Stroke windows keep opening wider

An expert reviews the latest data on ischemic stroke.

It was just last year that Nerissa U. Ko, MD, reviewed the latest in ischemic stroke care at the annual meeting of the American Academy of Neurology, but there was already a lot of new information to convey when the group met again in Philadelphia in May.

Image by Getty Images
Image by Getty Images

“This is a field that is changing rapidly,” said Dr. Ko, who is a neurointensivist and professor of neurology at the University of California, San Francisco.

One of the major changes is that the stroke treatment window continues to expand. Until recently, the cutoffs were 4.5 hours for tissue plasminogen activator (tPA) and 6 hours for thrombectomy. But in early 2018, the DAWN and DEFUSE-3 trials, which provided thrombectomy to patients who presented outside the 6-hour window after their strokes, were published in the New England Journal of Medicine.

“These were certainly the landmark trials that extended the window of thrombectomy to 24 hours in the perfusion imaging-selected patients,” said Dr. Ko.

The studies found an impressively low number needed to treat (NTT) for thrombectomy in patients with a large-vessel occlusion seen within 24 hours: two to three. That's actually even better than the NNT of five shown in the earlier trials of the intervention, she reported.

“It really set the standard that all strokes coming into your system should get a CT angio[gram] to really find the large-vessel-occlusive patient, even out to 24 hours,” Dr. Ko said. “This really obviously put a stress on our systems, but also identified patients now who could benefit from endovascular therapy.”

The window is expanding for more than just the patients who qualify for thrombectomy, she noted. “What about tPA?” she said. “There are a couple of recent clinical trials looking at 6- to 9- to 12-hour tPA and showing some efficacy in the right patient population.”

Perfusion imaging is also used to select these patients, and the expected adverse effects of thrombolysis also appear. “Obviously, the tradeoffs are different [with later intervention]. There are more hemorrhages in these patients, but the benefit is there,” said Dr. Ko.

One trial, published in the New England Journal of Medicine on Aug. 16, 2018, gave MRI-guided thrombolysis to patients who woke up with a stroke. “Last-seen-normal times are over 10 hours in these patients,” she said. At 90 days, the patients who received tPA had better functional outcomes than those receiving placebo, although at the cost of an increased, but not statistically significantly so, risk of hemorrhage.

“If you select the right patients, you can give tPA in these wake-up-stroke patient populations,” said Dr. Ko. A trial published by the New England Journal of Medicine on May 9 added evidence supporting a longer tPA window, and more data is expected to be published in the next year or so, she said.

However, the benefits that researchers are currently finding with late treatment probably won't be entirely replicable in practice. “When you start to take these trials into the broader community, the outcomes aren't always reproducible. Those numbers needed to treat in single digits, they are not getting [them] universally in the community-based treatments,” she said.

Successful implementation of these therapies requires high-quality systems of care, Dr. Ko noted. “Rapidly picking these patients, getting your radiologists on board, having support networks that should, I would argue, include a neurointensivist to manage these patients after the intervention—all of these things matter in a comprehensive stroke care model,” she said.

One question is whether such systems should provide stroke care more like emergency cardiology. “Do we bypass the EDs altogether and go straight to an angio suite model? Talk about stress on the system of care. These are some of the issues that are pushing the envelope for these hyperacute treatment systems,” she said.

Some health systems are speeding care by placing CT angiograms in ambulances, while hospitals without on-site neurologists are using telemedicine consults. “There are now many, many hospitals that are seeing late-window patients, and we need to be able to support our colleagues in the community with teleneurology to help decide if this is a patient who should be transferred,” said Dr. Ko.

One recent advance might simplify such transfers. “If you've ever tried to transfer a patient in the midst of a bolus of tPA, it is probably the biggest time-killer of all. You can't get an ambulance to transfer these patients; everyone's nervous about transferring a thrombolysis patient, with the drips hanging in place, the blood pressure you can't control,” said Dr. Ko.

Tenecteplase may offer a solution, according to a study published by the New England Journal of Medicine on April 26, 2018, involving patients who were within 4.5 hours of their ischemic stroke. The randomized trial found that those who received tenecteplase before thrombectomy had a higher incidence of reperfusion and better functional outcome than those who got alteplase.

A major benefit is that tenecteplase can be given as a single bolus, rather than an infusion. “So I wouldn't be surprised if you started to see more tenecteplase use [as more clinical trial data becomes available],” said Dr. Ko. “You don't have to worry about the blood pressure modifying over the hour of infusion time. It's actually fairly well tolerated.”

In other bad news for tPA, recent evidence also suggests that it might be overused in some stroke patient populations, specifically those with minor deficits. “It turns out that tPA doesn't help them that much,” said Dr. Ko. “Maybe we pushed tPA too fast in some of the minor stroke patients who don't need it.”

A study published in JAMA on July 10, 2018, compared aspirin to tPA in patients with minor nondisabling acute ischemic stroke and found similar functional outcomes. “But the ICH [intracranial hemorrhage] rates were significantly different,” she said. “Just some food for thought.”

Experts are also chewing over the appropriate indications for perfusion imaging. “We've been pushing perfusion imaging on everyone. Many of you are trying to upgrade your CTs,” said Dr. Ko. “Do we need it? Is the [noncontrast] CT enough?” Research suggests that that some patients' treatment paths will be clear enough without perfusion imaging, she said.

Other unanswered questions in the field include possible treatments for patients who show up too late for thrombolysis or thrombectomy. Interventions under study include matrix metalloproteinase (MMP-9) inhibitors, sulfonylureas, hypothermia, and progesterone. “As we move forward on the hyperacute window, similarly we also need to look at the neuroprotectives and ways to help with brain that isn't going to get saved by these types of interventions,” she said.

In addition to pushing forward with these novel discoveries, clinicians and health systems also have to focus on getting the new basics of stroke care right, Dr. Ko added. “There's a lot of discrepancy in delivery depending on where you live, how close you are to a comprehensive center,” she said. “Twenty-four hours is your new acute stroke window, and I think we're not quite prepared to handle that in all systems of care.”