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Comparative Efficacy and Safety of Tissue Plasminogen Activators (tPA) in Acute Ischemic Stroke: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials

Authors:
  • Khawaja Muhammad Safdar Medical College, Pakistan, Sialkot

Abstract and Figures

Background Intravenous alteplase (ALT) is the standard treatment for acute ischemic stroke (AIS). However, recent trials comparing other tissue plasminogen activators (tPAs) like tenecteplase (TNK) and reteplase with ALT have yielded conflicting results. This necessitated a network meta-analysis to compare the efficacy and safety of various tPAs in AIS patients. Methods We searched MEDLINE, Embase, and CENTRAL (until September 15, 2024) for randomized controlled trials (RCTs) comparing TNK or reteplase (any dose) with ALT (0.9 mg/kg) in AIS patients. A frequentist network meta-analysis was performed using risk ratio (RR) and 95% CI for each comparison, and P-scores ranked treatments. Analyses were done using R Software 4.2.3. Results Sixteen RCTs (9259 patients, 62.1% males) were included. Reteplase 18+18 mg significantly improved excellent functional recovery (mRS 0-1) (RR: 1.13; p<0.01) and independent ambulation (mRS 0-2) at 3 months (RR: 1.07; p<0.01) compared to ALT. The 0.25 mg/kg TNK group also showed improved functional recovery (mRS 0-1) (RR: 1.06; p<0.01). For safety, 0.1 mg/kg TNK was associated with a higher incidence of symptomatic intracranial hemorrhage (s-ICH) (RR: 7.27; p<0.01). No significant differences in ICH or all-cause mortality were found between ALT and other treatments. Reteplase 18+18 mg ranked highest for functional recovery (P-score=0.9638) and ambulation (P-score=0.9749), while ALT ranked highest for s-ICH (P-score=0.8060). No significant differences were observed between reteplase and TNK. Conclusion Reteplase 18+18 mg and TNK 0.25 mg/kg demonstrated higher efficacy and comparable safety to ALT. Larger trials are needed to further explore these agents as alternatives to ALT.
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Comparative efcacy and safety of tissue plasminogen activators (tPA) in
acute ischemic stroke: A systematic review and network meta-analysis of
randomized controlled trials
Sufyan Shahid, MBBS
a
, Humza Saeed, MBBS
b
, Minahil Iqbal, MBBS
c
, Ayesha Batool, MBBS
c
,
Muhammad Bilal Masood, MBBS
d
, Muhammad Husnain Ahmad, MD
e,*
,
Aqeeb Ur Rehman, MD
f
, Muhammad Aemaz Ur Rehman, MD
f
, Fahd Sultan, MD
g
a
Khawaja Muhammad Safdar Medical College, Sialkot, Pakistan
b
Rawalpindi Medical University, Rawalpindi, Pakistan
c
Allama Iqbal Medical College, Lahore, Pakistan
d
Wah Medical College, Wah Cantt, Pakistan
e
Tentishev Satkynbai Memorial Asian Medical Institute, Kant, Bishkek, Kyrgyzstan
f
University of Alabama at Birmingham, Birmingham, AL, USA
g
University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
ARTICLE INFO
Keywords:
Acute ischemic stroke
Tissue plasminogen activator
Alteplase
Tenecteplase
Reteplase
Network meta-analysis
ABSTRACT
Background: Intravenous alteplase (ALT) is the standard treatment for acute ischemic stroke (AIS). However,
recent trials comparing other tissue plasminogen activators (tPAs) like tenecteplase (TNK) and reteplase with
ALT have yielded conicting results. This necessitated a network meta-analysis to compare the efcacy and
safety of various tPAs in AIS patients.
Methods: We searched MEDLINE, Embase, and CENTRAL (until September 15, 2024) for randomized controlled
trials (RCTs) comparing TNK or reteplase (any dose) with ALT (0.9 mg/kg) in AIS patients. A frequentist network
meta-analysis was performed using risk ratio (RR) and 95 % CI for each comparison, and P-scores ranked
treatments. Analyses were done using R Software 4.4.1.
Results: Sixteen RCTs (9259 patients, 62.1 % males) were included. Reteplase 18+18 mg signicantly improved
excellent functional recovery (mRS 0-1) (RR: 1.13; p <0.01) and independent ambulation (mRS 0-2) at 3 months
(RR: 1.07; p <0.01) compared to ALT. The 0.25 mg/kg TNK group also showed improved functional recovery
(mRS 0-1) (RR: 1.06; p <0.01). For safety, 0.1 mg/kg TNK was associated with a higher incidence of symp-
tomatic intracranial hemorrhage (s-ICH) (RR: 7.27; p <0.01). No signicant differences in ICH or all-cause
mortality were found between ALT and other treatments. Reteplase 18+18 mg ranked highest for functional
recovery (P-score=0.9638) and ambulation (P-score=0.9749), while ALT ranked highest for s-ICH (P-
score=0.8060). No signicant differences were observed between reteplase and TNK.
Conclusion: Reteplase 18+18 mg and TNK 0.25 mg/kg demonstrated higher efcacy and comparable safety to
ALT. Larger trials are needed to further explore these agents as alternatives to ALT.
Introduction
Stroke is a signicant global health concern, affecting approximately
15 million individuals worldwide each year, with an estimated 87 % of
all strokes being ischemic.
1
Acute Ischemic Stroke (AIS) occurs when a
sudden blockage of a cerebral artery interrupts blood ow, leading to
rapid neuronal damage and severe neurological decits. Reperfusion
therapy with tissue Plasminogen Activators (tPA) is an extremely
effective evidence-based intervention for AIS in the early stages, with
intravenous alteplase (ALT) considered as the standard thrombolytic
* Corresponding author.
E-mail addresses: sufyanshahid09@gmail.com (S. Shahid), hamzasaeed309@gmail.com (H. Saeed), minahil.iqbal131@gmail.com (M. Iqbal), ayeshabinteakbar@
gmail.com (A. Batool), bilal.masood23.bm@gmail.com (M.B. Masood), husnainahmad601@gmail.com (M.H. Ahmad), aqeebrehman57@gmail.com (A.U. Rehman),
maemazurrehman@uabmc.edu (M. Aemaz Ur Rehman), Fahd-sultan@ouhsc.edu (F. Sultan).
Contents lists available at ScienceDirect
Journal of Stroke and Cerebrovascular Diseases
journal homepage: www.elsevier.com/locate/jstroke
https://doi.org/10.1016/j.jstrokecerebrovasdis.2025.108230
Received 12 December 2024; Received in revised form 2 January 2025; Accepted 8 January 2025
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
Available online 9 January 2025
1052-3057/© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-
nc-nd/4.0/ ).
agent used within 4.5 h of symptom onset. ALT is given in a dose of 0.9
mg/kg, 10 % of which is administered as a bolus, and the rest is given as
a continuous infusion over the subsequent hour.
