Optimal dose for stroke thrombolysis in Asians: low dose may have similar safety and efficacy as standard dose

Authors


Mu-Chien Sun, Department of Neurology, Changhua Christian Hospital, #135, Nanhsiao Street, Changhua 500, Taiwan.
Tel.: +886 4 723 8595; fax: +886 4 722 8289.
E-mail: sunmc@yahoo.com

Abstract

Summary.  Background:  Although intravenous tissue-type plasminogen activator (t-PA) at a standard dose of 0.9 mg kg−1 is effective for patients with acute ischemic stroke, concerns have been raised regarding Asians.

Objectives:  To compare the safety and efficacy between low and standard doses for stroke thrombolysis.

Patients/Methods:  Consecutive patients receiving t-PA treatment were recruited according to the prespecified dosing policy from two medical centers in Taiwan: low dose (0.7 mg kg−1) at National Cheng Kung University Hospital (NCKUH) from August 2006 to June 2009, or standard dose (0.9 mg kg−1) at NCKUH from July 2009 to December 2010 and at Changhua Christian Hospital from May 2008 to December 2010. The primary safety outcome was the occurrence of symptomatic intracerebral hemorrhage (SICH). The secondary efficacy outcome was the proportion of patients with a modified Rankin Scale (mRS) grade of ≤ 1 at 3 months.

Results:  From August 2006 to December 2010, 261 patients were recruited, of whom 105 and 156 received low and standard doses, respectively. The occurrence of SICH was non-significantly lower in the standard-dose group than in the low-dose group (2.6% vs. 4.8%, respectively; = 0.34). The favorable outcome of mRS grade of ≤ 1 at 3 months was similar (38.4% and 41.1%, respectively; = 0.676). A review of other case series of low vs. standard doses in Asians also showed similar safety and efficacy.

Conclusion:  Our study, as well as other case series on Asians, revealed that standard-dose thrombolysis for acute ischemic stroke in an Asian population carries no increased risk of symptomatic intracerebral hemorrhage when compared with the low dose.

Introduction

More than half of the global population now lives in Asia. With rapid economic transition, the burden of stroke is becoming an important issue in Asian countries [1,2]. Intravenous tissue-type plasminogen activator (t-PA) at a dose of 0.9 mg kg−1 has been proved to be effective in Western countries for patients with acute ischemic stroke within 3 h of onset [3,4]. However, this standard-dose t-PA poses several concerns for Asians, including its safety profile and cost. On the basis of experience from duteplase trials and racial differences in blood coagulation, a single-arm study conducted in Japan, the Japan Alteplase Clinical Trial (J-ACT), using 0.6 mg kg−1 t-PA for stroke thrombolysis, reported similar efficacy and bleeding risk as those found with the standard dose [5]. On the other hand, several studies in other Asian populations outside Japan, focusing on the dose regimen and safety/efficacy, reported contradictory results [6–9]. However, none of these studies was randomized, and the definition of low dose was diverse, with t-PA doses ranging from 0.6 to 0.85 mg kg−1 [6–9] or to a cap of a maximum of 50 mg, owing to concerns over cost [7–9]. Therefore, it was not possible to determine the optimal dose of t-PA for Asian patients with acute ischemic stroke.

This study compared the safety and efficacy of two prespecified doses – low dose (0.7 mg kg−1) and standard dose (0.9 mg kg−1) – in two medical centers with resident-based stroke treatment protocols and high-volume thrombolysis in Taiwan.

Methods

Our retrospective, two-center, open study comparing low-dose (0.7 mg kg−1) and standard-dose (0.9 mg kg−1) t-PA was designed with a target sample size of 100 patients in each group.

Study population

National Cheng Kung University Hospital (NCKUH) and Changhua Christian Hospital (CCH) are the two hospitals with the highest volume of intravenous t-PA treatment (approximately 30–40 patients per year) in Taiwan, with a t-PA administration rate of 5–7% for all hospitalized patients with acute ischemic stroke. Patients were prospectively registered in both hospitals according to the description of the Taiwan Stroke Registry [10]. Both hospitals’ Institutional Review Boards approved the conduct of the registry. In addition, these two hospitals have prespecified t-PA doses, and treatment decisions were determined by residents after discussion with patients or family members. Residents would consult attending staff only if they were unsure about treatment decisions. Written informed consent was obtained from all patients.

