Late-Breaking Science reveals findings on adjunct intra-arterial thrombolysis, TNK, tirofiban and more
Results from six Late-Breaking Science trials were presented during the #ISC26 Thursday Main Event. Research found that:
- OCEANIC-STROKE showed Factor XI benefit for secondary stroke prevention.
- OPTION showed functional benefit for thrombolysis up to 24 hours after non-LVO stroke.
- ATTENTION-LATE showed no benefit for TNK before thrombectomy for BAO in late window.
- TNK-PLUS found no benefit from adding TNK to EVT in late window stroke. EMBOLISE showed embolization superior to standard care for mild symptomatic SDH.
- STRATEGY found no benefit from early intensive antiplatelet treatment for BAD-related strokes IBAN.
Inhibiting Factor XI reduced secondary stroke risk in multiple stroke types
The first completed phase 3 trial of asundexian, an oral inhibitor of Factor XIa, demonstrated consistent and significant risk reduction for recurrent ischemic strokes following multiple types of strokes without increasing major bleeding over placebo. Genetic deficiency of FXI is associated with a reduced risk of ischemic stroke and a low risk of spontaneous bleeding.
The OCEANIC-STROKE trial included patients following large artery atherosclerosis, small vessel occlusion and undetermined stroke as well as high-risk transient ischemic attacks. Compared to placebo, asundexian reduced the risk of recurrent ischemic stroke by 26%.
Mike Sharma, MD
OCEANIC-STROKE randomized 12,327 participants worldwide between January 2023 and February 2025 within 72 hours of acute noncardioembolic ischemic stroke or high-risk transient ischemic event to either asundexian or placebo once daily. All participants had planned single or dual antiplatelet therapy and history of either atherosclerosis, imaging evidence of atherosclerosis in intra- or extracranial vessels (which did not have to be causal, stenosing or anatomically related to the index event), or a visualized nonlacunar infarct.
Nearly all participants, 95%, had an ischemic stroke as the index event, and 27% had intravenous thrombolysis and/or thrombectomy before trial entry. The index stroke subtypes were large artery atherosclerosis (43%), small vessel occlusion (22%), undetermined (30%) or cardioembolic (2%).
The primary endpoint was time to second ischemic stroke. The primary safety endpoint was time to first major bleeding.
Patients in the asundexian arm had 26% fewer second events, 384 vs. 518 in the placebo arm, hazard ratio 0.74 (95% CI 0.65-0.84, p < 0.001). Disabling or fatal strokes were less common with asundexian HR 0.69 (95% CI 0.55-0.87).
There was no increase in major bleeding or hemorrhagic stroke with asundexian compared to placebo.
“The risk of a second stroke remains high even with currently available therapies,” Sharma said. “These are the largest and the most consistent effects in secondary stroke prevention we have seen in any clinical trial of long-term antithrombotics for noncardioembolic stroke and TIA. That we saw no increase in major bleeding associated with asundexian underlies the safety of this approach to stroke prevention.”
Thrombolysis improved functional outcomes up to 24 hours after non-LVO strokes
Intravenous thrombolysis (IVT) with tenecteplase showed a significant improvement in functional outcomes for patients with an acute nonlarge vessel occlusion stroke treated between 4.5 and 24 hours after last known well. Patients receiving thrombolysis were 32% more likely to have a modified Rankin Scale (mRS) score of 0-1 at 90 days than patients receiving standard medical care. There was no significant difference in death within 90 days between the two groups.
“We observed a higher proportion of patients with higher functional outcomes in the intravenous thrombolysis group,” said Ran Mo, MD, department of neurology at Capital Medical University in Beijing. “The mRS scores of 0-2 were higher in the tenecteplase groups, and patients in the TNK group had a higher proportion of early clinical response.
Endovascular therapy (EVT) is a primary intervention for patients with a large vessel occlusion, but up to 76% of acute ischemic strokes are caused by a non-LVO. There is little evidence to suggest EVT benefits non-LVO patients and intravenous thrombolysis is generally approved only within the first 4.5 hours of stroke onset.
