Comparing Low- or Standard-Dose Alteplase in Endovascular Thrombectomy: Insights From a Nationwide Registry

Abstract

BACKGROUND:

Timely intravenous thrombolysis and endovascular thrombectomy are the standard reperfusion treatments for large vessel occlusion stroke. Currently, it is unknown whether a low-dose thrombolytic agent (0.6 mg/kg alteplase) can offer similar efficacy to the standard dose (0.9 mg/kg alteplase).

METHODS:

We enrolled consecutive patients in the multicenter Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke who had received combined thrombolysis (within 4.5 hours of onset) and thrombectomy treatment from January 2019 to April 2023. The choice of low- or standard-dose alteplase was based on the physician’s discretion. The outcomes included successful reperfusion (modified Thrombolysis in Cerebral Infarction score, 2b–3), symptomatic intracerebral hemorrhage, 90-day modified Rankin Scale score, and 90-day mortality. The outcomes between the 2 groups were compared using multivariable logistic regression and inverse probability of treatment weighting-adjusted analysis.

RESULTS:

Among the 2242 patients in the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke, 734 (33%) received intravenous alteplase. Patients in the low-dose group (n=360) were older, had more women, more atrial fibrillation, and longer onset-to-needle time compared with the standard-dose group (n=374). In comparison to low-dose alteplase, standard-dose alteplase was associated with a lower rate of successful reperfusion (81% versus 87%; adjusted odds ratio, 0.63 [95% CI, 0.40–0.98]), a numerically higher incidence of symptomatic intracerebral hemorrhage (6.7% versus 3.9%; adjusted odds ratio, 1.81 [95% CI, 0.88–3.69]), but better 90-day modified Rankin Scale score (functional independence [modified Rankin Scale score, 0–2], 47% versus 31%; adjusted odds ratio, 1.91 [95% CI, 1.28–2.86]), and a numerically lower mortality rate (9% versus 15%; adjusted odds ratio, 0.73 [95% CI, 0.43–1.25]) after adjusting for covariates. Similar results were observed in the inverse probability of treatment weighting-adjusted models. The results were consistent across predefined subgroups and age strata.

CONCLUSIONS:

Despite the lower rate of successful reperfusion and higher risk of symptomatic intracerebral hemorrhage with standard-dose alteplase, standard-dose alteplase was associated with a better functional outcome in patients receiving combined thrombolysis and thrombectomy.

In patients with acute ischemic stroke (AIS) caused by large vessel occlusion (LVO), a timely reperfusion strategy with intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) is the cornerstone of treatment.¹ In thrombolysis-eligible patients, the standard treatment is 0.9 mg/kg recombinant tissue-type plasminogen activator (alteplase).¹ In Japan, a low dose of alteplase, 0.6 mg/kg, is universally applied based on their official recommendation.² The results of the ENCHANTED trial (Enhanced Control of Hypertension and Thrombolysis Stroke Study) did not support the noninferiority of low-dose alteplase use in AIS.³ However, EVT was not included as a standard treatment in the era of the ENCHANTED trial. Among the 6 major randomized controlled trials comparing bridging therapy with direct thrombectomy in patients with LVO, only the SKIP trial (Direct Mechanical Thrombectomy in Acute LVO Stroke) from Japan used the low-dose (0.6 mg/kg) alteplase.⁴ Whether a lower dose of thrombolytic agent could offer comparable efficacy to the standard dose in bridging therapy (combined IVT and EVT) remained unknown. One study compared the effects of low-dose versus standard-dose alteplase in bridging therapy among these 6 randomized controlled trials and found similar key efficacy and safety outcomes.⁵ However, the comparison was indirect (intertrial), because the study settings, baseline characteristics of included patients, and outcome definitions differed between trials. Moreover, the case number was limited as there were only 103 patients using low-dose alteplase in the analysis.