2
Despite a signicant
surge in thrombolysis demand, marked by a 60.3 % increase from 2015
to 2019, with 22.9 % of patients receiving treatment within 4.5 h of
symptom onset, there remains a pressing need for more effective and
affordable thrombolytic agents to meet this growing demand.
3
Comparative analysis reveals that tenecteplase (TNK) and reteplase
possess superior pharmacological and practical proles relative to ALT.
Notably, TNK treatment is associated with reduced lifetime costs and
enhanced clinical outcomes, versus ALT.
4
Despite ALT being the long-recommended treatment in international
guidelines, only a small percentage (5.6416.3 %) of stroke patients
globally receive intravenous thrombolysis (IVT) due to a strict time
window and high costs.
3
Recent studies show TNK, a modied version of
ALT, provides similar benets without an increased incidence of adverse
outcomes, leading to its recommendation alongside ALT in guidelines.
5
Reteplase, another tPA delivered in a double-bolus regimen, has also
been gaining popularity. Reteplase offers a simpler administration
method, is more affordable, and has an extended plasma half-life.
6,7
Reteplase has also been approved for acute myocardial infarction (AMI)
treatment in several regions.
8
Meta-analyses have found no signicant
differences in mortality or incidence of disabling stroke incidence be-
tween reteplase and ALT in acute myocardial infarction patients.
9
The contradictory and inconsistent ndings from randomized
controlled trials (RCTs) comparing the efcacy and safety of TNK,
reteplase, and ALT in patients with AIS warrant a comprehensive meta-
analysis to resolve these uncertainties, which could have a signicant
impact on real-world stroke outcomes and clinical decision-making. Our
meta-analysis offers a comprehensive comparison of ALT, TNK, and
reteplase, incorporating the latest trials and addressing signicant
knowledge gaps. We include the most recent TNK versus ALT studies and
are the rst to meta-analyze reteplase versus ALT. Our network meta-
analysis compares all three tPAs at different doses, providing the most
up-to-date understanding of their relative efcacy. This study distin-
guishes itself from previous research, providing valuable insights for
clinicians, researchers, and guideline developers.
Methods
This study followed the guidelines of the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA), NMA extension.
10
The protocol for this study has been registered with the International
Prospective Register of Systematic Reviews, PROSPERO database (ID
CRD42024565938).
Search Strategy
Three extensive databases i.e. MEDLINE (via PubMed), Embase and
the Cochrane Controlled Register of Trials (CENTRAL) (via the Cochrane
Library) were searched from their inception to September 15, 2024
without any language restrictions using the following keywords com-
bined by the Boolean operators AND and OR: reteplase, ten-
ecteplase, alteplase, TNK, ALT, tPA, tissue plasminogen
activators, "cerebrovascular disease," acute ischemic stroke and
stroke. The detailed search strategy is available in the supplementary
le. Additionally, reference lists of relevant studies were also manually
curated to identify any potential studies.
Eligibility criteria and outcomes
We included randomized controlled trials in our meta-analysis if they
included adult patients (i.e. age 18) undergoing thrombolysis within
4.5 h of AIS, compared one or more tPA at any dose, and had at least one
outcome of interest concerning the efcacy and/or safety of tPAs.
Studies other than RCTs i.e. non-randomized trials, single arm trials,
observational studies, case reports, review articles, study protocols and
pre-clinical studies were excluded.
The primary efcacy and safety outcomes included functional status
at three months/90 days [modied Rankin Scale (mRS) score of 01 and
modied Rankin Scale (mRS) score of 02] and symptomatic intracra-
nial hemorrhage (sICH) within 36 h. Secondary outcomes included early
neurological improvement, intracranial hemorrhage (ICH), and mor-
tality. The denitions of outcomes were the same as in the included
RCTs. Excellent functional outcome was dened as a score of 0 or 1 on
the mRS and good functional outcome was dened as a score of 0, 1 or 2
on the mRS at 3 months. Early neurological improvement was dened
by a reduction of 8 or more points from the baseline NIHSS score at 24 h
(or closest to 24 h).
The different doses of TNK and reteplase employed by included trials
were categorized into different tiers: three (0.1 mg/kg, 0.25 mg/kg, 0.4
mg/kg) in case of TNK and two for reteplase (18+18 mg, 12+12 mg).
Study selection and data extraction
The search results were transferred to Rayyan software, where after
removing the duplicates, two reviewers (SS and AB) independently
screened the remaining studies based on their titles and abstracts. They
selected potentially eligible RCTs and went for their full-text review.
Any disagreements between the two reviewers were settled by discus-
sion and a third reviewer (HS) in case a consensus could not be reached.
Following data was extracted from the included studies as recommended
in the guidelines of the Cochrane Collaboration: the authors, year of
publication, the country of the study where the RCT was conducted,
study design, total number, mean age and sex of participants, in-
terventions (with doses) received by the participants, and various ef-
cacy and safety outcomes at that dose.
Quality assessment
The revised Cochrane Risk of Biasassessment tool for randomized
controlled trials (RCTs) version 2 (RoB 2.0) was used to evaluate the risk
of bias in the included trials by two authors (AB and SS) with dis-
agreements resolved by consensus. The RoB-2 graded the risk of bias of
the included studies as low risk, some concerns, or high risk and assessed
studies across ve domains: bias arising from the randomization process,
bias due to deviations from intended interventions, bias due to missing
outcome data, bias in the measurement of the outcome, and bias in the
selection of the reported result
11
. Additionally, the risk of bias for the
network estimates was evaluated and presented using bar graphs,
illustrating the percentage of information for each comparison derived
from studies with low, moderate, or high risk of bias, considering both
randomization and compliance to treatment for all direct comparisons.
Two authors (SS and AB) independently assessed the certainty of
evidence using the minimally contextualized Grading of Recommenda-
tions, Assessment, Development, and Evaluation (GRADE) framework.
12
Any disagreements were resolved through a consensus discussion
involving a third author (HS). Certainty of evidence for each comparison
was evaluated based on factors such as risk of bias, inconsistency,
indirectness, publication bias, intransitivity, incoherence, and impreci-
sion. Each outcomes certainty was categorized as very low, low, mod-
erate, or high.