At least one major trial, TRACE-III, has shown IVT can improve functional outcomes for patients with ischemic stroke due to LVO up to 24 hours after onset when EVT is not available. The OPTION trial was designed to compare IVT with tenecteplase for non-LVO stroke when administered between 4.5 and 24 hours after onset in patients with salvageable tissue based on imaging.
The investigator-initiated OPTION trial randomized 282 patients to tenecteplase and 284 to standard medical care. Patients had a median age of about 68 years, about 35% female, and the median NIHSS score was 7. Median time from last known well to randomization was 12 hours.
The primary outcome was mRS of 0-1 at 90 days. Secondary outcomes included mRS measures, reperfusion at 24 hours, infarct volume measured by CT scan, NIHSS change from baseline at 7 days (or at discharge if earlier), and patient reported functional measures/quality of life at 90 days. Safety outcomes included symptomatic intracranial hemorrhage within 36 hours, moderate or severe systemic bleeding at 90 days and mortality at 90 days.
More patients in the tenecteplase arm had mRS 0-1 at 90 days, 43.6% vs. 34.2% in the usual care arm, unadjusted risk ratio 1.28 (95% CI 1.04 – 1.57, p=0.02). There was no difference in infarct volume at 24 hours, change in NIHSS score at 7 days or patient reported outcomes, but all other secondary outcomes favored tenecteplase.
There were more symptomatic intracranial hemorrhages with tenecteplase, 2.8% vs. 0% for usual care, p=0.004, but no differences in systemic bleeds or death within 90 days. There were no differences across prespecified subgroups.
“Intravenous tenecteplase administered 4.5 to 24 hours after stroke onset in patients with nonlarge vessel occlusions and salvageable brain tissue resulted in a higher likelihood of an excellent function outcome although at an increased risk of symptomatic intracranial hemorrhage than standard medical care,” Mo said. “These results support extending the thrombolysis time window in this patient population.”
The OPTION trial was published simultaneously in JAMA.
No additional benefit from TNK before thrombectomy in BAO between 4.5 and 24 hours from symptom onset
The most recent trial of tenecteplase (TNK) in acute basilar artery occlusion (BAO) found that combining thrombolysis with thrombectomy did not improve outcomes for patients treated beyond the standard 4.5-hour window. There were no significant differences in safety outcomes from delivering bridging TNK before endovascular thrombectomy for patients between 4.5 and 24 hours from stroke onset and no difference in functional independence at 90 days.
“Recent trials have firmly established endovascular thrombectomy as the standard of care for BAO in the extended time window, up to 24 hours after stroke,” said Chungrung Tao, MD, PhD, The First Affiliated Hospital of the University of Science and Technology of China in Hefei, China. “While recent studies have explored TNK in the extended window, 4.5-24 hours, for anterior stroke, evidence for BAO, a particularly devastating form of stroke, has been lacking in this late timeframe. The most notable finding was the disconnect between early successful reperfusion and final clinical outcome. Angiographic improvement did not translate into a clinical benefit.”
The open-label ATTENTION-LATE trial randomized 166 BAO patients presenting between 4.5 and 24 hours after last known well to TNK + thrombectomy and 164 patients to thrombectomy alone. The primary outcome was functional independence as assessed by modified Rankin Scale score of 0 –2 at 90 days.
Tao reported treatment with TNK increased rates of successful reperfusion before thrombectomy. While improved reperfusion would be expected to improve functional outcomes, no change in mRS 0 – 2 was seen at 90 days, 30.3% for the TNK + thrombectomy group and 30.5% for the thrombectomy-alone group.
Symptomatic intracranial hemorrhage was more common in the combination therapy group, 5.1% vs. 4.0%, in the thrombectomy-alone group, but the difference was not statistically significant. Mortality at 90 days was similar between the groups, 40.0% for combination therapy and 42.7% for thrombectomy alone.