Patients presenting to the emergency room within 3 h of stroke symptoms were rapidly evaluated by a neurology resident (second to fifth year of training) for eligibility for thrombolysis. The National Institute of Health Stroke Scale (NIHSS) scores were assessed by neurology residents with certified training. The inclusion and exclusion criteria were similar to those of the SITS-MOST study, but without an upper age limit [4]. All thrombolyzed patients were admitted to the neurology intensive care unit for at least 24 h, and then transferred to the neurology ward if no clinical deterioration occurred.

Prespecified t-PA doses at study hospitals

The dose was set at 0.7 mg kg−1 at NCKUH from August 2006, and changed to 0.9 mg kg−1 after July 2009, owing to the absence of any increase in hemorrhagic complications at the 0.7 mg kg−1 dose. At CCH, the dose was fixed at 0.9 mg kg−1 from May 2008. We included patients after adoption of the prespecified t-PA dosing policy.

Before t-PA treatment, body weight was either determined from a patient/family member (NCKUH) or measured with a bed scale (CCH). Briefly, t-PA was administered at a dose of 0.7 or 0.9 mg kg−1 body weight (maximum dose of 90 mg), with 10% given as a bolus followed by delivery of the remaining 90% as a constant infusion over a period of 60 min. The actual body weight was assessed with a bed scale at NCKUH after admission to the intensive care unit or stroke ward. The t-PA dose (mg kg−1) was calculated as the total t-PA administered (mg) divided by body weight (kg) as measured with a bed scale. We divided the t-PA dose into a low dose (< 0.85 mg kg−1) and a standard dose (≥ 0.85 mg kg−1). The cut-point was set at 0.85 mg kg−1, because this dose has been shown to have similar efficacy as 0.95 mg kg−1 in the t-PA dose escalation study [11].

Imaging studies and outcome measures

All patients received brain scans (either computed tomography [CT] or magnetic resonance imaging) before t-PA. A second brain scan was performed within 36 h after thrombolysis. The radiologic definition of hemorrhagic events followed the European Cooperative Acute Stroke Study classification [12]. Parenchymal hemorrhage (PH) was categorized as follows: PH1 – blood clots in ≤ 30% of the infarcted area, with some slight space-occupying effect; and PH2 – blood clots in > 30% of the infarcted area, with a substantial space-occupying effect. All brain images were read by two neuroradiologists (C.M.T. and W.L.C.), who were blinded to the study design and patient information. The decision was made when two readers had concordant readings. If the radiologists’ readings were different, a reading from a neurologist (C.Y.H.) was added to reach a conclusion.

This study aimed to determine whether the standard-dose t-PA resulted in a higher rate of intracerebral hemorrhagic complications than the low-dose t-PA. Therefore, the primary outcome was symptomatic intracerebral hemorrhage (SICH), which was defined as any neurologic deterioration (National Institute of Neurological Disorders and Stroke [NINDS] criteria, NIHSS score increase of ≥ 1 points or death) within 36 h and a PH on brain CT in a location compatible with the clinical symptoms [3]. We also added SICHs defined in SITS-MOST [4] (The hemorrhage is either local or remote PH2 on the 22-h to 36-h post-treatment CT scan, combined with an NIHSS score increase of ≥ 4 points or leading to death).

The secondary outcome was efficacy, which was defined as: (i) the proportion of patients with a modified Rankin Scale (mRS) grade of ≤ 2 at discharge; and (ii) the proportion of patients with an mRS grade of ≤ 1 at 3 months. The in-hospital mortality and proportion of patients that could be discharged to home were also measured as parameters of efficacy outcome. Patients with a prestroke mRS grade of > 2 were excluded.

Statistical analysis

The baseline characteristics, safety and efficacy outcome were analyzed. Comparisons between the low dose and the standard dose were performed with the t-test, the Mann–Whitney test, Fisher’s exact test, or the chi-square test, whenever applicable. Multiple logistic regression analysis was performed to examine the odds ratio (OR) of possible independent predictors of safety and efficacy outcome. A two-tailed P-value of < 0.05 was considered to be statistically significant.

Results

Patient characteristics

A total of 261 patients receiving t-PA treatment were registered, including 146 at NCKUH from August 2006 to December 2010, and 115 at CCH from May 2008 to December 2010.

