Highlights
The TRACE-5 trial provides robust evidence for the use of tenecteplase in late-window posterior circulation strokes. Key highlights include:
- Tenecteplase (0.25 mg/kg) significantly increased the proportion of patients achieving functional independence (mRS 0-1) at 90 days compared to standard medical treatment.
- The therapeutic benefit was observed within a broad window of up to 24 hours from symptom onset or last known well time.
- Safety profiles were comparable between groups, with no significant increase in symptomatic intracranial hemorrhage (sICH) or all-cause mortality.
- The findings support tenecteplase as a viable pharmacological intervention, both as a standalone therapy and as a bridge to endovascular thrombectomy in basilar artery occlusion (BAO).
Introduction: The Challenge of Basilar Artery Occlusion
Basilar artery occlusion (BAO) represents one of the most devastating forms of ischemic stroke, historically associated with mortality rates as high as 80-90% if recanalization is not achieved. Unlike anterior circulation strokes, which often present with clear hemispheric deficits, BAO can manifest with a wide spectrum of symptoms—ranging from isolated cranial nerve palsies to locked-in syndrome and coma—making early diagnosis challenging.
The therapeutic window for intravenous thrombolysis (IVT) in acute ischemic stroke has traditionally been restricted to 4.5 hours. While endovascular thrombectomy (EVT) has revolutionized the management of large vessel occlusions, its availability is often limited to comprehensive stroke centers. Furthermore, the evidence for IVT in the late window (beyond 4.5 hours) or specifically for BAO has been sparse compared to anterior circulation data. The TRACE-5 trial was designed to address this critical gap, evaluating whether tenecteplase, a genetically engineered variant of alteplase, could extend the window of benefit for these high-risk patients.
Evolution of Thrombolysis: Why Tenecteplase?
Tenecteplase (TNK-tPA) offers several pharmacological advantages over the traditional gold standard, alteplase. It possesses a higher fibrin specificity, which theoretically reduces the depletion of systemic fibrinogen and lowers the risk of bleeding complications. Additionally, tenecteplase has a longer half-life, allowing for a single-bolus administration rather than a continuous infusion. This makes it particularly attractive in the emergency setting and for ‘drip-and-ship’ protocols where rapid transfer to an intervention-capable center is required.
Prior studies, such as EXTEND-IA TNK, have suggested that tenecteplase may be superior to alteplase in achieving early recanalization in large vessel occlusions. The TRACE-5 trial builds upon this momentum, specifically targeting the posterior circulation and the extended 24-hour timeframe.
TRACE-5 Study Design and Methodology
TRACE-5 was a multicenter, prospective, randomized, open-label, blinded-endpoint, superiority, phase 3 trial conducted across 66 specialized stroke centers in China. The study aimed to provide a definitive comparison between tenecteplase and standard medical treatment (SMT) in the 24-hour window.
Patient Population and Inclusion Criteria
The trial enrolled 452 patients aged 18 years or older. Eligible participants had a confirmed stroke due to BAO and were within 24 hours of symptom onset or their last known well time. A key inclusion criterion was a pre-stroke modified Rankin scale (mRS) score of 3 or less, ensuring that the study population had a reasonable baseline functional status. Patients were required to be eligible for intravenous thrombolytics per the investigator’s assessment.
Intervention and Control Arms
Participants were randomly assigned in a 1:1 ratio to receive either:
- Tenecteplase Group: A single intravenous bolus of 0.25 mg/kg (maximum 25 mg).
- Standard Medical Treatment (SMT) Group: This included intravenous alteplase (0.9 mg/kg, max 90 mg) if within the 4.5-hour window, anticoagulation, or antiplatelet therapy.
Crucially, both groups were permitted to undergo endovascular thrombectomy (EVT) if indicated, reflecting real-world clinical practice where thrombolysis often serves as a bridge to mechanical intervention.
Primary and Secondary Endpoints
The primary efficacy outcome was a favorable functional outcome at 90 days, defined as an mRS score of 0-1 or a return to the baseline pre-stroke mRS score (for those who started with a score of 2-3). Safety endpoints included the incidence of symptomatic intracranial hemorrhage (sICH) within 36 hours and all-cause mortality at 90 days.
