“DAWN” of the Mismatch Era

It wasn’t truly so long ago the treatment for an acute stroke was virtually nonexistent. Then, it progressed, with patients eligible for treatment within 3 hours … then 4.5 hours … then 6 … and, now, 24 hours. Whatever happened to “time is brain”? How can we possibly be treating patients out to a day after onset of symptoms?

This is the DAWN trial, randomizing patients with acute ischemic stroke to endovascular intervention or medical management within 6 or 24 hours of symptom onset. Eligibility criteria included occlusion of the internal carotid or proximal middle cerebral artery paired with one of three different clinical syndrome/infarct core mismatches based on CT or MRI perfusion imaging: three cohorts with NIHSS of 10 or 20, with differing sizes of infarct cores. The underlying theory here stems from observations of the viability of cerebral tissue as dependent upon collateral circulation, rather than simply the linear passage of time.

This is, as you might already have gathered from the press releases, a positive study. Unfortunately, it was so positive it was stopped early for benefit based on a primary outcome these authors almost certainly created uniquely to support early termination of these sorts of trials: the “utility-weighted modified Rankin scale”. Rather than use the traditional mRS as in all other stroke trials, or, even, the statistically flawed “ordinal shift analysis”, these authors assigned point values to the various mRS categories, those with the least disability receiving the most points. This resulted in the potential enrollment of 500 patients being stopped at the earliest possible pre-specified interim analysis with a mere 200 patients enrolled.

Tossing out their nonsensical fake outcome measure for the more easily approachable mRS categories, 52 of 107 (49%) of thrombectomy patients were functionally independent (mRS 0-2) at 90 days versus 13 of 99 (13%) of those in the control group. These results were roughly consistent across their various subgroup analyses, although, with such a small trial, the confidence intervals get awfully wide, awfully quickly. That said, despite all the other associated trial shenanigans, it is fairly obvious this sort of treatment is helpful to patients. I’ve been preaching tissue-based approaches to therapy for a couple years now, and despite this trial’s individual issues, in a Bayesian sense these results are consistent with prior evidence.

Of course, this does not actually indicate the window for screening ought to be 24 hours as will likely be justified from these data – the bounds of eligibility for the study do not simply translate subsequently to clinical policy recommendations. The study design does explicitly stratify patients to 6 to 12 hour and 12 to 24 hour cohorts, but the IQR range for “time from symptom onset” for the entire cohort is 10.2 to 16.3 hours, implying approximately half the 12 to 24 hour cohort was actually randomized between 12 and 16 hours. This leaves a paucity – approximately 25 patients in each arm – of data to inform treatment in the 16 to 24 hour window. Contrariwise, these data also do not explicitly exclude patients beyond 24 hours as potential candidates for intervention, as this is a tissue-based, not time-based, paradigm. Further prospective study will be needed to determine the precise time window at which perfusion screening for large vessel occlusions ultimately becomes so low-yield there is no value in the pursuit.

These authors also do not provide useful information regarding the number of patients screened for possible inclusion. Much will be made of these results, with a likely profound impact on our approach to stroke. To properly design stroke systems of care and project resource utilization, physicians and policy makers need data regarding the clinical characteristics of all patients evaluated and those features best identifying those who ought be triaged or transferred to specialized centers.

Finally, of course, there is the perpetual elephant in the room – heavy involvement from the sponsor in the conduct of the study, along with multiple authors on the payroll. These financial conflicts of interest always threaten internal and external validity by limiting generalizability and amplifying apparent effect sizes. All this said, however, this is probably an important step forward in the evolution in our approach to stroke.

“Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct”