Authors: Mark Winstanley, Chris Connolly, Becky Maxwell, Andy Neill, Dave McCreary, Rob Hirst / Codes: CP2, ResP2, SLO1 / Published: 01/02/2021

Clinical Question:

In patients eligible for thrombectomy does tPA add anything?


Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke


Yang 2020 NEJM


EM has a somewhat tenuous relationship to tPA for stroke. There has been an ongoing undercurrent of sceptism towards the evidence base for lysis for stroke driven by the great Jerry Hoffman and several EM societies producing statements emphasising the ambiguity surrounding the evidence.

Since thrombectomy has come along this has somewhat faded into the background as there have been multiple trials showing fairly impressive outcomes in those eligible for thrombectomy. For these large vessel occlusions it’s been fairly well accepted that lysis is a pretty poor treatment (recanalisation rates are pretty poor) so the question before us has been – does giving the tPA before transfer for thrombectomy really add anything. Now we have an RCT.


This was a non inferiority RCT was open label conducted in China and recruited patients who met eligibility for thrombectomy and lysis. So they would have had to have large vessel occlusions proven on angiography and no contra indications to lysis.

– as a result they had to be under 4.5 hrs (as you can’t really get tPA beyond this) whereas typical guidelines will allow thrombectomy beyond this.
– primary outcome was a 90 day mRS (which is not a perfect outcome measure by any means and is open to some biases especially when it’s an open label trial)
– I’m no stats expert but it seems they were aiming for 4% non inferiority margin. ie if thrombectomy without lysis was within 4% of the outcomes for thrombectomy and lysis then it was declared non inferiority.


– 650 patients from 40 centres over a year or so
– NIHSS of 17 or so (which is pretty significant stroke burden – NINDS was 11-12)
– no difference between the groups (and for what it’s worth thrombectomy alone met the non inferiority margin)
– there was a higher bleeding rate in the tPA group which is hardly surprising


– it seems that giving lytics to a large vessel occlusion doesn’t add much when they’re already going for a thrombectomy.
– for now the NICE guidelines still recommend tPA and thrombectomy together but it’s probably reasonable to maintain some sceptism of the value of the tPA in this scenario.

Further reading:

– some papers on non inferiority trials



1) what is the non inferiority margin?

– These trials are suitable when you are testing something that you assume will be at best non inferior. For example face to face versus telephone consultation – no one expects telephone to be better but it might be non inferior. So instead of assuming the null hypothesis (that there is no difference between treatments – this is what we normally assume in superiority trials) and trying to disprove it; in a non inferiority trial the null hypothesis is that the new intervention is not as good and you are trying to prove that is non inferior.
– You must specify a noninferiority margin – for it to be a positive trial the primary outcome has to be within a certain margin of the existing treatment. Selection of this margin is unavoidably subjective and is open to all kinds of fudging.When assessing the non inferiority margin ask “does this seem clinically reasonably to me?”
Read more:

2) this is an open label trial. How might lack of blinding affect the results?

– blinding occurs following randomisation – as opposed to allocation concealment which occurs prior to randomisation.
– blinding is designed to ensure measuring of outcomes is free from bias

3) review your own hospital’s stroke protocol. Is is consistent with national guidance eg NICE. Would this paper encourage you to make a change to your current procedures?