Intravenous recombinant tissue plasminogen activator (r-tPA) with 0.9 mg/kg is an effective and guideline-recommended treatment for acute ischemic stroke (AIS) worldwide (1–3). Given the possible dose-related difference in effectiveness and safety in a different population, the optimal dose of r-tPA has been a research focus.

The Japan alteplase clinical trial firstly showed the possibly comparable benefits of 0.6 mg/kg r-tPA to the 0.9 mg/kg (4). However, subsequent several studies in Asian regions showed inconsistent results of low-dose versus standard-dose in AIS (5–10). The enhanced control of hypertension and thrombolysis stroke study did not demonstrate the non-inferior effect of low-dose r-tPA to the standard-dose but indicated fewer symptomatic intracranial hemorrhage (sICH) with low-dose r-tPA (11). Given that previous studies mostly focused on the “rigid” dose of r-tPA (0.6 or 0.9 mg/kg) in AIS, the optimal dose of r-tPA deserves further investigation, especially in a large-sample cohort with multiple doses used.

INtravenous Thrombolysis REgistry for Chinese Ischaemic Stroke (INTRECIS) within 4.5 h of onset is a “real world,” national, and multi-center registry study in China, which included patients with AIS treated with multiple doses of r-tPA (12). In the present study, we compared the effectiveness and safety outcomes of multi-dose r-tPA in the INTRECIS cohort, aiming to determine the optimal dose of r-tPA for AIS in China.

In the INTRECIS cohort, 2,666 patients receiving intravenous r-tPA within 4.5 h were included in the present study: 156 patients in 0.60 mg/kg group, 117 patients in 0.65 mg/kg group, 127 patients in 0.70 mg/kg group, 188 patients in 0.75 mg/kg group, 154 patients in 0.80 mg/kg group, 359 patients in 0.85 mg/kg group, and 1,565 patients in 0.90 mg/kg group (Figure 1). Baseline characteristics of patients in each group were shown in Table 1. Table 2 showed the effectiveness and safety outcomes in groups. The highest proportion of mRS 0–1 (79.5%) and mRS 0–2 (86.3%) was found in the 0.65 mg/kg group (Table 2; Figure 2A).

Compared with the 0.90 mg/kg group, only 0.65 mg/kg group was found to have higher proportion of excellent functional outcome with significant difference after adjusting for baseline characteristics (79.5 vs. 71.4%, OR = 1.833, 95% CI = 1.006–3.341, adjusted p = 0.048; Figure 2B). In addition, mRS distribution at 90 days showed significant different in 0.65 vs. 0.90 mg/kg group before (OR = 1.493, 95% CI = 1.051–2.119, p = 0.025) and after adjusting for baseline characteristics (OR = 1.672, 95% CI = 1.125–2.487, adjusted p = 0.011), while other outcomes showed no significant difference (Table 3). Subgroup analysis showed no significant differences in the excellent functional outcome between the 0.65 and 0.90 mg/kg group by age, gender, NIHSS score at admission, onset to thrombolysis time, and TOAST classification (Figure 3).

Furthermore, we performed univariate and multivariate analysis for the predictors of excellent functional outcome and sICH in all patients, the results of which were respectively shown in Tables 4, 5.

The present study investigated the effectiveness and safety of intravenous thrombolysis with multi-dose r-tPA for Chinese AIS in a prospective, national, multi-center, and large-sample cohort. Compared with 0.90 mg/kg for AIS, we first found that 0.65 mg/kg may be an optimal dose of r-tPA for mild to moderate stroke, which exhibited a higher proportion of excellent functional outcome and similar safety profile.