Statistical analysis
We performed a random-effects frequentist network meta-analysis
(NMA) to compare the efcacy and safety of different tPAs in patients
of AIS. This approach allowed us to simultaneously compare different
therapies and doses and therefore accommodate trials with multiple
groups. The network plots generated using the NMA studio software
showed different therapies as nodes, and the connected nodes indicated
that the two therapies were directly compared. The number of studies
S. Shahid et al.
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
2
that made direct comparison between therapies were shown on the lines
that connected the nodes. Dichotomous outcomes were evaluated using
risk ratios (RR) and 95 % condence intervals (CIs) within a frequentist
network meta-analysis framework. This analysis included direct, indi-
rect and overall network effect sizes, and inconsistencies were tested
globally and locally. Between-study variance using
τ
2\tau^2 was esti-
mated to assess heterogeneity across the network for each outcome,
assuming a common random-effects variance for all comparisons within
that outcome. Data was presented in the form of league tables (summary
statistics) for all possible network comparisons along with effect sizes for
all direct comparisons. The three tPAs at different doses were ranked
based on their probability of being the best using the probability score
(P-score) values. Potential publication bias was evaluated by visually
inspecting the symmetry of the funnel plots and by calculating p-values
of eggers test. All statistical analyses were performed using R Software
version 4.4.1 (R Foundation for Statistical Computing, Vienna, Austria).
The signicance threshold for all tests was set at p <0.05.
Results
Study selection
Our extensive database search yielded 2155 records, which was
narrowed down to 1688 unique records after duplicate removal (n =
467). Upon title and abstract screening, 1561 studies were excluded,
leaving 127 articles for full-text evaluation. After applying the pre-
dened inclusion criteria, 16 randomized controlled trials (RCTs) were
identied and selected for quantitative analysis
6,7,1325
, as illustrated in
the PRISMA owchart (Fig. 1).
Study and patient characteristics
After an extensive literature review, we included sixteen studies with
9259 patients (about 62.1 % male) from 2010 to 2024.
6,7,1325
The mean
age across the studies varied, with a general age range between 54 and
75 years. The prevalence of hypertension also varied across the studies,
with some studies reporting up to 79.5 % and others without available
data. The time from symptom onset to intervention was within 4.5 h and
follow-up duration was 3 years for all included trials. Table 1 summa-
rizes the characteristics of included trials.
Primary outcomes
1. Excellent functional recovery (mRS 0-1):
All sixteen included trials, involving 9,254 patients, described the
outcome of excellent functional recovery (mRS 0-1) at 3 months and
included a total of six interventions, with non-signicant global
inconsistency (p=0.39). The network evidence plot is presented in
Fig. 2A. Compared to ALT, excellent functional recovery (mRS 0-1)
was signicantly better in the 0.25 mg/kg TNK (RR: 1.06; 95% CI:
Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) owchart for the included studies.
S. Shahid et al.
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
3
Table 1
Baseline characteristics of the included trials.
Study Intervention and
dose
Control
and dose
No. of Patients, n Age of patients, Mean years (SD) Hypertension,
%
Prior Stroke
or TIA, %
Needle
Time
Male
patients, %
NIHSS Score, median (range) Maximum
Follow-up
Intervention Control Intervention Control Intervention Control
Haley 2010 0.1/0.25/0.4 mg/
kg TNK
0.9 mg/kg
ALT
31/31/19 31 67 (19)/ 69 (15)/ 68
(16)
72 (16) 79.5 22.3 <3 hrs 52 8 (5-11)/ 10 (6-
15)/ 9 (5-17)
13 (5-17) 3 months
Parsons
2012
0.1/0.25 mg/kg
TNK
0.9 mg/kg
ALT
25/25 25 72 (6.9)/ 68 (9.4) 70 (8.4) 62.7 nr <3 hrs 51 14.5 (2.3)/ 14.6
(2.3) (mean)
14.0 (2.3)
(mean)
3 months
ATTEST 2015 0.25 mg/kg TNK 0.9 mg/kg
ALT
47 49 71 (13) 71 (12) 50 24 <4.5 hrs 63.5 12 (9-18) 11 (8-16) 3 months
NOR-TEST
2017
0.4 mg/kg TNK 0.9 mg/kg
ALT
549 551 70.8 (14.4) 71.2
(13.2)
43.8 12.7 <3 hrs 60 4 (2-7) 4 (2-8) 3 months
Campbell
2018
0.25 mg/kg TNK 0.9 mg/kg
ALT
101 101 70.4 (15.1) 71.9
(13.7)
nr nr <3 hrs 54.5 17 (12-22) 17 (12-22) 3 months
Rajappa
2018
0.2 mg/kg TNK 0.9 mg/kg
ALT
42 84 54 (median) 54
(median)
nr nr <3 hrs nr 11.2 11.2 3 months
TASTE-A
2022
0.25 mg/kg TNK 0.9 mg/kg
ALT
55 49 75.3 (5.3) 72.6 (4.2) 58.6 24 <4.5 hrs 60.5 8 (5-14) 8 (5-14) 3 months
AcT 2022 0.25 mg/kg TNK 0.9 mg/kg
ALT
806 771 74 (3.2) 73 (3.3) nr nr <3 hrs 52 9 (6-16) 10 (6-17) 3 months
NOR-TEST 2
2022
0.4 mg/kg TNK 0.9 mg/kg
ALT
100 104 73.2 (12.6) 68.6
(15.6)
51 13.2 <4.5 hrs 48 11.5 (8-17) 11.5 (8-
17)
3 months
TRACE 2022 0.1/0.25/0.32 mg/
kg TNK
0.9 mg/kg
ALT
60/57/60 59 62.4 (11.1)/ 64.3
(12.8)/ 64.8 (12.1)
66.5
(12.6)
66.5 nr <3 hrs 72 7/8/7.5 8 3 months
Campbell
2020
0.4 mg/kg TNK 0.25 mg/
kg TNK
150 150 71.7 (11.3) 73.8
(12.8)
65.7 nr <3 hrs 53 17 (11-21) 16 (9-20) 3 months
Trace-2 2023 0.25 mg/kg TNK 0.9 mg/kg
ALT
710 707 67 (2.4) 65 (2.2) 72 nr <4.5 hrs 68.5 7 (5-10) 7 (6-10) 3 months
Li 2023 18 +18mg/ 12 +
12 mg reteplase
0.9 mg/kg
ALT
66/60 50 62.8 (10.1)/ 61.9
(9.5)
63.3 (9.5) 67 35.8 <4.5 hrs 73.9 6.0 (5.08.5)/ 6.0
(5.08.0)
8 (5-10) 3 months
Raise 2024 18 +18 mg
reteplase
0.9 mg/kg
ALT
707 705 63 (2.2) 63 (2.2) 74.8 nr <4.5 hrs 70.5 6 (5-8) 6 (5-8) 3 months
TASTE 2024 0.25 mg/kg TNK 0.9 mg/kg
ALT
339 341 75 (2.9) 73 (3.1) 62.9 11.6 <4.5 hrs 61.8 7 (4-11) 7 (5-10) 3 months
ORIGINAL
2024
0.25 mg/kg TNK 0.9 mg/kg
ALT
732 733 66 (3.75) 65 (4.0) nr 1.8 <4.5 hrs 69.6 6 (5-8.5) 6 (5-9) 3 months
TNK: Tenecteplase; ALT: alteplase; TIA: transient ischemic stroke: NIHSS: National Institute of Health Stroke Scale; SD: standard deviation; nr: not reported.
