Intra-arterial verapamil post-thrombectomy is feasible, safe, and neuroprotective in stroke.
Large vessel ischemic stroke represents the most disabling subtype. While t-PA and endovascular thrombectomy can recanalize the occluded vessel, good clinical outcomes are not uniformly achieved. We propose that supplementing endovascular thrombectomy with superselective intra-arterial (IA) verapamil immediately following recanalization could be safe and effective. Verapamil, a calcium channel blocker, has been shown to be an effective IA adjunct in a pre-clinical mouse focal ischemia model. To demonstrate translational efficacy, mechanism, feasibility, and safety, we conducted a group of translational experiments. We performed in vivo IA dose-response evaluation in our animal stroke model with C57/Bl6 mice. We evaluated neuroprotective mechanism through in vitro primary cortical neuron (PCN) cultures. Finally, we performed a Phase I trial, SAVER-I, to evaluate feasibility and safety of administration in the human condition. IA verapamil has a likely plateau or inverted-U dose-response with a defined toxicity level in mice (LD50 16-17.5 mg/kg). Verapamil significantly prevented PCN death and deleterious ischemic effects. Finally, the SAVER-I clinical trial showed no evidence that IA verapamil increased the risk of intracranial hemorrhage or other adverse effect/procedural complication in human subjects. We conclude that superselective IA verapamil administration immediately following thrombectomy is safe and feasible, and has direct, dose-response-related benefits in ischemia.
['Fraser|Justin F|JF|', 'Maniskas|Michael|M|', 'Trout|Amanda|A|', 'Lukins|Doug|D|', 'Parker|Lindsey|L|', 'Stafford|W Lane|WL|', 'Alhajeri|Abdulnasser|A|', 'Roberts|Jill|J|', 'Bix|Gregory J|GJ|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D000818:Animals D000889:Anti-Arrhythmia Agents D002545:Brain Ischemia D016923:Cell Death D002478:Cells, Cultured D004305:Dose-Response Relationship, Drug D005260:Female D006801:Humans D002534:Hypoxia, Brain D007269:Injections, Intra-Arterial D008297:Male D008810:Mice, Inbred C57BL D008875:Middle Aged D016501:Neurites D018696:Neuroprotective Agents D061251:Primary Cell Culture D020521:Stroke D017131:Thrombectomy D016896:Treatment Outcome D014700:Verapamil
verapamil neuroprotection Ischemic stroke thrombectomy emergent large vessel occlusion