Novel Per-conditioning Strategy Disappoints in Stroke

June 05, 2019

A novel intervention known as remote per-conditioning — in which transient ischemia is induced in a limb in an effort to protect the brain from the larger ischemic effects of a stroke — has failed to show a reduction in infarct size in a new clinical trial in acute stroke patients.  

The results of the RESCUE BRAIN study were presented at the recent 5th European Stroke Organisation Conference (ESOC) 2019 by Fernando Pico, MD, PhD, Versailles Hospital and University, Le Chesnay, France.

Pico explained that the study was based on preclinical research that has shown this approach to be successful in protecting against myocardial infarction (MI) and stroke. He said the mechanism is believed to involve the transient ischemia triggering endogenous cytoprotective substances and increased blood flow.   

An initial clinical study in MI patients, published in The Lancet in 2010, showed promising results with a reduction in infarct size, and a larger trial in MI patients is now ongoing, he noted.    

"The field started after it was observed that patients with angina pectoris before an MI often had smaller infarcts than those who didn't have angina beforehand. This led to the idea of pre-conditioning — when a transient ischemia may protect against a subsequent larger ischemic event. Per-conditioning is the same principle, but the transient ischemia is induced during or soon after the larger ischemic event," Pico said.

"There is a major unmet need for a neuroprotective agent in stroke patients and animal studies have suggested that inducing transient ischemia in another region of the body soon after a stroke starts may have potential as a neuroprotective strategy," he told Medscape Medical News.

For the RESCUE BRAIN study, 188 patients within 6 hours of onset of ischemic stroke were randomized to the per-conditioning intervention or control.

Per-conditioning was induced by a cuff placed around the thigh on the opposite side of the body to the stroke which was inflated to 110 mm Hg above systolic blood pressure for 5 minutes at a time. This was repeated four times over a total duration of 40 minutes. In the control group, patients had the cuff placed but not inflated.

Patients received the treatment in hospital at a median time of 3 hours 40 minutes after stroke onset. The average National Institutes of Health Stroke Scale (NIHSS) score was 10, and the vast majority of patients also received recanalization therapy; 90% were treated with thrombolysis and 34% received thrombectomy.

The primary endpoint was volume of brain infarct on MRI diffusion weighted imaging at 24 hours. This was not significantly different between the two groups, with the mean (log) change from baseline being 0.30 in the treated group vs 0.37 in the control group, (P = .57).

Secondary outcomes including NIHSS scores at 24 hours, reperfusion rates and modified Rankin Scale (mRS) scores at 90 days were also not different between the two groups.

Safety results were also similar in the two groups, with symptomatic intracerebral hemorrhage occurring in 4.6% of both groups (P = .97).

"Despite good rates of recanalization therapy and quite speedy treatment times, we still didn't see any signal of efficacy of per-conditioning in this study," Pico said.  

He noted that there has been one previous randomized study of this per-conditioning intervention in stroke patients by a Danish group — which was also neutral — but post hoc voxel analyses suggested the intervention may have had some benefit.

Pico reported that there are five further studies of per-conditioning in stroke now underway.

"A couple of these are testing this intervention in the pre-hospital setting, so it will be interesting to see if a shorter time to treatment makes any difference. And some of the other studies are investigating repeating the intervention over a few days," he noted.

Commenting on the current study for Medscape Medical News, session comoderator Jesse Dawson, MD, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom, couldn't help but lament the findings from RESCUE BRAIN, especially considering the results from other studies.

"The RESCUE BRAIN results are disappointing, as there has been a lot of promise in smaller studies of lower limb ischemic per-conditioning and there is good science behind it in that we do see changes at the molecular level," Dawson said. "It seems to induce a response to ischemia that reduces damage from stroke in experimental studies."

"This is the first study that has looked at really detailed imaging of the stroke — a very strong surrogate marker and a difference wasn’t seen," he said. "It is hard to expect a change on clinical outcomes if we don't see change in infarct volume."

Still, he added, "We don’t know if the current results were because this intervention doesn't work or perhaps it hasn't been implemented optimally in terms of patient selection, timing and dose. There is definitely more work to be done. It will be interesting to see what the further studies show."

The RESCUE BRAIN study was funded by the French Ministry of Health. Pico has disclosed no relevant financial relationships.

5th European Stroke Organisation Conference (ESOC) 2019:
Presented May 22, 2019.  

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