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Abstract

Background and Purpose:

Accumulating evidence from randomized controlled clinical trials suggests that tenecteplase may represent an effective treatment alternative to alteplase for acute ischemic stroke. In the present systematic review and meta-analysis, we sought to compare the efficacy and safety outcomes of intravenous tenecteplase to intravenous alteplase administration for acute ischemic stroke patients with large vessel occlusions (LVOs).

Methods:

We searched MEDLINE (Medical Literature Analysis and Retrieval System Online) and Scopus for published randomized controlled clinical trials providing outcomes of acute ischemic stroke with confirmed LVO receiving intravenous thrombolysis with either tenecteplase at different doses or alteplase at a standard dose of 0.9 mg/kg. The primary outcome was the odds of modified Rankin Scale score of 0 to 2 at 3 months.

Results:

We included 4 randomized controlled clinical trials including a total of 433 patients. Patients with confirmed LVO receiving tenecteplase had higher odds of modified Rankin Scale scores of 0 to 2 (odds ratio, 2.06 [95% CI, 1.15–3.69]), successful recanalization (odds ratio, 3.05 [95% CI, 1.73–5.40]), and functional improvement defined as 1-point decrease across all modified Rankin Scale grades (common odds ratio, 1.84 [95% CI, 1.18–2.87]) 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%). No difference in the outcomes of early neurological improvement, symptomatic intracranial hemorrhage, any intracranial hemorrhage, and the rates of modified Rankin Scale score 0 to 1 or all-cause mortality at 3 months was detected between patients with LVO receiving intravenous thrombolysis with either tenecteplase or alteplase.

Conclusions:

Acute ischemic stroke patients with LVO receiving intravenous thrombolysis with tenecteplase have significantly better recanalization and clinical outcomes compared with patients receiving intravenous alteplase.
Although alteplase remains to date the only approved intravenous thrombolytic medication for acute ischemic stroke (AIS),1 accumulating evidence from clinical trials suggests that tenecteplase may represent an effective treatment agent compared with alteplase for AIS.2,3 In a recently published randomized controlled clinical trial (RCT), tenecteplase administration was associated with a 2-fold increase in the odds of successful recanalization of AIS patients with large vessel occlusion (LVO) before the initiation of endovascular treatment compared with patients receiving pretreatment with intravenous alteplase. Patients randomized to intravenous tenecteplase before endovascular treatment also had better functional outcomes at 3 months compared with patients receiving intravenous alteplase.4
In the present systematic review and meta-analysis, we sought to compare the efficacy and safety outcomes of intravenous tenecteplase to intravenous alteplase administration for AIS patients with confirmed LVO.

Methods

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).

Results

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).
Table. Overview of Analyses and Summary Evidence for Each Outcome of Interest
OutcomesNo. of participants (studies); follow-upCertainty of the evidence (GRADE)Relative effect (95% CI)Anticipated absolute effects
Effect with alteplaseEffect difference with TNK
SR315 (3 studies); before EVT⨁⨁⨁Moderate*OR, 3.05 (1.73–5.40)227 per 1000245 more per 1000 (109 more to 385 more)
mRS 0–2277 (2 studies); 3 mo⨁⨁⨁ModerateOR, 2.06 (1.15–3.69)500 per 1000173 more per 1000 (35 more to 287 more)
mRS 0–1433 (4 studies); 3 mo⨁⨁⨁ModerateOR, 1.49 (0.95–2.32)368 per 100097 more per 1000 (12 fewer to 207 more)
Functional improvement315 (3 studies); 3 mo⨁⨁⨁Moderate*cOR, 1.84 (1.18–2.87)
ENI395 (3 studies); 72 h◯◯◯Very low*‡§OR, 1.09 (0.37–3.16)510 per 100022 more per 1000 (232 fewer to 257 more)
Mortality395 (3 studies); 3 mo⨁⨁◯◯Low*‡OR, 0.93 (0.31–2.80)130 per 10008 fewer per 1000 (86 fewer to 165 more)
Symptomatic ICH395 (3 studies); 48 h⨁⨁◯◯Low*‡OR, 0.66 (0.19–2.23)31 per 100010 fewer per 1000 (25 fewer to 36 more)
Any ICH395 (3 studies); 48 h⨁⨁◯◯Low*‡OR, 0.87 (0.35–2.17)115 per 100013 fewer per 1000 (71 fewer to 105 more)
cOR indicates common odds ratio; ENI, early neurological improvement; EVT, endovascular treatment; GRADE, Grading of Recommendations Assessment, Development and Evaluation; ICH, intracranial hemorrhage; mRS, modified Rankin Scale; OR, odds ratio; SR, successful recanalization; and TNK, tenecteplase.
*
Three of 4 studies contributing to this outcome.
Two of 4 studies contributing to this outcome.
CI fails to exclude important benefit or important harms.
§
Significant heterogeneity between studies.
Figure. Outcomes of patients with acute large vessel occlusions receiving intravenous tenecteplase compared to intravenous alteplase. Forest plots on the odds of (A) successful recanalization, (B) modified Rankin Scale score of 0 to 2 at 3 mo, and (C) functional improvement at 3 mo between patients with acute large vessel occlusions randomized to intravenous tenecteplase or alteplase. ATTEST indicates Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis; EXTEND-IA, Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke; IV, inverse variance; and TNK, tenecteplase.
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).

