Standard-Dose Tenecteplase vs Low-Dose Alteplase for Acute Ischemic Stroke From Large-Vessel Occlusion: A Randomized Clinical Trial

Background

Acute ischemic stroke happens when a blood clot blocks blood flow to part of the brain. When the blockage involves a large brain artery, the stroke is often severe and can cause major disability or death. In these cases, two time-sensitive treatments are commonly used together: intravenous thrombolysis, which helps dissolve the clot, and mechanical thrombectomy, which removes the clot directly from the artery.

Tenecteplase and alteplase are both clot-busting medicines. Alteplase has long been the standard intravenous thrombolytic for acute ischemic stroke in many countries. However, tenecteplase has practical advantages, including single-bolus administration and a longer half-life, which may make it easier to use before thrombectomy. In Japan and some other Asian countries, a low-dose alteplase regimen of 0.6 mg/kg is commonly used. The question addressed in this trial was whether standard-dose tenecteplase at 0.25 mg/kg could achieve better early reperfusion than low-dose alteplase in patients headed for thrombectomy.

Why This Study Matters

For patients with large-vessel-occlusion stroke, even a small head start in restoring blood flow may improve brain salvage and long-term recovery. If the artery partially or completely reopens before the thrombectomy procedure, the procedure may become easier, faster, or in some cases no longer needed. That is why the first angiogram after giving the thrombolytic drug is clinically important.

This study is especially relevant in regions where low-dose alteplase is already standard practice. If tenecteplase proves superior or at least comparable in safety and functional outcomes, it could become an important alternative and potentially support regulatory approval in settings where it is not yet widely approved for stroke.

Study Design

This was an investigator-initiated, multicenter, randomized, controlled, open-label superiority trial conducted in Japan from August 19, 2022, to March 13, 2025, with 3-month follow-up. It was the first randomized trial to directly compare standard-dose tenecteplase with low-dose alteplase for acute ischemic stroke in this clinical scenario.

A total of 221 patients with large-vessel-occlusion stroke who were eligible for intravenous thrombolysis within 4.5 hours of symptom onset and were scheduled for mechanical thrombectomy were randomized in a 1:1 ratio. After excluding patients who did not receive the study drug, 218 patients were included in the full analysis set: 107 received tenecteplase and 111 received alteplase.

The main outcome was substantial reperfusion on the initial angiogram, defined as modified Treatment in Cerebral Ischemia, or mTICI, grade 2b to 3, or no retrievable thrombus. In plain language, this means the clot had already reopened enough to restore meaningful blood flow, or there was no clot left to remove. Secondary outcomes included functional outcome at 90 days measured by the modified Rankin Scale, which is a widely used scale ranging from no symptoms to severe disability. Safety outcomes included symptomatic intracranial hemorrhage within 24 to 36 hours and death at 90 days.

Main Findings

The average age of the participants was 77.1 years, and about 42% were women. Substantial reperfusion on the initial angiogram occurred more often in the tenecteplase group than in the alteplase group: 10.3% versus 3.6%. The absolute difference was 6.5 percentage points, with a 90% confidence interval of 0.89 to 12.1. This met the study’s prespecified success criterion.

The functional outcome data suggested a favorable trend for tenecteplase. The estimated common odds ratio for a shift toward a better 90-day modified Rankin Scale outcome was 1.47, with a 95% confidence interval of 0.92 to 2.35. This means the results leaned toward benefit, although the confidence interval included the possibility of no clear difference.

Safety outcomes were reassuring. Symptomatic intracranial hemorrhage occurred in 2.8% of patients in the tenecteplase group and 1.8% in the alteplase group. Mortality at 90 days was 6.5% with tenecteplase and 9.9% with alteplase. These rates were broadly similar, suggesting no major safety disadvantage with tenecteplase in this trial.

Clinical Interpretation

The study suggests that standard-dose tenecteplase given before thrombectomy may improve early vessel reopening compared with low-dose alteplase. Early reperfusion is important because it can reduce the amount of brain tissue at risk, potentially improving recovery. Even when thrombectomy is still needed, a partially or fully reopened artery may make treatment easier and faster.

The findings also support the growing view that tenecteplase is a strong thrombolytic candidate for acute ischemic stroke, especially in systems where rapid workflow and single-bolus administration are valuable. Tenecteplase can be delivered more simply than alteplase, which requires a bolus followed by an infusion. In real-world stroke care, this simplicity may reduce treatment delays and logistics burden.

That said, this trial compared tenecteplase with low-dose alteplase, not with the standard alteplase dose used in many non-Asian regions. Also, the absolute reperfusion rates were relatively low overall, so the results should be interpreted in the context of a population already going on to thrombectomy. The study was designed to test superiority for a specific early imaging outcome, and although the direction of the functional outcome data was favorable, the trial was not powered to prove a definitive difference in long-term disability or mortality.

Practical Implications

For stroke teams, this trial adds important evidence that tenecteplase at 0.25 mg/kg may be an effective pre-thrombectomy thrombolytic option. If confirmed and incorporated into guidelines, it could influence how hospitals manage large-vessel-occlusion stroke, particularly in countries where low-dose alteplase remains standard.

The results may be especially relevant for emergency departments, interventional neuroradiology teams, and stroke units that need a treatment that is fast, reliable, and easy to administer. Tenecteplase’s single-bolus dosing may help streamline care, which matters because “time is brain” in ischemic stroke.

Patients and families should still understand that thrombolysis is only one part of stroke treatment. Rapid recognition of stroke symptoms, immediate hospital evaluation, brain imaging, and timely access to thrombectomy remain essential. The choice of thrombolytic drug depends on local approvals, institutional protocols, contraindications, and expert clinical judgment.

Limitations

Like any clinical trial, this study has limitations. It was open-label, meaning clinicians knew which drug was being used, although the primary angiographic outcome is relatively objective. The trial was conducted in Japan, so results may not fully generalize to other health systems or populations. The comparison was against low-dose alteplase, which is appropriate for the study setting but different from the alteplase dose used in many other regions.

The sample size was modest, and the study was not designed to definitively settle all questions about longer-term functional benefit or rare safety events. Additional studies in diverse populations will help clarify whether these findings should change routine care more broadly.

Conclusion

In this randomized clinical trial, standard-dose tenecteplase at 0.25 mg/kg produced higher early substantial reperfusion than low-dose alteplase at 0.6 mg/kg in patients with large-vessel-occlusion acute ischemic stroke scheduled for mechanical thrombectomy. Functional and safety outcomes were similar between groups, making tenecteplase a promising thrombolytic option in regions where low-dose alteplase is currently standard. The study provides meaningful evidence supporting the potential role of tenecteplase in modern stroke care.