SGEM#325: Thin Ice – Subgroup Analysis of the THAWS Trial

Date: March 31st, 2021 Guest Skeptic: Prof Daniel Fatovich is an emergency physician and clinical researcher based at Royal Perth Hospital, Western Australia. He is Head of the Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research; Professor of Emergency Medicine, University of Western Australia; and Director of Research for Royal Perth Hospital. Reference: Toyoda et al. MRI-guided thrombolysis (0.6 mg/kg) was beneficial for unknown onset stroke above a certain core size. THAWS RCT Substudy. Stroke 2021 Case: A 74-year-old man presents to the emergency department after waking up with left sided weakness. He was last seen well when going to bed at 10pm the night before. He has a history of hypertension and dyslipidemia. His medications include an angiotensin-converting enzyme inhibitor and a statin. The NIHSS score is 7. The MRI shows an occlusion of the right MCA-M2, the DWI-ASPECT is 9, and lesion volume is 3.5ml. Background: We have talked about stroke management a number of times recently including SGEM#297 on the reanalysis of ECASS-3 by Alper et al 2020.  The SGEM bottom line was that the "reanalysis of the original ECASS-3 data does not support the potential benefit of tPA given between 3-4.5 hours after onset of stroke symptoms and confirms the known potential harm". There have been 13 foundational trials looking at thrombolysis for acute ischemic stroke. Of the 13, eleven failed to show benefit for their primary outcome and four were stopped early due to harm or futility. Only two RCTs claimed benefit for their primary outcome. Those were ECASS-3 in 2008 and the NINDS trial from 1995. Both of those “positive” studies have been reanalyzed and question the potential efficacy while confirming the potential harm. Dr. Jackson We wrote an article together for the Lown Institute summarizing some of the stroke literature. The question asked was: will it take 50 or 100 years to get the right answer about tPA for acute ischemic stroke? One aspect that we did not address was the newer trials that are using advanced imaging techniques like MRI to extend the window beyond 4.5 hours after the onset of stroke symptoms (Extend NEJM 2019 and ECASS-4: Extend 2016). Both of these trials were stopped early which can introduce additional bias towards efficacy. The majority of patients included in the two trials extending the time window past 4.5 hours would now qualify for endovascular therapy (EVT) clot retrieval. EVT does have more robust evidence for efficacy and safety than systemic thrombolysis. A SRMA was published by Mistry et al Stroke 2017. This included 13 studies, three randomized control trials (25% of all patients) and ten observational studies (75% of all patients). Good neurologic outcome was defined as a modified Rankin Scale (mRS) score of 0-2. The number needed to treat (NNT) was 17. However, there was no statistical difference if you only look at the higher quality RCT data and excluded the lower quality observational data. Yang P et al. published a non-inferiority RCT in NJEM 2020 looking at this issue. The primary outcome was mRS at 90 days and found EVT alone was not non-inferior to EVT plus tPA. Two recent RCTs were published in JAMA investigating this issue. Suzuki et al failed to demonstrate non-inferiority while in contrast Zi et al found EVT alone was non-inferior to EVT plus tPA. These two EVT trials are going to be covered on a future episode of the SGEM in the near future. The trial we are reviewing today is a sub analysis of the THAWS (Thrombolysis for Acute Wake-Up and Unclear-Onset Stroke) randomized control trial of using low dose tPA in patients with symptoms on awaking or unknown time of onset. Clinical Question: Is MRI guided thrombolysis (0.6 mg/kg) beneficial for patients with an unknown stroke onset time? Reference: Toyoda et al. MRI-guided thrombolysis (0.6 mg/kg) was beneficial for unknown onset strok...