Impact of Antiplatelets and Anticoagulants on the Prognosis of Intracerebral Hemorrhage

ARTICLE IN PRESS

Impact of Antiplatelets and Anticoagulants on the Prognosis of Intracerebral Hemorrhage Masaaki Hokari,

MD, PhD,

Daisuke Shimbo, MD, PhD, Katsuyuki Asaoka, Kazuki Uchida, PhD, and Koji Itamoto, PhD

MD, PhD,

Background: Intracerebral hemorrhage (ICH) associated with antithrombotic therapy (AT) is becoming more common as the use of those medications increases in the aging population. Methods: This study included 490 consecutive patients hospitalized for nontraumatic ICH in a single center during an 8-year period, which was subdivided into former (2008-2011) and latter (2012-2015). Patients were classified into those with no antithrombotic drugs (NATs) and those with AT. The AT group was divided into 4 subgroups according to medications: antiplatelet (AP1), multiple antiplatelets (AP2), anticoagulant (AC), and antiplatelet and anticoagulant (APC). We evaluated the clinical characteristics and prognosis and compared the number of patients on AT between the former and latter groups. Results: There were 125 patients treated with AT (25.5%), including 50 (10.2%) on AP1, 14 (2.9%) on AP2, 32 (6.5%) on ACs, and 29 (5.9%) on APCs. Compared with the former group, the latter group had a higher number of patients on AT (19.3% versus 31.7%), AP1 (9.8% versus 10.6%), AP2 (1.6% versus 4.1%), ACs (4.9% versus 8.1%), and APCs (2.90% versus 8.9%). Compared with the NAT group, the patients in the AT group had a larger ICH volume, more frequent hematoma expansion, and higher rate of poor outcome, particularly for those on APCs. Conclusion: The number of ICH patients on AT has increased; these patients were more likely to have a poor prognosis than those who were not on AT. Care should be taken when giving a combination of antiplatelets and anticoagulants in ICH. Key Words: Intracerebral hemorrhage—antithrombotic drugs—antiplatelets—anticoagulants—prognosis. © 2017 Published by Elsevier Inc. on behalf of National Stroke Association.

Introduction The need for antithrombotic therapy (AT), which successfully prevents and treats vascular diseases,1 has increased in recent years. However, one of the most serious complications of AT is intracerebral hemorrhage (ICH). In fact, several reports showed poor outcomes and increased mortality in patients treated with AT.2-4 Some clinical From the Department of Neurosurgery, Teine Keijinkai Hospital, Sapporo, Japan. Received January 5, 2017; revision received April 28, 2017; accepted May 14, 2017. Address correspondence to Masaaki Hokari, MD, PhD, Department of Neurosurgery, Teine Keijinkai Hospital, Maeda 1-12, Teine-ku, Sapporo, 006-0811, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter © 2017 Published by Elsevier Inc. on behalf of National Stroke Association. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.05.016

trials on antiplatelets5-7 and anticoagulants8-12 reported that the annual incidence of ICH ranged from 0.23% to 0.84%. Furthermore, a prospective observational study on AT in Japan reported that the use of multiple antithrombotic drugs independently increased the risk for intracranial bleeding events.13 In addition, ICH associated with AT has become more common in Japan as the use of those medications has increased in the aging population.3 Therefore, we aimed to evaluate the impact of antiplatelets and anticoagulants on the prognosis of patients with ICH and to document the trend in the use of AT in the past years.

Patients and Methods Patients This study included 490 consecutive patients hospitalized with nontraumatic ICH in a single center during an 8-year period between January 2008 and December 2015.

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ICH patients who were hospitalized later than 24 hours of ICH onset were excluded. Patients were divided into a former group (from January 2008 to December 2011) and a latter group (from January 2012 to December 2015). The patients were classified into those with no antithrombotic drugs (NATs) and those with AT, which was subclassified into 4 groups according to drugs taken: 1 antiplatelet drug (AP1), multiple antiplatelets (AP2), anticoagulant (AC), and antiplatelet and anticoagulant (APC).

evacuations underwent a second CT immediately after the surgery. Hemorrhage expansion was defined as an increase of more than 33% in ICH volume.2 One month after the onset of ICH, clinical outcomes were evaluated using the modified Rankin Scale (mRS); an mRS score of 5 or 6 was regarded as a poor outcome. In patients who were transferred to other hospitals or nursing care facilities before 30 days, the mRS was evaluated at discharge.

