Co-administration Of Fingolimod And Alteplase In Acute Ischemic Stroke Within 4.5-6h After Disease Onset:A Pilot Study

Objective: Rapid administration of intravenous recombinant tissue-type plasminogen activator(r-t PA)to appropriate patients remains the mainstay of early treatment of acute ischemic stroke.Timely restoration of blood flow in ischemic stroke patients is effective in reducing long term morbidity.“Time is penumbra”.Penumbra represents the potentially reversible brain tissue,and will inevitably evolve into irreversible infarcts with time without efficient reperfusion.Secondary inflammation,microvascular thrombosis,and disruption of the blood-brain barrier(BBB)all contribute to limiting the narrow therapeutic window for alteplase to 4.5 hours in acute ischemic stroke.Fingolimod attenuates microvascular thrombo-inflammation and increased blood flow during the reperfusion phase by reducing lymphocyte–endothelial cell–platelet interactions.We aim to investigate the efficiency and safety of combining treatment with fingolimod and alteplase within 4.5 to 6 hours from symptom onset in acute ischemic stroke patients.Methods: In this multi-center,phase 2,nonrandomized,evaluator-blind study,patients were assigned into three groups: control group(conventional treatment adhered to current American Heart Association guidelines),standard dose alteplase group(0.9 mg/kg),and fingolimod plus alteplase group(standard dose alteplase and oral fingolimod).Blood samples for lymphocyte and cytokine analysis were collected from all subjects at baseline,24 h,day 3 and day 7.All patients underwentpretreatment and 24-hour perfusion/angiographic imaging with CT,and no-contrast CT at 7 days.Eligibility criteria included the infarct core volume less than 80 ml,meanwhile the perfusion lesion on transit-time maps that was at least 20% greater than the infarct-core lesion,with a volume of at least 15 ml,with an intracranial anterior circulation occlusion.The co-primary end points were penumbra(defined as tissue with relative delay time(r DT)?3 seconds)salvage on 24 h and improvement in the National Institutes of Health Stroke Scale(NIHSS)score between baseline and 24h.Results: The fingolimod plus alteplase group exhibited greater penumbra salvage(66.8±42.5vs30.9±38.9m L,P=0.045)and greater clinical improvement(3.4±2.5vs1.1±2.8,P=0.04)at 24 h,as compared with the alteplase-only group.Long-term outcome,as assessed by modified Rankin Scale(m RS)at 90 days,was not significantly improved in comparison with alteplase group.There were no significant differences between control group and alteplase treated patients in primary and secondary outcomes,except improvement in NIHSS scores between baseline and day 7(-1.5±4.6vs4.6+4.0,P=0.002).The incidence of intracerebral hemorrhage and other serious adverse events was not different in patients receiving fingolimod plus alteplase versus alteplase alone.Conclusions: Combined treatment with fingolimod and alteplase within 4.5-6h after the onset of acute ischemic stroke was well tolerated,attenuated infarct expansion,and improved patients' clinical outcomes at 24 h.For confirmation,further controlled,randomized,large clinical trials are well-warranted.Classification of evidence: This study provides Class ? evidence that in patients with acute ischemic stroke,fingolimod extends the therapeutic time window to 6h of alteplase.