What is the efficacy of tenecteplase for treating acute ischemic stroke in patients presenting between 4.5 to 24 hours after symptom onset?

PICO-Based Review: Tenecteplase for Acute Ischemic Stroke at 4.5 to 24 Hours

PICO Framework

Population: Adult patients with acute ischemic stroke presenting between 4.5 and 24 hours after symptom onset (or last known well)

Intervention: Intravenous tenecteplase (typically 0.25 mg/kg as single bolus)

Comparator: Standard care (no thrombolysis) or alteplase

Outcome: Functional outcomes (modified Rankin Scale), symptomatic intracranial hemorrhage, mortality

Current Guideline Framework

The use of tenecteplase beyond 4.5 hours is not currently supported by major stroke guidelines and should be considered investigational. The 2018 AHA/ASA guidelines establish that IV alteplase should not be administered to patients with ischemic stroke beyond 4.5 hours from last known well 1. The guidelines explicitly state that IV alteplase is not recommended in patients who have an unclear time or unwitnessed symptom onset when the time last known to be at baseline state is >4.5 hours (Class III: No Benefit) 1.

For tenecteplase specifically, the 2018 AHA/ASA guidelines note that tenecteplase at 0.4 mg/kg has not been proven superior or noninferior to alteplase but might be considered as an alternative to alteplase only in patients with minor neurological impairment and no major intracranial occlusion within the standard time window 1. Critically, there is no guideline support for tenecteplase use beyond 4.5 hours.

Pertinent Findings from Available Evidence

Evidence Supporting Extended Window Treatment

The most relevant recent evidence comes from a 2024 meta-analysis examining tenecteplase 0.25 mg/kg in the extended time window (>4.5 hours) 2. This systematic review included three randomized controlled trials comprising 556 patients treated with tenecteplase versus 560 controls presenting beyond 4.5 hours 2.

Key efficacy findings:

• Tenecteplase 0.25 mg/kg was associated with higher likelihood of excellent functional outcome at 3 months (mRS 0-1: RR 1.17,95% CI 1.01-1.36) 2
• No significant difference in good functional outcome (mRS 0-2: RR 1.05,95% CI 0.94-1.17) 2
• No significant difference in reduced disability across all mRS scores (adjusted common OR 1.14,95% CI 0.92-1.40) 2

Safety profile:

• Similar rates of symptomatic intracranial hemorrhage (RR 1.67,95% CI 0.70-4.00) 2
• Similar rates of any intracranial hemorrhage (RR 1.08,95% CI 0.90-1.29) 2
• Similar 3-month mortality (RR 1.10,95% CI 0.81-1.49) 2

Contradictory Evidence

A 2025 pooled analysis of the TETRIS and EVATRISP registries provides concerning observational data 3. This study compared 419 patients treated with tenecteplase 0.25 mg/kg versus 478 patients treated with alteplase 0.9 mg/kg, all presenting with last known well >4.5 hours 3.

Key findings suggesting caution:

• No significant difference in excellent functional outcome (mRS 0-1: PSOW-OR 0.92,95% CI 0.66-1.30), but the direction of effect did not favor tenecteplase 3
• Tenecteplase was associated with significantly higher odds of any intracranial hemorrhage (PSOW-OR 1.79,95% CI 1.25-2.57) 3
• The authors explicitly concluded that "the direction of the associations did not favor tenecteplase over alteplase" and recommended against routinely switching to tenecteplase in this population 3

Strengths of the Evidence Base

Methodological Rigor

• The 2024 meta-analysis by included only randomized controlled trials, providing Level B-R evidence 2
• Use of propensity score overlap weighting in the observational registry data attempted to control for confounding 3
• Consistent use of standardized outcome measures (modified Rankin Scale) across studies 2, 3

Clinical Relevance

• The studies address a genuine clinical need, as approximately 30-40% of stroke patients present beyond the 4.5-hour window 2
• Tenecteplase offers practical advantages with single-bolus administration versus 60-minute alteplase infusion 1, 4
• The 0.25 mg/kg dose has been consistently evaluated, providing dose-specific evidence 2, 5

Safety Monitoring

• Rigorous assessment of symptomatic intracranial hemorrhage using standardized definitions (ECASS III criteria) 2, 5
• Systematic evaluation of mortality outcomes 2, 3

Weaknesses and Critical Limitations

Fundamental Guideline Contradiction

The most significant weakness is that this approach directly contradicts Class III (No Benefit) guideline recommendations. The 2018 AHA/ASA guidelines explicitly state that IV thrombolysis should not be administered beyond 4.5 hours without advanced imaging selection 1. The evidence base for the extended window relies on trials that presumably used advanced imaging (MRI or perfusion CT) for patient selection 3, yet this critical selection criterion is not consistently reported or standardized across studies.

