JNS-13318; No of Pages 6 Journal of the Neurological Sciences xxx (2014) xxx–xxx
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Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator Tomoki Wada a,⁎, Hideo Yasunaga b, Ryota Inokuchi a, Hiromasa Horiguchi c, Kiyohide Fushimi d, Takehiro Matsubara a, Susumu Nakajima a, Naoki Yahagi a a
Department of Emergency and Critical Care Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Department of Clinical Epidemiology and Health Economics, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Department of Clinical Data Management and Research, Clinical Research Center, National Hospital Organization Headquarters, 2-5-21 Higashigaoka, Meguro-ku, Tokyo 152-8621, Japan d Department of Health Care Informatics, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan b c
a r t i c l e
i n f o
Article history: Received 10 April 2014 Received in revised form 21 June 2014 Accepted 8 July 2014 Available online xxxx Keywords: Acute ischemic stroke Thrombolysis Edaravone Neuroprotection Cohort study The Diagnosis Procedure Combination database Propensity-score matching
a b s t r a c t Background: We investigated whether edaravone could improve early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator (rtPA). Methods: We conducted a retrospective cohort study using the Japanese Diagnosis Procedure Combination database. We identified patients admitted with a primary diagnosis of ischemic stroke from 1 July 2010 to 31 March 2012 and treated with rtPA on the same day of stroke onset or the following day. Thereafter, we selected those who received edaravone on the same day of rtPA administration (edaravone group), and those who received rtPA without edaravone (control group). The primary outcomes were modified Rankin Scale (mRS) scores at discharge. One-to-one propensity-score matching was performed between the edaravone and control groups. An ordinal logistic regression analysis for mRS scores at discharge was performed with adjustment for possible variables as well as clustering of patients within hospitals using a generalized estimating equation. Results: We identified 6336 eligible patients for inclusion in the edaravone group (n = 5979; 94%) and the control group (n = 357; 6%) as the total population. In 356 pairs of the propensity-matched population, the ordinal logistic regression analysis showed that edaravone was significantly associated with lower mRS scores of patients at discharge (adjusted odds ratio: 0.74; 95% confidence interval: 0.57–0.96). Conclusions: Edaravone may improve early outcomes in acute ischemic stroke patients treated with rtPA. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Thrombolysis with recombinant tissue plasminogen activator (rtPA) is an established therapy for acute ischemic stroke patients [1]. At the same time, however, previous in vivo studies have demonstrated that tPA has toxic effects toward brains under ischemia, such as expanding the infarct volume [2,3]. Edaravone is a free radical scavenger and neuroprotectant given a grade B recommendation for use in acute ischemic stroke patients in the Japanese guideline for the management of ischemic stroke [4]. Some in vivo and in vitro studies have suggested that edaravone attenuated the tPA-related neurotoxicity [5–7]. Thus, there is a possibility that edaravone may improve the neurological outcomes in acute ischemic
⁎ Corresponding author. Tel.: +81 3 5800 8681; fax: +81 3 3814 6446. E-mail addresses: [email protected] (T. Wada), [email protected] (H. Yasunaga), [email protected] (R. Inokuchi), [email protected] (H. Horiguchi), [email protected] (T. Matsubara), [email protected] (S. Nakajima), [email protected] (N. Yahagi).
stroke patients treated with rtPA. However, clinical data supporting the effectiveness of edaravone were based on limited studies with small samples [8,9]. We therefore investigated whether edaravone could improve early outcomes of acute ischemic stroke patients treated with rtPA, using a Japanese national inpatient database. 2. Material and methods 2.1. Data source We conducted a retrospective cohort study using the Diagnosis Procedure Combination (DPC) database, which is a Japanese nationwide administrative claims and discharge abstract database. In total, 1075 hospitals, including all 82 university teaching hospitals, participated in the database in March 2012. The total number of recorded patients was approximately 7 million in 2011, which represents approximately 50% of all acute care inpatient hospitalizations in Japan. The database contained patients' general demographics, diagnoses, drugs used, surgical and medical procedures, hospital discharge status, and some detailed clinical data for specific diseases including date of stroke onset, modified Rankin scale (mRS) scores, and Japan Coma Scale
http://dx.doi.org/10.1016/j.jns.2014.07.018 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Wada T, et al, Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.018
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T. Wada et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
(JCS) scores for stroke patients. The primary diagnosis on admission, pre-existing comorbidities, and complications occurring after admission, were separately recorded with International Classification of Diseases and Related Health Problems, Tenth revision (ICD-10) codes and text data in the Japanese language. Drugs and procedures were recoded with the dates of their use or implementation. Physicians in charge were responsible for recording the diagnoses with reference to the medical charts. This study was approved by the Institutional Review Boards and Ethics Committee of the University of Tokyo. Informed consent was waived owing to the anonymous nature of the data. 2.2. Patient selection and data We identified patients who were admitted to hospitals with a primary diagnosis of ischemic stroke from 1 July 2010 to 31 March 2012, and received rtPA on the same day of stroke onset or the following day. We included patients who received rtPA on the following day of stroke onset because some patients may have suffered stroke little before midnight and received rtPA soon after midnight. Thereafter, we selected those who received edaravone on the same day of rtPA administration (edaravone group), and those who did not receive edaravone during hospitalization (control group). During the study period, intravenous rtPA administration was approved in Japan at a dose of 0.6 mg/kg and only for patients within 3 h after stroke onset, based on the Japan Alteplase Clinical Trial [10]. Intravenous edaravone administration was approved at a dose of 30 mg twice a day within 14 days [11]. The diagnosis of ischemic stroke was identified by ICD-10 code I63.x. The exclusion criteria were: pre-existing comorbidities of chronic renal failure (ICD-10 code N18.x or N19); presentation in a coma