In patients with "wake-up" stroke selected by noncontrast CT, treatment with tenecteplase did not significantly improve functional outcome at 90 days in the TWIST trial.
Although tenecteplase treatment was associated with a higher proportion of patients achieving an excellent functional outcome, this was not statistically significant, and symptomatic intracranial hemorrhage was numerically higher in the tenecteplase group.
The TWIST trial was presented by Melinda Roaldsen, MD, University Hospital of North Norway, at the recent European Stroke Organisation Conference 2022.
Wake-up stroke occurs when a patient goes to bed well and wakes up with stroke symptoms. Roaldsen explained that patients who wake up with stroke have previously been excluded from treatment with thrombolysis because of the unknown timing of the onset of stroke symptoms.
However, in recent years, this has started to change, with previous trials showing benefit of thrombolytic treatment in wake-up stroke patients where MRI or CT contrast perfusion imaging are used to identify salvageable tissue, but this advanced imaging is not universally available.
The aim of the TWIST trial was to determine whether thrombolytic treatment with tenecteplase at a dose of 0.25 mg/kg results in a better functional outcome than standard care (no thrombolysis) in patients with acute wake-up stroke selected by noncontrast CT.
"We chose to use noncontrast CT as our screening tool in this study to exclude patients with intracranial haemorrhage or large infarcts similar to what is used in routine practice in patients with known time of symptom onset," Roaldsen noted.
The researchers also chose to use tenecteplase rather than alteplase as the thrombolytic because of its pharmacologic advantages, which include higher fibrin specificity, a longer half-life, and a simpler administration route of a single-bolus dose.
Patients were recruited if they had a wake-up stroke characterized by limb weakness and a National Institutes of Health Stroke Scale (NIHSS) score of 3 or more, or aphasia, and were within 4.5 hours of waking.
Patents were excluded if they had an intracranial hemorrhage, a large infarct size (more than one-third of the middle cerebral artery territory), an NIHSS score over 25 or NIHSS consciousness score over 2, or a modified Rankin Scale (mRS) score of 3 or more.
Patients were randomized in a 1:1 ratio to either tenecteplase 0.25 mg/kg or no thrombolytic treatment.
The trial was stopped — because of the COVID-19 pandemic and difficulty accessing tenecteplase — when 578 of the planned 600 patients had been enrolled.
Baseline characteristics of the two groups were balanced with regard to age, gender, NIHSS score on admission (median, 6), and time from last known well to wake up (medium, 11 hours), but more patients in the control group than in the tenecteplase were treated with thrombectomy (14% vs 6%).
Results showed a trend toward improvement in the primary outcome of functional status, measured by the mRS ordinal shift analysis in the tenecteplase group, with an adjusted odds ratio (OR) of 1.18 (95% CI, 0.88 - 1.58)
The secondary outcome of an excellent functional outcome — mRS of 0 to 1 — was achieved by 45% of patients in the tenecteplase group and 38% of those in the control group. This again did not reach statistical significance (OR, 1.33; 95% CI, 0.94 - 1.87).
However, Roaldsen pointed out that the effect size was similar to that seen with thrombolysis in previous trials of patients in the 4.5-hour time window from known symptom onset.
There was no significant difference between the two groups with regard to safety, although the risk estimates for symptomatic intracranial hemorrhage (sICH) were higher in the tenecteplase group.
Rates of sICH defined by SITS-MOST were 3.1% in tenecteplase group and 1.0% in the control group (P = .09). When the IST-3 definition of sICH was used, rates were 4.2% and 2.8%, respectively (P = .36).
"In light of these results, it is clear that the estimated treatment effect when designing the study was too optimistic, so the trial was underpowered, which limits interpretation of the results," Roaldsen concluded.
"In addition, the unbalanced distribution between the two groups with regard to thrombectomy may also have affected the results," she added.
A subgroup analysis examining the effect of thrombectomy showed an increased effect estimate of tenecteplase in patients who did not receive thrombectomy, but no effect of the thrombolytic in those who underwent the endovascular procedure.
Roaldsen suggested that the positive results of two trials of alteplase in wake-up stroke — WAKE-UP and EXTEND — which were reported during the TWIST trial enrollment period could have caused a shift in the selection of patients.
"We cannot exclude that this may have led to patients being enrolled in TWIST who did not have imaging signs indicative of salvageable tissue while patients who did have such signs were more likely to be treated outside the trial," she noted.
Commenting on the study, Alastair Webb, MD, professor of neurology at the Wolfson Centre for Prevention of Stroke and Dementia, University of Oxford, United Kingdom, said TWIST was another interesting study that adds to the growing body of evidence on the use of tenecteplase.
"However, because the study was not powered to demonstrate benefit compared to placebo, it is very hard to draw conclusions on whether this patient group should receive thrombolysis with any agent without the advantage of the imaging strategies used in previous wake-up trials with positive outcomes," he noted.
"As such, in wake-up stroke patients, our management approach should still be driven by these previous trials," Webb concluded.
The TWIST trial was mainly funded by the Norwegian National Program for Clinical Research in the Specialist Health Services.
European Stroke Organisation Conference (ESOC) 2022. Presented May 6, 2022.
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Cite this: Uncertain Results for Tenecteplase in 'Wake-up' Stroke - Medscape - May 12, 2022.