Statistical Analysis Clinical Characteristics The medical records were reviewed for clinical variables, including age and gender, location and volume of hematoma, current antithrombotic treatment status and reasons for taking antithrombotic drugs, hemorrhage expansion and need for hematoma evacuation by craniotomy, and clinical outcomes. For hematoma evacuation by craniotomy, we used fresh frozen plasma for patients taking ACs and platelet concentrate for those taking antiplatelets. Hemorrhage volume was estimated by the formula ABC/ 2, where A was the greatest hemorrhage diameter on computed tomography (CT), B was the diameter perpendicular to A, and C was the approximate number of CT slices with hemorrhage multiplied by the slice thickness.14 We performed the second CT scan 2 hours after the initial CT in patients with relatively large ICH or those taking antithrombotic agents. However, in patients with small ICH, the second CT was performed the next day. Patients who had undergone emergent hematoma

All data were expressed as mean ± standard deviation. The study variables were compared by the χ2 test or the unpaired t-test, as appropriate (Ekuseru-Toukei 2015; Social Survey Research Information Co., Ltd., Tokyo, Japan). Univariate analysis was performed to determine the association of poor outcome with the clinical variables and to compare the ratio of patients on AT between the former and latter groups. A P value lower than .05 was considered statistically significant.

Results Characteristics of the Patients The characteristics of the study population are presented in Table 1. The mean age was 69.2 ± 12.1 years for the entire study population, 68.1 ± 11.9 years for the former group, and 70.3 ± 12.3 for the latter group. There was no significant difference in age between the former and latter groups. The latter group had a tendency for

Table 1. Clinical characteristic of the patients in this study

Number of the patients M/F (% of M) Age : AVERAGE ± SD (Y) History of hypertension (%) Hemodialysis (%) Hematoma location Putamen Thalamus Combined Caudate Subcortex Brainstem Cerebellar Hematoma volume (cm3 ± SD) Hematoma enlargement Patients treated with antithrombotic drugs (%) Patients performed hematoma removal (%) mRS 5-6

Total

2008-2011

2012-2015

490

244

246

P

M291/F189 59.4% 69.2 ± 12.1 387 79.0% 32 6.5%

M142/F102 58.2% 68.1 ± 11.9 188 77.1% 13 5.3%

M149/F97 60.6% 70.3 ± 12.3 199 80.9% 19 7.7%

.58 .051 .30 .28

133 (M90/F43) 27.1% 127 (M70/F57) 25.9% 19 (M10/F9) 3.9% 10 (M5/F5) 2.0% 111 (M52/F59) 22.7% 44 (M34/F10) 9.0% 46 (M31/F15) 9.4% 28.3 ± 40.1 34 6.9% 125 25.5%

67 (M43/F24) 27.4% 68 (M37/F30) 27.9% 7 (M5F2) 2.9% 3 (M1/F2) 1.2% 56 (M26/F30) 22.9% 22 (M18/F4) 9.0% 21 (M13/F8) 8.6% 30.3 ± 43.5 14 5.7% 47 19.3%

66 (M47/F19) 26.8% 59 (M33/F27) 24.0% 12 (M5/F7) 4.9% 7 (M4/F3) 2.8% 55 (M26/F29) 22.3% 22 (M16/F6) 8.9% 25 (M18/F7) 10.2% 26.3 ± 36.5 20 8.1% 78 31.7%

.92 .35 .24 .22 .91 1 .54 .27 .29 .001*

87

17.8%

45

18.4%

42

17.1%

.72

184

37.6%

82

33.6%

102

41.5%

.060

Abbreviations: F, female; M, male; mRS, modified Rankin Scale; SD, standard deviation.

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Table 2. A. The ratio of the patients with antithrombotic drugs. B. Antithrombotic drugs in this study A Total

2008-2011

2012-2015

Number of the patients

490

244

246

No antithrombotic drugs (NAT) Antithrombotic therapy (AT) Antiplatelet therapy (AP) Single (AP1) Multiple (AP2) Anticoagulant drug (AC) Antiplatelet and anticoagulant drugs (APCs) Novel oral anticoagulant (NOAC)

365 (74.5%) 125 (25.3%) 64 (13.1%) 50 (10.2%) 14 (2.9%) 32 (6.5%) 29 (5.9%) 10 (2.0%)

