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

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.

Figure 1.. Flow of Patients Through the PRISMS Trial

^aThe total number of patients assessed for eligibility is not available because screening log data were not available. The total number randomized does not reflect the enrolled population because in step-forward randomization, a “use next” drug kit was assigned prior to a potential trial candidate’s arrival at an emergency department. Many patients who arrived at an emergency department after a kit was designated were not eligible and were not enrolled in the trial. A patient was considered enrolled when the study treatment bolus was administered. ^bThese 2 patients received intravenous placebo instead of intravenous alteplase because of pharmacy error. ^cTwo patients received oral placebo instead of oral aspirin because of pharmacy error; 1 patient was determined to have an aspirin allergy after enrollment; and 1 patient had neurologic worsening and became eligible for intravenous alteplase treatment as standard of care. ^dMissing data were imputed using the 30-day modified Rankin Scale (mRS) score for 12 patients and hot-deck imputation for 3 patients. ^eMissing data were imputed using the 30-day mRS score for 13 patients and hot-deck imputation for 4 patients.

Figure 2.. Modified Rankin Scale Score Distributions at 90 Days by Treatment Group

These distributions, which were used for the primary outcome analysis, included imputation for missing 90-day scores.