In several Asian countries, including Taiwan, low-dose alteplase is commonly used due to anticipated lower rates of bleeding.⁶ A multicenter study from Taiwan suggested that low-dose alteplase is associated with a better outcome in older patients.⁷ In fact, low-dose alteplase was used in more than half of the thrombolysis patients in Taiwan.^7–10 Since 2019, the Taiwan Stroke Society has established the nationwide Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke (Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke). The registry prospectively enrolled patients who received thrombectomy for LVO-related stroke, including bridging therapy of IVT and EVT.¹¹ Whether the trend of dosage choice and its impact on the outcome in patients with LVO who received bridging therapy was unknown. This study aimed to compare the effects of low-dose versus standard-dose alteplase on successful reperfusion, symptomatic hemorrhage, functional outcome, and mortality in patients who received bridging therapy.

METHODS

Study Setting

The data that support the findings of this study are available from the corresponding author upon reasonable request. TREAT-AIS is an ongoing nationwide, multicenter, prospective observational registry that includes patients aged ≥20 years who received EVT for AIS in Taiwan (https://www.clinicaltrials.gov; Unique identifier: NCT05281055).¹¹ The registry comprises 19 sites, including 10 medical centers and 9 regional teaching hospitals. It was initiated in January 2019 and is supported by the Taiwan Stroke Society. Participating centers were encouraged to consecutively enroll all patients receiving EVT at their respective sites. The criteria for EVT were aligned with the guidelines from the American Heart Association/American Stroke Association and the Taiwan Stroke Society.^1,12 For a detailed study methodology of TREAT-AIS, refer to another publication.¹¹ The complete list of TREAT-AIS investigators and personnel is listed in Table S1. The registry received approval from the joint institutional review board of Taipei Medical University and the institutional review board of all participating hospitals. Informed consent was not required by the joint institutional review board. The study adhered to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the observational cohort study.

Study Participants

The present study only included patients who had received combined IVT (within 4.5 hours of onset) and EVT. In Taiwan, alteplase is the only proven medication for IVT. The Taiwan Food and Drug Administration approved the administration of 0.9 mg/kg as the standard dose for AIS. However, the Taiwan Food and Drug Administration also commented that low-dose (0.6 mg/kg) alteplase may be associated with a lower risk of symptomatic hemorrhage based on the results of the ENCHANTED and Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) studies.^3,7 In clinical practice, the choice of low- or standard-dose alteplase was based on the treating physician’s discretion, considering the initial evaluation of the patients, their comorbidities, and the risk of bleeding. Generally, physicians in Taiwan prefer to use low-dose alteplase in elderly patients (≥70 years).

The study patients will be classified into 2 groups based on the dosage of alteplase, namely: low dose (0.6 mg/kg) and standard dose (0.9 mg/kg). However, dosage may not be precise to 0.6 or 0.9 mg/kg in real-world practice. Among the patients currently enrolled, the median alteplase dose administered was 0.86 mg/kg (interquartile range, 0.63–0.90 mg/kg). Therefore, patients with alteplase dose of ≥0.85 mg/kg will be classified as standard dose, whereas those with alteplase dose of <0.85 mg/kg will be classified as low dose. Patients without actual alteplase dosage record will be excluded.

Collection of Variables

The registry collected the following variables: baseline demographic profile, vascular risk factors (hypertension, diabetes, hyperlipidemia, atrial fibrillation, prior stroke, and smoking), antithrombotic agents use (antiplatelets or anticoagulants), presumed cause of stroke (large artery atherosclerosis, cardioembolic, or others), stroke severity by the National Institutes of Health Stroke Scale (NIHSS), pre-EVT Alberta Stroke Program Early Computed Tomography Score (ASPECTS), and target vessels for recanalization. The time metrics of workflow included onset-to-needle, onset-to-puncture, puncture-to-recanalization, door-to-needle, and door-to-puncture time. Furthermore, the prestrike-modified Rankin Scale (mRS) was not initially required at the beginning of data collection but was later encouraged for inclusion.

Outcome Assessment

The study included the following 4 outcomes: successful reperfusion, symptomatic intracerebral hemorrhage (ICH), 90-day mRS score, and 90-day mortality. Successful reperfusion was defined as modified Thrombolysis in Cerebral Infarction (mTICI) score of 2b to 3 on the post-EVT angiography. Symptomatic ICH was defined as the presence of type 2 parenchymal hematoma on the post-EVT neuroimaging (either computed tomography or magnetic resonance imaging) at 24 to 36 hours, in conjunction with an increase of ≥4 points on the total NIHSS score from baseline. The 90-day mRS score was assessed at each study site by either an in-person visit or phone follow-up. An mRS score of 0 to 2 indicated an independent functional outcome. Due to the pragmatic nature of the registry, these outcomes were assessed by the local principal investigators and were not centrally adjudicated.

