Efficacy and safety of different doses of intravenous tissue plasminogen activator in Chinese patients with ischemic stroke

doi:10.1016/j.jocn.2009.12.005

Journal of Clinical Neuroscience

Volume 17, Issue 8, August 2010, Pages 988-992

https://doi.org/10.1016/j.jocn.2009.12.005 Get rights and content

Abstract

Intravenous tissue plasminogen activator (tPA) at 0.9 mg/kg improves outcome in acute ischemic stroke. The dose response to tPA may be different in Chinese patients compared with Western populations, but this has not been systematically examined. We aimed to compare the efficacy and safety of different doses of tPA in Chinese stroke patients. We included all acute ischemic stroke patients treated with tPA within 4.5 hours of onset. Patients were treated with three dose regimens of tPA (0.6–0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg). The following data were collected: patient demographics; vascular risk factors; neuroimaging results; time of tPA administration; clinical assessment before treatment, at 24 hours and 3 months; and modified Rankin Scale (mRS) score at 3 months. A total of 105 patients with stroke of Han Chinese origin were included in the study. The baseline characteristics of the three dose groups were well matched. In the 0.9 mg/kg group (n = 51), 51.1% had favorable outcome at 3 months, compared with 38.7% of patients in the 0.8 mg/kg group (n = 31) (odds ratio [OR] to 0.9 mg/kg group, 0.57; 95% CI, 0.19–1.73; p = 0.32) and 34.8% in the 0.6–0.7 mg/kg group (n = 23) (OR to 0.9 mg/kg group, 0.31; 95% CI, 0.08–1.16; p = 0.08). There were no statistically significant differences in the incidence of symptomatic intracerebral hemorrhage and mortality rate. There was a higher proportion of patients with good functional outcomes in the 0.9 mg/kg group. Although not significant, these results strongly support the feasibility and urgent need for a dose ranging trial to establish an optimal tPA dose in Chinese stroke patients.

Introduction

Stroke is one of the leading causes of disability and death in both developing and developed countries.[1], [2] In China, stroke, with an annual incidence of 219 people per 100,000 in a population of approximately 1.3 billion, is the second commonest cause of death and is a huge societal challenge.[2], [3] Intravenous thrombolysis with tissue plasminogen activator (tPA) is effective in the treatment of patients with acute stroke.[4], [5], [6], [7] Pooled meta-analysis has indicated that tPA for acute ischemic stroke is one of the most powerful treatments in internal medicine.⁴ The initial NINDS trial showed that patients treated with tPA were at least 30% more likely to have an excellent outcome at 3 months.⁷ A recent second positive trial has established a time window of 4.5 hours.⁵ However, only a small proportion of stroke patients in China are currently treated with tPA.

Previous studies predominantly enrolled patients from Western populations and there is little evidence in the literature regarding the efficacy of tPA in patients of Chinese origin. Furthermore, there is emerging evidence to support the view that Asian patients might have a different dose response to tPA than Caucasians, in both the coronary and cerebral circulations. In a dose response study of 169 Chinese patients with acute myocardial infarction (AMI), 79% of patients treated with a standard dose of 50 mg tPA reached a thrombolysis in myocardial infarction (TIMI) grading system grade 2 or 3, equivalent to rates achieved with 100 mg in Western populations.⁸ Similarly, two Japanese studies showed that lower doses of tPA in patients with AMI achieved similar rates of recanalization and clinical outcome compared with standard doses administered in Western patients.[9], [10] In the treatment of ischemic stroke in Japan, a 0.6 mg/kg dose of tPA has become the standard dose.¹¹ Two Chinese studies suggested that low dose tPA may be as effective as higher doses. However, multivariate analyses were not performed to account for potential confounding factors.[12], [13]

In the National Institute of Neurological Disorders and Stroke (NINDS), Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) and the European Cooperative Acute Stroke Study (ECASS) 3 trials, where the standard regime was 0.9 mg/kg, chiefly Caucasian patients were enrolled and the trial did not take into account any differences in ethnicity.[5], [7], [14] There has been no randomized controlled tPA trial in Chinese patients. Hence, there is no existing agreement on the optimal dose of tPA in China for acute ischemic stroke. As a result, the dose regimens of tPA used in Chinese stroke patients varies between 0.6 mg/kg and 0.9 mg/kg and the practice of acute stroke management deviates significantly from established international guidelines.[15], [16]

In this context, we performed a retrospective study in a major Chinese University Hospital, to examine the efficacy and safety of different doses of tPA in Chinese stroke patients.

