Recurrent ischemic stroke in atrial fibrillation with non-vitamin K antagonist oral anticoagulation

Recurrent ischemic stroke in atrial fibrillation with non-vitamin K antagonist oral anticoagulation

Journal of Clinical Neuroscience 64 (2019) 127–133 Contents lists available at ScienceDirect Journal of Clinical Neuroscience journal homepage: www...

656KB Sizes 6 Downloads 48 Views

Journal of Clinical Neuroscience 64 (2019) 127–133

Contents lists available at ScienceDirect

Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn

Clinical study

Recurrent ischemic stroke in atrial fibrillation with non-vitamin K antagonist oral anticoagulation Ho Geol Woo a, Inyoung Chung b, Dong Seok Gwak b, Baik Kyun Kim c, Beom Joon Kim d, Hee-Joon Bae d, Moon-Ku Han d,⇑ a

Department of Neurology, Ewha Womans University, College of Medicine, Seoul, Republic of Korea Department of Neurology, Seoul National University Bundang Hospital, Republic of Korea Department of Critical Care Medicine, Seoul National University Bundang Hospital, Republic of Korea d Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea b c

a r t i c l e

i n f o

Article history: Received 1 November 2018 Accepted 21 March 2019

Keywords: Non-vitamin K antagonist oral anticoagulants Major vessel occlusion Stroke

a b s t r a c t The etiology or rate of recurrent ischemic stroke according to dosing methods including drug adherence in patients taking non-vitamin K antagonist oral anticoagulants (NOACs) remain uncertain. We investigated the association between dosing methods including drug adherence achieved with NOACs and the presence of major vessel occlusion (MVO) in patients with ischemic stroke with non-valvular atrial fibrillation (NVAF). From July 2013 through December 2016, 120 patients with recurrent ischemic stroke with NVAF on NOACs were retrospectively analyzed. Patients taking non-standard doses of NOACs were divided into the missed dose group that discontinued NOACs for 48 h prior to arrival, and the underdose group that used lower doses of NOACs. A logistic regression analysis was performed to determine the association between MVO and dosing methods including drug adherence. There were 60 (50.0%), 39 (32.5%), and 21 (17.5%) patients, respectively, in the standard dose, under-dose, and missed dose groups. Twelve patients (20.0%) in the standard dose group, 15 (38.5%) in the under-dose group, and 13 (61.9%) in the missed dose group had MVO. MVO was significantly higher in the missed dose group than in the standard dose and under-dose groups (P = 0.002). In patients with ischemic stroke with NVAF, who are on NOACs, anticoagulation caused by missed or lowered doses of NOACs was significantly associated with MVO in patients with recurrent cardioembolic stroke. Ó 2019 Elsevier Ltd. All rights reserved.

1. Introduction Non-vitamin K antagonist oral anticoagulants (NOACs; dabigatran, rivaroxaban, apixaban, and edoxaban) have been increasingly used as alternatives to warfarin for the secondary prevention of ischemic strokes in patients with non-valvular atrial fibrillation (NVAF) [1]. Clinical trials have demonstrated that recurrent ischemic strokes can be equally prevented in patient with NVAF and previous ischemic stroke using NOACs and warfarin (NOAC: 1.8–2.9% per year; warfarin: 1.8–2.2% per year) [2–9], with equally less intracranial hemorrhages (ICH) [10]. Asian patients are more sensitive to warfarin and have unacceptably high rates of ICH even when the international normalized ratio (INR) is ideally maintained [11]. Therefore, NOACs are recognized to be important in ⇑ Corresponding author at: Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173 Beon-Gil, Seongnam, Gyeonggi-do 13620, Republic of Korea. E-mail address: [email protected] (M.-K. Han). https://doi.org/10.1016/j.jocn.2019.03.037 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.

