Looking back at ESOC 2024: New Trials for Tenecteplase

In the pursuit of improved outcomes for individuals with minor ischaemic stroke and intracranial occlusion, two randomized controlled trials exploring the impact of tenecteplase in people with minor and non-minor ischemic stroke were presented at ESOC 2024.

The TRACE-III study(1), conducted in China, aimed to investigate the effectiveness and safety of tenecteplase for treating acute ischemic stroke due to large-vessel occlusion beyond the traditional 4.5-hour window. The study involved 516 patients who were randomly assigned to receive either tenecteplase or standard medical treatment within 4.5 to 24 hours after stroke onset. The study focused on patients with acute ischemic stroke caused by large-vessel occlusion of ICA, M1 or M2 segments, and was based on perfusion imaging to identify salvageable brain tissue at the time of stroke. Of notice, patients were not planned for endovascular thrombectomy at the time of randomization, mainly in relation to unavailable treatment option.

The intervention in the study was the administration of tenecteplase at a dose of 0.25 mg per kilogram of body weight (maximum dose, 25 mg), as compared to medical treatment. Less than 2% of patients in both groups underwent rescue endovascular thrombectomy.

The results of the study showed that treatment with tenecteplase resulted in a significantly higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days compared to standard medical treatment (33.0% vs. 24.2%). Mortality at 90 days was similar between the two groups (13.3% with tenecteplase and 13.1% with standard medical treatment), as was the incidence of symptomatic intracranial hemorrhage within 36 hours after treatment was higher with tenecteplase (3.0% vs. 0.8%). For the latter, 9 patients among the 28 with sICH were protocol violations in relation to a missed diagnosis of a very large infarction at the time of stroke.

Overall, TRACE-III study provides additional evidence for the use of tenecteplase in the treatment of moderate-to-severe acute ischemic stroke beyond the traditional 4.5-hour window in settings with unavailable thrombectomy.

When it comes to minor stroke, on the contrary, things may be different.

In the TEMPO2 trial (2) led by Prof. Coutts, from the University of Calgary, a multicentre, prospective, randomized approach was used to establish the superiority of intravenous tenecteplase in patients with minor ischaemic stroke and intracranial occlusion compared to standard of care. Disappointingly, the study was halted prematurely due to futility, revealing no significant benefit from tenecteplase over standard care. Moreover, concerns arose regarding potential harm, as the tenecteplase group exhibited a higher mortality rate and more symptomatic intracranial hemorrhages. In TEMPO2, a total of 886 patients were enrolled between April 27, 2015, and Jan 19, 2024. The primary outcome, defined as a return to baseline functioning at 90 days, was reported in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group. The primary outcome rate was not different between groups, while a concerning trend emerged regarding mortality rates. In the tenecteplase group, 20 patients (5%) succumbed to the condition, compared to only five deaths (1%) in the control group. This marked difference in mortality yielded an adjusted hazard ratio of 3·8 (95% CI 1·4–10·2, p=0·0085), although supplementary analysis revealed causes of death to be not related to treatment overall.

The incidence of symptomatic intracranial hemorrhages was higher in the tenecteplase group as well, with eight patients (2%) vs only two (<1%) in the control group. A non-significant and yet notable trend to consider. These findings underscore the complexities of defining a tailored approach to hyperacute stroke treatment, with tenecteplase showing a potentially effective profile in LVO-related mild to moderate stroke and salvageable brain tissue, but also not emerging as a safe option in minor stroke with LVO. Real-world data and further randomized trials will address grey areas, as we proceed towards a personalized care.

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References

1 Chen et al. N Engl J Med. 2024;390(24):2345-2354.

2 Coutts et al. Lancet. 2024; 403: 2597-2605

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