Author: Vojtech Novotny
X: @vojtech_no
The pharmacokinetics and pharmacodynamics of tenecteplase have been proven superior to alteplase, and it has been used for myocardial infarction for over 25 years.¹ However, the adoption of tenecteplase as a thrombolytic for acute ischemic stroke (AIS) took more time. Several high-quality randomized controlled trials (RCTs) have tested tenecteplase for AIS in various settings in the last decade, ultimately leading to the implementation of tenecteplase 0.25 mg/kg in daily practice. The evidence for the 0–4.5h time window in patients with or without large vessel occlusion (LVO) has become robust enough to be incorporated into the European Stroke Organisation’s (ESO) guidelines.² Since then, evidence for the standard time window has grown even stronger, supported by results from RCTs such as ATTEST-2, TASTE, TRACE-2, and ORIGINAL.3
Is it really time to use tenecteplase in the extended time window as well? A meta-analysis of three RCTs (EXTEND, ECASS4-EXTEND, and EPITHET), supported by expert consensus, has provided sufficient evidence for the routine use of alteplase in the 4.5–9h time window, with CT perfusion mismatch used for patient selection.4 The use of tenecteplase in the extended time window remains off-label due to a lack of regulatory approvals, although the evidence continues to strengthen. Many centers have already started, or are starting, to use tenecteplase in the extended time window. But where do we currently stand in terms of evidence?
A meta-analysis of three RCTs investigating tenecteplase 0.25 mg/kg in the extended time window (ROSE-TNK, TWIST, and TIMELESS) demonstrated a favorable safety and efficacy profile of tenecteplase. However, the interpretation warrants caution, as different neuroimaging modalities were used across the trials.⁵ The TWIST trial, testing tenecteplase in wake-up stroke selected with plain CT, showed improved functional outcomes favoring tenecteplase, but the results were not statistically significant, as the study was likely underpowered.⁶ The ROSE-TNK phase 2 trial used DWI-FLAIR MRI mismatch for patient selection, randomizing patients to either tenecteplase 0.25 mg/kg or standard care in 4.5–24h time window. While the efficacy and safety profiles were similar between groups, early neurological improvement favored tenecteplase.⁷ The TIMELESS trial, which tested tenecteplase 0.25 mg/kg versus placebo in 458 patients selected by CT perfusion in 4.5–24h time window, showed no significant difference in functional outcomes. However, the inclusion criteria involved LVO (anterior circulation), and most patients underwent mechanical thrombectomy shortly after intravenous thrombolysis, potentially diluting the effect of tenecteplase.⁸ Importantly, the safety profile was comparable to alteplase, and tenecteplase appeared to enhance complete recanalization at 24 hours.
The TRACE III trial also randomized patients with AIS caused by LVO, using CT perfusion for selection, but focused on those without access to mechanical thrombectomy. Here, tenecteplase 0.25 mg/kg was superior to the control (antiplatelet therapy). Although the rate of symptomatic intracranial hemorrhage was higher in the tenecteplase group, it was comparable to previous trials in both standard and extended time window.⁹ These results are particularly important for low-income countries where access to mechanical thrombectomy is very limited.
The TEMPO-2 trial, which included 886 patients, evaluated tenecteplase in minor non-disabling strokes (NIHSS <6) with confirmed LVO. The results showed no benefit in the tenecteplase arm and even potential harm compared to standard care.¹⁰ These findings align with previous trials using alteplase in similar settings (PRISM and ARAMIS), which favored antiplatelet therapy for this patient group. Soon, there will be enough accumulated data to provide a stronger foundation of evidence. One of the ongoing RCTs, the Brazilian RESILIENT-EXTEND-IV trial, randomizes patients without LVO and within 4.5–12h time window, using CTP perfusion for patient selection (TNK 0.25 mg/kg vs placebo). The ETERNAL and POST-ETERNAL are examining tenecteplase 0.25 mg/kg vs standard care (which may include alteplase when indicated) in patients with LVO in the anterior and posterior circulations (basilar occlusion), respectively. The evidence for tenecteplase in the standard time window, as well as for alteplase in the extended time window, is robust. As such, any deviation from the current trend of using tenecteplase in the extended time window is unlikely with the upcoming data. However, evidence-based medicine remains the cornerstone of clinical decision-making, and the results from the ongoing RCTs are crucial for strengthening the evidence. --- References
- Tanswell, Paul, et al. “Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction.” Clinical pharmacokinetics41 (2002): 1229-1245.
- Alamowitch, Sonia, et al. “European Stroke Organisation (ESO) expedited recommendation on tenecteplase for acute ischaemic stroke.” European Stroke Journal8.1 (2023): 8-54.
- Palaiodimou, Lina, et al. “Tenecteplase vs alteplase in acute ischemic stroke within 4.5 hours: a systematic review and meta-analysis of randomized trials.” Neurology103.9 (2024): e209903.
- Campbell, Bruce CV, et al. “Extending thrombolysis to 4· 5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data.” The Lancet394.10193 (2019): 139-147.
- Palaiodimou, Lina, et al. “Tenecteplase for the treatment of acute ischemic stroke in the extended time window: a systematic review and meta-analysis.” Therapeutic Advances in Neurological Disorders 17 (2024): 17562864231221324.
- Roaldsen, Melinda B., et al. “Safety and efficacy of tenecteplase in patients with wake-up stroke assessed by non-contrast CT (TWIST): a multicentre, open-label, randomised controlled trial.” The Lancet Neurology 22.2 (2023): 117-126.
- Wang, Lu, et al. “Intravenous tenecteplase for acute ischemic stroke within 4.5–24 hours of onset (ROSE-TNK): a phase 2, randomized, multicenter study.” Journal of Stroke 25.3 (2023): 371.
- Albers, Gregory W., et al. “Tenecteplase for stroke at 4.5 to 24 hours with perfusion-imaging selection.” New England Journal of Medicine390.8 (2024): 701-711.
- Xiong, Yunyun, et al. “Tenecteplase for ischemic stroke at 4.5 to 24 hours without thrombectomy.” New England Journal of Medicine 391.3 (2024): 203-212.
- Coutts, Shelagh B., et al. “Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.” The Lancet 403.10444 (2024): 2597-2605.
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