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In America and Europe, the current recommended dose of recombinant tissue-type plasminogen activator (r-tPA) for

acute ischemic stroke is 0.9 mg/kg, but a similar study with this dosage has never been replicated in a controlled trial in East Asia. A lower dose (0.6 mg/kg) of r-tPA was used in Japan and was proved to have similar outcomes compared with a dose of 0.9 mg/kg in Western countries.1,2 However, the Safe Implementation of Thrombolysis in Stroke-Non-European Union World (SITS-NEW) study demonstrated that the safety and efficacy of the dose of 0.9 mg/kg of r-tPA in an Asian population was similar to those of the Safe Implementation

of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) study in the European population.3,4

Our previous study, the Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) study, was the first to determine whether the thrombolytic therapy in routine clin-ical use was as safe and effective in Chinese patients as in white patients.5 The preliminary results showed that the group receiving a dose of 0.9 mg/kg had higher rates of symptomatic intracerebral hemorrhage (SICH), dependence, and mortality within 3 months than the low-dose group (<0.85 mg/kg). This finding was more prominent in older patients aged ≥70 years.

Background and Purpose—The relationship between the dose of recombinant tissue-type plasminogen activator (r-tPA) and its safety/efficacy for ischemic stroke has not been well evaluated in the East Asian population. We assessed the safety/efficacy of different doses of r-tPA for acute ischemic stroke in Chinese patients.

Methods—A total of 1004 eligible patients were classified according to the dose of r-tPA received for managing acute ischemic stroke: 0.9 mg/kg (n=422), 0.8 mg/kg (n=202), 0.7 mg/kg (n=199), and 0.6 mg/kg (n=181). The safety outcome was symptomatic intracerebral hemorrhage and death within 3 months. The efficacy outcome was good functional outcome (modified Rankin Scale ≤1) at 3 months.

Results—There was a significant trend for symptomatic intracerebral hemorrhage with age (P=0.002). With multivariate logistic regression analysis, a dose of 0.9 mg/kg was a predictor of symptomatic intracerebral hemorrhage (P=0.0109), and a dose ≤0.65 mg/kg was a predictor of good functional outcome (P=0.0369). In patients aged 71 to 80 years, there was a significant trend of increasing symptomatic intracerebral hemorrhage (P=0.0130) and less good functional outcome (P=0.0179) with increasing doses of r-tPA. There was also a trend of increasing mortality (P=0.0971) at 3 months in these patients.

Conclusions—These results did not support the dose of 0.9 mg/kg of r-tPA being optimal for all patients in the East Asian population. In elderly patients (71–80 years), a lower dose of 0.6 mg/kg is associated with a better outcome. Confirmation of the results through randomized trial is required. (Stroke. 2014;45:2359-2365.)

Key Words: cerebral hemorrhage ◼ stroke

Different Doses of Recombinant Tissue-Type Plasminogen Activator for Acute Stroke in Chinese PatientsA-Ching Chao, MD, PhD; Ching-Kuan Liu, MD, PhD; Chih-Hung Chen, MD;

Huey-Juan Lin, MD; Chung-Hsiang Liu, MD; Jiann-Shing Jeng, MD, PhD; Chaur-Jong Hu, MD; Chih-Ping Chung, MD, PhD; Hung-Yi Hsu, MD, PhD;

Wen-Yung Sheng, MPH; Han-Hwa Hu, MD; on behalf of the Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) Study Group

Received February 24, 2014; accepted June 2, 2014.From the Graduate Institute of Clinical Medicine and Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung,

Taiwan (A.-C.C., C.-K.L.); Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan (A.-C.C., C.-K.L.); Department of Neurology, College of Medicine, National Cheng Kung University, Tainan, Taiwan (C.-H.C.); Department of Neurology, Chi-Mei Medical Center, Tainan, Taiwan (H.-J.L.); Department of Neurology, China Medical University Hospital, Taichung, Taiwan (C.-H.L.); Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan (J.-S.J.); Graduate Institute of Clinical Medicine and Department of Neurology, College of Medicine, Taipei Medical University, Taipei, Taiwan (C.-J.H., H.-H.H.); Department of Neurology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan (C.-P.C., W.-Y.S.); and Department of Neurology, Tungs’ Taichung Metro Harbor Hospital and Department of Neurology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan (H.-Y.H.).