S. Shahid et al.
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
4
1.02 to 1.11; p<0.01) and 18 +18 mg reteplase (RR: 1.13; 95% CI:
1.06 to 1.20; p<0.01) groups (Fig. 3A). All other comparisons be-
tween the six interventions (including between TNK and reteplase)
yielded non-signicant results (Table 2A) in addition to the non-
signicant local inconsistencies between direct and indirect com-
parisons (Supplementary Table 2). Among the six interventions, 18 +
18 mg reteplase had the highest probability of being the best treat-
ment (P-score=0.9638), while 0.1 mg/kg TNK had the least proba-
bility of being the best (P-score=0.1523) (Table 3, Supplementary
Fig. 1A). The between-study variance (
τ
2\tau^2 =0.0020) indicates
low heterogeneity, suggesting consistent treatment effects across
studies with minimal unexplained variability (Supplementary
Table 3).
2. Independent Ambulation (mRS 0-2)
Fourteen trials, involving 9,016 patients, described the outcome of
Independent Ambulation (mRS 0-2) at 3 months and included a total
of six interventions, with non-signicant global inconsistency (p =
0.17). The network evidence plot is presented in Fig. 2B. Compared
to ALT, Independent Ambulation (mRS 0-2) was signicantly better
in the 18 +18 mg reteplase (RR: 1.07; 95 % CI: 1.02 to 1.12; p <
0.01) group (Fig. 3B). All other comparisons between the six in-
terventions (including between TNK and reteplase) yielded non-
Fig. 2. The network evidence plots generated using the NMA studio software showing different therapies as nodes, and the connected nodes indicating that the two
therapies were directly compared. a. Excellent functional recovery (mRS 0-1) b. Independent ambulation (mRS 0-2) c. Symptomatic intracranial hemorrhage (s-ICH)
d. Any intracranial hemorrhage (any ICH) e. All-cause mortality f. Early neurological improvement g. Excellent functional recovery (mRS 0-1)
S. Shahid et al.
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
5
signicant results (Table 2B) in addition to the non-signicant local
inconsistencies between direct and indirect comparisons (Supple-
mentary Table 2). Among the six interventions, 18 +18 mg reteplase
had the highest probability of being the best treatment (P-
score=0.9749), while 0.1 mg/kg TNK had the least probability of
being the best (P-score=0.1995) (Table 3, Supplementary Fig. 1B).
The between-study variance for the outcome of independent ambu-
lation (
τ
2\tau^2 =0.0025) reects low heterogeneity, indicating
minimal unexplained variability and consistent treatment effects
across the included studies (Supplementary Table 3).
3. Symptomatic Intracranial Hemorrhage (s-ICH)
All sixteen trials, involving 9,259 patients, described the outcome
of S-ICH within 36 h and included a total of six interventions, with
non-signicant global inconsistency (p =0.12). The network evi-
dence plot is presented in Fig. 2C. Compared to ALT, the incidence of
S-ICH was signicantly higher in the 0.1 mg/kg TNK group (RR:
7.27; 95 % CI: 2.77 to 19.06; p <0.01) (Fig. 3C). In addition, 0.1 mg/
kg ALT had a higher risk of incidence of s-ICH compared to 0.25 mg/
kg TNK (RR: 7.28; 95 % CI: 2.68 to 19.78; p <0.05), 0.4 mg/kg TNK
(RR: 4.18; 95 % CI: 1.57 to 11.13; p <0.05) and 18 +18 mg reteplase
(RR: 5.50; 95 % CI: 1.51 to 19.98; p <0.05) (Table 2C). All other
comparisons between the six interventions (including between TNK
and reteplase) yielded non-signicant results (Table 2C) in addition
to the non-signicant local inconsistencies between direct and
Fig. 2. (continued).
S. Shahid et al.
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
6
indirect comparisons (Supplementary Table 2). ALT had the highest
probability of being the best treatment (P-score=0.8060), while 0.1
mg/kg TNK had the lowest (P-score=0.0227) (Table 3, Supplemen-
tary Fig. 1C). For the outcome of s-ICH, the between-study variance
(
τ
2\tau^2 =0.0945) indicates low to moderate heterogeneity across
the included studies (Supplementary Table 3).
Secondary outcomes
1. Any Intracranial Hemorrhage:
Twelve trials, involving 6,705 patients, described the outcome of
any ICH and included a total of six interventions, with non-
signicant global inconsistency (p =0.62). The network evidence
plot is presented in Fig. 2D. All comparisons of any ICH between the
six interventions yielded non-signicant results (Fig. 3D, Table 2D)
in addition to the non-signicant local inconsistencies between
direct and indirect comparisons (Supplementary Table 2). Among
the six interventions, 12 +12 mg reteplase had the highest proba-
bility of being the best treatment (P-score=0.7917), while 0.4 mg/kg
TNK had the least probability of being the best (P-score=0.0701)
(Table 3, Supplementary Fig. 1D). The between-study variance was
τ
2\tau^2 =0.0439, indicating low heterogeneity (Supplementary
Table 3).
2. All-cause Mortality:
All sixteen trials, involving 9,234 patients, described the outcome
of all-cause mortality and included a total of six interventions, with
Fig. 2. (continued).
S. Shahid et al.
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
7
non-signicant global inconsistency (p =0.73). The network evi-
dence plot is presented in Fig. 2E. All comparisons of any ICH be-
tween the six interventions yielded non-signicant results (Fig. 3E,
Table 2E) in addition to the non-signicant local inconsistencies
between direct and indirect comparisons (Supplementary Table 2).
Among the six interventions, 0.1 mg/kg TNK had the highest prob-
ability of being the best treatment (P-score=0.6471), while 0.4 mg/
kg TNK had the least probability of being the best (P-score=0.2796)
(Table 3, Supplementary Fig. 1E). For the outcome of all-cause
mortality, the between-study variance was
τ
2\tau^2 =0.0631,
indicating low to moderate heterogeneity (Supplementary Table 3).
