Article In Brief
Distribution of Modified Rankin Scale scores at 90 days after stroke: Scores on the modified Rankin Scale show a favoring of the alteplase group compared with the placebo group for both. Modified Rankin Scale scores range from 0 to 6 (0, no symptoms; 1, no clinically significant disability; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability; and 6, death).
Researchers reported that intravenous alteplase appeared to be as effective in patients with lacunar stroke as in those with nonlacunar stroke.
Patients with lacunar infarcts may benefit from intravenous alteplase as much as non-lacunar ischemic stroke patients do, according to a post-hoc analysis of a previously published study.
Doctors sometimes hesitate to administer alteplase to lacunar stroke patients because there is some debate over whether the clot-dissolving drug helps such patients, as well as a concern that thrombolysis might increase their risk of intracranial hemorrhage.
The new findings are based on a post-hoc analysis of data collected for the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke, also known as the WAKE-UP trial. The researchers used magnetic resonance imaging (MRI) to determine if a stroke of unknown onset likely occurred within 4.5 hours and then randomized eligible patients to treatment with either intravenous alteplase or placebo. For this follow-up report, researchers examined the data on 90-day outcomes for just the patients with imaging-defined lacunar stroke.
“While the WAKE-UP trial was not powered to demonstrate the efficacy of treatment in subgroups of patients, the results indicate that the association of intravenous alteplase with functional outcomes does not differ in patients with imaging-defined lacunar infarcts compared with those experiencing other stroke subtypes,” the investigators reported in the March 25 online edition of JAMANeurology.
The stroke treatment guidelines already support the use of intravenous alteplase for all acute ischemic stroke regardless of subtype, but this new analysis could provide another nudge.
An accompanying editorial affirmed that: “These new data are likely enough to strongly favor the stance that thrombolysis is efficacious in the treatment of lacunar infarction.”
Lacunar strokes account for about 20 percent of all strokes, but there is much still to be learned about them, the study authors noted. According to background information in the new study, “the vascular pathology underlying lacunar infarcts remains incompletely understood,” though they are believed “to result from the occlusion of small penetrating arteries owing to microatheroma and lipophylinosis.”
“The role of thrombosis in the pathophysiology of lacunar infarcts is uncertain, and consequently, researchers have questioned whether lacunar strokes would benefit from clot-dissolving pharmacological treatment,” the study authors noted.
Lacunar strokes have also been traditionally thought as rather benign strokes, another reason why the use of thrombolysis, with its potential for intracranial hemorrhaging, might be questioned.
Previous clinical trials have addressed the safety and outcome of intravenous thrombolysis in subtypes of stroke including lacunar infarcts, but that characterization was based mostly on clinical presentation. The WAKE-UP trial data, which included MRI at the time of presentation, provided a good opportunity to take a closer look at how lacunar strokes respond to thrombolysis.
“Just because a stroke is mild, or what could be considered mild, doesn't mean people can't have significant disability at 90 days.”
—DR. SHARYL MARTINI
The WAKE-UP trial was a European, multicenter, randomized trial designed to study the safety and efficacy of intravenous thrombolysis with alteplase in patients who had a stroke of unknown onset. Under the study protocol, an acute ischemic lesion visible on MRI diffusion-weighted imaging (DWI) with no corresponding marked parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR) served as a surrogate indicator that stroke onset was likely 4.5 hours or less. Eligible patients were then assigned to either intravenous alteplase or placebo.
The primary endpoint was a favorable outcome at 90 days, defined as a score of 0 or 1 on the modified Rankin scale (mRS). The original WAKE-Up results, published in May 2018 in the New England Journal of Medicine, showed significantly better functional outcomes in the alteplase group, though there were also more cases of hemorrhaging, compared with the placebo group.
“The response to thrombolytic therapy, as suggested by this study and others, implies that a thrombus must be involved. What we currently call a lacunar infarct based on clinical presentation and/or imaging is probably a mix of pathology.”
—DR. KYRA J. BECKER
For the post-hoc analysis, researchers considered 108 patients (of the original 503 participants) who had lacunar infarcts based on MRI. In the analysis, the lacunar patients tended to be younger on average (63 years old) than the nonlacunar patients (66 years old) and less severely affected by stroke—as assessed by the National Institutes of Health Stroke Scale (NIHSS) score of 5 points compared with 6 for non-lacunar patients. They were also less likely to have atrial fibrillation. Median DWI lesion volume was smaller for patients with lacunar infarcts, 0.7 mL compared with 3.8 mL for the nonlacunar stroke group.
Of the 108 patients with lacunar stroke, 55 were assigned to alteplase and 53 to placebo. Follow-up data was available on 105 of them. Among those receiving alteplase, 31 of 53 (59 percent) had a favorable outcome at 90 days compared with 24 of 52 (46 percent) of the placebo group. Those results were comparable to what was reported in the WAKE-UP trial for all ischemic stroke patients who received alteplase. The distribution of mRS scores at 90 days showed a statistically nonsignificant shift toward better outcomes for those who received the treatment.
