November 17, 2017
Thrombectomy for patients with acute ischemic stroke can still be beneficial after 6 hours from symptom onset in patients who have salvageable brain tissue identified by a small infarct core on imaging, results of the DAWN trial show.
The study was published online this week in the New England Journal of Medicine to coincide with its presentation at the Society of Vascular and Interventional Neurology annual meeting in Boston, Massachusetts. It was also presented previously at the 3rd European Stroke Organisation Conference in May.
Results showed that disability outcomes were better with thrombectomy plus standard medical care than with standard medical care alone among patients with acute stroke who received treatment 6 to 24 hours after they had last been known to be well and who had a mismatch between the severity of the clinical deficit and the infarct volume.
"Our take-home message is that selection for endovascular therapy in acute ischemic stroke should not be made on time alone. Physiological criteria also need to be considered," senior author, Tudor Jovin, MD, University of Pittsburgh Medical Center Stroke Institute, Pennsylvania, told Medscape Medical News.
The DAWN trial enrolled patients who presented later than 6 hours and were identified as having salvageable brain tissue on the basis of "clinical-core mismatch": that is, patients who have a clinical deficit disproportionate to that expected from imaging the infarct.
"The principle of mismatch is simple," Dr Jovin explained. "When a vessel in the brain becomes blocked, a small area of brain dies off initially. This is what we call the core. But a larger area supplied by this vessel is threatened. This is referred to as the penumbra. The penumbra area will also eventually die if left untreated, but it can survive for several hours if the collateral circulation is good.
"For our trial we defined mismatch as patients with symptoms of a severe stroke signalling that a large area of brain tissue is not functioning properly, but on imaging they are found to still have only a small core of tissue that has actually died," he said.
"Early on almost everyone has mismatch, but for most patients the whole area has died by 6 hours — these are fast progressers. But for some patients — the slow progressers — they still have viable brain tissue in the susceptible area many hours later despite having had a large stroke as judged by clinical symptoms."
First author of the study, Raul Nogueira, MD, Marcus Stroke & Neuroscience Center, Grady Memorial Hospital, Atlanta, Georgia, commented to Medscape Medical News: "It all comes down to physiology — how much the collateral flow can compensate for the ischemia caused by the clot in the main vessel. Good collateral flow buys you time for treatment."
"Despite longer times to presentation, the treatment effect size observed in the DAWN trial is the highest out of any stroke trial performed to date," he added. "This indicates that the presence of clinical-core mismatch is a critical predictor of treatment response independent of time to presentation. Therefore, time alone should no longer be a disqualifier for thrombectomy."
These results will increase the number of acute stroke patients eligible for thrombectomy. The researchers note that approximately one third of the patients with occlusion of a proximal anterior cerebral vessel who present within 6 to 24 hours after the onset of stroke may meet the imaging-based eligibility criteria that were used in this trial.
The population enrolled in the study included patients with wake-up strokes (those who were discovered to have had a stroke during their sleep, so the actual time of onset is not known), Dr Nogueira commented. "Wake-up strokes are quite common (accounting for about 25% of strokes) and these patients have not been eligible for thrombectomy based on time criteria, but our results open the possibility of this treatment to this group if they are found to have the right physiology."
The DAWN trial enrolled 206 patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours previously, and who had a large clinical deficit (National Institutes of Health Stroke Scale scores of 10 or more). They used MRI/computed (CT) tomography perfusion imaging to identify those with a small core, with entry criteria on core size varying with age. They were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone.
At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis.
The trial had two co-primary endpoints using the utility-weighted modified Rankin scale, which ranges from 0 (death) to 10 (no symptoms or disability), and the rate of functional independence (scores of 0, 1, or 2) on the more traditional modified Rankin scale. Both endpoints showed significant benefits for the thrombectomy group.
The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group vs 3.4 in the control group, giving an adjusted difference (Bayesian analysis) of 2.0 points.
And the rate of functional independence at 90 days was 49% in the thrombectomy group vs 13% in the control group (adjusted difference, 33 percentage points).
For every 2 patients who underwent thrombectomy, 1 additional patient had a better score for disability at 90 days vs results in the control group; for every 2.8 patients who underwent thrombectomy, 1 additional patient had functional independence at 90 days.
The researchers note that the rate of functional independence in the thrombectomy group in this study (49%) with a mean treatment time of 12 to 13 hours was similar to the rate reported in a pooled analysis of five thrombectomy trials in which patients were treated within 6 hours (46%).
In contrast, the rate of functional independence in the control group in the current trial was much lower than in the trials of earlier patients (13% vs 26%), which the researchers suggest may be due to earlier patients receiving thrombolysis.
"We included patients 6 to 24 hours from symptom onset, and we found benefit of treatment across the whole time window with no difference in treatment effect," Dr Jovin said.
However, he added that fewer patients at the later times would have had mismatch and therefore would be qualified for inclusion in the trial. "So, of course, time is of the utmost importance, but once a patient has been identified as still having salvageable brain tissue they have a similar benefit regardless of time of presentation."
"We think these results will be particularly relevant to developing countries where patients tend to take longer to present, but these countries are less likely to have sophisticated imaging available so we need to find simpler ways to measure the core," he noted. "This may be able to be done on a plain CT scan — this just might be good enough to make a reasonable estimate."
Dr Nogueira noted that results of a second similar trial — DEFUSE-3 — are to be presented early next year.
"We know this trial has also shown a positive result, and details will be released at the International Stroke Conference in January. The two trials will be considered together to make recommendations on patient care for those presenting after 6 hours."
In an editorial accompanying publication of the DAWN study, Werner Hacke, MD, University of Heidelberg, Germany, says the study has "strikingly positive results," but he cautions that only a limited proportion of patients who present late will fulfill the criteria for thrombectomy. Thus, "reducing the time from the onset of stroke to treatment remains essential and results in the best outcomes."
The DAWN trial was supported by Stryker Neurovascular. Dr Jovin reports personal fees or other support from Silk Road Medical, Anconda Biomed, Route 92 Medical, Blockade Medical, FreeOx Biotech, Codman Neurovascular, and Neuravi outside the submitted work. Dr Nogueira has disclosed no relevant financial relationships.
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SOURCE: Medscape, November 17, 2017. N Engl J Med. Published online November 11, 2017.