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The DAWN and DEFUSE 3 trials show that perfusion imaging can identify patients who benefit 6 to 24 hours after stroke onset.


LOS ANGELES, CA—Yesterday, the recommended treatment window for mechanical thrombectomy in patients with acute ischemic strokes caused by large-vessel occlusions was up to 6 hours. Starting today, select patients with salvageable brain tissue on imaging will be eligible for treatment up to 24 hours after they are last seen well.

The change comes in updated guidelines for the early management of patients with acute ischemic stroke released here at the International Stroke Conference. The recommendations are based on evidence from the previously released DAWN trial, as well as data from the DEFUSE 3 trial, presented just hours before the guidelines were made public, showing that the addition of thrombectomy to standard medical therapy improves functional outcomes in carefully selected patients treated in late time windows.

The speed with which the science was translated into guidelines is unprecedented, according to American Stroke Association spokesperson Peter Panagos, MD (Washington University in St. Louis, MO), who was not involved in either trial.

“I see this as a call of action for many of the people at this meeting to go back to their communities, educate everyone within the stroke system of care, and then come up with innovative ways to make this work for their communities,” Panagos told TCTMD.

He pointed out, however, that the importance of early treatment with IV thrombolytics in eligible patients shouldn’t be lost; despite the excitement over thrombectomy, the newer technique would still just be used in a small fraction of those with acute ischemic strokes.

DAWN and DEFUSE 3 “open up an opportunity for a new group of patients that historically we’ve excluded from treatment,” Panagos said, but “IV thrombolysis is still the earliest, quickest, and most efficient way to treat these patients.”

Expanding the Treatment Window

In a 2015 focused update of the 2013 comprehensive acute stroke guidelines, thrombectomy with stent retrievers was strongly recommended for patients meeting certain criteria who could be treated within 6 hours of symptom onset based on the results of several trials. The DAWN trial showed, however, that treatment with the Trevo stent retriever (Stryker Neurovascular) improved functional outcomes in the 6-to-24-hour window in patients selected on the basis of a mismatch involving severe clinical deficits but a small infarct size on imaging.

When those results were released, DEFUSE 3, which was enrolling patients presenting within 6 to 16 hours after they were last known well (including those with wake-up strokes), was suspended and ultimately stopped after an interim analysis revealed superior outcomes in patients receiving thrombectomy.

Here at the meeting, Gregory Albers, MD (Stanford Stroke Center, Palo Alto, CA), reported the results of DEFUSE 3, which were published simultaneously online in the New England Journal of Medicine.

DEFUSE 3, conducted at 38 US centers, included patients with a proximal middle cerebral artery or internal carotid artery occlusion on CT angiography or magnetic resonance angiography, an initial infarct size smaller than 70 mL, a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more, and absolute volume of potentially reversible ischemia of at least 15 mL. The volume of salvageable tissue was estimated using RAPID software (iSchemaView), which was also employed for patient selection in DAWN.

The trial randomized 182 patients to thrombectomy with any commercially available device on top of standard medical therapy or medical therapy alone. Medical therapy included IV thrombolytics in eligible patients, but intra-arterial thrombolytics were prohibited.

The primary outcome was the shift in modified Rankin Scale (mRS) scores at 90 days, and the intervention arm came out on top (unadjusted common OR 2.77; 95% CI 1.63-4.70). The number needed to treat was just two.

Thrombectomy also increased the percentage of patients who were functionally independent (45% vs 17%; P < 0.001).

“We were really astounded to see the spectacular results from this study,” Albers said at a press conference, reporting that the results were consistent across various subgroups, including those with wake-up strokes and those treated toward the end of the time window.

Although there was a nonsignificantly higher rate of symptomatic intracranial hemorrhage in the thrombectomy arm (6.5% vs 4.4%; P = 0.75), the 90-day mortality rate was marginally significantly lower (14% vs 26%; P = 0.05).