Section snippets

Patients and methods

We retrospectively included 105 consecutive patients with acute stroke who received tPA at the Branch of Shanghai Jiao Tong University Affiliated First People’s Hospital from 1998 to 2008. Ethics approval for this project was granted by the hospital ethics committee.

The following clinical parameters at presentation were recorded: age, gender, vascular risk factors, stroke onset, National Institutes of Health Stroke Scale (NIHSS) score, modified Rankin Scale (mRS) score and neuroimaging results.

Results

The baseline characteristics were well matched in the three treatment groups. These included age, NIHSS, time to treatment and vascular risk factors. A total of 105 patients of Chinese origin were included in this study. Demographic characteristics and baseline clinical characteristics were calculated separately for the three tPA dose groups and are shown in Table 1. Statistically significant baseline differences were observed in gender (p < 0.001) and systolic blood pressure (p = 0.04) between the

Discussion

There is emerging interest in the differing responses to tPA therapy in different racial groups. In comparison with Western patients, patients of Asian origin have lower plasma concentration of fibrinogen, lower plasminogen activator inhibitor-I levels and lower factor XIII activity.[18], [19], [20] This led to the hypothesis that Asian patients are more responsive than their Western counterparts to thrombolytic treatment with tPA in both the coronary and cerebral circulations. Some clinical

Acknowledgments

The Royal Melbourne Hospital Neurosciences Foundation (Melbourne, Australia) and Neurology Foundation (the Branch of Shanghai Jiao Tong University Affiliated First People’s Hospital, Shanghai, China) supported this study. We would like to thank Dr. Jian-Dao Yang (J.D.Y.) and Dr. Jiang-Sheng Yang (J.S.Y.) for their assistance in collecting the data.

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Cited by (41)

