LOS ANGELES — New results show that using thrombolysis in patients with a stroke of unknown onset is safe and feasible.
Patients were selected for treatment on the basis of imaging findings, a pattern of diffusion-weighted imaging (DWI)-positive and fluid-attenuated inversion recovery (FLAIR)-negative findings that has been associated with strokes with onset less than 3 hours earlier. The DWI image becomes positive immediately, and the FLAIR image, showing edema, takes 3 to 4 hours to become visible.
"About 30% of patients arrive at the hospital having had the onset of their stroke unwitnessed," Lee H. Schwamm, MD, executive vice chair of neurology, director of Acute Stroke Services at Massachusetts General Hospital, Boston, said at a press conference. Clinically, they meet all the criteria for treatment with tissue plasminogen activator (tPA), except for the time issue, he said.
"The question is, in the absence of a human witness, could there be some other witness to tell us this stroke happened very recently?" Dr Schwamm asked. Their results suggest that using thrombolysis in a population selected by using these imaging criteria was safe and feasible.
Findings from this study, the MR WITNESS trial, were presented here at the International Stroke Conference (ISC) 2016.
Last Seen Well
Currently, patients who have stroke of unknown onset, such as those who wake up with symptoms, have limited options for reperfusion therapies, Dr Schwamm said. In MR WITNESS, investigators tested the safety and feasibility of using intravenous (IV) tPA in patients with this pattern of DWI-positive, FLAIR-negative (DPFN) imaging, treated within 4.5 hours of symptom discovery.
The trial was an open-label, phase 2, single-arm, multicenter study using IV tPA in selected patients. MRI was performed at screening, and computed tomography (CT) was done at 24 hours for the presence of intracerebral hemorrhage (ICH). Patients then had follow-up MRI at 30 days, and clinical outcome was assessed at 90 days.
Patients were included if they qualified clinically for tPA by typical criteria, had last been seen well 4.5 to 24 hours previously, were able to receive tPA within less than 4.5 hours of the time of symptom discovery, and had the DPFN imaging pattern with a signal intensity ratio of less than 1.15.
The primary outcome was the rate of symptomatic ICH, defined as any ICH associated with a 4-point increase in the National Institutes of Health Stroke Scale score. This is no different from that seen in the ECASS 3 trial, which established the safety and efficacy of treating with tPA out to 4.5 hours.
Prespecified secondary analyses included good functional outcome, defined as a modified Rankin Scale (mRS) score of 0 to 1 at 90 days, and rates of asymptomatic hemorrhage.
A total of 80 patients were enrolled between 2011 and 2015 at 10 sites. Most strokes (35%) were cardioembolic; 26% were lacunar. Of the 80 patients, 71% had symptoms discovered at wake-up, and 29% at other times. In these patients, tPA treatment was started at a median of 11.3 hours since the patient was last seen well. The time from discovery to tPA administration was 3.85 hours, ranging from 2.83 to 4.25 hours.
"We found, to our delight, that there was only 1 patient with symptomatic hemorrhage, so 1 out of 80 patients, 1.25%," Dr Schwamm said (range, 0.03% to 6.80%).
The rate was lower, but not significantly so, than the ECASS 3 rate of 5.30% (range, 3.30% to 7.80%; P = .15), with only 80 patients. Likely as many as 200 patients would be required to show that definitively, he noted, "but it's definitely no different than the rate in ECASS 3. So our primary outcome measure was met, the drug is definitely safe, and the trial was very feasible."
Asymptomatic ICH at 24 hours occurred in 21 of the 80 patients, for a rate of 26.3%, also similar to that seen in ECASS 3 (21.8%). Mortality was 8.8%.
Although the study was not powered to look at clinical outcomes, the researchers found that among the 69 patients who did not already have disability at study entry, 31 (44%) had an mRS score of 0 to 1 at 90 days.
Because this group hasn't been studied before, it's unclear what the expected rate would be, Dr Schwamm said, but in ECASS 3, the rate of responders was about 50% for those who were treated and about 45% for those who received placebo. That may seem to indicate no effect in the MR WITNESS patients, he said, "but if we look at the pooled data [on tPA], the response rates there are closer to 20% to 30%, so we think the true effect is probably somewhere between 45% and 48%, and we're guessing from a lot of other data that looked at pooled, randomized data that the response rate in this population might be around 40%.
"So we think the effect size will be similar to what was seen in ECASS 3," he said.
Another MRI-based study, called WAKE-UP, is ongoing now in Europe, and currently is at about 40% of its recruitment goal.
These investigators are planning to submit an application to the National Institutes of Health's (NIH's) StrokeNet for another trial, called Imaging-Window Thrombolysis iN Emergent Stroke Syndromes (I-WITNESS), a placebo-controlled, randomized, controlled trial of IV tPA in unwitnessed stroke using CT or MRI for patient selection, to see whether CT can be used in this setting.
"Typically we don't see CT changes till 6 hours after the start of symptoms, but CT scanners have been getting better and better," he said. "We actually think that the question is such a compelling one that we need to answer it for CT and MR, because if it could be done with CT, it opens up the generalizability of this treatment to pretty much every hospital in this country. If it requires an emergency MRI, it still limits to some degree the number of patients who could benefit from this treatment."
Another study, the DAWN study, is looking at the use of thrombectomy as the intervention for large proximal occlusions in patients with wake-up or unwitnessed stroke, and DEFUSE 3, a recently funded NIH study, will look at patients between 6 and 16 hours in order to capture many wake-up strokes as well.
"We're not targeting the wake-up strokes that have proximal occlusions," Dr Schwamm noted. "We think thrombectomy probably is the most appropriate and effective treatment for those, but we suspect that these milder, more distal strokes, that are still very disabling, are the ones that are most likely to respond to intravenous tPA, so those are our target."
Philip B. Gorelick, MD, director of Hauenstein Neuroscience Center at Saint Mary's Health Care, clinical professor of translational science and molecular medicine at the Michigan State University College of Human Medicine in Grand Rapids, and a spokesperson for the American Stroke Association, commented on the findings for Medscape Medical News.
"This is a tissue-based approach that's very novel," he said. If the main phase trials bear out these findings, he added, "I think this is huge, because it might make another 15% to 20% of people eligible for tPA, which would be a good thing.
He called it "a nicely presented, nicely done study, and I think the technology's going to drive a larger absolute number of people to be treated with intravenous tPA within the 0- to 4-and-a-half-hour window."
How thrombectomy will factor into this mix is the next question, he said. Work by Greg Albers, MD, at Stanford University in California has been critical to describing infarct growth, Dr Gorelick said, and it's now clear that growth varies between patients. "So in some people, the infarct may be growing for hours, slowly, and so you still may have a chance to pull that clot out. In other people it may occur very quickly."
Some of this variability is dictated by the presence or absence of collaterals, and Dr Albers' imaging work has begun to describe collaterals in individual patients, which may push the treatment window further and further. "It won't be for everybody, but there will be people who, based on those technological metrics that we get back, they will be able to have more aggressive therapy, thrombectomy, so I think that's where we're headed," Dr Gorelick said.
MR WITNESS was funded by the National Institute of Neurological Disorders and Stroke.
International Stroke Conference (ISC) 2016. Abstract LB23. Presented February 19, 2016
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Cite this: MR WITNESS: Thrombolysis for 'Wake-Up' Stroke Safe, Feasible - Medscape - Mar 03, 2016.