SGEM#297: tPA Advocates Be Like – Never Gonna Give You Up

Date: June 30th, 2020 Guest Skeptic: Professor 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: Alper et al. Thrombolysis with alteplase 3–4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances. BMJ Evidence Based Medicine 2020 Case: A 65-year-old man arrives from home to the emergency department by EMS with right-sided weakness beginning three hours prior. Advance neuroimaging demonstrates he does not qualify for endovascular clot retrieval. He has an NIHSS score of 11 and no contra-indications for systemic thrombolysis. Background: Thrombolysis for acute ischemic stroke has to be one of, if not the most, controversial subjects of my career. The debate dates back to the classic NINDS paper published in the NEJM in 1995. We reviewed that publication with Dr. Anand Swaminathan on SGEM#70. Some people might argue that it’s less relevant now because of endovascular clot retrieval, but it’s a living example of issues with research methodology, critical appraisal, bias, conflicts of interest, etc. These elements are continuously present in medicine – look at all the COVID-19 literature – made worse by the preprint archives of non-peer reviewed papers. Thrombolysis in acute ischaemic stroke. The Lancet 2012 Truth, thinking and thrombolysis. EMA 2016 Response from Prof. Fatovich to Stroke thrombolysis: Leaving the past, understanding the present and moving forward. EMA 2013 The “Fragility” of Stroke Thrombolysis. TMJ 2020 Believing is seeing: Stroke thrombolysis remains unproven after the third international stroke trial (IST-3). EMA 2012 Don't Just Do Something, Stand There! The Value and Art of Deliberate Clinical Inertia. EMA 2018 Dr. Jerome Hoffman It was Dr. Jerome Hoffman that introduced me to this issue and was a basis of my skepticism. I used to think if the study was published in a high-impact journal it must be true. His mentorship and teaching are why I consider Dr. Hoffman a legend of emergency medicine. We have covered the issue of thrombolysis for acute ischemic stroke a number of times on the SGEM. I have also published a review on the topic of thrombolytics for stroke beyond three hours (Carpenter et al JEM 2011). More recently, I published a pro/con debate on the subject with Dr. Eddy Lange looking at the evidence (Milne et al CJEM 2020). SGEM#29: Stroke Me, Stroke Me SGEM Xtra: Walk of Life SGEM Xtra: No Retreat, No Surrender SGEM#269: Pre-Hospital Nitroglycerin for Acute Stroke Patients? SGEM#290: Neurologist Led Stroke Teams – Working 9 to 5 There has been a lot of skepticism around thrombolysis in acute ischemic stroke since the beginning. A reanalysis of the NINDS data by Dr. Hoffman and Dr. Schriger was published in Annals of Emergency Medicine in 2009. At least one other reanalysis has questioned the 2009 reanalysis (Saver et al Ann Emerg Med 2010).  Thus, there is a degree of uncertainty in the NINDS-II results. The major takeaway from this reanalysis was that the baseline imbalance in stroke severity led to the difference in outcomes. If tPA really works, we should see a bigger change in the NIHSS score in the tPA group vs. the placebo group. Yet the difference was 0.0. People can forget that a clinical trial has internal validity if and only if the imbalance between groups, bias in the assessment of outcome, and chance, have been excluded as possible explanations for the difference in outcomes. Baseline imbalance is a recurring theme. So, replication studies are hugely important. It was the NINDS trial that changed guidelines and practices to provide thrombolysis in patients with stroke symptoms less ...