Highlights
The OPTION randomized clinical trial provides pivotal data on the use of tenecteplase for a historically underserved patient population: those with non-large vessel occlusion (non-LVO) ischemic stroke presenting in the late window (4.5 to 24 hours). Key findings include:
- Tenecteplase (0.25 mg/kg) significantly increased the rate of excellent functional outcomes (mRS 0-1) at 90 days compared to standard medical treatment (43.6% vs. 34.2%).
- Imaging-based selection using perfusion criteria was essential for identifying patients with salvageable brain tissue who might benefit from late-window intervention.
- While efficacious, tenecteplase was associated with a higher incidence of symptomatic intracranial hemorrhage (sICH) (2.8% vs. 0%).
- Mortality rates at 90 days did not differ significantly between the groups, suggesting a manageable safety profile relative to the functional gains.
Background: The Challenge of the Late-Window Stroke
For decades, the therapeutic window for intravenous thrombolysis in acute ischemic stroke was strictly limited to within 4.5 hours of symptom onset. This timeframe was based on early clinical trials suggesting that the risk of hemorrhage outweighed the benefits of reperfusion as time progressed. However, the advent of advanced neuroimaging—specifically CT perfusion (CTP) and MR perfusion—has shifted the focus from ‘time-clock’ to ’tissue-clock.’ We now understand that the rate of infarct core expansion varies significantly between individuals, and many patients retain salvageable penumbral tissue well beyond the 4.5-hour mark.
While mechanical thrombectomy has revolutionized the treatment of large vessel occlusions (LVO) in the late window (up to 24 hours), patients with non-LVO strokes—who represent the majority of ischemic stroke cases—have had fewer evidence-based options beyond the traditional window. Tenecteplase, a genetically engineered variant of alteplase with higher fibrin specificity and a longer half-life, has emerged as a promising alternative due to its ease of administration (single bolus) and potentially superior efficacy. The OPTION trial was designed to address whether tenecteplase could safely extend the treatment window for these non-LVO patients.
Study Design and Methodology
The OPTION (Tenecteplase for Acute Non-Large Vessel Occlusion 4.5 to 24 Hours After Ischemic Stroke) trial was a multicenter, randomized, open-label clinical trial with blinded end-point assessment. Conducted across 48 centers in China, the study recruited 566 patients between June 2023 and August 2025.
Patient Selection
Eligibility criteria were stringent to ensure the inclusion of patients most likely to benefit. Participants had to present between 4.5 and 24 hours after they were last seen well. Crucially, they were required to have non-LVO stroke and evidence of salvageable tissue, defined by perfusion imaging (a mismatch between the ischemic core and the hypoperfused penumbra). Patients with visible large vessel occlusions on CTA or MRA were excluded, as they are typically candidates for thrombectomy.
Intervention
Patients were randomized in a 1:1 ratio to receive either:
- Tenecteplase Group: A single intravenous bolus of tenecteplase at 0.25 mg/kg (maximum dose of 25 mg).
- Control Group: Standard medical treatment, which typically included antiplatelet therapy and intensive risk factor management as per current guidelines.
Endpoints
The primary efficacy outcome was an ‘excellent functional outcome,’ defined as a score of 0 or 1 on the modified Rankin Scale (mRS) at 90 days. Secondary outcomes included various mRS shifts and neurological improvement scales. Safety outcomes focused on the incidence of symptomatic intracranial hemorrhage (sICH) within 36 hours and all-cause mortality within 90 days.
Results: Efficacy and Safety of Late-Window Tenecteplase
The study results provide a compelling case for the efficacy of tenecteplase in this specific cohort. Of the 566 patients included in the primary analysis, the median age was 68 years, and 34.6% were female.
Primary Efficacy Outcome
The tenecteplase group demonstrated a significantly higher proportion of patients achieving an mRS of 0-1 at 90 days compared to the control group. Specifically, 43.6% (123/282) of patients in the tenecteplase arm reached this endpoint, compared to 34.2% (97/284) in the standard care arm. This resulted in a risk ratio (RR) of 1.28 (95% CI, 1.04-1.57; P = .02), indicating a 28% relative increase in the likelihood of a favorable recovery.
Safety Profile
The improvement in functional outcomes came with a measurable increase in bleeding risk. Symptomatic intracranial hemorrhage (sICH) occurred in 2.8% of the tenecteplase group, whereas no cases (0%) were reported in the standard medical treatment group (risk difference, 2.85%; P = .004). This finding highlights the inherent risk of introducing a potent thrombolytic agent in the late window, even when tissue is deemed salvageable.
Mortality and Other Outcomes
Despite the increased risk of sICH, the 90-day mortality rate was not significantly different between the two groups (5.0% for tenecteplase vs. 3.2% for control; RR, 1.57; P = .28). This suggests that while hemorrhages did occur, they did not lead to a statistically significant increase in the overall death rate within the study period.
Clinical Implications and Expert Interpretation
The OPTION trial is a landmark study because it fills a critical gap in stroke care. For clinicians, the trial provides evidence-based justification for considering thrombolysis in non-LVO patients who arrive late but show a ‘favorable’ imaging profile. However, the results necessitate a nuanced clinical approach.
The Role of Perfusion Imaging
The success of the OPTION trial was predicated on the use of perfusion imaging to select patients. This reinforces the shift toward a physiology-based approach to stroke treatment. Without CTP or MRI perfusion, it would be impossible to distinguish between a patient with a completed infarct and one with a large penumbra at risk. Facilities wishing to implement these findings must have robust, rapid imaging protocols in place.
Balancing Benefit and Risk
The 2.8% sICH rate in the tenecteplase group is a critical data point. While the absolute risk is relatively low, it is not zero. Clinicians must weigh the 9.4% absolute increase in excellent functional outcomes against the 2.8% increase in sICH. In many cases, particularly for younger patients or those with high baseline functional status, the trade-off may be highly favorable. For others with multiple comorbidities or high bleeding risks, the decision remains complex.
Tenecteplase vs. Alteplase
While OPTION did not compare tenecteplase directly to alteplase in this window, tenecteplase’s pharmacological profile—specifically its higher fibrin specificity—makes it an attractive candidate for late-window use. The single-bolus administration is also a significant practical advantage in busy emergency departments or when transferring patients between facilities.
Conclusion: A Shift in the Thrombolytic Paradigm?
The OPTION trial successfully demonstrates that the therapeutic window for intravenous tenecteplase can be extended up to 24 hours in carefully selected patients with non-LVO ischemic stroke. This study challenges the traditional 4.5-hour cut-off and expands the population of patients who can benefit from reperfusion therapy. While the increased risk of sICH requires cautious patient selection and informed consent, the potential for achieving an excellent functional recovery is a significant step forward in stroke medicine.
Future research should focus on refining the imaging criteria to further minimize bleeding risks and determining if these results can be replicated in more diverse global populations. For now, the OPTION trial offers a new beacon of hope for late-presenting stroke patients who were previously considered beyond the reach of thrombolytic therapy.
Trial Information
- Funding: The study was supported by various national medical research grants in China.
- ClinicalTrials.gov Identifier: NCT05752916
- Reference: Ma G, Mo R, Zuo Y, et al. Tenecteplase for Acute Non-Large Vessel Occlusion 4.5 to 24 Hours After Ischemic Stroke: The OPTION Randomized Clinical Trial. JAMA. 2026. doi:10.1001/jama.2026.0210.