Benefit of Late Thrombolysis in Large Vessel Strokes?

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.

Why M1 Occlusions?

Albers said the results in the M1 and M2 occlusion strokes were not what was expected.

“There were three types of occlusion in this study: The ICA occlusions which are very big clots, the M1s which are intermediate size, and the M2s which are smaller clots. We had anticipated that the thrombolytic would work best for the smaller M2 clots and not as well for larger clots. That is because in the large clots the thrombolytic can only access the surface of the clot — it can’t get at a lot of the clot,” he explained.

The current results show that, as expected, the ICA occlusions did not benefit from thrombolysis, but surprisingly, the larger M1 occlusions showed a benefit while the smaller M2 occlusions did not, observations that the TIMELESS researchers are still trying to understand.

“We are taking a deep dive into the M2 data to see if we can find an explanation for the lack of benefit seen in this group,” Albers noted.

He suggested that more distal M2 occlusions may not be great candidates for thrombectomy.

“It is hard to get a catheter down into these vessels that far and the rate of complications may be higher,” he said. “Also, these M2 occlusions tend to cause smaller strokes in general, so if a complication did occur then it could make the patient worse than if they had just been left alone. So, there is a push now going on with studies underway trying to figure out whether we should be doing thrombectomy in these distal M2 occlusions or not. This is something that will be looking at more closely in further analysis of our data.”

Commenting on these latest TIMELESS findings for theheart.org | Medscape Cardiology, Michael Hill, MD, professor of neurology at the University of Calgary, Calgary, Alberta, Canada, pointed out that although the subgroup analysis did not provide statistically significant findings, he found the nominal directions of effect interesting, particularly regarding the M1 vs M2 observations.

Hill pointed out that that the previous INTERRSeCT study also suggested that the ideal occlusion location for intravenous thrombolysis was the mid-M1 middle cerebral artery.

“Further analysis is needed on TIMELESS examining vessel recanalization in the group that underwent angiography to understand this phenomenon better,” he commented.

Hill believes that thrombolysis in the late window may still be possible. “But it will need to be very carefully considered and will very likely not be widely generalizable,” he said.

In an editorial accompanying the TIMELESS publication in The New England Journal of Medicine, Dana Leifer, MD, Weill Cornell Medical College, New York City, concluded that: “The trial results tentatively suggest that pretreatment with tenecteplase before thrombectomy may be beneficial in patients with occlusions in the M1 segment when administered in the 4.5- to 24-hour window, but they also suggest that tenecteplase is probably unlikely to help patients who present with large vessel occlusions and do not undergo thrombectomy.”

She pointed out that the trial excluded patients who did not have large vessel occlusions, so it did not provide evidence about tenecteplase treatment in such patients.

Leifer added that further research is needed to look more closely at all these different scenarios.

The TIMELESS trial was supported by Genentech. Albers reported being a consultant for Genentech and iSchemaView. Leifer reported no relevant disclosures.