The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 114.005245/-/DC1.

Correspondence to A-Ching Chao, MD, PhD, Department of Neurology, Kaohsiung Medical University and Hospital, Kaohsiung 80756, Taiwan. E-mail achch@cc.kmu.edu.tw or Han-Hwa Hu, MD, Department of Neurology and Graduate Institute of Clinical Medicine,Taipei Medical University and Hospital, Taipei 11031, Taiwan. E-mail hanhwa@hotmail.com

© 2014 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.114.005245

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Because the ranges of the lower dose observed in the study were wide (from 0.55 to 0.84 mg/kg) and the population of 241 was relatively small, we conducted the Taiwan Thrombolytic Therapy for Acute Ischemic Stroke Study II (TTT-AIS II) to determine the optimal dose of r-tPA for acute ischemic stroke in Chinese or East Asian patients by prospective patient regis-tration and dose/safety/efficacy analysis.

MethodsStudy Design and ParticipantsThe TTT-AIS II was the continuation of the TTT-AIS study, which was a prospective multicenter observational study performed in most hospitals using r-tPA treatment for acute ischemic stroke in Taiwan. It was similar to the SITS-MOST study, which was an Internet-based, academic, interactive thrombolysis therapy registration.4 The detailed study design has been published elsewhere.5 The r-tPA indications and exclusion criteria were similar to the SITS-MOST study, including an upper age limit of 80 years. Because several studies implied that it is more appropriate to use a lower dose of anticoagulants or r-tPA in Chinese patients than in white patients, some neurologists in Taiwan inferred that the dose of r-tPA for acute ischemic stroke should also be reduced for safety concerns.6,7 Some doctors applied r-tPA to pa-tients aged >80 years, which was officially considered off-label use of r-tPA in Taiwan. In this study, we asked investigators to enter the total dose of r-tPA administered in the emergency room and then enter the exact body weight when the patients were later weighed during their hospitalization. The exact unit dose was calculated as the total dose divided by the exact body weight. Kaohsiung Medical University Hospital’s institutional review board approved the study proposal, and we obtained written informed consent from all patients. The registra-tion started in December 2004 and ended in November 2011.

Outcome MeasuresThe safety outcome of the TTT-AIS II study was the occurrence of SICH and death within 3 months. We defined SICH as the National

Institute of Neurological Disorders (NINDS) study did: ICH with the deterioration of any neurological symptoms (National Institutes of Health Stroke Scale score ≥1) or death.8 The radiological definition of hemorrhagic events followed the European Cooperative Acute Stroke Study (ECASS) classification.9 In the safety analysis, patients aged >80 years were excluded from the analysis because they were not considered eligible for r-tPA treatment in Taiwan. The efficacy out-come was functional outcomes, including the modified Rankin Scale (mRS) and the Barthel index, at 3 months after treatment. An mRS score of 0 to 1 was considered a good functional outcome; an mRS score of 0 to 2 was considered functional independence. Only 840 pa-tients, aged ≤80 years and with a prestroke disabled state mRS score of 0 to 1, were included in the efficacy analysis, because patients with a prestroke disabled state mRS score >1 have no chance of getting good clinical outcomes with mRS 0 to 1. For comparison with other studies reported in the literature, data from the total 1004 patients were included, and we also added the outcome of the incidence rate of SICH as defined in the SITS-MOST and ECASS studies.

Statistical AnalysisData were analyzed using SAS 9.2 software. The means±SD (for continuous variables) or percentages (for discrete variables) were cal-culated for all baseline data. Groups were compared using the Student t test for continuous variables and the χ2 test for discrete variables. Mantel–Haenszel extension χ2 tests were conducted for trend analy-ses of dose responses to SICH. Odds ratios were calculated for all discrete variables to identify risk factors in univariate and multivari-ate analyses for SICH and good functional outcome. Multiple logistic regression with backward elimination was conducted to evaluate the risk factors associated with SICH and good functional outcome. All statistically significant levels were defined as P<0.05.

