Circulation Journal ORIGINAL ARTICLE Circ J 2019; 83: 441 – 446 doi: 10.1253/circj.CJ-18-0938

Safety of Anticoagulant Therapy Including Direct Oral Anticoagulants in Patients With Acute Spontaneous Intracerebral Hemorrhage

Yuki Sakamoto, MD; Chikako Nito, MD, PhD; Yasuhiro Nishiyama, MD, PhD; Satoshi Suda, MD, PhD; Noriko Matsumoto, MD, PhD; Junya Aoki, MD, PhD; Takashi Shimoyama, MD, PhD; Takuya Kanamaru, MD, PhD; Kentaro Suzuki, MD; Takuya Nishimura, MD; Masahiro Mishina, MD, PhD; Kazumi Kimura, MD, PhD

Background: Because the efficacy and safety of anticoagulant therapy in patients with acute intracerebral hemorrhage (ICH) are not fully known, present study aimed to elucidate the current status and the safety of anticoagulant therapy, mainly direct oral anticoagulants (DOACs), for acute ICH and anticoagulant-indicated patients.

Methods and Results: From September 2014 through March 2017, consecutive patients with acute (<7 days from onset), sponta- neous ICH were retrospectively enrolled from a prospective registry. Whether to start anticoagulation was at the attending physicians’ discretion, and thromboembolic or hemorrhagic events during hospitalization were analyzed. A total of 236 patients (80 women [34%]; median age 69 [interquartile range 61–79] years; National Institutes of Health stroke scale score 7 [3–16]) were enrolled. Of them, 47 patients (20%) had an indication for anticoagulant therapy (33 had atrial fibrillation, 14 developed deep ), and 41 of 47 patients (87%) were actually treated with anticoagulant therapy (DOACs were used in 34 patients) after a median of 7 days from ICH onset. There was neither hematoma expansion nor excessive hemorrhagic complications during hospitalization after starting anticoagulant therapy.

Conclusions: Anticoagulant therapy was conducted for approximately 90% of anticoagulation-indicated patients after a median of 7 days from ICH onset. The predominant anticoagulant medications were DOACs. Anticoagulant therapy started from the acute phase of ICH should be safe.

Key Words: Atrial fibrillation; ; Direct oral anticoagulants; Intracerebral hemorrhage; Safety

ntracerebral hemorrhage (ICH) is a devastating patients only with anticoagulation-related ICH. The safety hemorrhagic event associated with high mortality or and effectiveness of anticoagulant therapy in patients I severe neurological sequelae.1 One of the areas of with acute spontaneous intracerebral, not intracranial, uncertainty in managing ICH patients is whether to provide hemorrhage are not fully known. Moreover, the safety or anticoagulant therapy for those needing anticoagulation,2,3 effect of direct oral anticoagulants (DOACs) after ICH is especially in acute settings; ICH patients have a high risk also unknown. DOACs are theoretically more suitable of thromboembolic disease,4 but patients with a history of for patients with non-valvular atrial fibrillation (AF) or ICH carry a significant risk of recurrent ICH when treated deep vein thrombosis (DVT) and ICH, because ICH has with a vitamin K antagonist (VKA) after initial ICH.5 Past occurred less frequently in patients treated with DOACs retrospective studies suggested that initiating anticoagulant compared with those treated with a VKA in clinical trials.12–17 therapy after ICH in patients needing anticoagulation Thus the aims of the present study were to elucidate the might be beneficial, though optimal timing for starting current status and safety of anticoagulant therapy, including treatment was undetermined.6–10 However, the patients DOACs, for acute spontaneous ICH patients in real-world included in many past studies were heterogeneous in terms settings. of the type of hemorrhage (intracranial, not intracerebral, hemorrhage including traumatic, subarachnoid, subdural, and epidural hemorrhage),11 and most studies included

Received August 22, 2018; revised manuscript received September 26, 2018; accepted November 17, 2018; J-STAGE Advance Publication released online December 27, 2018 Time for primary review: 27 days Department of Neurological Science (Y.S., C.N., Y.N., S.S., N.M., J.A., T.S., T.K., K.S., T.N., K.K.), Department of Neuro-pathophysiological Imaging (M.M.), Graduate School of Medicine, Nippon Medical School, Tokyo, Japan Mailing address: Yuki Sakamoto, MD, Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. E-mail: [email protected] ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

