Functional Outcome Improvements Not Observed in Tenecteplase-Treated Wake-Up Stroke

Author(s):

After 90 days, investigators found that tenecteplase was not associated with improvements in functional outcome, nor did it differ from placebo on mortality.

Melinda B. Roaldsen, MD, PhD

Recently published data from the global TWIST study showed that treatment with tenecteplase was not associated with better functional outcome in patients with wake-up stroke at 90 days. The findings added to the growing literature not supporting treatment with tenecteplase in patients selected with non-contrast CT scan.

In the study, adults with acute ischemic stroke symptoms upon awakening were randomly assigned to either single bolus of tenecteplase (n = 288) 0.25 mg per kg of bodyweight or control (n = 290). The median age of the cohort was 73.7 (IQR, 65.9-81.1) years, with changes in function at 90 days, the primary outcome, assessed through the modified Rankin Scale (mRS) score. Patients entering the study had limb weakness, a National Institutes of Health Stroke Scale score of 3 or higher or aphasia, a non-contrast CT examination of the head, and the ability to receive tenecteplase within 4.5 hours of awakening.

Led by Melinda B. Roaldsen, MD, PhD, associate professor, University Hospital of North Norway, TWIST was an investigator-initiated, multicenter trial with blinded end point assessment conducted at 77 hospitals. Patients with intracranial hemorrhage or infarct comprising hypoattenuation in more than a third of the middle cerebral artery territory on acute non-contrast CT were excluded to avoid inclusion of patients with a large infarct core who are at higher risk of intracerebral hemorrhage and less likely to benefit from treatment.

All told, at the end of the 90-day observation period, treatment with tenecteplase was not associated with better functional outcome, as shown by scores on mRS (adjusted OR, 1.18; 95% CI, 0.88-1.58; P = .27). Between the groups, 45% and 37% of tenecteplase-treated and non-treated patients, respectively, achieved excellent functional outcome (adjusted OR, 1.34; 95% CI, 0.95-1.88). Neurological deterioration from initial ischemic stroke occurred in 17 (6%) patients in the tenecteplase group versus 20 (7%) in the control group, whereas recurrent ischemic stroke occurred in four (1%) versus two (1%) patients.

Mortality at 90 days did not differ significantly between the groups either, as 10% (n = 28) of tenecteplase-treated patients and 8% (n = 23) of controls died (adjusted HR, 1.29; 95% CI, 0.74-2.26). Any intracranial hemorrhage was recorded in 11% (n = 33) of patients on tenecteplase vs 10% (n = 30) of those on controls (adjusted OR, 1.14; 95% CI, 0.67-1.94). Among a subgroup of patients (n = 50; 9%) who received thrombectomy, symptomatic intracranial hemorrhage occurred in 1 (6%) of 18 individuals in the tenecteplase group vs 2 (5%) of 42 individuals in the control group as per the SITS-MOST definition and in 2 (11%) vs 6 (14%) as per the International Stroke Trial-3 definition.

The WAKE-UP trial, originally published in the New England Journal of Medicine in 2018, was the first randomized controlled trial to show benefit from thrombolytic treatment with alteplase in patients with stroke of unknown time of onset.² Since then, 3 trials—EXTEND, THAWS, and ECASS-4—investigated the effect of alteplase vs placebo or no thrombolysis in patients with unknown onset of stroke. Although a positive effect in favor of thrombolysis was found in EXTEND, findings from THAWS and ECASS-4 did not show significant differences between patients with and without thrombolysis.^3,4

Roaldsen et al noted that the findings from TWIST add value to the previous trials in patients with wake-up stroke by using a different thrombolytic agent and imaging technique. “Tenecteplase has several pharmacological advantages compared with alteplase, including a longer free plasma half-life, allowing easy and quick administration as a single intravenous bolus dose,” the study investigators wrote.

Previous studies have used either DWI-FLAIR mismatch techniques or CT or MR perfusion imaging for selecting patients, with the underlying assumption that these techniques are more likely to identify patients with salvageable tissue or short duration of ischemia. "MRI or perfusion imaging are not universally available, and access is often limited, even in hospitals that have the necessary equipment, whereas CT scanners are more widely available and used for acute stroke imaging in clinical practice. Fair to moderate observer agreement with regards to recognizing and quantifying early ischemic changes on non-contrast CT has been reported and might be a concern when applying this imaging approach. There is also less potential for quantification of ischemic core and viable penumbra with non-contrast CT,” Roaldsen et al wrote.¹

REFERENCES
1. Roaldsen MB, Eltoft A, Wilsgaard T, et al. Safety and efficacy of tenecteplase in patients with wake-up stroke assessed by non-contrast CT (TWIST): a multicentre, open-label, randomized controlled trial. Lancet Neurol. 2023;22(2):117-126. doi:10.1016/S1474-4422(22)00484-7
2. Thomalla G, Simonsen CZ, Boutite F, et al. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379:611-622. doi:10.1056/NEJMoa1804355
3. Ringleb P, Bendszus M, Bluhmki E, et al. Extending the time window for intravenous thrombolysis in acute ischemic stroke using magnetic resonance imaging-based patient selection. Int J Stroke. 2019;14(5):483-490. doi:10.1177/1747493019840938
4. Koga M, Yamamoto H, Inoue M, et al. Thrombolysis with alteplase at 0.6 mg/kg for stroke with unknown time of onset: a randomized controlled trial. Stroke. 2020;51:1530-1538