ResultsFrom December 2004 to November 2011, eligible patients with acute ischemic stroke who received thrombolytic ther-apy at 23 hospitals in Taiwan were registered. Five patients’

Table 1. Demographics and Baseline Characteristics of Patients Receiving a Dose of 0.9 mg/kg and Lower Dose of Recombinant Tissue-Type Plasminogen Activator

Variables Total (n=1004) 0.6 mg/kg (n=181) 0.7 mg/kg (n=199) 0.8 mg/kg (n=202) 0.9 mg/kg (n=422) P Value

Age 67.4±12.4 70.1±10.9 68.0±12.9 66.9±13.5 66.1±12.0 0.0028

Sex (male) 628 (62.5%) 105 (58.0%) 123 (61.8%) 128 (63.4%) 272 (64.4%) 0.5031

Hospital (C/M) 431/573 68/113 78/121 88/114 197/225 0.1264

Body weight, kg 65.0±12.2 67.0±13.0 63.9±12.9 64.6±12.1 64.9±11.6 0.0832

Hypertension 699 (69.6%) 139 (76.8%) 139 (69.9%) 140 (69.3%) 281 (66.6%) 0.0998

Diabetes mellitus 283 (28.2%) 61 (33.7%) 51 (25.6%) 50 (24.8%) 121 (28.7%) 0.2045

Hyperlipidemia 336 (33.5%) 49 (27.1%) 44 (22.1%) 69 (34.2%) 174 (41.2%) <0.0001

Coronary artery disease 168 (16.7%) 28 (15.5%) 39 (19.6%) 28 (13.9%) 73 (17.3%) 0.4450

Atrial fibrillation 336 (33.5%) 78 (43.1%) 70 (35.2%) 70 (34.6%) 118 (28.0%) 0.0034

Smoking

Current 269 (26.8%) 46 (25.4%) 42 (21.1%) 49 (24.3%) 132 (31.3%) 0.0376

Previous 134 (13.3%) 18 (9.9%) 22 (11.1%) 33 (16.3%) 61 (14.5%) 0.1931

Alcohol 100 (10.0%) 15 (8.3%) 16 (8.0%) 20 (9.9%) 49 (11.6%) 0.4459

Aspirin 209 (20.8%) 36 (19.9%) 52 (26.1%) 38 (18.8%) 83 (19.7%) 0.2276

Clopidogrel/ticlopidine 62 (6.2%) 14 (7.7%) 14 (7.0%) 7 (3.5%) 27 (6.4%) 0.3067

Cilostazol/dipyridamole 28 (2.8%) 4 (2.2%) 8 (4.0%) 3 (1.5%) 13 (3.1%) 0.4343

Anticoagulant 71 (7.1%) 11 (6.1%) 13 (6.5%) 16 (7.9%) 31 (7.4%) 0.8895

NIHSS 14.9±6.9 14.4±6.1 14.7±6.4 15.2±6.5 15.0±7.7 0.7067

Time to treatment 141.4±47.1 147.7±41.7 140.4±36.7 145.5±36.0 137.3±57.3 0.0001

C/M indicates community hospitals/medical centers; and NIHSS, National Institutes of Health Stroke Scale.

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data were excluded because r-tPA administration was stopped prematurely during infusion because of a rapid deterioration of the patients’ vital signs; these patients initially fulfilled the indications for r-tPA treatment. Thus, the data from 1004 patients were included for safety, efficacy, and dose–response analyses. Of these, 976 (97.2%) completed the 1-month fol-low-up and 960 (95.6%) completed the 3-month mRS; all patients completed the baseline image reports and the follow-up image reports.

We classified an average dose of 0.9 mg/kg (0.86–0.95; 422 patients; mean, 0.91±0.05 mg/kg; median, 0.9 mg/kg; range, 0.86–1.26 mg/kg) as the dose of 0.9 mg/kg group. Doses ≤0.85 mg/kg were categorized as the low-dose group, which was further divided into 3 subgroups: 0.8 mg/kg (202 patients; mean, 0.81±0.03 mg/kg; median, 0.81 mg/kg; range, 0.76–0.85 mg/kg), 0.7 mg/kg (199 patients; mean, 0.71±0.02 mg/kg; median, 0.71 mg/kg; range, 0.68–0.75 mg/kg), and 0.6 mg/kg (181 patients; mean, 0.62±0.04 mg/kg; median, 0.61 mg/kg; range, 0.55–0.65 mg/kg). In total, 42.0% of the patients were treated with the dose of 0.9 mg/kg, and 58.0% were treated with a lower dose (20.1% with 0.8 mg/kg, 19.8% with 0.7 mg/kg, and 18.0% with 0.6 mg/kg). The distributions of the r-tPA dose used in medical centers and community hos-pitals were similar. Table 1 shows the baseline data and demo-graphics of the patients with various doses. As a result of the observational nature of study design, baseline characteristics were not completely comparable among different treatment arms. Patients given the lower dose were more likely to be

