Clinical benefit of tenecteplase despite failed recanalization in late-window ischemic stroke: a post hoc analysis of the TRACE-3 trial

BACKGROUND: The TRACE-3 trial established the efficacy of intravenous tenecteplase for patients with acute ischemic stroke and large vessel occlusion in the late time window. It remains unclear whether intravenous tenecteplase confers clinical benefits specifically in the subpopulation of patients who did not achieve successful large vessel recanalization. METHODS: This is a post-hoc analysis of the TRACE-3 trial, a multicenter randomized controlled trial comparing tenecteplase with standard medical therapy in patients with large vessel occlusion between 4.5 and 24 h of symptom onset. The analysis included participants who had failed recanalization (defined as an Arterial Occlusive Lesion [AOL] score of 0) on follow-up angiography at 24 h. Primary outcome of current study was functional independence (modified Rankin Scale [mRS] score 0-2) at 90 days. We assessed effect modification by baseline characteristics, including stroke severity (National Institutes of Health Stroke Scale [NIHSS]) and collateral circulation status. RESULTS: Among 288 patients with failed recanalization (123 in the tenecteplase group and 165 in the control group), tenecteplase was associated with a significantly higher rate of functional independence at 90 days compared with standard medical therapy (42.3% vs. 29.7%; adjusted risk ratio [RR] 1.37, 95% CI [Confidence Interval] 1.00-1.86, P = 0.048). Tenecteplase also resulted in greater reduction in NIHSS scores at 7 days (adjusted β 0.31, P = 0.028). A significant interaction was observed between treatment effect and baseline stroke severity (P for interaction = 0.02). The benefit of tenecteplase was significant in patients with moderate-to-severe stroke (NIHSS ≥ 10; RR 2.75, 95% CI 1.30-5.79) but not significant in those with minor-to-moderate stroke (NIHSS < 10). Collateral status did not significantly modify the treatment effect (P for interaction = 0.35). CONCLUSIONS: In patients with ischemic stroke treated in the late time window, tenecteplase was associated with improved functional outcomes despite persistent large vessel occlusion. Our findings suggest that tenecteplase may confer therapeutic efficacy through mechanisms beyond proximal arterial reopening. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05141305.