3. Early Neurological Improvement:
Twelve trials, involving 5,906 patients, described the outcome of
early neurological improvement and included a total of six in-
terventions, with a signicant global inconsistency among the com-
parisons (p =0.02). The network evidence plot is presented in
Fig. 2F. All network comparisons of any ICH between the six in-
terventions yielded non-signicant results; however, the comparison
of direct and indirect evidence showed signicant inconsistency for
the comparisons of 0.1 mg/kg TNK with 0.25 mg/kg TNK and 12+12
mg reteplase (p-values for inconsistency <0.05) (Fig. 3F, Table 2F).
Among the six interventions, 0.25 mg/kg TNK had the highest
probability of being the best treatment (P-score=0.8543), while 0.1
mg/kg TNK had the least probability of being the best (P-
score=0.1098) (Table 3, Supplementary Fig. 1F). For the outcome of
early neurological development, the between-study variance was
τ
2
\tau^2 =0.0045, indicating low heterogeneity (Supplementary
Table 3).
Quality assessment, condence rating and publication bias
All included trials, except one
17
, which showed some concerns due to
deviations from intended interventions, were assessed as having a low
risk of bias across all ve key domains (Supplementary Table 4). Sup-
plementary Fig. 2AF present bar graphs illustrating the percentage of
information for each comparison derived from studies based on their
risk of bias, showing that the majority of comparisons for each outcome
originated from studies with a low risk of bias. The condence or cer-
tainty of evidence across all GRADE domains for all comparisons of each
outcome are reported in Supplementary Tables 5A-5F, which highlight
variable condence ratings across comparisons, ranging from very low
to high. Visual inspection of the funnel plots revealed no notable
asymmetry, a nding further supported by non-signicant p-values from
Eggers tests for all outcomes, except early neurological improvement (p
=0.0116). Collectively, these results suggest minimal to no risk of
publication bias (Supplementary Fig. 3AF).
Fig. 3. Network analysis plots compared to alteplase (ALT) 0.9 mg/kg for: a. Excellent functional recovery (mRS 0-1) b. Independent ambulation (mRS 0-2) c.
Symptomatic intracranial hemorrhage (s-ICH) d. Any intracranial hemorrhage (any ICH) e. All-cause mortality f. Early neurological improvement
S. Shahid et al.
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
8
Discussion
To our knowledge, this is the rst and largest meta-analysis to sys-
tematically evaluate reteplase trials and compare the efcacy and safety
of reteplase and TNK with ALT in AIS. Pharmacologically, TNK and
reteplase offer several pharmacological and practical advantages over
ALT, making them promising alternatives for AIS treatment. They offer
longer half-lives, greater brin specicity, and reduced binding afnity
to Plasminogen Activator Inhibitor (PAI). Specically, reteplase has a
half-life of 1316 min, nearly twice that of ALTs 67 min, and a lower
afnity for PAI-1, enhancing its thrombolytic effect and reducing sys-
temic bleeding risk. These pharmacological advantages, combined with
simplied administration regimens, provide practical benets for hos-
pital staff and patients. TNKs single-bolus administration and rete-
plases two-bolus regimen streamline treatment, reducing needle time,
bleeding risk, and monitoring needs. Additionally, reteplase longer shelf
life and simpler storage requirements facilitate handling and storage.
Overall, reteplases unique prole makes it a valuable treatment option
for patients with acute myocardial infarction or AIS, particularly those
at high risk of bleeding, positioning it as a benecial alternative to ALT
in clinical settings.
3,26
This network meta-analysis, encompassing 16 randomized
controlled trials, systematically compared the efcacy of six distinct
interventions for AIS. The primary ndings indicate that treatment with
0.25 mg/kg TNK and 18 +18 mg reteplase yielded signicantly superior
excellent functional recovery rates (modied Rankin Scale [mRS] 0-1) at
three months compared to ALT. Furthermore, 18 +18 mg reteplase
demonstrated improved Independent Ambulation (mRS 0-2) outcomes.
Conversely, the 0.1 mg/kg TNK regimen was associated with a sub-
stantially higher incidence of Symptomatic Intracerebral Hemorrhage
(S-ICH) within 36 h. In addition, ALT exhibited the highest probability
of minimizing S-ICH risk. Notably, no signicant interventional differ-
ences were observed in all-cause mortality rates. Ranking the treat-
ments efcacy, 18 +18 mg reteplase emerged as the top option for
excellent functional recovery and Independent Ambulation, while ALT
proved optimal for S-ICH prevention. Additionally, 0.25 mg/kg TNK
showed the highest probability of achieving early neurological
improvement.
Contrary to previous meta-analysis by Rehman et al. comparing TNK
to ALT showing no signicant difference in S-ICH rates between TNK
and ALT
27
, our study found higher incidence of S-ICH with 0.1 mg/kg
TNK. Recent meta-analyses by Wu et al. and Srisurapanont et al. also
compared TNK and ALT in AIS, sharing similarities in safety and func-
tional outcomes, but differing in objectives and populations.
28,29
Our
study uniquely compared six interventions involving TNK, reteplase,
and ALT in the general AIS population, revealing that 0.25 mg/kg TNK
and 18+18 mg reteplase outperformed ALT for excellent functional re-
covery. Notably, our ndings align with Wu et al.s results showing
TNKs superiority to ALT for successful recanalization, and Srisur-
apanont et al.s identication of 0.25 mg/kg TNK as the optimal dose.
Fig. 3. (continued).
S. Shahid et al.
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
9
Fig. 3. (continued).
S. Shahid et al.
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
10
Table 2
League Tables (Summary statistics) of each outcome showing direct evidence effect sizes above the diagonal while network evidence effect sizes below the
diagonal. Each statistically signicant (p <0.05) effect size is highlighted in bold format.
S. Shahid et al.
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
11
However, safety proles varied: our study linked 0.1 mg/kg TNK to
higher S-ICH risk, whereas Wu et al. found no increased risk, and Sri-
surapanont et al. noted higher TNK doses increase S-ICH and paren-
chymal hemorrhage risk. Importantly, our study was the rst to compare
reteplase with ALT, revealing signicant improvement in excellent
functional recovery with 18+18 mg reteplase.
Our study utilized a random-effects model within a frequentist sta-
tistical framework, thereby minimizing potential biases associated with
subjective prior assumptions and yielding more objective and reliable
outcomes. By employing network meta-analysis (NMA), we integrated
both direct and indirect evidence, providing a more comprehensive
comparison of various tPAs beyond what traditional meta-analysis of-
fers. However, it is essential to acknowledge that NMAs reliance on
indirect evidence necessitates cautious interpretation of the results, as
indirect evidence may introduce potential biases. Consequently, future
head-to-head clinical trials will play a critical role in validating and
rening these ndings.
