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Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients
Journal of Clinical Neuroscience xxx (xxxx) xxx
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Clinical study
Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients Ho Geol Woo a, Inyoung Chung b, Dong Seok Gwak b, Baik Kyun Kim c, Ji Hoon Kang d, Beom Joon Kim d, Hee-Joon Bae d, Moon-Ku Han d,⇑ a
Department of Neurology, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, 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 18 September 2018 Accepted 24 October 2018 Available online xxxx Keywords: Anticoagulants Atrial fibrillation Cerebral hemorrhage Warfarin
a b s t r a c t Non-valvular atrial fibrillation patients receiving non-vitamin K antagonist oral anticoagulants (NOACs) have half the incidence of intracerebral hemorrhage (ICH) compared to those receiving warfarin. However, the differences in outcomes of NOAC-associated ICH (NICH) and warfarin-associated ICH (WICH) remain controversial. In this study, we investigated the clinical outcome and radiologic findings of ICH in Asian patients receiving NOACs or warfarin. We retrospectively reviewed the medical records of 544 ICH patients admitted to our hospital from January 2013 through December 2017, and compared the baseline demographics, clinical characteristics, ICH-related radiologic findings, and clinical outcome between the WICH and NICH groups. WICH and NICH were diagnosed in 46 and 13 patients, respectively. Lesions were located more frequently in the supratentorial deep area (45.7% and 46.2%) than the lobar area (30.4% and 30.8%) or brainstem and cerebellum (23.9% and 23.1%) in the WICH and NICH groups, respectively. The hematoma expansion and concomitant intraventricular hemorrhage (IVH) rate was significantly higher in the WICH group than in the NICH group (58.7% versus 7.7%, P = 0.001 and 50.0% versus 15.4%, P = 0.030, respectively). Hematoma expansion (odds ratio [OR]: 50.546; 95% confidence interval [CI]: 2.763–924.748; P = 0.008) and concomitant IVH (OR: 9.240; 95% CI: 1.450–58.892; P = 0.019) were independently associated with mortality at three months, after adjustment for confounding variables. Our results indicate that the radiological findings and clinical outcome at three months in patients with ICH are more favorable in those receiving NOAC therapy than in those receiving warfarin treatment. Ó 2018 Published by Elsevier Ltd.
1. Introduction Intracranial hemorrhage (ICH) related to use of oral anticoagulants, one of the most challenging complications in patients with atrial fibrillation (AF), has been associated with a higher morbidity and mortality [1,2]. Although recent randomized trials in patients with AF have shown that the incidence of ICH in patients receiving non-vitamin K antagonist oral anticoagulants (NOACs) is about half that in patients receiving warfarin, and the 3-month mortality of NOAC-associated ICH (NICH) is similar to that of warfarinassociated ICH (WICH) [3–7]. However, some studies have shown
⇑ 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).
that, compared with WICH, NICH is associated with a higher risk of both hematoma expansion and unfavorable clinical outcomes [4,7]. Because of the increasing usage of NOACs in clinical practice and the current unavailability of specific reversal agents, it is important to investigate the outcomes of NICH [8,9]. Moreover, the clinical characteristics and radiologic findings of NICH remain unknown. Asian populations with AF have different characteristics than non-Asian populations with AF do. Asian patients taking warfarin are more prone to bleeding, including ICH, and less likely to achieve optimal control of international normalized ratio (INR) because of polymorphisms in genes such as CYP2C9 and vitamin K epoxide reductase complex 1 (VKORC1), which determine an individual’s warfarin sensitivity [10,11]. Currently, although small case series and multicenter prospective studies that compared the outcomes of NICH and WICH have reported, most prior studies
https://doi.org/10.1016/j.jocn.2018.10.102 0967-5868/Ó 2018 Published by Elsevier Ltd.
Please cite this article as: H. G. Woo, I. Chung, D. S. Gwak et al., Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2018.10.102
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H.G. Woo et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
have been conducted in non-Asian populations, and the few studies conducted in Asian populations have only reported outcomes on discharge [6,7,12–17]. Therefore, in the present study, we investigated clinical and radiological findings, and sought to identify factors associated with 3-month outcomes in Asian patients with ICH receiving anticoagulation therapy with either warfarin or NOACs. 2. Materials and methods The institutional review board approved this retrospective study, and informed consent was waived. 2.1. Subjects Initially, 544 consecutive patients with ICH who were treated at our institution between January 2013 and December 2017 were retrospectively selected from our institutional database. Of these 544 patients, 68 patients with a history of oral anticoagulant use were included in the study. WICH was defined as an INR of >1.5, as previously described [18], and NICH was defined as NOAC usage within the 24 h prior to the onset of clinical symptoms of ICH. Patients with predominant subarachnoid hemorrhage or secondary causes of ICH, such as major head trauma in the previous 24 h, vascular malformations, tumors, cavernomas, aneurysms, other known coagulopathy, or hemorrhagic transformation of an infarct were excluded from further evaluation. Finally, a total of 59 patients who met the inclusion criteria were enrolled in this study. These included 46 patients with a diagnosis of NICH (NICH group) and 13 patients with a diagnosis of WICH (WICH group; Fig. 1). 2.2. Evaluation of outcomes, and clinical and radiological characteristics Brain computed tomography (CT) was performed for all patients both at baseline and at follow-up within 72 h after admission. CT findings were interpreted by two neuroradiologists with over 10 years of experience evaluating brain CT scans at our institution, who were blinded to the patients’ clinical data. Imaging data included ICH volumes at baseline and follow-up CT, which were calculated using ABC/2 measurement, with blinding of anticoagulant type and outcome data. In addition, ICH volume at baseline was analyzed according to three categories based on hematoma volume (<30 cm3, 30–60 cm3, and >60 cm3) [19]. Hematoma expansion (HE) in ICH was defined as an increase in hematoma volume of >33% or >6 mL from the baseline to follow-up CT scan in patients who did not undergo subsequent intracranial
Fig. 1. Flowchart of patient inclusion.
