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

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 (LD 50 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.

Verapamil is an adjunct therapy to reduce tPA toxicity in hyperglycemic stroke: implication of TXNIP/NLRP3 inflammasome

“…On the other hand, in a phase I clinical trial the safety and efficacy of adjuvant verapamil administered IA post-thrombectomy did not change the incidence of intracranial hemorrhage (Fraser et al, 2017). However, upon reproducing a comparable preclinical set up, we found a notable mitigation in hemorrhagic transformation with addition of IV verapamil.…”

Drug Development for Central Nervous System Diseases Using In vitro Blood-brain Barrier Models and Drug Repositioning

“…Furthermore, these trials used various forms of pre-thrombectomy imaging criteria and/or time limitations to exclude patients with significant infarcted cores. Thus, while clinical outcomes continue to lag behind the high rates of technical success, there may be an opportunity to use adjuvant neuroprotectants to extend the window for intervention or to reverse damage that is currently viewed as unsalvageable based on radiographic imaging alone, thereby increasing the number of patients eligible for thrombectomy [ 220 ]. Considering these facts, combining neuroprotection with intravenous or intra-arterial reperfusion therapy is now an important next step in the development of acute stroke therapies.…”

“…Mechanical thrombectomy is now at the forefront of the treatment of large-vessel acute ischemic stroke [ 221 ]. Selective intra-arterial access has opened a new avenue for neuroprotection in acute ischemic stroke that has the potential to maximize the local benefits while minimizing systemic effects [ 220 , 221 ].…”

“…In animal models of acute ischemic stroke, verapamil, nitroglycerin, erythropoietin, and platelet-rich plasma have been evaluated via the intra-arterial route [ 220 , 222 , 223 ]. Among them, one possible candidate neuroprotectant for stroke therapy, verapamil, a calcium channel blocker, was an effective intra-arterial adjunct in a preclinical mouse focal ischemia model [ 220 , 221 ]. Fraser et al .…”

“…Furthermore, they have already conducted a human Phase I trial, Superselective Administration of Verapamil During Recanalization in Acute Ischemic Stroke (SAVER-I), to evaluate the feasibility and safety of the drug’s administration in the human disease. The SAVER-I clinical trial showed no evidence that IA verapamil increased the risk of intracranial hemorrhage or other adverse effects/procedural complications in human subjects [ 220 ]. Since mechanical thrombectomy is now the gold standard for acute ischemic stroke treatment, neuroprotective strategies via the intra-arterial route are highly anticipated.…”