at admission; and initial edaravone use on the next day of rtPA administration or later. We excluded patients with chronic renal failure because edaravone had a warning of the risk of renal disorder development [12]. We excluded patients in a coma in accordance with two previous randomized control trials on the efficacy of radical scavengers [11,13]. A comatose state was identified by JCS scores of 100–300. The JCS is a scale for impaired consciousness that is widely used in Japan [14,15]. A score of 0 indicates alert consciousness, single-digit scores of 1–3 indicate mildly impaired consciousness with spontaneous eye-opening, double-digit scores of 10–30 indicate moderately impaired consciousness with eye-opening when patients receive stimuli, and triple-digit scores of 100–300 indicate coma. The JCS is well-correlated with the Glasgow Coma Scale [16]. We collected patients' pre-existing comorbidities including atrial fibrillation (I48) and heart failure (I50.x). As indicators of the post-stroke neurological status, the JCS scores and mRS scores at admission were used. In accordance with the ICD-10 codes recorded for the patients, the infarction subtypes were divided into three groups: arterial thrombosis (I630, I633); arterial embolism (I631, I634); and others or unspecified (I632, I635, I636, I638, I639). We examined whether patients received intravenous administration of antihypertensive drugs on the same day as stroke onset (urgent use of antihypertensive drugs) as an indicator of high blood pressure at admission. These drugs included diltiazem and nicardipine, both of which are commonly used for stroke patients in Japan [17]. We also collected the following factors: route of rtPA administration (intravenous or intra-arterial); admission to a Stroke Care Unit for at least 1 day during hospitalization; type of hospital (university hospital or community hospital); date of admission (weekday or weekend); and medications prescribed after admission including statins and eicosapentaenoic acid (EPA). The primary outcomes of interest were mRS scores at discharge. We defined functional independence as mRS scores of 0–2. The secondary outcomes of interest were 7-day mortality, the occurrence of intracranial hemorrhage (ICH) after admission, and length of hospital stay. We chose 7-day mortality with reference to the understanding that provision of acute stroke care and prevention of complications are generally
achieved within the first 7 days [18]. Intracranial hemorrhage was identified by ICD-10 codes I60.x, I61.x, I62.x, and I638 combined with the text data “hemorrhagic infarction”. 2.3. Statistical analysis We performed one-to-one propensity-score matching between the edaravone and control groups. This matching tried to enhance the baseline comparability between the two groups in this retrospective study. To estimate a propensity score for each patient, we used a logistic regression model for receipt of edaravone with adjustment for possible confounding variables including patient age, sex, pre-existing comorbidities on admission, JCS score at admission, mRS score at admission, infarction subtype, urgent use of antihypertensive drugs, route of rtPA administration, Stroke Care Unit admission, hospital type, date of admission, and medications prescribed during hospitalization. The C-statistic was calculated to evaluate the goodness-of-fit for the model. Each patient in the edaravone group was matched with a patient in the control group with the closest estimated propensity on the logit scale within a specified range (≤0.25 of the pooled standard deviation of estimated logits) [19]. In both the total population and the matched population, categorical data were compared between the edaravone group and the control group using the chi-square test or Fisher's exact test as appropriate, while continuous data were compared using the Mann–Whitney U test. Ordinal logistic regression analyses were performed for mRS scores at discharge with adjustment for several variables as well as clustering of patients within hospitals using a generalized estimating equation. The threshold for significance was P b 0.05. All statistical analyses were performed using SPSS Statistics version 20.0 (IBM SPSS, Armonk, NY, USA). 3. Results The selection process for the study cohort is described in Fig. 1. During the survey periods, 7591 patients with acute ischemic stroke were treated with rtPA on the same day or the following day of stroke onset. After excluding patients with chronic renal failure, in a coma, with missing data and with delayed use of edaravone, 6336 patients were eligible for our study as the total population. The edaravone group included 5979 (94%) patients, while the control group included 357 (6%) patients. By one-to-one propensity-score matching, 356 pairs of patients in the edaravone and control groups were selected. The Cstatistic for goodness-of-fit was 0.68. Table 1 shows baseline characteristics of the edaravone and control groups in the total population and the matched population. In the total population, the baseline characteristics were heterogeneous between the edaravone and control groups. The patients in the edaravone group were younger (median age [interquartile range]: 74 [66–81] years vs. 80 [71–85] years; P b 0.001), had a lower proportion of heart failure as a preexisting comorbidity (8.1% vs. 17.6%; P b 0.001), had less impaired consciousness at admission (51.9% vs. 54.9% with JCS scores of 1–3; 27.0% vs. 32.2% with JCS scores of 10–30; P = 0.001), and were more likely to be admitted to hospital on a weekday (74.0% vs. 66.9%; P = 0.003) compared with the patients in the control group. In the matched population, the patient baseline distributions were well balanced between the two groups. Table 2 shows univariate comparisons of the outcomes in the matched population. The proportion of functional independence at discharge tended to be higher in the edaravone group than in the control group, although the difference was not significant (35.1% vs. 28.7%; P = 0.06). On the other hand, there were no significant differences between the two groups in 7-day mortality, the occurrence of ICH after admission, and length of hospital stay. Table 3 shows the adjusted odds ratios of various factors in the matched population for mRS scores at discharge derived from the ordinal logistic regression analyses. Edaravone was significantly associated with reduction of mRS scores at discharge (adjusted
Please cite this article as: Wada T, et al, Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.018
T. Wada et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
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Fig. 1. Selection process of the edaravone and control groups. rtPA, recombinant tissue plasminogen activator, ICD-10, the International Classification of Diseases and Related Health Problems, Tenth revision.