Asian patients who are prone to major bleeding, including ICH [2,11]. A meta-analysis showed that NOACs at the standard dose had superior efficacy and safety when compared with warfarin, whereas lower doses of NOACs were might not be as effective for prevention against ischemic stroke but safer than warfarin for ICH in Asian patients [12]. Therefore, the use of low dose NOACs in clinical practice is more common in Asia than in Europe and North America [13–15]. However, evidence on reduced-dose regimens of NOACs from clinical practice is still insufficient. Although low dose rivaroxaban has been approved in Japan and Taiwan for use in stroke prevention based on a Japanese reduced-dose trial, a recent metaanalysis among Asian patients demonstrated that standard-dose NOACs represent a more appropriate therapeutic option than low-dose NOACs [16,17]. In other clinical trials, that have randomized patients with NVAF, higher doses of NOACs were found to be associated with greater reductions in ischemic stroke, whereas lower doses were associated with smaller reductions or increases in stroke [2,4].

128

H.G. Woo et al. / Journal of Clinical Neuroscience 64 (2019) 127–133

Major vessel occlusion (MVO) is associated with poor outcomes compared with cases of ischemic stroke without large vessel occlusion [18]. A previous study reported a correlation between the intensity of anticoagulation and the clinical outcome and predicted MVO in patients with recurrent acute ischemic stroke who were taking warfarin [19]. However, the etiology or rate of recurrent ischemic stroke according to dosing methods including drug adherence in patients taking NOACs remain uncertain. We hypothesized that dosing methods including drug adherence in Asian patients with acute ischemic stroke and NVAF who are on NOACs is associated with MVO. 2. Methods The institutional review board approved this retrospective study and waived the need for an informed consent. 2.1. Subjects We retrospectively reviewed patients suspected to have acute stroke at one tertiary stroke center from July 2013 through December 2016. Among these patients, all patients who met the following inclusion criteria were included: (1) patients with a history of transient ischemic attack or ischemic stroke, (2) patients taking NOACs for NVAF, and (3) patients diagnosed with cardioembolic stroke

according the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) classification by the magnetic resonance imaging (MRI)based algorithm for acute ischemic stroke subtype classification (MAGIC) [20,21]. Patients with any of the following were excluded: (1) poor quality of computerized tomography angiography (CTA) and magnetic resonance angiography (MRA) images, (2) lost to follow-up (Fig. 1). 2.2. Clinical assessment The baseline demographics (age, sex, body weight, and height), clinical characteristics (risk factors, concomitant antiplatelet, time from onset of symptoms to arrival, pre-modified Rankin Scale [mRS], and initial National Institute of Health Stroke Severity Scale [NIHSS] score), dosage of NOACs administered, and TOAST classification were documented. Routine laboratory results of tests done in the emergency room, including coagulation tests (activated partial thromboplastin time [aPTT], prothrombin time [PT], and INR), and renal function (creatinine, and estimated glomerular filtration rate [eGFR]), were collected from the registry. From these data, we calculated CHA2DS2-VASc score, designed to predict the risk of ischemic stroke in patients with NVAF. The radiologic findings were collected at admission. A vessel occlusion was defined as the complete signal loss of distal flow to the site of occlusion on CTA or MRA. MVOs were defined as

Fig. 1. Flowchart of patient inclusion.

H.G. Woo et al. / Journal of Clinical Neuroscience 64 (2019) 127–133

occlusions in the internal carotid artery (ICA), the middle cerebral artery (MCA) (M1 and M2 segments), the basilar artery (BA), the posterior cerebral artery (PCA) (P1 segment), the anterior cerebral artery (ACA) (A1 segment), and the vertebral artery (VA). The angiographic data were read by an experienced neuroradiologist and reviewed by two neurologists. The sites of occlusion were established by two-reader consensus (M.K.H and H.G.W). There are contemporary guidelines that suggest using reduced dosing regimens in certain patient conditions. The use of 110 mg of dabigatran twice a day is suggested in patients 80 years old, or with an eGFR of 30–49 mL/min. The use of 15 mg of rivaroxaban once a day is suggested if the eGRF is 30–49 mL/min. The use of 2.5 mg of apixaban twice a day is suggested, if two of the following three criteria are present: age 80 years, serum creatinine level 1.5 mg/dL, and body weight 60 kg. The use of 30 mg of edoxaban once a day is suggested if the eGFR is 30–50 mL/min, the body weight is 60 kg, or if there is concomitant use of P-glycoprotein inhibitors [22,23]. Patients were classified into the three groups according to dosing patterns including drug adherence with NOACs: standard dose of NOAC, under-dose of NOAC, and missed dose of NOAC. The criteria for the standard doses of NOACs were specific to each NOAC, according to patient characteristics including renal function, weight, age, and concomitant medications. Under-dose of NOAC was defined as the use of an off-label dose of NOAC in patients who did not fit the dose reduction criteria for NOACs. Missed dose of NOAC was defined as the discontinuation of NOACs where the last dose of NOAC was taken 48 h prior to the ischemic stroke. The time period of 48 h was chosen since it amounts to four times the duration of the plasma half-live of NOACs, depending on the renal function of the patient. In addition, patients could be considered for thrombolysis after this period has lapsed.

