“The main reason to reappraise the concept of neuroprotection in acute stroke is the [advent] of effective thrombectomy, which de facto has led to the development of a reversible middle cerebral artery (MCA) occlusion model in humans. By reliably combining neuroprotection with reperfusion in patients undergoing thrombectomy, we can finally replicate previously successful animal models in human clinical trials,” concluded Tudor Jovin, of the Cooper Neurological Institute and Cooper Medical School of Rowan University, Camden, USA) at the Live Interventional Neuroradiology & Neurosurgery Course (LINNC; 3–5 June, Paris, France).
Introducing the unfortunate story of neuroprotection so far, Jovin said, “Neuroprotection has been the graveyard of acute stroke trials. None of the many hundreds of neuroprotectant agents, with proven efficacy in animal models, could be shown to be effective in human trials.” While he acknowledged that previously, the lack of this MCA occlusion model in humans was the main reason for the “disconnect” between preclinical animal models of neuroprotection and human clinical trials, he outlined an array of issues that continue to hinder the replicability of animal models.
“In the animal model, we used to look at the primary endpoint being infarct size, but in clinical trials in humans, we measure the effect of the treatment with clinical outcome measures. Preclinical models have to take into account more behavioural and clinical outcomes as well, not just infarct size,” said Jovin. Moreover, he acknowledged that stroke is most prevalent in elderly people, whereas most preclinical studies have tested young animals. Due to the fact that stroke is more prevalent in people with comorbidities, Jovin argued that preclinical models of healthy, young animals fail to capture the complex nature of the human population.
Alluding to certain biases that are present in preclinical versus clinical studies, he said, “All of these reasons explain the disappointing story of neuroprotection in stroke. But now”, he reiterated, “we have a reversible model of MCA occlusion in humans; this is the number one reason for why we should reappraise the concept”.
“What are the goals of neuroprotectants?” Jovin asked the LINNC audience, answering that, “They either protect the brain from cell death or enhance recovery. One of the most important potential consequences of neuroprotection is extension of the therapeutic window for reperfusion.”
“If you have good collaterals, you are going to be a slow progressor, but if you have bad collaterals, you are going to be a fast progressor—meaning that, in the presence of large vessel occlusion, you are going to grow your infarct faster than the slow progressor. That is one prime target in neuroprotection. In my opinion, if we give it [the drug] early enough, ideally in the field—as soon as the stroke occurs—then we can transform fast progressors into slow progressors,” he added.
Referring to data from REVASCAT, he said that in this trial, patients who were all randomised within six hours of symptoms onset were considered to be slow versus fast progressors based on their ASPECTS scores; those with an ASPECTS score of less than eight were considered “fast progressors” while those with a score of eight and above were considered “slow progressors”. “In the latter, there is no relationship between time to treatment and outcome. But, in fast progressors, you find a very strong relationship, they are obviously very sensitive to time. So if we can treat them with neuroprotection, early, we can transform them into slow progressors and expand the time window for which reperfusion can still be effective.”
However, Jovin also told the LINNC audience that the ischaemic cascade is a “complex phenomenon”, and “comprises many mechanisms”. With this in mind, he put forward that any neuroprotectant drugs should be tailored and administered at the time points where certain mechanisms come into play. The drugs administered early, he said, should address excitotoxicity, which is when neuronal injury occurs. “Inflammation and apoptosis kick in a bit later. So, you have to give these drugs at the right time, according to the mechanisms that they address,” he surmised.
Acknowledging the importance of the treatment setting, Jovin said, “The most exciting setting for transforming fast progressors into slow progressors is the prehospital setting, especially with drugs that work on excitotoxicity or collateral enhancing drugs.”
Ultimately, Jovin referred to hyperthermia as “the mother of all neuroprotective strategies”. He said that it has been shown to work in virtually “every stage of the ischaemic cascade, whether acute or subacute”. Moreover, according to Jovin, it has been shown to be effective in adults with cardiac arrest and in neonates with ischaemic hypoxic encephalopathy. “But, it has failed in brain trauma and moreover, in human ischaemic stroke, the results have been disappointing,” he added, attributing this to the fact that “we have not figured out the right time window, duration, depth of hypothermia, and the right complication prevention strategies.
Further, Jovin touched on the existing trials examining neuroprotection. “The most exciting in my opinion is the ESCAPE-NA1 trial, because it is a trial that is almost ready to be completed. NA1 is a drug that works in the early stage of the ischaemic cascade on excitotoxicity, and it has very good preclinical as well as clinical data. It has been shown to reduce ischaemic lesions in patients undergoing aneurysm coiling where patients who received NA1 had a lower burden of ischaemic lesions on MRI.” He added that regardless of its outcome, the trial, which has currently enrolled over 1,000 patients, is “going to make a big difference in the way we look at neuroprotection and reperfusion”.
In terms of other promising approaches, Jovin put forward that uric acid has been shown to be safe in a randomised trial of reperfusion (predominantly tPA) patients. While he said that the corresponding trial did not meet its efficacy endpoint, he pointed to its intriguing results in a prespecified subanalysis of the trial in which patients undergoing thrombectomy had better clinical outcomes if treated with uric acid (treatment group) compared to those who only underwent thrombectomy (control group). Additionally—according to Jovin— the oral-antidiabetic, glyburide, prevents oedema formation. Alluding to trials that have shown that this drug significantly reduces oedema in patients with large strokes, he said, “It works best early and has been shown to reduce mortality in these giant strokes,” and put forward that the drug represents “an interesting approach before thrombectomy, as an anti-oedema agent” as it may transform fast progressors into slow progressors.
Lastly, Jovin explained a novel neuroprotective strategy that aims to increase collaterals. Recently published in The Lancet, the study involved stimulating the sphenopalatine ganglion by inserting an electrode in the soft palate under CT guidance. “The trial showed that in patients with cortical infarcts, there was a 10% difference in improvement beyond expectation in patients with acute stroke. The trial missed its endpoint, but was very close to significance,” he said, and remarked, “This is another neuroprotective strategy that aims to increase collaterals, and I think that there will be some interesting applications in patients with large vessel occlusion, before, or even after thrombectomy.”
Concluding his talk, Jovin said, “I think that neuroprotection is not ready for prime time yet, but there is a new era in reperfusion therapies for stroke, and the reversible model of MCA occlusion in humans justifies the reappraisal of the concept of neuroprotection combined with reperfusion. So stay tuned, there will be some exciting developments in the near future.”