Speed Still Critical for Endovascular Therapy Patients Treated Soon After Stroke: MR CLEAN

Delays in endovascular therapy for patients treated within 6.5 hours of stroke onset are tightly linked to worse functional outcome and higher mortality, according to data from the MR CLEAN Registry published recently in Circulation.

“We’ve known for a long time that ‘time is brain’ when you’re talking about stroke treatment. That’s not the new message. The novelty is that this is the first study of patients given endovascular treatment in current clinical practice, not in a clinical trial setting,” lead author Maxim J.H.L. Mulder, MD, PhD (Erasmus University Medical Center, Rotterdam, the Netherlands), commented to TCTMD.

The MR CLEAN Registry findings might spur confusion given the recently updated American Heart Association/American Stroke Association guidelines that endorse, with some caveats, the use of mechanical thrombectomy in the 6- to 24-hour window based on data from the DAWN and DEFUSE 3 trials. But these trials involved advanced imaging to select patients who, even at these time points, were thought to be most likely to benefit from treatment. Many centers lack the capability to perform the level of imaging done in DAWN and DEFUSE 3, Mulder said.

In MR CLEAN, the absence of such imaging selection is “one of the main reasons that the association of time with outcome after the treatment is so great, and is even stronger than in all the previous trials,” he commented. “In our point of view, this paper represents the closest estimation of the true time association with functional outcome.”

Within approximately 6 hours of stroke, the patient population is heterogeneous, Peter Panagos, MD (Washington University in St. Louis, MO), and DEFUSE 3 principal investigator Gregory W. Albers, MD (Stanford University, Palo Alto, CA), both noted to TCTMD. Some patients have infarcts that grow unusually fast, and some for whatever reason, be that good collaterals or preconditioning, have brains that develop damage much more slowly. Others fall in the middle. All have varying potential to benefit from treatment, Albers notes in an editorial published online ahead of the April 2018 issue of Stroke.

The key question in their minds is how to balance the need for speed with the information that can be gleaned from advanced imaging.

Worse Function and Higher Mortality

The MR CLEAN Registry, still ongoing, collected data on all 1,488 patients who underwent endovascular therapy for acute ischemic stroke at one of 16 participating centers in the Netherlands between March 2014 and June 2016. All had intracranial proximal arterial occlusion in the anterior circulation or middle or anterior cerebral artery on CT angiography, magnetic resonance angiography, or digital subtraction angiography.

Around half of the patients were transferred to the intervention center from a primary stroke center, having received IV alteplase if indicated. Median time from stroke onset to arrival at the intervention center was 134 minutes, with a median of 208 minutes between onset and the start of endovascular therapy. It took a median of 67 minutes to get patients from the emergency department to the start of therapy. Total procedure time was a median of 63 minutes and was shorter in cases with successful reperfusion (median 57 vs 85 minutes; P < 0.01).

At 90 days, 38% of patients were functionally independent, as defined by a modified Rankin Scale score of 0 to 2. The 90-day death rate was 29%, and the rate of symptomatic intracranial hemorrhage was 5.8%.

Longer time between symptom onset and artery puncture in the angiography suite was linked to worse functional outcome (adjusted common OR 0.83 per hour; 95% CI 0.77-0.89). Each added hour from stroke onset to the start of endovascular therapy carried a 5.3% absolute decrease in the likelihood of functional independence and a 2.2% absolute increase in mortality.

When successful reperfusion was the litmus test, the influence of time was even more robust: each hour-long delay carried a 7.7% decrease in the odds of functional independence.

Clock vs Brain

Panagos, an emergency physician who serves as vice chair of the American Heart Association’s Stroke Council, told TCTMD that on first glance, the latest MR CLEAN Registry results are “really daunting” and perhaps even confusing.

“You’re hearing different messages from the stroke community: faster, earlier is better . . . but all of a sudden you can treat out to 24 hours,” he explained, adding, “Those seem to conflict with one another.”

