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

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

doi:10.1253/circj.CJ-18-0938

Abstract

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), spontaneous 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 vein thrombosis), 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.

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

Methods

Subjects

From September 2014 through March 2017, consecutive patients with acute (<7 days from onset), spontaneous ICH admitted to our Stroke Unit (SU) were retrospectively enrolled from a prospective registry. In general, acute ICH patients were admitted to the SU and antihypertensive treatment started as soon as possible, targeting systolic blood pressure (BP) <140 mmHg. Patients with secondary ICH and/or who underwent surgical intervention in the acute phase (<7 days from onset) were excluded. This study was approved by the institutional ethics committee. Written, informed consent was obtained from all patients or their next-of-kin.

Clinical Characteristics

Clinical background characteristics, including sex, age, cardiovascular risk factors, and past medical histories, were recorded on admission. Cardiovascular risk factors were defined as: (1) hypertension, history of using antihypertensive agents, systolic BP ≥140 mmHg, or diastolic BP ≥90 mmHg before or ≥2 weeks after stroke onset; (2) diabetes mellitus, use of hypoglycemic agents, random glucose level ≥200 mg/dL, or glycosylated hemoglobin ≥6.5% on admission; (3) hyperlipidemia, use of antihyperlipidemic agents, or a serum total cholesterol level ≥220 mg/dL; (4) current smoker; and (5) daily alcohol intake. The HAS-BLED score was calculated based on the published guideline.¹⁸ Aortic plaque was not assessed as a component of the score. Because the present study aimed to assess the safety of anticoagulant therapy after ICH, the index ICH was counted as “history of hemorrhagic stroke”. Neurological severity was assessed using the National Institutes of Health Stroke Scale (NIHSS), and functional outcomes were evaluated using the modified Rankin Scale (mRS). Anthropometric measurements and routine blood biochemistry examinations were performed on admission. Hematoma volume was evaluated with non-contrast computed tomography (CT) on admission using the ABC/2 method. Magnetic resonance imaging, including T2*-gradient echo imaging (T2*), was performed during admission, and the presence and location of cerebral microbleeds were assessed using previously reported criteria.¹⁹ Cerebral amyloid angiopathy (CAA) was diagnosed using modified Boston criteria.²⁰ AF was diagnosed with 12-lead ECG or cardiac monitoring during the SU stay. DVT was diagnosed using lower extremity ultrasonography or enhanced CT. Any thromboembolic and hemorrhagic events during hospitalization were collected from the medical charts.

Anticoagulant Therapy and Follow-up Imaging

Whether to start anticoagulation was at the attending physicians’ discretion. Detailed anticoagulant therapy information, if started, including the timing, class (VKA, DOAC, or other), and dose, were collected. Hematoma expansion after starting anticoagulant therapy was assessed with follow-up cranial CT.

Statistical Analysis

All patients were divided into 2 groups: those treated with anticoagulant therapy during hospitalization (AC group) and those not (Non-AC group). First, clinical background characteristics were compared between groups. In addition, clinical background characteristics were analyzed between anticoagulant-indicated patients who received anticoagulant therapy (and belonged to the AC group) and those who did not. Next, the number of days from ICH onset to anticoagulant therapy and the rate of hematoma expansion after anticoagulant therapy were assessed. Finally, thromboembolic and hemorrhagic events were compared between the AC and Non-AC groups. Univariate analyses were performed using the chi-squared test, Fisher’s exact test, or the Mann-Whitney U test, as appropriate. The data are presented as median values (interquartile range [IQR]) or numbers (%). All statistical analyses were performed using PASW for Windows version 17.0 software (SPSS Inc., Chicago, IL, USA). Results were considered significant at P<0.05.