surgery before follow-up imaging. Hematoma location was categorized as follows: supratentorial deep area (basal ganglia and thalamus), brainstem and cerebellum, and lobar area. Baseline laboratory parameters, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and INR, were measured routinely in all patients on warfarin or NOAC therapy. All eligible patients were treated according to the current guidelines for the management of spontaneous ICH [20]. As soon as ICH was diagnosed by brain CT, warfarin or NOACs were stopped. The effects of warfarin were reversed immediately by intravenous administration of vitamin K. Blood pressure was lowered to 140 mm Hg with intravenous nicardipine. Intubation, surgical decompression, or external ventricular drainage was performed on a case-by-case basis depending on neurologic deterioration and findings on the repeat CT scan [20]. Clinical outcomes were evaluated according to the National Institutes of Health Stroke Scale (NIHSS) scores at admission and discharge, and modified Rankin scale (mRS) score at discharge and 3-month follow-up. The initial and follow-up clinical evaluations were performed by three experienced stroke neurologists. In addition, we evaluated the in-hospital and 3-month mortality rates. 2.3. Statistical methods Statistical analysis was performed using SPSS 22.0 for Windows (IBM Corp. Armonk, NY, USA). Demographics, clinical characteristics, radiological findings, and clinical outcomes were compared between the WICH and NICH groups. Normally distributed data of continuous variables were evaluated with the KolmogorovSmirnov test. For normally distributed data, we used an independent t-test. For data with non-normal distribution, we used the Mann–Whitney U test. Data were summarized using standard descriptive statistics. All normally distributed variables are reported as mean ± standard deviation, and non-normally distributed variables are presented as median (interquartile range). Categorical variables are presented as frequency and percentage. Pearson chi square test was performed for comparison of categorical variables. Logistic regression analysis was performed to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between outcome at 3 months and all variables. A two-tailed P-value < 0.05 was considered statistically significant. 3. Results 3.1. Baseline patient demographics and comparison of clinical characteristics between the NICH and WICH groups The mean age of the 59 patients was 71.5 ± 9.7 years, and 52.5% of them were male. Three NOACs had been prescribed to 13 patients (22.0%), with different dosing regimens according to patient age, body weight, and renal function: dabigatran 110 mg twice a day (n = 1), rivaroxaban 20 mg once a day (n = 3), rivaroxaban 15 mg once a day (n = 6), apixaban 2.5 mg twice a day (n = 1), and apixaban 2.5 mg twice a day (n = 2). Table 1 summarizes the clinical characteristics of patients according to group. Patients in the NICH group were significantly older than those in the WICH group (75.4 ± 8.15 versus 70.4 ± 9.84, P = 0.036). No significant between-group differences were found in sex, cardiovascular risk factors, concomitant use of statins and antiplatelet medication, NIHSS and Glasgow Coma Scale (GCS) scores at admission, and time from symptom onset to arrival. No differences were found in baseline laboratory parameters, except for significantly higher INR (3.3 ± 2.0 versus 1.5 ± 0.6, P < 0.001), aPTT (56.3 ± 18.7 s versus 42.3 ± 12.2 s, P = 0.005) and
Please cite this article as: H. G. Woo, I. Chung, D. S. Gwak et al., Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2018.10.102
H.G. Woo et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
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Table 1 Comparison of the demographics and clinical characteristics between NICH group and WICH group. WICH group (n = 46)
NICH group (n = 13)
P value
Demographics Age, mean (SD) Male sex, n (%)
70.4 (9.84) 26 (56.5)
75.4 (8.15) 5 (38.5)
0.036 0.348
Cardiovascular risk factors, n (%) Congestive heart failure Hypertension Diabetes mellitus Hyperlipidemia Smoking Alcohol Previous stroke Chronic kidney disease
7 (15.2) 37 (80.4) 15 (32.6) 20 (43.5) 12 (26.1) 12 (26.1) 21 (45.7) 13 (28.3)
2 (15.4) 10 (76.9) 2 (15.4) 7 (53.8) 3 (23.1) 1 (7.7) 9 (69.2) 1 (7.7)
1.000 0.716 0.310 0.508 1.000 0.260 0.209 0.159
Concomitant medication, n (%) Antiplatelet Statin
10 (21.7) 18 (39.1)
1 (7.7) 8 (61.5)
0.426 0.209
3.3 (2.0) 56.3 (18.7) 31.7 (14.1) 1.40 (1.5) 71.6 (33.2) 10.5 (4.8– 19.3) 10.5 (6.0– 15.0) 572.1 (1154.0)
1.5 (0.6) 42.3 (12.2) 17.4 (5.4) 0.90 (0.2) 75.9 (12.5) 14.0 (3.0– 19.5) 12.0 (7.5– 15.0) 485 (334.5)
<0.001 0.005 <0.001 0.249 0.654 0.749
Laboratory finding, mean (SD) International Normalized Ratio aPTT, sec PT, sec Creatinine, mg/dL eGFR Initial NIHSS, median (IQR) Baseline GCS, median (IQR) Symptom onset to arrival time, minutes, mean (SD)
0.956 0.076
Abbreviations: NICH, Non-vitamin K antagonist oral anticoagulant-associated intracerebral hemorrhage; WICH, Warfarin-associated intracerebral hemorrhage; SD, Standard deviation; aPTT, activated partial thromboplastin time; PT, prothromb in time; eGFR, estimated glomerular filtration rate; NIHSS, National Institute of Health Stroke Severity Scale; IQR, Interquartile Range; GCS, Glasgow coma scale.
PT (31.7 ± 14.1 s versus 17.4 ± 5.4 s, P < 0.001) in the WICH group than in the NICH group. 3.2. Comparisons of the radiological findings between the NICH and WICH groups In both the WICH group and the NICH group, hematomas was more frequently in the supratentorial deep area (45.7% and 46.2%, respectively) than in the lobar area (30.4% and 30.8%, respectively), and brainstem and cerebellum (23.9% and 23.1%, respectively). There was no significant difference in ICH location between the two groups (Fig. 2A). Hematoma volumes in the NICH and WICH groups are shown in Fig. 2B. There was no difference in the distribution of the three hematoma volume-based categories (<30 cm3, 30–60 cm3, and >60 cm3) between the WICH and NICH groups (Fig. 2C). The prevalence of hematoma expansion was significantly lower in the NICH group than in the WICH group (7.7% versus 58.7%, P = 0.001). Moreover, the prevalence of concomitant intraventricular hemorrhage (IVH) was significantly lower in the NICH group than in the WICH group (15.4% versus 50.0%, P = 0.030; Table 2). 3.3. Comparisons of treatment and clinical outcome between the NICH and WICH groups and association of variables with clinical outcome Administration of vitamin K (84.8% versus 0.0%, P < 0.001) and fresh frozen plasma (76.1% versus 23.1%, P = 0.001) was more frequent in the WICH group than in the NICH group. No patient in the NICH group underwent invasive procedures, including neurosurgery. NIHSS score at discharge and mRS score at discharge and 3-month follow-up were not significantly different between the two groups. However, in-hospital mortality was higher in the
Fig. 2. Comparisons of the radiological finding between NICH group and WICH group. A. The supratentorial deep area was included by thalamus and basal ganglia. The supratentorial deep area (45.7% [thalamus: 23.9%, basal ganglia: 21.7%] and 46.2% [thalamus: 30.8%, basal ganglia: 15.4%], respectively) was more frequent than lobar location (30.4% and 30.8%, respectively) and brainstem and cerebellum location (23.9% [brainstem: 10.9%, cerebellum: 13.0%] and 23.1% [brainstem: 7.7%, cerebellum: 15.4%], respectively) in both WICH group and NICH group. B. Hematoma volume in the NICH group and WICH group was shown. C. Distribution of volume of ICH using three categories of hematoma volume (<30 cm3, 30–60 cm3, and >60 cm3) was shown. hematoma volume<30 cm3 was more often in both WICH group and NICH group (63.0% and 46.2%) but there was no significant difference.
