EXTEND study: More evidence on thrombolysis beyond traditional time windows

Intravenous thrombolysis improved outcomes in ischemic stroke patients between 4.5-9 hours after symptom onset based on perfusion Imaging.

After the WAKE-UP study showed that intravenous thrombolysis improved outcomes in ischemic stroke patients with unknown symptom onset based on advanced MRI imaging, the EXTEND study now provides new insights on thrombolysis beyond the traditional time window of 4.5 hours.
In this multicentre, randomized, placebo-controlled trial, patients with ischemic stroke were included if their symptom onset was between 4.5 and 9 hours or on awakening (if the midpoint of sleep was within 9 hours) and if they had a NIHSS of 4-26 as well as salvageable tissue detected on automated perfusion imaging.
About two thirds of patients had awoken with stroke symptoms, 69 % had a large vessel occlusion (mechanical thrombectomy had not been recommended in guidelines at the time of study, patients in which mechanical thrombectomy was considered were not included in the trial).
Intravenous thrombolysis with Alteplase improved outcomes in patients, 35.4% vs. 29.5% had an excellent outcome (defined as mRS 0-1 at 90 days, p=0.04, adjusted risk ratio 1.44). More patients reached mRS 0-2 at 90 days, but there was no statistically significant mRS ordinal shift. However, symptomatic intracranial bleeding also occurred more frequently in the thrombolysis group (6.2% vs 0.9%, p=0.05).

Compared to the WAKE-UP study, where only patients without known onset of stroke were included, patients in EXTEND had more severe strokes (median NIHSS 12 vs 6 in the respective treatment groups), more frequently large vessel occlusions and were selected using either CT perfusion or MRI diffusion-perfusion-mismatch with a ratio≥1.2), while in the WAKE-UP study, MRI DWI-FLAIR mismatch was used.

In conclusion, advanced neuroimaging has been shown to have an important role in selection of patients for both thrombolysis and thrombectomy beyond traditional time windows or unknown symptom onset. However, thrombectomy might be a more effective therapy in patients with a large vessel occlusion beyond traditional time windows. If thrombectomy is not available or patients have no large vessel occlusion, thrombolysis based on advanced neuroimaging should be considered.

Key Points:

- Inclusion criteria included symptom onset between 4.5-9 hours or on awakening, NIHSS 4-26 and salvageable tissue detected on automated perfusion imaging

- Patients in the thrombolysis group had better 90-day outcomes, but also more symptomatic intracranial bleedings.

- Extending data from the WAKE-UP study, thrombolysis should be considered in patients outside of traditional time windows on basis of advanced neuroimaging


Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019;380:1795–1803.