Time Window to Treat Stroke Longer Than Previously Thought

By Jamie Santa Cruz

Findings of a new meta-analysis indicate there is some benefit to catheter-based treatments as long as seven hours and 18 minutes after a stroke's onset.

"Time saved is brain saved." It's the mantra of stroke treatment. A new meta-analysis led by researchers at UCLA offers fresh evidence about exactly how important it is to obtain early treatment—but the research simultaneously shows that the time window in which treatment may be beneficial is longer than previously thought. Specifically, data from the meta-analysis show that endovascular treatments can continue to offer benefit for some patients more than seven hours after the onset of stroke.1

The findings come on the heels of multiple randomized clinical trials in the last three years demonstrating improved outcomes with the use of catheter-based thrombectomy devices for treatment of ischemic stroke.2-6 Those recent breakthrough findings led to the release last year of updated guidelines from the American Heart Association (AHA)/American Stroke Association (ASA) recommending use of endovascular treatments for acute stroke care.7

The new meta-analysis, published in the Journal of the American Medical Association, relies on data from five recent clinical trials of thrombectomy devices (primarily stent retrievers) involving nearly 1,300 people. The purpose of the study, according to Jeffrey Saver, MD, director of the UCLA Comprehensive Stroke Center and the lead author of the study, was to better understand the significance of the timing of treatment. While it was already clear that catheter-based therapies resulted in improved outcomes, the researchers sought to determine how long after the onset of stroke endovascular treatment can still be beneficial, as well as how much benefit there is in treating early.

According to Saver, previous individual studies on the timing of treatment have focused primarily on the first six hours after onset, and current AHA/ASA guidelines recommend treatment within six hours. But the findings of the new meta-analysis demonstrate that there is some benefit to catheter-based treatments as long as seven hours and 18 minutes after onset.

Although the time window during which treatment can be beneficial is longer than previously thought, the study was also able to quantify the benefits of treating earlier rather than later. According to the data, for every four minutes that pass without opening the occluded artery, 1% of patients will have a worse final outcome. Likewise, for every six minutes that pass, one additional patient will become dependent.

"We've known for a long time that the longer the brain (or any organ) goes without oxygen and nutrients, the more of it will be injured," Saver says. "But the investigators were surprised by the strength of the relationship between time and outcome. Even just four minutes results in 1% fewer patients having as good an outcome as they might." He adds, "Physicians and nurses need to look at their hospital systems and ensure that the door-to-puncture time [is shortened] as much as possible."

Endovascular Treatments: A Revolution in Stroke Treatment
The introduction of catheter-based therapies has revolutionized acute management of stroke, according to Alexander Khalessi, MD, MS, vice chairman of clinical affairs and director of neurovascular surgery at the University of California, San Diego, who was not involved in the new meta-analysis. Previously, he says, the only treatment was tissue plasminogen activator (tPA), a blood thinner. However, many patients, including postsurgical patients, are tPA ineligible. Furthermore, he adds, success rates with blood-thinning medications are low, and the likelihood of opening the blocked artery with blood thinners drops with more significant blockage.

By contrast, Khalessi says, a significant benefit of catheter-based therapies is that the larger arteries, which tend to be responsible for more severely disabling strokes, are easier to open. In the five trials on which the UCLA-led study was based, he says, only 10% to 15% of patients with large vessel occlusion were functionally independent at three months if they had received only tPA as treatment. Among those receiving catheter-based therapies, however, the percentage who were functionally independent at three months was upward of one-half. For most things physicians do in medicine, he adds, the number needed to treat in order to spare a patient severe disability or to save a life is in the midteens, whereas the number needed to treat in the thrombectomy trials was only three to four. "Those are massive numbers and really on the order of the treatment of sepsis with penicillin," Khalessi says.

Catheter-based thrombectomy devices first became available in the 1990s, according to Khalessi, but randomized clinical trials for the second generation of the devices began approximately two years ago. Two main types of devices are currently available: stent retrievers, which retrieve clots mechanically, and large-bore catheters that rely on aspiration or suction. Although most of the available data relate to stent retrievers, the skill set required for the two kinds of devices is similar, and most physician operators use both, Khalessi says. The etiology of the patient's stroke typically dictates the technical choice of which type of device to use. The organized, calcific plaques seen in patients with arrhythmias of the heart, for instance, call for the use of a stent retriever, but for a softer clot such as in a periprocedural embolism, aspiration technology might be preferable.

