Effects of Antioxidant DI-3-N-Butylphthalide on Hemorrhagic Transformation Assessed by Propensity Score Matching in a...

Hemorrhagic transformation (HT) remains a major complication limiting the clinical utility of intravenous thrombolysis with alteplase in acute ischemic stroke (AIS) patients. Dl-3-N-butylphthalide (dl-NBP), a neuroprotective agent, which has beneficial effects on post-ischemic microcirculation, oxidative stress, and blood-brain barrier integrity, may potentially mitigate this risk.

Using propensity score matching (1:1), this study analyzed 1,541 AIS patients of the prospective Dalian Single-center Study on Intravenous Thrombolysis for Ischaemic Stroke (DATIS) cohort treated at Central Hospital of Dalian University of Technology. Patients were stratified into combination therapy (alteplase + dl-NBP, n = 674) and monotherapy (alteplase alone, n = 674) groups. Dl-NBP (25 mg in 100 ml, 0.9% saline) was administered within 12 h after admission and followed by twice-daily doses of the same fomulation during hospitalization in the combination therapy group. Primary outcomes included the incidence of HT assessed post-thrombolysis and symptomatic intracranial hemorrhage (sICH) defined as radiographic hemorrhage occurring within 7 days post-thrombolysis and accompanied by clinical deterioration or an increase in NIHSS score ≥ 4 points. Neurological deficits at admission and at discharge were assessed using the National Institutes of Health Stroke Scale (NIHSS).

After propensity score matching (674 patients combination therapy vs. 674 patients monotherapy), baseline characteristics were balanced (p > 0.05 for all influence variables). The alteplase + dl-NBP combination therapy group demonstrated significantly lower HT rates (2.2% vs. 6.7%, p < 0.001) and sICH incidence (0.9% vs. 3.4%, p < 0.001) than the alteplase monotherapy group. Multivariate analysis identified dl-NBP adjuvant as protective against HT (OR = 0.32, 95%CI: 0.18-0.58), while fasting glucose (OR = 1.10) and high-density lipoprotein levels (OR = 2.25) were independent risk factors. The percentage of patients exhibiting NIHSS improvements during hospitalization was significantly increased in combination therapy group compared with monotherapy group (60.8 vs. 55.3%, p = 0.041). Hospitalization costs were slightly higher in the combination therapy group (¥20,781 vs. ¥19,771, p < 0.001).

Early adjunctive dl-NBP administration in addition to alteplase-induced thrombolysis significantly reduces hemorrhagic complications. To our knowledge, this is the first large-scale real-world study to demonstrate that dl-NBP reduces the risk of post-thrombolytic brain hemorrhage, supporting its antioxidant benefits in a clinical setting.