197 (80.7%) 47 (19.3%) 28 (11.5%) 24 (9.8%) 4 (1.6%) 12 (4.9%) 7 (2.9%) 0 (0%)

168 (68.3%) 78 (31.7%) 36 (14.6%) 26 (10.6%) 10 (4.1%) 20 (8.1%) 22 (8.9%) 10 (4.1%)

P

.001 .28 .76 .10 .14 .004

B AP1

AP2

AC

APC

50

14

32

29

As 42 Th 4 Cil 4

As + Th 9 As + Cl 4 Th + Cil 1

Wa 28 NOAC 4

Wa + As 20 Wa + Th 2 Wa + As + Th 1 NOAC + As 3 NOAC + Cl 1 NOAC + Th 1 NOAC + As + Th 1

Abbreviations: As, aspirin; Cil, cilostazol; NOAC, novel oral anticoagulant; Th, thienopyridine; Wa, warfarin.

a slightly higher incidence of combined and caudate ICH locations compared with the former group, but this was not significant. The overall mean hematoma volume was 28.3 ± 40.1 cm3. The overall incidence rates of hematoma expansion and removal were 6.9% (34 of 490) and 17.8% (87 of 490), respectively, and did not differ between the groups. Patients with poor prognosis were more frequently observed in the latter group (41.5%) than in the former group (33.6%), but this was not statistically significant. The ratio of the patients on AT was significantly higher in the latter group than in the former group (31.7% versus 19.3%; P < .001). Table 2 shows in detail the ratio of patients on antithrombotic drugs. During the 8-year study period, there were 125 patients treated with AT (25.5%), including 50 patients (10.2%) on AP1, 14 patients (2.9%) on AP2, 32 patients (6.5%) on ACs, and 29 patients (5.9%) on APCs. Compared with the former group, the latter group had a higher number of patients on AT (19.3% versus 31.7%; P < .001), AP1 (9.8% versus 10.6%), AP2 (1.6% versus 4.1%), ACs (4.9% versus 8.1%), and APCs (2.90% versus 8.9%; P < .001). The specific antithrombotic drugs that were used in this study population are described in Table 2, B. The most frequently used APC drugs were aspirin and warfarin. In the former group, there were no patients taking novel

oral anticoagulants (NOACs). On the other hand, 10 patients in the latter group were taking NOACs; of these, 6 patients were on APCs and 4 patients were on ACs. The reasons for taking antithrombotic drugs are shown in Figure 1. Cerebral infarction was the most common reason for AP1 intake and was present in 8 asymptomatic patients. The most common reason for taking AP2 was ischemic heart disease, and only 4 cases were for cerebral infarction. Therefore, the clinical background of the patients was quite different between the AP1 and AP2 groups. In the AC and APC groups, there were many patients with heart disease, but 2 patients had cerebral infarction without heart disease even while on APCs.

Location of Intracerebral Hemorrhage The characteristics of patients according to the location of the ICH are shown in Table 3. Patients with putamen and brainstem ICH were relatively young, whereas those with subcortical ICH comprised the oldest among the groups. The incidence rates of ICH associated with AT were high in patients with cerebellar (41.3%), caudate (40.0%), and subcortical (28.8%) locations. Furthermore, the incidence of ICH associated with AC use was relatively high in patients with cerebellar and caudate lesions.

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Figure 1. Reasons for taking antithrombotic drugs were shown in the upper-left (AP1), upper-right (AP2), lower-left (AC), and lower-right (APC) portions. Abbreviations: AC, anticoagulant; AP1, 1 antiplatelet; AP2, multiple antiplatelets; APC, antiplatelet and anticoagulant.

Impact of Antithrombotic Drugs on Patients with Intracerebral Hemorrhage Table 4 shows the impact of antiplatelets and ACs on the study population. The mean ages of the AT, AP1, AC, and APC groups were significantly higher than the mean age of the NAT group. Moreover, compared with the NAT group, the AT group had a larger mean volume of hematoma (41.7 cm3 versus 23.6 cm3; P < .001) and a more frequent occurrence of hematoma expansion (15.2% versus 4.1%; P < .001). The number of patients who underwent hematoma evacuation by craniotomy was slightly higher in the AT group than in the NAT group (21.6% versus 16.4%) but was not significant. Remarkably, a higher rate of poor outcome was observed in the AT group than in the NAT group (56.0% versus 31.2%; P < .001), especially in the APC group (65.5%). Of the 10 patients who were taking NOACs in the latter group, 2 needed hematoma evacuation. We also investigated whether the outcomes of multiple antithrombotic agent groups were worse than those of the AP1 or AC group. The use of AP2 did not worsen the outcome compared with that in the NAT and AP1 groups. However, the APC group had a significantly more frequent occurrence of hematoma expansion than the AP (AP1 and AP2) and AC groups. Univariate analysis showed that age, hematoma volume, hematoma expansion, hematoma evacuation, and use of AT, AP1, AC, and APC were significantly associated with poor outcomes (Table 5). In other words, age and AT were the poor prognostic factors before onset. Although there