Results

Overall, 268 consecutive patients with ICH were admitted to the SU during the study period. Of these, 29 who underwent surgery in the acute phase were excluded, and 3 patients diagnosed as having secondary ICH caused by minor trauma, arteriovenous malformation, or cerebral venous thrombosis, respectively, were also excluded. Finally, 236 patients (80 women [34%]; median age 69 [IQR 61–79] years; NIHSS score 7 [3–16]; onset to arrival 3.2 [1.1–18.0] h; and length of hospital stay 17 [11–26] days) were enrolled. Of these 236 patients, 41 (17%) were treated with anticoagulant therapy (AC group), and the remaining 195 (83%) were not (Non-AC group). Table 1 shows the baseline background characteristics of the included patients. Patients in the AC group had a more frequent past history of ischemic stroke (24% vs. 6%, P=0.001), an estimated glomerular filtration rate (60 [43–74] mL/min/1.73 m² vs. 72 [59–85] mL/min/1.73 m², P=0.002) that was lower, and a length of hospital stay (21 [14–31] days vs. 16 [10–26] days, P=0.026) that was longer than those in the Non-AC group.

Table 1. Patients’ Baseline Clinical Characteristics

Variable	AC group (n=41)	Non-AC group (n=195)	P value
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 (%)
Hypertension	35 (85)	163 (84)	1.000
Diabetes 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
Blood 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.

Of the 236 patients included in the present study, 47 (20%) had indications for anticoagulant therapy (33 had AF; 14 developed DVT during admission, Supplementary Table), and 41 of 47 patients (87%, 29 AF and 12 DVT) were actually treated with anticoagulant therapy (DOACs in 34 patients [22 (65%) administered lower-dose treatment, and 11 (50%) of the 22 lower-dose cases were inappropriate, in terms of our domestic label] and VKA in 7). The body mass index was lower (18.9 [17.5–22.5] kg/m² vs. 23.0 [20.2–24.9] kg/m², P=0.045), the mRS score at discharge was higher (5 [5–5] vs. 4 [3–5], P=0.013), and the proportion of in-hospital deaths or discharge directly to a nursing home was higher (50% vs. 10%, P=0.035) in patients who did not receive anticoagulant therapy despite having an indication than in those treated with anticoagulant therapy (Table 2). The presence of lobar microbleeds or satisfying probable CAA criteria did not differ between patients with and without anticoagulant therapy.

Table 2. Baseline Clinical Characteristics of Anticoagulant-Indicated Patients With and Without Anticoagulation

Variable	Started AC (n=41)	Not started AC (n=6)	P value
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.

Anticoagulant therapy started after a median of 7 (6–12) days from ICH onset (Table 3, Figure). Oral anticoagulant medication was used in all 41 patients, and intravenous or subcutaneous anticoagulation, including unfractionated or low-molecular-weight heparin, was never used. Similarly, simultaneous antiplatelet therapy was never used. Follow-up imaging after anticoagulant therapy was performed in 30 of 41 (73%) patients at a median of 7 [4–13] days after starting anticoagulation, and no hematoma expansion was observed. In the Non-AC group, 7 (3.6%) hemorrhagic events occurred during hospitalization. In the AC group, 1 case of non-fatal diverticular bleeding occurred 7 days after starting anticoagulant therapy, and anticoagulant therapy was ceased. Continuing anticoagulant medications were prescribed at hospital discharge in 39 of 40 patients who survived to discharge.

Table 3. Thromboembolic and Hemorrhagic Events During Hospitalization

Variable	AC group (n=41)	Non-AC group (n=195)	P value
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	1^b (2.4)	5^c (2.6)	1.000
After AC	2^d (4.9)	NA	NA
Hemorrhagic event, n (%)
Before AC	0 (0)	7^e (3.6)	0.608
After AC	1^f (2.4)	NA	NA

^aNo follow-up imaging in 11 patients. ^b1 ischemic stroke. ^c3 ischemic strokes 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.

Discussion

The present study showed that 20% of acute spontaneous ICH patients had an indication for anticoagulant therapy, and anticoagulant therapy, mainly DOACs, was started in approximately 90% of such patients after a median of 7 days from ICH onset. Anticoagulant therapy was withheld from patients with severe neurological symptoms, but was initiated irrespective of lobar microbleeds or the patient satisfying probable CAA criteria. There seemed to be no excess risk of hematoma expansion or hemorrhagic complications after starting anticoagulant therapy in patients with acute ICH.