“Based on our findings, routinely adding TNK before thrombectomy in the 4.5 to 24-hour window does not improve functional outcomes and carries a numeric, though not statistically significant increase in the risk of intracranial hemorrhage,” Tao said. “For patients presenting in this late window at thrombectomy-capable centers, clinicians can confidently proceed directly to thrombectomy without the delay or potential risks associated with adjunctive thrombolysis.”
Tao said current BAO guidelines recommend bridging therapy with thrombolysis + thrombectomy in the early window, <4.5 hours. But it is unclear what benefit thrombolysis might add to the current generation of thrombectomy devices. A randomized controlled trial comparing combination therapy vs. thrombectomy alone in the early window is under way. If thrombectomy alone is noninferior, omitting thrombolysis could streamline global stroke treatment for BAO.
TNK-PLUS found no benefit from adding TNK to EVT in late window stroke
Yunyun Xiong, MD, PhD
“We found no evidence of benefit of adding TNK to EVT in the late time window (of 4.5 – 24 hours) when EVT was immediately available,” said Yunyun Xiong, MD, PhD, chief physician and assistant professor of neurology at Beijing Tiantan Hospital, Capital Medical University in Beijing. “The results do not apply to patients being transferred for EVT, and that scenario is the subject of future trials.”
The open label, blinded endpoint TNK-PLUS trial followed earlier findings that intravenous TNK before EVT can improve 90-day functional independence compared to EVT alone for patients with large vessel occlusion treated within 4.5 hours of stroke onset. Earlier trials also showed that TNK within the same late window can significantly reduce disability without safety concerns in patients with anterior circulation large vessel occlusions with salvageable tissue who could not access EVT. There were also suggestions of benefit for TNK + EVT in patients with occlusions to the first segment (M1) of the middle cerebral artery,
TNK-PLUS compared TNK + EVT vs. EVT alone in ischemic stroke patients within 4.5-24 hours after last known well with acute ischemic stroke due to a MCA-M1 or proximal M2 occlusion of the MCA. A total of 391 patients across 40 centers in China were randomized to either TNK + EVT (199 patients) or direct EVT alone (192 patients). The median age of patients was 68, about 60% were male, and the mean NIHSS score at admission was 13. The median time from stroke onset to randomization was about 10 hours and 90 minutes from hospital admission to TNK administration.
The primary outcome was modified Rankin Scale (mRS) score of 0-2 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage within 36 hours of randomization and mortality within 90 days.
There was no difference in mRS 0-2 at 90 days, 44.2% in the TNK+EVT arm and 43.2% in the EVT-only arm, an effect size of 1.01 (95% CI 0.83-1.24, p=0.89). There were more bleeds in the TNK arm, 5.1% vs. 2.6% in the EVT-only arm, but the difference was not statistically significant. There was no difference in 90-day mortality.
Workflow times in the trial were relatively long, Dr. Xiong noted, and the trial was conducted entirely in China, where intracranial atherosclerosis is more prevalent than in other populations. The results are not generalizable to centers that cannot provide EVT.
Embolization beat standard care for mild symptomatic subacute or chronic SDH
Nonsurgical embolization of the middle meningeal artery (MMA) is more effective than observation for the treatment of mild symptomatic subdural hematoma (SDH) that is not appropriate for surgical management. MMA embolization using the Onyx Liquid Embolic System had a two-fold reduction in surgical rescue or poor/deteriorated clinical outcome at 90 days with no difference in mortality between the two arms. Data presented at ISC 2024 showed similar benefit for embolization plus surgery over surgical management alone for patients with severe symptomatic SDH.