Patient characteristics are presented in Table 1. At NCKUH, three of the 95 patients (3.2%) intended to receive the low dose were actually given ≥ 0.85 mg kg−1 and were included in the standard-dose group; and seven of 51 patients (13.7%) in the prespecified 0.9 mg kg−1 group actually received < 0.85 mg kg−1, and were thus included in the low-dose group. At CCH, six of the included 115 patients (5.2%) received < 0.85 mg kg−1 because of gingival or gastrointestinal bleeding during t-PA infusion. They were therefore included in the low-dose group for analysis. The actual median (interquartile range) t-PA doses were 0.700 mg kg−1 (0.658–0.739) and 0.900 mg kg−1 (0.900–0.900) for the low (= 105) and standard (= 156) doses, respectively. The mean age was 67.9 years in both groups, and there was a male preponderance. The interval from emergency room to t-PA treatment was longer in the low-dose group than in the standard-dose group (77 vs. 67 min; = 0.002). However, the duration from onset to t-PA was similar in both groups (144 and 141 min, respectively). There were 11 patients who developed in-hospital stroke and received t-PA treatment (seven at the low dose; four at the standard dose). Other characteristics, including past medical history and stroke severity, were similar for both groups (Table 1).

Table 1.  Baseline characteristics of the study patients (= 261)
CharacteristicsTotal
(= 261)
Low dose
(= 105)
Standard dose
(= 156)
P-value
  1. CCH, Changhua Christian Hospital; DBP, diastolic blood pressure; ER, emergency room; IQR, interquartile range; NCKUH, National Cheng Kung University Hospital; NIHSS, National Institute of Health Stroke Scale; SBP, systolic blood pressure; SD, standard deviation; t-PA, tissue-type plasminogen activator. *Excluding in-hospital stroke (seven in the low-dose group; four in the standard-dose group).

Hospital, NCKUH/CCH, n146/11599/647/109<0.001
Weight (kg), mean (SD)63.6 (12.6)63.7 (13.2)63.6 (12.2)0.932
Actual t-PA dose (mg kg−1), median (IQR)0.900 (0.709–0.900)0.700 (0.658–0.739)0.900 (0.900–0.900)<0.001
Age (years), mean (SD)67.9 (12.5)67.9 (12.8)67.9 (12.3)0.979
Male sex, n (%)167 (64.0)65 (61.9)102 (65.4)0.566
Onset to ER (min) (SD)*69 (41)63 (42)72 (41)0.087
ER to t-PA (min) (SD)*71 (25)77 (27)67 (23)0.002
Onset to t-PA (min) (SD)142 (40)144 (41)141 (39)0.498
Initial SBP (mmHg) (SD)159 (29)159 (27)159 (30)0.917
Initial DBP (mmHg) (SD)93 (19)93 (19)92 (20)0.923
Platelet count (103 mm−3) (SD)211 (56)215 (58)208 (55)0.282
Past medical history, n (%)
 Hypertension194 (74.3)79 (75.2)115 (73.7)0.783
 Diabetes77 (29.5)35 (33.3)42 (26.9)0.265
 Prior stroke44 (16.9)17 (16.2)27 (17.3)0.813
 Atrial fibrillation83 (31.8)36 (34.3)47 (30.1)0.479
 Smoking104 (39.8)45 (42.9)59 (37.8)0.415
 Prestroke mRS grade of 220 (7.7)10 (9.5)10 (6.4)0.354
NIHSS score, mean (SD)13.2 (6.3)13.3 (6.2)13.1 (6.3)0.852
 NIHSS score of ≤ 9, n (%)100 (38.3)40 (38.1)60 (38.5) 
 NIHSS score of 10–17, n (%)93 (35.6)39 (37.1)54 (34.6) 
 NIHSS score of 18–25, n (%)68 (26.1)26 (24.8)42 (26.9)0.893
Stroke subtypes, n (%)
 Large artery42 (16.1)20 (19.0)22 (14.1)0.015
 Small vessel disease74 (28.4)22 (21.0)52 (33.3)
 Cardioembolic34 (13.0)9 (8.6)25 (16.0)
 Undetermined104 (39.8)52 (49.5)52 (33.3)
 Other determined7 (2.7)2 (1.9)5 (3.2)

Intracerebral hemorrhage and discharge outcome in the low-dose and standard-dose groups

There were 11 and eight patients with post-t-PA PH in the low-dose group (10.5%) and the standard-dose (5.1%) group, respectively (= 0.103) (Table 2). Only two patients (1.3%) in the standard-dose group developed PH2, which was a lower number than in the low-dose group (4.8%; = 0.121).

Table 2.  Intracerebral hemorrhage (ICH) and discharge outcome in the low-dose and standard-dose groups
ICHTotal (= 261)Low dose (n = 105)Standard dose (= 156) P-value
  1. ECASS, European Cooperative Acute Stroke Study; mRS, modified Rankin Scale; NINDS, National Institute of Neurological Disorders and Stroke; PH, parenchymal hemorrhage; SD, standard deviation; SICH, symptomatic intracranial hemorrhage; SITS-MOST, safe implementation of thrombolysis in stroke-monitoring study.

