Similar outcomes between vitamin K and non-vitamin K antagonist oral anticoagulants associated intracerebral hemorrhage

Similar outcomes between vitamin K and non-vitamin K antagonist oral anticoagulants associated intracerebral hemorrhage

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Journal of the Formosan Medical Association xxx (xxxx) xxx

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.jfma-online.com

Original Article

Similar outcomes between vitamin K and non-vitamin K antagonist oral anticoagulants associated intracerebral hemorrhage Szu-Ju Chen a,b, Shin-Joe Yeh a, Sung-Chun Tang a, Shin-Yi Lin c, Li-Kai Tsai a,*, Jiann-Shing Jeng a a

Department of Neurology and Stroke Center, National Taiwan University Hospital, Taipei, Taiwan Department of Neurology, En Chu Kong Hospital, New Taipei City, Taiwan c Department of Pharmacy, National Taiwan University Hospital, Taiwan b

Received 26 July 2018; received in revised form 13 October 2018; accepted 22 February 2019

KEYWORDS Intracerebral hemorrhage; Non-vitamin K antagonist oral anticoagulant; Outcome; Vitamin K antagonist

Background: The application of non-vitamin K antagonist oral anticoagulant (NOAC) reduces the risk of intracerebral hemorrhage (ICH) in comparison with vitamin K antagonist (VKA). However, the features and outcomes of NOAC-associated ICH are still unclear, especially for Asian populations. Methods: We retrospectively analyzed 49 consecutive patients who had spontaneous ICH while using NOAC or VKA. We compared the clinical characteristics, ICH volume, 7-day and 3-month mortality, and functional outcomes at discharge and 3 months post-stroke using the modified Rankin Scale (mRS) between NOAC- and VKA-associated ICH. The clinical features, ICH volume, ICH location, and/or treatment methods were statistically adjusted. Results: Among the 49 ICH patients, 15 (30.6%) were using NOAC and 34 (69.4%) were taking VKA. There were no significant differences in the initial ICH volume between groups (mean volume 34.2  43.8 vs. 59.4  46.5 mL, p Z 0.061). The percentage of early mortality (within 7 days post-ICH) was significantly lower in the NOAC group (13.3% vs. 44.1%; p Z 0.047), but the 3-month mortality was similar (33.3% vs. 47.1%; p Z 0.294). The functional outcome was equally poor in both groups at discharge (p Z 0.670) and 3 months post-ICH (mean mRS score 4.7  1.3 vs. 4.6  1.7, p Z 0.766). Conclusions: There were no significant differences in initial ICH volume, 90-day mortality, or functional outcomes between NOAC and VKA-associated ICH in Asians. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

* Corresponding author. Department of Neurology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 100, Taiwan. Fax: þ886 2 23418395. E-mail addresses: [email protected] (S.-J. Chen), [email protected] (S.-J. Yeh), [email protected] (S.-C. Tang), [email protected] gmail.com (S.-Y. Lin), [email protected] (L.-K. Tsai), [email protected] (J.-S. Jeng). https://doi.org/10.1016/j.jfma.2019.02.008 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Chen S-J et al., Similar outcomes between vitamin K and non-vitamin K antagonist oral anticoagulants associated intracerebral hemorrhage, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.02.008

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2

Introduction

S.-J. Chen et al. interventions included intracerebral hematoma evacuation (5 in NOAC group and 9 in VKA group) and extraventricular drainage (3 in NOAC group and 4 in VKA group). Blood pressure was controlled by intravenous infusion of nicardipine to achieve the target of systolic blood pressure below either 140 mmHg (53% in NOAC group and 65% in VKA group) or 160 mmHg.