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Table 1. Patients’ Baseline Clinical Characteristics AC group Non-AC group Variable P value (n=41) (n=195) Female sex, n (%) 13 (32) 67 (34) 0.857 Age, years, median (IQR) 72 (65–80) 68 (59–78) 0.115 BMI, kg/m2, median (IQR) 23.0 (20.2–24.9) 22.2 (20.1–24.4) 0.416 Prior history of ischemic stroke, n (%) 10 (24) 11 (6) 0.001 Prior history of hemorrhagic stroke, n (%) 1 (2) 19 (10) 0.213 Vascular risk factor, n (%) 35 (85) 163 (84) 1.000 mellitus 13 (32) 35 (18) 0.056 Hyperlipidemia 12 (29) 50 (26) 0.697 Current smoking 10 (24) 54 (28) 0.847 Daily alcohol intake 23 (56) 100 (51) 0.609 Preadmission mRS score, median (IQR) 0 (0–1) 0 (0–0) 0.923 Initial NIHSS score, median (IQR) 11 (3–19) 7 (3–15) 0.336 Initial hematoma volume, ml, median (IQR) 8.0 (4.5–27.0) 6.6 (2.6–14.0) 0.119 Lobar hemorrhage, n (%) 10 (24) 29 (15) 0.164 test results at admission, median (IQR) Hemoglobin, g/dL 13.7 (11.8–15.5) 13.6 (12.5–15.0) 0.735 Platelet count, ×104/μL 19.4 (16.8–22.7) 20.7 (16.8–24.6) 0.278 eGFR, mL/min/1.73 m2 60 (43–74) 72 (59–85) 0.002 Length of hospital stay, days, median (IQR) 21 (14–31) 16 (10–26) 0.026 mRS score at discharge, median (IQR) 4 (3–5) 4 (2–4) 0.445 AC group: patients treated with anticoagulant therapy during hospitalization. Non-AC group: patients not treated with anticoagulant therapy during hospitalization. AC, anticoagulation; BMI, body mass index; eGFR, estimated glomerular filtration rate; ICH, intracerebral hemorrhage; IQR, interquartile range; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale.

Methods index ICH was counted as “history of hemorrhagic stroke”. Neurological severity was assessed using the National Subjects Institutes of Health Stroke Scale (NIHSS), and functional From September 2014 through March 2017, consecutive outcomes were evaluated using the modified Rankin Scale patients with acute (<7 days from onset), spontaneous (mRS). Anthropometric measurements and routine blood ICH admitted to our Stroke Unit (SU) were retrospectively biochemistry examinations were performed on admission. enrolled from a prospective registry. In general, acute ICH Hematoma volume was evaluated with non-contrast patients were admitted to the SU and antihypertensive computed tomography (CT) on admission using the ABC/2 treatment started as soon as possible, targeting systolic method. Magnetic resonance imaging, including T2*- (BP) <140 mmHg. Patients with secondary gradient echo imaging (T2*), was performed during admis- ICH and/or who underwent surgical intervention in the sion, and the presence and location of cerebral microbleeds acute phase (<7 days from onset) were excluded. This were assessed using previously reported criteria.19 Cerebral study was approved by the institutional ethics committee. amyloid angiopathy (CAA) was diagnosed using modified Written, informed consent was obtained from all patients Boston criteria.20 AF was diagnosed with 12-lead ECG or or their next-of-kin. cardiac monitoring during the SU stay. DVT was diagnosed using lower extremity ultrasonography or enhanced CT. Clinical Characteristics Any thromboembolic and hemorrhagic events during Clinical background characteristics, including sex, age, hospitalization were collected from the medical charts. cardiovascular risk factors, and past medical histories, were recorded on admission. Cardiovascular risk factors Anticoagulant Therapy and Follow-up Imaging were defined as: (1) hypertension, history of using antihy- Whether to start anticoagulation was at the attending pertensive agents, systolic BP ≥140 mmHg, or diastolic BP physicians’ discretion. Detailed anticoagulant therapy ≥90 mmHg before or ≥2 weeks after stroke onset; (2) information, if started, including the timing, class (VKA, diabetes mellitus, use of hypoglycemic agents, random DOAC, or other), and dose, were collected. Hematoma glucose level ≥200 mg/dL, or glycosylated hemoglobin expansion after starting anticoagulant therapy was assessed ≥6.5% on admission; (3) hyperlipidemia, use of antihyper- with follow-up cranial CT. lipidemic agents, or a serum total level ≥220 mg/dL; (4) current smoker; and (5) daily alcohol Statistical Analysis intake. The HAS-BLED score was calculated based on the All patients were divided into 2 groups: those treated with published guideline.18 Aortic plaque was not assessed as a anticoagulant therapy during hospitalization (AC group) component of the score. Because the present study aimed and those not (Non-AC group). First, clinical background to assess the safety of anticoagulant therapy after ICH, the characteristics were compared between groups. In addition,