2.3. Study outcomes The neurological severity of the stroke at admission was determined using the NIHSS score. Functional disability was determined by the mRS score at discharge. A poor functional outcome was defined as a severe disability at discharge (mRS of 3–6) or inhospital mortality (mRS of 6).

2.4. Statistical analysis Statistical analyses were performed using SPSS 22.0 for Windows (IBM Corp. Armonk, NY, USA). The clinical and laboratory findings and outcomes were compared between the groups with and without MVO. The outcomes were also compared between the three groups based on the dose of NOACs used. The normal distributions of continuous variables were evaluated using the Kolmogorov-Smirnov test. If the variable was normally distributed, the independent t test was used. If the variable was not normally distributed, the Mann-Whitney test was performed. Data were summarized using standard descriptive statistics. All normally distributed variables were reported as mean ± standard deviation, and non-normally distributed variables were presented as medians (interquartile range). Categorical variables were presented as frequencies and percentages. The Pearson chi-square test was performed. P value below 0.05 was considered statistically significant. A logistic regression analysis was performed to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs) of the association between MVOs and dosing methods including drug adherence with NOACs.

129

3. Results 3.1. Study population From our initial database of 5482 patients, 862 patients were excluded as they had hemorrhagic strokes. Of the 4620 remaining patients, 999 patients had a history of either transient ischemic attack or ischemic stroke. Among them, 145 patients took NOAC for NVAF before admission. The final study population included 120 patients with recurrent cardioembolic ischemic strokes according to the TOAST classification by MAGIC, including 27 patients treated with dabigatran (22.5%), 51 patients treated with rivaroxaban (42.5%), 30 patients treated with apixaban (25.0%), and 12 patients treated with edoxaban (10.0%) (Fig. 1).

3.2. Baseline characteristics and clinical characteristics of the patients with and without major vessel occlusion The mean age of the 120 patients was 74.1 ± 9.0 years, and 59.2% of patients were male. MVOs were noted in 40 (33.3%) of the study subjects. The site of vessel occlusion, in the order of frequency, was as follows: MCA M1 (41, 34.2%), MCA M2 (27, 22.5%), ICA (19, 15.8%), PCA (13, 10.8%), VA (12, 10.0%), BA (7, 5.8%), and ACA (1, 0.8%). The baseline demographics and clinical characteristics of the patients with and without MVO are listed in Table 1. No significant differences were found in the demographic information, risk factors, and concomitant antiplatelet between the two groups. The mean time between the onset of symptoms and arrival was not different between the two groups. The INR value in patients with MVO was significantly lower than that in patients without MVO (P = 0.002). No other significant differences were found among the laboratory findings between the two groups. Six (15.0%) patients were treated with intravenous (IV) tissue plasminogen activator (tPA), and 20 patients (50.0%) were treated with intraarterial (IA) thrombectomy. No significant difference in pre-mRS was found between the two groups at admission. The median NIHSS scores at admission in patients with MVO were significantly higher than in patients without MVO (P < 0.001). The rates of MVO were significantly lower in patients receiving standard doses of NOACs (20.0%) than those in patients receiving under-doses of NOACs (38.5%) and those in patients who had missed doses of NOACs (61.9%) (P = 0.002) (Table 1). The median NIHSS scores at discharge, and mRS at discharge, at three months, and at one year in patients without MVO were significantly lower than those in patients with MVO (P < 0.001, P < 0.001, P = 0.016, and P = 0.031, respectively). The rate of favorable functional outcomes at discharge was significantly higher in patients without MVO than in patients with MVO (P = 0.001), The rates of favorable functional outcomes at three months and at one year also tended be higher in patients without MVO than in patients with MVO. However, they were not significantly different between the two groups (P = 0.117 and P = 0.117, respectively). The mortality rates in patients without MVO at three months and at one year (5.0% and 7.5%, respectively) were not significantly different from those in patients with MVO (7.5% and 7.5%, respectively) (Table 2). Table 3 shows the clinical outcomes of the patients in relation to the dosing methods including with drug adherence of NOACs. Sixty patients (50.0%) were using standard doses of NOACs, 39 (32.5%) were undertreated with under-doses of NOACs, and 21 (17.5%) had missed doses of NOACs. There were no significant differences between the dosing methods including with drug adherence among the different NOACs. The median duration of NOACs caseation in the missed dose group was 3 days. The median initial