ICH, n (%)
 PH (ECASS definition)19 (7.3)11 (10.5)8 (5.1)0.103
  PH112 (4.6)6 (5.7)6 (3.8) 
  PH27 (2.7)5 (4.8)2 (1.3) 
 SICH as per NINDS9 (3.4)5 (4.8)4 (2.6)0.340
 SICH as per SITS-MOST6 (2.3)4 (3.8)2 (1.3)0.182
Discharge status
 Admission days, mean (SD)17.1 (14.6)18.6 (16.9)16.0 (12.8)0.172
 Discharge to home, n (%)198 (75.9)82 (78.1)116 (74.4)0.489
 In-hospital mortality, n (%)17 (6.5)8 (7.6)9 (5.8)0.553
 Discharge mRS grade of 0–2, n (%)97 (37.2)38 (36.2)59 (37.8)0.789

The rate of SICH according to the NINDS definition was non-significantly lower in the standard-dose group than in the low-dose group (2.6% vs. 4.8%, respectively; = 0.34). For the patients aged ≥ 70 years (= 138), the rates of PH (7.1% vs. 13.0%, respectively; = 0.371) and SICH (4.8% vs. 5.6%, respectively; = 1.000) were similar in both groups.

The median length of hospital stay was not different between the standard-dose group (16.0 days) and the low-dose group (18.6 days; = 0.172). The proportion of patients who could be discharged to home was similar in both groups (74.4% and 78.1%, respectively; = 0.489). Seventeen patients died during their hospital stay: nine (5.8%) in the standard-dose group and eight (7.6%) in the low-dose group (= 0.553). The favorable outcome at discharge (defined as an mRS grade of 0–2) was not different between the standard-dose group and the low-dose group (37.8% and 36.2%, respectively; = 0.789; Table 2).

To evaluate the independent predictors of SICH and mortality, logistic regression analysis was applied. The variables entered were age, sex, initial NIHSS score on admission, dose (standard vs. low), interval between onset and t-PA treatment, hypertension, diabetes mellitus, atrial fibrillation, prior stroke, smoking, initial systolic blood pressure, platelet count, and stroke subtype. The independent predictor for SICH was the presence of diabetes mellitus (OR 10.207, 95% confidence interval [CI] 1.702–61.235). Dose was not a predictor for SICH (standard vs. low dose; OR 0.624, 95% CI 0.113–3.434). There were three predictors for mortality: initial NIHSS score (OR 1.124, 95% CI 1.015–1.243), platelet count (OR 0.982, 95% CI 0.967–0.997), and stroke subtype (OR 2.709, 95% CI 1.312–5.593).

Functional outcome in low-dose and standard-dose groups

The secondary outcome was the relative efficacy of the low and standard doses (Fig. 1). The favorable outcome (mRS grade of ≤ 1 at 3 months) was assessed in patients with a prestroke mRS grade of ≤ 1 (= 241). There was no difference between the standard-dose and the low-dose groups for favorable outcome (38.4% and 41.1%, respectively; = 0.676; Fig. 1). The independent predictors for favorable outcome were initial NIHSS score (OR 0.816, 95%  CI 0.765–0.872) and interval from onset to t-PA treatment (OR 0.991; 95% CI 0.984–0.999). Dose was not a predictor for favorable outcome (standard vs. low dose; OR 0.729, 95% CI 0.390–1.362).

Figure 1.

 Outcome of the modified Rankin Scale (mRS) at 3 months with prestroke mRS grade of ≤ 1 (= 241).

Discussion

The present study demonstrates two important facts regarding t-PA doses. First, the standard-dose intravenous t-PA treatment protocol is safe, with similar rates of SICH and mortality as the low-dose protocol. Second, the favorable functional outcome is not different between low and standard doses. Our findings show that diabetes mellitus is the only independent predictor for SICH. Stroke severity and interval from onset to t-PA treatment can predict functional outcome.

Concerns about the standard t-PA dose in Asians

Besides cost considerations, the main reason for using low-dose t-PA in Asians is the concern about safety. The standard dose is supposed to lead to a higher rate of SICH than the lower dose. A preliminary study [13] in Taiwan using standard-dose t-PA showed higher rates of SICH and mortality (20% and 32%, respectively) than those found in the NINDS trial. The results of J-ACT [5] demonstrated that, in Japanese patients, 0.6 mg kg−1 t-PA had efficacy and an incidence of SICH (5.8%) similar to published data for 0.9 mg kg−1 t-PA (6.4%) in the USA [3]. However, other studies from Taiwan [14], Korea [15] and Thailand [16] using standard-dose t-PA showed a similar SICH rate (ranging from 4.7–6.6%) to that in the NINDS trial [3].