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Table 2. Baseline Clinical Characteristics of Anticoagulant-Indicated Patients With and Without Anticoagulation Started AC Not started AC Variable P value (n=41) (n=6) Female sex, n (%) 13 (32) 2 (33) 1.000 Age, years, median (IQR) 72 (65–80) 83 (73–83) 0.239 BMI, kg/m2, median (IQR) 23.0 (20.2–24.9) 18.9 (17.5–22.5) 0.045 Prior history of ischemic stroke, n (%) 10 (24) 0 (0) 0.317 Prior history of hemorrhagic stroke, n (%) 1 (2) 1 (17) 0.241 Vascular risk factor, n (%) Hypertension 35 (85) 5 (83) 1.000 Diabetes mellitus 13 (32) 1 (17) 0.653 Hyperlipidemia 12 (29) 0 (0) 0.315 Current smoking 10 (24) 0 (0) 0.317 Daily alcohol intake 23 (56) 2 (33) 0.398 AC before admission, n (%) 25 (61) 3 (50) 0.674 Preadmission mRS score, median (IQR) 0 (0–1) 1 (0–3) 0.115 Initial NIHSS score, median (IQR) 11 (3–19) 18 (6–28) 0.214 Initial hematoma volume, mL, median (IQR) 8.0 (4.5–27.0) 30.0 (7.0–94.0) 0.124 Lobar hemorrhage, n (%) 10 (24) 2 (33) 0.637 Presence of lobar microbleeds, n (%)* 19 (56) 1 (50) 1.000 Probable CAA, n (%) 5 (12) 0 (0) 1.000 Blood test results at admission, median (IQR) Hemoglobin, g/dL 13.7 (11.8–15.5) 12.9 (10.5–14.0) 0.373 Platelet count, ×104/μL 19.4 (16.8–22.7) 20.6 (15.6–25.9) 0.652 eGFR, mL/min/1.73 m2 60 (43–74) 68 (50–91) 0.279 Atrial fibrillation, n (%) 29 (71) 4 (67) 1.000 DVT during admission, n (%) 12 (29) 2 (33) 1.000 HAS-BLED score after index ICH, median (IQR) 3 (3–5) 4 (4–6) 0.279 Length of hospital stay, days, median (IQR) 21 (14–31) 41 (23–52) 0.082 mRS score at discharge, median (IQR) 4 (3–5) 5 (5–5) 0.013 In-hospital death or discharge to nursing home, n (%) 4 (10) 3 (50) 0.035 *For 36 patients (34 in Started AC and 2 in Not started AC groups) underwent T2* imaging. CAA, cerebral amyloid angiopathy; DVT, deep vein thrombosis. Other abbreviations as in Table 1.

