TRACE-5 — Tenecteplase for Basilar Artery Occlusion within 24h

1. Publication

• Title: Tenecteplase versus standard medical treatment for basilar artery occlusion within 24 h
• Acronym: TRACE-5
• Year & Journal: The Lancet, published February 5, 2026 (2026;407(10530):763-772)
• Citation: Xiong Y, Alemseged F, Cao Z, et al. Tenecteplase versus standard medical treatment for basilar artery occlusion within 24 h (TRACE-5): a multicentre, prospective, randomised, open-label, blinded-endpoint, superiority, phase 3 trial. Lancet. 2026;407(10530):763-772. doi:10.1016/S0140-6736(25)02633-9

2. Context & Rationale

Background: Basilar artery occlusion (BAO) accounts for ~1% of all strokes but is among the most devastating, with mortality/disability rates reaching 80–90% without recanalization. Thrombolysis is established within 4.5h and EVT benefits select cases in the extended window, but randomized evidence on IV thrombolysis beyond the conventional 0–4.5h window was scarce for BAO specifically. Tenecteplase's higher fibrin specificity and longer half-life (vs alteplase) made it an attractive candidate for extended-window use.

Research Question/Hypothesis: In patients with BAO presenting within 24 hours of symptom onset, does IV tenecteplase improve functional outcome compared with standard medical treatment?

Why This Matters: Randomized evidence for pharmacologic reperfusion in BAO outside the conventional window was essentially absent; a positive result would extend a simple, widely deployable treatment (IV thrombolysis) to a much larger time window for one of the deadliest stroke subtypes, including in endovascular-limited settings.

3. Design & Methods

• Study Type: Prospective, randomized, open-label, blinded-endpoint, superiority, phase 3 trial
• Setting & Centers: 66 stroke centers, China
• Population:
• Inclusion: Confirmed BAO, presenting within 24h of onset
• Exclusions: Intracerebral hemorrhage, extensive ischemic changes (posterior circulation ASPECTS <6), significant cerebellar mass effect, acute hydrocephalus, clear hypodensity on noncontrast CT, bilateral extensive brainstem ischemia
• Intervention: IV tenecteplase (with or without subsequent EVT, per standard practice)
• Comparator: Standard medical treatment (no tenecteplase)
• Blinding: Open-label treatment, blinded outcome assessment
• Statistical Power & Follow-Up: 452 patients randomized. Primary outcome: mRS 0–1 or return to baseline mRS at 90 days.

4. Key Results

5. Internal Validity Assessment

• Randomization & Allocation: Randomized across 66 centers; specific allocation-concealment mechanics not detailed in available trial text.
• Protocol Adherence & Separation: Open-label drug administration with blinded endpoint assessment — meaningfully reduces detection bias for the functional-outcome primary endpoint despite unblinded treatment delivery.
• Blinding & Detection Bias: Blinded-endpoint design is a genuine methodological strength for an open-label drug trial.
• Missing Data & Sensitivity Analyses: Not detailed in available trial text; per independent commentary, several secondary endpoints did not reach significance, an important nuance alongside the positive primary result.
• Overall Internal Validity Conclusion: Moderate-to-good — blinded-endpoint assessment strengthens an open-label design; the positive primary result (38% vs 29%, NNT~11) is a meaningful effect size, though the mixed secondary-endpoint picture warrants some caution before treating the result as unambiguous across every outcome domain.

6. External Validity Assessment

• Population Representativeness: Single-ethnicity Chinese population; specific BAO imaging-based exclusions (extensive ischemic change, mass effect, hydrocephalus) narrow the target population to those without contraindicating imaging features.
• Practice Context: The tenecteplase formulation used is a Chinese biosimilar not available outside China; no perfusion imaging was required for inclusion, which may aid generalizability to centers without advanced imaging, but the specific drug formulation limits direct practice transfer elsewhere.
• Overall External Validity Conclusion: Moderate — meaningful for Chinese and similar health systems, and methodologically informative globally, but the specific biosimilar tenecteplase formulation and single-ethnicity population limit direct generalizability to other regions without confirmatory data using globally available tenecteplase formulations.

