score, HAS-BLED score and treatment for stroke or TIA.

Study endpoints

The safety endpoint of this study was sICH. sICH was defined as any ICH leading to neurologic deterioration (increase NIHSS>4 points^[17]). The efficacy endpoint was recurrent ischemic events similar to the prior study that focuses on anticoagulation after AIS or TIA.^{[7],[18],[19]} Recurrence of ischemic events was defined as a new clinical event with neurological deficit consistent with AIS or TIA during follow-up.^{[7],[18],[19]}

Statistical analyses

For categorical variables, the number and the proportions are presented and the groups were compared using Chi-square tests or the continuity correction Chi-square tests. For continuous variables, the mean and standard deviations or medians with IQRs are presented and the groups were compared using the Mann–Whitney U-test if not normally distributed or the t-test if normally distributed; the safety and efficacy endpoint was progression-free survival assessed by the log-rank test. The significance level was set at P < 0.05. Statistical analysis was performed using SPSS version 23 (Armonk, NY, IBM Inc.).

Results

Between January 1, 2017 to December 31, 2019, 973 patients with AIS (n = 864), and TIA (n = 109) with nonvalvular AF were included in this study from our hospital. Ninety eight patients did not complete MRI, and 290 patients completed MRI but did not show cerebellar vascular disease. A total of 585 people who were eligible for follow-up, 43 of whom individuals who changed their treatment regimen midway in our follow-up; our final analysis included 542 participants in this study.

Compared with patients receiving DOACs and warfarin, the proportion of patients with AIS or TIA as the index event were well balanced (AIS 80% in DOACs group versus 84% in the warfarin group, P = 0.29, and TIA 20% in DOACs group versus 16% in warfarin group; P = 0.88). There were no significant differences in vascular risk factors (such as age, previous stroke, hypertension, diabetes, hyperlipidemia, smoking) between DOACs and warfarin groups [Table 1].

Table 1: Baseline characteristics of patients with atrial fibrillation and cerebral small vessel disease indirect, non-Vitamin K antagonist oral anticoagulant and warfarin groups

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There were no significant differences in NIHSS score at baseline or CHA2DS2-VASc score among DOACs and warfarin groups. Patients in the DOACs group had a higher HAS-BLED score compared with patients in the warfarin group (4 vs. 3, P < 0.04) [Table 1]. In the DOACs group, 18% of patients received recombinant tissue type plasminogen activator treatment, 21% of patients received mechanical thrombectomy, and 1% of patients received intra-arterial therapy including bridging. In the warfarin group, 20% of patients received t-PA treatment, 23% of patients received mechanical thrombectomy, and 1% of patients received intra-arterial including bridging. There were significant differences in the time from index event to anticoagulation among the DOACs and warfarin groups (6 days vs. 9 days, P < 0.04) [Table 1]. Patients in the DOACs group had shorter length of stay in the hospital compared with patients in the warfarin group (8 vs. 12, P < 0.03) [Table 1].

There were no significant differences in the TOAST (Trial of Org 10172 in Acute Stroke Treatment) subtype of stroke (cardioembolic, large vessel disease, small artery disease, and multiple causes) between DOACs and warfarin groups [Table 1]. There were no significant differences in total white matter hyperintensity (age-related white matter changes) score from MRI imaging between the two groups. There were a significant differences in CMBs presents compared with DOACs and warfarin groups (7 vs. 4, P = 0.03).

There was no occurrence of a patient developing sICH during follow-up in both groups within 1 month of the index event. There were two patients with recurrent event (TIA) in the DOACs group and one patient with recurrent event (AIS) in the warfarin group during follow-up within 1 month. There was one patient with sICH which occurred during follow-up in the 2–12 months periods while there were 4 patients in the warfarin group with sICH which occurred during follow-up in the 2–12 periods. There was a significant difference in sICH between the two groups (P = 0.03). Recurrent events during 2–12 months follow-up did not differ between the two groups (5% vs. 4%, P = 0.68) [Table 2] and [Figure 1].

Table 2: Endpoints for patients in direct, non-Vitamin K antagonist oral anticoagulant and warfarin groups during follow-up

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Figure 1: Survival curves are shown for freedom from symptomatic intracranial hemorrhage and stroke in patients with atrial fibrillation and cerebral small vessel disease. DOACs: Direct, nonVitamin K antagonist oral anticoagulant

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Discussion

The present study demonstrates that (1) DOACs exert an equivalent effect compared with warfarin in preventing recurrence stroke in AIS or TIA patients with AF and CSVD when followed over 12 months (recurrent event 5% vs. 4%). (2) DOACs demonstrated a lower risk of bleeding compared to warfarin in AIS patients with AF and CSVD followed over 12 months (sICH 0.3% vs. 2%). (3) DOACs can be used earlier than warfarin and do not increase the risk of bleeding after stroke in 1 month (6 days vs. 9 days). and (4) patients in the DOACs group had a shorter length of stay in the hospital compared with patients in the warfarin group (8 days vs. 12 days).