130

H.G. Woo et al. / Journal of Clinical Neuroscience 64 (2019) 127–133

Table 1 Baseline demographics and clinical characteristics among patients with and without major vessel occlusion (MVO). MVO (+) (n = 40)

MVO () (n = 80)

P value

Demographics Age, mean (SD) Sex, male/female, n (%)

75.0 (8.7) 22/18 (55.0/45.0)

73.7 (9.2) 49/31 (61.3/38.8)

0.486 0.511

Intensity of NOACs, n (%) Standard dose Under-dose Missed dose

12 (20.0) 15 (38.5) 13 (61.9)

48 (80.0) 24 (61.5) 8 (38.1)

Comorbidities, n (%) Hypertension Diabetes mellitus Hyperlipidemia Congestive heart failure Cancer Smoking

31 (77.5) 13 (32.5) 19 (47.5) 8 (20.0) 0 13 (32.5)

68 (85.0) 30 (37.5) 38 (47.5) 16 (20.0) 4 (5.0) 28 (35.0)

0.002

0.308 0.590 1.000 1.000 NC 0.785

Concomitant antiplatelet

18 (22.5)

5 (12.5)

0.226

CHA2DS2-VASc score, mean (SD)

4.6 (1.5)

4.4 (1.5)

0.667

Symptom onset to arrival time, minutes, mean (SD)

75.5 (8.5)

74.3 (9.2)

0.507

Laboratory finding, mean (SD) Initial eGFR Blood urea nitrogen, mg/dL Creatinine, mg/dL Glucose, mg/dL Glycated hemoglobin (HbA1c) Total cholesterol, mg/dL HDL cholesterol, mg/dL Triglyceride, mg/dL LDL cholesterol, mg/dL International Normalized Ratio

71.9 (23.8) 17.7 (4.8) 1.0 (0.3) 143.9 (59.1) 6.4 (1.6) 171.5 (140.6) 68.6 (151.2) 118.2 (149.6) 106.6 (148.2) 1.2 (0.2)

80.1 (22.7) 16.8 (5.8) 0.9 (0.3) 135.9 (51.8) 6.2 (0.9) 140.2 (34.4) 43.8 (9.7) 100.1 (40.5) 77.4 (27.3) 1.4 (0.5)

0.068 0.426 0.431 0.450 0.351 0.062 0.307 0.458 0.089 0.002

Intravenous thrombolysis, n (%) Intraarterial thrombectomy, n (%) Pre mRS, median (IQR) Initial NIHSS, median (IQR)

6 (15.0) 20 (50.0) 0 (0.0–1.0) 16.5 (12.0–20.8)

0 0 0 (0.0–1.0) 3.0 (1.0–6.8)

NC NC 0.227 <0.001

Abbreviations: SD, Standard deviation; NOACs, non-vitamin K antagonist oral anticoagulants; eGFR, estimated glomerular filtration rate; HDL, high density lipoprotein; LDL, low density lipoprotein; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Severity Scale; IQR, Interquartile Range.