clinical background characteristics were analyzed between years; NIHSS score 7 [3–16]; onset to arrival 3.2 [1.1–18.0] anticoagulant-indicated patients who received anticoagulant h; and length of hospital stay 17 [11–26] days) were therapy (and belonged to the AC group) and those who enrolled. Of these 236 patients, 41 (17%) were treated with did not. Next, the number of days from ICH onset to anticoagulant therapy (AC group), and the remaining 195 anticoagulant therapy and the rate of hematoma expansion (83%) were not (Non-AC group). Table 1 shows the baseline after anticoagulant therapy were assessed. Finally, throm- background characteristics of the included patients. Patients boembolic and hemorrhagic events were compared between in the AC group had a more frequent past history of the AC and Non-AC groups. Univariate analyses were ischemic stroke (24% vs. 6%, P=0.001), an estimated performed using the chi-squared test, Fisher’s exact test, or glomerular filtration rate (60 [43–74] mL/min/1.73 m2 vs. the Mann-Whitney U test, as appropriate. The data are 72 [59–85] mL/min/1.73 m2, P=0.002) that was lower, and presented as median values (interquartile range [IQR]) or a length of hospital stay (21 [14–31] days vs. 16 [10–26] numbers (%). All statistical analyses were performed using days, P=0.026) that was longer than those in the Non-AC PASW for Windows version 17.0 software (SPSS Inc., group. Chicago, IL, USA). Results were considered significant at Of the 236 patients included in the present study, 47 P<0.05. (20%) had indications for anticoagulant therapy (33 had AF; 14 developed DVT during admission, Supplementary Results Table), and 41 of 47 patients (87%, 29 AF and 12 DVT) were actually treated with anticoagulant therapy (DOACs Overall, 268 consecutive patients with ICH were admitted in 34 patients [22 (65%) administered lower-dose treatment, to the SU during the study period. Of these, 29 who and 11 (50%) of the 22 lower-dose cases were inappropriate, underwent surgery in the acute phase were excluded, and in terms of our domestic label] and VKA in 7). The body 3 patients diagnosed as having secondary ICH caused by mass index was lower (18.9 [17.5–22.5] kg/m2 vs. 23.0 minor trauma, arteriovenous malformation, or cerebral [20.2–24.9] kg/m2, P=0.045), the mRS score at discharge , respectively, were also excluded. Finally, was higher (5 [5–5] vs. 4 [3–5], P=0.013), and the proportion 236 patients (80 women [34%]; median age 69 [IQR 61–79] of in-hospital deaths or discharge directly to a nursing

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Table 3. Thromboembolic and Hemorrhagic Events During Hospitalization AC group Non-AC group Variable P value (n=41) (n=195) Days from ICH onset to starting AC, days, median (IQR) 7 (6–12) NA NA Days from starting AC to follow-up CT, days, median (IQR) 7 (4–13)a NA NA Hematoma expansion after AC, n (%) 0 (0) NA NA Thromboembolic event, n (%) Before AC 1b (2.4) 5c (2.6) 1.000 After AC 2d (4.9) NA NA Hemorrhagic event, n (%) Before AC 0 (0) 7e (3.6) 0.608 After AC 1f (2.4) NA NA aNo follow-up imaging in 11 patients. b1 ischemic stroke. c3 ischemic and 2 DVT. d1 ischemic stroke and 1 DVT. e1 ICH, 1 genital, and 5 gastrointestinal bleeds. f1 gastrointestinal bleed. AC group: patients treated with anticoagulant therapy during hospitalization. Non-AC group: patients not treated with anticoagulant therapy during hospitalization. CT, computed tomography; NA, not applicable. Other abbreviations as in Tables 1,2.

Figure. Distribution of days from ICH onset to starting anticoagulant therapy in AF patients treated with DOACs (black bars) or VKA (white bars), and in DVT patients treated with DOACs (dotted bars) or VKA (lined bars). ICH, intracerebral hemorrhage; DOAC, direct oral anticoagulant; VKA, vitamin K antagonist.

home was higher (50% vs. 10%, P=0.035) in patients who case of non-fatal diverticular occurred 7 days did not receive anticoagulant therapy despite having an after starting anticoagulant therapy, and anticoagulant indication than in those treated with anticoagulant therapy therapy was ceased. Continuing anticoagulant medications (Table 2). The presence of lobar microbleeds or satisfying were prescribed at hospital discharge in 39 of 40 patients probable CAA criteria did not differ between patients with who survived to discharge. and without anticoagulant therapy. Anticoagulant therapy started after a median of 7 (6–12) Discussion days from ICH onset (Table 3, Figure). Oral anticoagulant medication was used in all 41 patients, and intravenous or The present study showed that 20% of acute spontaneous subcutaneous anticoagulation, including unfractionated or ICH patients had an indication for anticoagulant therapy, low-molecular-weight heparin, was never used. Similarly, and anticoagulant therapy, mainly DOACs, was started in simultaneous antiplatelet therapy was never used. Follow-up approximately 90% of such patients after a median of 7 imaging after anticoagulant therapy was performed in 30 days from ICH onset. Anticoagulant therapy was withheld of 41 (73%) patients at a median of 7 [4–13] days after from patients with severe neurological symptoms, but was starting anticoagulation, and no hematoma expansion was initiated irrespective of lobar microbleeds or the patient observed. In the Non-AC group, 7 (3.6%) hemorrhagic satisfying probable CAA criteria. There seemed to be no events occurred during hospitalization. In the AC group, 1 excess risk of hematoma expansion or hemorrhagic