Intracerebral hemorrhage (ICH) associated with oral anticoagulant (OAC) accounts for 2.2e11.8% of ICH and is increasing yearly with the prescription of OAC.1e3 Compared to traditional vitamin K antagonist (VKA), nonvitamin K antagonist oral anticoagulant (NOAC) has half the risk of ICH with similar efficacy in the prevention of ischemic stroke and systemic embolism.4 Nevertheless, about 0.2% of NOAC users develop ICH (NOAC-ICH) per year.5 Furthermore, studies on the outcomes of NOAC-ICH are still limited and have inconsistent results (Supplemental table 1).6e17 For example, some studies report smaller initial ICH volume, less hospital mortality, and better discharged functional outcome in NOAC-ICH than in VKA-associated ICH (VKA-ICH),6e13 while others show similar outcomes between groups.10e17 The inconsistent results thus require additional studies for further validation and confirmation. Asians have different characteristics of ICH compared to non-Asians. Asians are 4 times more prone to developing VKA-ICH than white populations.18 In addition, patients using NOAC have reduced risk of ICH in comparison to those using warfarin, which is more prominent in Asians than nonAsian groups.19 Therefore, the features of NOAC-ICH should be clarified in the Asian population. We compared the characteristics of ICH and outcomes between NOAC-ICH and VKA-ICH in Asian patients from a single medical center in Taiwan.

The initial ICH volume was calculated by using the ABC/2 method on the first CT scan.21 Hematoma expansion was specified as an increase of ICH volume >6 mL or >33% measured in a follow-up brain imaging study (CT scan or MRI) within 72 h in patients who did not receive intracerebral hematoma removal before the follow-up image.16 ICH locations were classified as lobar ICH (supratentorial hemispheric parenchymal bleeding), deep nuclei (thalamus or basal ganglia), the brainstem, and the cerebellum. ICH features and outcomes were described by the initial ICH volume, proportion of patients with hematoma expansion, mortality at 7 days and 90 days post-ICH, and functional outcome measured by mRS at discharge and at 3 months post-ICH. Early mortality was defined as mortality within 7 days post-ICH. Unfavorable outcome was defined as mRS >3 at 3 months post-ICH. Death and mRS were reported by trained study nurses attending the outpatient departments, chronic care facilities, or the homes of patients in person or via phone calls.

Methods

Statistics

Patients

We compared the characteristics of NOAC-ICH and VKA-ICH using the ManneWhitney test for continuous variables and Fisher’s exact test for categorical variables. ICH volume was adjusted with BoxeCox transformation to satisfy the statistical assumption of a normal distribution. A multivariable linear regression model was applied with the BoxeCox transformed ICH volume as a dependent variable and the type of anticoagulants as an independent variable while adjusting for confounding factors. These variables showed significant influences on the BoxeCox transformed ICH volume in the univariate linear regression analysis. The KaplaneMeier method was applied to estimate survival probabilities at 7 days and 90 days for both groups, and a log-rank test was used to measure differences between groups. We assessed the relative mortality risk using a Cox proportional hazard model with 90-day mortality as the endpoint and factors of interest as covariates, which were the variables that showed correlations with mortality in the univariate model. The functional outcome at 3 months was analyzed using a binary logistic regression model with unfavorable outcomes (mRS >3) as a dependent variable and the types of anticoagulants as an independent variable while adjusting for confounding factors. The confounding factors were those that had a significant association with unfavorable outcomes in the univariate binary logistic regression analysis. Two-tailed p values 0.05 were deemed statistically significant. XLSTAT-Biomed software (Addinsoft, New York, NY, USA) was used for the statistical analyses.