Table 2 Clinical outcome at discharge, three months, and one year after major vessel occlusion (MVO). MVO (+) (n = 40)

MVO () (n = 80)

P value

NIHSS, median (IQR) Discharge mRS, median (IQR)

4.0 (2.0–12.0)

2.0 (1.0–4.0)

<0.001

Discharge 3 months 1 year

4.0 (2.0–5.0) 3.0 (1.0–4.0) 3.0 (1.0–4.0)

2.0 (1.0–4.0) 1.0 (0.0–4.0) 1.0 (1.0–4.0)

<0.001 0.016 0.031

mRS  2, n (%) Discharge 3 months 1 year

13 (32.5) 19 (47.5) 19 (47.5)

51 (63.8) 50 (62.5) 50 (62.5)

0.001 0.117 0.117

Mortality at 3 months, n (%) Mortality at 1 year, n (%)

3 (7.5) 3 (7.5)

4 (5.0) 6 (7.5)

0.582 1.000

the three groups. The values of INR between the 3 groups in standard dose, under-dose, and missed dose group were 1.4 ± 0.5, 1.3 ± 0.4, and 1.1 ± 0.3, respectively (P = 0.002). Moreover, levels of aPTT between the 3 groups in standard dose, under-dose, and missed dose group were 44.2 ± 11.7 sec, 43.9 ± 14.4 sec, and 35.4 ± 1.7 sec, respectively (P < 0.001). In subgroup analysis, values of INR and levels of aPTT were significantly different between the standard dose group and the missed dose group (P < 0.001 and P < 0.001, respectively) and between the under-dose group and the missed dose group (P = 0.001 and P = 0.006, respectively). However, there are no significant difference in values of INR and levels of aPTT between the standard dose group and the under-dose group. Other laboratory findings were not significantly different in between the groups (Table 3).

Abbreviations: NIHSS, National Institute of Health Stroke Severity Scale; IQR, Interquartile Range; mRS, modified Rankin Scale.

3.3. Relationships between predictors and major vessel occlusion

NIHSS scores was significantly lower in patients who received standard doses of NOACs (P = 0.007) than in those who received under-doses and missed doses of NOACs. In post hoc subgroup analysis, significant differences were found between the standard dose group and the missed dose group and between the underdose group and the missed dose group (P = 0.002 and P = 0.043, respectively). But, no significant differences were found between the standard dose group and the under-dose group. The median NIHSS scores at discharge and median mRS at discharge, three months, and one year were not significantly different between

Receiving an under-dose of NOACs was associated with a higher rate of MVO (OR 2.50; 95% CI 1.01–6.17; P = 0.047). And missing doses of NOACs was associated with an even higher rate of MVO (OR 6.50; 95% CI 2.20–19.22; P = 0.001). This association remained even after adjustment for the initial NIHSS score and INR (Table 4). The calculated area under the receiver operating characteristic (ROC) curve for the unadjusted model, for model 2 (adjusted for INR), and for model 3 (adjusted for initial NIHSS and INR) were 0.68 (95% CI 0.58–0.78; P = 0.001), 0.75 (95% CI 0.66–0.84; P < 0.001), and 0.91 (95% CI 0.85–0.97; P < 0.001), respectively (Fig. 2).

131

H.G. Woo et al. / Journal of Clinical Neuroscience 64 (2019) 127–133 Table 3 Clinical outcome at discharge, after three months, and after one year in relation to the intensities of non-vitamin K antagonist oral anticoagulants (NOACs). Standard dose (n = 60)

Under-dose (n = 39)

Missed dose (n = 21)

P value

NOACs, n (%) Dabigatran Rivaroxaban Apixaban Edoxaban

17 (28.3) 22 (36.7) 16 (26.7) 5 (8.3)

8 (20.5) 18 (46.2) 8 (20.5) 5 (12.8)

2 (9.5) 11 (52.4) 6 (28.6) 2 (9.5)

Duration of NOACs caseation, median (IQR)

0

0

3.0 (2.0–8.5)