Low-dose alteplase for the management of acute ischemic stroke in South Asians: A systematic review on cost, efficacy and safety
2022, Journal of Clinical Neuroscience
South Asia is responsible for more than 40% of the stroke burden and stroke mortality in the developing world. South Asia, which is home to one-fourth of the world's population, is the most densely populated and one of the poorest regions. The majority of patients in this region are unable to afford intravenous thrombolysis (IVT) for acute ischemic stroke (AIS). If low-dose alteplase proves effective and safe in South Asians, it may be a more cost-effective treatment option.
The study was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and meta-Analyses) guideline. Researchers searched PubMed, EMBASE, and Google Scholar for English literature from 2005 to 2021. END, ENI, good functional outcome, SICH, and all-cause mortality were used to assess efficacy and safety.
In the low-dose alteplase treated patients, different studies reported 32 to 57% ENI 24 h after IVT, and 7% to 9.7% END. At 3 months follow-up, good functional outcome was achieved by 48%–76.92% of low-dose alteplase treated patients. SICH rates ranged from 0% to 16.6% across studies. Asymptomatic ICH occurred in 5–14% of patients. The mortality rate in all included studies varied from none to 25%.
Our systematic review demonstrates that the use of low-dose alteplase for AIS in the South Asians offer comparable efficacy and reduced risk of SICH at a significantly lower cost than standard alteplase dose. Future well-randomized clinical trials are necessary to validate the findings of our study.
Safety and efficacy of a new modified intravenous recombinant tissue plasminogen activator (rt-PA) regimen in Chinese patients with acute ischemic stroke: A descriptive retrospective cohort study with subgroup-analysis of different rt-PA dose
2022, Journal of Clinical Neuroscience
Evidence for effects of the dose of recombinant tissue plasminogen activator(rt-PA) in Asian populations is inconclusive. The standard dose may cause drug waste and increase economic burden in developing country. Therefore, we preliminarily describe the safety and efficacy of a new modified dose of rt-PA regimen(0.6 or 0.9 mg/kg, with a maximum dose of 50 mg) in real world settings. 265 consecutive patients with ischemic stroke were treated with intravenous(IV) rt-PA alone from all the 323 consecutive patients treated with reperfusion therapy between January 1, 2017 and March 31, 2020. Safety and Efficacy was assessed by early neurological improvement(ENI), early neurological deterioration(END), symptomatic intracranial hemorrhage(sICH) and 90-day outcome defined by modified Rankin scale(mRS). Subgroup analysis was conducted to draw comparisons between different dose groups ([0.5,0.6)mg/kg, [0.6,0.7)mg/kg, [0.7,0.8)mg/kg, [0.8,0.9]mg/kg). Among the 265 patients, 150(56.60%) had a favorable outcome at 3 months(3 M); Mortality occurred in 17(6.40%) in 3 M; sICH in 12(4.50%); ENI in 70(26.40%); END₂ in 29(10.90%) and END₄ in 18(6.80%). In subgroup analysis, there was a significant difference in sICH that more patients developed sICH in [0.8–0.9]mg/kg group(P = 0.044) in univariate analysis of different dose. After adjusting, there was no significant difference between 4 dosage groups. Significant differences were seen in gender, atrial fibrillation and baseline NIHSS in the multivariable model of favorable outcome at 3 M. Our study preliminarily shows a good safety and efficacy of our modified rt-PA regimen, indicating that this regimen should be worthy of further study especially in developing country to reduce the financial burden of patients and avoid drug waste.
Low-dose versus standard-dose intravenous alteplase for octogenerian acute ischemic stroke patients: A multicenter prospective cohort study
2019, Journal of the Neurological Sciences
The optimal dose of alteplase for acute ischemic stroke among geriatric patients is unclear. We aimed to assess the efficacy and safety of a low-dose (0.6 mg/kg) and standard-dose (0.9 mg/kg) alteplase for varying severity of Asian geriatric stroke patients.
The favorable functional outcome on day 90 after stroke onset, and the symptomatic intracranial hemorrhage (SICH) rate following 24–36 h of intravenous alteplase were measured. The baseline NIHSS of 4–8, 9–13, ≥14 were defined as mild, moderate, and high severity, respectively.
Totally, 249 geriatric patients treated with low-dose (n = 108) and standard-dose (n = 141) alteplase. Compared to standard-dose alteplase, low-dose alteplase had decrease in favorable functional outcome (22.2% versus 34.8%), and no difference in SICH rates was observed. For mild severity patients, the mortality was significantly increased with standard-dose alteplase (the NNT/NNH = 22.9/8.0 for mild severity, the NNT/ NNH = 15.0/14.7 for moderate severity, and the NNT/NNH = 13.5/19.6 for high severity).
Standard-dose and low-dose alteplase were comparable in reducing major disability, but low-dose alteplase for mild stroke showed much reduced mortality on day 90 for octogenarians.
Low- versus Standard-Dose Intravenous Tissue-Type Plasminogen Activator for Acute Ischemic Stroke: An Updated Meta-Analysis
2018, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
Harbord's modified test also confirmed these results (P = .83). The data for functional independence (mRS of 0-2) were available from 8 studies.3-6,9,14-16 The pooled average proportion of independence outcome retrieved from these studies was 57.1%, with 57.3% in the low-dose group and 57.0% in the full-dose group.
We performed a meta-analysis to compare the efficacy and safety between low- and standard-dose intravenous (IV) tissue-type plasminogen activator (tPA) for acute ischemic stroke (AIS) patients within 4.5 hours of symptom onset.
We searched PubMed and EMBASE for relevant studies from inception to June1, 2017. Cohort or randomized controlled studies for AIS within 4.5 hours of symptom onset with comparison between low-dose and standard-dose tPA were included. The primary efficacy end point was favorable functional outcome (modified Rankin scale scores [mRS] of 0-1) at 90 days. The primary safety end point was the incidence rate of symptomatic intracerebral hemorrhage (sICH). The secondary end points were independent functional outcome (mRS scores of 0-2) and mortality.