were only 10 patients and 6 of the 10 were in APC, taking NOACs was also a poor prognostic factor.

Representative Case A 78-year-old man with hypertension and diabetes mellitus was first admitted to our hospital for weakness of his right extremities secondary to a small left frontal subcortical hematoma (Fig 2, A). He had been prescribed cilostazol 200 mg twice daily for an asymptomatic multiple lacunar cerebral infarction and warfarin for atrial fibrillation. APC medications were stopped immediately after the admission. After the acute phase of therapy, he was transferred to a rehabilitation hospital and was subsequently discharged. Thereafter, he was started on warfarin and clopidogrel at the outpatient clinic for reasons that were unknown to us. Then, 1 year after the initial ICH admission, he was brought to our hospital for loss of consciousness. His blood pressure was 232/103 mmHg, his Glasgow Coma Scale score was 3, and his left pupil was dilated. A CT scan revealed a large, combinedtype, left basal ganglia hematoma (Fig 2, B). PT-INR was 1.8. He died the next day at the age of 79.

Discussion This study clearly showed that the number of ICH patients treated with AT has increased in recent years, reaching as high as 31.7% between 2011 and 2015. Moreover, the number of patients taking a combination of APC

ARTICLE IN PRESS M/F (% of M) M291/F189 (59.4%) M90/F43 (67.7%) M70/F57 (55.1%) M10/F9 (52.6%) M5/F5 (50.0%) M52/F59 (46.8%) M34/F10 (77.3%) M31/F15 (67.4%) Age : AVERAGE ± SD (Y) 69.2 ± 12.1 66.4 ± 13.4 69.0 ± 11.4 72.0 ± 10.6 65.3 ± 10.0 73.6 ± 10.6 63.6 ± 12.6 72.3 ± 9.9 History of hypertension (%) 387 (79.0%) 104 (78.2%) 111 (87.4%) 15 (78.9%) 8 (80.0%) 78 (70.3%) 42 (95.5%) 35 (76.1%) No antithrombotic drugs 365 (74.5%) 100 (75.2%) 100 (78.7%) 14 (73.7%) 6 (60.0%) 79 (71.2%) 39 (88.6%) 27 (58.7%) Antithrombotic therapy 125 (25.3%) 33 (24.8%) 27 (21.3%) 5 (26.3%) 4 (40.0%) 32 (28.8%) 5 (11.4%) 19 (41.3%) Antiplatelet therapy 64 (13.1%) 18 (13.5%) 12 (9.4%) 4 (21.0%) 0 (0%) 18 (16.2%) 1 (2.3%) 11 (23.9%) Single (AP1) 50 (10.2%) 14 (10.5%) 10 (7.9%) 4 (21.0%) 0 (0%) 13 (11.7%) 0 (0%) 9 (19.6%) Multiple (AP2) 14 (2.9%) 4 (3.0%) 2 (1.6%) 0 (0%) 0 (0%) 5 (4.5%) 1 (2.3%) 2 (4.3%) Anticoagulant drug 32 (6.5%) 9 (6.8%) 11 (8.7%) 1 (5.3%) 2 (20.0%) 5 (4.5%) 4 (9.1%) 0 (0%) Antiplatelet and 29 (5.9%) 6 (4.5%) 4 (3.1%) 0 (0%) 2 (20.0%) 9 (8.1%) 0 (0%) 8 (17.4%) anticoagulant drugs Novel oral anticoagulant 10 (2.0%) 1 (0.8%) 3 (2.4%) 0 (0%) 1 (10.0%) 3 (2.7%) 1 (2.3%) 1 (2.2%)

46 44 111 10 19 Number of the patients

490

133

127

Caudate Combined Thalamus Putamen Total

Table 3. Characteristic of the hematoma locations in this study

Subcortical

Brainstem

Cerebellar

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drugs has increased by 3-fold. A high rate of poor outcomes was confirmed among patients on AT, especially those who were taking both APC drugs.