The primary data used in this study were obtained from the National Taiwan University Hospital Stroke Registry. We prospectively gathered all cases of stroke since 1995 in our hospital, which is one of the major tertiary referral centers in Taiwan.20 The Research Ethics Committee of National Taiwan University Hospital approved the stroke registry. Between February 2012 and June 2018, we retrospectively collected data from the stroke registry on adult patients (18 years old) who had been treated with OAC at the time of ICH. NOAC-ICH refers to patients using NOAC before ICH occurred within 12 h for dabigatran and apixaban and within 24 h for rivaroxaban. VKA-ICH was defined by the occurrence of an international normalized ratio (INR) 1.3 at admission for ICH in those using VKA. Patients were excluded if they had had secondary causes of ICH (head trauma, vascular malformation, hemorrhagic transformation of an infarct and brain tumors). Patients who had combined ICH with subdural hemorrhage were also excluded even without a clear history of head injury because a traumatic cause of ICH could not be totally ruled out. Demographic data, medical history, pre-morbid modified Ranking Scale (mRS), creatinine clearance rate (Ccr), INR, and initial systolic blood pressure (SBP) were collected from medical records. Reversal agents were defined as idarucizumab or 4-factor prothrombin complex concentrate (PCC) in the NOAC group and as fresh frozen plasma (FFP) or 4-factor PCC plus vitamin K in the VKA group. Surgical

ICH features and outcomes

Please cite this article as: Chen S-J et al., Similar outcomes between vitamin K and non-vitamin K antagonist oral anticoagulants associated intracerebral hemorrhage, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.02.008

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Outcome of NOAC-associated intracerebral hemorrhage

Results Features of ICH Of the 55 consecutive patients with OAC-associated spontaneous ICH, six patients were excluded for concomitant subdural hemorrhage. Among the remaining 49 patients (age 69.2  11.9 years; 61.2% men), 15 patients (30.6%) were taking NOAC [dabigatran at 220 mg/day (n Z 2); rivaroxaban at 20, 15, or 10 mg/day (n Z 8); or apixaban at 10 or 5 mg/day (n Z 5)]. The other 34 (69.4%) were using VKA. OAC was used for atrial fibrillation in 100% and 62% of the patients in the NOAC and VKA groups (p Z 0.005),

Table 1

3 respectively. Other patients used VKA for valvular heart disease (n Z 9), deep vein thrombosis (n Z 2), coronary arterial disease (n Z 1), or hepatocellular carcinoma after liver transplantation (n Z 1). The median INR value in the VKA group was 2.8 (IQR, 2.2e4.3), and only 11 (32%) patients had an INR within the optimal therapeutic range (INR 2e3) upon admission. Patients in the NOAC group were older (p Z 0.002) and had higher CHA2DS2-VASc scores (p Z 0.003), higher initial SBP (p Z 0.015), and lower INR levels (p < 0.001) than the VKA group. Other clinical features were similar between the two groups (Table 1). There was no significant difference in the initial ICH volume between NOAC-ICH and VKA-ICH (mean volume

Patient characteristics, treatments and clinical outcomes among different anticoagulants.

Variables

NOAC (N Z 15)

VKA (N Z 34)

p-value

Age, years, mean (SD) Sex, male, n (%) Underlying disease Atrial fibrillation, n (%) Hypertension, n (%) Diabetes mellitus, n (%) CAD, n (%) CHF, n (%) Old ischemic stroke or TIA, n (%) Liver disease Malignancy Pre-morbid mRS, mean (SD) Ccr, mL/min, mean (SD) CHA2DS2-VASc, mean (SD) HAS-BLED, mean (SD) Concomitant antiplatelet use, n (%) Initial INR, median (IQR) Initial SBP, mmHg, mean (SD) Initial ICH volume, mL, mean (SD) ICH location Lobar ICH, n (%) Infratentorial ICH, n (%) Intraventricular hemorrhage, n (%) Initial GCS, mean (SD) Hematoma enlargement, n (%) Final ICH volume Treatment Reversal agents, n (%) Operation, n (%) mRS at discharge, mean (SD) mRS at 3 months, mean (SD) Unfavorable outcome (mRS >3 at 3 months), n (%) Mortality at 7 days, n (%) Mortality at 90 days, n (%)

77.1 (8.2) 10 (67%)

65.7 (11.7) 20 (59%)

