Saturday 29 June 2019

Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke: how fragile can we be?

The biggest, baddest controversy in Emergency Medicine just got worse.

Yes, it’s stroke lysis.

This multicentre RCT enrolled adult patients in whom alteplase or placebo could be given between 4.5 to 9 hours after onset of stroke or on awakening with stroke symptoms. A prerequisite for inclusion was a perfusion deficit (area of ischemic but not infarcted brain) on CT or MRI.

The primary outcome was a score of 0-1 on a modified Rankin scale (mRS) adjusted for age and baseline severity of stroke. Of course, they looked at many secondary outcomes including the classic ordinal shift analysis and some safety measures.

They estimated a sample size of 400 patients would be needed in order to have 80% to detect a difference of 15% in the primary outcome.

Recruitment was slow going. They only enrolled 225 patients over 8 years in in 28 centres! That’s about one patient per centre per year! Yikes. No wonder they called it quits early. They claimed the WAKE-UP trial published in May 2018 caused them to lose clinical equipoise and they terminated early. I think they probably had enough anyway…


40 (35%) patients in the alteplase group were mRS 0-1 vs. 33 (29.5%) in the placebo group (adjusted risk ratio, 1.44 95% confidence interval 1.01 to 2.06; P=0.04). Symptomatic ICH was 6% vs. 1%.

Thrombolysis is a winner!??!!

Unfortunately, it is not so clear.

There was no statistical difference in the primary outcome when they used their originally proposed logistic regression modelling rather than a different method introduced during recruitment. The unadjusted analysis; no difference. There was no difference in the ordinal shift analysis (which ironically was touted as the saviour of IST-3). But most of all, the results are just plain fragile.


The fragility index was less than one. Put another way, if one less patient in the alteplase group did not meet the primary outcome, the trial would have been negative. This seems far from a definitive trial.

The authors claim that “further trials of thrombolysis in this time window are required.” This seems rather contradictory when they claim to have stopped their trial due to lack of clinical equipoise.

What to think?

If I was calling the shots, I would not extend my window. But at the same time, others may interpret this study differently. 

However, much of this might be a storm in a teacup. The vast majority of patients in this window derive neither harm nor benefit from thrombolysis (NNT 17 if you believe the results). In addition, clot retrieval is all the rage now.  


Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Eng J Med 2019;380:1795-803.[link to article]

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