Statistical Analysis

The categorical variables were presented as N (%), and continuous variables as median (interquartile range). The baseline characteristics between the standard- and low-dose groups were compared by χ² test or Mann-Whitney U test accordingly. Logistic regression models were applied for all binary outcomes (successful reperfusion, symptomatic ICH, independent functional outcome, and mortality), whereas an ordinal logistic regression model was applied for the mRS score (shift analysis).

Because there was likely confounding by indication bias in choosing standard- versus low-dose alteplase, outcome analyses largely relied on covariates adjustment and matching strategies. In the adjusted models, covariates include age, sex, hypertension, diabetes, atrial fibrillation, NIHSS (≥15 versus <15), ASPECTS (6–10 versus 0–5), onset-to-puncture time (every 30 minutes increase), and successful reperfusion (except for the successful reperfusion outcome itself). Due to fewer cases of symptomatic ICH, only age, diabetes, ASPECTS, and successful reperfusion were adjusted. The later 3 variables were selected based on the literature review showing their associations with symptomatic ICH.¹³ Furthermore, an inverse probability treatment weighted (IPTW) matching was applied to obtain average treatment effects across different alteplase doses. The underlying propensity model included age (continuous), sex, hypertension, diabetes, atrial fibrillation, NIHSS, ASPECTS, and onset-to-puncture time. We used a complete case analysis, excluding patients with missing data on key covariates or outcomes.

Furthermore, the effects of standard- versus low dose on independent functional outcome and symptomatic ICH in the predefined subgroups were examined. These subgroups included (1) age (<70 versus ≥70), (2) sex, (3) hypertension, (4) diabetes, (5) atrial fibrillation, (6) antiplatelet use, (7) NIHSS score (≥15 versus <15), and (8) ASPECTS score (6–10 versus 0–5). The rationale of selecting antiplatelet use comes from the ENCHANTED trial subgroup analysis, which showed the potential benefit of low dose in prior antiplatelet users.¹⁴

Finally, we would explore whether age had differential effects on radiological and clinical outcomes in the 2 dose tiers. A P_interaction was derived from the interaction term (age×dose) in the fully adjusted model in the full data set. Then, the effect size of age (per 10-year increase) would be calculated in the low- and standard-dose groups, respectively.

The statistical analysis was performed by SAS 9.4 (Cary, NC). P<0.05 was considered statistically significant. As an explorative analysis, all P values were not adjusted for multiple comparisons.

RESULTS

Baseline Characteristics

From January 2019 to April 2023, a total of 2242 patients were enrolled in the TREAT-AIS; 145 patients were excluded due to data uncompleted. Of them, 734 (33%) patients received intravenous alteplase and were included in the current analysis (Figure S1). A total of 374 (51%) patients received standard-dose alteplase, while 360 (49%) patients received low dose. All baseline characteristics are reported in Table 1. Compared with the standard-dose group, patients in the low-dose group were significantly older (median age; 77 [interquartile range, 65–84] versus 67 [59–74] years; P<0.01), more likely to be women (50% versus 38%; P<0.01), and had higher proportion of atrial fibrillation (56% versus 47%; P=0.01). Furthermore, patients in the low-dose group had longer onset-to-needle time (116 [89–164] versus 107 [81–142] minutes; P=0.01) and door-to-needle time (53 [44–68] versus 50 [42–60] minutes; P<0.01). Nevertheless, the needle-to-puncture, onset-to-puncture, and puncture-to-recanalization time were comparable between the 2 groups.

Table 1.