odds ratio: 0.74; 95% confidence interval: 0.57–0.96). Advanced age groups of 80 years or older, impaired consciousness at admission, higher mRS scores at admission, and urgent use of antihypertensive drugs were significantly associated with higher mRS scores at discharge. On the other hand, following factors had no statistically significant associations with mRS scores of the patients at discharge: patients' sex, the comorbidity of atrial fibrillation as well as heart failure, infarction subtypes, the routes of rtPA administration, SCU admission, hospital types, the date of admission, and medications prescribed during hospitalization. 4. Discussion The present propensity-matched analysis using a national inpatient database suggested that edaravone was associated with lower mRS scores at discharge for acute ischemic stroke patients treated with rtPA. On the other hand, we could not find significant effects of edaravone on 7-day mortality, the occurrence of ICH after admission, or the length of hospital stay for those patients. To our knowledge, the present study had the largest samples regarding the effect of edaravone on thrombolytic therapy with rtPA for ischemic stroke. Previously, only two clinical studies with small samples addressed the effect; one study had 40 patients [8], and the other had 129 patients [9]. Both studies also suggested that edaravone improved outcomes of acute ischemic stroke patients treated with rtPA. The present study had 712 patients, and performed a propensity score analysis, which improved the comparability between the edaravone group and control group. A previous in vivo study has shown that edaravone may protect against tPA-induced oxidative stress [7]. In addition, the two clinical study have suggested that edaravone may enhance early arterial recanalization in acute ischemic stroke patients treated with rtPA [8,9]. These mechanisms would support the beneficial effect of edaravone on the mRS scores of patients at discharge in the present study. Although prior in vivo studies also have shown that edaravone could reduce
hemorrhagic transformation after tPA administration [5,6], we could not find a significant effect of edaravone on the occurrence of ICH during hospitalization. Our results showed that the difference in length of stay was not significant between the edaravone and control groups in the matched population. In addition, a previous study showed that mRS scores at days 7–10 were well correlated with those at day 90 in ischemic stroke patients [20]. Therefore, the difference in length of stay would have little influence on the difference in mRS scores at discharge between the edaravone and control groups in the present study. Although the National Institute of Health Stroke Scale score at admission is an established prognostic factor in neurological status, the DPC database did not include this score [21,22]. Instead, we used mRS scores as well as JCS scores at admission as variables indicating post-stroke neurological status at admission. In fact, previous studies suggested that mRS at admission [23] and JCS at admission [15] were reliable predictors of stroke outcomes. We believe that the baseline neurological status of patients was successfully adjusted with mRS scores and JCS scores at admission in the present study. Previous studies showed that blood pressure at admission was another established prognostic factor for stroke patients [24–26]. In the present study, we used urgent use of antihypertensive drugs in substitution for the presence of hypertension at admission because the DPC database did not include actual data on blood pressure. According to the guideline for the intravenous application of rtPA in Japan, intravenous administration of antihypertensive drugs is recommended to keep patients' blood pressure ≤180/105 mm Hg [17]. Presumably, urgent use of antihypertensive drugs can be an appropriate substitution for blood pressure measurement. Although the difference was not significant, the patients treated with statins during hospitalization appeared to achieve lower mRS scores at discharge than those without statins. A previous retrospective cohort study showed that statin use was associated with better outcomes in acute ischemic stroke patients treated with rtPA [27]. To
Please cite this article as: Wada T, et al, Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.018
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T. Wada et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
Table 1 Baseline characteristics of the edaravone and control groups in the total population and the matched population.a Total population
Sex (male), n (%) Age groups (years), n (%) b60 60–69 70–79 80–89 ≥90 Comorbidities, n (%) Atrial fibrillation Heart failure JCS score at admission, n (%) 0 1–3 10–30 mRS at admission 0 1 2 3 4 5 Infarction subtype Arterial thrombosis Arterial embolism Others or unspecified Urgent use of antihypertensive drugs, n (%) Route of rtPA administration, n (%) Intravenous Intra-arterial SCU admission Hospital type Community hospital University hospital Date of admission Weekday Weekend Medications prescribed during hospitalization, n (%) Statins Eicosapentaenoic acid Duration of edaravone (days), median [IQR]
P value
Edaravone group (n = 5979)
Control group (n = 357)
3593 (60.1)
203 (56.9)
718 (12.0) 1421 (23.8) 2056 (34.4) 1513 (25.3) 271 (4.5)
Matched population
P value
Edaravone group (n = 356)
Control group (n = 356)
0.23
196 (55.1)
202 (56.7)
0.65
25 (7.0) 51 (14.3) 97 (27.2) 143 (40.1) 41 (11.5)
b0.001
26 (7.3) 45 (12.6) 103 (28.9) 155 (43.5) 27 (7.6)
25 (7.0) 51 (14.3) 97 (27.2) 143 (40.2) 40 (11.2)
0.47
1967 (32.9) 485 (8.1)
111 (31.1) 63 (17.6)
0.48 b0.001
98 (27.5) 68 (19.1)
111 (31.2) 62 (17.4)
0.29 0.56
1258 (21.0) 3104 (51.9) 1617 (27.0)
46 (12.9) 196 (54.9) 115 (32.2)
0.001
47 (13.2) 196 (55.1) 113 (31.7)
46 (12.9) 195 (54.8) 115 (32.3)
0.99
86 (1.4) 94 (1.6) 258 (4.3) 542 (9.1) 2005 (33.5) 2994 (50.1)
1 (0.3) 9 (2.5) 18 (5.0) 25 (7.0) 116 (32.5) 188 (52.7)
0.17
0 (0) 10 (2.8) 15 (4.2) 24 (6.7) 110 (30.9) 197 (55.3)
1 (0.3) 9 (2.5) 18 (5.1) 25 (7.0) 115 (32.3) 188 (52.8)
0.89
1606 (26.9) 3161 (52.9) 1212 (20.3) 2122 (35.5)
88 (24.6) 188 (52.7) 81 (22.7) 126 (35.3)
0.45
95 (26.7) 177 (49.7) 84 (23.6) 125 (35.1)
88 (24.7) 187 (52.5) 81 (22.8) 126 (35.4)
0.74
5887 (98.5) 92 (1.5) 813 (13.6)
355 (99.4) 2 (0.6) 60 (16.8)
0.18
354 (99.4) 2 (0.6) 49 (13.8)
354 (99.4) 2 (0.6) 59 (16.6)
N 0.99
5197 (86.9) 782 (13.1)
315 (88.2) 42 (11.8)
0.47
316 (88.8) 40 (11.2)
314 (88.2) 42 (11.8)
0.81
4424 (74.0) 1555 (26.0)
239 (66.9) 118 (33.1)
0.003
242 (68.0) 114 (32.0)
238 (66.9) 118 (33.1)
0.75
1280 (21.4) 139 (2.3) 8 [6–12]
68 (19.0) 6 (1.7) 0
0.29 0.58 N/A
68 (19.1) 4 (1.1) 8 [6–12]
68 (19.1) 6 (1.7) 0
N 0.99 0.75 N/A
0.94
0.09
0.94
0.30
IQR: interquartile range; JCS: Japan Coma Scale; N/A: not applicable; and rtPA: recombinant tissue plasminogen activator. a The edaravone group included patients who received edaravone on the same day of rtPA administration. The control group included patients who received rtPA but did not receive edaravone during hospitalization.
