Some patients with large vessel occlusion strokes may still benefit from being given thrombolysis even if they present later than the traditional 4.5-hour time window, new analysis of the TIMELESS trial suggested.
Main results of the trial, which were presented last year, failed to show a significant improvement in the primary endpoint — the ordinal score on the modified Rankin scale (mRS) — with the thrombolytic, tenecteplase compared with placebo. Patients selected for the study presented between 4.5 and 24 hours with an occlusion of the middle cerebral artery (M1 or M2) or of the internal carotid artery (ICA). They also had to have evidence of salvageable tissue as determined on perfusion imaging.
New results of subgroup analyses from the trial, however, have identified several patient groups who may possibly derive a benefit from tenecteplase. These include patients with M1 occlusions, those who received tenecteplase at a primary stroke center before being transferred for thrombectomy, and those who were given the thrombolytic right at the time of thrombectomy.
These new results were presented at last week's International Stroke Conference (ISC) 2024 in Phoenix, Arizona. They were also published online, along with the main results of the trial, in The New England Journal of Medicine.
"The good news from the main TIMELESS results is that safety was established for administration of thrombolysis out to 24 hours in these patients with salvageable brain tissue identified on imaging," lead investigator Gregory Albers, director of the Stanford Stroke Center, told theheart.org | Medscape Cardiology. "But the downside was that the overall population enrolled in the study did not show a significant benefit from the treatment."
He said the new analyses "focus on the various subgroups, which are pretty interesting, and suggest several possible avenues for follow up studies."
For years, it has been thought too dangerous to give stroke patients thrombolysis after 4.5 hours, but now we know if we choose the patients appropriately with imaging-based selection, we have a group that we are not going to harm with thrombolysis. The next challenge is to identify which patients are going to benefit," he commented.
The largest subgroup of patients in the trial included those with M1 occlusions, which occur in the proximal part of the middle cerebral artery, who accounted for around half the patients in the trial.
"In that group, there was a pretty compelling treatment effect seen with thrombolysis both in the primary and the secondary endpoints," Albers noted.
The primary endpoint showed a shift in the Rankin disability score toward less disability in the tenecteplase group with a common odds ratio of 1.59 (95% CI, 1.00-2.52).
The secondary outcome was the percentage of patients who were functionally independent (mRS 0-2), and there was a substantial 15% increase in that outcome with tenecteplase in the patients with an M1 occlusion, Albers reported.
The second group of interest included patients who were enrolled and received study drug in an outside hospital and were then transferred to a comprehensive stroke center for thrombectomy. "While this group is very underpowered as there was only a small number of patients in this category, they showed a strong trend toward benefit with tenecteplase," Albers reported.
This observation fits with findings from other studies showing that if thrombolysis is given more time to work, it can bring about a substantial rate of vessel opening before thrombectomy is conducted, he said.
He pointed out that on average in the TIMELESS trial, there were only 16 minutes between thrombolysis administration and the start of thrombectomy. "That isn't giving the thrombolytic much time to have a benefit. But if the thrombolytic is given at an outside hospital and the patient is transferred, then the delay to thrombectomy is much longer giving time for the clot dissolving action to take effect."
The third group that may have benefitted from thrombolysis in the study included those treated right at the time of thrombectomy, who also showed a robust trend toward improvement, Albers noted.
"In this situation, the drug didn't really have time to do very much at all before the thrombectomy, but we think it might be working by dissolving fragments of the clot that are often left after thrombectomy," he suggested.
Abers noted that up to 30%-40% of patients can still show a perfusion deficit straight after thrombectomy, which is probably caused by clot fragments travelling downstream into smaller arteries.
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