older, have atrial fibrillation, have a longer time to treatment, and also have less hyperlipidemia and less current smoking.

The safety and efficacy results compared with other studies are summarized in Table I in the online-only Data Supplement. Overall, the occurrence of SICH per the NINDS definition and death after r-tPA were comparable with the results of the SITS-MOST, NINDS, Japan Alteplase Clinical Trial (J-ACT), Japan Post-Marketing Alteplase Registration Study (J-MARS), and SITS-NEW studies, but the percentage of good functional out-comes at 3 months (30.6%) was less than that in those studies and in our previous report (39.3%).5

The univariate analyses of safety showed that using a dose of r-tPA of 0.9 mg/kg, age, hypertension, coronary heart dis-ease, clopidogrel/ticlopidine use, and aspirin use influenced the occurrence of SICH per the NINDS definition. In contrast, current smoking was negatively associated with the occur-rence of SICH. After adjusting for potential confounders, mul-tiple regression analysis showed that using a dose of 0.9 mg/kg of r-tPA, hypertension, and coronary heart disease were the independent predictors of SICH occurrence after r-tPA treat-ment; in addition, current smoking was a protective factor for SICH occurrence (Table 2).

The efficacy of r-tPA treatment was expressed as the per-centage of patients who had a good functional outcome (mRS score 0–1) at 3 months. Univariate analyses showed that dose ≤0.65 mg/kg, baseline National Institutes of Health Stroke Scale score, age, and absence of diabetes mellitus were the predictors of good clinical outcomes. Multivariate analyses

Table 2. Predictors of Symptomatic Intracerebral Hemorrhage per the National Institute of Neurological Disorders Definition in 884 Patients*: Univariate and Multivariate Analyses

Univariate Analysis Multivariate Analysis

Characteristics OR (95% CI) P Value OR† (95% CI) P Value

Sex, male vs female 0.65 (0.37–1.15) 0.1360

Age, > vs ≤70 y 2.15 (1.21–3.80) 0.0076

Unit dose > vs ≤0.86 1.77 (1.00–3.13) 0.0483 2.15 (1.19–3.86) 0.0109

NIHSS at baseline, > vs ≤8 1.88 (0.79–4.48) 0.1478

Body weight, > vs ≤60 kg 1.35 (0.76–2.39) 0.3096

Time from onset, > vs ≤120 min 0.74 (0.40–1.39) 0.3532

Teaching hospital, yes vs no 1.31 (0.74–2.33) 0.3507

Hypertension, yes vs no 2.55 (1.18–5.50) 0.0136 2.61 (1.19–5.73) 0.0170

Diabetes mellitus, yes vs no 1.24 (0.67–2.28) 0.4971

Atrial fibrillation, yes vs no 1.47 (0.82–2.63) 0.1910

Hyperlipidemia, yes vs no 0.56 (0.29–1.09) 0.0865 0.51 (0.26–1.01) 0.0544

Coronary artery disease, yes vs no 2.54 (1.37–4.73) 0.0024 2.15 (1.13–4.07) 0.0190

Smoking

Current, yes vs no 0.37 (0.16–0.83) 0.0124 0.41 (0.18–0.93) 0.0322

Previous, yes vs no 0.53 (0.19–1.49) 0.2183

Aspirin, yes vs no 1.95 (1.05–3.62) 0.0306

Clopidogrel/ticlopidine, yes vs no 2.79 (1.19–6.53) 0.0142

Cilostazol/dipyridamole, yes vs no 2.42 (0.70–8.39) 0.1516

Anticoagulant, yes vs no 1.06 (0.37–3.03) 0.9159

CI indicates confidence interval; NIHSS, National Institutes of Health Stroke Scale; and OR, odds ratio.*Patients aged >80 y are excluded, but those with modified Rankin Scale scores ≥2 before the index stroke were included.†Adjusted OR.