<0.001

NIHSS, median (IQR) Initial Discharge

4.0 (2.0–9.0) 2.0 (1.0–6.0)

7.0 (2.0–17.0) 2.0 (1.0–4.0)

14.0 (5.0–20.0) 4.0 (2.0–9.0)

0.007 0.397

mRS, median (IQR) Discharge 3 months 1 year

2.0 (1.0–4.0) 2.0 (0.0–4.0) 2.0 (0.0–4.0)

2.0 (1.0–4.0) 2.0 (0.0–3.0) 1.0 (0.0–3.0)

3.0 (1.0–4.0) 2.0 (1.0–4.0) 2.0 (1.0–4.0)

0.780 0.609 0.572

IV therapy, n (%) IA therapy, n (%)

0 5 (25.0)

0 8 (40.0)

6 7 (35.0)

NC 0.022

0.596

Abbreviations: IQR, Interquartile Range; NIHSS, National Institute of Health Stroke Severity Scale; mRS, modified Rankin Scale; IV, intravenous; IA, intraarterial.

Table 4 Association between the intensity of non-vitamin K antagonist oral anticoagulants (NOACs) and major vessel occlusion.

Intensity of NOACs Standard dose Under-dose Missed dose y à

Model 1, Unadjusted, Odd ratio (95% CI)

P value

Model 2, yOdd ratio (95% CI)

Model 3, àOdd ratio (95% CI)

Reference 2.50 (1.01–6.17) 6.50 (2.20–19.22)

0.047 0.001

Reference 2.34 (0.92–5.97) 4.27 (1.35–13.5)

Reference 1.54 (0.42–5.68) 1.60 (0.32–8.00)

Adjusted for international normalized ratio (INR). Adjusted for initial National Institute of Health Stroke Severity Scale (NIHSS) and INR.

4. Discussion

Fig. 2. Receiver operating characteristic (ROC) curve for the different models of predictors for major vessel occlusion. The calculated area under the ROC curve for the unadjusted model, model 2 (adjusted for international normalized ratio [INR]), and model 3 (adjusted for initial National Institute of Health Stroke Severity Scale [NIHSS] score and INR) were 0.68 (95% CI: 0.58–0.78; P = 0.001), 0.75 (95% CI: 0.66– 0.84; P < 0.001), and 0.91(95% CI: 0.85–0.97; P < 0.001), respectively.

In this study, we demonstrated that dosing methods including drug adherence of NOACs were associated with MVO in patients with recurrent cardioembolic stroke. The incidence of major vessel occlusive stroke was significantly lower in patients receiving a standard dose of NOACs (20.0%) than in those receiving an under-dose of NOACs (38.5%) and in patients who had missed doses of NOACs (61.9%) (P = 0.002). These results provide additional information to existing literature regarding the association between low intensity anticoagulation and MVO [19]. The clinical outcomes, which are NIHSS scores at discharge, and mRS at discharge, at three months, and at one year, were significantly worse in patients with MVO than in patients without MVO (P < 0.001, P < 0.001, P = 0.016, and P = 0.031, respectively). These results are consistent with previous findings [18,19]. Moreover, the median initial NIHSS score, in patients with recurrent ischemic strokes, was significantly higher in patients receiving under-doses and missed doses of NOACs (P = 0.007) than in patients receiving a standard doses of NOACs. However, no significant difference was found between dosing methods including with drug adherence of NOACs received and the clinical outcome at discharge, at three months, and at one year, because the use of IV and IA therapy was higher in the under-dose group and the missed dose groups than in the standard dose group, since MVOs were significantly higher in the under-dose group and the missed-dose groups than in the standard dose group. This suggests that in Asian patients with NVAF, taking a standard dose of NOACs might be considered as a proper therapy for reduced rate of MVO in recurrent cardioembolic stroke rather than taking under-doses of NOACs or missed doses of NOACs [12,16,24,25]. However, to our knowledge, there is no study that studied the association between