Our study pioneers a comprehensive comparison of reteplase, TNK,
and ALT dosing regimens, offering new perspectives for clinicians and
researchers. This meta-analysis provides the rst systematic dose-based
comparison of reteplase and TNK with ALT across outcomes, a distinc-
tion that sets it apart from previous research. Notably, it represents the
largest and most up-to-date pooling of RCTs data on this topic. A key
strength lies in the consistent absence of signicant differences between
direct and indirect comparisons across most outcomes, including mor-
tality, functional outcomes, and adverse events, which demonstrates the
robustness and reliability of our ndings. This consistency enhances the
validity and generalizability of our results, underscoring the studys
contribution to understanding treatment effects.
Limitations
Despite the robustness of our results, there are certain limitations.
First, the limited number of studies evaluating reteplase restricts the
generalizability of its ndings, despite its promising efcacy. Second,
the lack of long-term outcome data prevents a comprehensive under-
standing of the sustained benets and risks of the treatments. Third, the
analysis excluded observational studies, which could provide valuable
insights into real-world effectiveness. Fourth, while subgroup analyses
by comorbidities and other baseline characteristics were not performed
owing to limited data available, these could further rene the under-
standing of treatment efcacy and safety. Lastly, signicant in-
consistencies and publication bias for certain outcomes, such as early
neurological improvement, highlight the need for cautious interpreta-
tion and validation through future research.
Conclusion
This network meta-analysis demonstrates that 18+18 mg reteplase
and 0.25 mg/kg TNK offer superior efcacy compared to ALT in
achieving excellent functional recovery and independent ambulation at
three months in AIS patients, with comparable safety proles for most
outcomes. However, 0.1 mg/kg TNK was associated with a signicantly
higher risk of sICH, highlighting ALT as the safest option for minimizing
sICH. While the ndings emphasize the potential of reteplase and TNK as
alternatives to ALT, further large-scale trials, long-term outcome studies,
and cost-effectiveness analyses are necessary to validate these results
and optimize stroke management strategies globally.
Financial support and sponsorship
This research received no specic grant from any funding agency in
the public, commercial, or not-for-prot sectors.
Ethical considerations
No ethical approval was required for this study design, as all data
were obtained from publicly available sources.
CRediT authorship contribution statement
Sufyan Shahid: Writing review & editing, Writing original draft,
Project administration, Methodology, Investigation, Formal analysis,
Data curation, Conceptualization. Humza Saeed: Writing review &
editing, Writing original draft, Supervision, Software, Methodology,
Investigation, Formal analysis, Data curation. Minahil Iqbal: Writing
review & editing, Writing original draft, Supervision, Project admin-
istration, Investigation, Formal analysis, Data curation. Ayesha Batool:
Writing review & editing, Writing original draft, Validation, Soft-
ware, Methodology, Formal analysis. Muhammad Bilal Masood:
Writing review & editing, Writing original draft, Resources, Project
administration, Methodology, Formal analysis, Data curation.
Muhammad Husnain Ahmad: Writing review & editing, Writing
original draft, Visualization, Methodology, Investigation, Formal anal-
ysis, Data curation. Aqeeb Ur Rehman: Writing review & editing,
Writing original draft, Visualization, Validation, Supervision, Meth-
odology, Investigation, Formal analysis, Data curation. Muhammad
Aemaz Ur Rehman: Writing review & editing, Writing original draft,
Visualization, Validation, Software, Resources, Formal analysis, Data
curation. Fahd Sultan: Writing review & editing, Validation, Soft-
ware, Project administration, Methodology, Formal analysis, Data
curation, Conceptualization.
Declaration of competing interest
The authors declare that they have no known competing nancial
interests or personal relationships that could have appeared to inuence
the work reported in this paper.
Table 3
P-scores for each intervention and endpoint.
Intervention Excellent functional
recovery (mRS 0-1)
Independent
Ambulation (mRS 0-2)
Symptomatic Intracranial
Hemorrhage (s-ICH)
Any Intracranial
Hemorrhage (ICH)
Early Neurological
Development
All-cause
mortality
18þ18 mg
Reteplase
0.9638 0.9749 0.5978 0.6503 0.4241 0.3497
0.25 mg/kg
TNK
0.7405 0.7161 0.7982 0.6504 0.8543 0.5964
0.4 mg/kg TNK 0.4210 0.3097 0.4052 0.0701 0.5763 0.2796
0.9 mg/kg ALT 0.3865 0.5519 0.8060 0.3861 0.5430 0.6168
12þ12 mg
Reteplase
0.3358 0.2480 0.3701 0.7917 0.4924 0.5103
0.1 mg/kg TNK 0.1523 0.1995 0.0227 0.4515 0.1098 0.6471
*The interventions with the highest P-scores for each endpoint are highlighted in bold, indicating the highest probability of being the best option.
mRS: modied ranking scale; TNK: tenecteplase; ALT: alteplase.
S. Shahid et al.
Journal of Stroke and Cerebrovascular Diseases 34 (2025) 108230
12
Acknowledgments
The authors have no acknowledgments to declare.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.jstrokecerebrovasdis.2025.108230.
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Article
Full-text available
Background The benefits and risks of tenecteplase (TNK) versus alteplase (ALT) have recently been assessed in acute ischemic stroke (AIS) patients undergoing mechanical thrombectomy (MT) with diverse results. Due to its high fibrin specificity and lack of excitotoxicity, TNK may have a higher efficacy and safety profile. This study aimed to evaluate the benefits and risks of TNK compared to ALT in AIS patients prior to thrombectomy. Methods We systematically searched four key databases, PubMed, Embase, Web of Science and Cochrane Library until January 27, 2024 for clinical studies evaluating the effects of TNK versus ALT in patients with large vessel occlusion undergoing MT. A random-effect meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Ten studies involving 3722 patients receiving TNK (1266 patients) or ALT (2456 patients) were included (age: 69.05 ± 14.95 years; 55.64% male). Compared to ALT-treated patients, TNK-treated patients demonstrated significantly higher rates of early recanalization (odds ratio 2.02, 95%-confidence interval 1.20–3.38, p = 0.008) without increased risk of symptomatic intracerebral hemorrhage (1.06, 0.64–1.76, p = 0.82) or intracerebral hemorrhage (1.21, 0.66–2.25, p = 0.54). TNK-treated patients showed similar rates of functional independence at 90 days (1.13, 0.87–1.46, p = 0.37) as ALT-treated patients, but lower rates of mortality within 90 days (0.65, 0.44–0.96, p = 0.03). Conclusion TNK is superior to ALT in achieving early recanalization and is associated with lower mortality within 90 days in AIS patients undergoing MT. Compared with ALT, TNK does not significantly alter functional independence at 90 days, symptomatic intracerebral hemorrhage or intracerebral hemorrhage.