The Characteristics in the 2 Alteplase Dose Groups (n=734)

Radiological Outcomes

Table 2 presents the outcomes in the 2 alteplase dose groups. Successful reperfusion was achieved in 302 (81%) patients in the standard-dose group and 313 (87%) patients in the low-dose group. In both unadjusted (odds ratio [OR], 0.67 [95% CI, 0.44–1.00]; P=0.05), multivariable-adjusted (OR, 0.63 [95% CI, 0.40–0.98]; P=0.04), and IPTW-adjusted analyses (OR, 0.61 [95% CI, 0.45–0.83]; P=0.002), it was indicated that the standard-dose group had a lower chance of successful reperfusion compared with the low-dose group. Symptomatic ICH occurred in 25 (6.7%) patients in the standard-dose group and 14 (3.9%) patients in the low-dose group. In the unadjusted and multivariable-adjusted analyses, the differences were nonsignificant. However, the risk of symptomatic ICH was higher in the IPTW-adjusted analysis for the standard-dose group (OR, 2.09 [95% CI, 1.27–3.44]; P<0.01).

Table 2.

The outcomes in the 2 Alteplase Dose Groups

Clinical Outcomes

Regarding 90-day outcome, the median mRS score was 2 [1 to 4] in the standard-dose group and 3 [2 to 4] in the low-dose group (Figure 1). Independent functional outcome (mRS score, 0–2) was achieved in 47% and 31% of the standard- and low-dose groups, respectively. In the ordinal analysis of mRS score, the standard-dose group was associated with higher odds for a lower mRS category in both unadjusted, multivariable-adjusted, and IPTW-adjusted analyses (common OR from 1.49 to 1.87; all P<0.05). Similar findings were observed for independent functional outcome. That is, the standard-dose group was associated with a 2-fold odds of being functional independence (OR from 1.91 to 2.10; all P<0.05; see Table 2).

Figure 1.

Ninety-day modified Rankin Scale distribution.

Furthermore, the 90-day mortality was 9% in the standard-dose and 15% in the low-dose group. This suggested a lower risk of mortality in the unadjusted analysis (OR, 0.56 [95% CI, 0.36–0.88]; P=0.01) but not in the multivariable-adjusted and IPTW-adjusted analyses (see Table 2).

Because of 16.2% missing data on prestroke mRS score, we performed an additional analysis incorporating prestroke independence (mRS score, 0–1) as a covariate in the above models. We also performed another sensitivity analysis, which only included patients with prestroke mRS score, 0 to 1 (standard dose, n=311; low dose, n=261). The results remained consistent with the original models (Tables S2 and S3 ).

Subgroup Analysis

We performed subgroup analyses on the 2 main outcomes, 90-day functional independence and symptomatic ICH (Figure 2). Regarding 90-day functional independence, an interaction was observed between dose and hypertension (P_interaction=0.04). Patients without hypertension benefited more from the standard-dose alteplase (OR, 3.42 [95% CI, 1.83–6.36]) than those with hypertension (OR, 1.60 [95% CI, 1.10–2.33]). There was no observed interaction between predefined subgroups and alteplase dose on symptomatic ICH.

Figure 2.

Subgroup analyses. The figures showed subgroup analyses of alteplase dose (standard vs low) on (A) 90-d modified Rankin Scale (mRS) score 0 to 2, and (B) symptomatic intracerebral hemorrhage (ICH). aOR indicates adjusted odds ratio; ASPECTS, Alberta Stroke Program Early Computed Tomography Score; and NIHSS, National Institutes of Health Stroke Scale.

Interaction Between Age and Alteplase Dose on Outcomes

We further examined whether age had differential effects on the outcomes between 2 dose groups (Table 3; Figure 3). There was no apparent interaction between age and dose regarding successful reperfusion, symptomatic ICH, functional independence, and mortality (Table 3; Figure S2). Furthermore, the proportion of independent functional outcome was consistently higher in the standard-dose group across all age strata (Figure 3).

Table 3.

Interaction Between Age (Per 10-Year) and Alteplase Dose On Outcomes

Figure 3.

Proportion of outcomes between standard- and low-dose groups, stratified by age. A, Successful reperfusion. B, Symptomatic intracerebral hemorrhage (ICH). C, Ninety-day modified Rankin Scale (mRS) score 0 to 2. D, Ninety-day mortality. mTICI indicates modified Thrombolysis in Cerebral Infarction.

