EXTEND Published: tPA Success Up to 9 Hours After Stroke

May 09, 2019

Using perfusion imaging to identify patients with salvageable brain tissue following ischemic stroke looks to be the key to extending the window for thrombolysis out to 9 hours.

The results of the EXTEND trial show that more patients presenting between 4.5 and 9 hours treated with tPA (alteplase) under these conditions achieved a score of 0 or 1 on the modified Rankin scale (indicating no deficits or minimal deficits, respectively) than those give placebo.

The EXTEND trial is published in the May 9 issue of The New England Journal of Medicine. The results were first presented at the International Stroke Conference (ISC) in Hawaii earlier this year.

"These results open up the possibility of treating many more stroke patients with thrombolysis," senior author Geoffrey Donnan, MD, Royal Melbourne Hospital, Australia, told Medscape Medical News.

"Our study is positive and provides level 1 evidence for tPA out to 9 hours (including wake-up strokes) in patients with suitable imaging showing that brain tissue is salvageable. However, it probably does need to be validated," he said.  

Donnan noted that there have been two previous studies looking at late tPA with a similar design — ECASS-4 and EPITHET, and a meta-analysis of all three trials is about to be presented at this month's European Stroke Organisation Conference (ESOC) meeting in Milan, Italy. "If this is positive, then that might be the validation we need," he commented.  

For the trial, 225 patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep).

The primary outcome (a score of 0 or 1 on the modified Rankin scale at 90 days) occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = .04).

Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = .05).

Donnan said this was "in line with the rate of ICH seen with tPA in other studies, and the benefits outweighed the harm."

A secondary ordinal analysis of the distribution of scores on the modified Rankin scale narrowly missed significance (common odds ratio, 1.55; 95% CI, 0.96 to 2.49).

But a modified Rankin scale score of 0 to 2 (indicating functional independence) was significant, being attained by 49.6% of patients in the alteplase group and by 42.9% of those in the placebo group (adjusted risk ratio, 1.36; 95% CI, 1.06 to 1.76).

The authors note that the EXTEND trial was stopped early because of positive results from the WAKE-UP trial that showed a benefit of tPA in patients with a stroke of unknown time of onset but identified by MRI as likely to be within 4.5 hours.

However, they point out that the patient population and imaging selection differed in the two trials. The clinical severity of stroke was milder in the WAKE-UP trial, with a median NIHSS score of 6 compared to 11 in EXTEND.  In terms of imaging, the WAKE-UP trial used MRI to identify patients with stroke onset within the standard 4.5-hour window for thrombolysis, whereas in EXTEND, hypoperfused but salvageable regions of brain were detected by CT perfusion imaging or perfusion-diffusion MRI, and results processed with the RAPID automated software program.

Donnan suggested that the use of CT perfusion imaging rather than MRI would make the EXTEND approach viable for most hospitals.  

"Our results suggest that every ischemic stroke patient arriving within 9 hours of stroke onset or 'last known well' will need to be imaged," he said. "I believe this is feasible. One of the major advantages of our approach is that it can be done in primary stroke centers. CT scans are available in most centers, they just need a simple software upgrade for this purpose. This is much easier than using MRI. If clinicians feel they require further expertise, then perhaps they can be linked into a telemedicine program."

Following the Example of Thrombectomy

In an accompanying editorial, Randolph S. Marshall, MD, Columbia University, New York City, says the success of this trial is attributable to an image-guided approach to patient selection that has already brought success to mechanical thrombectomy performed many hours after the onset of stroke symptoms and is based on the observation that up to 50% of patients with large-vessel occlusions have infarct cores that grow slowly, probably because of collateral flow in the penumbra.

After success with late thrombectomy in patients with suitable brain imaging, "the EXTEND investigators hypothesized that there would be no reason that revascularization with a pharmacologic agent could not produce the same reperfusion and functional outcomes as mechanical revascularization," Marshall writes.     

He agrees with Donnan that these results could increase the numbers of ischemic stroke patients receiving thrombolysis, which are currently very low (6.5% in 2013 in the US). He also reiterates Donnan's point that most stroke centers could treat patients many hours after the onset of stroke symptoms without the need for an interventionalist to be present.

Marshall cautions that the EXTEND trial will need to be validated and further similar studies are warranted. But he concludes by heaping praise on EXTEND's achievement: "Despite the work to be done, the EXTEND trial shattered an important barrier to the treatment of acute stroke."

The EXTEND trial was supported by the Australian National Health and Medical Research Council and the Commonwealth Scientific and Industrial Research Organization Flagship Program. Donnan reports receiving advisory board fees from AstraZeneca Australia, Bayer, Boehringer Ingelheim, Merck, Pfizer, and Servier. Marshall has disclosed no relevant financial relationships.

N Engl J Med. Published May 9, 2019. Abstract, Editorial

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