Results: Efficacy and Safety of Tenecteplase
Between January 2024 and June 2025, the trial successfully randomized 221 patients to the tenecteplase arm and 231 to the SMT arm. The mean age was 66.4 years, and approximately 71% were male. Notably, 49% of the total cohort underwent subsequent mechanical thrombectomy.
Primary Outcome: Functional Independence
The primary outcome was achieved in 38% (83/221) of patients in the tenecteplase group compared to 29% (66/231) in the SMT group. The adjusted relative rate (aRR) was 1.50 (95% CI 1.09-2.08, p=0.014). This represents a statistically significant and clinically meaningful improvement in functional recovery. The absolute risk difference suggests that for every 11 patients treated with tenecteplase instead of standard care, one additional patient achieves functional independence.
Safety Profile: sICH and Mortality
Safety is a paramount concern when extending the thrombolysis window. TRACE-5 demonstrated that tenecteplase did not compromise patient safety. Symptomatic intracranial hemorrhage within 36 hours occurred in only 2% (4/221) of the tenecteplase group versus 3% (7/231) in the SMT group (aRR 0.58, 95% CI 0.17-1.99). All-cause mortality at 90 days was also similar between the groups (29% vs. 31%), as was the proportion of patients with severe disability (mRS 5-6).
Subgroup Analyses and Procedural Context
Preliminary subgroup analyses indicated that the benefit of tenecteplase was consistent regardless of whether patients underwent subsequent EVT. This suggests that tenecteplase provides value both as a standalone treatment in centers without thrombectomy capabilities and as a bridging agent that may facilitate easier clot retrieval or reperfusion of microvasculature distal to the main occlusion.
Clinical Interpretation and Expert Commentary
The TRACE-5 results are poised to change the management paradigms for posterior circulation strokes. The traditional hesitation to use IVT in the late window is largely based on the fear of hemorrhagic transformation in infarcted tissue. However, the low sICH rate in TRACE-5 suggests that the posterior circulation may be more resilient or that the pharmacological profile of tenecteplase is particularly suited for this extended window.
Extending the Window: Biological Plausibility
The 24-hour window for BAO is biologically plausible due to the nature of the collateral circulation in the posterior fossa. The presence of robust collaterals can maintain a ‘penumbra’ of salvageable brainstem tissue for a longer duration than is typically seen in the middle cerebral artery territory. By providing a fibrin-specific thrombolytic in this window, clinicians can potentially salvage critical respiratory and motor pathways that would otherwise be lost to infarction.
Limitations and Generalizability
While the results are compelling, some limitations must be considered. The study was conducted entirely within a Chinese population, which may have a higher prevalence of intracranial atherosclerotic disease (ICAD) compared to Western populations. Whether these results translate directly to populations with more cardioembolic stroke etiologies remains to be confirmed. Additionally, the open-label design, while mitigated by blinded endpoint assessment, carries an inherent risk of bias in peri-procedural management.
Conclusion: A Shift in the Management of Posterior Circulation Stroke
The TRACE-5 trial marks a significant milestone in stroke neurology. By demonstrating that tenecteplase is both safe and effective for basilar artery occlusion up to 24 hours after onset, the study provides a powerful new tool for clinicians. As tenecteplase continues to replace alteplase in stroke protocols worldwide, the evidence from TRACE-5 suggests that we should be more aggressive in treating late-presenting posterior circulation occlusions.
Funding and Trial Registration
This study was funded by the Noncommunicable Chronic Diseases-National Science and Technology Major Project, the Beijing Municipal Science Fund for Distinguished Young Scholars, the National Natural Science Foundation of China, and China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou). The trial is registered with ClinicalTrials.gov, NCT06196320.
References
1. Xiong Y, 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 Feb 5. doi: 10.1016/S0140-6736(25)02633-9.
2. Campbell BCV, et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018;378(17):1573-1582.
3. Jovin TG, et al. Trial of Thrombectomy 6 to 24 Hours after Stroke due to Basilar-Artery Occlusion. N Engl J Med. 2022;387(15):1373-1384.