Discussion

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 evidence1,4 and corroborates further the results of previous meta-analyses2,3 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

Footnote

Nonstandard Abbreviations and Acronyms

AIS
acute ischemic stroke
ICH
intracranial hemorrhage
LVO
large vessel occlusion
mRS
modified Rankin Scale
RCT
randomized controlled clinical trial
TASTEa
Tenecteplase Versus Alteplase for Stroke Thrombolysis Evaluation Trial in the Ambulance

Supplemental Material

File (str_stroke-2020-030220_supp1.pdf)

References

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History

Received: 14 April 2020
Revision received: 26 July 2020
Accepted: 29 September 2020
Published online: 4 December 2020
Published in print: January 2021

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Keywords

  1. brain ischemia
  2. humans
  3. odds ratio
  4. reperfusion
  5. tenecteplase

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Authors

Affiliations

Aristeidis H. Katsanos, MD
Division of Neurology, McMaster University/Population Health Research Institute, Hamilton, Canada (A.H.K., A.S.).
Apostolos Safouris, MD
Second Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Greece (A. Safouris, G.T.).
Stroke Unit, Metropolitan Hospital, Piraeus, Greece (A. Safouris, G.M.).
Department of Neurology, UT Houston, TX (A. Sarraj).
Stroke Unit, Metropolitan Hospital, Piraeus, Greece (A. Safouris, G.M.).
Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (R.R.L.).
Department of Neurology, University of Cincinnati, OH (P.K.).
Charlotte Cordonnier, MD https://orcid.org/0000-0002-5697-6892
University of Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience and Cognition, France (C.C., D.L.).
Didier Leys, MD
University of Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience and Cognition, France (C.C., D.L.).
Ashkan Shoamanesh, MD
Division of Neurology, McMaster University/Population Health Research Institute, Hamilton, Canada (A.H.K., A.S.).
Niaz Ahmed, MD
Department of Neurology, Karolinska University Hospital, Stockholm, Sweden (N.A.).
Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden (N.A.).
Andrei V. Alexandrov, MD
Department of Neurology, University of Tennessee Health Science Center, Memphis (A.V.A., G.T.).
Georgios Tsivgoulis, MD [email protected]
Second Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Greece (A. Safouris, G.T.).
Department of Neurology, University of Tennessee Health Science Center, Memphis (A.V.A., G.T.).

Notes

This manuscript was sent to Harold P. Adams, Jr, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
For Sources of Funding and Disclosures, see page 311.
The Data Supplement is available with this article at Supplemental Material.
Correspondence to: Georgios Tsivgoulis, MD, Second Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, Iras 39, Gerakas Attikis, Athens 15344, Greece. Email [email protected]

Disclosures

Dr Cordonnier is a member of the DSMB of ATTEST-2 (unpaid), serves as associate editor of Stroke, and has received lecture fees from Boerhinger-Ingelheim. Dr Ahmed reports that he is the Chairman of SITS International, which receives grants from Boehringer-Ingelheim, Ferrer International, EVER Pharma, Stryker, Covidien, and Phenox in collaboration with Karolinska Institutet for a recently completed study. Dr Ahmed reports no personal grants or financial support from these companies. The department of Dr Khatri has received grant support from Cerenovus and Nervive (NIH SBIR), and consulting fees from Lumosa and Diamedics, for her research efforts. Dr. Khatri is an unpaid consultant to EmstopA, Inc. Dr Leys reports grants from Bayer Pharma, Boehringer-Ingelheim, and Pfizer and other research support from European Stroke Organization and John Wiley & Sons outside the submitted work. Dr Leker has received lecture fees from Boerhinger-Ingelheim. The other authors report no conflicts.

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  1. Ethnic Differences in the Safety and Efficacy of Tenecteplase Versus Alteplase for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis, Journal of Stroke, 26, 3, (371-390), (2024).https://doi.org/10.5853/jos.2024.01284
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  2. Systems-level computational modeling in ischemic stroke: from cells to patients, Frontiers in Physiology, 15, (2024).https://doi.org/10.3389/fphys.2024.1394740
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  3. Advances in thrombectomy in the acute ischemic stroke, Russian Journal of Preventive Medicine, 27, 10, (137), (2024).https://doi.org/10.17116/profmed202427101137
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  4. The Time Has Come. The Time Is Now. IV Alteplase, Will You Please Go Now?, Neurology, 103, 9, (2024).https://doi.org/10.1212/WNL.0000000000209961
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  5. Tenecteplase vs Alteplase in Acute Ischemic Stroke Within 4.5 Hours, Neurology, 103, 9, (2024).https://doi.org/10.1212/WNL.0000000000209903
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  9. Comprehensive Review of Tenecteplase for Thrombolysis in Acute Ischemic Stroke, Journal of the American Heart Association, 13, 9, (2024)./doi/10.1161/JAHA.123.031692
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  10. Tenecteplase thrombolysis for stroke up to 24 hours after onset with perfusion imaging selection: the umbrella phase IIa CHABLIS-T randomised clinical trial, Stroke and Vascular Neurology, 9, 5, (551-559), (2024).https://doi.org/10.1136/svn-2023-002820
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