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MR WITNESS

Intravenous Thrombolysis in Unwitnessed Stroke Onset: MR WITNESS Trial Results

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Year of Publication: 2018

Authors: Schwamm LH, Wu O, Song SS, ..., on behalf of the MR WITNESS Investigators

Journal: Annals of Neurology

Citation: Ann Neurol. 2018;83(5):980-993.

Link: https://doi.org/10.1002/ana.25100

PDF: https://pmc.ncbi.nlm.nih.gov/articles/PM...nihms959612.pdf

Clinical Question

Is IV alteplase administered within 4.5 hours of symptom discovery safe in patients with acute ischemic stroke of unwitnessed onset selected by quantitative diffusion-FLAIR mismatch (qDFM) on MRI?

Bottom Line

IV alteplase in qDFM-selected unwitnessed stroke was safe: sICH rate 1.3% (1/80; 95% CI 0.0-6.8%), not significantly different from ECASS-3 benchmark of 5.3% (RR=0.24; P=0.07). At 90 days, 38.8% achieved mRS 0-1 overall, 43.5% without pre-stroke disability, and 48% in non-LVO patients. Median time from last known well to treatment was 11.24 hours. This phase 2a safety trial supported larger RCTs (WAKE-UP) of MRI-guided thrombolysis.

        Major Points
        sICH rate 1.3% (1/80) — well below the 5.3% ECASS-3 benchmark (RR=0.24; P=0.07).
Median time from last known well to treatment was 11.24h (IQR 9.46-13.26), far beyond the standard 4.5h guideline window.
qDFM doubled potential enrollment vs qualitative DFM: 50% of enrolled were FLAIR-positive but SIR <1.15 (quantitative threshold), which would have been excluded by qualitative assessment.
38.8% achieved mRS 0-1 at 90 days; 43.5% among those without pre-stroke disability; 48.1% in non-LVO subgroup — comparable to witnessed stroke thrombolysis trials.
71.3% had wakeup stroke (most common unwitnessed subtype); wakeup-to-non-wakeup ratio 2.5:1.
No lacunar patients developed aICH at 24h (0/11 vs 21/69 non-lacunar; P<0.001).
Higher NIHSS independently predicted both worse outcome (OR 0.76/point; P<0.001) and aICH (OR 1.22/point; P=0.001).
22.9% had ICA/M1 LVO; non-LVO patients had significantly better outcomes (48.1% vs 18.8% mRS 0-1; P=0.045).
Symptomatic brain edema 3.8% (3/80), less than ECASS-3 rate of 6.9% (RR=0.54; P=0.19).
Phase 2a single-arm safety trial (n=80) across 14 US sites; supported rationale for WAKE-UP and subsequent MRI-guided thrombolysis trials.

      

Design

Study Type: Phase 2a, open-label, single-arm safety trial

Randomization:

Blinding: Open-label; independent medical monitor and neuroradiology core adjudicated all ICH and brain edema events.

Enrollment Period: January 31, 2011 to October 4, 2015

Follow-up Duration: 90 ± 14 days

Centers: 14

Countries: United States

Sample Size: 80

Analysis: One-sided one-sample exact binomial tests for primary safety; Fisher's exact and Wilcoxon Rank-Sum for secondary; logistic regression for predictors.

Inclusion Criteria

Age 18-85 years (upper limit raised from 80 in 2012).
Acute ischemic stroke of unwitnessed symptom onset.
Last known well 4.5-24 hours prior to presentation.
Able to receive treatment within 4.5 hours of symptom discovery.
Disabling neurological deficit lasting ≥30 minutes.
Confirmed ischemic stroke on MRI (DWI-positive).
Quantitative diffusion-FLAIR mismatch (qDFM): FLAIR-negative lesion or minimal FLAIR signal with SIR <1.15.

Exclusion Criteria

NIHSS >25.
DWI lesion >1/3 MCA territory by visual inspection or >100 cm³.
Dabigatran use within 24h with abnormal clotting studies.
Diabetes plus prior stroke (removed in 2012 amendment).
Uninterpretable MR images.
No DWI lesion.
Prior macroscopic intracranial hemorrhage on MRI.
Microbleeds in a pattern suggestive of amyloid angiopathy.

