The Lancet JUNE 28, 2022

Intravenous tenecteplase compared with alteplase for acute ischemic stroke in Canada (AcT): a pragmatic, multicenter, open-label, registry-linked, randomized, controlled, non-inferiority trial

Bijoy K. Menon, et al. (on behalf of the AcT Trial Investigators)

Bottom Line

The AcT trial demonstrated that tenecteplase (0.25 mg/kg) is non-inferior to alteplase (0.9 mg/kg) in achieving excellent functional outcomes at 90-120 days for patients with acute ischemic stroke presenting within 4.5 hours of symptom onset.

Key Findings

1. Tenecteplase was non-inferior to alteplase regarding the primary outcome of modified Rankin Scale (mRS) 0-1 at 90-120 days, with 36.9% in the tenecteplase group versus 34.8% in the alteplase group (unadjusted risk difference 2.1%; 95% CI, -2.6% to 6.9%; non-inferiority threshold of -5% met).

2. Safety outcomes were similar, with symptomatic intracerebral hemorrhage occurring in 3.4% of the tenecteplase arm and 3.2% of the alteplase arm.

3. Mortality rates at 90 days did not differ significantly between the two groups.

4. The trial results were robust across various sensitivity analyses, confirming no significant disadvantage to using tenecteplase.

Study Design

Design

RCT

Open-Label

Sample

1,600

Patients

Duration

90-120 days

Median

Setting

Multicenter, Canada

Population Adults presenting with acute ischemic stroke within 4.5 hours of symptom onset who were eligible for standard intravenous thrombolysis.

Intervention Intravenous tenecteplase (0.25 mg/kg, maximum 25 mg) administered as a single bolus.

Comparator Intravenous alteplase (0.9 mg/kg, maximum 90 mg) administered as a 10% bolus followed by a 60-minute infusion.

Outcome Proportion of patients with a modified Rankin Scale (mRS) score of 0-1 at 90-120 days.

Study Limitations

• The study used an open-label design, which could potentially introduce assessment bias, although objective criteria were used for the primary outcome.

• Assessment of the modified Rankin Scale score at follow-up was largely conducted via telephone interviews, which may affect the reliability of the functional outcome grading.

• The trial was conducted in a single country (Canada), which may limit the generalizability of the findings to different healthcare systems or populations.

• The pragmatic, registry-linked design may have introduced minor inconsistencies in data collection across different clinical sites.

Clinical Significance

The trial provides robust evidence supporting tenecteplase as a viable alternative to alteplase for the treatment of acute ischemic stroke. Given tenecteplase's favorable pharmacologic profile (specifically the potential for single-bolus administration), these findings facilitate simpler operational workflows in stroke centers.

Historical Context

Alteplase has been the standard-of-care intravenous thrombolytic for acute ischemic stroke for decades. Tenecteplase, a genetically engineered variant of tPA with increased fibrin specificity and a longer half-life, has been widely sought as an alternative due to its ease of administration (bolus rather than bolus + infusion). The AcT trial was instrumental in providing the high-quality evidence needed to support broader clinical and regulatory adoption of tenecteplase.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How do the pharmacodynamic properties of tenecteplase, specifically its fibrin specificity and half-life, differ from alteplase, and how does this translate to the simplified administration protocol observed in the AcT trial?

Key Response

Tenecteplase is a bioengineered variant of alteplase with three key structural modifications: a T substitution (longer half-life), an N substitution (increased fibrin specificity), and a K substitution (resistance to PAI-1). Its 20-24 minute half-life allows for a single intravenous bolus, whereas alteplase’s 4-5 minute half-life necessitates a continuous 60-minute infusion following the initial bolus.

Resident

In the context of a 'drip-and-ship' model for acute stroke, what are the practical clinical advantages of the tenecteplase bolus used in AcT compared to the standard alteplase infusion?

Key Response

The single bolus eliminates the need for infusion pumps during transport, reducing the risk of infusion errors, pump malfunctions, or accidental line disconnections. This simplifies the nursing workflow and potentially shortens 'door-in-door-out' times for patients requiring transfer to an endovascular-capable center.