“For treatment response, which defines the target mRS score depending on the initial symptom severity, there was a significant benefit of alteplase treatment, with an absolute increase of 22 percent of patients showing a treatment response,” the new analysis reported.
One person in the treatment group developed symptomatic intracranial hemorrhage, which was fatal. The researchers said the patient was a “protocol violation” and should not have received alteplase due to significant hypertension.
“We have been the first to study and prove the efficacy and safety of alteplase among patients with an imaging-defined lacunar infarct in a randomized, clinical trial,” said Ewgenia Barow, MD, a study coauthor at University Medical Center Hamburg-Eppendorf in Hamburg, Germany, in an email to NeurologyToday. “Based on our results, we conclude that treatment with intravenous alteplase should not be withheld in patients with lacunar stroke.”
The study's limitations include the fact that it is a post hoc analysis and the original WAKE-UP study was not powered to show treatment efficacy in subgroups of patients, the authors noted. The study also relied on MRI for assessing patients before treatment, which is not often the case in everyday stroke practice, where CT is performed.
The accompanying editorial by Pooja Khatri, MD, professor of neurology at University of Cincinnati, noted that “even in high-income countries, most hospitals that receive patients with strokes do not have expeditious access to MRI.”
Sharyl Martini, MD, PhD, medical director of the VA's National TeleStroke Program, said the newly reported results on using alteplase for lacunar infarcts “will make people feel better about what they are already doing” in stroke treatment.
She said there has been a growing recognition among stroke doctors that lacunar strokes, while tending to be smaller and less severe than strokes caused by large-vessel occlusion, are not as benign as once thought.
“Just because a stroke is mild, or what could be considered mild, doesn't mean people can't have significant disability at 90 days,” Dr. Martini said. She said the decision on whether to use intravenous alteplase with patients who present with minor symptoms including lacunar stroke syndromes can sometimes be a tough call and the answer may depend on the circumstance of the patient.
She said, for instance, that while the “lacunar dysarthria-clumsy hand syndrome may not be disabling for some people, it would disable others, for example, those who use their hands for a living.”
In that case, treating with alteplase may be the right call, despite the risk of intracranial hemorrhage, she said.
Joshua Willey, MD, assistant professor of neurology at Columbia University, said despite wider use of thrombolysis, there is still “sort of a sense out there that if we don't see a large clot, why do we have to treat it?” To the contrary, “just because a stroke is tiny doesn't mean the deficit is going to be tiny or the disability is going to be tiny,” he said.
The post-hoc analysis of the WAKE-UP data underscored that point, noting “although most patients with lacunar infarct in this trial presented with only mild to moderate symptom severity, the outcome of lacunar stroke was far from benign, with less than 50 percent of patients in placebo group reaching a favorable outcome after 90 days.”
Dr. Willey said he hoped the latest favorable findings on using thrombolysis with alteplase for lacunar stroke, while more confirmatory than game-changing, will result in more patients being given the chance to benefit from the approach.
Kyra J. Becker, MD, professor of neurology and neurologic surgery at University of Washington, said there is a lot that remains to be learned about “the nature of what we call lacunar infarcts in the MRI era” and why they seem to be responsive to clot-dissolving therapy even though “the classic pathological description does not invoke a clot per se” in the small penetrating arteries that are involved.
“The response to thrombolytic therapy, as suggested by this study and others, implies that a thrombus must be involved,” Dr. Becker said. “What we currently call a lacunar infarct based on clinical presentation and/or imaging is probably a mix of pathology.”
David Y. Hwang, MD, FAAN, associate professor of neurology at Yale School of Medicine, said the WAKE-UP data “provided a unique opportunity” to analyze the safety and efficacy of thrombolysis with alteplase for lacunar stroke specifically because it used MRI assessment to guide patient selection for the trial. He said the new analysis “basically confirmed the strong suggestion from the literature that lacunar strokes don't differ from other (ischemic) strokes in terms of tPA (tissue plasminogen activator).”
Dr. Hwang said one of the most important take-aways from the new study is the reminder it provides that minor strokes can be problematic.
“It's not about whether your number (on the stroke scale) is 5, it's about whether the stroke is going to be disabling or not, and is the patient going to have a deficit that affects them down the road?” he said.
The answer isn't always clear, but Dr. Hwang said he believes there is enough evidence to show that “if you have any doubt in your mind as to whether a stroke is disabling or not, err on the side of giving tPA if the patient otherwise qualifies.”
Dr. Martini had no competing interests. Dr. Willey has received consulting fees from Medtronic, serves on the clinical endpoint committee for a clinical trial for the Cardiovascular Research Foundation, and is a clinical trial investigator for the National Institutes of Health, and Genentech for the PRISMS and TIMELESS trials. Dr. Hwang's spouse has received salary/grant support from Regeneron Pharma. Dr. Becker has received reimbursement for travel expenses as a member of the data and safety monitoring board for Bristol Myers Squibb, and Novo-Nordisk for outcomes adjudication, as well as compensations from Fibrogen for outcomes adjudication.