tPA 4.5 to 9h or Wake-Up Stroke – New Meta-analysis

Written by Alex Chen

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Compared to the placebo group, patients who presented with ischemic stroke (4.5-9h from onset or wake-up stroke) with salvageable brain tissue identified on perfusion imaging and received tPA, had a slight improvement in functional outcome (mRS of 0-1) at 3 months (36% vs 29%) with higher rates of symptomatic intracerebral hemorrhage (5% vs <1%).

Why does this matter?
Ischemic stroke is a disease entity with significant morbidity and mortality. Prior to endovascular therapy, there was little we could offer patients if they fell outside of the 0-4.5h window. This is a meta-analysis and systematic review of the efficacy and safety of tPA outside of the window (4.5-9h or wake-up stroke) with evidence of salvageable brain on perfusion imaging. 

tPA – I put that 💩on everything?
The authors identified three trials that met eligibility criteria (EXTEND, ECASS4-EXTEND, and EPITHET) for a total of 414 patients. The primary outcome of this meta-analysis was the proportion of patients with excellent functional outcome (mRS of 0-1) at 3 months adjusted for pre-treatment NIHSS. Safety outcomes included symptomatic intracerebral hemorrhage within 36h of treatment, neurological deterioration ≥4 NIHSS points, or death.

In the alteplase group, 76/211 (36%) achieved mRS of 0-1 at 3 months compared to 58/199 (29%) of the placebo group for an OR of 1.86 (95% CI 1.15-2.99). However, this was accompanied by a higher symptomatic ICH rate for the alteplase group 10/213 (5%) compared to placebo 1/201 (<1%) for an OR of 9.7, 95%CI 1.23-76.55. The authors note that the adjusted OR mentioned previously are slightly better than those achieved in the 0-3h tPA window or the 3-4.5h window (OR 1.75 and 1.26 respectively). The rate of ICH was 4.7% in this extended tPA window compared to 3.4% in the 0-4.5h tPA window.

It is important to note that the patients included in this meta-analysis were very carefully selected. 62% of the tPA group and 60% of the placebo group were identified to have large-vessel occlusions. The patients were also found to have a relatively small ischemic core with an area of salvageable brain. These should be the ideal patients for treatment, yet the effect of tPA was not very impressive. In the current practice environment, many of these patients will go for thrombectomy instead. I think this gives us some information about the risks and benefits of giving tPA to patients who are outside of the window without access to a center that does endovascular treatment.

Extending thrombolysis to 4·5-9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data. Lancet. 2019 Jul 13;394(10193):139-147. doi: 10.1016/S0140-6736(19)31053-0. Epub 2019 May 22.

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Reviewed by Thomas Davis

2 thoughts on “tPA 4.5 to 9h or Wake-Up Stroke – New Meta-analysis”


    I just reviewed this among others for my hospital’s stroke committee. None of the trials included met power for the primary endpoint they were assessing in the meta. The trials included were also a convenience sample masquerading as systematically selected as the authors were investigators for the included trials. WAKE-UP, which was still underpowered yet more homogeneous with ECASS-4 and EXTEND than EPITHET, was excluded (selection bias). EPITHET had a completely different trial structure and primary endpoint. This SRMA seems like a an attempt at data dredging (inflation bias).


      I ran this by Alex – completely agree. Alex’s snarky and hilarious remark about putting tPA on everything (like Frank’s Red Hot sauce) reflects this skepticism as well. Thanks for this comment and clarification.

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