Circulation Journal Vol.83, February 2019 Anticoagulant Therapy in Acute ICH 445 complications after starting anticoagulant therapy in not extremely severe. The present study may offer safety patients with acute ICH. information only for aggressive anticoagulant therapy in Anticoagulant therapy was performed in approximately patients with acute ICH and whose symptoms are not 90% of indicated patients in the present study. The rate of extremely severe, rather than information about the safety patients with anticoagulant therapy after ICH was much of anticoagulant therapy after ICH. Second, patients with higher than in previous reports, in which the proportion of AF and those with DVT were handled together as belonging patients receiving anticoagulant therapy after ICH ranged to the AC group in the present study. Patients with AF and from 6.3% to 48%.7 Moreover, anticoagulant therapy was those with DVT should be assessed separately; indeed, the conducted as early as a median of 7 days from ICH onset, clinical background characteristics, including preceding irrespective of lobar microbleeds or satisfying probable anticoagulant therapy before ICH (Supplementary Table), CAA criteria. This probably reflected our traditional timing of starting anticoagulant therapy (Figure), and custom of aggressively administering anticoagulant medi- clinical purpose of anticoagulant therapy (prevention or cation to patients with a high thromboembolic risk. In treatment) were different between patients with AF and addition, it was partly because our domestic guideline21 did those who developed DVT. However, the relatively small not address anticoagulation-withholding for patients with number of included and anticoagulated patients precluded lobar hemorrhage, as in another guideline.10 Indeed, a further analyses. Third, only thromboembolic/hemorrhagic nationwide survey in Japan found that 91% of physicians events during hospitalization were analyzed, and there was agreed with restarting anticoagulation after ICH for no long-term follow-up. The results of the present study patients with AF,22 and a multicenter, observational study should be confirmed with prospective randomized, con- conducted in Japan showed that anticoagulation was trolled trials.24 resumed for 37 of 44 (84%) patients needing anticoagulation In conclusion, anticoagulant therapy was initiated for after VKA-related ICH.23 The timing of starting antico- approximately 90% of patients for whom anticoagulation agulation in the present study was also similar to both the was indicated after a median of 7 days from ICH onset. domestic survey22 and observational study.23 Therefore, Anticoagulant therapy was conducted for almost all though the proportion of patients who received anticoagu- patients, except for those with severe neurological symp- lant therapy after ICH was high, and anticoagulant therapy toms, irrespective of lobar microbleeds and a diagnosis of was started early after ICH in the present study, the probable CAA. The predominant anticoagulant medica- proportion and timing seemed to reflect daily clinical prac- tions used were DOACs. Anticoagulant therapy started tice in Japan. On the other hand, 50% of the prescribed from the acute phase of ICH seemed to be safe. DOACs were inappropriately lower-dose, and heparins were never used, despite the fact that preceding heparin Conflict of Interest / Study Funding therapy is indicated for DVT treatment on the DOAC None. label. In the real-world setting, anticoagulant-indicated acute ICH patients seemed to be aggressively treated with Acknowledgments intensity-reduced anticoagulant therapy. The authors express their deepest gratitude to all members of the Few studies have investigated the safety or effectiveness Stroke Unit and Radiology and Emergency departments in our of administering DOACs for acute ICH. In the present institution. We also thank Miyuki Nakagawa and Chie Ushiki for study, more than 80% of the patients in the AC group were their assistance with database registration. administered DOACs, and anticoagulant therapy was References initiated a median of 7 days from ICH onset (Figure). Aggressive anticoagulant therapy after ICH mainly with 1. Sacco S, Marini C, Toni D, Olivieri L, Carolei A. Incidence and 10-year survival of intracerebral hemorrhage in a population- DOACs may be safe, because hematoma expansion or based registry. Stroke 2009; 40: 394 – 399. excessive bleeding events observed after starting antico- 2. Schulman S. Resumption of oral anticoagulation after warfarin- agulation in the AC group were comparable to those in the associated intracerebral hemorrhage: No. Stroke 2011; 42: 3663 – Non-AC group, at least during hospitalization. Of the 3664. 3. Steiner T. 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