Intra-arterial verapamil post-thrombectomy is feasible, safe, and neuroprotective in stroke

Justin F. Fraser, Michael Maniskas, Amanda Trout, Doug Lukins, Lindsey Parker, W. Lane Stafford, Abdulnasser Alhajeri, Jill Roberts, Gregory J. Bix

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish
Pages (from-to)3531-3543
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume37
Issue number11
DOIs
StatePublished - Nov 1 2017

Bibliographical note

Publisher Copyright:
© 2017, © The Author(s) 2017.

Keywords

  • Ischemic stroke
  • emergent large vessel occlusion
  • neuroprotection
  • thrombectomy
  • verapamil

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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