WICH group than in the NICH group (17.4% versus 0%, respectively). Moreover, mortality at 3 months was significantly higher in the WICH group than in the NICH group (30.4% versus 0%, P = 0.026; Table 3). In univariate regression analyses, concomitant antiplatelet medication usage, baseline GCS score, initial NIHSS score, ICH volume at baseline and follow-up, hematoma volume >60 mL, hematoma expansion, concomitant IVH, and ICH occurrence in the lobar area were significantly associated with mortality at 3 months (Table 4). After adjustment for demographics, ICH occurrence in the lobar area (OR: 5.484, 95% CI: 1.230–24.451) was significantly associated with mortality at 3 months. However, after additional adjustment for other parameters, no associations were found between ICH occurrence in the lobar area and mortality at 3 months. After adjustment for demographics, ICH volume at baseline (OR: 1.018, 95% CI: 1.003–1.033) and follow-up (OR: 1.021, 95% CI: 1.008–1.035) and hematoma volume >60 mL (OR: 7.402, 95% CI: 1.676–32.692) were significantly associated with mortality at 3 months. The association remained significant after additional adjustment for concomitant antiplatelet medication usage. How-
Please cite this article as: H. G. Woo, I. Chung, D. S. Gwak et al., Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2018.10.102
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H.G. Woo et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
Table 2 Comparison of the radiological finding between NICH group and WICH group. WICH group (n = 46) Location of ICH, n (%) Supratentorial deep area Brainstem and cerebellum Lobar area ICH volume at baseline, cm3, median (IQR) ICH volume at baseline, n (%) < 30 cm3 30–60 cm3 > 60 cm3 Time to baseline imaging, hour, mean (SD) ICH volume at follow-up, cm3, median (IQR) Time to follow up imaging, hour, mean (SD) Hematoma expansion, n (%) Concomitant IVH, n (%)
NICH group (n = 13)
P value 0.998
21 (45.7) 11 (23.9) 14 (30.4) 14.1 (5.8–72.5)
6 (46.2) 3 (23.1) 4 (30.8) 36.5 (8.1– 62.0)
29 (63.0) 4 (8.7) 13 (28.3) 10.4 (20.2)
6 (46.2) 4 (30.8) 3 (23.1) 9.4 (6.8)
35.9 (6.6–80.9)
0.390
31.9 (58.1)
25.9 (9.0– 43.1) 26.0 (17.9)
27 (58.7) 23 (50.0)
1 (7.7) 2 (15.4)
0.001 0.030
0.609 0.121
0.867
0.718
Abbreviations: ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage.
Table 3 Comparison of the treatment and clinical outcome between NICH group and WICH group. WICH group (n = 46)
NICH group (n = 13)
P value
39 (84.8) 35 (76.1) 19 (41.3) 8.0 (3.0–24.0)
0 3 (23.1) 0 15.0 (3.5–20.5)
<0.001 0.001 0.005 0.777
mRS, median (IQR) Discharge Three months
4.0 (3.0–5.0) 4.0 (3.0–6.0)
5.0 (2.5–5.0) 4.0 (3.0–5.0)
0.956 0.628
Mortality (%) In-hospital Three months
8 (17.4) 14 (30.4)
0 0
0.180 0.026
Treatment, n (%) Vitamin K FFP Neurosurgery Discharge NIHSS, median (IQR)
Abbreviations: FFP, fresh frozen plasma; mRS, modified Rankin Scale.
ever, no associations were found after additional adjustment for initial NIHSS score. After adjustment for demographics, concomitant IVH (OR: 19.601, 95% CI: 3.540–108.515) and hematoma expansion (OR: 30.598, 95% CI: 3.612–259.217) were significantly associated with mortality at 3 months. The association remained significant after additional adjustment for concomitant antiplatelet medication usage (OR: 17.002, 95% CI: 2.943–98.224 and OR: 70.529, 95% CI: 4.482–1109.874, respectively) and initial NIHSS score (OR: 9.240, 95% CI: 1.450–58.892 and OR: 50.546, 95% CI: 2.763–924.748, respectively; Table 5). 4. Discussion To our knowledge, this is the first study that compared the clinical outcomes of NICH and WICH at 3 months in an Asian population. Our results show that the radiological findings and clinical outcome at 3 months are more favorable in the NICH group than in the WICH group. More specifically, we showed that even though the baseline hematoma volume in patients with NICH was larger than that in patients with WICH, the hematoma volume at follow-up, hematoma expansion, and mortality at the 3 months were lower in the NICH group. In addition, we demonstrated that hematoma expansion and concomitant IVH were independently associated with mortality at 3 months, after adjustment for confounding variables.
Table 4 Risk factors associated with mortality at 3 months. OR (95% CI)
P value
Demographics Age Male Sex
0.988 (0.931–1.049) 1.043 (0.322–3.376)
0.700 0.693
Comorbidities Congestive heart failure Hypertension Diabetes mellitus Hyperlipidemia Smoking Alcohol Previous stroke Chronic kidney disease
2.836 1.029 1.333 1.050 1.700 0.850 0.799 1.944
(0.649–12.401) (0.238–4.437) (0.377–4.710) (0.324–3.401) (0.471–6.141) (0.200–3.618) (0.247–2.585) (0.530–7.132)
0.166 0.970 0.655 0.935 0.418 0.826 0.708 0.316
Concomitant medication Antiplatelet Statin Baseline GCS Initial NIHSS
5.200 1.151 0.635 1.146
(1.294–20.890) (0.355–3.735) (0.501–0.804) (1.052–1.249)
0.020 0.609 <0.001 0.002
Image analysis ICH volume at baseline < 30 cm3 30–60 cm3 > 60 cm3 ICH volume at follow-up Hematoma expansion Concomitant IVH
1.016 (1.003–1.030) 1 (reference) 2.000 (0.312–12.840) 6.000 (1.536–23.428) 1.021 (1.008–1.034) 30.000 (3.581–251.344) 17.333 (3.397–88.453)
0.465 0.010 0.002 0.002 0.001
Location of ICH Supratentorial deep area Brainstem and cerebellum Lobar area
1 (reference) 1.568 (0.298–8.251) 4.600 (1.122–18.866)
0.595 0.034
0.015
Abbreviations: OR, Odd ratio; CI, confidence interval.