Currently, Panagos noted, the guidelines advise against doing advanced imaging such as perfusion studies in patients who present within the 6-hour window. “The reason for that is to not sacrifice time over the fidelity to be completely perfect,” he observed. “So in the grand scheme of things, would imaging make a difference in this under-7-hour group? Probably it would. It may select out patients who may not benefit from therapy, but the tradeoff, as we’re learning from the MR CLEAN Registry is that for every hour we delay treatment, there’s less opportunity of achieving a good outcome.”

He asserted that in these “ultra-early” presenters it’s most important to get them to “definitive treatment” quickly.

“We always want to move as fast as possible,” Albers agreed. However, he continued, “the issue with a study like MR CLEAN, where they’re not doing more advanced imaging, is that some of those patients that they’re treating have no salvageable tissue.”

Rather than going by “any particular time clock, you look at the patient’s brain,” he suggested. “If they come in at 3 hours and there’s nothing to save, we’re not going to do the treatment. We’re not going to do the procedure because we’re not going to help them [and] we might hurt them. And it’s very expensive. But if they come in at 18 hours and they’ve got a lot to save, you don’t want to look at the MR CLEAN [numbers] and say oh my god, the good outcome rate’s going to be terrible at 18 hours.”

At 1 hour, advanced imaging is not apt to pick up on many unlikely candidates for endovascular therapy, he conceded. However, by 3 hours around 15% of patients will “have very little or no salvageable tissue,” Albers estimated, adding, “So I think it’s clearly worth it if you get beyond 3 hours.”

Mulder said that, beyond confirming the presence of large-vessel occlusion, additional imaging isn’t needed for treating patients within 6 hours. “I think the registry shows that imaging selection, apart from a proven proximal occlusion, does not play a role within the 6-hour time window,” he commented.

Moreover, there’s no evidence to support using collateral or perfusion score during these early hours, Mulder said. “Maybe there are one or two [people] you could pick out who will not benefit, but if you look at the large picture, there’s no substantial evidence that any imaging selection by itself could be used for selecting these patients. Recently, we even showed that patients without collaterals or [with] a poor ASPECT score could benefit from endovascular treatment within this time window.”

No Matter What, Act Quickly

According to Albers, the additional imaging isn’t a burden if integrated into your workflow—CT perfusion takes about 5 minutes to perform and another 2 minutes for processing the images, he said. “You don’t have control over how long it takes between when the stroke started and when the patient arrives, what you have control over is how quickly you can act from the time they’ve arrived to the time that you can treat them. [At Stanford] we feel like if you put that extra 5 minutes of imaging in there, you’re going to be making much smarter treatment decisions.”

The oft-repeated maxim “time is brain” still holds true amid the expanding horizons offered by DAWN and DEFUSE 3, Panagos said. Reducing delays, he said, requires a multipronged approach: educating patients to recognize stroke symptoms and promptly call 911, training emergency medical services to properly assess and transfer patients, and taking measures to speed up care once patients get to the hospital.

While many comprehensive stroke centers are aggressively trying to winnow down door-to-groin time, the bulk of treatment delays happen prior to arrival at the treating hospital. The potential to bring door-to-groin time down to 60 or even 30 minutes “is within our grasp and we have control over that,” Panagos said. “That great sink of time before the patient arrives to the comprehensive center is where the greatest opportunity for gains is.”

One reassuring thing is that the overall results from the MR CLEAN Registry, from which the time-to-treatment analysis was derived, reaffirm the original MR CLEAN trial, Panagos said. MR CLEAN, published 3 years ago in the New England Journal of Medicine, was “essentially first across the finish line in the new endovascular era” to show that patients with large-vessel occlusions could benefit from intraarterial treatment in the setting of IV thrombolysis, Panagos said.

Another iteration of the trial, known as MR CLEAN LATE, is now exploring whether patients presenting between 6 to 24 hours could be better selected with collateral score as an additional imaging parameter, Mulder noted. Only patients without any collaterals at all would be excluded. This might increase the proportion of people who are eligible for endovascular treatment, he suggested. “But that’s of course to be learned from this trial. I think we’re not done yet with just DAWN and DEFUSE 3. They’re just the first step towards a broader patient population that may be treated after the 6-hour window.”