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after adjusting for the covariates showed that r-tPA dose ≤0.65 mg/kg, age, National Institutes of Health Stroke Scale score, and absence of diabetes mellitus were independently related to an mRS score of 0 to 1 at 3 months (Table 3).

The safety and efficacy outcomes of the 4 groups with dif-ferent r-tPA doses are shown in Table II in the online-only Data Supplement. Overall, there were no differences in safety or efficacy outcomes among the 4 dose groups. However, after accounting for age and dose interaction, there were differ-ences in both the safety and efficacy outcomes in patients aged >70 years (71–80 years) among the 4 dose groups. The effects of interactions between age and r-tPA dose on the occurrence of SICH are illustrated in Figure 1. The occurrence of SICH increased after r-tPA treatment as age increased (P=0.002; Figure 1A), but SICH increased with increasing doses of r-tPA only in patients aged >70 years (71–80 years; P=0.0130; Figure 1B). This trend was not observed in younger patients.

In patients aged >70 years, as the dose of r-tPA increased, the frequency of a better functional outcome at 3 months decreased (P=0.0179 for mRS 0–1 and P=0.0180 for mRS 0–2; Figure 2A and 2B) and the mortality rates increased (P=0.0971; Figure 2C). We also found that using a lower r-tPA dose of 0.6 mg/kg compared with a dose of 0.9 mg/kg was associated with higher rates of good functional outcomes (mRS 0–1; 41.3% versus 22.9%; absolute difference, 18.4%; relative increase in good functional outcome, 80.4%), inde-pendent functional outcomes (mRS 0–2; 54.0% versus 33.6%; absolute difference, 20.4%; relative increase in independent

functional outcome, 60.7%), and a lower mortality rate at 3 months (4.6% versus 12.4%; absolute difference, 7.8%; rela-tive mortality reduction, 72.8%; Table III in the online-only Data Supplement).

DiscussionThis study did not support the dose of 0.9 mg/kg of r-tPA for all Chinese patients, especially for patients aged >70 years. In our study population, a dose of 0.9 mg/kg of r-tPA was related to more SICH, and a dose of ≤0.65 mg/kg was associated with a good functional outcome in a multivariate logistic regres-sion analysis. In patients aged >70 years, an r-tPA dose of 0.6 mg/kg has better safety (lower SICH and mortality rates) and functional outcomes at 3 months compared with higher doses. Our study suggests an optimal dose of 0.6 mg/kg of r-tPA, which has better safety and efficacy in aged Chinese patients with acute ischemic stroke. In this study, 120 patients who received thrombolytic therapy were >80 years of age, which accounted for ≈12% of all the patients given thrombolytic therapy, although they are not officially considered eligible for r-tPA therapy in Taiwan. The analysis of the data in patients aged >80 years revealed no significant differences among groups of different r-tPA doses. It was mainly because of poor clinical outcomes, in general, across the groups of different r-tPA doses and small number of patients in each dose group. Owing to inconclusive results and failure to provide useful information after the analysis of data among the patients aged >80 years, we did not present the results of those patients.

Table 3. Predictors of Good Functional Outcome With 3-Month Modified Rankin Scale Score (0–1) in 840 Patients*: Univariate and Multivariate Analyses

