By Inna Lutsenko, neurologist and specialist, Center for Distance Learning and Advanced Training, Kyrgyz State Medical Academy after I.K.Akhunbaev; twitter: @inna_lutsenko
Kateriine Orav, Department of Neurology, North Estonia Medical Center, Tallinn, Estonia

Thrombolysis in unknown stroke onset: broadening the horizon with advanced brain imaging.

A great opportunity of the virtual ESO-WSO 2020 conference is the possibility to rewatch and analyse the data presented for large clinical trials that will likely have a big impact on our practice. There were a lot of impressions on one of the most highlighted post in Twitter, made by @ESOStroke about Götz Thomalla’s presentation on the meta-analysis of 4 thrombolysis trials in ischemic stroke (IS) patients with unknown symptoms onset: WAKE-UP, EXTEND, THAWS and ECASS-4.

Unknown onset of stroke is a frequent condition, leaving 20% of patients with IS ineligible for thrombolytic therapy. Aiming to analyse the safety of thrombolytic therapy in this patient group, the results of two trials have already been widely presented in 2018 and 2019: WAKE-UP and EXTEND. WAKE-UP trial demonstrated the benefit of intravenous thrombolysis in unknown stroke onset guided by DWI-FLAIR mismatch on MRI in 503 patients [2]. In WAKE-UP trial mismatch was defined as a combination of the visible ischemic lesion on DWI sequence and no marked parenchymal hyperintensity in the corresponding images on the FLAIR sequence. Patients with mismatch on MRI imaging were considered to be in the hyperacute stroke phase and were likely to benefit from thrombolysis in this trial. In the EXTEND trial authors demonstrated the benefit of thrombolytic treatment in 146 patients with less than 9 hours of symptom onset or wake-up stroke guided by perfusion imaging. This so-called “penumbral imaging” (MRI or CT perfusion) is targeted to detect a small ischemic core and a large area of “tissue at risk” defined by perfusion imaging [3].

The Steering Committee made a systematic review of 249 abstracts and the results of 4 randomized controlled trials were included in the analysis. In addition to WAKE-UP and EXTEND, the analysis included the THAWS trial with the concept of DWI-FLAIR mismatch vs. standard care in 131 IS patients and ECASS-4 trial which analysed MRI perfusion mismatch guided thrombolytic therapy vs. placebo in the extended time window or in unknown stroke onset in 63 patients. In total 843 patients were included in the meta-analysis where 429 (51%) received thrombolysis and 414 (49%) placebo or standard of care and the primary favourable outcome was mRS 0-1 (no disability or no significant disability) at 90 days. The reason for unknown time of stroke onset was overnight sleep in 90% in the treatment and 88% in the control group.

Treatment with thrombolysis was associated with a significant higher odds of achieving a favourable outcome at 90 days with the adjusted OR 1.49 (1.10-2.03), p=0.011. Despite an increased risk of symptomatic intracranial haemorrhage, a net benefit was observed for all functional outcomes.

An important finding of this meta-analysis is that treatment benefit was consistent across a wide range of subgroups including patients with large vessel occlusion. This study strengthens the evidence for the use of DWI/FLAIR or perfusion mismatch to guide thrombolysis treatment in patients with stroke with an unknown time of onset. Many questions arose about the preferred method of imaging to which Götz Thomalla responded in the Q&A that this should be individual for different centers depending on what they are familiar with and what is accessible, but more importantly, some kind of advanced imaging should be available.

Selection for stroke treatment based on physiological changes (visualisation of the penumbra and the infarction core) with perfusion mismatch and recovering still functioning neurons was warmly welcomed by the general audience during the session and later, in the retweets. The findings of the meta-analysis were aptly summarized with “imaging again revolutionises acute stroke management” (Professor Geoffrey Donnan AO, @GeoffreyDonnan), opening more opportunities in the future to widen the therapeutic window for pathogenetic therapy in the acute ischemic stroke.

1. Gotz Thomalla for the ESO collaborators. Thrombolysis in Unknown Onset Stroke Guided by Advanced Imaging – Individual Patient Data Meta-Analysis from WAKE-UP, THAWS, EXTEND, ECASS-4 AND MR WITNESS. Materials of the ESOWSO2020 online conference.
2. Gotz Thomalla et. al. 2018. N Engl J Med 2018; 379 (7): 611-22.
3. Ma et al. 2019. N.Engl J Med 2019; 380 (19): 1795 – 803