ANNALS OF EMERGENCY MEDICINE JOURNAL CLUB

Tenecteplase to Replace Alteplase? Comparing

Thrombolytic Therapies for Acute Ischemic Stroke
June 2023 Annals of Emergency Medicine Journal Club
Guest Contributors
Eriny Hanna, MD; Tyler W. Barrett, MD, MSCI
0196-0644/$-see front matter
Copyright © 2023 Published by Elsevier, Inc on behalf of the American College of Emergency Physicians
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Editor’s Note: Annals of Emergency Medicine Journal Club and 7 days; any intracranial, significant hemorrhagic event,
monthly provides a succinct review of high-impact articles from or death within 90 days.
this and other premier medical journals relevant to emergency Sponsors: China Shijiazhuang Pharmaceutical Company
medicine. The reviews are followed by questions demonstrating Recomgen Pharmaceutical (Guangzhou) and multiple
principles by which readers—be they clinicians, academics, Chinese national research foundations.
residents, or medical students—may critically appraise the
literature. We are interested in receiving feedback about this
How Did the Authors Interpret the Results?
feature. Please e-mail [email protected] with your
A total of 1430 patients were enrolled, with 716 patients
comments.
in the tenecteplase group and 714 in the alteplase group.
Median NIH stroke scale was 7 (interquartile range 6 to
ARTICLE IN REVIEW 10) and median time from stroke onset was approximately
Wang Y, Li S, Pan Y, et al. Tenecteplase versus alteplase 3 hours in both groups. Using modified intention-to-treat
in acute ischaemic cerebrovascular events (TRACE-2): A groups, authors found excellent neurologic outcome at 90
Phase 3, multicentre, open-label, randomised controlled, days (mRS 0 to 1) in 62% of patients who received
non-inferiority trial. Lancet. 2023;401(10377):645-654. tenecteplase and 58% of patients who received alteplase
Published correction appears in Lancet. (relative risk [RR] 1.07; 95% confidence interval [CI] 0.98
2023;401(10382):1078 to 1.16). The lower limit of the CI was more than the
noninferiority margin of 0.94. Symptomatic intracranial
What Question Did This Investigation Aim to Answer? hemorrhage occurred at similar rates (2% versus 2%; RR
In patients with acute ischemic stroke, is tenecteplase 1.18, 95% CI 0.56 to 2.50). There was no difference in
noninferior to alteplase for intravenous thrombolytic mortality at 90 days (7% versus 5%; RR 1.31, 95% CI
therapy? 0.86 to 2.01). The authors concluded tenecteplase was
noninferior and not superior to alteplase for acute ischemic
stroke.
What Study Design Did the Authors Choose?
Design: Open-label, blinded-endpoint randomized
controlled trial. How Might This Study Impact Your Clinical Practice
Setting: Fifty-three centers in China. in the Emergency Department?
Population: Adult patients within 4.5 hours of stroke Multiple meta-analyses and systematic reviews have
onset with National Institutes of Health (NIH) stroke scale concluded tenecteplase is as safe as alteplase, and associated
of 5 to 25, modified Rankin Scale (mRS) 0 or 1, and not with statistically significant odds of better clinical
initial candidates for endovascular thrombectomy. outcomes, including recanalization success, functional
Intervention: Tenecteplase (0.25 mg/kg, maximum 25 scores, and neurologic improvement without difference in
mg) versus alteplase (0.9 mg/kg, maximum 90 mg). bleeding complications.1-3 A recent study also
Primary Outcomes: Excellent functional outcome, demonstrated reduced workflow times and hospital cost
which is defined as mRS 0 or 1 at 90 days, and with use of tenecteplase.4 This study, TRACE-2, increases
symptomatic intracranial hemorrhage within 36 hours. the generalizability of the use of tenecteplase given the
Secondary Outcomes: Functional and quality-of-life study population was of a different ethnicity compared
outcomes at 90 days; improvement in NIHSS score at 1 with previous trials. The study’s major limitation was the

