DAWN Trial May Lay Groundwork for Extending Treatment Window for Acute Stroke Therapy

Thrombectomy with a stent retriever improves functional outcomes in patients who wake up or present late with an acute ischemic stroke, at least when there is an initial mismatch consisting of substantial clinical deficits but a small infarct size, the randomized DAWN trial shows.

In this population, intervention resulted in a 48.6% rate of functional independence at 90 days, compared with a rate of just 13.1% in patients treated with medical management alone. That works out to a number needed to treat (NNT) of only 2.8.

“The treatment effect size in DAWN is the highest out of any stroke trials to date and suggests that the presence of clinical-core mismatch is a critical predictor of treatment effect independent of time to presentation,” co-principal investigators Tudor Jovin, MD (University of Pittsburgh, PA), and Raul Nogueira, MD (Emory University, Atlanta, GA), reported last week at the European Stroke Organisation Conference in Prague, Czech Republic.

Although thrombectomy was beneficial in patients presenting up to 24 hours after stroke onset, gains were greatest when the intervention was performed early.

Extending the Treatment Window

Currently, guidelines for endovascular therapy in acute ischemic stroke state that stent retrievers should be used only when treatment can be initiated within 6 hours of symptom onset. However, a substantial proportion of patients with large vessel occlusions (30% to 40%) wake up in the midst of a stroke—and thus don’t know when it started—or present beyond the recommended treatment window. There are no established therapies for these groups.

There is accumulating evidence that basing treatment on physiologic characteristics and not time may identify patients who can benefit from endovascular therapy well beyond 6 hours from stroke onset.

For DAWN, which was stopped after an interim analysis indicated a high likelihood of benefit, the investigators enrolled 206 patients who presented with an acute ischemic stroke caused by a large vessel occlusion 6 to 24 hours after they were last seen well. All patients had a clinical-core mismatch defined by age, National Institutes of Health Stroke Scale score, and size of the infarct core by diffusion-weighted imaging and CT perfusion.

Those randomized to thrombectomy with Trevo (Stryker Neurovascular) plus medical management were more likely than those in the control group to have a wake-up stroke (64.5% vs 47.5%). The average time between when patients were last seen well and when they presented was about 13 hours in both arms of the trial.

The primary safety endpoint was stroke-related mortality, which was numerically but not significantly lower in the intervention arm at 90 days (13.0% vs 18.0%; P = 0.6). Other safety endpoints, including symptomatic intracranial hemorrhage at 24 hours and all-cause mortality at 90 days, did not differ between groups. Overall, the safety of thrombectomy was similar to what has been seen in trials evaluating treatment within 6 hours.

In terms of efficacy, thrombectomy provided a higher rate of functional independence (defined as a modified Rankin Scale [mRS] score of 0 to 2) at 90 days and demonstrated an advantage over medical management alone on a utility-weighted mRS. The number needed to treat for any lower disability was 2.0.

Don’t Adjust Guidelines Just Yet

Colin Derdeyn, MD (University of Iowa, Iowa City), vice chair of the writing committee for the 2015 guideline update regarding endovascular therapy, said DAWN is “extremely promising but not conclusive.”

He told TCTMD that while this is the first trial to demonstrate a benefit of thrombectomy for wake-up or late-presenting strokes, the sample size was “not particularly large” and there were imbalances in some baseline characteristics between arms. In particular, the higher proportion of wake-up strokes in the intervention arm could influence the findings, he noted.

Moreover, Derdeyn said, it will be important to wait for the full publication of the results, because results can sometimes change after their initial presentation: “Oral abstracts aren’t actionable. You need to see the whole picture.”

Nonetheless, he predicted stent retrievers will eventually be shown conclusively to have a significant benefit in patients presenting beyond the standard 6-hour treatment window. In the ongoing DEFUSE 3 trial, which is also evaluating thrombectomy in extended time windows, about half of patients are similar to those included in the DAWN trial, according to Derdeyn. He said combining data from both studies—assuming DEFUSE 3 also yields positive results—might provide enough evidence to change guidelines.

The greatest impact will likely be for patients with wake-up strokes, because it is hoped that the other types of patients—those presenting more than 6 hours from stroke onset—will become less and less common over time, Derdeyn said.

“In an ideal world, we have good patient education, good EMS education, good systems of care, and nearly everybody with a big stroke ends up in the system within the first few hours and gets treated appropriately,” he said.

But no matter how good the system gets, people will still have wake-up strokes, and “that is where I think we’ll see a lot translation of these things into practice,” Derdeyn said.