Changing the Concept and Time Window for Acute Ischemic Stroke Treatment: Results of the DAWN and DEFUSE 3 Acute Stroke Treatment Trials

The words “revolutionary” and “ground breaking” are used frequently to announce apparent “therapeutic breakthroughs” only to have the medical community see these “game-changing” clinical trial results vanish from the practical therapeutic arena in the years that follow. The recent presentation and publication of the DAWN and DEFUSE3 acute ischemic stroke treatment clinical trials have already changed the way we think about acute stroke treatment and will certainly deliver acute treatment to a new group of patients for the disease that is the #1 cause of adult disability in the United States.

The era of acute ischemic stroke treatment began in the United States in June 1996 with the FDA approval of intravenous alteplase for patients presenting stroke within the first 3 hours from symptom onset. This time window was extended to 4.5 hours in Europe but the FDA refused Genentech’s application for this time window in the United States; the American Heart Association/American Stroke Association conditionally recommends alteplase in this time window.  

Based on studies published in 2014, it was demonstrated for the first time that for intracranial large vessel acute embolic occlusion, thrombectomy devices could effectively reduce the disability of stroke when treating up to 6 hours.

All of these acute stroke treatments had time as the only metric for determining whether a stroke patient could be treated. The development of MR and CT perfusion imaging enabled investigators to study patients up to 24 hours based on the hypothesis that the degree of hypoperfusion correlates with the salvageability of tissue (Figure1).

Figure 1: 

CTperfusionimaging

Example of CT perfusion imaging; the purple area corresponds to extremely low flow state with no expectation of salvageability (core), the green area shows decreased flow but likely salvageability (penumbra).

The DAWN clinical trial evaluated patients in the 6-24 hour time window with intracranial internal carotid or proximal middle cerebral artery embolic occlusions with very small core areas of infarction as identified on CT or MR perfusion imaging. Results were presented at the European Stroke Organisation Conference in May 2017 and published in the New England Journal of Medicine on January 4, 2018.

The DEFUSE 3 clinical trial evaluated patients with intracranial internal carotid or proximal middle cerebral artery embolic occlusions with penumbra/core ratios of 1.8 or greater with a core infarction of 70 mL or less. This study was stopped early based on the presentation of the DAWN study.

Both of these studies enrolled patients with large vessel anterior circulation strokes who were randomized to standard medical management versus thrombectomy. Of patients treated with thrombectomy in DAWN, 49% were independent at 3 months versus 13% in those receiving medical management only. In DEFUSE 3, 45% of patients who underwent thrombectomy were independent at 3 months versus 17% of those medically managed; in DEFUSE 3 the number needed to treat for a good outcome was 2. Safety outcomes in both studies were equal in the thrombectomy versus medical management groups. 

These are real-time, practice-changing results: the American Heart Association/American Stroke Association has already issued a level IA recommendation supporting thrombectomy in these extended time windows. The concept of early symptom recognition and EMS activation for stroke has not changed. The time window in which we can treat and reduce death and disability for acute large vessel ischemic strokes has changed dramatically.