evaluate the efficacy of statins on stroke outcomes, randomized control trials are needed. The present study has revealed that few patients received rtPA without edaravone in Japan. One of the possible reasons for the lack of use of edaravone for patients is that physicians may be less likely to use edaravone for severe patients. Among the total population in the present study, the patients in the control group had more advanced age, higher JCS scores at admission, and higher proportion of heart failure as a preexisting comorbidity than those in the edaravone group. These
Table 2 Outcomes in the edaravone and control groups in the matched population. Matched population
P value
Edaravone group Control group (n = 356) (n = 356) mRS score of 0 to 2 at discharge, n (%) 7-Day mortality, n (%) ICH during hospitalization, n (%) Length of hospital stay, median [IQR]
125 (35.1) 22 (6.2) 13 (3.7) 29 [16–47]
102 (28.7) 29 (8.1) 10 (2.8) 32 [16–52]
0.06 0.31 0.53 0.42
mRS: modified Rankin Scale; ICH: intracranial hemorrhage; IQR: interquartile range; and rtPA: recombinant tissue plasminogen activator.
factors were successfully balanced between the edaravone group and the control group in the matched population. The proportion of weekend admission also differed significantly between the edaravone group and the control group in the total population. The difference between weekday and weekend admissions may be attributed to various factors including disease severity and quality of care [28]. Thus, we could not identify the contributing factors to the difference in edaravone use between weekday and weekend admissions. Nevertheless, the date of admission was successfully balanced in the matched population. Several limitations should be acknowledged. First, the results of propensity score matching in this study can be generalized only among those in the range of propensity scores included in the paired analysis, and they may not be applicable to those who are out of this range. In fact, patients in the edaravone group of matched population were biased to older age, higher proportion of heart failure as a preexisting comorbidity, and higher JCS scores at admission, compared with the edaravone group of total population. Second, the c-statistic for the propensity scores was as low as 0.68. Thus, there is a possibility that unmeasured factors might have affected physicians' decisions for edaravone use, such as differences in treatment strategies by the admitting care teams.
Please cite this article as: Wada T, et al, Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.018
T. Wada et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx Table 3 Adjusted odds ratios of edaravone use and other baseline characteristics for mRS score at discharge in the matched population.a mRS score at discharge
P value
Adjusted OR (95% CI) Edaravone Sex (female) Age groups (years) b60 60–69 70–79 80–89 ≥90 Comorbidities Atrial fibrillation Heart failure JCS score at admission 0 1–3 10–30 mRS at admission 0–3 4 5 Infarction subtype Arterial thrombosis Arterial embolism Others or unspecified Urgent use of antihypertensive drugs Intra-arterial rtPA use SCU admission University hospital Weekend admission Medications during hospitalization Statins Eicosapentaenoic acid
0.74 (0.57–0.96) 1.12 (0.85–1.49)
0.024 0.43
Reference 1.51 (0.81–2.81) 1.15 (0.63–2.10) 2.07 (1.18–3.63) 2.61 (1.21–5.63)
0.20 0.65 0.01 0.01
0.95 (0.67–1.35) 1.18 (0.82–1.70)
0.78 0.37
Reference 2.43 (1.61–3.68) 3.09 (1.97–4.83)
b0.001 b0.001
Reference 2.84 (1.87–4.32) 12.4 (8.08–19.2)
b0.001 b0.001
Reference 0.95 (0.67–1.35) 1.04 (0.72–1.51) 1.43 (1.07–1.90) 5.75 (0.54–61.7) 0.93 (0.64–1.35) 1.26 (0.79–2.01) 1.25 (0.96–1.64)
0.77 0.84 0.01 0.15 0.70 0.33 0.10
0.74 (0.52–1.04) 1.23 (0.45–3.42)
0.08 0.69
CI: confidence interval; JCS: Japan Coma Scale; mRS: modified Rankin Scale; OR: odds ratio; rtPA: recombinant tissue plasminogen activator. a Results of ordinal logistic regression analyses.
Third, as a study using an administrative database, we cannot eliminate the possibility of miscoding or uncoding. Fourth, the clock times for the dates of the procedures could not be identified in the database. For this reason, we could not identify the exact timing or sequence of the procedures performed on the same calendar day. Finally, the database did not have several important factors to predict stroke outcomes including time window from onset to rtPA administration, blood glucose levels and diagnostic imaging findings. In conclusion, our study suggested that edaravone improved early outcomes of acute ischemic stroke patients treated with rtPA. Because the present results were based on a retrospective observational study, future randomized control trials will be needed to confirm the effect of edaravone on early outcomes in acute ischemic stroke patients treated with rtPA.
Conflict of interest statement The authors declare that there are no conflicts of interest.
Acknowledgment This study was funded by a Grant-in-Aid for Research on Policy Planning and Evaluation from the Ministry of Health, Labour and Welfare, Japan (No. H22-Policy-031), and a grant from the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST program) from the Council for Science and Technology Policy, Japan (No. 0301002001001).