Increased Incidence of Intracerebral Hemorrhage Secondary to AT A study by Kato et al on 14,599 Japanese patients with hypertensive ICH between 2000 and 2012 revealed that the frequency of antithrombotic agent use increased with age and reached its peak (26.7%) in patients in their 80s.3 Japan has the fastest-aging society in the world, and the number of patients with thrombotic disease has been increasing.1 Although an accurate documentation of census is difficult, the number of patients using antithrombotic agents has certainly increased in Japan. In fact, the Japanese Standard Stroke Registry Study reported an increase in the incidence of ICH patients taking antithrombotic agents from 11.6% in 1999-2004 to 22.3% in 2009-2012.15 Our results showed a similarly high incidence of 19.3% in 2008-2011 and a further increase to up to 31.7% in 20122015. This incidence was higher than incidences previously reported in Japan.3,15 This study implies an important emerging clinical situation of ICH associated with antithrombotic drugs in Japan.

Impact of Antithrombotic Drugs on Patients with Intracerebral Hemorrhage As mentioned earlier, several previous studies and our present study reported poor outcomes and increased mortality in patients treated with AT.2-4 Toyoda et al reported that prior intake of antiplatelet agents, warfarin, or both was predictive of hematoma enlargement and early death.4 Kato et al also reported that antithrombotic drugs played a significant role in the development of ICH in elderly patients.3 They insisted that a combination of both drugs had an additive effect on the outcome. Interestingly, they also demonstrated that the use of antithrombotic agents did not result in worse outcomes in younger patients. Corresponding to previous reports, our study demonstrated a 56.0% rate of poor outcomes in patients on AT, especially those on APCs (65.5%). In this study, univariate analyses showed that age and AT were poor prognostic factors before the onset of ICH, but the use of AP2 did not make the outcome worse compared with the use of the other ATs. This might be explained by the fact that majority of these patients were relatively young and took AP2 for ischemic heart disease.

Association of NOAC Use with Intracerebral Hemorrhage NOACs are now in widespread use, frequently as substitutes for warfarin because of more favorable safety and efficacy profiles.8-12 With regard to the association between NOAC use and ICH, several reports demonstrated

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Table 4. Impact of antithrombotic therapy on intracerebral hemorrhage non-AT

AT

Number of the patients

490

365

125

P

50

P (versus NAT)

M/F Age (y ± SD) Hematoma volume (cm3 ± SD) Hematoma enlargement Patients performed hematoma removal (%) mRS 5-6 (%)

M291/F189 (59.4%) 69.2 ± 12.1 28.3 ± 40.1 34 (6.9%) 87 (17.8%) 184 (37.6%)

M213/F152 (58.4%) 67.4 ± 12.6 23.6 ± 34.4 15 (4.1%) 60 (16.4%) 114 (31.2%)

M78/F47 (62.4%) 73.8 ± 11.2 41.7 ± 51.2 19 (15.2%) 27 (21.6%) 70 (56.0%)

.42 <.001* <.001* <.001* .19 <.001*

M27/F23 (54%) 74.2 ± 10.6 44.2 ± 54.3 4 (8.0%) 10 (20%) 27 (54%)

.56 <.001* .009 .22 .53 .001

AP2

AC

AP1

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Total

APC

Number of the patients

14

P (versus NAT)

P (versus AP1)

32

P (versus NAT)

29

P (versus NAT)

P versus AP)

P (versus AC)

M/F Age (y ± SD) Hematoma volume (cm3 ± SD) Hematoma enlargement Patients performed hematoma removal (%) mRS 5-6 (%)

M10/F4 (71.4%) 71.6 ± 9.1 25.4 ± 31.3 1 (7.1%) 3 (21.4%) 5 (35.7%)

.33 .10 .83 .58 .62 .072

.24 .41 .11 .92 .91 .23

M22/F10 (68.8%) 74.9 ± 6.4 35.1 ± 47.0 6 (18.8%) 5 (15.6%) 19 (59.4%)

.25 <.001* .17 <.001* .91 .001

M19/F10 (65.5%) 75.2 ± 8.8 53.7 ± 57.0 8 (27.6%) 9 (31.0%) 19 (65.5%)

.45 <.001* .005* <.001* .047 <.001*

.46 .48 .25 .008* .24 .15

.32 .85 .17 .019* .27 .32

Abbreviations: AC, anticoagulant; AP1, 1 antiplatelet; AP2, multiple antiplatelets; APC, antiplatelet and anticoagulant; F, female; M, male; mRS, modified Rankin Scale; NAT, no antithrombotic drug; SD, standard deviation . M. HOKARI ET AL.

