TREND, SPAN, RODIN and GOLDEN BRIDGE-II results revealed
Late-Breaking Science presented during Thursday’s Main Event revealed:
- IV tirofiban shows reduced risk for early neurologic deterioration without increasing bleeding risk.
- Uric acid supplementation shows significant cerebroprotective activity in animal models.
- Nelonemdaz may improve functional outcomes when administered early.
- AI-based decision support system showed 26% reduction in subsequent vascular events following acute ischemic stroke.
IV tirofiban shows reduced risk for early neurologic deterioration
The TREND trial showed that intravenous tirofiban can reduce the risk of early neurologic deterioration (ND) following ischemic stroke without increasing the risk of bleeding. IV tirofiban reduced the risk of early ND by 68% versus oral aspirin with no difference in 90-day mortality and no severe bleeding events.
“The remarkable efficacy of tirofiban in preventing neurological deterioration surpassed our initial predictions,” said Wenbo Zhao, MD, PhD, Department of Neurology at Xuanwu Hospital, Capital Medical University in Beijing, China. “However, the incidence of neurological deterioration in the control group and the incidence of intracerebral hemorrhage in this study population are much lower than we expected, which could be attributed to the relatively minor neurological impairments observed in our study population.”
Tirofiban is widely used in coronary artery disease, Dr. Zhao noted. Multiple trials have demonstrated that tirofiban is safe and beneficial in patients with acute ischemic stroke. And because dysphagia is a common issue following stroke, an IV antiplatelet agent has clear treatment advantages over an oral agent.
This investigator-initiated study compared IV tirofiban (214 patients) versus oral aspirin (212 patients) across 10 comprehensive stroke centers in China. Patients were randomized to receive IV tirofiban or oral aspirin for 72 hours within 24 hours of onset of acute, non-cardioembolic stroke. All patients then received oral aspirin for 90 days.
The primary outcome was early ND, an increase of NIHSS ≥4 points within 72 hours of randomization. The primary safety outcome was symptomatic intracerebral hemorrhage.
Early ND occurred in 4.2% of the tirofiban group versus 13.2% of the aspirin group. None of the patients in the tirofiban group experienced intracerebral hemorrhage, and there was no significant difference in 90-day mortality, 1.3% in the tirofiban group versus 1.5% in the aspirin group.
“This trial has shown that tirofiban effectively prevents neurological deterioration in these patients despite the absence of significant differences in excellent 90-day outcomes, a modified Rankin Score of 0-1 due to the small sample size,” Dr. Zhao said.
“In future clinical practice, particularly in East Asian countries like China, physicians would be inclined to utilize IV tirofiban during the acute phase of ischemic stroke to prevent neurological deterioration. This approach may enhance patients’ adherence to treatment and foster stronger trust between patients and doctors."
Dr. Zhao added that a follow-up trial of IV tirofiban following intravenous thrombolysis to improve functional outcomes through reducing ND is being planned.
Uric acid supplementation provided cerebroprotection across multiple animal models
A recent secondary analysis of the Stroke Preclinical Assessment Network (SPAN) 1.0 multicenter preclinical (animal) trial of six potential cerebroprotective interventions has confirmed the benefits of uric acid (UA) exogenous supplementation across multiple subgroups. These results reinforce both the cerebroprotective benefits of UA and the usefulness of including multiple animal models in translational stroke research.
UA is a potent endogenous scavenger of peroxynitrite and other reactive species generated in the cerebrovascular unit during and after acute cerebral ischemia. The University of Iowa proposed UA as its candidate intervention for SPAN 1.0. In addition to UA, SPAN 1.0 tested tocilizumab, veliparib, fingolimod, fasudil and remote ischemic conditioning that were proposed by five other U.S. institutions. This secondary analysis assessed only UA along with IV control.
SPAN brings clinical trial design and methodology to preclinical research to reduce or eliminate the biases that can reduce scientific rigor and improve replicability of results generated in multiple laboratories. Using a randomized, placebo-controlled, blinded, multilaboratory, multistage, multi-arm approach improves the selection of stroke cerebroprotectants that have a higher likelihood of success in human clinical trials.
Animal models included young, aging and diet-induced obese mice, young rats and spontaneously hypertensive rats. All animals were randomized to receive an intravenous injection of UA 16 mg/kg or vehicle for 20 minutes, starting 5 minutes before reperfusion of a middle cerebral artery filament occlusion.
The primary outcome was the modified corner test, a standard assessment of sensorimotor dysfunction. Animals enter a corner and the direction in which they turn is recorded. Following stroke, which causes contralateral limb deficits, animals tend to use their ipsilateral limb to turn back from the corner. Animals without sensorimotor dysfunction do not show a preference for either direction when turning away from the corner.
“The primary analysis of SPAN 1.0 did not specifically address the results by subgroups of different species, sex, age and co-morbidities,” said Rakeshkumar Patel, PhD, postdoctoral research fellow at the University of Iowa. “We assessed cerebroprotection across subgroups using the same intent-to-treat population as SPAN 1.0 and the same primary outcome, a modified corner test. The UA-treated animals had a significantly higher probability of a better corner test score than control treated animals (Pr 0.56, 95% CI 0.52-0.6; P<0.006). We also analyzed the secondary outcome, mortality. The UA-treated animals had significantly higher survival (HR=1.41, 95 % CI 1.08; 1.83; P<0.011), a higher probability of a lesser midline shift index (Pr=0.43, 95% CI 0.38-0.48; P<0 .004) than control mice.
