Unconfirmed results of Tenecteplase in ‘wake-up’ stroke

In patients with ‘wake-up’ stroke selected by CT scan without contrast, 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 with excellent functional outcomes, 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, Northern Norway University Hospital, at the recent European Stroke Organization 2022 conference.

A wake-up stroke occurs when a patient goes to bed well and wakes up with stroke symptoms. Roldsen explained that patients who wake up with a stroke have previously been excluded from thrombolysis therapy because of the unknown timing of stroke symptoms.

However, in recent years this is beginning to change, as previous trials have shown the benefit of thrombolytic therapy in awake stroke patients where MRI or contrast perfusion tomography is used to identify reparable 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 functional outcomes that are better than standard care (without thrombolysis) in patients with acute awakening stroke selected by CT without contrast.

“We chose to use non-contrast CT as a screening tool in this study to exclude patients with intracranial hemorrhages or large infarcts similar to what is used in routine practice in patients with a known time to symptom onset,” Roldsen noted.

The researchers also chose to use tenecteplase instead of alteplase as a coagulant due to its pharmacological advantages, which include higher fibrin specificity, longer half-life, and simpler route of administration for a single dose.

Patients were recruited if they had a waking stroke characterized by limb weakness and a score of 3 or more on the National Institutes of Health Stroke Scale (NIHSS), or aphasia, and were within 4.5 hours of waking up.

Patents were excluded if they had intracranial hemorrhage, large infarct size (more than one third of the middle cerebral artery area), NIHSS score greater than 25 or NIHSS consciousness score greater than 2, or modified Rankin scale (mRS). 3 or more.

Patients were randomized at a 1:1 ratio to tenecteplase 0.25 mg/kg or without thrombolytic therapy.

The trial was halted – due to the COVID-19 pandemic and difficulty in accessing tenecteplase – when 578 out of 600 patients were enrolled.

Baseline characteristics of the two groups were balanced with respect to age, gender, NIHSS score on admission (median, 6), and time from last well-known time to wake up (median, 11 hours), but the number of patients in the control group was greater than in the tenecteplase treated with excision. thrombus (14% vs. 6%).

The results showed a trend toward improvement in the primary outcome of functional status, as measured by analysis of the mRS ordinal shift 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 0 to 1 – was achieved by 45% of patients in the tenecteplase group and 38% in the control group. This again did not reach statistical significance (OR, 1.33; 95% CI, 0.94–1.87).

However, Roaldsen noted that the effect size was similar to that seen with thrombolysis in patients’ previous trials in a 4.5-hour time window from the onset of known symptoms.

There was no significant difference between the groups regarding safety, although risk estimates for symptoms of intracranial hemorrhage (sICH) were higher in the tenecteplase group.

The sICH rates determined by SITS-MOST were 3.1% in the tenecteplase group and 1.0% in the control group (s = .09). When the IST-3 definition for sICH was used, the rates were 4.2% and 2.8%, respectively (s = .36).

“In light of these findings, it is clear that the treatment effect estimated when designing the study was very optimistic, so the trial was weak, which limits interpretation of the results,” Roldsen concluded.

“In addition, the unbalanced distribution between the two groups regarding thrombectomy may also have affected the results,” she added.

A subgroup analysis examining the effect of thrombectomy showed an overestimation of the effect of tenecteplase in patients who did not undergo thrombectomy, but there was no effect of the thrombolysis in those who underwent endovascular surgery.

Roaldsen suggested that the positive results of two trials of alteplase in arousal stroke – WAKE-UP and EXTEND – that were reported during the TWIST trial’s enrollment period could cause a shift in patient selection.

She noted, “We cannot rule out that this may have resulted in patients enrolling in TWIST who did not have imaging markers indicative of reparable tissue while patients who exhibited such markers were more likely to be treated outside the trial.”

Commenting on the study, Alastair Webb, MD, professor of neuroscience at the Wolfson Center for the Prevention of Stroke and Dementia, University of Oxford, UK, said TWIST was another interesting study adding to the growing body of evidence for the use of tenecteplase.

“However, because the study was not supported to demonstrate a benefit compared to placebo, it is very difficult to draw conclusions about whether this group of patients should receive thrombolysis with any factor without benefiting from the imaging strategies used in previous wake trials with positive results. Results “.

“As such, in awake stroke patients, our management approach must remain motivated by these previous experiences,” Webb concluded.

The TWIST trial was funded primarily by the Norwegian National Program for Clinical Research in Specialized Health Services.

European Stroke Organization (ESOC) Conference 2022. Presented on 6 May 2022.

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