It is important to evaluate the risk-benefit balance of antithrombotic drugs in patients with AF. OAC can reduce the risk of stroke recurrence by two-thirds and is associated with a lower risk of ICH.^[4] CHA2DS2-VASc score^[20] is the most popular score to evaluate the risk of ischemia event recurrence, and HAS-BLED^[21] score is used to identify patients at the highest risk of bleeding.

Our findings demonstrated that the rate of the complication with ICH in the DOACs group was less than two thirds the rate in warfarin group, indicating an important advantage of DOACs compared with warfarin in patients in AIS or TIA with AF and CSVD. The rate of ICH in all patients was 0.9%/years, which is similar to the CROMIS-2 trials.^[11] The CROMIS-2^[11] study recruited 1,490 participants with AIS and AF and determined that the ICH rate in patients with CMBs was 9.8/1,000 patient-years, compared with 2.6/1,000 patient-years in those without CMBs. This finding indicated that compared with those who remained free of ICH, patients who had an ICH during follow-up were more likely to have been treated with warfarin than a DOACs. In patients with CSVD with higher HAS-BLED scores, DOACs had a lower risk of ICH and a better safety profile than warfarin in long-term clinical use.

The observed recurrence rate (AIS or TIA) is 4.6%/years in all patients, with 4.8%/years in DOACs group and 4.2%/years in warfarin group. DOACs demonstrated the same effect of recurrence event prevention compared with warfarin. However, the observed recurrence rate was higher than previously observed studies, such as RELY (0.92%/years)^[18] ARISTOTLE (0.97%/years),^[22] and ROCKET-AF (1.34%/years).^[23] There are three main reasons: (1) all patients enrolled in this study had stroke or TIA, while only a small proportion of patients in other studies had stroke or TIA (20% in RELY,^[18] 19% in ARISTOTLE,^[22] 52% in ROCKET-AF^[23]), (2) the CHA2DS2-VASc score, an important index used to evaluate the recurrence of stroke in AF, is higher in this study (5 scores) than in the other three studies (the CHADS scores: RELY^[18] with 2.2 scores, ARISTOTLE^[22] with 2.1 scores, ROCKET-AF^[23] with 3.5 scores), and (3) patients with CSVD are associated with increasing risk of recurrence events.

Our findings showed that patients in the DOACs group had shorter hospital length of stay when compared with patients in the warfarin group (8 days vs. 12 days). Prior studies^[24] revealed that hospitalization length was reduced with rivaroxaban compared with warfarin (4.0 days vs. 6.0 days). There are two main reasons. First, patients in the DOACs groups were started on an anticoagulant earlier than in warfarin groups (6 days vs. 9 days). Clinicians are more likely to write a prescription for an anticoagulant during hospitalization rather than after discharge, and earlier anticoagulant initiation may shorten the length of the hospital stay. A prospective cohort study^[19] revealed that DOACs can be started early after AIS in the majority of patients (with a median delay of 5 days) and showed that early start of DOACs did not result in ICH occurrence. Randomized trials^[10] have investigated the risks and benefits of early DOACs initiation (most with a median delay of 3–5 days) in mild-to-moderate AF-associated ischemic stroke. These studies demonstrated that early DOAC treatment was associated with a low frequency of clinically sICH or surrogate hemorrhagic lesions on MRI scans. Starting DOACs early,^[19] especially while the patient is still hospitalized, may have beneficial effects beyond a reduction of early recurrent ischemic events, as well as potentially enhancing the patient's clinical medication compliance than if drugs have to be started after hospital discharge. Second, warfarin needs to be adjusted according to the coagulation index INR value (the general target range of INR is 2–3), and many foods and drugs can affect the action of warfarin and the INR value. Warfarin was initially used in combination with low molecular weight heparin within 3–5 days for rapid anticoagulant action, which may prolong length of hospitalization. Alternatively, DOACs can be taken in fixed doses with no need to monitor coagulation indicators.

There may be some possible limitations in this study. First, we report on a single center and not a multicenter registry, which limits the generalizability of our results. Secondly, this is a retrospective study and not a randomized controlled study, with the selection of anticoagulant drugs (warfarin vs. DOACs) decided by attending physician and patient together instead of using randomization, necessitating a prospective RCT research.

Conclusion

In this study, DOACs were associated with lower risks of sICH and similar risks of the ischemic event than warfarin in AIS or TIA patients with AF and CSVD. Patients in the DOACs group had a shorter length of hospital stay in the hospital compared with patients in the warfarin group. DOACs can be used earlier than warfarin without increased risk of sICH in patients with AF and CSVD. Starting DOACs early may have beneficial effects except for a reduction of early recurrent ischemic events, as well as can enhance the patient's clinical medication compliance. DOACs may be a better option than warfarin for stroke prevention in AF with CSVD.

