EXTEND: More Evidence of tPA Benefit 9 Hours After Stroke

Pauline Anderson

February 13, 2019

HONOLULU — Extending the time window for thrombolytic therapy to 9 hours for patients selected using automated computed tomography (CT) perfusion imaging can result in excellent functional outcomes, final results of a new study suggest.

"The study confirms that we should move toward tissue-based selection for reperfusion therapy rather than basing selection on time," study author Mark Parsons, PhD, director of neurology and professional chair of neurology at University of Melbourne in Australia, told Medscape Medical News.

The study, EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND), was presented here during the International Stroke Conference (ISC) 2019.

The new results showing the validity of CT perfusion imaging for patient selection match those of a study reported last year by European investigators, the current study authors say. The WAKE-UP trial showed that tPA was safe and effective in patients with wake-up stroke that had occurred more than 4.5 hours before treatment, but that study used magnetic resonance imaging (MRI), not CT perfusion, for patient selection.

In many stroke centers, CT perfusion imaging is much more available than MRI, the researchers note.

The current guideline for thrombolysis in acute ischemic stroke is administration within 4.5 hours of stroke onset, but advanced neuroimaging studies suggest that the ischemic penumbra can exist for up to 24 hours and salvaging tissue can lead to improved clinical outcome, lead author Henry Ma, MD, adjunct senior lecturer, Monash University, Melbourne, Australia, told delegates during his presentation.

EXTEND was a phase 3, multicenter, double-blind trial in which patients were randomized to receive either intravenous (IV) tissue plasminogen activator (tPA) at 0.9 mg/kg, or to placebo.

Researchers stratified patients into 3 groups according to time of randomization after stroke: 4.5 to 6 hours; more than 6 to 9 hours; and "wake up" stroke, where the precise time of the stroke is unknown.

Automated Processing

An important element of the study was the use of CT perfusion or MR perfusion imaging and RAPID software for automated image processing, said Ma. The software interprets images and indicates whether a patient has a small infarct core and a large area of salvageable brain.

This information can be used to decide if a particular patient might benefit from thrombolysis.

Ma did not report how many patients underwent imaging with CT and how many had MRI, but he hinted that CT was used for a majority of cases.

The penumbral mismatch criteria in the study were as follows: a hypoperfusion to core volume ratio of more than 1.2; perfusion lesion to core absolute difference of more than 10 mL; and ischemic core lesion of less than or equal to 70 mL.

The study was stopped last June — after 225 of the planned 310 patients were recruited — following publication of the WAKE-UP trial, the researchers note, on the recommendation of the Data and Safety Monitoring Board. 

Of patients enrolled by that date, 112 received placebo and 113 received thrombolysis.

The primary outcome was modified Rankin Scale (mRS) score of 0 to 1 at 90 days. In the intention to treat (ITT) analysis, this occurred in 35% of the tPA group and 29% of the placebo group

The relative risk (RR), adjusted for admission National Institutes of Health Stroke Scale (NIHSS) score and age, was 1.44 (95% confidence interval [CI] 1.01 - 2.06; P = .04.)

Ma reported new results of a per protocol analysis that included 99 tPA patients and 105 placebo patients; some patients were excluded for not meeting imaging criteria and for other reasons, he said. Patients receiving tPA tended to be older (74 vs 71 years) and have a slightly higher NIHSS score (mean 12 vs 11).

In this per protocol analysis, most patients (65%) fell into the wake-up stroke category, followed by 25% in the 6 to 9-hour group, and 10% in the 4.5 to 6-hour group.

The median time from "last known well" to tPA therapy was 9.9 hours vs 8.9 hours for placebo.

Baseline imaging showed that the median ischemic core volume for the tPA group was 4.45 mL vs 6.33 mL for the placebo group. The median perfusion lesion was 74.24 mL in the tPA group and 79 mL for placebo group.

No Thrombectomy

Importantly, 70% of tPA patients and 72% of placebo patients had large vessel occlusion, which could be amenable to thrombectomy. Ma noted, though, that none of the EXTEND patients received thrombectomy.

Results for the primary endpoint of mRS 0-1 were similar in the per protocol analysis as in the ITT analysis (37% in the tPA group vs 29% in the placebo group). The adjusted RR was 1.45; 95% CI, 1.01 - 2.10 (P = .045).

A secondary outcome was mRS 0-2 at 90 days. Here, in the per protocol analysis, 51% in the tPA group achieved this outcome compared to 43% of the placebo group (P = .049).

For other outcomes in the per protocol analysis, including recanalization and early neurologic improvement (NIHSS reduction of 8 points or more, or NIHSS score of 0-1 at 24 hours), results for the tPA group were significantly better compared with the placebo group.

As for safety outcomes in the per protocol analysis, the mortality rate at 90 days was 9.5% in placebo and 11.1% in tPA subjects (P = .77).

More Hemorrhage

Symptomatic intracranial hemorrhage at 36 hours occurred in 1% of placebo and 6% of tPA patients, with an adjusted RR of 6.9 (P = .066).

"This is consistent with other thrombolytic therapy trials, but it was not associated with increased mortality, and did not negate the positive results of improved rate of functional outcome," said Ma.

EXTEND "is the first positive thrombolysis trial in an extended time window using automated penumbral imaging," noted Ma.

CT perfusion imaging and automated image processing were used to select stroke patients for mechanical thrombectomy in an extended time window in the previously reported DAWN trial and in the DEFUSE 3 trial.

Commenting on the new EXTEND trial results for Medscape Medical News, Ralph Sacco, MD, President of the American Academy of Neurology and chair of neurology at the University of Miami Miller School of Medicine in Florida, said the results are promising in that they offer more evidence that the time window to administer tPA may be extended in certain patients.

"It gives us hope that maybe we can extend the time window for tPA beyond the 4.5-hour window," he said. He added that the safety outcomes in the new study were "reasonable."

Sacco said he would like to see more research in this patient population, perhaps a study of tPA in combination with thrombectomy.

Win for Patients

Also commenting on the study, Nicole R. Gonzales, MD, associate professor of neurology at the University of Texas Health Science Center in Houston, said that such research that may lead to "helpful treatments" for more people "is always a win for patients."

She noted that the majority of the cases in the study were wake-up cases. "Wake-up strokes very often are not offered thrombolytic treatment," because the time of the stroke onset is unknown, said Gonzales, who was not involved with the current research.

Using advanced imaging to pick patients most likely to respond "is novel for IV thrombolysis," said Gonzales. "This gives us a tool to be able to identify the patients most likely to benefit from the treatment."

A question going forward, however, is how to make the advanced imaging software available outside of large centers, she said.

"The issue is how do you make it applicable to community hospitals who don't have this resource and don't have the people to interpret the data."

Ma, Parsons, Sacco, and Gonzales have disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2019: Abstract LB21.
Presented February 8, 2019.

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