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PRISMS - Alteplase Minor Stroke

Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits

Year of Publication: 2018

Authors: Pooja Khatri; Dawn O. Kleindorfer; Thomas Devlin; Robert N. Sawyer Jr; Matthew Starr; Jennifer Mejilla; Joseph Broderick; Anjan Chatterjee; Edward C. Jauch; Steven R. Levine; Jose G. Romano; Jeffrey L. Saver; Achala Vagal; Barbara Purdon; Jenny Devenport; Andrey Pavlov; Sharon D. Yeatts; for the PRISMS Investigators

Journal: JAMA

Citation: JAMA. 2018;320(2):156-166. doi:10.1001/jama.2018.8496

Link: https://doi.org/10.1001/jama.2018.8496

PDF: https://jamanetwork.com/journals/jama/fullarticle/2687354

Clinical Question

In patients with acute ischemic stroke who have NIHSS 0–5 and deficits judged not clearly disabling, does intravenous alteplase given within 3 hours improve 90-day functional outcome compared with aspirin?

Bottom Line

Among patients with minor, nondisabling acute ischemic stroke, alteplase did not increase the likelihood of favorable 90-day functional outcome compared with aspirin, and symptomatic intracranial hemorrhage occurred only in the alteplase group.

        Major Points
        Phase 3b, double-blind, double-placebo, multicenter randomized trial; enrollment from May 30, 2014 to December 20, 2016 with final follow-up March 22, 2017.
313 patients randomized within 3 hours of onset: 156 to alteplase and 157 to aspirin; median NIHSS 2.
Primary outcome (mRS 0–1 at 90 days): 78.2% alteplase vs 81.5% aspirin; adjusted risk difference −1.1% (95% CI −9.4% to 7.3%).
Symptomatic intracranial hemorrhage within 36 hours: 3.2% (5/156) with alteplase vs 0% with aspirin.
Trial terminated early for slow enrollment; results underpowered for definitive conclusions.

      

Design

Study Type: Phase 3b, double-blind, double-placebo, multicenter randomized clinical trial

Randomization: 1

Blinding: Participants and investigators blinded; intravenous and oral placebos matched to maintain blinding

Enrollment Period: May 30, 2014 – December 20, 2016 (final follow-up March 22, 2017)

Follow-up Duration: 90 days

Centers: 53

Countries: United States

Sample Size: 313

Analysis: Primary analysis as adjusted risk difference via linear model (covariates: age, time to treatment, baseline NIHSS); secondary ordinal mRS via proportional odds model; global favorable recovery via generalized estimating equations; prespecified sensitivity and exploratory analyses

Inclusion Criteria

Clinical diagnosis of acute ischemic stroke
Age ≥18 years
NIHSS score 0–5
Deficits judged not clearly disabling at presentation
Treatment initiation feasible within 3 hours of symptom onset or last known well

Exclusion Criteria

Pre-stroke mRS ≥2
Dysphagia precluding timely oral study drug where required
Intracranial hemorrhage on acute neuroimaging
Standard contraindications to intravenous alteplase as per contemporary guidelines

Baseline Characteristics

Characteristic	Control	Active
Age, mean (SD), y	61 (13)	62 (14)
Sex - Male	59%	49%
Race - White	80.3%	75.0%
Race - Black/African American	17.2%	22.4%
Race - American Indian/Alaska Native	1.9%	0.6%
Race - Asian	0.6%	0%
Race - ≥2 races	0%	0.6%
Race - Unknown	0%	1.3%
Ethnicity - Hispanic or Latino	11.5%	9.0%
Hypertension	79.0%	81.3%
Hyperlipidemia	72.6%	73.1%
Diabetes mellitus	28.0%	36.5%
Previous stroke	15.3%	17.9%
Atrial fibrillation	10.8%	14.7%
Antiplatelet agents prior to onset	37.6%	41.0%
Anticoagulant agents prior to onset	0.6%	0.6%
Onset-to-IV study bolus 0–2 h	22.9%	16.0%
Onset-to-IV study bolus >2–3 h	75.8%	80.8%
Onset-to-IV study bolus >3 h	1.3%	3.2%
Onset-to-IV study bolus, median (IQR), h	2.6 (2.1–2.9)	2.7 (2.2–2.9)
Onset-to-oral study treatment, median (IQR), h	2.8 (2.4–3.1)	2.9 (2.5–3.1)
Baseline NIHSS 0	4.5%	4.5%
Baseline NIHSS 1	31.8%	24.4%
Baseline NIHSS 2	31.8%	33.3%
Baseline NIHSS 3	19.1%	20.5%
Baseline NIHSS 4	10.2%	13.5%
Baseline NIHSS 5	2.5%	3.8%
Baseline NIHSS, mean (SD)	2.0 (1.2)	2.3 (1.2)
Glucose, mean (SD), mg/dL	132.1 (61.8)	141.2 (72.9)
Systolic BP >140 mm Hg	71.3%	53.2%
Diastolic BP >90 mm Hg	28.0%	19.9%
International normalized ratio >1.1	33.1%	26.9%
Baseline ASPECTS, median (range)	10 (7–10)	10 (7–10)

Arms

Field	Intravenous alteplase + oral placebo	Control
Intervention	Intravenous alteplase 0.9 mg/kg (standard dosing) with matching oral placebo	Intravenous placebo with oral aspirin 325 mg
Duration

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR
Favorable functional outcome defined as modified Rankin Scale (mRS) score 0–1 at 90 days	Primary	81.5%	78.2%	3.30%
Ordinal mRS shift at 90 days	Secondary			0.81
Global favorable recovery (composite)	Secondary			0.86
Barthel Index 95 or 100 at 90 days (adjusted)	Secondary	88.7%	79.3%	0.5
NIHSS 0–1 at 90 days (adjusted)	Secondary	81.7%	85.7%	1.3
Recurrent ischemic stroke	Secondary	6	5
Mortality within 90 days	Secondary	0	1 (0.6%)
Symptomatic intracranial hemorrhage within 36 h	Adverse	0%	3.2% (5/156)
Any radiologic intracranial hemorrhage within 36 h	Adverse	3.3% (5/157)	7.1% (11/156)
Symptomatic intracranial hemorrhage within 36 h (SITS-MOST definition)	Adverse	0%	1.3% (2/156)
Serious adverse events	Adverse	13.1%	26.0%

Subgroup Analysis

No heterogeneity of treatment effect detected by age (P=.92), baseline NIHSS (P=.10), or time from onset to treatment (P=.70).

Criticisms

Early termination due to slow enrollment led to underpowering and uncertainty around estimates.
Potential selection bias toward enrolling patients with very mild deficits despite standardized tools.
Subjective determination of 'not clearly disabling' deficits across sites.
Relatively high loss to follow-up at 90 days with reliance on imputation.
Findings not generalizable to patients with clearly disabling deficits or to populations outside trial criteria.

Funding

Genentech Inc funded the trial and participated in design and conduct; decision to terminate enrollment was made by the sponsor.

Based on: PRISMS - Alteplase Minor Stroke (JAMA, 2018)