Efficacy and safety outcomes of Tenecteplase versus Alteplase for thrombolysis of acute ischemic stroke: A meta-analysis of 9 randomized controlled trials.
In recent years, Tenecteplase (TNK), a genetically modified variant of alteplase, has been verified as a potential substitute for alteplase in the reperfusion therapy of acute ischemic stroke (AIS). Given the emergence of new randomized controlled trials (RCTs) of this subject, a meta-analysis was conducted to evaluate the present comparative evidence regarding the efficacy and safety outcomes of TNK and alteplase in thrombolysis for AIS.
Following predefined inclusion criteria, we searched the databases of PubMed, Web of Science, and Cochrane Library. RCTs satisfying our inclusion criteria were selected for meta-analysis. Outcome indicators were categorized into efficacy outcomes (early vessel recanalization, excellent recovery, good recovery and early neurological improvement) and safety outcomes (poor recovery, symptomatic intracerebral hemorrhage, parenchymal hemorrhage type 2(PH2) post thrombolysis, and mortality). We extracted data on efficacy outcomes and safety outcomes for patients with AIS in the TNK group at a dose of 0.25 mg/kg and the alteplase group at a dose of 0.9 mg/kg, and expressed the relative risks between the 2 groups as odds ratios (ORs) and 95% confidence intervals (CIs) using the Mantel-Haenszel method. For further insight, we performed a network meta-analysis using a Bayesian framework to compare different doses of TNK (0.1, 0.25, 0.32, and 0.4 mg/kg) with alteplase (0.9 mg/kg).
A total of 2994 patients in 9 RCTs comparing efficacy and safety outcomes in patients with AIS treated with TNK and alteplase were included. In a pairwise analysis of TNK 0.25 mg/kg and alteplase 0.9 mg/kg, regarding efficacy outcomes, the aggregated results show that TNK 0.25 mg/kg statistically significant increased early vessel recanalization (N = 368, TNK vs. alteplase, OR: 2.07,95%CI: [1.19,3.59], I2 = 0%) and excellent recovery (N = 3548, TNK vs. alteplase, OR: 1.15,95%CI: [1.01,1.32], I2 = 0%). There was no significant difference in good recovery (N = 3486, TNK vs. alteplase, OR: 1.38,95%CI: [0.89,2.15], I2 = 84%) or early neurological improvement (N = 1686, TNK vs. alteplase, OR: 1.06,95%CI: [0.87,1.28], I2 = 24%) between the TNK 0.25 mg/kg group and the alteplase 0.9 mg/kg group. In the safety outcomes, pooled results showed no significant difference in poor recovery (N = 3548, TNK vs. alteplase, OR: 0.94,95%CI: [0.81,1.10], I2 = 0%) and symptomatic intracerebral hemorrhage (N = 3567, TNK vs. alteplase, OR: 1.06,95%CI: [0.70,1.60], I2 = 0%) and PH2(N = 3103, TNK vs. alteplase, OR: 1.26,95%CI:[0.39,4.07], I2 = 56%)and mortality (N = 3447, TNK vs. alteplase, OR: 0.99,95%CI: [0.80,1.23], I2 = 33%) between the TNK group and the alteplase group. In a network meta-analysis, competing treatments were not significantly different from one another (TNK 0.1 mg/kg, TNK 0.25 mg/kg, TNK 0.32 mg/kg, TNK 0.4 mg/kg, alteplase 0.9 mg/kg) in either efficacy outcomes or safety outcomes.
In this analysis of 9 RCTs in patients with AIS, TNK 0.25 mg/kg was comparable to alteplase 0.9 mg/kg from the perspective of efficacy outcomes and safety outcomes after thrombolysis within 4.5 h of AIS occurrence.
Wang Y
，Cai X
，Fang Q
，Zhu J
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Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.
Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging.
This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed.
Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]).
The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible.
Australian National Health Medical Research Council; Boehringer Ingelheim.
Parsons MW
，Yogendrakumar V
，Churilov L
，Garcia-Esperon C
，Campbell BCV
，Russell ML
，Sharma G
，Chen C
，Lin L
，Chew BL
，Ng FC
，Deepak A
，Choi PMC
，Kleinig TJ
，Cordato DJ
，Wu TY
，Fink JN
，Ma H
，Phan TG
，Markus HS
，Molina CA
，Tsai CH
，Lee JT
，Jeng JS
，Strbian D
，Meretoja A
，Arenillas JF
，Buck BH
，Devlin MJ
，Brown H
，Butcher KS
，O'Brien B
，Sabet A
，Wijeratne T
，Bivard A
，Grimley RS
，Agarwal S
，Munshi SK
，Donnan GA
，Davis SM
，Miteff F
，Spratt NJ
，Levi CR
，TASTE investigators
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