Univariate Analysis Multivariate Analysis

Characteristics OR (95% CI) P Value OR† (95% CI) P Value

Sex, male vs female 1.13 (0.83–1.54) 0.4264

Age, > vs ≤70 y 0.65 (0.48–0.88) 0.0048 0.69 (0.51–0.95) 0.0209

Unit dose > vs ≤0.65 0.72 (0.49–1.04) 0.0770 0.67 (0.45–0.98) 0.0369

NIHSS at baseline, > vs ≤8 0.37 (0.26–0.52) <0.0001 0.37 (0.26–0.52) <0.0001

Body weight, > vs ≤60 kg 1.26 (0.94–1.68) 0.1219

Time from onset, > vs ≤120 min 0.88 (0.64–1.21) 0.4340

Teaching hospital, yes vs no 0.84 (0.62–1.12) 0.2247

Hypertension, yes vs no 0.80 (0.59–1.59) 0.1612

Diabetes mellitus, yes vs no 0.64 (0.45–0.90) 0.0096 0.61 (0.43–0.86) 0.0056

Atrial fibrillation, yes vs no 0.81 (0.59–1.11) 0.1935

Hyperlipidemia, yes vs no 1.17 (0.86–1.58) 0.3170

Coronary artery disease, yes vs no 0.90 (0.61–1.33) 0.5944

Smoking

Current, yes vs no 1.12 (0.82–1.53) 0.4876

Previous, yes vs no 1.31 (0.87–1.97) 0.1946

Aspirin, yes vs no 0.99 (0.69–1.42) 0.9528

Clopidogrel/ticlopidine, yes vs no 0.59 (0.30–1.18) 0.1343

Cilostazol/dipyridamole, yes vs no 0.84 (0.32–2.19) 0.7227

Anticoagulant, yes vs no 1.06 (0.61–1.85) 0.8376

CI indicates confidence interval; NIHSS, National Institutes of Health Stroke Scale; and OR, odds ratio.*Patients aged >80 y and those with modified Rankin Scale score ≥2 before the index stroke are excluded.†Adjusted OR.

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However, the study of the safety and efficacy of the patients aged >80 years is underway in Taiwan, initiated by Taiwan Stroke Society, and hopefully, we can provide more informa-tion in the near future.

The impact of different r-tPA doses on patient outcomes is rarely discussed in international neurological societies, with the exception of a few small studies in certain Asian coun-tries.10,11 The present study is the first that registered enough East Asian patients receiving various doses of r-tPA to analyze the relationship between the dose and the safety/efficacy in acute ischemic stroke. Our study echoes the findings of previ-ous studies that higher doses of thrombolytic agents increase the risk of hemorrhage and reveals higher rates of SICH per the NINDS definition (12.4%) in elderly patients (71–80 years) receiving 0.9 mg/kg of r-tPA (Table III in the online-only Data Supplement).12–14 In the SITS-NEW study in Asian countries, which used 0.9 mg/kg of r-tPA for acute ischemic stroke, the rate of SICH per the NINDS definition (8.7%) was higher than those r-tPA studies previously reported (Table I in the online-only Data Supplement), despite the fact that the patient population was younger in the SITS-NEW study than in the TTT-AIS II study (median age, 64 versus 68 years).

In this study, the risk factors for SICH were similar to those reported elsewhere.15 Interestingly, the findings in this study echo the so-called smoking–thrombolysis paradox, that is,

significantly less ICH occurs in smokers after thrombolytic therapy.16 Patients with current or recent smoking were also reported to paradoxically have higher rates of recanalization and better outcomes than nonsmokers after thrombolytic ther-apy.17 However, our present study did not find an association between smoking and functional outcome.

For comparison with other studies reported in the literature, data from the total 1004 patients were included. Although our present study had comparable rates of SICH and mortality, the rate of good functional outcome (30.6%) was lower than our previous TTT-AIS study (39.3%) and the SITS-NEW

Figure 1. Symptomatic intracerebral hemorrhage (SICH) per the National Institute of Neurological Disorders definition within 3 months. A, SICH increased with age. A significant trend for SICH with age was demonstrated (right bar chart), but no difference in SICH among different doses of r-tPA was observed (left bar chart). B, After considering the age and dose interaction, a sig-nificant trend for SICH with dose was also found in patients aged 71 to 80 years (right bar chart). SICH rates were lower in younger patients with various doses and in those aged 71 to 80 years using the lowest dose.

Figure 2. Distribution of modified Rankin Scale (mRS) scores (0–1, 0–2) at 3 months and death within 3 months in patients aged ≤70 and 71 to 80 years treated with different doses. Better outcomes were observed in the younger patients with various doses and in those aged 71 to 80 years who received the lowest dose. A, A significant trend for good functional outcome (mRS 0–1) with dose was observed in patients aged 71 to 80 years (right bar chart), and no difference in the younger patients with various doses was observed (left bar chart). B, A significant trend for mRS 0 to 2 with dose was also observed in patients aged 71 to 80 years (right bar chart), and no difference for mRS 0 to 2 in the younger patients was observed (left bar chart). C, A trend toward less mortality using the lowest dose compared with a dose of 0.9 mg/kg in patients aged 71 to 80 years was observed (right bar chart).