132

H.G. Woo et al. / Journal of Clinical Neuroscience 64 (2019) 127–133

dosing methods including with drug adherence of NOACs and MVO in recurrent cardioembolic ischemic strokes. Although the use of a standard dose of NOACs in Asian patients is as effective as warfarin in preventing strokes and has a significantly reduced the risk of ICH when compared with warfarin [10,12], the use of lower than standard doses of NOACs are common in actual clinical practice in Asia [13,14]. The use of lower than standard doses of NOACs, which is not recommended in any guidelines, is reported in clinical practice in Europe and North America as well [26,27]. This might be attributed to the complexity of treating patients with impaired renal and/or hepatic function, or to the overestimation of the risk of bleeding by clinicians, who had experienced patients with major bleeding who underwent warfarin therapy [28–30]. The absolute rate of ischemic stroke occurrence with low doses of NOACs was higher in Asian patients than in non-Asian patients [31,32]. Our study provides additional information that MVO is associated with under-doses NOACs (OR 2.50, 95% CI 1.01–6.17) and missed doses NOACs (OR 6.50, 95% CI 2.20– 19.22). Recently, Chang et al demonstrated an inverse correlation between the INR value and MVO in patients with high-risk of cardioembolic events who were taking warfarin [19]. This was because the higher intensity of anticoagulation resulted in smaller, more resolvable thrombus formation, leading to the rapid and spontaneous recanalization of occluded arteries [33]. This could be the reason why a preadmission INR value of 2.0 was more likely to cause strokes of lesser severity that led to good outcomes [19]. However, unlike warfarin, the dose of which can be adjustment based on the INR value, the anticoagulant effects of NOACs cannot be accurately quantified by any of the general tests of coagulation [34]. Also, special commercial coagulation assays with drug-specific calibrators are not widely available [35]. Therefore, currently, a therapeutic range for the laboratory monitoring of individual NOACs cannot be defined. Our study showed that using standard doses of NOACs was more likely to reduce the severity of stroke and lead to good outcomes in circumstances where useful laboratory monitoring was not available. In addition to the retrospective nature of this study, our study has a few limitations. The dose groups were not randomized. Residual or unmeasured confounding factors may have existed and may have introduced bias in the results. All subjects of study were Korean. A follow-up study with a larger study population including any other Asian subjects would be desirable. Moreover, future research about intensity of anticoagulation in direct measurement of blood levels or therapeutic activity of NOCAs will be helpful.

5. Conclusion In Asian patients with atrial fibrillation and a history of transient ischemic attack or ischemic stroke, the standard doses of NOACs reduce the MVO in recurrent stroke patients who received NOACs.

Sources of funding The authors received no specific funding for this study.

Declaration of interest The authors have declared that no competing interests exist.

Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.03.037.

