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Broader Group May Benefit from Late Thrombectomy

— Stent retriever use at 6 to 16 hours improved outcomes in DEFUSE 3

Last Updated November 28, 2018
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LOS ANGELES -- An extended window for endovascular thrombectomy appears safe for a broader range of acute ischemic stroke patients, with improved outcomes over medical therapy alone, researchers found in the DEFUSE 3 trial.

When performed 6 to 16 hours after patients were last known well and had favorable brain perfusion characteristics, stent retriever use along with medical therapy reduced death and disability, with a 2.77-fold greater odds that modified Rankin scale score at 90 days would be shifted favorably (P<0.001).

Good functional outcome -- survival to be independent in activities of daily living, modified Rankin scale of 0 to 2 -- favored thrombectomy as well (45% versus 17%, P<0.001), Gregory Albers, MD, of Stanford University in California, and colleagues reported here at the , with the data published simultaneously online in the .

Combination treatment held a numerical advantage over use of medical therapy alone for 90-day mortality (14% versus 26%, P=0.05).

The biggest adverse event concern -- symptomatic intracranial hemorrhage -- was not significantly worse with thrombectomy than without it (7% versus 4%, P=0.75). Serious adverse events overall were similar between groups (43% versus 53%, P=0.18).

"Previous trials of endovascular treatment of acute stroke have suggested that a limited proportion of patients had a favorable clinical outcome when reperfusion was instituted later than 7 or 8 hours after stroke onset," the researchers noted.

However, the DAWN trial subsequently showed an advantage of thrombectomy for outcomes in patients treated with wake-up strokes and those presenting 6 to 24 hours after last time known well.

"Our findings confirm and extend those of the DAWN trial, which used the same automated perfusion software (RAPID) as in our trial to measure the volume of the early infarct and to measure hypoperfused volume," Albers et al added.

Broader Criteria

DAWN used somewhat narrower selection criteria, with smaller core infarctions than those in DEFUSE 3, with participants in DAWN also having more severe stroke symptoms. About 40% of DEFUSE 3 participants would not have met the DAWN selection criteria, Albers's group noted.

“This is as exciting as Nashville,” commented Bruce Campbell, MBBS, PhD, of Australia’s Royal Melbourne Hospital — referring to the panel of trials presented there at the 2015 Stroke conference that created the mandate for mechanical thrombectomy in this type of stroke by confirming the initial positive results from the MR CLEAN trial. “We’ve been working toward this for 20 years.”

DEFUSE 3 is an advance because the criteria are broader and easier to remember, Campbell said, which he expects to increase the number of patients that can be treated.

Remarkably, DAWN and DEFUSE 3 have had bigger treatment effects than seen in the 6-hour trials, apparently because of the poor outcomes of those treated medically outside the standard window for thrombolytics.

“We were really astounded to see the spectacular results from this study,” Albers said at a press conference for the late-breaking clinical trial session, noting that the the odds ratio found for the primary outcome in DEFUSE 3 was “the largest odds ratio ever reported for a thrombectomy study, so it indicates a major shift.”

Selection criteria likely also played a role, because patients had scans showing tissue that was ischemic but not yet infarcted and thus potentially salvageable, the researchers said.

A separate analysis presented at the session looking at numbers needed to treat and other metrics of individual-level benefit by Jeffrey Saver, MD, of UCLA, showed a number needed to treat of just two in DAWN.

For every 100 patients treated with mechanical thrombecomy as in DAWN, 50 would have improved disability-related quality of life, including functional independence in 36 of them.

The same was true for the early (6 to 12 hours) and later (more than 12 up to 24 hours) time windows considered separately, with about half of patients benefitting in both periods. But the shift was to lesser degrees of disability in the earlier- than in the later-treated group, emphasizing the importance of treating as soon as possible, Saver noted.

In DEFUSE 3, the results were similar, with 48 of every 100 patients treated having lower disability with thrombectomy.

“A new era dawned with DAWN and now with DEFUSE it can diffuse out there, so it’s a nice matched set,” Saver quipped at a press briefing.

Consistent Results

The open-label DEFUSE 3 trial included 182 patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion who were deemed eligible due to initial infarct volume under 70 mL, a ratio of ischemic tissue volume to initial infarct volume of at least 1.8, and an absolute penumbra of at least 15 ml by either CT perfusion or MRI diffusion. The trial was stopped early for efficacy.

While treatment up to 16 hours after last known well time, including wake-up strokes, was allowed, the median from symptom onset to baseline imaging was 10 hours 29 minutes, with a quarter occurring after 11 hours 40 minutes.

Early termination of the trial before full enrollment limited its power for subgroup comparisons, the researchers cautioned. However, given that, "the beneficial effect of endovascular therapy was consistent in patients with a known time of stroke onset and those with an unknown time of onset, in patients treated 9 to 12 hours after onset and those treated more than 12 hours after onset (but not those treated <9 hours after onset), and in patients selected on the basis of diffusion and perfusion MRI and those selected on the basis of CT perfusion imaging."

In the group of 50 patients treated between 6 and 9 hours after stroke symptoms were discovered, the odds of functional independence favored thrombectomy, but not significantly so (RR 1.43, 95% CI 0.65-3.15).

General anesthesia, which has been controversial with thrombectomy, was used in 26 patients (28%).

Disclosures

The trial was funded by the National Institute of Neurological Disorders and Stroke.

Albers reported a financial relationship with iSchemaView, personal fees from Medtronic outside DEFUSE 3, and a patent licensed to Stanford University for automated detection of arterial input function and venous output function voxels in medical imaging.

Primary Source

New England Journal of Medicine

Albers GW, et al "Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging" New Engl J Med 2018; DOI: 10.1056/NEJMoa1713973.