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
Negligible absolute difference
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 at 75 US stroke-hospital networks; 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. Stopped early (futility). 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