Compared with non-Asian patients, Asian patients with nonvalvular AF have different characteristics and a two-fold higher rate of ICH [21,22]. Moreover, Asian patients receiving warfarin therapy for non-valvular AF have a significantly higher risk of ICH than non-Asian patients do, with a hazard risk of 4.1 [23]. However, all clinical trials of NOACs reported a significantly lower incidence of ICH [24–27], which was evident in Asian populations [28–30]. Furthermore, the relatively better efficacy and safety of NOACs over warfarin appears to be greater in Asians than in nonAsians [10,21,31]. A previous multicenter international study revealed that NICH is associated with smaller baseline ICH volume and lower prevalence of hematoma expansion compared to that in WICH [13]. However, another study showed that baseline ICH volume and prevalence of hematoma expansion in the NICH group were similar to corresponding values in the WICH group, although the values tended to be higher in the NICH group [14]. Since most of these studies did not include any Asians or included only a small number of Asians, their results are not generalizable to Asian populations. Moreover, two previous studies found that mortality at 3 months in the NICH group was not significantly different from that in the WICH group [13,14]. Furthermore, some small studies with non-Asian patients have reported that NICH is associated with higher rates of mortality and unfavorable outcomes, and more frequent hematoma expansion [7,32]. In some Japanese studies, the NICH group had smaller hematoma volumes, with a lower rate of expansion and mortality than that in the WICH group [15– 17,33,34]. However, analysis of only the mRS score at discharge might not reflect long-term outcome. Therefore, we conducted this study to compare the outcome at 3 months between NICH and WICH in an Asian population. Our study showed that the mortality at 3 months was independently related to hematoma expansion and concomitant IVH, after adjusting for well-known confounding factors. This finding is consistent with the results of previous studies of anticoagulant-related
Please cite this article as: H. G. Woo, I. Chung, D. S. Gwak et al., Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2018.10.102
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H.G. Woo et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 5 Association between the mortality at 3 months and following dependent variables. Unadjusted OR (95% CI)
y à §
*
Model 1 yOR (95% CI) *
Model 2 àOR (95% CI) *
Model 3 §OR (95% CI)
ICH volume at basaline < 30 cm3 30–60 cm3 > 60 cm3 ICH volume at follow-up Hematoma expansion Concomitant IVH
1.016 (1.003–1.030) 1 (reference) 2.000 (0.312–12.840) 6.000 (1.536–23.428)* 1.021 (1.008–1.034)* 30.000 (3.581–251.344)* 17.333 (3.397–88.453)*
1.018 (1.003–1.033) 1 (reference) 2.111 (0.301–14.803) 7.402 (1.676–32.692)* 1.021 (1.008–1.035)* 30.598 (3.612–259.217)* 19.601 (3.540–108.515)*
1.020 (1.004–1.035) 1 (reference) 1.651 (0.194–14.024) 8.304 (1.704–40.475)* 1.020 (1.006–1.033)* 70.529 (4.482–1109.874)* 17.002 (2.943–98.224)*
1.013 (0.996–1.030) 1 (reference) 2.309 (0.272–19.615) 4.404 (0.749–25.904) 1.014 (0.999–1.029) 50.546 (2.763–924.748)* 9.240 (1.450–58.892)*
Location of ICH Supratentorial deep area Brainstem and cerebellum Lobar area
1 (reference) 1.568 (0.298–8.251) 4.600 (1.122–18.866)*
1 (reference) 1.695 (0.313–9.189) 5.484 (1.230–24.451)*
1 (reference) 1.719 (0.297–9.945) 4.604 (0.958–22.130)
1 (reference) 1.235 (0.175–8.728) 2.516 (0.456–13.888)
* p < 0.05. Adjusted for demographics. Adjusted for demographics and concomitant antiplatelet medication usage. Adjusted for demographics, concomitant antiplatelet medication usage, and Initial NIHSS score.
ICH [35–38]. Furthermore, even though baseline hematoma volume in patients with NICH was larger than that in patients with WICH, and there were no significant between-group differences in both time to baseline imaging and time to follow-up imaging, the prevalence rates of hematoma expansion and concomitant IVH were significant lower in the NICH group than in the WICH group. In addition, no deaths occurred in the NICH group, even without neurosurgery. Although more evidence is needed from well-designed studies to verify the predictive values of hematoma expansion and concomitant IVH in NICH and to clarify the pathophysiology underlying this relationship, the present study indicates that hematoma expansion and concomitant IVH are significantly associated with mortality at 3 months in Asian patients with NICH. Our results are supported by findings of previous studies, which indicated that concomitant antiplatelet medication usage, higher NIHSS score at admission, higher baseline GCS score, and larger hematoma volume in patients with anticoagulant-related ICH was associated with higher mortality rates [38–40]. In the present study, ICH occurrence in the lobar area was associated with a higher mortality at the 3-month follow-up than occurrence of ICH in the brainstem or cerebellum, or the supratentorial deep area. The association after adjusting for hematoma volume is consistent with the results of previous studies [14]. NOACs are preferentially indicated in Asian patients because of their greater efficacy and safety in this population, although the underlying mechanism remains unclear [10]. One potential explanation is that genetic polymorphism in the cytochrome P450 enzyme CYP2C9, and variations in the gene for vitamin K epoxide reductase complex 1 (VKORC1) may affect the optimal dose of warfarin or the response of patients to warfarin [41,42]. Another potential explanation is that NOACs exert an inhibitory action on thrombin or Xa but not on other coagulation factors, whereas warfarin is known to inhibit multiple coagulation factors and interact with tissue factor VIIa. In addition, NOAC does not inhibit platelet aggregation [43,44]. Furthermore, the half-life of NOACs (10–17 h) is shorter than that of warfarin (36–42 h) [45]. These differences between NOAC and warfarin could explain the lower prevalence of hematoma expansion during NOAC therapy in the present study in Asian patients, which is consistent with reports from other Japanese studies and a study of three NOACs in Asian patients [15,17,28–30,33,34]. Taken together, these data indicate that NOACs are safe and efficacious in Asian patients with nonvalvular AF. In addition to its retrospective nature, our study has a few other limitations. First, our results are limited to a single medical center with relatively few cases, and therefore, may not be representative
of other dissimilar settings. Moreover, it could be too underpowered to detect significant differences in some of the clinical outcomes between the two groups. A follow-up study with a larger study population and a longer follow-up period is warranted. Second, the timing of administration of the last anticoagulant or antiplatelet agent prior to ICH was not available. Third, we were unable to perform subgroup analyses according to NOAC type because of the low number of patients in each of the three NOAC subgroups. This analysis may be clinically relevant because distinct bleeding patterns and bleeding risks have been reported for different NOACs [35]. 5. Conclusion In this study, we found that the prevalence rates of hematoma expansion and concomitant IVH were significantly lower in Asian patients with NICH than in those with WICH. In addition, the radiological findings and clinical outcome at 3 months were more favorable in patients with NICH than in those with WICH. Declarations of interest The authors have declared that no competing interests exist. Funding The authors received no specific funding for this study. Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2018.10.102. References [1] 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. [2] Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke 1995;26:1471–7. [3] 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. [4] Katsanos AH, Mavridis D, Parissis J, Deftereos S, Frogoudaki A, Vrettou AR, et al. Novel oral anticoagulants for the secondary prevention of cerebral ischemia: a network meta-analysis. Ther Adv Neurol Disord 2016;9:359–68.
