Quantifying the amount of greater brain ischemia protection time with pre-hospital vs. in-hospital neuroprotective agent start

But does nerinetide even work?

This from February 2020 says it failed:

Hopes for Novel Stroke Drug Dashed in Trial

The latest here:

Quantifying the amount of greater brain ischemia protection time with pre-hospital vs. in-hospital neuroprotective agent start

Vartan Matossian^1*, Sidney Starkman², Nerses Sanossian³, Samuel Stratton⁴, Marc Eckstein⁵, Robin Conwit⁶, David S. Liebeskind⁷, Latisha Sharma⁷, May-Kim Tenser³ and Jeffrey L. Saver⁷

• ¹MSTAR Program, Department of Geriatrics, University of California, Los Angeles, Los Angeles, CA, United States
• ²Stroke Center and Department of Emergency Medicine, University of California, Los Angeles, Los Angeles, CA, United States
• ³Department of Neurology, University of Southern California, Los Angeles, CA, United States
• ⁴Department of Emergency Medicine, University Harbor-UCLA Medical Center, Los Angeles, CA, United States
• ⁵Department of Emergency Medicine, University of Southern California, Los Angeles, CA, United States
• ⁶Division of Extramural Research, National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
• ⁷Stroke Center and Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States

The objective of this study is to quantify the increase in brain-under-protection time that may be achieved with pre-hospital compared with the post-arrival start of neuroprotective therapy among patients undergoing endovascular thrombectomy. In order to do this, a comparative analysis was performed of two randomized trials of neuroprotective agents: (1) pre-hospital strategy: Field administration of stroke therapy-magnesium (FAST–MAG) Trial; (2) in-hospital strategy: Efficacy and safety of nerinetide for the treatment of acute ischemic stroke (ESCAPE-NA1) Trial. In the FAST-MAG trial, among 1,041 acute ischemic stroke patients, 44 were treated with endovascular reperfusion therapy (ERT), including 32 treated with both intravenous thrombolysis and ERT and 12 treated with ERT alone. In the ESCAPE-NA1 trial, among 1,105 acute ischemic stroke patients, 659 were treated with both intravenous thrombolysis and ERT, and 446 were treated with ERT alone. The start of the neuroprotective agent was sooner after onset with pre-hospital vs. in-hospital start: 45 m (IQR 38–56) vs. 122 m. The neuroprotective agent in FAST–MAG was started 8 min prior to ED arrival compared with 64 min after arrival in ESCAPE–NA1. Projecting modern endovascular workflows to FAST–MAG, the total time of “brain under protection” (neuroprotective agent start to reperfusion) was greater with pre-hospital than in-hospital start: 94 m (IQR 90–98) vs. 22 m. Initiating a neuroprotective agent in the pre-hospital setting enables a faster treatment start, yielding 72 min additional brain protection time for patients with acute ischemic stroke. These findings provide support for the increased performance of ambulance-based, pre-hospital treatment trials in the development of neuroprotective stroke therapies.

Introduction

The longer it takes to treat an ischemic stroke, the worse is the outcome (1). The most effective therapy for acute ischemic stroke is restoring cerebral perfusion by endovascular thrombectomy (EVT). However, EVT treatment can only attain reperfusion after a substantial time delay from stroke onset, after the patient or a witness has activated the emergency medical services system, ambulances have responded and identified a stroke in progress, pre-hospital personnel transport the patient to a receiving stroke center, initial brain and vessel imaging are performed, the patient is transported to the neuro-interventional suite, the arterial puncture is performed, catheter systems are navigated to the occluded artery, and an EVT retriever device deployed. As a result, by the time reperfusion is achieved with EVT, the preponderance of patients has already suffered some degree of irreversible infarction, limiting their eventual functional outcome.

Neuroprotective agents have been identified as a class of therapeutics with great promise as a complementary treatment with EVT, slowing infarct progression in the pre-reperfusion period and yielding more salvageable tissue at the time of reperfusion. Treatment by the neuroprotective agent involves the use of drugs or devices with the capacity to interrupt the cellular, biochemical, and metabolic processes that lead to brain injury during ischemia (2).

Two strategies for the delivery of neuroprotective agents prior to EVT have been explored in large randomized clinical trials: (1) pre-hospital initiation by paramedics in the field soon after EMS activation; and (2) in-hospital initiation after imaging has confirmed acute cerebral ischemia. The advantage of pre-hospital initiation is an earlier treatment start, resulting in a longer period in which the brain is under protection prior to EVT. The advantage of an in-hospital start is a more certain diagnosis of acute cerebral ischemia. To inform the decision regarding which approach to take, it is important to know the extent of the time lost—information gained tradeoff between the two strategies. However, to our knowledge, the exact amount of brain protection time gained with the use of pre-hospital vs. in-hospital treatment start has not previously been characterized.

The present study was therefore undertaken with the objective of quantifying the additional amount of time the brain is under protection by a potential neuroprotective agent with pre-hospital compared to in-hospital start by comparing workflow metrics in two exemplar large clinical trials, one of pre-hospital and the other of post-arrival neuroprotection start.

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