7. Strengths & Limitations

Strengths:

• Large (452-patient), well-powered superiority trial addressing a genuine evidence gap (extended-window BAO thrombolysis)
• Blinded-endpoint assessment strengthens an otherwise open-label design
• Meaningful effect size (NNT~11) with no apparent increase in symptomatic hemorrhage or mortality
• Extends treatment options to endovascular-limited settings, not just EVT-capable centers

Limitations:

• Single-ethnicity Chinese population
• Biosimilar tenecteplase formulation only available in China
• No perfusion imaging used for selection
• Several secondary endpoints did not reach statistical significance despite the positive primary result

8. Interpretation & Practice Impact

• Clinical Implications: Supports IV tenecteplase up to 24 hours after BAO onset in both EVT-capable and EVT-limited settings, per the lead investigator — a potentially significant expansion of treatment options for one of the most lethal stroke subtypes.
• Mechanistic Coherence: Consistent with tenecteplase's established pharmacological advantages (higher fibrin specificity, longer half-life) over alteplase, though this trial did not directly compare the two agents.
• Systems-Level Takeaway: Could meaningfully extend thrombolytic treatment access to BAO patients in settings without endovascular capability, pending confirmation with globally available tenecteplase formulations.

9. Controversies & Subsequent Evidence

• Editorial Commentary: An accompanying Lancet commentary (Tsivgoulis et al.) addresses the trial's implications alongside the broader extended-window BAO literature.
• Contrasting evidence: The separate ATTENTION-LATE trial, examining tenecteplase bridging before EVT in late-window BAO (a different clinical question — pharmacologic bridging prior to mechanical thrombectomy, not thrombolysis alone vs standard care), found no functional benefit from adding tenecteplase before EVT (mRS 0–2 at 90 days: 30.3% vs 30.5%; adjusted RR 0.92, 95% CI 0.67–1.25). This suggests tenecteplase's benefit in BAO may depend heavily on whether it is used as a standalone extended-window thrombolytic (TRACE-5's question, positive) versus as a bridging agent before EVT (ATTENTION-LATE's question, negative) — an important distinction for guideline interpretation.
• Guideline Integration: Not yet reflected in major international guidelines at time of this handbook's compilation; represents an active, evolving area given the contrast between TRACE-5 (positive, standalone) and ATTENTION-LATE (negative, bridging) results.

10. Summary & Executive Takeaway

Summary: TRACE-5 randomized 452 Chinese patients with BAO presenting within 24 hours to IV tenecteplase or standard medical treatment. Excellent functional outcome (mRS 0–1) at 90 days was achieved in 38% vs 29% (NNT~11), with no significant increase in symptomatic hemorrhage or mortality, though several secondary endpoints did not reach significance.

Overall Takeaway: TRACE-5 supports extending IV tenecteplase to 24 hours after BAO onset as a standalone thrombolytic strategy, a potentially important treatment expansion especially for EVT-limited settings — but this should be distinguished from the separate, negative finding for tenecteplase as an EVT-bridging agent in the late window (ATTENTION-LATE), and confirmation with globally available tenecteplase formulations in non-Chinese populations would strengthen generalizability.

11. Bibliography

• Langezaal LCM, van der Hoeven EJRJ, Mont'Alverne FJA, et al. Endovascular therapy for stroke due to basilar-artery occlusion. N Engl J Med. 2021;384:1910-1920.
• Nogueira RG, Jovin TG, Liu X, et al. Endovascular therapy for acute vertebrobasilar occlusion (VERITAS): systematic review and IPD meta-analysis. Lancet. 2025;405:61-69.
• ATTENTION-LATE Investigators. Tenecteplase bridging before EVT in late-window basilar artery occlusion. Presented at ISC 2026.