Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial results

Abstract

Objective: Most acute ischemic stroke (AIS) patients with unwitnessed symptom onset are ineligible for intravenous thrombolysis due to timing alone. Lesion evolution on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) correlates with stroke duration, and quantitative mismatch of diffusion-weighted MRI with FLAIR (qDFM) might indicate stroke duration within guideline-recommended thrombolysis. We tested whether intravenous thrombolysis ≤4.5 hours from the time of symptom discovery is safe in patients with qDFM in an open-label, phase 2a, prospective study (NCT01282242).

Methods: Patients aged 18 to 85 years with AIS of unwitnessed onset at 4.5 to 24 hours since they were last known to be well, treatable within 4.5 hours of symptom discovery with intravenous alteplase (0.9mg/kg), and presenting with qDFM were screened across 14 hospitals. The primary outcome was the risk of symptomatic intracranial hemorrhage (sICH) with preplanned stopping rules. Secondary outcomes included symptomatic brain edema risk, and functional outcomes of 90-day modified Rankin Scale (mRS).

Results: Eighty subjects were enrolled between January 31, 2011 and October 4, 2015 and treated with alteplase at median 11.2 hours (IQR = 9.5-13.3) from when they were last known to be well. There was 1 sICH (1.3%) and 3 cases of symptomatic edema (3.8%). At 90 days, 39% of subjects achieved mRS = 0-1, as did 48% of subjects who had vessel imaging and were without large vessel occlusions.

Interpretation: Intravenous thrombolysis within 4.5 hours of symptom discovery in patients with unwitnessed stroke selected by qDFM, who are beyond the recommended time windows, is safe. A randomized trial testing efficacy using qDFM appears feasible and is warranted in patients without large vessel occlusions. Ann Neurol 2018;83:980-993.

Conflict of interest statement

Potential Conflicts of Interests

Genentech provided alteplase free of charge to the study for distribution to all sites except to the NINDS intramural branch, and starting in year 2 provided modest supplemental site payments to permit expansion to 14 sites. Genentech received details on the occurrence and nature of sICH and had the right to view the manuscript prior to submission, but had no control over design, data collection, analysis, interpretation, or publication decision. LHS has been a consultant for Lundbeck on their International Steering Committee for DIAS3 and DIAS4 trials which tested desmoteplase in late window acute ischemic stroke. MHL has been a consultant to General Electric Healthcare, which manufactures MRI devices. The other authors declare no relevant conflicts.

© 2018 American Neurological Association.

Figures

Figure 1

Flowchart demonstrating how to apply the Quantitative diffusion-FLAIR mismatch for enrollment

Figure 2

Trial Profile. *This number only includes patients deemed clinically eligible to undergo MRI screening. Other patients were not systematically tracked. The total does not include patients who refused study participation despite meeting MRI eligibility criteria (n=4). **At one site, the 24h imaging study was performed using MRI per site protocol. †Five subjects died by the 30±7 d assessment. ‡Seven subjects died by the 90±14 d assessment.

Figure 3

Examples of enrolled and non-enrolled subjects. (A) MRI from an enrolled subject obtained approximately 3 hours after symptom discovery in a 77 year old female presenting with unwitnessed symptom onset and right-sided weakness, numbness and aphasia. Her NIHSS score was 10. (B) MRI from a non-enrolled subject obtained approximately 1.25 hours after symptom discovery in a 78 year old female presenting with unwitnessed symptom onset and left-sided weakness, last known well the night before. Her NIHSS score was 15.

Figure 4

Modified Rankin Scale scores at day 90 in all treated subjects (n=80), and in the subset of subjects (n=69) who were without disability (mRS 0,1) prior to the index stroke.