Intra-Arterial Verapamil Post-Thrombectomy Is Feasible, Safe, and Neuroprotective in Stroke

Authors

Justin F. Fraser, University of KentuckyFollow
Michael E. Maniskas, University of KentuckyFollow
Amanda L. Trout, University of KentuckyFollow
Douglas E. Lukins, University of KentuckyFollow
Lindsey Parker, University of KentuckyFollow
W. Lane Stafford, University of Kentucky
Abdulnasser Alhajeri, University of KentuckyFollow
Jill Roberts, University of KentuckyFollow
Gregory J. Bix, University of KentuckyFollow

Abstract

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.

Document Type

Article

Publication Date

11-1-2017

Notes/Citation Information

Published in Journal of Cerebral Blood Flow and Metabolism, v. 37, issue 11.

© The Author(s) 2017

Digital Object Identifier (DOI)

https://doi.org/10.1177/0271678x17705259

Funding Information

This publication was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR001998.

Repository Citation

Fraser, Justin F.; Maniskas, Michael E.; Trout, Amanda L.; Lukins, Douglas E.; Parker, Lindsey; Stafford, W. Lane; Alhajeri, Abdulnasser; Roberts, Jill; and Bix, Gregory J., "Intra-Arterial Verapamil Post-Thrombectomy Is Feasible, Safe, and Neuroprotective in Stroke" (2017). Neurosurgery Faculty Publications. 11.
https://uknowledge.uky.edu/neurosurgery_facpub/11