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Clinical study
Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients Ho Geol Woo a, Inyoung Chung b, Dong Seok Gwak b, Baik Kyun Kim c, Ji Hoon Kang d, Beom Joon Kim d, Hee-Joon Bae d, Moon-Ku Han d,⇑ a
Department of Neurology, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, 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 18 September 2018 Accepted 24 October 2018 Available online xxxx Keywords: Anticoagulants Atrial fibrillation Cerebral hemorrhage Warfarin
a b s t r a c t Non-valvular atrial fibrillation patients receiving non-vitamin K antagonist oral anticoagulants (NOACs) have half the incidence of intracerebral hemorrhage (ICH) compared to those receiving warfarin. However, the differences in outcomes of NOAC-associated ICH (NICH) and warfarin-associated ICH (WICH) remain controversial. In this study, we investigated the clinical outcome and radiologic findings of ICH in Asian patients receiving NOACs or warfarin. We retrospectively reviewed the medical records of 544 ICH patients admitted to our hospital from January 2013 through December 2017, and compared the baseline demographics, clinical characteristics, ICH-related radiologic findings, and clinical outcome between the WICH and NICH groups. WICH and NICH were diagnosed in 46 and 13 patients, respectively. Lesions were located more frequently in the supratentorial deep area (45.7% and 46.2%) than the lobar area (30.4% and 30.8%) or brainstem and cerebellum (23.9% and 23.1%) in the WICH and NICH groups, respectively. The hematoma expansion and concomitant intraventricular hemorrhage (IVH) rate was significantly higher in the WICH group than in the NICH group (58.7% versus 7.7%, P = 0.001 and 50.0% versus 15.4%, P = 0.030, respectively). Hematoma expansion (odds ratio [OR]: 50.546; 95% confidence interval [CI]: 2.763–924.748; P = 0.008) and concomitant IVH (OR: 9.240; 95% CI: 1.450–58.892; P = 0.019) were independently associated with mortality at three months, after adjustment for confounding variables. Our results indicate that the radiological findings and clinical outcome at three months in patients with ICH are more favorable in those receiving NOAC therapy than in those receiving warfarin treatment. Ó 2018 Published by Elsevier Ltd.
1. Introduction Intracranial hemorrhage (ICH) related to use of oral anticoagulants, one of the most challenging complications in patients with atrial fibrillation (AF), has been associated with a higher morbidity and mortality [1,2]. Although recent randomized trials in patients with AF have shown that the incidence of ICH in patients receiving non-vitamin K antagonist oral anticoagulants (NOACs) is about half that in patients receiving warfarin, and the 3-month mortality of NOAC-associated ICH (NICH) is similar to that of warfarinassociated ICH (WICH) [3–7]. However, some studies have shown
⇑ 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).
that, compared with WICH, NICH is associated with a higher risk of both hematoma expansion and unfavorable clinical outcomes [4,7]. Because of the increasing usage of NOACs in clinical practice and the current unavailability of specific reversal agents, it is important to investigate the outcomes of NICH [8,9]. Moreover, the clinical characteristics and radiologic findings of NICH remain unknown. Asian populations with AF have different characteristics than non-Asian populations with AF do. Asian patients taking warfarin are more prone to bleeding, including ICH, and less likely to achieve optimal control of international normalized ratio (INR) because of polymorphisms in genes such as CYP2C9 and vitamin K epoxide reductase complex 1 (VKORC1), which determine an individual’s warfarin sensitivity [10,11]. Currently, although small case series and multicenter prospective studies that compared the outcomes of NICH and WICH have reported, most prior studies
https://doi.org/10.1016/j.jocn.2018.10.102 0967-5868/Ó 2018 Published by Elsevier Ltd.
Please cite this article as: H. G. Woo, I. Chung, D. S. Gwak et al., Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2018.10.102
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have been conducted in non-Asian populations, and the few studies conducted in Asian populations have only reported outcomes on discharge [6,7,12–17]. Therefore, in the present study, we investigated clinical and radiological findings, and sought to identify factors associated with 3-month outcomes in Asian patients with ICH receiving anticoagulation therapy with either warfarin or NOACs. 2. Materials and methods The institutional review board approved this retrospective study, and informed consent was waived. 2.1. Subjects Initially, 544 consecutive patients with ICH who were treated at our institution between January 2013 and December 2017 were retrospectively selected from our institutional database. Of these 544 patients, 68 patients with a history of oral anticoagulant use were included in the study. WICH was defined as an INR of >1.5, as previously described [18], and NICH was defined as NOAC usage within the 24 h prior to the onset of clinical symptoms of ICH. Patients with predominant subarachnoid hemorrhage or secondary causes of ICH, such as major head trauma in the previous 24 h, vascular malformations, tumors, cavernomas, aneurysms, other known coagulopathy, or hemorrhagic transformation of an infarct were excluded from further evaluation. Finally, a total of 59 patients who met the inclusion criteria were enrolled in this study. These included 46 patients with a diagnosis of NICH (NICH group) and 13 patients with a diagnosis of WICH (WICH group; Fig. 1). 2.2. Evaluation of outcomes, and clinical and radiological characteristics Brain computed tomography (CT) was performed for all patients both at baseline and at follow-up within 72 h after admission. CT findings were interpreted by two neuroradiologists with over 10 years of experience evaluating brain CT scans at our institution, who were blinded to the patients’ clinical data. Imaging data included ICH volumes at baseline and follow-up CT, which were calculated using ABC/2 measurement, with blinding of anticoagulant type and outcome data. In addition, ICH volume at baseline was analyzed according to three categories based on hematoma volume (<30 cm3, 30–60 cm3, and >60 cm3) [19]. Hematoma expansion (HE) in ICH was defined as an increase in hematoma volume of >33% or >6 mL from the baseline to follow-up CT scan in patients who did not undergo subsequent intracranial
Fig. 1. Flowchart of patient inclusion.
