Systematic Review - Combining Neuroprotection With Reperfusion in Acute Ischemic Stroke

 We've known for years that neuroprotection studies have failed. 1000+ according to Dr. Michael Tymianski, of the Toronto Western Hospital Research Institute in Canada states;  over the last half-century, there have been more than 1,000 drugs (So what are they?)aimed at preventing brain damage that have failed to work in people, even though they worked well in mice or rats. If you called it by the correct name, neuronal cascade of death, it sounds like it needs solving immediately rather than the milquetoast term 'neuroprotection'.

Systematic Review - Combining Neuroprotection With Reperfusion in Acute Ischemic Stroke

E. M. Vos^1*, V. J. Geraedts^1,2, A. van der Lugt³, D. W. J. Dippel⁴, M. J. H. Wermer², J. Hofmeijer^5,6, A. C. G. M. van Es^7,8, Y. B. W. E. M. Roos⁹, C. M. P. C. D. Peeters-Scholte² and I. R. van den Wijngaard^1,2

• ¹Department of Neurology, The Hague Medical Center, The Hague, Netherlands
• ²Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
• ³Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
• ⁴Department of Neurology, Erasmus University Medical Center, Rotterdam, Netherlands
• ⁵Department of Neurology, Rijnstate Hospital, Arnhem, Netherlands
• ⁶Department of Clinical Neurophysiology, Technical Medical Centre, University of Twente, Enschede, Netherlands
• ⁷Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
• ⁸Department of Radiology, The Hague Medical Center, The Hague, Netherlands
• ⁹Department of Neurology, Amsterdam University Medical Center, Amsterdam, Netherlands

Background: Clinical trials of neuroprotection in acute ischemic stroke (AIS) have provided disappointing results. Reperfusion may be a necessary condition for positive effects of neuroprotective treatments. This systematic review provides an overview of efficacy of neuroprotective agents in combination with reperfusion therapy in AIS.

Methods: A literature search was performed on the following databases, namely PubMed, Embase, Web of Science, Cochrane Library, Emcare. All databases were searched up to September 23rd 2021. All randomized controlled trials in which patients were treated with neuroprotective strategies within 12 h of stroke onset in combination with intravenous thrombolysis (IVT), endovascular therapy (EVT), or both were included.

Results: We screened 1,764 titles/abstracts and included 30 full reports of unique studies with a total of 16,160 patients. In 15 studies neuroprotectants were tested for clinical efficacy, where all patients had to receive reperfusion therapies, either IVT and/or EVT. Heterogeneity in reported outcome measures was observed. Treatment was associated with improved clinical outcome for: 1) uric acid in patients treated with EVT and IVT, 2) nerinetide in patients who underwent EVT without IVT, 3) imatinib in stroke patients treated with IVT with or without EVT, 4) remote ischemic perconditioning and IVT, and 5) high-flow normobaric oxygen treatment after EVT, with or without IVT.

Conclusion: Studies specifically testing effects of neuroprotective agents in addition to IVT and/or EVT are scarce. Future neuroprotection studies should report standardized functional outcome measures and combine neuroprotective agents with reperfusion therapies in AIS or aim to include prespecified subgroup analyses for treatment with IVT and/or EVT.

Introduction

Intravenous thrombolytic therapy (IVT) has become standard care for acute ischemic stroke (AIS), but only a small minority (12%) of patients is eligible for IVT because of the limited time window and contra-indications (1). The absolute benefit of treatment with IVT is limited and is estimated to be 4–10% (2). In the last decade, endovascular therapy (EVT) to mechanically reopen the occluded cerebral artery has led to an improvement of functional outcome in patients with AIS caused by large vessel occlusion (LVO) (3). However, despite high recanalization rates (70–90%) chances of good functional outcome after EVT remain relatively low (30–60%) (3, 4). Currently only 10% of patients after EVT are without stroke symptoms at 3 months follow-up with a modified Rankin Scale (mRS) score of 0 (3, 5). This implies the need for additional treatment and systems-based interventions to further improve recovery of patients with AIS. A wide range of neuroprotective agents has been investigated in the past to reduce brain injury and thereby improve patient recovery. Despite promising results from animal studies, none of the tested neuroprotective strategies appeared effective in clinical trials (6). Earlier trials may have failed due to a lack of recanalization in treating patients with AIS. As ischemic tissue will eventually become infarcted if blood flow is not restored, adequate reperfusion is probably a necessary condition for recovery with or without additional neuroprotective treatments (4, 7–9). The four primary treatment targets are reduction of excitotoxicity, oxidative stress, inflammation, and cellular apoptosis (10). In patients with adequate recanalization, another targeted mechanism is reducing reperfusion injury (7, 11). With the introduction of IVT and EVT, drugs with neuroprotective properties can now be investigated in combination with reperfusion therapy. This systematic review provides an overview of randomized controlled trials (RCTs) of neuroprotective agents in AIS as an adjunct to IVT and/or EVT.

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