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study (Table I in the online-only Data Supplement). This can be partially explained by the fact that the current study population had a higher mean age, a higher baseline National Institutes of Health Stroke Scale score, a longer mean time from stroke onset to treatment, and higher frequencies of hypertension, diabetes mellitus, atrial fibrillation, and aspi-rin and clopidogrel use. In addition, patients with recur-rent stroke (12%) and a prestroke mRS score ≥2 were still included for thrombolytic therapy in the present study. All the above-mentioned factors may be legitimate reasons for the lower rate of good functional outcomes observed in the present study.

It has been reported that the incidence of ICH was 2-fold higher in Asians compared with whites, and the prevalence of microbleeds and the susceptibility to spontaneous ICH were also higher in Asians compared with non-Asians.18,19 There is evidence that supports that maintaining a lower international normalized ratio level of warfarin for the secondary preven-tion of stroke in patients with nonvalvular atrial fibrillation is better for Chinese and Japanese patients compared with white patients.20,21 A recent study revealed that bleeding complica-tion rates on warfarin were higher in Asians compared with non-Asians.22 Thus, we speculate that racial/genetic difference is one of the determinant factors for drug dose, not only for anticoagulants (warfarin) but also probably for thrombolytic agents (r-tPA).

Many neurologist in Asian countries may use lower dose or variable dose of r-tPA regimens for acute ischemic stroke because of the fact that (1) Asians are more prone to bleed-ing, (2) the r-tPA dose of 0.9 mg/kg has never been replicated with controlled trial in East Asians, (3) the 0.6 mg/kg dose of r-tPA for stroke was approved and used in Japan, and (4) the cost of r-tPA. So, our present study, in addition to the previous TTT-AIS study, suggests a need for a randomized clinical trial to study the r-tPA dose in East Asian population, especially in the elderly patients. To date, there is no single randomized controlled trial published that has compared the safety/efficacy of r-tPA between the current 0.9 mg/kg dose and other lower doses. Of note, our results support the current ongoing study, the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), with the dose of 0.6 versus 0.9 mg/kg.23 We think that observational studies and randomized trials can complement each other; otherwise people will still argue why other lower dose such as 0.7 mg/kg or 0.8 mg/kg compared with 0.9 mg/kg is not used.

Our study design has limitations. Although the registration was prospective, the r-tPA dose selection was not randomized, and physicians might have selected the dose according to patients’ clinical conditions, such as patient’s imaging findings and medical comorbidity, which might influence the results of dose/safety/efficacy analysis. It is notable that patients who had unfavorable factors for stroke outcome, such as older age, atrial fibrillation, and longer time to r-tPA treatment, were more likely to receive a lower r-tPA dose (Table 1)24,25 and, thus, would underestimate the benefits of the lower doses. However, we included all the clinical characteristics of the patients in the study and adjusted them for further dose out-come analyses.

In conclusion, the present study is the first to show the out-comes of thrombolytic therapy with various doses of r-tPA, and the dose of 0.6 mg/kg correlated to a better outcome for aged Chinese patients. Given the nature of the present study, randomized controlled trials are warranted to confirm the cur-rent findings.

AcknowledgmentsWe thank all the individuals who have participated in the study.

Sources of FundingThe study protocol was funded by Yen Tjing Ling Medical Foundation and Kaohsiung Medical University and Hospital (KMUH101-1R56).

DisclosuresNone.

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Han-Hwa HuJiann-Shing Jeng, Chaur-Jong Hu, Chih-Ping Chung, Hung-Yi Hsu, Wen-Yung Sheng and

A-Ching Chao, Ching-Kuan Liu, Chih-Hung Chen, Huey-Juan Lin, Chung-Hsiang Liu,Chinese Patients

Different Doses of Recombinant Tissue-Type Plasminogen Activator for Acute Stroke in

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1

SUPPLEMENTAL MATERIAL

Supplemental Table I.