surgery before follow-up imaging. Hematoma location was categorized as follows: supratentorial deep area (basal ganglia and thalamus), brainstem and cerebellum, and lobar area. Baseline laboratory parameters, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and INR, were measured routinely in all patients on warfarin or NOAC therapy. All eligible patients were treated according to the current guidelines for the management of spontaneous ICH [20]. As soon as ICH was diagnosed by brain CT, warfarin or NOACs were stopped. The effects of warfarin were reversed immediately by intravenous administration of vitamin K. Blood pressure was lowered to 140 mm Hg with intravenous nicardipine. Intubation, surgical decompression, or external ventricular drainage was performed on a case-by-case basis depending on neurologic deterioration and findings on the repeat CT scan [20]. Clinical outcomes were evaluated according to the National Institutes of Health Stroke Scale (NIHSS) scores at admission and discharge, and modified Rankin scale (mRS) score at discharge and 3-month follow-up. The initial and follow-up clinical evaluations were performed by three experienced stroke neurologists. In addition, we evaluated the in-hospital and 3-month mortality rates. 2.3. Statistical methods Statistical analysis was performed using SPSS 22.0 for Windows (IBM Corp. Armonk, NY, USA). Demographics, clinical characteristics, radiological findings, and clinical outcomes were compared between the WICH and NICH groups. Normally distributed data of continuous variables were evaluated with the KolmogorovSmirnov test. For normally distributed data, we used an independent t-test. For data with non-normal distribution, we used the Mann–Whitney U test. Data were summarized using standard descriptive statistics. All normally distributed variables are reported as mean ± standard deviation, and non-normally distributed variables are presented as median (interquartile range). Categorical variables are presented as frequency and percentage. Pearson chi square test was performed for comparison of categorical variables. Logistic regression analysis was performed to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between outcome at 3 months and all variables. A two-tailed P-value < 0.05 was considered statistically significant. 3. Results 3.1. Baseline patient demographics and comparison of clinical characteristics between the NICH and WICH groups The mean age of the 59 patients was 71.5 ± 9.7 years, and 52.5% of them were male. Three NOACs had been prescribed to 13 patients (22.0%), with different dosing regimens according to patient age, body weight, and renal function: dabigatran 110 mg twice a day (n = 1), rivaroxaban 20 mg once a day (n = 3), rivaroxaban 15 mg once a day (n = 6), apixaban 2.5 mg twice a day (n = 1), and apixaban 2.5 mg twice a day (n = 2). Table 1 summarizes the clinical characteristics of patients according to group. Patients in the NICH group were significantly older than those in the WICH group (75.4 ± 8.15 versus 70.4 ± 9.84, P = 0.036). No significant between-group differences were found in sex, cardiovascular risk factors, concomitant use of statins and antiplatelet medication, NIHSS and Glasgow Coma Scale (GCS) scores at admission, and time from symptom onset to arrival. No differences were found in baseline laboratory parameters, except for significantly higher INR (3.3 ± 2.0 versus 1.5 ± 0.6, P < 0.001), aPTT (56.3 ± 18.7 s versus 42.3 ± 12.2 s, P = 0.005) and
Please cite this article as: H. G. Woo, I. Chung, D. S. Gwak et al., Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2018.10.102
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Table 1 Comparison of the demographics and clinical characteristics between NICH group and WICH group. WICH group (n = 46)
NICH group (n = 13)
P value
Demographics Age, mean (SD) Male sex, n (%)
70.4 (9.84) 26 (56.5)
75.4 (8.15) 5 (38.5)
0.036 0.348
Cardiovascular risk factors, n (%) Congestive heart failure Hypertension Diabetes mellitus Hyperlipidemia Smoking Alcohol Previous stroke Chronic kidney disease
7 (15.2) 37 (80.4) 15 (32.6) 20 (43.5) 12 (26.1) 12 (26.1) 21 (45.7) 13 (28.3)
2 (15.4) 10 (76.9) 2 (15.4) 7 (53.8) 3 (23.1) 1 (7.7) 9 (69.2) 1 (7.7)
1.000 0.716 0.310 0.508 1.000 0.260 0.209 0.159
Concomitant medication, n (%) Antiplatelet Statin
10 (21.7) 18 (39.1)
1 (7.7) 8 (61.5)
0.426 0.209
3.3 (2.0) 56.3 (18.7) 31.7 (14.1) 1.40 (1.5) 71.6 (33.2) 10.5 (4.8– 19.3) 10.5 (6.0– 15.0) 572.1 (1154.0)
1.5 (0.6) 42.3 (12.2) 17.4 (5.4) 0.90 (0.2) 75.9 (12.5) 14.0 (3.0– 19.5) 12.0 (7.5– 15.0) 485 (334.5)
<0.001 0.005 <0.001 0.249 0.654 0.749
Laboratory finding, mean (SD) International Normalized Ratio aPTT, sec PT, sec Creatinine, mg/dL eGFR Initial NIHSS, median (IQR) Baseline GCS, median (IQR) Symptom onset to arrival time, minutes, mean (SD)
0.956 0.076
Abbreviations: NICH, Non-vitamin K antagonist oral anticoagulant-associated intracerebral hemorrhage; WICH, Warfarin-associated intracerebral hemorrhage; SD, Standard deviation; aPTT, activated partial thromboplastin time; PT, prothromb in time; eGFR, estimated glomerular filtration rate; NIHSS, National Institute of Health Stroke Severity Scale; IQR, Interquartile Range; GCS, Glasgow coma scale.
PT (31.7 ± 14.1 s versus 17.4 ± 5.4 s, P < 0.001) in the WICH group than in the NICH group. 3.2. Comparisons of the radiological findings between the NICH and WICH groups In both the WICH group and the NICH group, hematomas was more frequently in the supratentorial deep area (45.7% and 46.2%, respectively) than in the lobar area (30.4% and 30.8%, respectively), and brainstem and cerebellum (23.9% and 23.1%, respectively). There was no significant difference in ICH location between the two groups (Fig. 2A). Hematoma volumes in the NICH and WICH groups are shown in Fig. 2B. There was no difference in the distribution of the three hematoma volume-based categories (<30 cm3, 30–60 cm3, and >60 cm3) between the WICH and NICH groups (Fig. 2C). The prevalence of hematoma expansion was significantly lower in the NICH group than in the WICH group (7.7% versus 58.7%, P = 0.001). Moreover, the prevalence of concomitant intraventricular hemorrhage (IVH) was significantly lower in the NICH group than in the WICH group (15.4% versus 50.0%, P = 0.030; Table 2). 3.3. Comparisons of treatment and clinical outcome between the NICH and WICH groups and association of variables with clinical outcome Administration of vitamin K (84.8% versus 0.0%, P < 0.001) and fresh frozen plasma (76.1% versus 23.1%, P = 0.001) was more frequent in the WICH group than in the NICH group. No patient in the NICH group underwent invasive procedures, including neurosurgery. NIHSS score at discharge and mRS score at discharge and 3-month follow-up were not significantly different between the two groups. However, in-hospital mortality was higher in the
Fig. 2. Comparisons of the radiological finding between NICH group and WICH group. A. The supratentorial deep area was included by thalamus and basal ganglia. The supratentorial deep area (45.7% [thalamus: 23.9%, basal ganglia: 21.7%] and 46.2% [thalamus: 30.8%, basal ganglia: 15.4%], respectively) was more frequent than lobar location (30.4% and 30.8%, respectively) and brainstem and cerebellum location (23.9% [brainstem: 10.9%, cerebellum: 13.0%] and 23.1% [brainstem: 7.7%, cerebellum: 15.4%], respectively) in both WICH group and NICH group. B. Hematoma volume in the NICH group and WICH group was shown. C. Distribution of volume of ICH using three categories of hematoma volume (<30 cm3, 30–60 cm3, and >60 cm3) was shown. hematoma volume<30 cm3 was more often in both WICH group and NICH group (63.0% and 46.2%) but there was no significant difference.
