ZODIAC, RESILIENT-Extend and MOST Late-Breaking Science presented
Three Late-Breaking Science results delivered at the #ISC24 Opening Session.
Late-Breaking Science presented during the #ISC24 Opening Main Event on Wednesday revealed that:
- Ischemic stroke thrombectomy patients have less early neurologic deterioration prior to clot extraction with head down versus elevated head positioning.
- RESILIENT-Extend showed thrombectomy benefit without advanced imaging versus best medical management.
- MOST showed no benefit from adjunctive anticoagulation or antiplatelet treatment after thrombolysis.
“Ischemic stroke patients who are candidates for thrombectomy should be positioned with the head flat, at zero degrees, to improve cerebral perfusion and reduce early neurologic deterioration (END) during transport and while waiting for thrombectomy,” said Anne W. Alexandrov, PhD, AGACNP-BC, ANVP-BC, FAAN, professor of nursing and of neurology at the University of Tennessee Health Science Center.
Practitioners have traditionally elevated the head of the bed by approximately 30 degrees in all types of stroke patients.
“Putting the head down at zero degrees increases the cerebral blood flow by 20%,” Dr. Alexandrov continued. “The longer these patients sit up at 30 degrees with a large vessel occlusion, the worse stroke symptoms get before thrombectomy. Maintaining the head at zero degrees until thrombectomy stabilizes blood flow and minimizes neurologic deterioration compared to 30 degrees.”
Dr. Alexandrov presented the initial results of Zero Degree Head Positioning in Hyperacute Large Artery Ischemic Stroke (ZODIAC), the largest randomized trial exploration of head positioning in acute ischemic stroke thrombectomy candidates to date. Researchers randomized 92 patients across 12 U.S. hospitals newly diagnosed with large vessel occlusion to zero-degree head positioning or the usual 30-degree head elevation until initiation of thrombectomy.
The primary endpoint was END based on the National Institute of Health Stroke Scale (NIHSS) measured every 10 minutes from initiation of positioning until initiation of thrombectomy, or 2 hours, whichever came first. Secondary endpoints included NIHSS at 24 hours, 7 days, and 90 days post-thrombectomy.
Head-down positioning is a method to maximize blood flow and stabilize patient condition until definitive treatment begins following a large vessel occlusion, Dr. Alexandrov said. ZODIAC showed that END can begin within minutes of head-up positioning in large vessel occlusion thrombectomy candidates and is typically seen within 20-30 minutes. Transportation time and transfer to appropriate stroke treatment centers can delay treatment by several hours, contributing to END if the head is positioned at 30 degrees before definitive treatment can begin. The trial was halted early due to efficacy at a second planned interim analysis.
Thrombectomy imparts such a tremendous effect on patient improvement that investigators expected to find no difference in their exploratory post-thrombectomy endpoints. They were surprised to find that patients in the zero-degree group had significantly improved NIHSS scores at 24 hours and again at discharge/7 days after thrombectomy compared to the 30-degree head elevation group. There was no difference in NIHSS at 90 days.
“This is a remarkable difference, less early disability and faster recovery, just from keeping the head down instead of elevated,” Dr. Alexandrov said. “We expect that this may translate into less time and money spent on rehabilitation. Our work suggests that zero-degree head positioning in the pre-thrombectomy phase should become standard of care from the moment a large vessel occlusion with salvageable brain is diagnosed. While this is important for all thrombectomy candidates, it is especially important for those requiring transfer/transport to a higher level-of-care hospital.”
Mechanical thrombectomy better than best medical therapy with NCCT/CTA assessment.
Mechanical thrombectomy (MT) is more effective than medical therapy alone to treat ischemic stroke due to large vessel occlusion in limited resource settings with little or no access to MRI. Based on CT and/or CT angiography imaging to confirm large vessel occlusion, MT performed up to 24 hours after last known well has an adjusted odds ratio of 2.56 (95% CI 1.24-5.29, p=0,012) for functional independence at 90 days compared to best medical therapy.
“The lack of advanced imaging capabilities should not be a reason not to perform MT,” said Raul G. Nogueira, MD, FAHA, FSVIN, director of the University of Pittsburgh Medical Center Stroke Institute, endowed professor and chief of cerebrovascular medicine, and professor of neurology and neurosurgery, University of Pittsburgh School of Medicine.
There is overwhelming evidence for the benefit of MT for the treatment of large vessel occlusion strokes up to 24 hours after an index event. Most MT studies were conducted in high-income countries using MRI assessment.
