IMPORTANCE: The efficacy and safety of intravenous tenecteplase in non-large vessel occlusion acute ischemic stroke beyond 4.5 hours after symptom onset remain uncertain.
OBJECTIVE: To assess the efficacy and safety of intravenous tenecteplase administered 4.5 to 24 hours after stroke onset in patients with non-large vessel occlusion and salvageable brain tissue.
DESIGN, SETTING, AND PARTICIPANTS: This randomized, open-label, blinded end-point clinical trial was conducted at 48 centers in China. A total of 566 patients with non-large vessel occlusion stroke and evidence of potentially salvageable tissue determined on perfusion imaging presenting within 4.5 to 24 hours of the time last seen well were recruited between June 2, 2023, and August 4, 2025 (final follow-up, October 28, 2025).
INTERVENTIONS: Patients were randomly assigned 1:1 using a minimization algorithm to receive intravenous tenecteplase (0.25 mg/kg; maximum dose, 25 mg; n = 282) or standard medical treatment (n = 284).
MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin Scale at 90 days. Safety outcomes included symptomatic intracranial hemorrhage within 36 hours and mortality within 90 days.
RESULTS: Among the 570 patients randomized, 566 were included in the primary analysis (median age, 68 [IQR, 59-75] years; 196 female [34.6%]). An excellent functional outcome was observed in 123 of 282 patients (43.6%) in the tenecteplase group and 97 of 284 (34.2%) in the control group (risk ratio, 1.28 [95% CI, 1.04-1.57]; P = .02). The incidence of symptomatic intracranial hemorrhage at 2.8% was higher with tenecteplase than with standard medical treatment at 0% (risk difference, 2.85% [95% CI, 1.16%-5.54%]; P = .004), and the mortality at 90 days was 5.0% and 3.2%, respectively (risk ratio, 1.57 [95% CI, 0.69-3.57]; P = .28).
CONCLUSIONS AND RELEVANCE: Among patients with non-large vessel occlusion acute ischemic stroke and salvageable brain tissue, intravenous tenecteplase administered 4.5 to 24 hours after onset resulted in a greater likelihood of an excellent functional outcome at 90 days than standard care but had an increased risk of symptomatic intracranial hemorrhage.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05752916.
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| Internal Medicine | |
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| Neurology | Coming Soon... |
These findings seem to replicate what is already known on this topic. The improvements in functional outcome seem to be partly or completely offset by the remarkable increase in bleeding risk. Although a systematic review of treatment in this same time window is warranted, shared decision-making is still essential in this situation.
This multicenter Chinese RCT included patients with non-LVO ischemic stroke between 4.5-24 hours of onset and randomized patients in a 1:1 fashion to IV tenecteplase 0.25mg/kg (max 25mg) or standard therapy. The primary outcome was excellent functional outcome (EFO) (mRS 0-1) at 90 days. The authors found EFO occurred in 43.6% of the tenecteplase group versus 34.2% of the standard therapy group (RR 1.28, 95% CI 1.04-1.57). However, symptomatic intracerebral hemorrhage was higher with tenecteplase (2.8% vs 0%, RR 2.85%), with a trend toward higher mortality in the tenecteplase group. Although the authors state this supports extending the treatment window, there are many limitations. First, this was conducted in China, impacting generalizability. Second, it was open-label and subject to bias. Modified Rankin score 0-2 was not statistically different. There are also limitations with imaging. Caution is warranted concerning the findings and deserves further study.
This moderately sized RCT provides further evidence that the "time is brain" mantra should probably be replaced by "imaging is brain." Outcomes were better with tenecteplase than without in these patients without an intervenable LVO, but with favorable perfusion imaging, and a median of 12 hours from symptom onset to randomization. The increase in symptomatic intracranial bleeding risk was about 3%. Confidence in the findings is dampened by the lack of a placebo in the control arm and because the benefit was not statistically significant if "good outcome" was defined as mRS 0-2 (as opposed to 0-1) and disappeared completely with a definition of mRS 0-3.
The 2015 American College of Emergency Physician's Clinical Policy on stroke thrombolysis was one of the most controversial in history (http://pmid.us/26304253) because many emergency medicine physicians are still skeptical of the weight of clinical evidence for thrombolytics within 4.5 hours and their ability to replicate the neurological exam and neuroimaging rigor of trials (for example, see http://pmid.us/22998705 and http://pmid.us/19464756 and http://pmid.us/23039286). Amidst this historical landscape, this RCT explores the efficacy and safety of tenecteplase up to 24 hours. Although their findings must await verification, the implications of extending non-LVO stroke thrombolysis up to 24 hours is likely to initiate another firestorm of debate across a subset of emergency medicine.
This study in patients with non-LVO in acute stroke presenting between 4.5-24 hours showed improvement in the primary outcome (mRS 0-1) with TNK (vs standard medical treatment). However, it's important to know that the fragility index in this study is very low. It'll be interesting to see how many patients who arrived in the later time frame (eg, 20 hours from last known normal) have similar improved outcomes.
Well-executed RCT. Findings will have to be reproduced in other populations before being generally accepted as the standard of care.
This area is always an interesting mix of benefit and harm.
While these findings showed some benefits, the increased risks for major, life-limiting, or life-altering negative effects were not given the emphasis they deserve. This study fills a gap in our knowledge and, as such, is important. However, a broader study (e.g., multiple international centers) would have been helpful for applying the information to real-world individual patients.
These results are a major advance and extend the benefits of thrombolysis to substantially more patients than previously. Time is not a complete barrier provided that CT perfusion suggests salvageable tissue. The rate of symptomatic ICH is increased but not out of keeping with rates seen with thrombolysis in less than 4.5 hours.
In many countries, tenecteplase has replaced tissue plasminogen activator as the agent of choice for intravenous thrombolysis for ischemic stroke. This trial in Chinese patients with ischemic stroke due to non-large-vessel occlusions (i.e., patients ineligible for mechanic thrombectomy) examined the efficacy and safety of tenecteplase vs standard antiplatelet-therapy in the 4.5 - 24h time window. No net benefit of tenecteplase in this time window was shown. A higher proportion of patients treated with tenecteplase had excellent functional outcome at 90 days; however, the risk for symptomatic intracranial hemorrhage and death was also higher in the tenecteplase group compared with standard medical treatment with antiplatelet therapy. Hence, the results mirror the data for tissue plasminogen activator in ischemic stroke in the time window beyond 4.5h.
, McMaster University