A total of 11 studies were pooled in this meta-analysis. The low-dose strategy appeared to be as effective as standard-dose tPA (43.4% versus 45.4%; odds ratio [OR] = 0.93, 95% confidence interval [CI]: 0.78-1.10; P = .38) in primary efficacy outcome. The secondary efficacy outcome produced similar results (57.3% versus 57.0%; OR = 0.95, 95% CI: 0.86-1.05; P = .33). There was no evidence of statistical difference for sICH (4.2% versus 4.9%; OR = 1.02 [0.66-1.55]; P = .94) and mortality (9.0% versus 10.6%; OR = 0.99 [0.74-1.31]; P = .92) at 90 days between low- and standard-dose therapy. In a subgroup analysis by ethnicity, there was no significant difference between patients of Asian and non-Asian descent for any of the end points.
This study showed that AIS patients receiving low-dose IV-tPA had comparably efficacy and safety to those receiving standard-dose IV-tPA. However, the effect is especially pronounced within the Asian population, which limits the generalizability of these results.
Low-Dose Tissue Plasminogen Activator in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
2018, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
Indeed, they showed that, at a high dose, the thrombolytic effect of tPA will no longer continue to rise; thus, moderate tPA doses exert the best effect in treating AIS.43 Several studies from countries other than Japan have been subsequently performed and reported inconsistent results.3,5,6,27-35 Of those, some reported similar findings to those in Japan,6,27-33 whereas others indicated that low-dose tPA may reduce the incidence of SICH, but have a lower efficacy than that of standard-dose tPA.3,5,34,35
Intravenous thrombolysis using tissue plasminogen activator (tPA) improves significantly the neurologic function in patients with acute ischemic stroke (AIS). However, it brings financial burden to patients and is associated with symptomatic intracranial hemorrhage (SICH). Whether low-dose tPA can effectively reduce SICH and has the same efficacy as standard-dose tPA is still controversial.
We searched for English clinical trials published before March, 2017on the comparison of the efficacy and safety between low and standard dose of tPA in the treatment of AIS using MEDLINE, Embase, and Cochrane Library. The modified Rankin scale (mRS) score was used as the primary efficacy outcome. The mRS1 corresponded to 0-1, whereas mRS2 corresponded to 0-2. The SICH and mortality were adopted as primary safety outcomes.
Twelve high-quality studies were selected, including 7686 patients (low-dose: 2888, standard-dose: 4798). With no statistical heterogeneity, the fixed effects model was adopted in the analysis. Similarly to standard doses, low-dose tPA improved the mRS scores (mRS1: odds ratio [OR] = .92, 95% confidence interval [CI] .84-1.02; P = .12; mRS2: OR = .97, 95% CI .88-1.08; P = .57). Compared with standard-dose tPA, low-dose tPA reduced the incidence of SICH (by National Institute of Neurological Disorders and Stroke [NINDS] definition: OR = .71, 95% CI .57-0.89; P = .003; by Safe Implementation of Thrombolysis in Stroke Monitoring Study [SITS-MOST] definition: OR = .64, 95% CI .42-0.99; P = .04), while both reduced mortality (OR = .87, 95% CI .74-1.02; P = .08).
Low-dose tPA is comparable to standard-dose tPA in improving the neurologic function and reducing mortality in AIS patients. Moreover, low-dose tPA can reduce the incidence of SICH compared with standard-dose tPA. Therefore, low-dose tPA is highly recommended in AIS patients.
Early partial recanalization after intravenous thrombolysis leads to prediction of favorable outcome in cases of acute ischemic stroke with major vessel occlusion
2017, Journal of Clinical Neuroscience
Citation Excerpt :
The standard rTPA dosage of 0.9 mg/kg is widely used based on the results of previous dose finding studies [17,18]. Zhou et al. demonstrated that higher dose of rTPA (0.9 mg/kg) was associated with improved functional outcome with similar rate of hemorrhagic transformation among Chinese patients [19]. In contrast, the result of Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) study revealed that symptomatic hemorrhage and mortality within 3 months were doubled in the standard dose group compared with the lower dose group.
We investigated the association between early recanalization degree after intravenous thrombolysis (IVT), occurrence of hemorrhagic transformation, and functional outcome. We also evaluated whether recombinant tissue plasminogen activator (rTPA) dosing error could influence the outcome. Patients with ischemic stroke with major vessel occlusion (n = 256) who underwent IVT were included. Recanalization status (no recanalization, partial recanalization, and complete recanalization) was confirmed by subsequent magnetic resonance or conventional angiography. Association between early recanalization degree and favorable outcome (modified Rankin Scale score ≤2) was evaluated using logistic regression analysis. Early partial recanalization was achieved in 33 (12.9%), and complete recanalization in 7 (2.7%) patients. Patients with the highest quintile of rTPA dosage achieved complete recanalization more frequently than the lower four quintiles (8.0% vs 2.0%, P = 0.03). Hemorrhagic transformation tended to occur more frequently in patients with complete recanalization as compared with patients with partial recanalization (57.1% vs 21.2%, P = 0.15). The proportion of favorable outcome was significantly lower in patients with the highest quintile of rTPA dosage used as compared with the patients with lower four quintiles (40.8%, 57.0%, P = 0.04). In multivariable analysis, partial recanalization was significantly associated with favorable outcome (adjusted odds ratio, 3.15; 95% CI, 1.06–9.35), but complete recanalization was not. Early partial recanalization after IVT may be an indicator of favorable outcome with low occurrence of any hemorrhagic transformation.

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Clinical StudyEfficacy and safety of different doses of intravenous tissue plasminogen activator in Chinese patients with ischemic stroke

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Acknowledgments

Lancet Neurol

Lancet

Am Heart J

Blood

Cost of stroke in Europe

Eur J Neurol

Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials

Lancet

Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke

N Engl J Med

Tissue plasminogen activator for acute ischemic stroke