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 (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.

Keywords: Ischemic stroke; emergent large vessel occlusion; neuroprotection; thrombectomy; verapamil.

Figure 1.

In vivo dose–response experiments to evaluate IA verapamil. (a) Infarct volume was mapped against the dose-dependent mortality. All animals died at 17.5 mg/kg, with an estimated LD₅₀ between 16 and 17.5 mg/kg. Infarct volume reduction demonstrated a likely plateau or inverted-U curve in dose-dependent efficacy up to the mortality curve. Examples of NeuN immunohistochemistry and TTC infarct volumes are shown (NeuN green fluorescence; TTC white is ischemia) (b) and plotted (c), demonstrating an expected inverse relationship between reduction of infarct volume with verapamil and improvement in NeuN staining that matches.

Figure 2.

Verapamil promotes cell survival and preservation of neurons after administration immediately following exposure to 30 min of OGD. An example shows the process of labeling each neuron to count the dendritic branches (a). OGD significantly reduced neuron survival, as well as dendritic branching in all levels (b). Addition of verapamil, in an increasing dose–response manner, resulted in rescuing of some neurons from the effects of OGD (c). Examples of the damaging effect of OGD and neuroprotective effect of verapamil can be seen (d).

Figure 3.

Enrollment schedule for the SAVER-I Study. Eleven subjects were successfully enrolled of 104 eligible patients. Of the 93 patients not enrolled, 31 also received 10 mg of IA verapamil outside the study protocol, while 62 did not; there was no significant difference in the rate of significant intracranial hemorrhage between those groups.

Figure 4.

Illustrations demonstrating the study protocol. This includes performing the thrombectomy (the illustration shows a stent-triever device) (a) followed by microcatheter navigation to the site of the thrombus and infusion of the study agent (b).

Figure 5.

Case illustration of a study subject. A 32-year-old male smoker with migraine, diabetes, and hyperlipidemia presented with last known normal time of 0830 with an NIH Stroke Scale of 18 (aphasia, right hemisensory loss, and right hemiparesis). The subject received intravenous t-PA. CTA (a) and angiography demonstrated a left ICA distal occlusion extending to the MCA, with a CTA collateral score of 1. He underwent TICI 3 recanalization via thrombectomy approximately 3.5 h after last known normal (b). IA verapamil was administered per study protocol. Postoperative MRI demonstrated a small stroke (34.2 cc) limited to the basal ganglia (c). The subject was discharged to acute rehabilitation, and had an mRS score of 1 at 90 days.