DEFUSE 3 shows favourable outcomes for late-window patients and triggers expanded guidelines for treatment eligability


The study results show that endovascular therapy, given alongside standard medical therapy, results in better functional outcome than standard medical therapy alone for ischaemic stroke patients with salvageable tissue on brain imaging, who are treated between six to 16 hours after the patient was last known to be well: the number of patients that needed to be treated to reduce the degree of disability in one patient was just two. These results, combined with those from the DAWN trial, have triggered the release of updated guidelines from the AHA/ASA extending the treatment window for thrombectomy. The study results were presented at the International Stroke Conference (ISC; 24–26 January 2018, Los Angeles, USA) by Gregory Albers (lead investigator, Stanford University Medical Center, USA) and published simultaneously in the New England Journal of Medicine.

The culmination of a 20-year effort to establish if ischaemic stroke evolves in a unique manner, the study shows that treatment decisions should be personalised, rather than based on arbitrary timeframes.

Only one out of six patients receiving medical therapy in the DEFUSE 3 (endovascular therapy following imaging evaluation for ischaemic stroke) study showed favourable outcomes, indicated by a modified Rankin Scale (mRS) of 0–2, and 42% had a score of 5 or 6, which reflects extreme disability or death. The difference in disability between the medical and the endovascular treatment groups, as demonstrated by the full distribution of the modified Rankin Scale at 90 days, was the primary outcome of this study. At 90 days, this difference was reflected by a common odds ratio of 2.77; p˂0.0001. The number needed to treat to reduce the degree of disability in one patient was merely two patients, when adjusted for stratification factors the odds ratio increased to 3.4.

“The outcomes in the DEFUSE 3 thrombectomy group were quite astonishing,” said Albers, lead investigator, “Outcomes were markedly more favourable throughout the disability spectrum and they translate into the largest odds ratio ever reported for a thrombectomy trial.”

Gregory Albers

As previously reported in NeuroNews, a similar late window thrombectomy trial, DAWN, reported positive results in May 2017. Subsequently, DEFUSE 3 was placed on hold for an early interim analysis. Following this analysis the study was ended early, with 182 patients randomised at 38 sites.

The study started with the hypothesis that stroke patients with a middle cerebral artery and/or internal carotid artery occlusion and salvageable tissue, as identified by MR or CT (magnetic resonance or computed tomographic) perfusion imaging, would benefit from endovascular thrombectomy when the procedure was performed between six to 16 hours after the patient was last known well. Eligible patients were randomised to receive endovascular thrombectomy using any FDA approved device or to receive medical management based on AHA (American Heart Association) guidelines. Randomisation was stratified on a number of characteristics to ensure that the treatment groups would be well balanced and the clinical outcome was determined on the modified Rankin score by a blinded assessor at 90 days. The primary outcome was an odds ratio from an ordinal shift analysis spanning all levels of disability and the secondary outcome was functional independence, defined as a mRS of 0–2.

To be included in the study the patient had to be 90 years of age or younger, have a NIH (National Institute of Health) stroke scale score of ≥6, a pre-stroke mRS of 0–2 and the potential for endovascular therapy to be initiated between six to16 hours since the patient was last seen well. The key neuro-imaging criteria were occlusion of cervical or intracranial internal carotid artery or proximal middle cerebral artery and the target mismatch profile on CT or MR perfusion imaging, based on the RAPID automated imaging software (iSchemaView) which was installed at each study site.

By enrolling patients with ischaemic core values of up to 70ml, NIHSS scores as low as six, pre-stroke Rankin scores of up to two, and having an extended time window, the study was able to enrol a substantially broader population than most prior thrombectomy trials. Because of the broad inclusion criteria enrolment was completed in less than one year, nearly twice the anticipated enrolment rate.

Outcomes were markedly more favourable throughout the disability spectrum for the thrombectomy group and this translated into the largest odds ratio every reported for a thrombectomy trial— the common odds ratio was 2.77, with a p value of <0.0001. When adjusted for stratification factors the odds ratio increased to 3.4 and the number needed to treat to reduce the degree of disability in one patient was merely two patients.

Functional independence was achieved in 45% of the patients in the thrombecto­my group, nearly three times more often than in the control group. In addition, there was a very substantial reduction in the stroke, severe disability and death, which were cut in half— from 42% to 22%. This degree of difference has not been seen before. Perfusion imaging at 24 hours revealed a fourfold increase in complete or near complete reperfusion in the endovascular group, as well a similar increase in complete recanalisation on follow up MR angiography.

Primary safety outcomes were death and symptomatic intracranial haemor­rhage and there was a non-statistically significant increase in symptomatic intracranial haemorrhage in the endovas­cular arm. Of the endovascular patients, five of the six with symptomatic intrac­ranial haemorrage died, compared to two out of four in the medical group. Despite this, there was a 45% relative risk reduc­tion for mortality in the endovascular group, from 26% to 14%, with a p value of 0.05.

About 60% of the DEFUSE 3 patients would have qualified for enrolment in the DAWN study, which also used RAPID to determine the volume of the ischaemic core. For the 40% that would not have quali­fied for DAWN, the most common reason was that the ischaemic core size was too large. The second most common reason was the NIHSS score was less than 10. The treatment effect on the primary outcome on the DAWN ineligible patients was just as robust as in DAWN eligible patients and statistical significance was achieved in both subgroups. This means that DEFUSE 3 has not only confirmed the results of DAWN but extended the benefits of late window therapy to an additional group of patients.

Wake up stroke patients made up 50% of the DEFUSE 3 population and for these patients the actual time between stroke on­set and randomisation is unknown. Among the patients with known onset times, the median time to randomisation was nine and a half hours. The treatment effect for the primary outcome was identical, and statistically significant in both of these sub­groups. This demonstrates that DEFUSE 3 treatment benefit is not explained by potentially shorter onset to treatment times in the wake-up group. The median time from symptom onset to randomisation was 11 hours and there was a strong trend sug­gesting a larger treatment effect in patients who were randomised in the greater than 11 hours subgroup, with a p value of 0.07.

AHA/ASA guideline change

The embargoed copies of both DEFUSE 3 and DAWN were provided to the AHA stroke guideline committee and provided the basis for new late window treatment guidelines that were also an­nounced at ISC.

A major new recommendation in­creases the time window to 24 hours for selected acute ischaemic stroke patients to receive mechanical thrombectomy, a procedure only advisable in clots that block large vessels. The new recom­mendation will likely result in more pa­tients becoming eligible for thrombec­tomy since more patients will be treated based on clinical presentation rather than a time cut-off alone.

The new guideline, based on the most recent science available, recommends that large vessel strokes can safely be treated with mechanical thrombectomy up to 16 hours after a stroke in selected patients. The expanded treatment window from six to 16 hours is based on clinical evidence from the DAWN and DEFUSE 3 trials. Under certain conditions, based on advanced brain imaging, some pa­tients may have up to 24 hours for treat­ment with mechanical thrombectomy, based on the DAWN Trial criteria. The previous time limit was six hours.

The purpose and scope of 2018 American Heart Association/American Stroke Association guidelines were presented by William J Powers, Chapel Hill, USA at ISC.

“The purpose of these guidelines is to provide an up-to-date comprehensive set of recommendations for clinicians car­ing for adult patients with acute arterial ischaemic stroke in a single document. They address prehospital care; urgent and emergency evaluation; treatment with intravenous and intra-arterial therapies; and in-hospital management including secondary prevention measures that are appropriately instituted within the first two weeks,” said Powers, the guideline writing group chair and professor of neurology, University of North Carolina.

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