Treatment with alteplase vs. aspirin did not improve functional outcomes at 90 days in patients with minor nondisabling acute ischemic stroke in the randomized phase 3b PRISMS trial.
At 90 days following a minor stroke judged to be nondisabling, a favorable functional outcome – defined as modified Rankin Scale (mRS) score of 0 or 1 – occurred in 122 (78.2%) of 156 patients who received alteplase and in 128 (81.5%) of 157 who received aspirin (adjusted risk difference, –1.1%), wrote, of the University of Cincinnati, and her colleagues. The report was published in the .
The PRISMS (Potential of rtPA for Ischemic Strokes with Mild Symptoms)was intended as a 948-patient, double-blind, placebo-controlled U.S. trial comparing alteplase and aspirin for emergent stroke in patients with National Institutes of Health Stroke Scale (NIHSS) scores of 0-5 at presentation whose stroke-related neurologic deficits were not clearly disabling and in whom the study treatment could be initiated within 3 hours. However, the trial was terminated early by the sponsor – prior to unblinding or interim analyses – because of below-target enrollment. An original plan to measure the difference in favorable functional outcome in the treatment and placebo groups by Cochran-Mantel-Haenszel hypothesis test with stratification by pretreatment NIHSS score, age, and time from onset to treatment was therefore revised to examine the risk difference of the primary outcome by a linear model adjusted for those factors, the authors explained.
Patients in the study had a mean age of 62 years and mean NIHSS score of 2, and were enrolled between May 30, 2014, and Dec. 20, 2016. They received either intravenous alteplase at a standard dose of 0.9 mg/kg with oral placebo, or oral aspirin at a dose of 325 mg with intravenous placebo, and were followed until March 22, 2017.
The primary safety endpoint of the analysis was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous alteplase; this occurred in 5 (3.2%) of the alteplase-treated patients and in none of aspirin-treated patients (risk difference, 3.3%).
“Secondary outcomes, including the ordinal analysis of mRS scores (odds ratio, 0.81) and global favorable recovery (OR, 0.86), did not significantly favor either group,” the investigators added.
The findings are noteworthy because more than half of all patients with acute ischemic stroke have minor neurologic deficits, the investigators said, and while prior studies of alteplase included patients with low NIHSS score, few included patients who had no clearly disabling deficits. They added that while “alteplase is the standard of care for patients with ischemic stroke and disabling deficits regardless of severity judged by NIHSS scores, the optimal management of patients with not clearly disabling deficits is unclear.
“The study results raise the hypothesis that even a 6% treatment effect might be unlikely. However, the very early study termination precludes any definitive conclusions,” they wrote, noting that the study has several other limitations, including possible selection bias, relatively high loss to follow-up, and the subjective nature of the definition of “not clearly disabling.”
Additional research may be warranted, they said.
In an editorial, William J. Powers, MD, of the University of North Carolina at Chapel Hill, wrote that despite the limitations of the PRISMS trial, the findings help define the role for intravenous alteplase in the management of acute ischemic stroke.
“Even with early study termination and resultant wide 95% confidence intervals, the excellent outcome in the aspirin group and the numerically similar outcomes between the two groups render it unlikely that intravenous alteplase treatment meaningfully improves functional outcome in patients with initial NIHSS scores of 5 or lower with nondisabling deficits,” he wrote.
He noted, however – as did the study authors – that these conclusions do not apply to all patients with mild stroke. Rather, the findings provide “more certain, but not definitive, evidence” of a lack of benefit with alteplase over aspirin in this patient population ().
The findings do suggest that “for these patients, treatment with aspirin along with close monitoring may be an appropriate course of action.”
The PRISMS trial was sponsored by Genentech. Dr. Khatri and many of her colleagues reported receiving personal fees from Genentech, some of which were for serving on the steering committee of the trial. Many investigators reported various financial ties to companies involved in cerebrovascular disease treatment.
Dr. Powers reported having no disclosures.