0.002 0.370

15 (100%) 11 (73%) 7 (47%) 6 (40%) 5 (33%) 10 (67%) 1 (3%) 3 (9%) 1.4 (1.8) 53.6 (24.3) 5.3 (1.5) 2.6 (0.8) 1 (7%) 1.1 (1.0e1.2) 189.3 (39.5) 34.2 (43.8)

21 (62%) 21 (62%) 14 (41%) 7 (21%) 10 (29%) 12 (35%) 1 (7%) 2 (13%) 1.3 (1.7) 51.3 (29.0) 3.9 (1.4), n Z 21a 2.4 (1.2) 4 (12%) 2.8 (2.2e4.3)b 155.4 (45.1) 59.4 (46.5)

0.005 0.526 0.762 0.508 >0.99 0.063 0.523 0.160 0.678 0.541 0.003 0.878 >0.99 <0.001 0.015 0.061

6 (40%) 6 (40%) 4 (27%) 10.2 (5.3) 2 (29%), n Z 7c 36.0 (42.9)

17 (50%) 5 (15%) 22 (65%) 9.4 (4.0) 6 (67%), n Z 9c 64.2 (47.3)

0.552 0.069 0.028 0.507 0.315 0.038

3 (20%) 5 (33%) 4.9 (1.1) 4.7 (1.3) 12 (80%) 2 (13%) 5 (33%)

17 (50%) 12 (35%) 4.9 (1.3) 4.6 (1.7) 27 (79%) 15 (44%) 16 (47%)

0.064 >0.99 0.670 0.766 >0.99 0.047d 0.294d

Abbreviations: CAD, coronary arterial disease; Ccr, creatinine clearance rate; CHF, congestive heart failure; GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; INR, international normalized ratio; IQR, interquartile range; mRS, modified Ranking Scale score; NOAC, non-vitamin K antagonist oral anticoagulant; SBP, systolic blood pressure; SD, standard deviation; TIA, transient ischemic attack; VKA, vitamin K antagonist. a Number of patients in the VKA group who had atrial fibrillation. b INR valued above 10 was calculated as 10. c Number of patients who received follow-up brain images without undergoing hematoma evacuation surgery within 72 h after stroke onset. d Analysis with Log-rank test.

Please cite this article as: Chen S-J et al., Similar outcomes between vitamin K and non-vitamin K antagonist oral anticoagulants associated intracerebral hemorrhage, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.02.008

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4 34.2  43.8 vs. 59.4  46.5 mL, p Z 0.061) (Table 1). The ICH location was also similar between groups (lobar ICH 40% vs. 50%, p Z 0.552; infratentorial ICH 40% vs. 15%, p Z 0.069). However, the rate of concomitant intraventricular hemorrhage was significantly lower in the NOAC group (27% vs. 65%, p Z 0.028). According to the linear regression analysis, only ICH located in the lobar regions was a major determinant for larger initial hematoma size (p < 0.001), while the type of OAC was not a significant factor affecting initial ICH volume (Supplemental table 2). There were 7 and 9 patients in the NOAC-ICH and VKA-ICH groups, respectively, who received follow-up brain imaging without undergoing hematoma evacuation surgery within 72 h after stroke onset. In these 16 patients, there was no significant difference in the percentage of patients with hematoma expansion between groups (29% vs. 67%, p Z 0.315) (Table 1).

Mortality and functional outcome The 90-day mortality was 33.3% [95% confidence interval (CI) 16.3e68.2] in the NOAC group and 47.1% (95% CI 32.9e67.2) in the VKA group (p Z 0.294) (Fig. 1A). The majority of deaths were caused by brain herniation and ICH-related brainstem failure except for 4 patients, who died from infection, pulmonary hemorrhage, or congestive heart failure. According to a Cox proportional hazard model, a higher initial GCS score was associated with lower 90-day mortality, while the type of OAC was not a significant determinant for 90-day mortality (Table 2). However, early mortality rate (within 7 days after stroke onset) was significantly lower in the NOAC-ICH group (13.3%; 95% CI, 3.7e48.4) than the VKA-ICH group (44.1%; 30.2e64.4) (p Z 0.047). Patients in both the NOAC and VKA groups generally had poor functional outcomes at discharge (mean mRS score 4.9  1.1 vs. 4.9  1.3, p Z 0.670) and at 3 months (mean mRS score 4.7  1.3 vs. 4.6  1.7, p Z 0.766) (Fig. 1B). Only