Results of the TTT-AIS-II, J-MARS, SITS-MOST, NINDS, J-ACT, TTT-AIS, and SITS-NEW studies

TTT-AIS II J-MARS SITS-MOST NINDS J-ACT TTT-AIS SITS-NEW

SICH per NINDS 6.8% N/A 7.3% 6.4% 5.8% 7.9% 8.70%

SICH per ECASS 5.1% N/A 4.6% N/A N/A 5.4% 5.64%

SICH per

SITS-MOST 2.2% N/A 1.7% N/A N/A 3.7% 1.87%

Death within 3

months 9.05% 17% 11.3% 17.0% 9.7% 10.0% 10.19%

mRS 0–1 at 3

months 30.56% 33% 38.9% 39.0% 36.9% 39.3% 42.66%

mRS 0–2 at 3

months 45.5% N/A 54.8% N/A N/A 53.4% 62.52%

BI 95–100 at 3

months 43.4% N/A N/A 50.0% 48.5% 43.6% N/A

NIHSS

improvement

(by ≥ 4 points or

decreased to 0 at

24 hr)

38.5%

N/A

N/A

47.0%

49.5%

39.0%

N/A

2

Supplemental Table II.

Comparisons of treatment results between patients receiving dose of 0.9 mg/kg and those receiving lower

doses of rt-PA

Variables

0.6 mg/kg

(n=181) 0.7 mg/kg

(n=199) 0.8 mg/kg

(n=202) 0.9 mg/kg

(n=422) p value§

SICH per NINDS 10 (5.52%) 10 (5.03%) 12 (5.94%) 31 (7.35%) 0.2711

SICH per ECASS 10 (5.52%) 6 (3.02%) 11 (5.45%) 21 (4.98%) 0.8323

SICH per

SITS-MOST 5 (2.76%) 4 (2.01%) 5 (2.48%) 7 (1.66%) 0.4324

Mortality within 3

months 14 (7.7%) 19 (9.6%) 18 (8.9%) 35 (8.3%) 0.9927

mRS 0-1 at 3 months* 56 (38.4%)† 44 (28.2%)‡ 46 (26.9%)# 124 (33.8%)& 0.7003

mRS 0-2 at 3 months* 78 (53.4%)† 69 (44.2%)‡ 76 (44.4%)# 173 (47.1%)& 0.4042

mRS 5-6 at 3 months* 29 (19.9%)† 35 (22.4%)‡ 44 (25.7%)# 69 (18.8%)& 0.6084

* Patient with aged ≤ 80 and those who completed a 3-month assessment. †:n=146, ‡:n=156, #:n=171, &:n=367.

§ Mantel-Haenszel chi-square test for trend.

3

Supplemental Table III.

Comparisons of treatment results between patients aged 71–80 years receiving dose of 0.9 mg/kg or lower

doses of rt-PA

Variables

0.6 mg/kg

(n=65) 0.7 mg/kg

(n=63) 0.8 mg/kg

(n=81) 0.9 mg/kg

(n=137) p value§

SICH per NINDS 2 (3.08%) 3 (4.76%) 8 (9.88%) 17 (12.41%) 0.0130

SICH per ECASS 1 (1.54%) 2 ( 3.17%) 7 (8.64%) 11 (8.03%) 0.0406

SICH per

SITS-MOST 1 (1.54%) 1 (1.59%) 4 (4.94%) 3 (2.19%) 0.6670

Mortality within 3

months 3 (4.62%) 6 (9.52%) 8 (9.88%) 17 (12.41%) 0.0971

mRS 0-1 at 3 months* 26 (41.3%)† 15 (24.2%)‡ 18 (22.80%)# 30 (22.9%)& 0.0179

mRS 0-2 at 3 months* 34 (54.0%)† 22 (35.5%)‡ 29 (36.7%)# 44 (33.6%)& 0.0180

mRS 5-6 at 3 months* 14 (22.2%)† 18 (29.0%)‡ 27 (34.2%)# 35 (26.7%)& 0.5948

* Patients aged 71-80 years and those who completed a 3-month assessment. †:n=63, ‡:n=62, #:n=79, &:n=131.

§ Mantel-Haenszel chi-Square test for trend.