Anticoagulant therapy was performed in approximately 90% of indicated patients in the present study. The rate of patients with anticoagulant therapy after ICH was much higher than in previous reports, in which the proportion of patients receiving anticoagulant therapy after ICH ranged from 6.3% to 48%.⁷ Moreover, anticoagulant therapy was conducted as early as a median of 7 days from ICH onset, irrespective of lobar microbleeds or satisfying probable CAA criteria. This probably reflected our traditional custom of aggressively administering anticoagulant medication to patients with a high thromboembolic risk. In addition, it was partly because our domestic guideline²¹ did not address anticoagulation-withholding for patients with lobar hemorrhage, as in another guideline.¹⁰ Indeed, a nationwide survey in Japan found that 91% of physicians agreed with restarting anticoagulation after ICH for patients with AF,²² and a multicenter, observational study conducted in Japan showed that anticoagulation was resumed for 37 of 44 (84%) patients needing anticoagulation after VKA-related ICH.²³ The timing of starting anticoagulation in the present study was also similar to both the domestic survey²² and observational study.²³ Therefore, though the proportion of patients who received anticoagulant therapy after ICH was high, and anticoagulant therapy was started early after ICH in the present study, the proportion and timing seemed to reflect daily clinical practice in Japan. On the other hand, 50% of the prescribed DOACs were inappropriately lower-dose, and heparins were never used, despite the fact that preceding heparin therapy is indicated for DVT treatment on the DOAC label. In the real-world setting, anticoagulant-indicated acute ICH patients seemed to be aggressively treated with intensity-reduced anticoagulant therapy.

Few studies have investigated the safety or effectiveness of administering DOACs for acute ICH. In the present study, more than 80% of the patients in the AC group were administered DOACs, and anticoagulant therapy was initiated a median of 7 days from ICH onset (Figure). Aggressive anticoagulant therapy after ICH mainly with DOACs may be safe, because hematoma expansion or excessive bleeding events observed after starting anticoagulation in the AC group were comparable to those in the Non-AC group, at least during hospitalization. Of the patients with AF, approximately 80% of subjects were treated with anticoagulants before admission (Supplementary Table) and accordingly most of the AF patients resumed anticoagulant therapy, rather than newly starting it after ICH. Therefore, restarting anticoagulant therapy after ICH may also be safe.

Study Strengths and Limitations

The strengths of the present study were the relatively homogeneous patient population; all index events were intracerebral, not intracranial, hemorrhages, and consecutive ICH patients were included, irrespective of prior anticoagulant therapy. However, there are several limitations that need to be addressed. First, because the present study was retrospective and whether to start anticoagulation was at the attending physicians’ discretion, there were severe imbalances between patients treated with and without anticoagulant therapy; anticoagulant therapy was administered for almost all anticoagulant-indicated patients whose neurological symptoms after ICH were not extremely severe. The present study may offer safety information only for aggressive anticoagulant therapy in patients with acute ICH and whose symptoms are not extremely severe, rather than information about the safety of anticoagulant therapy after ICH. Second, patients with AF and those with DVT were handled together as belonging to the AC group in the present study. Patients with AF and those with DVT should be assessed separately; indeed, the clinical background characteristics, including preceding anticoagulant therapy before ICH (Supplementary Table), timing of starting anticoagulant therapy (Figure), and clinical purpose of anticoagulant therapy (prevention or treatment) were different between patients with AF and those who developed DVT. However, the relatively small number of included and anticoagulated patients precluded further analyses. Third, only thromboembolic/hemorrhagic events during hospitalization were analyzed, and there was no long-term follow-up. The results of the present study should be confirmed with prospective randomized, controlled trials.²⁴

In conclusion, anticoagulant therapy was initiated for approximately 90% of patients for whom anticoagulation was indicated after a median of 7 days from ICH onset. Anticoagulant therapy was conducted for almost all patients, except for those with severe neurological symptoms, irrespective of lobar microbleeds and a diagnosis of probable CAA. The predominant anticoagulant medications used were DOACs. Anticoagulant therapy started from the acute phase of ICH seemed to be safe.

Conflict of Interest / Study Funding

None.

Acknowledgments

The authors express their deepest gratitude to all members of the Stroke Unit and Radiology and Emergency departments in our institution. We also thank Miyuki Nakagawa and Chie Ushiki for their assistance with database registration.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-0938

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