Three times as many patients treated with intravenous (IV) tenecteplase (TNK) administered up to 24 hours after symptom onset achieve major reperfusion without symptomatic intracranial hemorrhage (sICH) compared to those receiving best medical treatment not including TNK, results of new research showed.
But patients taking TNK don’t have a better functional outcome, the phase 2b CHABLIS-T II trial showed.
The trial provides new evidence of the effectiveness and safety of IV TNK in patients with acute stroke in an extended time window, study author Xin Cheng, MD, PhD, associate professor and vice chair, Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China, told Medscape Medical News.
Xin Cheng, MD
“But whether sufficient and safe reperfusion could translate into an improvement in functional outcome” requires further research.
The findings were presented at the International Stroke Conference (ISC) 2024 held in Phoenix, Arizona.
Evidence shows IV TNK is noninferior to alteplase in patients with acute ischemic stroke presenting within 4.5 hours after stroke onset. However, only a very limited number of patients receive IV thrombolytic treatment within this time frame, so efforts are under way to expand that time frame.
The earlier CHABLIS-T trial found both TNK 0.25 mg/kg and 0.32 mg/kg have promising efficacy in terms of achieving substantial reperfusion without sICH in patients with anterior large/medium vessel occlusion presenting up to 24 hours from last seen well.
The current CHABLIS-T II included 224 adult Chinese patients with large/medium vessel occlusion, mean age about 64 years and mostly male, presenting at 23 sites in mainland China from 4.5-24 hours of last being known well.
Researchers randomized these patients into two groups: 0.25 mg/kg TNK or best medical management (excluding TNK). Best medical management included IV alteplase if patients met criteria and endovascular thrombectomy (EVT) at the discretion of local stroke neurologists (54% of study subjects underwent EVT).
Researchers chose the 0.25 mg/kg dose based on results of CHABLIS-T and other TNK-related randomized controlled trials, said Cheng.
Balanced Groups
The two groups were mostly balanced; for example, the median National Institutes of Health Stroke Scale (NIHSS) score at randomization in both groups was 9, and large artery atherosclerosis was the most common etiology in both groups.
The primary outcome was major reperfusion without sICH at 24-48 hours. Researchers assessed reperfusion depending on whether patients underwent EVT.
For those without bridging EVT, major reperfusion was defined as restoration of blood flow to greater than 50% of the involved ischemic territory; for patients with bridging EVT, major reperfusion was considered a modified thrombolysis in cerebral infarction score of 2b or greater at the initial imaging.
Symptomatic sICH was defined as any ICH with at least a four-point increase in the NIHSS score from baseline.
The primary outcome was achieved in 33% of patients in the TNK group and 10% in best medical treatment group, with an adjusted risk ratio (aRR) of 3.0 (95% CI, 1.5-5.7; P=.001).
As for the secondary outcome of recanalization at 4-6 hours, the study found this was achieved in 35% of the TNK group and 14% of the control group, with an aRR of 2.5 (95% CI, 1.4-4.4; P=.002).
No Difference in Functional Outcome
There were no significant differences between groups in secondary outcomes including NIHSS score at 24-48 hours, infarct growth at 3-5 days, and modified Rankin Scale (mRS) score at 90 days. The lack of effect of TNK on functional outcomes is mainly due to the limited sample size, said Cheng, who stressed the trial was not designed to show clinical benefit.
“It would need at least 5000 eligible acute ischemic stroke patients in an extended time window to prove the benefit of intravenous TNK in a randomized trial if EVT is allowed. We may need to wait for post hoc analyses to provide additional explanations.”
Looking at safety outcomes, there was no significant difference between groups regarding sICH at 24-48 hours, any intracranial hemorrhage, parenchymal hematoma type 2 (PH2), and 90-day poor functional outcome (mRS, 5-6). Cheng noted, however, the prevalence of PH2 was numerically higher in the TNK group (9.0% vs 3.5%).
Most of the analyses examining various subgroups, including different occlusion sites, time from last known well to randomization, and stroke onset type (witnessed or not), seemed to be consistent with the main analysis, although these were underpowered to make firm conclusions.
Timing May Not Be Fast Enough
However, Cheng noted a trend toward TNK increasing the risk for larger infarct growth volume and worse clinical outcomes in patients with EVT. This, she said, might be explained by either a higher bleeding risk for bridging therapy in patients with large artery atherosclerotic stroke or the time from initiation of the IV thrombolysis to initial angiographic assessment (which was a median 51 minutes) “was not fast enough to prevent infarct growth.”
This was a phase 2b study with limited sample size. Another study limitation was it used a surrogate primary endpoint instead of 3-month functional outcomes. The study included only Chinese patients, in whom the course of stroke differs from those in White patients. And reperfusion was assessed through two different imaging modalities.
Commenting on the research, Larry B. Goldstein, MD, professor and chair, Department of Neurology, and associate dean for Clinical Research, University of Kentucky, Lexington, Kentucky, stressed the study was not designed to assess functional outcomes. “TNK treatment did lead to better reperfusion but with no impact on clinical outcome.”
He pointed to another trial — TIMELESS, a phase 3 trial testing efficacy of TNK in participants with occlusions of the middle cerebral artery or internal carotid artery, most also treated with mechanical thrombectomy. That study also looked at outcomes between 4.5 and 24 hours after symptom onset and found no difference in clinical outcomes at 90 days compared to placebo, he said.
“Taken together, although treatment with TNK 4.5-24 hours after symptom onset in selected patients might improve recanalization, there’s no evidence at this time that it leads to better patient outcomes in this population.”
The study received support from the Clinical Research Plan of Shanghai Hospital Development Center. TNK was donated by Guangzhou Recomgen Biotech Co Ltd.
Cheng and Goldstein had no relevant conflicts of interest.
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