Prevalence of Endovascular Treatments and Barriers to Use
Although endovascular treatments became part of the standard of care in 2015, several barriers to access mean that many stroke patients don't receive them. Currently, according to Khalessi, there are about 12,000 catheter-based thrombectomies performed per year in the United States, which is far below the number of patients with ischemic stroke who would benefit from the procedure. The number of thrombectomies performed each year is rising, according to Khalessi, but unlike in other areas of medicine, the workforce required to perform endovascular procedures is relatively small, and lack of physicians qualified to perform the treatments presents an ongoing problem.

An additional barrier to access is the comparatively small number of comprehensive stroke centers that offer catheter-based therapies. Unlike a simple drug treatment such as tPA that can be offered at almost any hospital, thrombectomy devices like stent retrievers are used mostly at large tertiary medical centers. Currently, Khalessi says, there are only about 50 such stroke centers in the United States offering the treatments.

One key to improving access to endovascular treatments is revision of regional systems of care to ensure that patients who have had a stroke and would benefit from thrombectomies are transported as quickly as possible to comprehensive stroke centers offering the procedure. Khalessi notes that many smaller hospitals do not currently have a rigorous plan in place to manage those patients who need treatment at a more advanced care center.

Another area of need for further research, according to Saver, lies in determining the best method for routing patients who are en route to the hospital. "If it takes one minute longer to go to a thrombectomy hospital, it seems clear that you should go past the smaller stroke center to the larger one," he says. "If it takes an hour and a half to get there, then it is clear that you should go to the closer hospital first and get the drug treatment as your first treatment. And somewhere in between is the best time cutoff at which it makes sense to route patients directly to comprehensive stroke centers."

Benefit to Treatment Beyond Seven Hours?
The UCLA-led meta-analysis was able to show a benefit to treatment up to seven hours and 18 minutes hours after onset, but according to Saver, it is likely that the time window in which endovascular therapy could be beneficial extends even beyond that. Extended benefits are especially likely, he says, in patients for whom brain imaging shows that their stroke has not yet completed after 10 or 12 hours. According to Khalessi, there is at least one trial currently under way at Stanford University seeking to study the period between six and 16 hours after the onset of stroke to see how long the benefits continue.

Allowing that the upper bound of time over which treatment is effective has yet to be established, the current findings of the UCLA-led study suggest that physicians should have latitude to offer treatment even if the six-hour window currently recommended for treatment has already passed. "There is not a substitute on the ground for clinical judgment," Khalessi says. "If you have someone come in with a stroke, you get imaging of their brain, and that stroke is not completed on that imaging, I wouldn't necessarily withhold therapy from that person if they came in at six hours and one minute. The reason these kinds of leading-edge articles are important is because they provide some flexibility to providers to make those judgments."

In particular, Khalessi says, the findings have relevance for the treatment of wake-up strokes, which represent a full one-quarter of all strokes and are particularly important in older patients. If an individual wakes up in the morning with a deficit after sleeping all night, the time of onset is typically closer to when the person woke up than when he or she went to bed, but there is no way to know for sure, according to Khalessi. The first duty of a physician is to do no harm, and therefore physicians have faced a quandary in offering treatment for wake-up strokes that may have begun more than six hours prior. But the new findings of extended benefits of treatment suggest that physicians should have greater flexibility in treating wake-up strokes, Khalessi says.

Even though there may be benefit to delayed treatment, the primary emphasis should remain on treating stroke as early as possible. According to Khalessi, it's important to continue underscoring to patients and the public that if they see a loved one with a deficit, they should steamroll any resistance on the part of their loved one and immediately call 911. "There's not a medical situation that's a greater emergency than a stroke," he says. "No question."

— Jamie Santa Cruz is a freelance writer based in Englewood, Colorado.

References
1. Saver JL, Goyal M, van der Lugt A, et al. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis. JAMA. 2016;316(12):1279-1288.

2. Fransen P, Berkhemer O, Lingsma H, et al. Time to reperfusion and effect of intra-arterial treatment in the MR CLEAN Trial. American Heart Association website. http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_471830.pdf. Accessed October 27, 2016.

3. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019-1030.

4. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285-2295.

5. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009-1018.

6. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372(24):2296-2306.

7. Powers WJ, Derdeyn CP, Biller J, et al. 2015 American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(10):3020-3035.