References [1] Olesen JB, Sorensen R, Hansen ML, Lamberts M, Weeke P, Mikkelsen AP, et al. Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naive atrial fibrillation patients: danish nationwide descriptive data 2011–2013. Europace 2015;17:187–93. [2] 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. [3] 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. [4] 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. [5] 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. [6] 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. [7] 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. [8] 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. [9] Rost NS, Giugliano RP, Ruff CT, Murphy SA, Crompton AE, Norden AD, et al. Outcomes with edoxaban versus warfarin in patients with previous cerebrovascular events: findings from ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial FibrillationThrombolysis in Myocardial Infarction 48). Stroke 2016;47:2075–82. [10] Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, 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. Lancet 2014;383:955–62. [11] Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol 2007;50:309–15. [12] Wang KL, Lip GY, Lin SJ, Chiang CE. Non-vitamin K antagonist oral anticoagulants for stroke prevention in Asian patients with nonvalvular atrial fibrillation: meta-analysis. Stroke 2015;46:2555–61. [13] Suzuki S, Sagara K, Otsuka T, Kano H, Matsuno S, Takai H, et al. ‘‘Blue letter effects”: changes in physicians’ attitudes toward dabigatran after a safety advisory in a specialized hospital for cardiovascular care in Japan. J Cardiol 2013;62:366–73. [14] Chan YH, Yen KC, See LC, Chang SH, Wu LS, Lee HF, et al. Cardiovascular, bleeding, and mortality risks of dabigatran in Asians with nonvalvular atrial fibrillation. Stroke 2016;47:441–9. [15] Nguyen E, White CM, Patel MR, Fields LE, Peacock WF, Crivera C, et al. Doses of apixaban and rivaroxaban prescribed in real-world United States cardiology practices compared to registration trials. Curr Med Res Opin 2016;32:1277–9. [16] Wang KL, Giugliano RP, Goto S, Chiu CC, Lin CY, Lai EY, et al. Standard dose versus low dose non-vitamin K antagonist oral anticoagulants in Asian patients with atrial fibrillation: a meta-analysis of contemporary randomized controlled trials. Heart Rhythm 2016;13:2340–7. [17] Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation – the JROCKET AF study. Circulat J: Off J Jpn Circulat Soc 2012;76:2104–11. [18] Smith WS, Lev MH, English JD, Camargo EC, Chou M, Johnston SC, et al. Significance of large vessel intracranial occlusion causing acute ischemic stroke and TIA. Stroke 2009;40:3834–40. [19] Chang JY, Jung S, Park H, Han MK. Major vessel occlusion may predict subtherapeutic anticoagulation intensity and feasibility of administration of intravenous thrombolytics. PLoS One 2017:12. [20] Ko Y, Lee S, Chung JW, Han MK, Park JM, Kang K, et al. MRI-based algorithm for acute ischemic stroke subtype classification. J Stroke 2014;16:161–72. [21] Adams Jr HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org 10172 in acute stroke treatment. Stroke 1993;24:35–41. [22] Diener HC, Aisenberg J, Ansell J, Atar D, Breithardt G, Eikelboom J, et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 2. Eur Heart J 2017;38:860–8.

H.G. Woo et al. / Journal of Clinical Neuroscience 64 (2019) 127–133 [23] Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–47. [24] Nielsen PB, Skjoth F, Sogaard M, Kjaeldgaard JN, Lip GY, Larsen TB. Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2017;356:j510. [25] Steinberg BA, Shrader P, Thomas L, Ansell J, Fonarow GC, Gersh BJ, et al. Offlabel dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II registry. J Am Coll Cardiol 2016;68:2597–604. [26] Camm AJ, Amarenco P, Haas S, Hess S, Kirchhof P, Kuhls S, et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2016;37:1145–53. [27] Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015;131:157–64. [28] Beyer-Westendorf J, Ebertz F, Forster K, Gelbricht V, Michalski F, Kohler C, et al. Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost 2015;113:1247–57.

133

[29] Hecker J, Marten S, Keller L, Helmert S, Michalski F, Werth S, et al. Effectiveness and safety of rivaroxaban therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost 2016;115:939–49. [30] Steinberg BA, Kim S, Thomas L, Fonarow GC, Hylek E, Ansell J, et al. Lack of concordance between empirical scores and physician assessments of stroke and bleeding risk in atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Circulation 2014;129:2005–12. [31] Hori M, Connolly SJ, Zhu J, Liu LS, Lau CP, Pais P, et al. Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation. Stroke 2013;44:1891–6. [32] Yamashita T, Koretsune Y, Yang Y, Chen SA, Chung N, Shimada YJ, et al. Edoxaban vs. Warfarin in East Asian patients with atrial fibrillation – an ENGAGE AF-TIMI 48 subanalysis. Circulat J: Off J Jpn Circulat Soc 2016;80:860–9. [33] Nakamura A, Ago T, Kamouchi M, Hata J, Matsuo R, Kuroda J, et al. Intensity of anticoagulation and clinical outcomes in acute cardioembolic stroke: the Fukuoka Stroke Registry. Stroke 2013;44:3239–42. [34] Dale BJ, Chan NC, Eikelboom JW. Laboratory measurement of the direct oral anticoagulants. Br J Haematol 2016;172:315–36. [35] Gouin-Thibault I, Freyburger G, de Maistre E, Susen S, Delavenne X, Golmard JL, et al. Evaluation of dabigatran, rivaroxaban and apixaban target-specific assays in a multicenter French study. Thromb Res 2017;158:126–33.