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Please cite this article as: Wada T, et al, Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.018
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Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator Tomoki Wada a,⁎, Hideo Yasunaga b, Ryota Inokuchi a, Hiromasa Horiguchi c, Kiyohide Fushimi d, Takehiro Matsubara a, Susumu Nakajima a, Naoki Yahagi a a
Department of Emergency and Critical Care Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Department of Clinical Epidemiology and Health Economics, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Department of Clinical Data Management and Research, Clinical Research Center, National Hospital Organization Headquarters, 2-5-21 Higashigaoka, Meguro-ku, Tokyo 152-8621, Japan d Department of Health Care Informatics, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan b c
a r t i c l e
i n f o
Article history: Received 10 April 2014 Received in revised form 21 June 2014 Accepted 8 July 2014 Available online xxxx Keywords: Acute ischemic stroke Thrombolysis Edaravone Neuroprotection Cohort study The Diagnosis Procedure Combination database Propensity-score matching
a b s t r a c t Background: We investigated whether edaravone could improve early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator (rtPA). Methods: We conducted a retrospective cohort study using the Japanese Diagnosis Procedure Combination database. We identified patients admitted with a primary diagnosis of ischemic stroke from 1 July 2010 to 31 March 2012 and treated with rtPA on the same day of stroke onset or the following day. Thereafter, we selected those who received edaravone on the same day of rtPA administration (edaravone group), and those who received rtPA without edaravone (control group). The primary outcomes were modified Rankin Scale (mRS) scores at discharge. One-to-one propensity-score matching was performed between the edaravone and control groups. An ordinal logistic regression analysis for mRS scores at discharge was performed with adjustment for possible variables as well as clustering of patients within hospitals using a generalized estimating equation. Results: We identified 6336 eligible patients for inclusion in the edaravone group (n = 5979; 94%) and the control group (n = 357; 6%) as the total population. In 356 pairs of the propensity-matched population, the ordinal logistic regression analysis showed that edaravone was significantly associated with lower mRS scores of patients at discharge (adjusted odds ratio: 0.74; 95% confidence interval: 0.57–0.96). Conclusions: Edaravone may improve early outcomes in acute ischemic stroke patients treated with rtPA. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Thrombolysis with recombinant tissue plasminogen activator (rtPA) is an established therapy for acute ischemic stroke patients [1]. At the same time, however, previous in vivo studies have demonstrated that tPA has toxic effects toward brains under ischemia, such as expanding the infarct volume [2,3]. Edaravone is a free radical scavenger and neuroprotectant given a grade B recommendation for use in acute ischemic stroke patients in the Japanese guideline for the management of ischemic stroke [4]. Some in vivo and in vitro studies have suggested that edaravone attenuated the tPA-related neurotoxicity [5–7]. Thus, there is a possibility that edaravone may improve the neurological outcomes in acute ischemic
⁎ Corresponding author. Tel.: +81 3 5800 8681; fax: +81 3 3814 6446. E-mail addresses: [email protected] (T. Wada), [email protected] (H. Yasunaga), [email protected] (R. Inokuchi), [email protected] (H. Horiguchi), [email protected] (T. Matsubara), [email protected] (S. Nakajima), [email protected] (N. Yahagi).
stroke patients treated with rtPA. However, clinical data supporting the effectiveness of edaravone were based on limited studies with small samples [8,9]. We therefore investigated whether edaravone could improve early outcomes of acute ischemic stroke patients treated with rtPA, using a Japanese national inpatient database. 2. Material and methods 2.1. Data source We conducted a retrospective cohort study using the Diagnosis Procedure Combination (DPC) database, which is a Japanese nationwide administrative claims and discharge abstract database. In total, 1075 hospitals, including all 82 university teaching hospitals, participated in the database in March 2012. The total number of recorded patients was approximately 7 million in 2011, which represents approximately 50% of all acute care inpatient hospitalizations in Japan. The database contained patients' general demographics, diagnoses, drugs used, surgical and medical procedures, hospital discharge status, and some detailed clinical data for specific diseases including date of stroke onset, modified Rankin scale (mRS) scores, and Japan Coma Scale
http://dx.doi.org/10.1016/j.jns.2014.07.018 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Wada T, et al, Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.018
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(JCS) scores for stroke patients. The primary diagnosis on admission, pre-existing comorbidities, and complications occurring after admission, were separately recorded with International Classification of Diseases and Related Health Problems, Tenth revision (ICD-10) codes and text data in the Japanese language. Drugs and procedures were recoded with the dates of their use or implementation. Physicians in charge were responsible for recording the diagnoses with reference to the medical charts. This study was approved by the Institutional Review Boards and Ethics Committee of the University of Tokyo. Informed consent was waived owing to the anonymous nature of the data. 2.2. Patient selection and data We identified patients who were admitted to hospitals with a primary diagnosis of ischemic stroke from 1 July 2010 to 31 March 2012, and received rtPA on the same day of stroke onset or the following day. We included patients who received rtPA on the following day of stroke onset because some patients may have suffered stroke little before midnight and received rtPA soon after midnight. Thereafter, we selected those who received edaravone on the same day of rtPA administration (edaravone group), and those who did not receive edaravone during hospitalization (control group). During the study period, intravenous rtPA administration was approved in Japan at a dose of 0.6 mg/kg and only for patients within 3 h after stroke onset, based on the Japan Alteplase Clinical Trial [10]. Intravenous edaravone administration was approved at a dose of 30 mg twice a day within 14 days [11]. The diagnosis of ischemic stroke was identified by ICD-10 code I63.x. The exclusion criteria were: pre-existing comorbidities of chronic renal failure (ICD-10 code N18.x or N19); presentation in a