WICH group than in the NICH group (17.4% versus 0%, respectively). Moreover, mortality at 3 months was significantly higher in the WICH group than in the NICH group (30.4% versus 0%, P = 0.026; Table 3). In univariate regression analyses, concomitant antiplatelet medication usage, baseline GCS score, initial NIHSS score, ICH volume at baseline and follow-up, hematoma volume >60 mL, hematoma expansion, concomitant IVH, and ICH occurrence in the lobar area were significantly associated with mortality at 3 months (Table 4). After adjustment for demographics, ICH occurrence in the lobar area (OR: 5.484, 95% CI: 1.230–24.451) was significantly associated with mortality at 3 months. However, after additional adjustment for other parameters, no associations were found between ICH occurrence in the lobar area and mortality at 3 months. After adjustment for demographics, ICH volume at baseline (OR: 1.018, 95% CI: 1.003–1.033) and follow-up (OR: 1.021, 95% CI: 1.008–1.035) and hematoma volume >60 mL (OR: 7.402, 95% CI: 1.676–32.692) were significantly associated with mortality at 3 months. The association remained significant after additional adjustment for concomitant antiplatelet medication usage. How-
Please cite this article as: H. G. Woo, I. Chung, D. S. Gwak et al., Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2018.10.102
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Table 2 Comparison of the radiological finding between NICH group and WICH group. WICH group (n = 46) Location of ICH, n (%) Supratentorial deep area Brainstem and cerebellum Lobar area ICH volume at baseline, cm3, median (IQR) ICH volume at baseline, n (%) < 30 cm3 30–60 cm3 > 60 cm3 Time to baseline imaging, hour, mean (SD) ICH volume at follow-up, cm3, median (IQR) Time to follow up imaging, hour, mean (SD) Hematoma expansion, n (%) Concomitant IVH, n (%)
NICH group (n = 13)
P value 0.998
21 (45.7) 11 (23.9) 14 (30.4) 14.1 (5.8–72.5)
6 (46.2) 3 (23.1) 4 (30.8) 36.5 (8.1– 62.0)
29 (63.0) 4 (8.7) 13 (28.3) 10.4 (20.2)
6 (46.2) 4 (30.8) 3 (23.1) 9.4 (6.8)
35.9 (6.6–80.9)
0.390
31.9 (58.1)
25.9 (9.0– 43.1) 26.0 (17.9)
27 (58.7) 23 (50.0)
1 (7.7) 2 (15.4)
0.001 0.030
0.609 0.121
0.867
0.718
Abbreviations: ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage.
Table 3 Comparison of the treatment and clinical outcome between NICH group and WICH group. WICH group (n = 46)
NICH group (n = 13)
P value
39 (84.8) 35 (76.1) 19 (41.3) 8.0 (3.0–24.0)
0 3 (23.1) 0 15.0 (3.5–20.5)
<0.001 0.001 0.005 0.777
mRS, median (IQR) Discharge Three months
4.0 (3.0–5.0) 4.0 (3.0–6.0)
5.0 (2.5–5.0) 4.0 (3.0–5.0)
0.956 0.628
Mortality (%) In-hospital Three months
8 (17.4) 14 (30.4)
0 0
0.180 0.026
Treatment, n (%) Vitamin K FFP Neurosurgery Discharge NIHSS, median (IQR)
Abbreviations: FFP, fresh frozen plasma; mRS, modified Rankin Scale.
ever, no associations were found after additional adjustment for initial NIHSS score. After adjustment for demographics, concomitant IVH (OR: 19.601, 95% CI: 3.540–108.515) and hematoma expansion (OR: 30.598, 95% CI: 3.612–259.217) were significantly associated with mortality at 3 months. The association remained significant after additional adjustment for concomitant antiplatelet medication usage (OR: 17.002, 95% CI: 2.943–98.224 and OR: 70.529, 95% CI: 4.482–1109.874, respectively) and initial NIHSS score (OR: 9.240, 95% CI: 1.450–58.892 and OR: 50.546, 95% CI: 2.763–924.748, respectively; Table 5). 4. Discussion To our knowledge, this is the first study that compared the clinical outcomes of NICH and WICH at 3 months in an Asian population. Our results show that the radiological findings and clinical outcome at 3 months are more favorable in the NICH group than in the WICH group. More specifically, we showed that even though the baseline hematoma volume in patients with NICH was larger than that in patients with WICH, the hematoma volume at follow-up, hematoma expansion, and mortality at the 3 months were lower in the NICH group. In addition, we demonstrated that hematoma expansion and concomitant IVH were independently associated with mortality at 3 months, after adjustment for confounding variables.
Table 4 Risk factors associated with mortality at 3 months. OR (95% CI)
P value
Demographics Age Male Sex
0.988 (0.931–1.049) 1.043 (0.322–3.376)
0.700 0.693
Comorbidities Congestive heart failure Hypertension Diabetes mellitus Hyperlipidemia Smoking Alcohol Previous stroke Chronic kidney disease
2.836 1.029 1.333 1.050 1.700 0.850 0.799 1.944
(0.649–12.401) (0.238–4.437) (0.377–4.710) (0.324–3.401) (0.471–6.141) (0.200–3.618) (0.247–2.585) (0.530–7.132)
0.166 0.970 0.655 0.935 0.418 0.826 0.708 0.316
Concomitant medication Antiplatelet Statin Baseline GCS Initial NIHSS
5.200 1.151 0.635 1.146
(1.294–20.890) (0.355–3.735) (0.501–0.804) (1.052–1.249)
0.020 0.609 <0.001 0.002
Image analysis ICH volume at baseline < 30 cm3 30–60 cm3 > 60 cm3 ICH volume at follow-up Hematoma expansion Concomitant IVH
1.016 (1.003–1.030) 1 (reference) 2.000 (0.312–12.840) 6.000 (1.536–23.428) 1.021 (1.008–1.034) 30.000 (3.581–251.344) 17.333 (3.397–88.453)
0.465 0.010 0.002 0.002 0.001
Location of ICH Supratentorial deep area Brainstem and cerebellum Lobar area
1 (reference) 1.568 (0.298–8.251) 4.600 (1.122–18.866)
0.595 0.034
0.015
Abbreviations: OR, Odd ratio; CI, confidence interval.