Declaration of ethical approval and patient consent

Ethics committee approval and patient consent were not applicable for the retrospective study.

Financial support and sponsorship

This work was supported by the National Nature Science Foundation of China (No.21707095, No.82072549 and No.81871838).

Conflicts of interest

Prof. Yuchuan Ding is an Editor-in-Chief and Prof. Xiaokun Geng is an Editorial Board member of Environmental Disease. The article was subject to the journal's standard procedures, with peer review handled independently of them and their research groups.

References

1.	Wu S, Wu B, Liu M, Chen Z, Wang W, Anderson CS, et al. Stroke in China: Advances and challenges in epidemiology, prevention, and management. Lancet Neurol 2019;18:394-405.
2.	Stone CR, Geng X, Ding Y. From big data to battling disease: Notes from the frontiers of cerebrovascular science. Neurol Res 2019;41:679-80.
3.	Marini C, De Santis F, Sacco S, Russo T, Olivieri L, Totaro R, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: Results from a population-based study. Stroke 2005;36:1115-9.
4.	Seiffge DJ, De Marchis GM, Koga M, Paciaroni M, Wilson D, Cappellari M, et al. Ischemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation. Ann Neurol 2020;87:677-87.
5.	Dowlatshahi D, Butcher KS, Asdaghi N, Nahirniak S, Bernbaum ML, Giulivi A, et al. Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke 2012;43:1812-7.
6.	Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
7.	Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
8.	Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
9.	Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
10.	Seiffge DJ, Werring DJ, Paciaroni M, Dawson J, Warach S, Milling TJ, et al. Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. Lancet Neurol 2019;18:117-26.
11.	Wilson D, Ambler G, Shakeshaft C, Brown MM, Charidimou A, Al-Shahi Salman R, et al. Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): A multicentre observational cohort study. Lancet Neurol 2018;17:539-47.
12.	Du H, Wilson D, Ambler G, Banerjee G, Shakeshaft C, Cohen H, et al. Small vessel disease and ischemic stroke risk during anticoagulation for atrial fibrillation after cerebral ischemia. Stroke 2021;52:91-9.
13.	Hert L, Polymeris AA, Schaedelin S, Lieb J, Seiffge DJ, Traenka C, et al. Small vessel disease is associated with an unfavourable outcome in stroke patients on oral anticoagulation. Eur Stroke J 2020;5:63-72.
14.	Yates PA, Villemagne VL, Ellis KA, Desmond PM, Masters CL, Rowe CC. Cerebral microbleeds: A review of clinical, genetic, and neuroimaging associations. Front Neurol 2014;4:205.
15.	Ungvari Z, Tarantini S, Kirkpatrick AC, Csiszar A, Prodan CI. Cerebral microhemorrhages: Mechanisms, consequences, and prevention. Am J Physiol Heart Circ Physiol 2017;312:H1128-43.
16.	Chen X, Wang J, Shan Y, Cai W, Liu S, Hu M, et al. Cerebral small vessel disease: Neuroimaging markers and clinical implication. J Neurol 2019;266:2347-62.
17.	Wityk RJ, Pessin MS, Kaplan RF, Caplan LR. Serial assessment of acute stroke using the NIH Stroke Scale. Stroke 1994;25:362-5.
18.	Diener HC, Connolly SJ, Ezekowitz MD, Wallentin L, Reilly PA, Yang S, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: A subgroup analysis of the RE-LY trial. Lancet Neurol 2010;9:1157-63.
19.	Seiffge DJ, Traenka C, Polymeris A, Hert L, Peters N, Lyrer P, et al. Early start of DOAC after ischemic stroke: Risk of intracranial hemorrhage and recurrent events. Neurology 2016;87:1856-62.
20.	Melgaard L, Gorst-Rasmussen A, Lane DA, Rasmussen LH, Larsen TB, Lip GY. Assessment of the CHA2DS2-VASc score in predicting ischemic stroke, thromboembolism, and death in patients with heart failure with and without atrial fibrillation. JAMA 2015;314:1030-8.
21.	Zhu W, He W, Guo L, Wang X, Hong K. The HAS-BLED score for predicting major bleeding risk in anticoagulated patients with atrial fibrillation: A systematic review and meta-analysis. Clin Cardiol 2015;38:555-61.
22.	Easton JD, Lopes RD, Bahit MC, Wojdyla DM, Granger CB, Wallentin L, et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: A subgroup analysis of the ARISTOTLE trial. Lancet Neurol 2012;11:503-11.
23.	Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: A subgroup analysis of ROCKET AF. Lancet Neurol 2012;11:315-22.
24.	Hong KS, Kwon SU, Lee SH, Lee JS, Kim YJ, Song TJ, et al. Rivaroxaban vs warfarin sodium in the ultra-early period after atrial fibrillation-related mild ischemic stroke: A randomized clinical trial. JAMA Neurol 2017;74:1206-15.