Given different races of populations receiving intravenous r-tPA and the side-effects of r-tPA (15–17), low-dose r-tPA for AIS has been investigated in Asian regions, however, the results were inconsistent. For example, Japan Alteplase Clinical Trial explored 0.6 mg/kg r-tPA and first showed similar benefits comparable with 0.9 mg/kg r-tPA in Japanese population (4), which was also found in Korean population (8). For Chinese population, several studies investigated the issue: (1) Taiwan Thrombolytic Therapy for Acute Ischemic Stroke study compared the efficacy and safety of 0.72 vs. 0.90 mg/kg r-tPA and found that 0.90 mg/kg r-tPA may not be optimal for treating aged Chinese patients due to the lower functional independence, higher sICH, and mortality (6); (2) Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China study suggested that the standard-dose r-tPA had more favorable outcome than low-doses (0.64 or 0.79 mg/kg) r-tPA (7); (3) Early efficacy and safety were found to be not significantly different among the low-dose (0.6, 0.7, and 0.8 mg/kg) and standard-dose groups (9); (4) A cluster data analysis showed the comparable efficacy at discharge and lower risk of sICH of low-dose r-tPA than the standard-dose in patients who had a moderate stroke (10). In addition, The Enhanced Control of Hypertension and Thrombolysis Stroke Study with 63% Asian patients did not demonstrate the non-inferior effect of 0.6–0.9 mg/kg r-tPA in Asians, but showed comparable effectiveness outcomes in some subgroups (11). Taken together, we found that: (1) most of these above studies mainly focused on the comparison between two “rigid” doses of r-tPA (low dose vs. standard dose); (2) two studies compared the efficacy and safety of multiple doses of r-tPA in Chinese AIS, but were limited by relatively small sample and wider dose interval of low-dose groups.

So far, the INTRECIS study enrolled the largest Chinese population receiving intravenous thrombolysis with multiple doses of r-tPA in a cohort. Different from previous studies (6, 7), seven groups with more refined r-tPA dose intervals (±0.025 mg/kg) were used in the present study. The results showed that the 0.65 mg/kg group had a significantly higher proportion of excellent functional outcome than the 0.90 mg/kg group with a similar safety profile among groups. Furthermore, subgroup analysis showed no evidence of differences in the odds of having a primary outcome between the two groups by age, gender, admission NIHSS, onset to thrombolysis time, and TOAST classification. Given the possible effect of age on the primary outcome (P interaction = 0.06), younger patients may benefit from the 0.65 mg/kg dose, which deserves further investigation. The proportion of excellent functional outcome in the 0.65 mg/kg group was higher than those in other studies with a specified dose of 0.6 mg/kg (79.5 vs. 32.4, 33.1, 46.8%) (5, 8, 11), which could possibly be due to the inclusion of patients with predominantly mild neurological deficits (NIHSS scores median: 5 vs. 15, 15, 8). For the safety profile, post-thrombolytic sICH was the most feared complication and was associated with poor outcomes in clinical practice (18). According to the definition of sICH in the ECASS-II (14), the rates of sICH in patients receiving intravenous r-tPA with 0.6 and 0.9 mg/kg were 3.5 and 4.6% in the previous studies, respectively (5, 19). In the present study, the rates of sICH in 0.65 mg/kg group and 0.90 mg/kg group were 0.0 and 1.1%, respectively. The lower rates could be explained by the inclusion of patients with mild neurological deficits (20). Our study showed a similar rate of sICH in the 0.65 mg/kg group and 0.90 mg/kg group, which was consistent with a recent meta-analysis (21).

The present study was a secondary analysis of the INTRECIS study (12), which was the largest-sample cohort that included multiple doses of intravenous r-tPA for Chinese AIS, however, several limitations still remained in the current analysis. First, as a secondary analysis of INTRECIS study, the lack of randomization and conduct was limited to Chinese consisted in the current analysis. Although we performed multivariable logistic regression with adjusting baseline characteristics, the confounding bias due to the nature of the registry study and unbalanced in the sample size of each dose group may be not fully weakened. Second, although refined dose division was used in the present study, a dose interval could not represent the specified dose actually. Last, the main characteristics of the population limited our conclusions to Chinese AIS with mild to moderate neurological deficits.

For the first time, our study suggested that 0.65 mg/kg may be an optimal dose of intravenous r-tPA for Chinese acute mild to moderate ischemic stroke, which warranted to be confirmed by random clinical trials in the future.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by General Hospital of Northern Theater Command Ethics Committee. The patients/participants provided their written informed consent to participate in this study.

H-SC conceived and designed the study. YC analyzed the data and wrote the first draft of the manuscript. Z-GY acquired the data. All authors contributed to the article and approved the submitted version.

This study was funded by grants from the National Key R&D Program of China (2017YFC1308203).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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