Studies comparing t-PA doses in Asians

Several case series in various Asian populations directly comparing the effect of dose difference on the safety and efficacy outcome have been reported, and the results are contradictory (Table S1) [6–9]. In those studies, the definition of low dose was diverse, with the t-PA dose ranging from 0.6 to 0.85 mg kg−1 [6–9] or to a cap of a maximum of 50 mg, owing to the cost issue [7–9]. None of these studies has shown that the standard dose leads to a significantly higher SICH rate than the low dose, except in a subgroup analysis from a study (TTT-AIS) in Taiwan [6], which showed higher SICH and mortality rates in patients aged ≥ 70 years receiving the standard dose than in those receiving the low dose [6]. In the present study, we did not find that standard-dose t-PA increased the SICH and mortality rates in patients aged ≥ 70 years (low vs. standard dose, 5.6% vs. 4.8%; = 1.00). These differences may be related to the different hospital experience and study periods of the two studies. The TTT-AIS study recruited 241 patients in 23 participating hospitals from December 2004 to July 2008. The limited experience in TTT-AIS hospitals (approximately three patients received t-PA per hospital per year) may have contributed to the higher SICH and mortality rates. Previous studies showed that hospitals that administered t-PA to fewer than five patients a year had higher SICH and mortality rates than those that treated five or more patients a year [17,18].

We conducted an analysis on relevant case series regarding t-PA dose in Asian populations (Fig. 2). There were 858 subjects from five studies (including the present study) comparing low-dose and standard-dose t-PA treatment. We found similar SICH rates in the low-dose and standard-dose groups (6.2% and 5.5%, respectively; OR 0.93, 95% CI 0.50–1.75). Contrary to the possibility of hemorrhagic complications, standard-dose t-PA might confer a better functional outcome than lower-dose tPA because of the dose–response effect demonstrated in the dose escalation study [11]. However, the percentages of patients with mRS grade 0–1 at 3 months in our meta-analysis were also similar in the low-dose and standard-dose groups (42.1% and 42.9%, respectively; OR 1.00, 95% CI 0.76–1.34). If the safety and efficacy outcomes are both similar, the low-dose t-PA regimen may be more cost-effective in Asian countries, especially the developing ones [19].

Figure 2.

 Meta-analysis of studies comparing tissue-type plasminogen activator doses in Asians. CI, confidence interval; OR, odds ratio; SICH, symptomatic intracerebral hemorrhage. TTT-AIS: the Taiwan thrombolytic therapy for acute ischemic stroke.

Strengths and limitations

The strength of this study is that both participating hospitals had a prespecified t-PA dose policy and a high t-PA treatment volume (30–40 patients per year). The fixed dose of 0.7 mg kg−1 in the low-dose group and similar experiences of thrombolytic therapy in the two groups made the comparison more valid. Nonetheless, our study had several limitations. For example, the assessment of mRS grade at 3 months was not blinded. However, our primary outcome was SICH, and neuroimaging findings were assessed by two neuroradiologists blinded to the used dose. The distributions of stroke subtype in the low-dose and standard-dose groups were different, and the percentages of cardioembolism and small vessel disease were higher in the standard-dose group than in the low-dose group. It is undetermined whether the difference in stroke subtype affects the rates of SICH and favorable outcome at 3 months. However, the pretreatment NIHSS score was not different between the groups. A previous study demonstrated that stroke subtype may not affect the outcome of thrombolytic therapy after adjustment for stroke severity [20].

Conclusion

In conclusion, the results from our study as well as other case series on Asians reveal that standard-dose thrombolysis for acute ischemic stroke in Asian populations carries no increased risk of SICH as compared with the low dose. Nonetheless, a randomized, multinational dose-comparative trial is warranted to determine the optimal dose of t-PA for Asian populations with acute ischemic stroke.

Acknowledgements

We thank all neurologic residents, as well as other healthcare professionals at NCKUH and CCH, for their contributions to this study. This study was supported by grants from the National Science Council (NSC 99-2628-B-006-033-MY3) and National Cheng Kung University Hospital (NCKUH-10 007 002).

Disclosure of Conflict of Interests

The authors state that they have no conflict of interest.

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