The DAWN trial: the experts’ point of view

Time might be brain, but many patients have a late limit

Jens Fiehler
Director of the Department of Diagnostic and Interventional Neuroradiology, University Medical Center of Hamburg-Eppendorf, Germany

Jens Fiehler

The DAWN study represents a breakthrough in stroke therapy as it is seen to disprove the dogma of a time window for treatment. This is very good news: first and foremost, because many more patients will have access to effective stroke therapy in the future. DAWN finally confirms that every stroke patient has an individual course of infarct evolution and that thrombectomy can be initiated as late as one day after symptom onset – provided of course that the patient is lucky with his or her collaterals and that the radiologist is well-trained and well-equipped.

The ancient concept of a time window suggested that stroke treatment, such as the use of intravenous tissue plasminogen activator or thrombectomy, had a clearly defined time window that determined its efficacy found somewhere between symptom onset and initiation of therapy. The clock showed decreasing probability for a pathophysiological condition in the classical stroke studies.
This, however, was a surrogate for better information concerning the condition of the individual patient. This “second best” concept was applied based on the limited means we had at our disposal for imaging-based patient selection. It grew into a dogma that potentially excluded many patients from effective therapy, even when good imaging information was available. Moreover, missing imaging information became incorporated as a dedicated design element in later trials, such as intra-arterial recanalisation studies, where there was no necessity of enrolling patients with arterial occlusions.

One of the drawbacks of the DAWN study is the complexity of its message. We will need to put much energy into keeping alive the slogan “time is brain”, in particular for referring physicians. The “time is brain” concept is just as valid as it always was and should be strictly followed.
As time proceeds after a stroke, fewer and fewer patients remain who have that combination of a small ischemic core and a persisting large artery occlusion, the DAWN imaging pattern. A treatment effect can be expected only as long as there is brain tissue left for the treatment to rescue.

DAWN was hugely successful in shifting the limits of stroke therapy in time. The next frontier to be explored is space. Future studies need to define the extent of tissue damage, in order to understand when there is still enough tissue left to be saved by endovascular therapy.

Acute Ischemic Stroke: « from dusk till DAWN »

Urs Fischer and Johannes Kaesmacher
Department of Neurology, University Hospital and University of Bern, Switzerland

Johannes Kaesmacher
Urs Fischer

The year 2015 will forever be known for witnessing the biggest breakthrough in the history of modern stroke treatment: in the first few months of 2015 more positive stroke trials were published than the last 20 years combined. Eight randomized controlled trials (MR CLEAN, REVASCAT, ESCAPE, EXTEND-IA, SWIFT PRIME, THRACE, THERAPY and PISTE) have now consistently shown that endovascular stroke treatment in combination with best medical treatment is superior to best medical treatment alone in patients with an acute occlusion of the internal carotid artery or the main stem of the middle cerebral artery.
Recanalization rates after endovascular therapy were significantly higher than in the control group and more patients survived in the endovascular group without a relevant handicap. According to an individual patient data meta-analysis of five of these trials, the number needed to treat was 2.6.

However, despite this major breakthrough, many issues in acute stroke treatment remain unresolved: How can we increase stroke care in Europe?
In many areas in Europe, intravenous thrombolysis and endovascular stroke treatment are still not available and efforts have to be made to increase the number of patients, treated with intravenous thrombolysis and mechanical thrombectomy.

How to select the right patient for endovascular stroke treatment?
Recently published studies suggest that only a minority of stroke patients meet all inclusion criteria of the above mentioned randomized studies on endovascular stroke treatment. Neurologists and neurointerventionalists don’t know whether patients with a large vessel occlusion in the anterior circulation beyond established guidelines would also benefit from endovascular treatment.
Should patients with an unknown time of symptom onset be treated if they have a persisting penumbra on multimodal imaging? Should patients with low NIHSS scores and those with low ASPECTS scores also be treated? What about patients with basilar artery occlusion? Is there a benefit of mechanical thrombectomy in patients with posterior circulation strokes? Is bridging therapy in patients with large vessel occlusion necessary if they can be immediately treated with mechanical thrombectomy? Which device should be used? 

The DAWN Trial

The DAWN trial (Diffusion Weighted Imaging [DWI] or Computerized Tomography Perfusion [CTP] Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention), has finally answered the question about whether patients with an unknown time of symptom onset should be treated. In this multicenter, prospective, randomized controlled study, patients with a relevant volume of potentially savable tissue with either unknown time of symptoms onset or a wake-up stroke were randomized either to mechanical thrombectomy or to the best possible medical treatment. The potential savable tissue was defined by a "mismatch" between clinical assessment and imaging. The study, presented at the "European Stroke Organization Conference" in Prague, had been prematurely stopped upon the recommendation of the "Data Safety Monitoring Board", after an interim analysis which included 206 patients.

The clinical results of the mechanical thrombectomy group were stunning. Whereas in the control group only 13% of patients were considered functionally independent three months after symptom onset, near half of the patients (49%) in the mechanical thrombectomy group fulfilled this criterion. These differences were observed in patients presenting relatively early (6-12 hours: 55% vs. 20%) as well as those presenting late (12-24 hours: 43% vs. 7%). In other words, it means that out of 100 patients treated with mechanical thrombectomy, 49 patients were less severely disabled and 36 patients were more independent compared to 100 patients treated with medical treatment only. These results show an evident benefit of the mechanical thrombectomy in stroke patients – if they are properly selected with advanced imaging – beyond the previously established time frames.

The DAWN trial is a big step forward, expanding the proportion of eligible patients for mechanical thrombectomy. For patients with a stroke of an unknown time of symptom onset or a wake-up stroke, a new therapeutic option is now available. However, mechanical thrombectomy should still be performed as quickly as possible, as numerous studies have shown that stroke patients treated early after symptom onset have a better outcome than patients treated late. The results of the DAWN trial have to be adopted in national and international recommendations and guidelines, and advanced imaging has to become the standard imaging approach in stroke centres performing mechanical thrombectomy.

Based on the results of the DAWN trial new studies have to assess whether even more stroke patients could benefit from mechanical thrombectomy, especially those patients presenting with a large infarct core, those with a low NIHSS score and patients with posterior circulation strokes. These studies will be necessary to determine the precise threshold for a more accurate and wider patient selection, allowing many to receive the best possible benefit out of one of the most effective treatment approaches of modern medicine.