S.-J. Chen et al. 20% and 21% of patients were able to walk without assistance in the respective groups at 3 months after ICH. The logistic regression analysis indicated that lower initial GCS was a significant determinant for unfavorable functional outcome at 3 months post-stroke (odds ratio 0.60; 95% CI 0.41e0.88; p Z 0.008). NOAC usage was not a significant factor associated with functional outcome compared with VKA (Table 3).

Discussion NOAC has become an alternative to VKA worldwide for its lower bleeding risk and convenience of use.22 However, NOAC users are still at risk of developing ICH, and studies on the outcomes of NOAC-ICH have had inconsistent results (Supplemental table 1).6e17 In this study, we compared the features and outcomes of NOAC-ICH and VKA-ICH in a Taiwanese medical center. We found that the initial hematoma size, 90-day mortality, and 3-month functional outcome were all similar between groups except for the better 7-day outcome in NOAC users. Our results thus support previous reports of NOAC-ICH sharing similar clinical features and outcomes with VKA-ICH.11e17 The hematoma size and location strongly influence the ICH outcome.23,24 We demonstrated that ICH volume was similar between NOAC-ICH and VKA-ICH, even after adjustment for ICH location, prior stroke or transient ischemic attack, and INR level. There was no significant difference in hematoma location between groups. Therefore, although NOAC usage reduced the risk of ICH in comparison with using VKA,4 the features of NOAC-ICH and VKA-ICH were similar once the cerebral artery ruptured. This finding is in accordance with previous reports analyzing initial ICH volume.6,14,16 In addition, hematoma located in lobar regions was associated with higher initial ICH volume in OAC users according to the multivariate analysis. Patients who presented with lobar ICH were likely to have cerebral amyloid angiopathy (CAA) according to the

Figure 1 (A) Survival curve comparing 90-day mortality between vitamin K antagonist and non-vitamin K antagonist oral anticoagulant associated intracerebral hemorrhage. (B) Functional outcome of vitamin K antagonist and non-vitamin K antagonist oral anticoagulant associated intracerebral hemorrhage at post-stroke 3 months.

Please cite this article as: Chen S-J et al., Similar outcomes between vitamin K and non-vitamin K antagonist oral anticoagulants associated intracerebral hemorrhage, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.02.008

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Outcome of NOAC-associated intracerebral hemorrhage Table 2

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Survival analysis with Cox proportional hazards models for the 90-day mortality. Multivariate modela

Univariate model

Age Sex (female as reference) Ccr NOAC use (VKA as reference) Initial GCS Initial SBP Transformed ICH volume Intraventricular hemorrhage Lobar ICH Infratentorial ICH Hematoma expansion Reversal agents Operation

HR

95% CI

p-value

0.98 0.78 1.00 0.60 0.83 1.00 1.80 1.54 1.03 0.77 2.31 0.82 0.37

0.94e1.01 0.33e1.86 0.98e1.01 0.22e1.64 0.00e0.92 0.99e1.01 1.24e2.62 0.64e3.74 0.44e2.43 0.26e2.29 0.21e25.53 0.34e1.98 0.13e1.11

0.181 0.576 0.554 0.316 0.001 0.879 0.002 0.336 0.946 0.639 0.496 0.662 0.075

HR

95% CI

p-value

0.55 0.83

0.19e1.59 0.00e0.95

0.267 0.005

1.37

0.94e2.01

0.104

Abbreviations: Ccr, creatinine clearance rate; CI, confidence interval; GCS, Glasgow Coma Scale; HR, hazard ratio; ICH, intracerebral hemorrhage; NOAC, non-vitamin K antagonist oral anticoagulant; SBP, systolic blood pressure; VKA, vitamin K antagonist. a NOAC and significant factors in the univariate model, including initial GCS, transformed ICH volume and operation, were analyzed in the multivariate model with mutual adjustment.