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Table 5. Prognostic factors of intracerebral hemorrhage mRS 0-4

mRS 5-6

Univariate

Multivariate

Number of the patients

306

184

P

P

Men/female (% male) Age Hematoma volume (cm3 ± standard deviation) Hematoma enlargement (%) Hematoma removal (%) Antithrombotic therapy Antiplatelet therapy Antiplatelets therapy Anticoagulant drug Antiplatelet and anticoagulant drugs Novel oral anticoagulant

180/126 (58.8%) 66.6 ± 11.6 13.0 ± 19.1 9 (2.9%) 41 (13.4%) 55 (18.0%) 23 (7.5%) 9 (2.9%) 13 (4.3%) 10 (3.2%) 3 (1.0%)

111/73 (60.3%) 73.5 ± 11.8 53.7 ± 51.5 25 (13.6%) 46 (25.0%) 70 (38.0%) 27 (14.7%) 5 (2.7%) 19 (10.3%) 19 (10.3%) 7 (3.8%)

.74 <.001 <.001 <.001 .0011 <.001 .011 .886 .008 .001 .032

.002 <.001 .062 .004 .029 .365 .102 .207 .174

Abbreviation: mRS, modified Rankin Scale.

Figure 2. CT scan showed a small left frontal subcortical hematoma (Fig 2, A) when the patient developed motor weakness of his right extremities at first admission. CT scan on the second admission revealed large left basal ganglia hematoma (Fig 2, B). Abbreviation: CT, computed tomography.

relatively smaller hematoma and more favorable functional outcomes compared with warfarin-associated ICH.16-18 Although the number of cases was small, the intake of NOACs in this study was associated with poor outcomes, probably because of the concomitant antiplatelet intake in 6 of 10 patients. Although the use of NOACs with antiplatelet(s) is prevalent because of favorable safety and efficacy profiles,8-12 care should still be taken in patients with ICH.

Reduction of Incidence of Intracerebral HemorrhageAssociated AT Generally speaking, the prognosis of ICH is worse than that of cerebral infarction and further worsens with the intake of antithrombotic drugs. Therefore, although AT can successfully prevent cerebral infarction, the risk of ICH should be kept in mind.1 The major risk factors of ICH during AT are advanced age, elevated blood pressure, use of multiple antithrombotic agents, and previous cerebral ischemia.19 Our study showed there were many patients with heart disease in the AP2 and APC groups. Therefore, to reduce the incidence of ICH-associated AT,

we have to consider heart disease. Recent topics in coronary artery stenting are to shorten the duration of dual antiplatelets, and Valgimigli et al recommended 6-12 months of dual antiplatelet duration.20 Besides, for the patients of AF with coronary stenting, AP2 and ACs are used within 12 months, and taking only AC is recommended 1 year after stenting.21 Although the accurate number is difficult to ascertain, the unnecessary intake of multiple antithrombotic drugs, like our representative case, seems to be not uncommon.

Limitation The limitations of this study are the following: (1) This was a retrospective study; (2) the application of hematoma evacuations and the use of hemostatic drugs were not conducted with a uniform strategy; (3) the intervals between the first and second CT scans were not fixed; and (4) in patients who were transferred to other hospitals or nursing care facilities before 30 days, the mRS was evaluated at discharge. With respect to (4), the mean length of hospitalization of 490 patients was 26.8 days. Actually, the mRS was evaluated for 181 patients (36.9%)

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prior to 30 days (except for 94 patients; mRS 6). However, the mRS 5 was evaluated in only 20 of 181 patients at the time of discharge prior to 30 days, and the mean length of hospitalization of these 20 patients was 22.0 days. Therefore, we think there is no major bias.

Conclusion The number of ICH patients on AT has increased; these patients were more likely to have poor prognosis than those who were not on AT. Care should be taken when giving a combination of antiplatelets and anticoagulants in ICH. Acknowledgments: The authors sincerely thank Yui Suzuki for her secretarial work.

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