Adjunctive cytoprotective therapies in acute ischemic stroke: a systematic review

Finally someone looking to solve the 5 causes of the neuronal cascade of death in the first week saving billions of neurons. The first mention of cascade of death I've seen is in a Rockefeller University paper in 2009. So 12 years to finally work on solving that. All as a result of NO LEADERSHIP AND NO STRATEGY IN STROKE. This is why we need survivors in charge, your children and grandchildren can't wait for that incompetence to continue forever.

Adjunctive cytoprotective therapies in acute ischemic stroke: a systematic review

• I. A. Mulder,
• E. T. van Bavel,
• H. E. de Vries &
• J. M. Coutinho 

Fluids and Barriers of the CNS volume 18, Article number: 46 (2021) Cite this article

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Abstract

With the introduction of endovascular thrombectomy (EVT), a new era for treatment of acute ischemic stroke (AIS) has arrived. However, despite the much larger recanalization rate as compared to thrombolysis alone, final outcome remains far from ideal. This raises the question if some of the previously tested neuroprotective drugs warrant re-evaluation, since these compounds were all tested in studies where large-vessel recanalization was rarely achieved in the acute phase. This review provides an overview of compounds tested in clinical AIS trials and gives insight into which of these drugs warrant a re-evaluation as an add-on therapy for AIS in the era of EVT. A literature search was performed using the search terms “ischemic stroke brain” in title/abstract, and additional filters. After exclusion of papers using pre-defined selection criteria, a total of 89 trials were eligible for review which reported on 56 unique compounds. Trial compounds were divided into 6 categories based on their perceived mode of action: systemic haemodynamics, excitotoxicity, neuro-inflammation, blood–brain barrier and vasogenic edema, oxidative and nitrosative stress, neurogenesis/-regeneration and -recovery. Main trial outcomes and safety issues are summarized and promising compounds for re-evaluation are highlighted. Looking at group effect, drugs intervening with oxidative and nitrosative stress and neurogenesis/-regeneration and -recovery appear to have a favourable safety profile and show the most promising results regarding efficacy. Finally, possible theories behind individual and group effects are discussed and recommendation for promising treatment strategies are described.

Significance statement

Dozens of clinical stroke trials have been performed in the search for additional therapeutic strategies next to thrombolysis, but all failed to consistently improve outcome. With the introduction of endovascular thrombectomy, a new era for treatment of AIS has arrived. We summarized therapeutic strategies and clinical trial results. This review will function as an important enchiridion for future clinical stroke trials and it will provide an insight into which of these drugs warrant a re-evaluation in combination with thrombectomy.

Introduction

About 25 years ago the NINDS trial established intravenous thrombolysis (IVT) with tPA as the first effective medical therapy for acute ischemic stroke (AIS) [1]. Still, a large proportion of patients are not eligible for, or do not benefit from IVT. In the following years, dozens of clinical trials have been performed in the search for additional therapeutic strategies to reduce infarct volume and improve clinical outcome. Preclinical evidence is usually the trigger for making the clinical translation. Unfortunately, none of the compounds tested in these trials consistently showed to improve patient outcome, despite promising pre-clinical data, illustrating a translational gap [2]

With the introduction of endovascular thrombectomy (EVT), a new era for treatment of AIS has arrived [3]. With EVT, rapid recanalization of the major vessels can be achieved in the vast majority of the patients with a large vessel occlusion [4]. Up to 38% of all acute ischemic strokes are large vessel occlusions [5]. Despite the much larger recanalization rate as compared to IVT alone, final outcome remains far from ideal, with approximately 50% of patients having a poor outcome at 90 days [4]. This raises the question if some of the previously tested neuroprotective drugs warrant re-evaluation, since these compounds were all tested in studies where large-vessel recanalization was rarely achieved in the acute phase. This question was also discussed in two extensive reviews by Savitz et al. [6, 7], where the whole aspect of “if, how and when” additional therapies next to reperfusion could be useful, is elaborated including recommendations and guidelines for clinical and per-clinical stroke trials.

After large vessel occlusion in the brain occurs, several multi-phased cascades start to unroll, with necrosis as devastating endpoints. Although these cascades are all intertwined and interact with one another, several main mechanisms can be identified, namely compounds acting on systemic haemodynamic, excitotoxicity, oxidative (and nitrosative) stress, neuro-inflammation and blood–brain barrier damage and vasogenic edema. In this review, we discuss the therapeutic strategies to target these pathways, and systematically review the results from clinical trials in which these various compounds have been tested. This review aims to provide an insight into which of these drugs may warrant a re-evaluation as an add-on therapy for acute ischemic stroke in the era of EVT.

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