Limited Sample Size and Statistical Power

• The meta-analysis included only three RCTs with a total of 1,116 patients 2
• Individual trials were likely underpowered for safety endpoints, particularly symptomatic intracranial hemorrhage 2
• Wide confidence intervals for key safety outcomes (sICH RR 1.67,95% CI 0.70-4.00) indicate substantial uncertainty 2

Heterogeneity in Patient Selection

• The observational registry data showed 86.6% of patients had unknown stroke onset time 3
• Imaging selection criteria varied across studies and were not consistently specified 2, 3
• The ORIGINAL trial (2024) established tenecteplase noninferiority to alteplase within 4.5 hours 5, but this does not extrapolate to the extended window

Conflicting Safety Signals

• The meta-analysis showed no significant increase in any intracranial hemorrhage 2
• The larger observational study showed significantly higher odds of any ICH with tenecteplase (PSOW-OR 1.79,95% CI 1.25-2.57) 3
• This discrepancy between RCT and real-world data raises concerns about external validity

Lack of Mechanistic Justification

• The biological rationale for thrombolysis efficacy diminishes with time as the ischemic penumbra converts to infarction 1
• Pooled analysis of earlier trials showed declining benefit: OR 2.81 within 1.5 hours, 1.55 within 1.5-3 hours, 1.40 within 3-4.5 hours, and only 1.15 (non-significant) within 4.5-6 hours 1
• Extending to 24 hours without rigorous imaging selection lacks physiological support

Ongoing Uncertainty

• The EXIT-BT2 trial is actively recruiting to investigate tenecteplase between 4.5-6 hours, acknowledging that current evidence is insufficient 6
• The trial requires 1,440 patients to adequately test the superiority hypothesis, indicating current evidence is underpowered 6

Common Pitfalls and Clinical Caveats

Pitfall 1: Assuming Tenecteplase Equivalence Across Time Windows

Do not extrapolate the noninferiority of tenecteplase to alteplase within 4.5 hours 5 to the extended time window. The time-dependent nature of thrombolysis benefit is well-established 1, and the risk-benefit ratio fundamentally changes beyond 4.5 hours.

Pitfall 2: Treating Without Advanced Imaging

The registry data suggesting potential benefit used MRI or perfusion CT for patient selection 3. Administering thrombolysis beyond 4.5 hours without demonstrating salvageable penumbra on advanced imaging violates current guidelines 1 and lacks evidence support.

Pitfall 3: Ignoring the Increased Hemorrhage Risk

While the meta-analysis showed no significant increase in symptomatic ICH 2, the observational data demonstrated nearly 80% increased odds of any intracranial hemorrhage 3. The clinical significance of asymptomatic hemorrhage and its impact on long-term outcomes remains uncertain.

Pitfall 4: Misinterpreting "Extended Window" Studies

Most "extended window" studies focus on 4.5-6 hours 2, 6, not the full 4.5-24 hour range implied by the meta-analysis title. The evidence base becomes progressively weaker as time extends beyond 6 hours, with essentially no data supporting treatment at 12-24 hours without advanced imaging selection.

Clinical Algorithm for Decision-Making

For patients presenting 4.5-24 hours after last known well:

1. Confirm time window: Establish last known well time, not symptom discovery time 1

2. Assess for endovascular therapy candidacy: Patients with large vessel occlusion should be evaluated for mechanical thrombectomy, which has established benefit up to 24 hours with appropriate imaging selection 1

3. If considering IV thrombolysis beyond 4.5 hours:

   • Obtain advanced imaging (MRI with DWI/FLAIR or perfusion CT) to demonstrate salvageable tissue 3
   • Recognize this is off-guideline use and should ideally occur within a clinical trial 6
   • Consider tenecteplase only if alteplase would be considered, as tenecteplase data are even more limited 2
   • Obtain informed consent discussing the lack of guideline support and uncertain benefit-risk ratio

4. Prioritize proven therapies: Focus on rapid endovascular therapy for large vessel occlusion rather than extending thrombolysis time windows without strong evidence 1

Summary of Evidence Quality

The evidence for tenecteplase in the 4.5-24 hour window is Level B-R at best (limited RCT data) 2, but contradicts Class III guideline recommendations 1. The most recent and highest quality single study is the 2025 pooled registry analysis, which showed no benefit and increased hemorrhage risk with tenecteplase versus alteplase beyond 4.5 hours 3. This real-world evidence should temper enthusiasm generated by smaller RCTs with selected populations.

The ongoing EXIT-BT2 trial 6 acknowledges that current evidence is insufficient to change practice, and routine use of tenecteplase beyond 4.5 hours cannot be recommended based on available data. Any use in this time window should be considered investigational and ideally occur within the context of a clinical trial with appropriate imaging selection and informed consent.