“These results suggest that UA has a broadly cerebroprotectant effect,” Dr. Patel said. “This supports that UA is a promising agent to be tested in patients with ischemic stroke undergoing reperfusion.”
Potential benefit from nelonemdaz with thrombectomy for acute ischemic stroke
The phase 3 Rescue on Reperfusion Damage in Cerebral Infarction by Nelonemdaz (RODIN) trial of the potential neuroprotectant nelonemdaz (nelo) administered in conjunction with thrombectomy for acute ischemic stroke failed to show benefit in functional outcomes in a population of over 400 patients. There was, however, a significant benefit for a subgroup of patients treated less than 60 minutes from arrival in the emergency department.
“This neuroprotective profile was similar to that shown in transient occlusion of the middle cerebral artery in rats,” said Sun Kwon, PhD, professor of neurology at Asan Medical Center at the University of Ulsan College of Medicine in Seoul, South Korea. “The beneficial effects of nelonemdaz likely depend on two factors: how long the ischemic time lasts, and when nelonemdaz is administered in relation to reperfusion.”
Nelo is a derivative of aspirin and sulfasalazine that acts as a selective NMDA receptor antagonist and potent antioxidant, Dr. Kwon said. The small molecule readily penetrates the blood-brain barrier to ameliorate NMDA receptor-mediated endotoxicity and reduce reactive oxygen species toxicity, both major pathways of brain cell death following acute ischemic stroke. Preclinical models demonstrated better safety and neuroprotection than NMDA receptor antagonists or antioxidants alone, early phase clinical trials demonstrated both safety and clear outcome trends suggesting efficacy.
RODIN randomized 496 thrombectomy patients with moderate-severe occlusion in the intracranial internal carotid artery or the M1 or M2 segments of the middle cerebral artery within 12 hours of onset to nelonemdaz infusion for five days or matching placebo. All patients had an ASPECT score of 4 and NIHSS ≥8 at screening.
The goal was to administer drug before reperfusion, but infusion was allowed up to 60 minutes after groin puncture for thrombectomy, Dr. Kwon said. The primary outcome was modified Rankin scale (mRS) at 90 days.
There was no difference in median mRS between the two groups 90 days after treatment, Dr. Kwon said, no difference in the proportion of patients with mRS 0-2, and no difference in adverse events. The only significant treatment effect was a statistically significant improvement in mRS for patients who were treated within 60 minutes of arrival in a post-hoc subgroup analysis. Another phase 3 trial of nelo is being planned for moderate-severe ischemic stroke patients who can receive the drug within 70 minutes of arrival at the emergency room and potentially before thrombectomy.
AI decision support system improved ischemic stroke outcomes
The global stroke burden is growing dramatically, particularly in China, the world’s most populous country. China also has a fast-aging population, boosting stroke prevalence and incidence. An artificial intelligence-based clinical decision support system (AI-CDSS) showed a 26% reduction in new vascular events 90 days after an initial stroke compared to conventional care.
“AI-based clinical decision for support based on AI is effective and feasible in hospitals in China,” said Zixiao Li, MD, PhD, Beijing Tiantan Hospital, Capital Medical University in Beijing, China.
The Phase 3 GOLDEN BRIDGE-II trial compared a stroke-specific AI-CDSS that integrated multiple hospital-based clinical information systems, stroke image analysis, stroke etiology classification and guideline-based treatment recommendations to conventional hospital-based care without AI-CDSS. The objective was to compare conventional care and stroke AI-CDSS in stroke care quality and clinical outcomes in patients with acute ischemic stroke.
The study population included 21,579 patients treated in 77 hospitals across China. The population was randomized at the hospital level, with 38 institutions and 11,085 patients in the AI-CDSS intervention group versus 39 hospitals and 10,604 patients in the conventional care control group. Patients were 66-67 years old and 24% female, with a mean NIHSS score of 3 at baseline.
The primary outcomes were new vascular events, a composite of ischemic stroke, hemorrhagic stroke, myocardial infarction or vascular death, within three months of a primary ischemic stroke. Secondary outcomes included evidence-based measures of acute ischemic stroke care and disability as measured by modified Rankin Scale score at three months. Safety outcomes included bleeding events and all-cause mortality within three months.
A total of 2.9% of AI-CDSS patients had a new vascular event versus 3.9% of conventional care patients, an adjusted odds ratio of 0.740 (95% CI 0.59-0.94, p=0.013). The reduction was driven largely by a 0.710 odds ratio for subsequent ischemic stroke (95% CI 0.55-0.91, p=0.008). Numeric decreases for new hemorrhagic stroke, myocardial infarction, and vascular death were not statistically significant.
AI-CDSS also improved stroke care, OR=1.26 (95% CI 1.19-1.33, p<0.001) with no difference in bleeding events or all-cause mortality.
“Compared with usual care, AI-CDSS reduced new vascular events and improved stroke care quality in this study,” Dr. Li said. “Further research is needed to fully evaluate the generalizability of these findings and the relative contribution of each quality performance measure to three-month vascular events.