Table 3

Binary logistic regression analysis for factors associated with unfavorable outcome (mRS >3) at post-ICH 90 days. Multivariate modela

Univariate model

Age Ccr NOAC Premorbid mRS Initial GCS Transformed ICH volume Lobar ICH Operation Reversal agents

OR

95% CI

p-value

1.03 0.99 1.04 1.49 0.63 1.34 0.52 1.17 0.37

0.97e1.10 0.97e1.02 0.23e4.71 0.85e2.61 0.45e0.89 0.61e2.95 0.13e2.12 0.26e5.27 0.09e1.55

0.311 0.625 0.962 0.159 0.008 0.462 0.358 0.841 0.175

OR

95% CI

p-value

2.36

0.37e14.97

0.362

0.60

0.41e0.88

0.008

Abbreviations: Ccr, creatinine clearance rate; CI, confidence interval; GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; mRS, modified Ranking Scale score; NOAC, non-vitamin K antagonist oral anticoagulant; OR, odds ratio. a NOAC and significant factors in the univariate model, including initial GCS and reversal agents, were analyzed in the multivariate model with mutual adjustment.

pathologically validated Boston criteria,25 and CAA-related ICH usually shows a larger hematoma size than other types of ICH.26 Since OAC may increase the risk of ICH in patients with CAA,27 it is still unclear whether CAA partially contributes to the lobar ICH in our OAC users, and the relationship between CAA- and OAC-related ICH requires further investigation. The only major determinants for 90-day mortality of OAC-associated ICH was the initial GCS score, and not the type of OAC used. The 90-day mortality rates of NOAC-ICH and VKA-ICH were similar (33.3% vs. 47.1%), which is consistent with all previous reports analyzing mortality at 90 days after stroke onset.11,16 However, we also found a significantly lower early-mortality rate (within 7 days postICH) in NOAC-ICH than VKA-ICH (13.3% vs. 44.1%). Our NOAC-ICH group showed a non-significant trend toward smaller hematoma volume (34.2  43.8 vs. 59.4  46.5 mL), lower risk for hematoma expansion (29% vs. 67%), and significantly lower rate of comorbid intraventricular

hemorrhage (27% vs. 65%), which may partly result in lower risk of early mortality in NOAC-ICH as compared to VKA-ICH. In addition, all but one mortality in VKA group was related to brainstem failure or brain herniation. Contrarily, only 2 of 5 patients in NOAC group directly died of ICH. The remaining 3 patients died of cardiac comorbidity or infection at the subacute stage of ICH. Three previous studies also showed that prior use of NOACs was associated with lower risk of in-hospital mortality compared with prior use of VKA.8,9,12 Therefore, the risk of early mortality tended to be lower for the NOAC users than VKA users, but the 90-day mortality was similar, which can partially explain the inconsistent results from previous studies analyzing postICH mortality.8e15,17 The functional outcomes were equally poor in both NOAC-ICH and VKA-ICH in that only 20% and 21% of our patients were able to walk at 3 months post-ICH without assistance in both groups, respectively. Nearly all previous studies analyzing functional outcome after OAC-related ICH

Please cite this article as: Chen S-J et al., Similar outcomes between vitamin K and non-vitamin K antagonist oral anticoagulants associated intracerebral hemorrhage, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.02.008

