Neutrophil to Lymphocyte Ratio and Neurological Outcome in Ischemic Stroke at 4.5 to 24 Hours: A Post Hoc Analysis of TRACE-III Trial

INTRODUCTION: Whether neutrophil to lymphocyte ratio (NLR), as a marker of increased inflammatory response, modifies the efficacy and safety of tenecteplase is uncertain in patients 4.5-24 h after stroke onset. We investigated this in the Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events-III (TRACE-III) trial. METHODS: TRACE-III was a phase 3, multicenter, prospective, open-label, randomized, blinded-endpoint trial that enrolled 516 patients from 58 centers in China between January 2022 and November 2023. Patients had anterior large vessel occlusion and evidence of salvageable brain tissue on perfusion imaging, presented 4.5-24 h after symptom onset, and were randomized 1:1 to intravenous tenecteplase (intervention) or standard medical treatment (control). The primary efficacy and safety outcomes were modified Rankin scale score of 0-1 at 90 days and symptomatic intracranial hemorrhage or death, respectively. This post hoc analysis in 513 patients with complete admission NLR data compared outcomes in patients with elevated NLR (> first quartile) and non-elevated NLR (≤ first quartile). RESULTS: In the elevated NLR group (> 3.0), tenecteplase was associated with increased functional independence (61 [30.2%] vs. 36 [19.6%]; adjusted relative rate [aRR] 1.51; 95% confidence interval [CI] 1.05-2.17; P = 0.03) compared to standard medical treatment. This benefit was not observed in the non-elevated NLR group (26 [41.9%] vs. 25 [38.5%]; aRR 1.12; 95% CI 0.73-1.73). Safety outcomes did not differ in either the elevated or non-elevated NLR groups. CONCLUSION: Baseline NLR may provide a potential signal for differential treatment response to intravenous tenecteplase in patients with acute ischemic stroke, although these exploratory findings require further validation in independent studies. TRIAL REGISTRATION: TRACE-III is registered with ClinicalTrials.gov, NCT05141305.