Albers said the findings build on the results of the DAWN trial, in that DEFUSE 3 included a broader patient population (38% would not have been eligible for the former trial). The benefits seen in DEFUSE 3 were consistent regardless of whether patients would have met criteria to be included in DAWN, he reported.

“We expect that this will have a substantial effect on how we think about stroke and how we triage and image stroke,” Albers said. “Now that we know that we can successfully treat patients in later time windows, it’s going to be important for primary stroke centers to be able to do the type of imaging that was done in the DEFUSE 3 and DAWN trials.”

The results of the two trials also provide “a new perspective on the mantra of stroke: time is brain,” he added. “It’s still very important to rush as quickly as possible to evaluate stroke patients because there are the unfortunate patients where brain tissue is dying at an extremely fast rate, but we found that about 50% of patients are much more fortunate. Their hourglass does not empty as quickly, and we have an opportunity to treat many of these patients at time windows that we never thought would be possible.”

As stated by Jeffrey Saver, MD (University of California, Los Angeles), who presented more detailed DAWN results at the meeting, “the world is moving from a time clock to a tissue clock” with publication of the two trials’ results.

Imaging Needed Beyond 6 Hours

That shift to tissue-based or imaging-based selection of patients for thrombectomy in later time windows has now been codified into the updated acute stroke guidelines, which were written by a group chaired by William Powers, MD (University of North Carolina at Chapel Hill), and published online in Stroke.

The comprehensive document covers prehospital care, urgent and emergency evaluation, use of IV and intra-arterial therapies, and in-hospital management, including early initiation of secondary prevention measures.

IV alteplase remains the first-line treatment for patients with acute stroke, Powers stressed at a press conference, pointing out that the new guidance clarifies who should and who should not be treated and highlights characteristics that are judgement calls.

The new guidance maintains a recommendation from the 2015 focused update calling for the development of regional systems of care for acute stroke, which should include hospitals that provide initial emergency care like IV thrombolytics and centers capable of providing endovascular stroke treatments and comprehensive periprocedural care.

That will be particularly important as the community works toward implementing the new recommendations regarding treatment during later time windows. There is a Class I recommendation for use of thrombectomy in patients who present 6 to 16 hours after last known normal, with a stroke caused by a large-vessel occlusion in the anterior circulation, and who meet DAWN or DEFUSE 3 eligibility criteria. The recommendation is weaker (Class IIa) for patients who present between 16 and 24 hours and meet DAWN criteria.

A new recommendation makes it clear that some type of imaging—CT perfusion, diffusion-weighted MRI, or MRI perfusion—is required to select patients with salvageable brain tissue for treatment in the 6-to-24-hour window.

Implementation Remains a Challenge

Saver said that the main challenge to implementation of these new recommendations will be the changes to systems of care in hospitals that haven’t been performing perfusion imaging. He pointed out, however, that making the change should be relatively easy for most secondary and tertiary centers.

On a broader scale, though, there is still a lot of work to be done on getting the regional systems of care recommended in the guidelines up and running, several experts agreed. Powers said the ability to set up such a system varies region by region based on their unique capabilities.

Saver noted that in the United States, there is an infrastructure already set up for delivering IV thrombolytics in a timely fashion that will have to be built out further to accommodate delivery of thrombectomy.

It’s helpful to have that infrastructure in place already, but “I don’t think we’re currently prepared for this science to hit the street at this point,” Panagos said. “But on the other hand, we welcome this news, and now the challenge is ours to go and translate this science and these guidelines into practice back in our communities.”

National societies can offer broad recommendations about best practices, he added, “but ultimately, the best stroke care is local care and all of this has to incorporate local strengths and weaknesses. . . . I think there’s going to be a tremendous amount of innovation that we’re going to hear about in the next several months to years on how people make this work efficiently.”

 

This story was originally published by  TCTMD.com on January 24, 2018. 

 

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