Jared Knopman, MD
The EMBOLISE trial compared MMA embolization with Onyx (101 patients) vs. standard-of-care observation only (99 patients). Patients’ mean age was about 72, and about 70% were male. All had mild symptoms, primarily headache, gait instability, dizziness, cognitive impairment or memory loss. The mean Markwalder Grading Scale score was 1.1 and modified Rankin Scale score (mRS) 1.8. About 45% of patients were on antiplatelet or anticoagulant therapy at symptom onset and the median hematoma thickness was 11.7 mm.
The primary endpoint was a composite of adjudicated need for surgical drainage or poor clinical outcome or clinical deterioration at 90 days. Secondary outcomes included the same composite outcome at 180 days and non-inferiority in deterioration in neurologic function by mRS at 90 days and 180 days.
A total of 11.9% of patients in the embolization arm met the 90-day primary outcome vs. 23.2% of the observation patients for a relative risk of 0.51 (95% CI 0.25 – 0.98, p=0.0411). Embolization patients showed numerical superiority in deterioration in neurologic function at 90 days and noninferiority to observation only at 180 days with a 1.89% risk difference (95% CI -9.66% – 13.45%, p=0.0432). Radiologic findings showed almost a 50% reduction in hematoma volume at 180 days in the embolization group compared to the observation group.
Six patients in the Onyx embolization arm had strokes vs. 0 patients in the observation arm. Three of the stroke patients had prior antiplatelet/anticoagulant therapy halted, two were likely caused by internal carotid artery catheterization, and one was associated with pre-existing comorbidities. There were no strokes related to the embolization agent, Onyx.
“Five of the six strokes were from factors that can be mitigated,” Knopman said. “The key takeaways are that anticoagulation should not be stopped in these patients, and to simplify the procedure so you don’t catheterize vessels that don’t need to be catheterized. By adhering to these recommendations, we avoid the risk of mitigating the robust primary endpoint reduction and hematoma volume contraction achieved with MMA embolization.
Intensive dual antiplatelet therapy did not reduce stroke or END following BAD-related stroke
Intensive antiplatelet therapy with tirofiban + aspirin did not reduce subsequent stroke or early neurovascular degeneration (END) in patients with strokes related to branch atheromatous disease (BAD). Patients on dual antiplatelet therapy showed improved modified Rankin Scale (mRS) scores compared to those in the placebo arm.
Yilong Wang, MD, PhD
Penetrating artery infarcts (PAI) account for about 25% of all ischemic strokes, Wang noted, and often appear mild on admission. But PAI involving BAD feature a microatheroma at the origin of the penetrating artery or a nonstenotic plaque from the parent artery blocking the branch artery. These BAD-associated strokes are more likely to progress or recur compared to other PAI-related strokes, and there is little clinical trial evidence to guide treatment decisions.
The STRATEGY trial randomized 939 patients with imaging-confirmed BAD to intensive tirofiban + aspirin (471 patients) or placebo + aspirin (468 patients) for 24.5 hours after randomization. The median age of patients was 63 years and 62.6% were male. The median NIHSS score was 3.
The primary endpoint was END within 7 days or new onset stroke within 90 days. Secondary endpoints included END/new onset stroke at 24 hours and 7 days, composite vascular events, disability or death within 90 days, improvement of neurological function, and change in quality of life. The primary safety endpoints included moderate or severe bleeding and all-cause mortality at 90 days.
The primary endpoint, END or new stroke, occurred in 17.1% of the tirofiban arm and 19.5% of the placebo arm, hazard ratio 0.88 (95% CI 0.65 – 1.19, p=0.39). There were no statistically significant differences for any of the secondary outcomes except the distribution in mRS. More patients in the tirofiban group had improved mRS 2-6 at 90 days, risk ratio 0.84 (95% CI 0.73 –0.97, p=0.02). There were no significant differences in moderate-severe bleeding or all-cause mortality between the groups. The only differences in subgroup analyses was a trend favoring tirofiban among patents with parent artery stenosis.
Wang added that future studies should define the optimal timing and duration of intensive antiplatelet therapy to reduce END and recurrent stroke.