Volume 81, no. 6 : June 2023 Annals of Emergency Medicine 759

Journal Club Hanna & Barrett

exclusion of patients who had severe stroke who were after randomization, declined the study treatment and
eligible for thrombectomy, who may have increased risk of received the control or an alternative therapy) or missing
hemorrhagic conversion. However, taken together with data. An intention-to-treat analysis can lead to a false
other published studies, TRACE-2 supports the growing positive of noninferiority by narrowing the difference
evidence tenecteplase has a similar efficacy and safety profile between the treatments.7 The per-protocol groups included
compared with the Food and Drug all participants who completed the assigned thrombolytic
Administration–approved thrombolytic therapy for acute without major violation of the trial protocol (eg, excludes
ischemic stroke within 4.5 hours of onset. patients who did not receive the assigned study treatment)
or missing data for primary outcomes. This allows for more
DISCUSSION POINTS accurate comparison of the therapies as it reduces
confounding. However, a per-protocol analysis may include
1. How does tenecteplase differ from alteplase? fewer participants and introduce postrandomization bias.7
Like alteplase, tenecteplase breaks apart clots by Therefore, both the intention-to-treat and per-protocol
converting plasminogen to plasmin in clots. Tenecteplase data sets are important.
differs from alteplase in 3 amino acid structures, resulting
in higher fibrin selectivity and 3 times the half-life.5 This Section editors: Tyler W. Barrett MD, MSCI; Ryan P. Radecki, MD,
allows tenecteplase to be administered as a single bolus over MS; Rory J. Spiegel, MD MED.
5 seconds as compared with alteplase, which is given Author affiliations: Department of Emergency Medicine, Vanderbilt
partially as a bolus followed by an infusion for more than University Medical Center, Nashville, TN.
an hour.3,5 Tenecteplase also costs less to produce in several All authors attest to meeting the four ICMJE.org authorship
countries.4,5 criteria:(1) Substantial contributions to the conception or design of
2. What is an open-label, blinded-endpoint study design? the work; or the acquisition, analysis, or interpretation of data for
How does it compare with a double-blinded study? the work; AND (2) Drafting the work or revising it critically for
important intellectual content; AND (3) Final approval of the
An open-label describes a study in which providers and version to be published; AND (4) Agreement to be accountable for
patients know which study treatment is being administered. all aspects of the work in ensuring that questions related to the
Blinded endpoint means that clearly defined study endpoints accuracy or integrity of any part of the work are appropriately
are evaluated by an independent committee who are blinded investigated and resolved.
to study intervention assignments. This study design is
commonly coined Prospective Randomized Open Blinded
End-Point (PROBE) and has been used successfully in several REFERENCES
oral drug therapy studies.6 The disadvantages compared to a 1. Katsanos AH, Psychogios K, Turc G, et al. Off-label use of tenecteplase
for the treatment of acute ischemic Stroke: A systematic review and
double-blinded study are the risks of introducing biases in meta-analysis. JAMA Netw Open. 2022;5:e224506.
clinicians and patients as a consequence of awareness of study 2. Katsanos AH, Safouris A, Sarraj A, et al. Intravenous thrombolysis with
arm. This study design can be more cost-effective and may be tenecteplase in patients with large vessel occlusions: systematic review
more similar to clinical practice while the reliability of and meta-analysis. Stroke. 2021;52:308-312.
3. Potla N, Ganti L. Tenecteplase vs. alteplase for acute ischemic stroke: a
endpoint data collection remains preserved.6 systematic review. Int J Emerg Med. 2022;15:1.
3. The authors analyzed the data in modified intention-to- 4. Warach SJ, Dula AN, Milling TJ, et al. Prospective observational cohort
treat groups as well as per-protocol groups. What is the study of tenecteplase versus alteplase in routine clinical practice.
Stroke. 2022;53:3583-3593.
utility of presenting both of these analyses in 5. Nordt TK, Bode C. Thrombolysis: newer Thrombolytic Agents and their
noninferiority studies? role in clinical medicine. Heart. 2003;89:1358-1362.
Intention-to-treat groups included study participants 6. Hansson L, Hedner T, Dahlöf B. Prospective randomized open blinded
end-point (PROBE) study: a novel design for intervention trials. Blood
who were randomly assigned to and received the allocated Press. 1992;1:113-119.
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760 Annals of Emergency Medicine Volume 81, no. 6 : June 2023