Article
Importance Tenecteplase is a bioengineered variant of alteplase with greater fibrin specificity and a longer half-life, allowing single-bolus administration. Evidence on the treatment effect of tenecteplase 0.25 mg/kg in Chinese patients with acute ischemic stroke (AIS) is limited. Objective To establish the noninferiority of tenecteplase to alteplase in patients with AIS within 4.5 hours of symptom onset. Design, Setting, and Participants The ORIGINAL study was a multicenter, active-controlled, parallel-group, randomized, open-label, blinded end point, noninferiority trial conducted between July 14, 2021, and July 14, 2023. Participants were recruited from 55 neurology clinics and stroke centers in China and were eligible if they had AIS with a National Institutes of Health Stroke Scale score of 1 to 25 with measurable neurologic deficit and were symptomatic for at least 30 minutes without significant improvement. Interventions Patients were randomized (1:1) within 4.5 hours of symptom onset to receive intravenous tenecteplase (0.25 mg/kg) or intravenous alteplase (0.9 mg/kg). Main Outcomes and Measures The primary outcome was the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 (no symptoms or no significant disability) at day 90, tested for noninferiority (risk ratio [RR] margin, 0.937). Safety end points included symptomatic intracerebral hemorrhage (per European Cooperative Acute Stroke Study III definition) and 90-day all-cause mortality. Results Among the 1489 patients randomized, 1465 patients were included in the full analysis set (732 in the tenecteplase group; 733 in the alteplase group) and 446 (30.4%) were female. The primary outcome occurred in 72.7% (532/732) of patients receiving tenecteplase and 70.3% (515/733) receiving alteplase (RR, 1.03 [95% CI, 0.97-1.09]; noninferiority threshold met). Symptomatic intracerebral hemorrhage occurred in 9 patients (1.2%) in each group (RR, 1.01 [95% CI, 0.37-2.70]). The 90-day mortality rate was 4.6% (34/732) in the tenecteplase group and 5.8% (43/736) in the alteplase group (RR, 0.80 [95% CI, 0.51-1.23]). Conclusions and Relevance In patients with AIS eligible for intravenous thrombolysis within 4.5 hours after stroke onset, tenecteplase was noninferior to alteplase with respect to excellent functional outcome (mRS score of 0 or 1) at 90 days and had a similar safety profile. Findings from this study support tenecteplase as a suitable alternative to alteplase in this setting. Trial Registration ClinicalTrials.gov Identifier: NCT04915729
Article
Background: Alteplase is the standard agent used in early reperfusion therapy, but alternative thrombolytic agents are needed. The efficacy and safety of reteplase as compared with alteplase in patients with acute ischemic stroke are unclear. Methods: We randomly assigned patients with ischemic stroke within 4.5 hours after symptom onset in a 1:1 ratio to receive intravenous reteplase (a bolus of 18 mg followed 30 minutes later by a second bolus of 18 mg) or intravenous alteplase (0.9 mg per kilogram of body weight; maximum dose, 90 mg). The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]) at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after symptom onset. Results: A total of 707 patients were assigned to receive reteplase, and 705 were assigned to receive alteplase. An excellent functional outcome occurred in 79.5% of the patients in the reteplase group and in 70.4% of those in the alteplase group (risk ratio, 1.13; 95% confidence interval [CI], 1.05 to 1.21; P<0.001 for noninferiority and P = 0.002 for superiority). Symptomatic intracranial hemorrhage within 36 hours after disease onset was observed in 17 of 700 patients (2.4%) in the reteplase group and in 14 of 699 (2.0%) of those in the alteplase group (risk ratio, 1.21; 95% CI, 0.54 to 2.75). The incidence of any intracranial hemorrhage at 90 days was higher with reteplase than with alteplase (7.7% vs. 4.9%; risk ratio, 1.59; 95% CI, 1.00 to 2.51), as was the incidence of adverse events (91.6% vs. 82.4%; risk ratio, 1.11; 95% CI, 1.03 to 1.20). Conclusions: Among patients with ischemic stroke within 4.5 hours after symptom onset, reteplase was more likely to result in an excellent functional outcome than alteplase. (Funded by China Resources Angde Biotech Pharma and others; RAISE ClinicalTrials.gov number, NCT05295173.).
Article
BACKGROUND Reteplase is a more affordable new-generation thrombolytic with a prolonged half-life. We aimed to determine the safety dose range of reteplase for patients with acute ischemic stroke within 4.5 hours of onset. METHODS This is a multicenter, prospective, randomized controlled, open-label, blinded-end point phase 2 clinical trial. Patients with acute ischemic stroke aged between 18 and 80 years who were eligible for standard intravenous thrombolysis were enrolled from 17 centers in China and randomly assigned (1:1:1) to receive intravenous reteplase 12+12 mg, intravenous reteplase 18+18 mg, or intravenous alteplase 0.9 mg/kg. The primary safety outcome was symptomatic intracranial hemorrhage (SITS definition) within 36 hours. The primary efficacy outcome was the proportion of patients with the National Institutes of Health Stroke Scale score of no more than 1 or a decrease of at least 4 points from the baseline at 14 days after thrombolysis. RESULTS Between August 2019 and May 2021, 180 patients were randomly assigned to reteplase 12+12 mg (n=61), reteplase 18+18 mg (n=67), or alteplase (n=52). Four patients did not receive the study agent. Symptomatic intracranial hemorrhage occurred in 3 of 60 (5.0%) in the reteplase 12+12 mg group, 1 of 66 (1.5%) in the reteplase 18+18 mg group, and 1 of 50 (2.0%) in the alteplase group ( P =0.53). The primary efficacy outcome in the modified intention-to-treat population occurred in 45 of 60 (75.0%) in the reteplase 12+12 mg group (odds ratio, 0.85 [95% CI, 0.35–2.06]), 48 of 66 (72.7%) in the reteplase 18+18 mg group (odds ratio, 0.75 [95% CI, 0.32–1.78]), and 39 of 50 (78.0%) in alteplase group. CONCLUSIONS Reteplase was well tolerated in patients with acute ischemic stroke within 4.5 hours of onset in China with a similar efficacy profile to alteplase. The efficacy and appropriate dosage of reteplase for patients with acute ischemic stroke need prospective validation. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04028518.