DISCUSSION

This registry-based analysis provided important findings concerning the effects of alteplase dose on patients with AIS with LVO who are eligible for combined thrombolysis and thrombectomy. The key messages are the following: (1) in clinical practice, older patients were more likely to receive low-dose alteplase; (2) standard-dose alteplase was associated with a better functional outcome across all subgroups and age strata; and (3) standard-dose alteplase was associated with a lower rate of successful reperfusion and a higher risk of symptomatic ICH.

Based on the results of the TTT-AIS study and the ENCHANTED trial, physicians in Taiwan tended to prescribe low-dose alteplase for older patients to avoid bleeding complications.^3,7 However, those studies were conducted before the era of EVT, and there has been no direct comparison of alteplase doses in the context of EVT. The concurrent use of 2 different doses in Taiwan provided a unique opportunity to conduct an analysis of patients undergoing bridging thrombectomy. Nevertheless, the results of the current nonrandomized, comparative effectiveness research were significantly influenced by the confounding bias resulting from differences in patient characteristics. Specifically, patients in the low-dose group were significantly older than those in the standard-dose group. The observed differences in outcomes may, therefore, primarily reflect the effect of age. Despite employing matching and statistical adjustment techniques, unadjusted confounding factors may still be present. Consequently, caution should be exercised when interpreting these results.

Our findings confirm the effectiveness of standard-dose alteplase in achieving functional independence in patients who received combined IVT and EVT. The effects were consistent across all predefined subgroups, including patients aged ≥70 years. These findings contrast with the results from the TTT-AIS study.⁷ Indeed, the results should be interpreted separately due to the different clinical scenario (pure IVT versus combined IVT and EVT). Nevertheless, our results delivered a clear message that dose reduction for alteplase is not necessary in patients receiving bridging thrombectomy even in older patients. One possibility is occurrence of the no-reflow phenomenon despite successful recanalization of the upstream occlusions after EVT.^15,16 Persistent occlusions of the cerebral arterioles and venules at the microcirculation level is associated with worse functional outcome.¹⁵ The German Stroke Registry showed that the functional outcome was better in patients with ongoing alteplase infusion at the time of final reperfusion achieved by EVT, compared with those who already completed their infusion before final reperfusion.¹⁷ Therefore, a higher dose of alteplase may help mitigate the persistent no-reflow phenomenon and improve clinical outcome. However, these hypotheses require validation in other studies.

We observed a lower rate of successful final angiographic reperfusion (mTICI score, 2b–3) in patients receiving the standard dose of alteplase. Theoretically, a higher dose of thrombolytic agent should produce a stronger fibrinolytic effect.¹⁸ The apparent contradictory finding may be explained by the following reasons. First, in patients who underwent combined IVT and EVT, the success of final reperfusion is largely dependent on the thrombectomy procedure itself, as reperfusion (mTICI score, 2b–3 on initial angiography) achieved by IVT occurred in only about 10% of the patients.^19,20 Therefore, the differences in successful reperfusion rates between the 2 groups may not be related to the dose effects but rather reflect the clinical characteristics of the 2 groups. Even after adjusting for some of the imbalances between the groups, residual unadjusted confounding may contribute to the higher reperfusion rates in the low-dose group. In addition, we found that in patients with unsuccessful reperfusion (mTICI score, 0–2a), receiving standard-dose alteplase provided higher chance of being functional independence compared with low-dose alteplase (adjusted OR, 4.31 [95% CI, 1.18–15.77]). This implied that in cases of unsuccessful reperfusion, a higher dose of alteplase might provide additional benefit in restoring microcirculation and improve outcome. Second, the current registry did not include patients who had planned for EVT but were recanalized by IVT (and did not receive EVT). If standard-dose alteplase did indeed lead to more complete early recanalization, it is possible that only patients with relatively firmer, more compacted, or calcified thrombi were enrolled in the current standard-dose group. Conversely, patients in the low-dose group might have thrombi that are more fragmented or easily retrievable, as these thrombi may have been partially treated by IVT. In other words, the selection bias may have contributed to the observed contradictory recanalization rates. Furthermore, when we redefined successful reperfusion as mTICI score, 3, we found that the rate was equal in both groups (46% versus 46%, crude OR, 1.00 [95% CI, 0.75–1.34]). Nevertheless, our findings may be influenced by bias from observational studies, and the results should be validated through further investigation in other registries or randomized controlled trials.

