N-acetylcysteine (NAC) as an adjunct to intravenous fibrinolysis in patients with acute ischemic stroke: a single group study (NAC-Safety).

Recombinant tissue plasminogen activator (alteplase) and its derivative tenecteplase are approved for acute ischemic stroke (AIS), but their low recanalization rates remain a limitation. Resistance to intravenous (IV) fibrinolysis may arise from platelet cross-linking during arterial thrombosis, mediated by von Willebrand factor (VWF) multimers. N-Acetylcysteine (NAC) has demonstrated potential to cleave large VWF multimers in preclinical studies, suggesting its potential as an adjunct therapy. The primary safety endpoint was the rate of symptomatic intracranial hemorrhagic (ICHs) transformation. Secondary endpoints included changes in circulating VWF multimer concentrations. We conducted a prospective, pilot, monocentric, single-arm phase IIa trial to evaluate the safety and effects of IV NAC (HIDONAC, 150 mg/kg) administered in adjunct of alteplase in AIS patients. The study was terminated early after enrolling 12 of the planned 19 patients due to the occurrence of two fatal ICHs among patients on prior antiplatelet therapy (17 %, exact 95 % confidence interval [2 % to 48 %]). Among the enrolled patients, 83 % (10/12) tolerated the combined NAC and alteplase therapy without severe adverse events. NAC administration resulted in a significant reduction in circulating large VWF multimers within hours of administration (-82 % for ULMWM-VWF, p < 0.001), aligning with preclinical findings. While NAC effectively cleaved circulating large VWF multimers in AIS patients, its combination with alteplase raises safety concerns, particularly in patients with a history of antiplatelet therapy.