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But the findings should not be used as an excuse to be complacent, says lead author.

 

Stroke patients who present with a clinical deficit that is more severe than expected based on their infarct volume can indeed benefit from thrombectomy far beyond the standard goalpost of 6 hours from symptom onset, according to the results of the DAWN trial. These findings were published in the January 4, 2018, issue of the New England Journal of Medicine.

Lead author Tudor Jovin, MD (Presbyterian University Hospital, Pittsburgh, PA), explained to Neurovascular Exchange that, given recent evidence to the contrary, it is time to “challenge the concept that was deeply ingrained in the minds of the stroke community and interventionalists that selection of patients for endovascular therapy for stroke and for indeed any reperfusion therapy should be based [primarily] on time.”

For DAWN, Jovin and colleagues enrolled patients who presented with occlusions of the intracranial internal carotid artery or proximal middle cerebral artery, had last been known to be well 6 to 24 hours earlier, and had a mismatch between the severity of clinical deficit and the infarct volume. Subjects were randomly assigned to receive thrombectomy plus standard care (n = 107) or to standard care alone (n = 99).

 

Mismatch was categorized according to age at a threshold of 80 years, and infarct volume was assessed via diffusion weighted magnetic resonance imaging (MRI) or perfusion CT. Patients fell into one of three groups:

 

 

DAWN was stopped early at 31 months because of the results of a prespecified interim analysis. At this point, the mean 90-day mRS score was significantly higher in the thrombectomy group than in the control group, with an adjusted difference (Bayesian analysis) of 2.0 points and posterior probability of superiority > 0.999.

The proportion of patients who reached functional independence at 90 days was also higher in the thrombectomy group, with an adjusted difference of 33 percentage points and posterior probability of superiority > 0.999.

The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups, nor did 90-day mortality.

 

Outcomes of Thrombectomy vs Standard Care

 

 

Thrombectomy

(n = 107)

Control

(n = 99)

Utility Weighted 90-Day mRS

5.5

3.4

90-Day Functional Independence

49%

13%

Symptomatic Intracranial Hemorrhage

6%

3%

90-Day Mortality

19%

18%

 

 

Apart from challenging the idea of a fixed window for reperfusion, DAWN also offers an alternative paradigm, Jovin said. “The pathophysiologic mechanism of each individual stroke patient matters more than time.”

For Jovin, the findings also debunk the myth that good outcomes among patients treated outside the 6-hour window are primarily due to “wake-up strokes” (ie, stroke patients who are only identified in bed in the morning, meaning that it is impossible to determine precisely when the stroke occurred). In DAWN, benefits were seen in patients whose symptoms were confirmed to have lasted longer than 6 hours, not just in those whose symptom onset was uncertain because their strokes occurred during sleep.

So far, the trial results have been “received with open arms” by the interventional community, Joven reported. This is likely because the field has been primed by earlier research, including data from landmark mechanical thrombectomy trials revealing good outcomes in subgroups patients who were treated outside of the standard 6-hour window, he said. At the same time, previous research on diffusion imaging mismatch has provided a solid pathophysiologic explanation as to why some patients can still do well with delayed treatment.

 

The “million-dollar question,” he added, is whether the majority of stroke centers will be able to accurately calculate mismatch. Jovin thinks they can.

 

Don’t Be Complacent

 

In DAWN, investigators used either MRI or the more common CT perfusion imaging combined with NIHSS score. While they had access to automated software to analyze imaging findings, less sophisticated methods can be used. For instance, there is increasing evidence for the predictive value of ASPECTS. Such methods may be less precise, but since the “treatment effect is so strong, we may not need to be that precise,” Jovin predicted. In DAWN, the number needed to treat was calculated to be only three, compared with 27 for percutaneous coronary intervention in MI.

 

Jovin said that the results of DAWN may have the most impact in the developing world, where systems are not in place to get suspected stroke patients to stroke-capable hospitals in as timely a manner. “DAWN has opened up a window of opportunity to get a big chunk of these patients to qualify [for reperfusion therapy],” he said.

 

He warned, however, that the results should not be used as an excuse to be complacent with stroke patients. “The fact that there is a treatment that is beneficial beyond 6 hours does not mean we can take our time and not view LVO stroke as an emergent condition. The earlier you are, the more likely you will have a favorable pathophysiology [and thus outcome],” he emphasized.

 

A New ‘DAWN’?

 

In an accompanying editorial, Werner Hacke, MD, PhD, DSc (University of Heidelberg, Germany), seems cautiously optimistic.

 

“These imaging-based approaches [to calculate mismatch] represent a new ‘DAWN’ for the selection of patients who are likely to benefit from thrombectomy that is performed far longer after the onset of stroke than current guidelines suggest, at least among patients who have severe stroke, vascular occlusion, and penumbral tissue,” he writes.

 

“However, the results of the DAWN trial do not support a general liberalization of the time window for thrombectomy or thrombolysis,” Hacke says. “Reducing the time from the onset of stroke to treatment remains essential and results in the best outcomes.”

 

For now, he concludes, there is only evidence that delayed reperfusion is beneficial in patients with mismatch.

 

 

 

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