Infarct Growth Rate and Tenecteplase Benefit in Ischemic Stroke at 4.5 to 24 Hours Without Thrombectomy ——A Secondary Analysis of the TRACE-Ⅲ Randomized Trial

Background: We aimed to explore whether the benefits of tenecteplase within 4.5-24 hours would be modified by the infarct growth rate (IGR). Methods: This study is a secondary analysis of the Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events–Ⅲ (TRACE-Ⅲ) trial, a phase 3, multicenter, prospective, open-label, randomized, blinded-outcome-assessment trial. In the TRACE-Ⅲ trial, patients with large-vessel occlusion at 4.5 to 24 hours without thrombectomy were enrolled at 58 centers in China and randomly assigned to receive 0.25 mg/kg tenecteplase or standard medical treatment. Of these, patients with witnessed stroke onset time were analyzed. IGR was calculated as baseline ischemic core volume divided by time since onset. The primary outcome was modified Rankin scale (mRS) 0-1 at 90 days. The treatment effect of tenecteplase versus standard medical treatment was assessed in 2 groups based on the median IGR cut point. A multiplicative interaction term for IGR*treatment was used to test for effect modification. Results: In 292 eligible patients, the median IGR was 1.4 ml/hour. 146 patients with IGR＜1.4 ml/hour were classified as ultraslow IGR (Tenecteplase, 70; Standard medical treatment, 76) and 146 patients with IGR≥1.4 ml/hour were classified as slow IGR (Tenecteplase, 73; Standard medical treatment, 73). The rate of no disability (mRS≤1) was significantly increased with tenecteplase in slow progressors (34.2% vs 15.1%; OR=2.94, 95% CI 1.32 to 6.55; P=0.009). The functional status was similar in ultraslow progressors (mRS 0-1: 37.1% vs 35.5%; OR=1.07, 95% CI 0.55 to 2.11; P=0.84). A P-value for interaction between IGR and treatment was 0.06. The incidence of sICH and mortality did not differ significantly between two treatment regimens in the IGR groups. Conclusion: Patients with late-window ischemic stroke who are not eligible for endovascular thrombectomy may derive greater benefit from tenecteplase compared with standard medical treatment among those with relatively faster infarct growth, although this finding should be considered exploratory. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT 05141305.