RCT: In patients with minor, nondisabling acute ischemic stroke, alteplase did not differ from aspirin for favorable functional outcome at 90 days.
Khatri P, Kleindorfer DO, Devlin T, 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 Jul 10;320(2):156-166. doi: 10.1001/jama.2018.8496.

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.

Ratings
Specialty Area Score
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Hospital Doctor/Hospitalists
Internal Medicine
Neurology
Comments from MORE raters

General Internal Medicine-Primary Care(US)

The trial was terminated early due to financial reasons and enrollment was low. However, I think this information can help guide physicians caring for stroke patients with minimal deficits.

Internal Medicine

As a physician treating strokes, I find this is a common question. Should we give Alteplase for "minor" strokes. The tragedy is the study was terminated early. However 300 patients gives us reasonable evidence that Alteplase should NOT be given for minor strokes. Harms were more and the benefit was more in the aspirin arm if any.

Neurology

As a neurologist, I find there is a dilemma sometimes regarding the best treatment option for acute stroke with low NIHSS score who come in window period. The most worrying thing in such cases is the risk of worsening of deficit i.e NIHSS score. This study has somewhat tried to help us in such condition but as mentioned more studies need to be done in order to give a more clear picture.

As a neuromuscular subspecialist, my expertise in stroke treatment is limited. However, this study provides important information regarding management of acute stroke in patients with mild, non-disabling deficits, and does not suggest superiority of tPA to aspirin. Although the study was terminated early, and the wide confidence intervals raise the possibility of clinically meaningful effects in either direction. The credible intervals for posterior probability in the post-hoc Bayesian analysis are also fairly wide. Despite a degree of imprecision, the results of this trial provide interesting clinical information; although, this requires replication as the authors note. I rated it 6 instead of 7 for this reason.

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