EXTEND – Alteplase Up to 9 Hours Out?

May 13, 2019

Written by Clay Smith

Spoon Feed
Use of alteplase from 4.5 to 9 hours or upon awakening in patients with ischemic stroke with salvageable brain on perfusion imaging was superior to placebo, NNT = 17 (adjusted risk ratio 1.44, 95%CI 1.01-2.06). Symptomatic hemorrhage was more common in the alteplase group, NNH = ~19.

Why does this matter?
The window for tPA has been 4.5 hours since ECASS III. DEFUSE 3 found that the window was up to 16 hours for thrombectomy when there was salvageable brain on perfusion imaging. Would an expanded imaging-based window apply to tPA as with thrombectomy?

Is there something fishy in the Poisson regression here?
This was a RCT of 225 patients with ischemic stroke who had salvageable hypoperfused brain on CT perfusion or perfusion-diffusion MRI and presented from 4.5 to 9 hours from symptom onset or upon awakening, if within 9 hours of the midpoint of sleep. Patients had NIH stroke scale (NIHSS) of 4 to 26; 65% were “wake-up strokes.” For the primary outcome of excellent neurological outcome (mRS 0-1), the unadjusted analysis showed no difference. However, with adjustment for age and NIHSS (Poisson regression), the alteplase group did better: 35.4% alteplase vs only 29.5% placebo, NNT = 17; aRR 1.44 (95%CI 1.01 to 2.06; P = 0.04). Results were statistically significant even though the study was halted early for “loss of equipoise” after the publication of WAKE-UP (intended enrollment 310).

There were more symptomatic intracranial hemorrhages (ICH) in the alteplase group than placebo: 6.2% vs 0.9%, respectively, NNH = 19; aRR 7.22 (95% CI 0.97 to 53.5; P = 0.05). Two of the alteplase patients died from ICH. Death at 7 and 90 days was similar between groups. Comparing the baseline characteristics of alteplase vs placebo groups, the alteplase group had slightly older patients (73.7 vs 71, respectively), higher median NIHSS 12 vs 10, and larger infarct core volume (4.6mL vs 2.8mL). So, the placebo group was slightly favored at baseline. The difference in risk of ICH lacked statistical significance, but 6% on alteplase was consistent with EPITHET, DAWN, and DEFUSE 3. Seven of the authors had received some form of support or compensation from Boehringer Ingelheimm, maker of alteplase in Europe. Since this study began in 2010, thrombectomy has become the treatment of choice for large vessel occlusion (LVO). In this study, ~70% had LVO, which would make use of tPA alone obsolete in the modern era of stroke care. Late alteplase may help slightly more people than it hurts, but this is risky business. Patients and families deserve to make an informed decision.

Another Spoonful

• REBEL EM covered WAKE-UP and EXTEND (when it was in its larval stages as an abstract) and has a helpful bit on understanding DWI/FLAIR on MRI.

• EM Lit of Note has a glowing review: EXTEND Alteplase Shenanigans!

• See why EM Nerd says this was a “brazen disregard” of the scientific method.

Source
Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019 May 9;380(19):1795-1803. doi: 10.1056/NEJMoa1813046.

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Reviewed by Thomas Davis