Intravenous Thrombolysis With Tenecteplase in Patients With Large Vessel Occlusions: Systematic Review and Meta-Analysis

The authors declare that all supporting data are available within the article and its Data Supplement. The present systematic review and meta-analysis is reported according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses statement.

We searched for published RCTs reporting outcomes of AIS patients with confirmed LVO randomized to intravenous thrombolytic treatment with either tenecteplase or alteplase. Further information on the literature search and data analysis is available in the Data Supplement.

Risk of bias for each included study was assessed with the Cochrane Collaboration risk-of-bias tool, while the quality of summary evidence for each outcome of interest was evaluated using the methodology developed by the Grading of Recommendations Assessment, Development and Evaluation Working Group.⁵

The primary outcome of interest was the odds of favorable functional outcome defined as a modified Rankin Scale (mRS) score of 0 to 2 at 3 months. Secondary outcomes of interest included the odds of (1) excellent outcome defined as 3-month mRS scores of 0 or 1, (2) 3-month all-cause mortality, (3) 3-month functional improvement (assessed with ordinal logistic regression analysis on the per 1-point decline in the ordinal mRS score [range, 0–6] at 3 months), (4) any intracranial hemorrhage (ICH), (5) symptomatic ICH (according to the definition used in each study), (6) successful recanalization (according to the definition used in each study), and (7) early neurological improvement (according to the definition used in each study).

Our literature search is outlined in Figure I in the Data Supplement. After excluding duplicate records (n=47), retrieved records from database search, or full-text articles (n=6) not qualifying our systematic review inclusion and exclusion criteria (Table I in the Data Supplement), we included 4 RCTs including a total of 433 patients (Table II in the Data Supplement).^4,6–8 Risk of other bias was marked as high in 2 publications reporting analyses on subgroups of patients with confirmed LVO randomized within the original RCTs. The risk for performance bias was considered unclear in all RCTs, since neither participants nor treating physicians but only the outcome assessors were blinded to treatment assignment (Figure II in the Data Supplement).

All analyses and quality of summary evidence for each outcome of interest are briefly summarized in the Table. Patients with confirmed LVO receiving tenecteplase had higher odds of successful recanalization (odds ratio, 3.05 [95% CI, 1.73–5.40]; Figure [A]), higher odds of mRS scores of 0 to 2 (odds ratio, 2.06 [95% CI, 1.15–3.69]; Figure [B]), and functional improvement (common odds ratio, 1.84 [95% CI, 1.18–2.87]; Figure [C]) at 3 months compared with patients with confirmed LVO receiving alteplase. There was little or no heterogeneity between the results provided from included studies regarding the aforementioned outcomes (I²≤20%; P for Cochran Q>0.25).

No treatment group differences in the outcomes of early neurological improvement, symptomatic ICH, any ICH, mRS score of 0 to 1, or all-cause mortality (Figures III through VII in the Data Supplement) at 3 months were detected. No evidence of funnel plot asymmetry was uncovered in any of the outcomes with >2 studies included in the meta-analysis (Figures VIII through XIII in the Data Supplement).

We found that AIS patients with LVO receiving intravenous thrombolysis with tenecteplase have a 3-fold higher odds of achieving successful recanalization and a 2-fold higher odds of having favorable clinical outcomes at 3 months compared with patients receiving intravenous alteplase.

The favorable outcomes of patients randomized to intravenous tenecteplase compared with alteplase could be attributed to the higher fibrin specificity and more potent clot dissolution with tenecteplase,¹ leading to faster vessel recanalization.⁹ The pharmacological properties of tenecteplase enable its administration as a single bolus injection compared with alteplase, which requires a 1-hour infusion after the initial bolus injection.^1,9 The ease of tenecteplase administration constitutes an indisputable advantage in the acute stroke setting, enabling prompt AIS treatment in the emergency department or even in an ambulance. The clinical benefit of tenecteplase compared with alteplase has been reported to be more pronounced for patients with viable penumbra and considerable mismatch in baseline neuroimaging,¹⁰ providing further support to the hypothesis that earlier and more complete tenecteplase-induced reperfusion in patients with LVO is likely the mechanism for the better clinical outcomes uncovered in the present systematic review and meta-analysis. Despite the higher rates of successful vessel recanalization and more favorable clinical outcomes of patients with LVO receiving tenecteplase compared with alteplase, further imaging evidence of infarct volume decrease will be needed to prove superiority. TASTEa (Tenecteplase Versus Alteplase for Stroke Thrombolysis Evaluation Trial in the Ambulance) will provide comparative estimates of infarct core growth within the first 24 hours from tenecteplase or alteplase administration.¹¹

Our meta-analysis adds to the accumulating evidence^1,4 and corroborates further the results of previous meta-analyses^2,3 highlighting the superiority of tenecteplase over alteplase for AIS treatment. Compared with previous meta-analyses,^2,3 our study population is restricted only in AIS patients with documented LVO. Moreover, our meta-analysis is the first to date that provides clear evidence of superiority for tenecteplase compared with alteplase for the treatment of AIS. Despite the strengths of our report, several limitations also need to be acknowledged. First, it should be highlighted that we included the subgroups of patients with confirmed LVO in 2 of the included trials. Subgroup analyses are known to suffer from low power and lack of prespecification. Second, although the risk of intracranial bleeding was not found to be significantly higher with tenecteplase compared with alteplase, CIs are wide, making the results inconclusive (Table). Third, despite that the same alteplase dose was used across trials (0.9 mg/kg), tenecteplase doses varied within included studies (Table II in the Data Supplement). However, in a recently published RCT, similar recanalization, bleeding, and functional outcomes were reported for AIS patients with LVO randomized to intravenous tenecteplase doses of either 0.40 or 0.25 mg/kg before endovascular treatment.¹² In addition to the differences in tenecteplase dose, considerable variability on patient populations, ancillary treatments (ie, endovascular treatment), treatment paradigms (drip and ship versus mothership), and outcome definitions that were not centrally adjudicated (ie, symptomatic ICH and early neurological improvement) also exist among included studies (Table II in the Data Supplement). Notably, a recent French report highlights that tenecteplase and alteplase may yield similar complete recanalization rates (21% versus 18%) in LVO patients pretreated with intravenous thrombolysis in the drip-and-ship setting.¹³ Despite these variations, no evidence of heterogeneity was detected in the vast majority of analyses. Finally, as included studies evaluated patients eligible for intravenous thrombolysis within the first 4.5 hours from stroke onset, the findings of the present report may not be valid for patients eligible for extended-time window intravenous thrombolysis administration. The safety and efficacy of tenecteplase administration outside the conventional 4.5-hour window is currently being investigated by 2 ongoing RCTs.^14,15