We also found that the low-dose alteplase was associated with a lower risk of symptomatic ICH. Although this finding aligns with the results from the ENCHANTED and TTT-AIS studies,^3,7 its interpretation may differ when considering the context of bridging thrombectomy. One of the risk factors for symptomatic ICH after EVT is unsuccessful reperfusion, which can lead to larger unperfused, necrotic brain tissue that is susceptible to hemorrhagic transformation.^13,21 This observation is evident in the standard-dose group who were <50 years old, where the successful reperfusion rate was low (≈70%), while the rate of symptomatic ICH rate was high (14%). However, these unfavorable radiological outcomes did not necessarily result in worse clinical outcomes. In fact, the standard-dose group still exhibited similar or even better functional independence compared with the low-dose group in each age stratum. Even when adjusted for symptomatic ICH in the multivariable-adjusted model, standard dose was still significantly associated with better functional outcome.

Overall, our findings were consistent across predefined subgroup. The only notable finding was that patients without history of hypertension benefited more from the standard-dose alteplase than patients with hypertension. However, the possibility of this result occurring by chance cannot be ruled out. Furthermore, in both groups of patients, the effect estimates favored standard-dose alteplase. In the ENCHANTED trial, standard-dose alteplase was associated with a higher risk of symptomatic ICH and poor functional outcome in individuals with prior antiplatelet use.¹⁴ There was no statistically significant difference regarding the dose effect between patients with and without prior antiplatelet use in our study.

To the best of our knowledge, this study represents the first real-world, direct comparison of different alteplase doses in patients who underwent bridging thrombectomy. The relatively large sample size facilitated an adequate matching strategy and subgroup analyses. However, our study had certain limitations. First, the nonrandomized, observational design restricted the ability to draw causal inferences. Confounding by indication was inevitable in this type of research, despite employing multivariable adjustment or IPTW matching method, thereby leaving the possibility of unadjusted confounding. Second, the outcomes were not centrally adjudicated in our pragmatic type of stroke registry. For example, the interpretation of symptomatic ICH and mTICI might have varied among investigators. Nonetheless, the rate of symptomatic ICH was comparable across study sites (data not shown). Furthermore, a meta-analysis demonstrated no evidence of superiority for central adjudication of outcomes over site investigators-adjudicated outcomes in stroke trials.²² Third, prestroke mRS was not required in the data collection initially, and the results were updated retrospectively. However, the results remain consistent when prestroke mRS was adjusted in the sensitivity analyses. Fourth, we did not document the result of the initial angiography after groin puncture, thus, precluding our ability to assess the differential effects of alteplase dose on the initial reperfusion status before thrombectomy. Finally, the study was on an East Asian population, and generalization of the findings to other ethnicities may be limited. Nevertheless, the findings supporting the superiority of standard-dose alteplase in terms of functional outcomes should encourage physicians to adopt clinical practices that favor standard-dose alteplase, even in countries where both dose strategies are available.

In conclusion, we observed that standard-dose alteplase was associated with better functional outcome in patients receiving combined IVT and EVT, although it had a lower rate of successful reperfusion and a higher risk of symptomatic ICH. These findings contribute to the growing body of evidence guiding clinical decision-making and encourage the use of standard-dose alteplase in this patient population to maximize functional outcomes. Nonetheless, our findings should be interpreted cautiously as these results were derived from an observational study in which dosing of alteplase was based on the treating physician’s discretion. Future studies, including randomized controlled trials, should further explore the optimal dose strategies for alteplase, or even tenecteplase, in patients undergoing combined IVT and EVT.

ARTICLE INFORMATION

Acknowledgments

The authors thank Tsung-Min Jeng and Jiao-Syuan Wang for their assistance with the collection and statistical analyses of individual data from all participating hospitals.

Sources of Funding

None.

Disclosures

None.

Supplemental Material

Tables S1–S3

Figures S1–S2

Supplementary Material

str-55-532-s001.pdf ^{(695.2KB, pdf)}

str-55-532-s002.pdf ^{(118.2KB, pdf)}