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

Overview

Acute ischemic stroke caused by a large-vessel occlusion is a medical emergency in which a major artery supplying the brain becomes blocked, cutting off blood flow to brain tissue. The fastest possible reopening of the blocked vessel is essential to limit permanent disability. In many patients, treatment begins with intravenous thrombolysis before mechanical thrombectomy, a catheter-based procedure that physically removes the clot.

This randomized clinical trial compared two clot-busting medicines given before thrombectomy: standard-dose tenecteplase at 0.25 mg/kg and low-dose alteplase at 0.6 mg/kg. The study is especially important in Japan and other Asian countries, where low-dose alteplase has been widely used and where evidence supporting tenecteplase has been limited.

Why This Study Matters

Tenecteplase and alteplase are both thrombolytic drugs, meaning they help dissolve blood clots. Alteplase has long been the standard intravenous treatment for acute ischemic stroke in many parts of the world. Tenecteplase is a newer agent with practical advantages, including single-bolus administration rather than a longer infusion, which can simplify emergency stroke care.

In Japan, however, low-dose alteplase at 0.6 mg/kg remains the standard regimen. This trial was designed to answer a clinically important question: in patients with large-vessel-occlusion stroke who are already planned for thrombectomy, does standard-dose tenecteplase lead to better early reperfusion than low-dose alteplase? The answer could influence future treatment guidelines and regulatory decisions in Japan.

Study Design

This was an investigator-initiated, multicenter, randomized, controlled, open-label superiority trial conducted from August 19, 2022, to March 13, 2025. The study included patients with acute ischemic stroke due to large-vessel occlusion who were eligible for intravenous thrombolysis within 4.5 hours of symptom onset and were scheduled to undergo mechanical thrombectomy.

A total of 221 patients were randomized. Of these, 218 patients who received trial medication were included in the full analysis set: 107 received tenecteplase and 111 received alteplase. The participants had a mean age of 77.1 years, and 92 were female and 126 were male. Outcomes were followed for 3 months.

Patients were randomly assigned in a 1:1 ratio to receive either intravenous tenecteplase or alteplase before thrombectomy. The study compared early vessel reopening on the initial angiogram, as well as longer-term disability and safety outcomes.

Main Outcome

The primary 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 practical terms, this means the clot had already broken down enough, or had disappeared sufficiently, that blood flow in the blocked vessel had been restored before the thrombectomy procedure fully began.

This early reperfusion is clinically meaningful because it may reduce the amount of clot that needs to be removed mechanically, shorten procedure time, and potentially improve brain recovery.

Results

Substantial reperfusion occurred in 10.3% of patients in the standard-dose tenecteplase group compared with 3.6% in the low-dose alteplase group. 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, indicating that tenecteplase performed better on the primary endpoint.

For functional outcome at 90 days, the estimated common odds ratio for a shift toward better disability status on the modified Rankin Scale was 1.47, with a 95% confidence interval of 0.92 to 2.35. This suggests a possible functional benefit with tenecteplase, although the confidence interval included no clear difference, so the finding was not definitive.

The safety results were reassuring. Symptomatic intracranial hemorrhage, the most feared complication of thrombolytic treatment, occurred in 2.8% of the tenecteplase group and 1.8% of the alteplase group. Mortality at 90 days was 6.5% with tenecteplase and 9.9% with alteplase. These differences were small and generally consistent with comparable safety between the two treatments in this study.

Interpretation

The key finding is that standard-dose tenecteplase achieved a higher rate of early substantial reperfusion than low-dose alteplase in patients with large-vessel-occlusion stroke who were headed for thrombectomy. Early reperfusion before catheter retrieval may be especially valuable because every minute of persistent vessel blockage increases the risk of irreversible brain injury.

Tenecteplase’s single-bolus administration is also operationally attractive in stroke systems of care. It can be delivered more quickly and may reduce complexity in busy emergency departments, ambulance-to-hospital workflows, and inter-hospital transfers. In thrombectomy-eligible patients, these advantages may translate into better coordination and faster progression to definitive treatment.

At the same time, this trial should be interpreted with appropriate caution. While the primary outcome favored tenecteplase, the study was not large enough to prove a definitive difference in long-term functional recovery. The 90-day functional outcome trended in the same direction but did not reach a clear statistically conclusive result. As with many stroke trials, the study was designed to detect early reperfusion differences, which are important but do not always map perfectly onto final disability outcomes.

Clinical Significance

For clinicians, this trial adds important evidence that standard-dose tenecteplase may be a strong alternative to low-dose alteplase in acute ischemic stroke from large-vessel occlusion, particularly when mechanical thrombectomy is planned. The data support the idea that tenecteplase can improve early clot dissolution without introducing an obvious major safety penalty.

For health systems in Japan and other regions where low-dose alteplase has been standard, the findings are especially relevant. They may help inform local practice changes, guideline updates, and regulatory review. Because the trial directly compared tenecteplase with the regionally standard alteplase dose, it addresses a real-world treatment question rather than an indirect comparison.

For patients and families, the study suggests that a newer clot-busting medicine may help reopen the blocked artery sooner, while maintaining a similar safety profile. However, the choice of treatment still depends on many factors, including time from symptom onset, imaging findings, stroke severity, access to thrombectomy, and the treating team’s protocols.

Background: Thrombolysis and Thrombectomy

Intravenous thrombolysis works best when given as early as possible after stroke onset. It is most effective for dissolving fresh clots and restoring flow before too much brain tissue has died. Mechanical thrombectomy is used for large clots in major arteries and has become a cornerstone of modern stroke care.

In many systems, these treatments are combined: the thrombolytic is administered immediately, and the patient is then taken for thrombectomy. This is often called bridging therapy. The aim is to achieve the fastest possible reperfusion, either through the medicine alone or by combining it with endovascular clot retrieval.

A medication that can produce more early reperfusion before thrombectomy can be valuable because some clots may partially or fully dissolve before the catheter procedure begins. This can improve the chance of quicker restoration of flow and may reduce the technical burden of thrombectomy.

Practical Takeaways

1. Standard-dose tenecteplase was more effective than low-dose alteplase for early substantial reperfusion in this trial.
2. Safety outcomes, including symptomatic intracranial hemorrhage and mortality, were similar between groups.
3. The study supports tenecteplase as a promising option before thrombectomy in large-vessel-occlusion stroke.
4. More evidence may still be needed to confirm whether the early reperfusion advantage translates into a consistent long-term disability benefit.

Conclusion

In this randomized clinical trial, standard-dose tenecteplase at 0.25 mg/kg produced higher early reperfusion rates than low-dose alteplase at 0.6 mg/kg in acute ischemic stroke due to large-vessel occlusion, without an obvious increase in major safety concerns. These findings strengthen the case for tenecteplase as a promising thrombolytic option in regions where low-dose alteplase has traditionally been the standard of care, and they provide evidence that may help guide future stroke treatment policies in Japan.