But early termination of randomized PRISM trial made findings not definitive
Functional outcomes were just as good with aspirin as with thrombolytic alteplase (Activase) for mild, non-disabling acute ischemic stroke in the PRISMS trial, although its early termination might have undermined the conclusions.
Favorable outcomes, with a modified Rankin score (mRS) of 0 or 1 at 90 days, occurred for 78.2% of alteplase-treated patients versus 81.5% of those receiving aspirin, a nonsignificant difference, Pooja Khatri MD, of the University of Cincinnati, and colleagues reported in Journal of the American Medical Association.
"We expected to see some evidence of benefit from alteplase, [because] prior trials of disabling stroke showed no treatment effect modification by stroke severity," Khatri told MedPage Today. "Unfortunately, we saw no evidence to suggest the likelihood of treatment benefit for the mildest strokes."
Critically, the trial "was stopped early by the sponsor because of slow enrollment and financial considerations, precluding meaningful conclusions," cautioned Larry Goldstein, MD, of the University of Kentucky in Lexington, in commenting to MedPage Today on the study, in which he was not involved.
The researchers agreed that "the very early study termination precludes any definitive conclusions," and suggested additional research may be warranted.
Also, the patient population might have been a tough one in which to show benefit, as William Powers, MD, of the University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
"The eligibility criterion of 'not clearly disabling' is essentially the same as the definition of the favorable outcome of an mRS score of 1," he wrote. "Thus, at enrollment, all patients met the criterion for success. To show a benefit, alteplase treatment would have to prevent patients from worsening, not improve recovery. This may have been a bridge too far."
PRISMS was designed to build on previous research with a unique focus on patients with low National Institutes of Health Stroke Scale (NIHSS) scores of 0 to 5 and without identifying disabling deficits.
The sample consisted of 313 people enrolled at one of 53 U.S. stroke network facilities (mean age 62, 46% women), who had a median NIHSS score of 2 and median time to treatment of 2.7 hours from onset. Participants were randomized double-blind to take either aspirin or IV alteplase within 3 hours of stroke onset.
The investigators noted that five alteplase-treated patients (3.2%) versus no aspirin-treated patients had a symptomatic intracranial hemorrhage (risk difference 3.3%, 95% CI 0.8%-7.4%).
Overall, patients in the trial "did better than we expected," Khatri noted. "We estimated a 30% rate of 90-day disability, but we observed a 20% rate of disability in both arms of the trial. This may have had to do with our stricter definitions and exclusions compared to the prior observational studies."
"Based on post hoc analysis, it is unlikely that the premature termination of the trial was responsible for the failure to demonstrate a benefit of alteplase," Powers wrote in his editorial. "The symptomatic intracranial hemorrhage rate of 3.2% (5/157) in the alteplase group was similar to previous data from patients with mild stroke and also was not sufficient to explain a lack of alteplase benefit."
While not a definitive trial, it makes the lack of functional outcome benefit from alteplase in mild, non-disabling ischemic stroke "more certain," Powers concluded. "[F]or these patients, treatment with aspirin along with close monitoring maybe an appropriate course of action."
Powers reports no relevant conflicts of interest.
Khatri reports payment to her university department for research efforts from Genentech, Neurospring, Lumosa, Cerenovus, and the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Khatri also reports fees from Biogen and Medpace/Novartis. Khatri was an unpaid consultant to EmstopA and received travel support from Neuravi.
The trial was funded by Genentech Inc.
Source Reference: Khatri P, et al "Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits: The PRISMS randomized clinical trial" JAMA 2018; DOI: 10.1001/jama.2018.8496
Source Reference: Powers W "Intravenous alteplase for mild nondisabling acute ischemic stroke: A bridge too far?" JAMA 2018; DOI: 10.1001/jama.2018.8511.
Read the original article on Medpage Today: Lytic No Better Than Aspirin for Mild Ischemic Stroke