“We need to show that MT can be extended to the 80% of the global population in middle- and low-income countries that do not have access to advanced imaging,” said Sheila Martins, MD, PhD, professor of neurology at the Universidade Federal do Rio Grande do Sul, and president of the World Stroke Organization.
The Randomization of Endovascular Treatment with Stent-retriever and/or Thromboaspiration versus Best Medical Therapy in Acute ischemic Stroke due to Large Vessel Occlusion Trial in the Extended Time Window (RESILIENT-Extend) trial comparted MT using non-contract CT/CT angiography selection.
The primary outcome was a shift analysis of modified Rankin Scale (mRS) scores at 90 days. Secondary endpoints included functional independence, mRS≤2, at 90 days and successful vessel recanalization. Safety endpoints included 90-day mortality and clinically significant intracerebral hemorrhage rates at 24 hours and procedural-related complications.
A total of 245 patients were randomized to MT + best medical management (126) or best medical management alone (119) 8-12 hours from time last seen well across 12 public health centers in Brazil. Patients were in their mid-60s and just under half were female. The median NIHSS score at baseline was 16 and median ASPECTS was 7-8. More than 90% of patients had NCCT/CTA imaging at baseline.
The proportional odds assumption was violated, obscuring the primary outcome, Dr. Nogueira reported. Significantly more MT patients showed functional independence at 90 days versus medical management, 25.4% versus 14.3%. There appeared to be an interaction between treatment and age with patients >68 years showing no benefit.
The number needed to treat for one additional independent outcome was 9, and there was no significant difference in symptomatic intracranial hemorrhage between the two groups.
No benefit from adding argatroban or eptifibatide to thrombolysis
The Multi-arm Optimization of Stroke Thrombolysis (MOST) trial comparing adjunctive treatment with argatroban, eptifibatide or placebo following endovascular thrombolysis for the treatment of ischemic stroke did not improve functional outcomes at 90 days. The mean utility-weighted modified Rankin score (mRS) was 6.8 for thrombolysis + placebo, 5.2 for thrombolysis + argatroban, and 6.3 for thrombolysis + eptifibatide 90 days after treatment.
“The addition of IV eptifibatide or IV argatroban to standard thrombolytic therapy did not significantly increase symptomatic intracranial hemorrhage not did it provide added benefit following thrombolysis,” said Andrew Barreto, MD, MS, FAHA, Associate Professor of Neurology, McGovern Medical School, The University of Texas Health Science Center.
Patients in the placebo group did better numerically than the intervention patients in terms of mean utility medicine scores, but there was no statistically significant difference between the groups.
“From all indications, it does not appear as though we had increased levels of harm with these adjunct treatments,” said Opeolu Adeoye, MD, MS, BJC HealthCare Distinguished Professor and Chair of Emergency Medicine at Washington University School of Medicine. “But these two drugs should not be given following thrombolysis, because they don’t seem to show any benefit.”
The phase 3 MOST trial followed early-stage trials suggesting that both argatroban, an anticoagulant, and eptifibatide, an anti-platelet agent, are safe when given following intravenous thrombolysis and could improve outcomes following ischemic stroke by enhancing thrombolysis. The adaptive trial was conducted at 57 sites in the United States. A total of 514 ischemic stroke patients were randomized to argatroban (59), eptifibatide (228) or placebo (227) given within 75 minutes of thrombolysis.
All patients received IV thrombolysis, and 44% also received endovascular thrombectomy as standard of care.
The primary outcome was the mean utility-weighted mRS at 90 days, the primary safety outcome was symptomatic intracranial hemorrhage.
There was no significant difference in mean utility-weighted mRS at 90 days. The posterior probability that argatroban was better than
to placebo was 0.002 (utility-weighted mRS posterior mean difference -1.5, posterior SD=0.5). The posterior probability that eptifibatide was better than placebo was 0.009 (mean difference -0.5, posterior SD=0.3).
There was no significant difference in rates of symptomatic bleeding, 3.7% for argatroban, 3.3% for eptifibatide and 1.8% for placebo.
There was an unexplained number of deaths in the argatroban arm in the first 150 patients treated, Dr. Adeoye noted. The independent safety monitor did not relate any of the argatroban deaths to treatment, but the adaptive trial design favored eptifibatide and placebo in the remaining patients, accounting for the lower number of patients treated with argatroban.
“Much to our surprise, these two drugs were decisively futile,” Dr. Adeoye said. “Neither argatroban nor eptifibatide, at least when given intravenously and systemically after thrombolysis, seemed to benefit patients any more than thrombolysis alone.”