Article
Background: There is increasing interest in replacing alteplase with tenecteplase as the preferred thrombolytic treatment for patients with acute ischaemic stroke. We aimed to establish the non-inferiority of tenecteplase to alteplase for these patients. Methods: In this multicentre, prospective, open-label, blinded-endpoint, randomised controlled, non-inferiority trial, adults with an acute ischaemic stroke who were eligible for standard intravenous thrombolysis but ineligible for endovascular thrombectomy were enrolled from 53 centres in China and randomly assigned (1:1) to receive intravenous tenecteplase (0·25 mg/kg, maximum dose of 25 mg) or intravenous alteplase (0·9 mg/kg, maximum dose of 90 mg). Participants had to be able to receive treatment within 4·5 h of stroke, have a modified Rankin Scale (mRS) score of no more than 1 before enrolment, and have a National Institutes of Health Stroke Scale score of 5-25. Patients and treating clinicians were not masked to group assignment; clinicians evaluating outcomes were masked to treatment type. The primary efficacy outcome was the proportion of participants who had a mRS score of 0-1 at 90 days, assessed in the modified intention-to-treat population (all randomly assigned participants who received the allocated thrombolytic), with a non-inferiority margin of 0·937 for the risk ratio (RR). The primary safety outcome was symptomatic intracranial haemorrhage within 36 h, assessed in all participants who received study drug and had a safety assessment available. The trial is registered with ClinicalTrials.gov, NCT04797013, and has been completed. Findings: Between June 12, 2021, and May 29, 2022, 1430 participants were enrolled and randomly assigned to tenecteplase (n=716) or alteplase (n=714). Six patients assigned to tenecteplase and seven to alteplase did not receive study product, and five participants in the tenecteplase group and 11 in the alteplase group were lost to follow-up at 90 days. The primary outcome in the modified intention-to-treat population occurred in 439 (62%) of 705 in the tenecteplase group versus 405 (58%) of 696 in the alteplase group (RR 1·07, 95% CI 0·98-1·16). The lower limit of the RR's 95% CI was greater than the non-inferiority margin. Symptomatic intracranial haemorrhage within 36 h was observed in 15 (2%) of 711 in the tenecteplase group and 13 (2%) of 706 in the alteplase group (RR 1·18, 95% CI 0·56-2·50). Mortality within 90 days occurred in 46 (7%) individuals in the tenecteplase group versus 35 (5%) in the alteplase group (RR 1·31, 95% CI 0·86-2·01). Interpretation: Tenecteplase was non-inferior to alteplase in people with ischaemic stroke who were eligible for standard intravenous thrombolytic but ineligible for or refused endovascular thrombectomy. Funding: National Science and Technology Major Project, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China, and China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou).
Article
Background Studies on tenecteplase have been yielding mixed results on several important variables at different doses, thus hampering objective guideline recommendations in acute ischemic stroke management. This meta-analysis stratifies doses in order to refine our interpretation of outcomes and quantify the benefits and harms of tenecteplase at different doses. Methods PubMed/MEDLINE, the Cochrane Library, and reference lists of the included articles were systematically searched. Several efficacy and safety outcomes were pooled and reported as risk ratios (RRs) with 95% confidence intervals (CIs). Network meta-analysis was used to find the optimal dose of tenecteplase. Meta-regression was run to investigate the impact of baseline NIHSS scores on functional outcomes and mortality. Results Ten randomized controlled trials with a total of 4140 patients were included. 2166 (52.32%) patients were enrolled in the tenecteplase group and 1974 (47.68%) in the alteplase group. Tenecteplase at 0.25 mg/kg dose demonstrated significant improvement in excellent functional outcome at 3 months (RR 1.14, 95% CI 1.04–1.26), and early neurological improvement (RR 1.53, 95% CI 1.03–2.26). There was no statistically significant difference between tenecteplase and alteplase in terms of good functional outcome, intracerebral hemorrhage (ICH), symptomatic intracerebral hemorrhage (sICH), and 90-day mortality at any dose. Meta-regression demonstrated superior tenecteplase efficacy with increasing stroke severity, however, the results were statistically nonsignificant. Conclusions Tenecteplase at 0.25 mg/kg dose is more efficacious and at least as safe as alteplase for stroke thrombolysis. Newer analyses need to focus on direct comparison of tenecteplase doses and whether tenecteplase is efficacious at longer needle times.
Article
Background: Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care. Methods: In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual. Findings: Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI - 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis. Funding: Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.
Article
Background Mobile stroke units (MSUs) equipped with a CT scanner reduce time to thrombolytic treatment and improve patient outcomes. We tested the hypothesis that tenecteplase administered in an MSU would result in superior reperfusion at hospital arrival, when compared with alteplase. Methods The TASTE-A trial is a phase 2, randomised, open-label trial at the Melbourne MSU and five tertiary hospitals in Melbourne, VIC, Australia. Patients (aged ≥18 years) with ischaemic stroke who were eligible for thrombolytic treatment were randomly allocated in the MSU to receive, within 4·5 h of symptom onset, either standard-of-care alteplase (0·9 mg/kg [maximum 90 mg], administered intravenously with 10% as a bolus over 1 min and 90% as an infusion over 1 h), or the investigational product tenecteplase (0·25 mg/kg [maximum 25 mg], administered as an intravenous bolus over 10 s), before being transported to hospital for ongoing care. The primary outcome was the volume of the perfusion lesion on arrival at hospital, assessed by CT-perfusion imaging. Secondary safety outcomes were modified Rankin Scale (mRS) score of 5 or 6 at 90 days, symptomatic intracerebral haemorrhage and any haemorrhage within 36 h, and death at 90 days. Assessors were masked to treatment allocation. Analysis was by intention-to-treat. The trial was registered with ClinicalTrials.gov, NCT04071613, and is completed. Findings Between June 20, 2019, and Nov 16, 2021, 104 patients were enrolled and randomly allocated to receive either tenecteplase (n=55) or alteplase (n=49). The median age of patients was 73 years (IQR 61–83), and the median NIHSS at baseline was 8 (5–14). On arrival at the hospital, the perfusion lesion volume was significantly smaller with tenecteplase (median 12 mL [IQR 3–28]) than with alteplase (35 mL [18–76]; adjusted incidence rate ratio 0·55, 95% CI 0·37–0·81; p=0·0030). At 90 days, an mRS of 5 or 6 was reported in eight (15%) patients allocated to tenecteplase and ten (20%) patients allocated to alteplase (adjusted odds ratio [aOR] 0·70, 95% CI 0·23–2·16; p=0·54). Five (9%) patients allocated to tenecteplase and five (10%) patients allocated to alteplase died from any cause at 90 days (aOR 1·12, 95% CI 0·26–4·90; p=0·88). No cases of symptomatic intracerebral haemorrhage were reported within 36 h with either treatment. Up to day 90, 13 serious adverse events were noted: five (5%) in patients treated with tenecteplase, and eight (8%) in patients treated with alteplase. Interpretation Treatment with tenecteplase on the MSU in Melbourne resulted in a superior rate of early reperfusion compared with alteplase, and no safety concerns were noted. This trial provides evidence to support the use of tenecteplase and MSUs in an optimal model of stroke care. Funding Melbourne Academic Centre for Health.