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Original Investigation
July 10, 2018

Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic DeficitsThe PRISMS Randomized Clinical Trial

Author Affiliations
  • 1University of Cincinnati, Cincinnati, Ohio
  • 2University of Tennessee College of Medicine, Chattanooga
  • 3University of Buffalo, Buffalo, New York
  • 4University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
  • 5Dayton Medical Center, Department of Veterans Affairs, Dayton, Ohio
  • 6University of Pennsylvania, Philadelphia
  • 7Medical University of South Carolina, Charleston
  • 8SUNY Downstate Medical Center, Brooklyn, New York
  • 9Kings County Hospital Center, Brooklyn, New York
  • 10University of Miami Miller School of Medicine, Miami, Florida
  • 11Comprehensive Stroke Center and Department of Neurology, University of California, Los Angeles
  • 12Genentech, South San Francisco, California
  • 13Everest Clinical Research, Markham, Ontario, Canada
JAMA. 2018;320(2):156-166. doi:10.1001/jama.2018.8496
Visual Abstract.
Visual Abstract.
Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits
Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits
Key Points

Question  Does intravenous alteplase benefit patients with ischemic stroke presenting with minor neurologic deficits that are judged not clearly disabling?

Findings  In this randomized clinical trial that included 313 of a planned 948 patients with acute ischemic stroke, there was no significant difference in the adjusted percentage with favorable functional outcome at 90 days for those treated with alteplase vs aspirin (78% vs 81%).

Meaning  Although the study did not demonstrate a significant benefit of alteplase for patients with minor nondisabling acute ischemic stroke, the very early study termination precludes any definitive conclusions.

Abstract

Importance  More than half of patients with acute ischemic stroke have minor neurologic deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation. Although prior major trials of alteplase included patients with low NIHSS scores, few without clearly disabling deficits were enrolled.

Objective  To evaluate the efficacy and safety of alteplase in patients with NIHSS scores of 0 to 5 whose deficits are not clearly disabling.

Design, Setting, and Participants  The PRISMS trial was designed as a 948-patient, phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase compared with aspirin for emergent stroke at 75 stroke hospital networks in the United States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS and judged not clearly disabling and in whom study treatment could be initiated within 3 hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with final follow-up on March 22, 2017.

Interventions  Participants were randomized to receive intravenous alteplase at the standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with intravenous placebo (n = 157).

Main Outcomes and Measures  The primary outcome was the difference in favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment. Because of early termination of the trial, prior to unblinding or interim analyses, the plan was revised to examine the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment.

Results  Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to treatment, 2.7 hours [IQR, 2.1-2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, −1.1%; 95% CI, −9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI, 0.8%-7.4%).

Conclusions and Relevance  Among patients with minor nondisabling acute ischemic stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable functional outcome at 90 days. However, the very early study termination precludes any definitive conclusions, and additional research may be warranted.

Trial Registration  ClinicalTrials.gov Identifier: NCT02072226

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