coma at admission; and initial edaravone use on the next day of rtPA administration or later. We excluded patients with chronic renal failure because edaravone had a warning of the risk of renal disorder development [12]. We excluded patients in a coma in accordance with two previous randomized control trials on the efficacy of radical scavengers [11,13]. A comatose state was identified by JCS scores of 100–300. The JCS is a scale for impaired consciousness that is widely used in Japan [14,15]. A score of 0 indicates alert consciousness, single-digit scores of 1–3 indicate mildly impaired consciousness with spontaneous eye-opening, double-digit scores of 10–30 indicate moderately impaired consciousness with eye-opening when patients receive stimuli, and triple-digit scores of 100–300 indicate coma. The JCS is well-correlated with the Glasgow Coma Scale [16]. We collected patients' pre-existing comorbidities including atrial fibrillation (I48) and heart failure (I50.x). As indicators of the post-stroke neurological status, the JCS scores and mRS scores at admission were used. In accordance with the ICD-10 codes recorded for the patients, the infarction subtypes were divided into three groups: arterial thrombosis (I630, I633); arterial embolism (I631, I634); and others or unspecified (I632, I635, I636, I638, I639). We examined whether patients received intravenous administration of antihypertensive drugs on the same day as stroke onset (urgent use of antihypertensive drugs) as an indicator of high blood pressure at admission. These drugs included diltiazem and nicardipine, both of which are commonly used for stroke patients in Japan [17]. We also collected the following factors: route of rtPA administration (intravenous or intra-arterial); admission to a Stroke Care Unit for at least 1 day during hospitalization; type of hospital (university hospital or community hospital); date of admission (weekday or weekend); and medications prescribed after admission including statins and eicosapentaenoic acid (EPA). The primary outcomes of interest were mRS scores at discharge. We defined functional independence as mRS scores of 0–2. The secondary outcomes of interest were 7-day mortality, the occurrence of intracranial hemorrhage (ICH) after admission, and length of hospital stay. We chose 7-day mortality with reference to the understanding that provision of acute stroke care and prevention of complications are generally
achieved within the first 7 days [18]. Intracranial hemorrhage was identified by ICD-10 codes I60.x, I61.x, I62.x, and I638 combined with the text data “hemorrhagic infarction”. 2.3. Statistical analysis We performed one-to-one propensity-score matching between the edaravone and control groups. This matching tried to enhance the baseline comparability between the two groups in this retrospective study. To estimate a propensity score for each patient, we used a logistic regression model for receipt of edaravone with adjustment for possible confounding variables including patient age, sex, pre-existing comorbidities on admission, JCS score at admission, mRS score at admission, infarction subtype, urgent use of antihypertensive drugs, route of rtPA administration, Stroke Care Unit admission, hospital type, date of admission, and medications prescribed during hospitalization. The C-statistic was calculated to evaluate the goodness-of-fit for the model. Each patient in the edaravone group was matched with a patient in the control group with the closest estimated propensity on the logit scale within a specified range (≤0.25 of the pooled standard deviation of estimated logits) [19]. In both the total population and the matched population, categorical data were compared between the edaravone group and the control group using the chi-square test or Fisher's exact test as appropriate, while continuous data were compared using the Mann–Whitney U test. Ordinal logistic regression analyses were performed for mRS scores at discharge with adjustment for several variables as well as clustering of patients within hospitals using a generalized estimating equation. The threshold for significance was P b 0.05. All statistical analyses were performed using SPSS Statistics version 20.0 (IBM SPSS, Armonk, NY, USA). 3. Results The selection process for the study cohort is described in Fig. 1. During the survey periods, 7591 patients with acute ischemic stroke were treated with rtPA on the same day or the following day of stroke onset. After excluding patients with chronic renal failure, in a coma, with missing data and with delayed use of edaravone, 6336 patients were eligible for our study as the total population. The edaravone group included 5979 (94%) patients, while the control group included 357 (6%) patients. By one-to-one propensity-score matching, 356 pairs of patients in the edaravone and control groups were selected. The Cstatistic for goodness-of-fit was 0.68. Table 1 shows baseline characteristics of the edaravone and control groups in the total population and the matched population. In the total population, the baseline characteristics were heterogeneous between the edaravone and control groups. The patients in the edaravone group were younger (median age [interquartile range]: 74 [66–81] years vs. 80 [71–85] years; P b 0.001), had a lower proportion of heart failure as a preexisting comorbidity (8.1% vs. 17.6%; P b 0.001), had less impaired consciousness at admission (51.9% vs. 54.9% with JCS scores of 1–3; 27.0% vs. 32.2% with JCS scores of 10–30; P = 0.001), and were more likely to be admitted to hospital on a weekday (74.0% vs. 66.9%; P = 0.003) compared with the patients in the control group. In the matched population, the patient baseline distributions were well balanced between the two groups. Table 2 shows univariate comparisons of the outcomes in the matched population. The proportion of functional independence at discharge tended to be higher in the edaravone group than in the control group, although the difference was not significant (35.1% vs. 28.7%; P = 0.06). On the other hand, there were no significant differences between the two groups in 7-day mortality, the occurrence of ICH after admission, and length of hospital stay. Table 3 shows the adjusted odds ratios of various factors in the matched population for mRS scores at discharge derived from the ordinal logistic regression analyses. Edaravone was significantly associated with reduction of mRS scores at discharge (adjusted
Please cite this article as: Wada T, et al, Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.018
T. Wada et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
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Fig. 1. Selection process of the edaravone and control groups. rtPA, recombinant tissue plasminogen activator, ICD-10, the International Classification of Diseases and Related Health Problems, Tenth revision.