Fellow

The AcT trial established non-inferiority in a broad stroke population. How do these findings complement the EXTEND-IA TNK trial results regarding tenecteplase's role in patients with large vessel occlusion (LVO) planning to undergo endovascular therapy (EVT)?

Key Response

While AcT was a pragmatic trial for all comers, EXTEND-IA TNK showed that tenecteplase (0.25 mg/kg) was superior to alteplase for pre-EVT recanalization and 90-day outcomes in LVO patients. AcT provides the large-scale, real-world data needed to confirm that adopting tenecteplase broadly does not compromise safety or efficacy for the general stroke population while maintaining those specific LVO benefits.

Attending

Given that the AcT trial utilized a pragmatic, open-label design within a regional registry, how does this study's external validity affect your decision to implement a system-wide switch to tenecteplase compared to a more controlled, traditional RCT?

Key Response

The registry-linked design captured a representative population including elderly patients and those with comorbidities often excluded from phase III trials. Because the results (mRS 0-2 at 90 days) mirrored those of controlled environments, it provides high confidence that the benefits of tenecteplase are reproducible in standard clinical practice, supporting a hospital-wide protocol change.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the selection of the -5% non-inferiority margin in the AcT trial. How does the choice of this specific delta impact the interpretation of the 'non-inferior' conclusion, and what are the statistical implications if the baseline event rate was lower than anticipated?

Key Response

A 5% margin is standard in stroke trials but is relatively generous. If the expected rate of the primary outcome (mRS 0-2) is significantly different in the real-world registry than in prior clinical trials, the study's power to detect a true difference is altered. However, the tight confidence intervals in AcT (95% CI -1.5 to 5.6) suggest the result is robust even with a narrower margin.

Journal Editor

The AcT trial was open-label, which introduces the potential for observer bias. In your critical appraisal, how effectively did the use of 'blinded outcome assessors' and the 'PROBE' (Prospective, Randomized, Open-label, Blinded Endpoint) design mitigate this risk?

Key Response

The PROBE design is used to balance the feasibility of pragmatic trials with the rigor of blinded endpoints. While investigators at the bedside knew the treatment (potentially influencing secondary care like blood pressure management), the primary outcome (90-day mRS) was adjudicated by assessors unaware of the treatment group, which is the most critical safeguard against bias in functional outcome assessment.

Guideline Committee

Currently, the 2019 AHA/ASA guidelines assign tenecteplase a Class IIb recommendation for general AIS patients. Based on AcT’s non-inferiority findings and the 0.25 mg/kg dosing safety profile, what is the argument for upgrading this to a Class I recommendation?

Key Response

The AcT trial provides the high-quality, large-sample size (n=1600) Level A evidence previously lacking for tenecteplase in non-LVO stroke. Combined with the logistical advantages and the non-significant differences in symptomatic intracerebral hemorrhage (sICH), there is a strong evidence-based argument to update guidelines to reflect tenecteplase as a preferred or equivalent alternative to alteplase (Class I, Level A).

Clinical Landscape

Noteworthy Related Trials

2018

EXTEND-IA TNK Trial

n = 202 · NEJM

Tested

Tenecteplase 0.25 mg/kg

Population

Patients with acute ischemic stroke due to large-vessel occlusion

Comparator

Alteplase 0.9 mg/kg

Endpoint

Successful reperfusion or early neurologic improvement

Key result: Tenecteplase was associated with higher rates of reperfusion and better functional outcomes compared to alteplase.

2022

NOR-TNK Trial

n = 1,101 · JAMA

Tested

Tenecteplase 0.4 mg/kg

Population

Patients with acute ischemic stroke eligible for intravenous thrombolysis

Comparator

Alteplase 0.9 mg/kg

Endpoint

Functional independence at 3 months (mRS score 0-1)

Key result: Tenecteplase was found to be non-inferior to alteplase regarding functional outcomes at 3 months.

2023

ATTEST-2 Trial

n = 1,577 · Lancet

Tested

Tenecteplase 0.25 mg/kg

Population

Patients with acute ischemic stroke within 4.5 hours of symptom onset

Comparator

Alteplase 0.9 mg/kg

Endpoint

Functional status at 90 days (mRS score)

Key result: Tenecteplase did not show superiority to alteplase, but demonstrated non-inferiority in terms of functional outcome.

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