Compared with non-Asian patients, Asian patients with nonvalvular AF have different characteristics and a two-fold higher rate of ICH [21,22]. Moreover, Asian patients receiving warfarin therapy for non-valvular AF have a significantly higher risk of ICH than non-Asian patients do, with a hazard risk of 4.1 [23]. However, all clinical trials of NOACs reported a significantly lower incidence of ICH [24–27], which was evident in Asian populations [28–30]. Furthermore, the relatively better efficacy and safety of NOACs over warfarin appears to be greater in Asians than in nonAsians [10,21,31]. A previous multicenter international study revealed that NICH is associated with smaller baseline ICH volume and lower prevalence of hematoma expansion compared to that in WICH [13]. However, another study showed that baseline ICH volume and prevalence of hematoma expansion in the NICH group were similar to corresponding values in the WICH group, although the values tended to be higher in the NICH group [14]. Since most of these studies did not include any Asians or included only a small number of Asians, their results are not generalizable to Asian populations. Moreover, two previous studies found that mortality at 3 months in the NICH group was not significantly different from that in the WICH group [13,14]. Furthermore, some small studies with non-Asian patients have reported that NICH is associated with higher rates of mortality and unfavorable outcomes, and more frequent hematoma expansion [7,32]. In some Japanese studies, the NICH group had smaller hematoma volumes, with a lower rate of expansion and mortality than that in the WICH group [15– 17,33,34]. However, analysis of only the mRS score at discharge might not reflect long-term outcome. Therefore, we conducted this study to compare the outcome at 3 months between NICH and WICH in an Asian population. Our study showed that the mortality at 3 months was independently related to hematoma expansion and concomitant IVH, after adjusting for well-known confounding factors. This finding is consistent with the results of previous studies of anticoagulant-related
Please cite this article as: H. G. Woo, I. Chung, D. S. Gwak et al., Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2018.10.102
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H.G. Woo et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 5 Association between the mortality at 3 months and following dependent variables. Unadjusted OR (95% CI)
y à §
*
Model 1 yOR (95% CI) *
Model 2 àOR (95% CI) *
Model 3 §OR (95% CI)
ICH volume at basaline < 30 cm3 30–60 cm3 > 60 cm3 ICH volume at follow-up Hematoma expansion Concomitant IVH
1.016 (1.003–1.030) 1 (reference) 2.000 (0.312–12.840) 6.000 (1.536–23.428)* 1.021 (1.008–1.034)* 30.000 (3.581–251.344)* 17.333 (3.397–88.453)*
1.018 (1.003–1.033) 1 (reference) 2.111 (0.301–14.803) 7.402 (1.676–32.692)* 1.021 (1.008–1.035)* 30.598 (3.612–259.217)* 19.601 (3.540–108.515)*
1.020 (1.004–1.035) 1 (reference) 1.651 (0.194–14.024) 8.304 (1.704–40.475)* 1.020 (1.006–1.033)* 70.529 (4.482–1109.874)* 17.002 (2.943–98.224)*
1.013 (0.996–1.030) 1 (reference) 2.309 (0.272–19.615) 4.404 (0.749–25.904) 1.014 (0.999–1.029) 50.546 (2.763–924.748)* 9.240 (1.450–58.892)*
Location of ICH Supratentorial deep area Brainstem and cerebellum Lobar area
1 (reference) 1.568 (0.298–8.251) 4.600 (1.122–18.866)*
1 (reference) 1.695 (0.313–9.189) 5.484 (1.230–24.451)*
1 (reference) 1.719 (0.297–9.945) 4.604 (0.958–22.130)
1 (reference) 1.235 (0.175–8.728) 2.516 (0.456–13.888)
* p < 0.05. Adjusted for demographics. Adjusted for demographics and concomitant antiplatelet medication usage. Adjusted for demographics, concomitant antiplatelet medication usage, and Initial NIHSS score.
ICH [35–38]. Furthermore, even though baseline hematoma volume in patients with NICH was larger than that in patients with WICH, and there were no significant between-group differences in both time to baseline imaging and time to follow-up imaging, the prevalence rates of hematoma expansion and concomitant IVH were significant lower in the NICH group than in the WICH group. In addition, no deaths occurred in the NICH group, even without neurosurgery. Although more evidence is needed from well-designed studies to verify the predictive values of hematoma expansion and concomitant IVH in NICH and to clarify the pathophysiology underlying this relationship, the present study indicates that hematoma expansion and concomitant IVH are significantly associated with mortality at 3 months in Asian patients with NICH. Our results are supported by findings of previous studies, which indicated that concomitant antiplatelet medication usage, higher NIHSS score at admission, higher baseline GCS score, and larger hematoma volume in patients with anticoagulant-related ICH was associated with higher mortality rates [38–40]. In the present study, ICH occurrence in the lobar area was associated with a higher mortality at the 3-month follow-up than occurrence of ICH in the brainstem or cerebellum, or the supratentorial deep area. The association after adjusting for hematoma volume is consistent with the results of previous studies [14]. NOACs are preferentially indicated in Asian patients because of their greater efficacy and safety in this population, although the underlying mechanism remains unclear [10]. One potential explanation is that genetic polymorphism in the cytochrome P450 enzyme CYP2C9, and variations in the gene for vitamin K epoxide reductase complex 1 (VKORC1) may affect the optimal dose of warfarin or the response of patients to warfarin [41,42]. Another potential explanation is that NOACs exert an inhibitory action on thrombin or Xa but not on other coagulation factors, whereas warfarin is known to inhibit multiple coagulation factors and interact with tissue factor VIIa. In addition, NOAC does not inhibit platelet aggregation [43,44]. Furthermore, the half-life of NOACs (10–17 h) is shorter than that of warfarin (36–42 h) [45]. These differences between NOAC and warfarin could explain the lower prevalence of hematoma expansion during NOAC therapy in the present study in Asian patients, which is consistent with reports from other Japanese studies and a study of three NOACs in Asian patients [15,17,28–30,33,34]. Taken together, these data indicate that NOACs are safe and efficacious in Asian patients with nonvalvular AF. In addition to its retrospective nature, our study has a few other limitations. First, our results are limited to a single medical center with relatively few cases, and therefore, may not be representative
of other dissimilar settings. Moreover, it could be too underpowered to detect significant differences in some of the clinical outcomes between the two groups. A follow-up study with a larger study population and a longer follow-up period is warranted. Second, the timing of administration of the last anticoagulant or antiplatelet agent prior to ICH was not available. Third, we were unable to perform subgroup analyses according to NOAC type because of the low number of patients in each of the three NOAC subgroups. This analysis may be clinically relevant because distinct bleeding patterns and bleeding risks have been reported for different NOACs [35]. 5. Conclusion In this study, we found that the prevalence rates of hematoma expansion and concomitant IVH were significantly lower in Asian patients with NICH than in those with WICH. In addition, the radiological findings and clinical outcome at 3 months were more favorable in patients with NICH than in those with WICH. Declarations of interest The authors have declared that no competing interests exist. Funding The authors received no specific funding for this study. Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2018.10.102. References [1] 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. [2] Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke 1995;26:1471–7. [3] 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. [4] Katsanos AH, Mavridis D, Parissis J, Deftereos S, Frogoudaki A, Vrettou AR, et al. Novel oral anticoagulants for the secondary prevention of cerebral ischemia: a network meta-analysis. Ther Adv Neurol Disord 2016;9:359–68.
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Please cite this article as: H. G. Woo, I. Chung, D. S. Gwak et al., Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2018.10.102