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6 used the parameter of discharge mRS.6e16 In comparisons between NOAC-ICH and VKA-ICH, six studies demonstrated better outcome in the NOAC-ICH group,6e11 while five studies showed similar functional outcomes.12e16 Only one study also analyzed functional outcome at 3 months postICH and revealed significantly lower mRS in the NOAC-ICH group than the VKA-ICH group (median mRS score 3 vs. 4),11 which is a different conclusion from the present study. This may be attributed to the significantly smaller initial hematoma size and fewer neurological deficits on admission recorded in the NOAC group in that study. Taken together, the results of comparing the functional outcomes between different OAC-related ICH are still inconsistent in both early and late stages post-stroke, and subgroup variability might be suspected. Large studies are thus necessary to clarify the outcomes between NOAC-ICH and VKA-ICH in various populations, such as ethnic subgroups, patients with certain comorbidity, and subjects receiving concomitant medication. The previous studies conducted in Asian population analyzed the outcome only at the early stage post-ICH and the results were heterogeneous.7,9,10,12,13 In our study, we also investigated the mortality and functional outcome at post-ICH 3 months and demonstrated that the results were similar between the NOAC and VKA groups. Since 38% patients in VKA group received anticoagulant not for atrial fibrillation, we performed a subgroup analysis with patients who received anticoagulants only for atrial fibrillation. The results were similar as those analyzed in all patients that there were no significant differences in initial ICH volume (p Z 0.386), mortality at post-ICH 90 days (p Z 0.328), mRS at discharge (p Z 0.595) and at post-ICH 3 months (p Z 0.688), and a trend toward a lower 7-day mortality in NOAC group (mortality 13.3% vs. 42.9%, p Z 0.069). One of our patients received idarucizumab to reverse the anticoagulation effect of dabigatran and showed relatively favorable outcome (3-month mRS Z 3) without hematoma expansion, despite a large initial ICH volume (60 mL). The early usage of NOAC-specific reversal agents, such as idarucizumab for dabigatran and andexanet alpha for Xa inhibitors, may reduce the risk of hematoma enlargement and further improve the functional outcome of NOAC-ICH in the future,28e31 considering the rapid onset and complete reversal of these agents.32,33 There are several limitations in this study. First, the relatively small sample size may have interfered with the statistical analysis. Although previous multicenter studies were able to enroll large numbers of patients, a singlehospital study has an advantage of collecting detailed clinical information and avoiding bias from different ethnic populations, variables in patient management, and measurement heterogeneity. Secondly, some of the baseline characteristics of patients are different between groups. Although we tried to adjust for some important variables during the comparison of outcomes, the statistical results should still be interpreted cautiously. Finally, this is a retrospective study, which potentially could have led to missing data and inevitable bias in patient treatment. We analyzed the data from our hospital-based stroke registry, which prospectively collected information including patient characteristics, lab data, and outcome within 3 months

S.-J. Chen et al. post-stroke. We thus did not have missing data except for the follow-up neuroimaging in some patients to analyze the hematoma enlargement. In summary, we demonstrated that there are no significant differences in initial hematoma size, 90-day mortality, or 3-month functional outcome between NOAC-ICH and VKA-ICH in a single medical center in Taiwan. With the development and early application of reversal agents of NOAC in life-threatening hemorrhage, the outcome of NOAC-ICH could potentially improve in the future.28 More prospective studies with large sample sizes, long-term follow-up, and subgroup analysis are necessary to compare the ICH characteristics between NOAC and VKA and to evaluate the efficacy and outcomes of reversal agents in NOAC-ICH.

Conflicts of interest The authors have no conflicts of interest relevant to this article.

Funding This research was supported by grants (108-A147 and 108-S4110) from the National Taiwan University Hospital, Taipei, Taiwan.

Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2019.02.008.

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Please cite this article as: Chen S-J et al., Similar outcomes between vitamin K and non-vitamin K antagonist oral anticoagulants associated intracerebral hemorrhage, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.02.008

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Outcome of NOAC-associated intracerebral hemorrhage

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Please cite this article as: Chen S-J et al., Similar outcomes between vitamin K and non-vitamin K antagonist oral anticoagulants associated intracerebral hemorrhage, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.02.008