odds ratio: 0.74; 95% confidence interval: 0.57–0.96). Advanced age groups of 80 years or older, impaired consciousness at admission, higher mRS scores at admission, and urgent use of antihypertensive drugs were significantly associated with higher mRS scores at discharge. On the other hand, following factors had no statistically significant associations with mRS scores of the patients at discharge: patients' sex, the comorbidity of atrial fibrillation as well as heart failure, infarction subtypes, the routes of rtPA administration, SCU admission, hospital types, the date of admission, and medications prescribed during hospitalization. 4. Discussion The present propensity-matched analysis using a national inpatient database suggested that edaravone was associated with lower mRS scores at discharge for acute ischemic stroke patients treated with rtPA. On the other hand, we could not find significant effects of edaravone on 7-day mortality, the occurrence of ICH after admission, or the length of hospital stay for those patients. To our knowledge, the present study had the largest samples regarding the effect of edaravone on thrombolytic therapy with rtPA for ischemic stroke. Previously, only two clinical studies with small samples addressed the effect; one study had 40 patients [8], and the other had 129 patients [9]. Both studies also suggested that edaravone improved outcomes of acute ischemic stroke patients treated with rtPA. The present study had 712 patients, and performed a propensity score analysis, which improved the comparability between the edaravone group and control group. A previous in vivo study has shown that edaravone may protect against tPA-induced oxidative stress [7]. In addition, the two clinical study have suggested that edaravone may enhance early arterial recanalization in acute ischemic stroke patients treated with rtPA [8,9]. These mechanisms would support the beneficial effect of edaravone on the mRS scores of patients at discharge in the present study. Although prior in vivo studies also have shown that edaravone could reduce
hemorrhagic transformation after tPA administration [5,6], we could not find a significant effect of edaravone on the occurrence of ICH during hospitalization. Our results showed that the difference in length of stay was not significant between the edaravone and control groups in the matched population. In addition, a previous study showed that mRS scores at days 7–10 were well correlated with those at day 90 in ischemic stroke patients [20]. Therefore, the difference in length of stay would have little influence on the difference in mRS scores at discharge between the edaravone and control groups in the present study. Although the National Institute of Health Stroke Scale score at admission is an established prognostic factor in neurological status, the DPC database did not include this score [21,22]. Instead, we used mRS scores as well as JCS scores at admission as variables indicating post-stroke neurological status at admission. In fact, previous studies suggested that mRS at admission [23] and JCS at admission [15] were reliable predictors of stroke outcomes. We believe that the baseline neurological status of patients was successfully adjusted with mRS scores and JCS scores at admission in the present study. Previous studies showed that blood pressure at admission was another established prognostic factor for stroke patients [24–26]. In the present study, we used urgent use of antihypertensive drugs in substitution for the presence of hypertension at admission because the DPC database did not include actual data on blood pressure. According to the guideline for the intravenous application of rtPA in Japan, intravenous administration of antihypertensive drugs is recommended to keep patients' blood pressure ≤180/105 mm Hg [17]. Presumably, urgent use of antihypertensive drugs can be an appropriate substitution for blood pressure measurement. Although the difference was not significant, the patients treated with statins during hospitalization appeared to achieve lower mRS scores at discharge than those without statins. A previous retrospective cohort study showed that statin use was associated with better outcomes in acute ischemic stroke patients treated with rtPA [27]. To
Please cite this article as: Wada T, et al, Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.018
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Table 1 Baseline characteristics of the edaravone and control groups in the total population and the matched population.a Total population
Sex (male), n (%) Age groups (years), n (%) b60 60–69 70–79 80–89 ≥90 Comorbidities, n (%) Atrial fibrillation Heart failure JCS score at admission, n (%) 0 1–3 10–30 mRS at admission 0 1 2 3 4 5 Infarction subtype Arterial thrombosis Arterial embolism Others or unspecified Urgent use of antihypertensive drugs, n (%) Route of rtPA administration, n (%) Intravenous Intra-arterial SCU admission Hospital type Community hospital University hospital Date of admission Weekday Weekend Medications prescribed during hospitalization, n (%) Statins Eicosapentaenoic acid Duration of edaravone (days), median [IQR]
P value
Edaravone group (n = 5979)
Control group (n = 357)
3593 (60.1)
203 (56.9)
718 (12.0) 1421 (23.8) 2056 (34.4) 1513 (25.3) 271 (4.5)
Matched population
P value
Edaravone group (n = 356)
Control group (n = 356)
0.23
196 (55.1)
202 (56.7)
0.65
25 (7.0) 51 (14.3) 97 (27.2) 143 (40.1) 41 (11.5)
b0.001
26 (7.3) 45 (12.6) 103 (28.9) 155 (43.5) 27 (7.6)
25 (7.0) 51 (14.3) 97 (27.2) 143 (40.2) 40 (11.2)
0.47
1967 (32.9) 485 (8.1)
111 (31.1) 63 (17.6)
0.48 b0.001
98 (27.5) 68 (19.1)
111 (31.2) 62 (17.4)
0.29 0.56
1258 (21.0) 3104 (51.9) 1617 (27.0)
46 (12.9) 196 (54.9) 115 (32.2)
0.001
47 (13.2) 196 (55.1) 113 (31.7)
46 (12.9) 195 (54.8) 115 (32.3)
0.99
86 (1.4) 94 (1.6) 258 (4.3) 542 (9.1) 2005 (33.5) 2994 (50.1)
1 (0.3) 9 (2.5) 18 (5.0) 25 (7.0) 116 (32.5) 188 (52.7)
0.17
0 (0) 10 (2.8) 15 (4.2) 24 (6.7) 110 (30.9) 197 (55.3)
1 (0.3) 9 (2.5) 18 (5.1) 25 (7.0) 115 (32.3) 188 (52.8)
0.89
1606 (26.9) 3161 (52.9) 1212 (20.3) 2122 (35.5)
88 (24.6) 188 (52.7) 81 (22.7) 126 (35.3)
0.45
95 (26.7) 177 (49.7) 84 (23.6) 125 (35.1)
88 (24.7) 187 (52.5) 81 (22.8) 126 (35.4)
0.74
5887 (98.5) 92 (1.5) 813 (13.6)
355 (99.4) 2 (0.6) 60 (16.8)
0.18
354 (99.4) 2 (0.6) 49 (13.8)
354 (99.4) 2 (0.6) 59 (16.6)
N 0.99
5197 (86.9) 782 (13.1)
315 (88.2) 42 (11.8)
0.47
316 (88.8) 40 (11.2)
314 (88.2) 42 (11.8)
0.81
4424 (74.0) 1555 (26.0)
239 (66.9) 118 (33.1)
0.003
242 (68.0) 114 (32.0)
238 (66.9) 118 (33.1)
0.75
1280 (21.4) 139 (2.3) 8 [6–12]
68 (19.0) 6 (1.7) 0
0.29 0.58 N/A
68 (19.1) 4 (1.1) 8 [6–12]
68 (19.1) 6 (1.7) 0
N 0.99 0.75 N/A
0.94
0.09
0.94
0.30
IQR: interquartile range; JCS: Japan Coma Scale; N/A: not applicable; and rtPA: recombinant tissue plasminogen activator. a The edaravone group included patients who received edaravone on the same day of rtPA administration. The control group included patients who received rtPA but did not receive edaravone during hospitalization.