Baseline Characteristics

All Subjects (N=80):

Age (mean±SD): 67.5±13.5
Male sex: 43 (53.8%)
White race: 47 (58.8%)
Lacunar subtype: 21 (26.6%)
Pre-stroke mRS 0-1: 69 (86.3%)
Hypertension: 58 (72.5%)
Current smoker: 18 (22.5%)
NIHSS median (IQR): 7 (4-13.5)
SBP median (IQR): 155.5 (143.5-171) mmHg
Blood glucose median (IQR): 120 (103.5-172.5) mg/dL
FLAIR negative: 40 (50.0%)
FLAIR positive (SIR <1.15): 40 (50.0%)
Stroke upon awakening: 57 (71.3%)
ICA/M1 LVO (of 70 with vessel imaging): 16/70 (22.9%)
Symptom discovery to thrombolysis median (IQR): 3.48h (2.90-4.01)
Last known well to thrombolysis median (IQR): 11.24h (9.46-13.26)
Arrival to MRI median (IQR): 0.85h (0.58-1.28)
MRI to thrombolysis median (IQR): 0.89h (0.68-1.05)

Arms

Field	IV Alteplase (single arm)
Intervention	IV alteplase 0.9 mg/kg (max 90 mg): 10% bolus over 1 minute, remainder infused over 1 hour. Administered within 4.5h of symptom discovery. Mean total dose 73.7±14.2 mg.
Duration	Single treatment + 90-day follow-up

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Symptomatic ICH (ECASS-2 definition: any brain blood + NIHSS ≥4 point increase or death)	Primary	ECASS-3 benchmark: 22/418 (5.3%)	1/80 (1.3%; 95% CI 0.0-6.8%)	4.01%	0.07 (RR=0.24 vs ECASS-3)
mRS 0-1 at 90 days (all)	Secondary	—	31/80 (38.8%)
mRS 0-1 at 90 days (no pre-stroke disability)	Secondary	—	30/69 (43.5%)
mRS 0-1 (non-LVO subgroup, n=54)	Secondary	—	48.1%	OR 4.02 vs LVO (18.8%)	0.045
Symptomatic brain edema	Secondary	ECASS-3: 29/418 (6.9%)	3/80 (3.8%)	RR 0.54	0.19
Asymptomatic ICH at 24h	Secondary	ECASS-3: 91/418 (21.8%)	21/79 (26.6%)	RR 1.22	0.38
90-day mortality	Secondary	ECASS-3: 32/418 (7.7%)	7/80 (8.8%)	RR 1.14	0.66
sICH (ECASS-2)	Adverse		1/80 (1.3%)	RR 0.24 vs ECASS-3
Any ICH at 24h	Adverse		22/80 (27.5%)
Symptomatic brain edema	Adverse		3/80 (3.8%)
90-day mortality	Adverse		7/80 (8.8%)

Subgroup Analysis

Predictors of good outcome (mRS 0-1): lower NIHSS (adjusted OR 0.76/point; P<0.001), no pre-stroke disability (OR 0.02; P=0.01), non-lacunar (OR 0.06; P=0.01), non-smoker (OR 0.03; P=0.002). Predictor of aICH: higher NIHSS (adjusted OR 1.22/point; P=0.001). No LVO vs LVO: mRS 0-1 in 48.1% vs 18.8% (OR 4.02; P=0.045).

Criticisms

No concurrent control arm — single-arm phase 2a safety study; cannot conclude efficacy.
Small sample size (n=80) — powered for safety only.
Open-label design with potential for assessment bias.
MRI-based selection limits generalizability — MRI less available than CT.
Slow enrollment (~3 patients/year per site) — feasibility questions.
LVO not excluded; majority (77.1%) were non-LVO — limits applicability to EVT-eligible patients.
Comparison to ECASS-3 is indirect (different population: witnessed, known onset 3-4.5h).
Median NIHSS 7 (lower than ECASS-3 median 9) — qDFM may exclude more severe strokes, improving safety profile.
No perfusion imaging for selection — cannot assess mismatch influence.

Funding

NIH NINDS SPOTRIAS (P50-NS051343), NINDS Division of Intramural Research, NIH grants. Genentech provided alteplase free of charge and supplemental site payments.

Based on: MR WITNESS (Annals of Neurology, 2018)