PRISMS Trial: Alteplase vs Aspirin in Minor Nondisabling Stroke
In patients with minor nondisabling acute ischemic stroke treated within 3 hours, does IV alteplase 0.9 mg/kg improve excellent 90-day functional outcome (mRS 0-1) compared with aspirin monotherapy?
Khatri P, et al. (JAMA 2018) · 313 patients
Population
Included
- Minor ischemic stroke not causing significant disability
- NIHSS ≤5 at enrollment
- Treatable within 3 hours of symptom onset
- Age 18 or older
- Clinical diagnosis of acute ischemic stroke
- Age 18 years or older
- A National Institutes of Health Stroke Scale (NIHSS) score of 0 to 5
- Deficits judged to be not clearly disabling at presentation (a clearly disabling deficit was operationally defined as a deficit that, if it remained unchanged, would prevent the patient from performing basic activities of daily living such as bathing, ambulating, toileting, hygiene, and eating, or from returning to work; this determination was made by local clinicians in consultation with patients and available family)
- Patients had to be able to walk unassisted (with or without an assistive device)
- Study treatment could be initiated within 3 hours of onset (time from witnessed onset or time last known well if unwitnessed)
Excluded
- Disabling neurological deficits (significant motor, language, or visual impairment)
- NIHSS >5
- Prior stroke with residual deficits
- Contraindication to alteplase or aspirin
- Prestroke disability (modified Rankin Scale score of 2 to 6)
- Dysphagia
- Intracranial hemorrhage on acute neuroimaging
- Other standard contraindications to intravenous alteplase as reflected in the clinical guidelines current during the trial
Source: Khatri P et al., JAMA 2018;320(2):156-166· Retrieved 2026-06-09
Primary Outcome
mRS 0-1 at 90 Days
Study Arms
- Agent
- Alteplase (intravenous recombinant tissue plasminogen activator) with matching oral aspirin placebo
- Dose
- 0.9 mg/kg (standard dose) intravenous alteplase, plus oral aspirin placebo
- Route
- Intravenous alteplase plus oral placebo
- Frequency
- Standard alteplase dosing (10% bolus, remainder infused over 60 minutes); oral placebo to maintain double-blind double-placebo masking
- Duration
- Alteplase infusion over about 60 minutes
- Co-interventions
- Double-blind, double-placebo design: placebos were identical in appearance to the active study drugs to preserve masking. Treatment initiated within 3 hours of onset.
Phase 3b, double-blind, double-placebo trial designed across 75 US stroke-hospital networks, with actual enrolment at 53 of them; enrolled 313 of a planned 948 patients before the sponsor (Genentech) terminated the trial for slow enrollment, leaving it underpowered. Design and intervention from Khatri JAMA 2018 p.157 (abstract, Study Intervention). ClinicalTrials.gov NCT02072226.
- Agent
- Aspirin with matching intravenous alteplase placebo
- Dose
- Aspirin 325 mg orally, plus intravenous placebo
- Route
- Oral aspirin plus intravenous placebo
- Frequency
- Single oral aspirin 325 mg dose; intravenous placebo administered to match the alteplase infusion schedule
- Duration
- Intravenous placebo infusion over about 60 minutes
- Co-interventions
- Double-blind, double-placebo design: the intravenous placebo was identical in appearance to active alteplase to preserve masking.
Control arm. Aspirin 325 mg was the active comparator against standard-dose alteplase. Source: Khatri JAMA 2018 p.157.
Safety
Symptomatic intracranial hemorrhage
3.2%
0%
sICH occurred in 3.2% of alteplase-treated patients and 0% of aspirin-treated patients. This hemorrhagic risk with no efficacy benefit is the core finding against routine alteplase in nondisabling minor stroke.
Trial Design
Type
- Phase 3b, double-blind, double-placebo randomized trial
- Minor nondisabling stroke within 3 hours
- IV alteplase vs aspirin
Timeline
United States; May 2014 to December 2016
N
313
Enrollment
313 of 948 planned patients. Terminated early by the sponsor for slow enrolment, not on a futility boundary. May 2014 to December 2016. Published JAMA 2018.
ClinicalTrials.gov
NCT02072226Bedside Pearl
PRISMS tested alteplase vs aspirin in minor nondisabling stroke and found no functional benefit with a 3.2% sICH rate vs 0% for aspirin. The trial was underpowered (stopped at 33%), so findings are inconclusive rather than definitively negative. In clinical practice: for clearly nondisabling minor stroke, shared decision-making about thrombolysis is appropriate, with aspirin or DAPT as reasonable alternatives.
See also