LOS ANGELES – A new potential neuroprotectant agent has been found to be beneficial for patients with acute ischemic stroke undergoing endovascular thrombectomy in a large placebo-controlled trial, but only for those patients who did not also receive thrombolysis.
Dr. Michael Hill
There was no difference between groups on the primary outcome in the main analysis of the trial, lead author Michael Hill, MD, reported.
However, “In our study, we found a dramatic interaction of nerinetide with alteplase. There was a large benefit of nerinetide in patients not given thrombolysis, but in patients who received alteplase, this benefit was completely obliterated,” Dr. Hill said in an interview.
“In patients not treated with thrombolysis, we found a large effect size with a 9.5% absolute improvement in patients having an independent outcome (modified Rankin Score [mRS] 0-2) and a number need to treat of 10 to 11,” he said. “We also found a mortality benefit and a reduction in the size of strokes, with all other secondary outcomes going in the right direction.
“The drug works really well in patients who do not get thrombolysis, but it doesn’t work at all in patients who have had thrombolysis. The thrombolytic appears to break the peptide down so it is inactive,” he added.
“This is the first evidence that neuroprotection is possible in human stroke. This has never been shown before,” Dr. Hill noted. “Many previous clinical trials of potential neuroprotectants have been negative. We think this is a major breakthrough. This is pretty exciting stuff with really tantalizing results.”
Dr. Hill, professor of neurology at the University of Calgary (Alta.), presented results of the ESCAPE-NA1 trial on Feb. 20 at the International Stroke Conference (ISC) 2020. The trial was also simultaneously published online (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30258-0).
Endogenous nitric oxide
The new agent – known as NA1 or nerinetide – is a 20-amino-acid peptide with a novel mechanism of action; it inhibits signaling that leads to neuronal excitotoxicity. “It reduces endogenous nitric oxide generated inside the cell during ischemia, which is one of the main biochemical processes contributing to cell death,” Dr. Hill explained. In a primate model of ischemia reperfusion that was published in Nature in 2012, it was highly protective, he added.
The drug is given just once at the time of thrombectomy. It is short lived in the blood but detectable in the brain for up to 24 hours, he said.
The trial included 1,105 patients who had experienced acute ischemic stroke due to large-vessel occlusion within a 12-hour treatment window and for whom imaging results suitable for thrombectomy were available. The patients were randomly assigned to receive either intravenous nerinetide in a single dose of 2.6 mg/kg or saline placebo at the time of thrombectomy.
Patients were stratified by intravenous alteplase treatment and by declared endovascular device choice.