evaluate the efficacy of statins on stroke outcomes, randomized control trials are needed. The present study has revealed that few patients received rtPA without edaravone in Japan. One of the possible reasons for the lack of use of edaravone for patients is that physicians may be less likely to use edaravone for severe patients. Among the total population in the present study, the patients in the control group had more advanced age, higher JCS scores at admission, and higher proportion of heart failure as a preexisting comorbidity than those in the edaravone group. These
Table 2 Outcomes in the edaravone and control groups in the matched population. Matched population
P value
Edaravone group Control group (n = 356) (n = 356) mRS score of 0 to 2 at discharge, n (%) 7-Day mortality, n (%) ICH during hospitalization, n (%) Length of hospital stay, median [IQR]
125 (35.1) 22 (6.2) 13 (3.7) 29 [16–47]
102 (28.7) 29 (8.1) 10 (2.8) 32 [16–52]
0.06 0.31 0.53 0.42
mRS: modified Rankin Scale; ICH: intracranial hemorrhage; IQR: interquartile range; and rtPA: recombinant tissue plasminogen activator.
factors were successfully balanced between the edaravone group and the control group in the matched population. The proportion of weekend admission also differed significantly between the edaravone group and the control group in the total population. The difference between weekday and weekend admissions may be attributed to various factors including disease severity and quality of care [28]. Thus, we could not identify the contributing factors to the difference in edaravone use between weekday and weekend admissions. Nevertheless, the date of admission was successfully balanced in the matched population. Several limitations should be acknowledged. First, the results of propensity score matching in this study can be generalized only among those in the range of propensity scores included in the paired analysis, and they may not be applicable to those who are out of this range. In fact, patients in the edaravone group of matched population were biased to older age, higher proportion of heart failure as a preexisting comorbidity, and higher JCS scores at admission, compared with the edaravone group of total population. Second, the c-statistic for the propensity scores was as low as 0.68. Thus, there is a possibility that unmeasured factors might have affected physicians' decisions for edaravone use, such as differences in treatment strategies by the admitting care teams.
Please cite this article as: Wada T, et al, Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.07.018
T. Wada et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx Table 3 Adjusted odds ratios of edaravone use and other baseline characteristics for mRS score at discharge in the matched population.a mRS score at discharge
P value
Adjusted OR (95% CI) Edaravone Sex (female) Age groups (years) b60 60–69 70–79 80–89 ≥90 Comorbidities Atrial fibrillation Heart failure JCS score at admission 0 1–3 10–30 mRS at admission 0–3 4 5 Infarction subtype Arterial thrombosis Arterial embolism Others or unspecified Urgent use of antihypertensive drugs Intra-arterial rtPA use SCU admission University hospital Weekend admission Medications during hospitalization Statins Eicosapentaenoic acid
0.74 (0.57–0.96) 1.12 (0.85–1.49)
0.024 0.43
Reference 1.51 (0.81–2.81) 1.15 (0.63–2.10) 2.07 (1.18–3.63) 2.61 (1.21–5.63)
0.20 0.65 0.01 0.01
0.95 (0.67–1.35) 1.18 (0.82–1.70)
0.78 0.37
Reference 2.43 (1.61–3.68) 3.09 (1.97–4.83)
b0.001 b0.001
Reference 2.84 (1.87–4.32) 12.4 (8.08–19.2)
b0.001 b0.001
Reference 0.95 (0.67–1.35) 1.04 (0.72–1.51) 1.43 (1.07–1.90) 5.75 (0.54–61.7) 0.93 (0.64–1.35) 1.26 (0.79–2.01) 1.25 (0.96–1.64)
0.77 0.84 0.01 0.15 0.70 0.33 0.10
0.74 (0.52–1.04) 1.23 (0.45–3.42)
0.08 0.69
CI: confidence interval; JCS: Japan Coma Scale; mRS: modified Rankin Scale; OR: odds ratio; rtPA: recombinant tissue plasminogen activator. a Results of ordinal logistic regression analyses.
Third, as a study using an administrative database, we cannot eliminate the possibility of miscoding or uncoding. Fourth, the clock times for the dates of the procedures could not be identified in the database. For this reason, we could not identify the exact timing or sequence of the procedures performed on the same calendar day. Finally, the database did not have several important factors to predict stroke outcomes including time window from onset to rtPA administration, blood glucose levels and diagnostic imaging findings. In conclusion, our study suggested that edaravone improved early outcomes of acute ischemic stroke patients treated with rtPA. Because the present results were based on a retrospective observational study, future randomized control trials will be needed to confirm the effect of edaravone on early outcomes in acute ischemic stroke patients treated with rtPA.
Conflict of interest statement The authors declare that there are no conflicts of interest.
Acknowledgment This study was funded by a Grant-in-Aid for Research on Policy Planning and Evaluation from the Ministry of Health, Labour and Welfare, Japan (No. H22-Policy-031), and a grant from the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST program) from the Council for Science and Technology Policy, Japan (No. 0301002001001).
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