SGEM Xtra: Here Comes the NINDS Again

Date: July 1st, 2022 Guest Skeptic: Dr. Ravi Garg is a Neurologist in the Department of Neurology, Division of Neurocritical Care at Loyola University Chicago. Reference: Garg R, Mickenautsch S. Risk of selection bias assessment in the NINDS rt-PA stroke study. BMC Med Res Methodol. 2022 Jun 15;22(1):172. This is an SGEM Xtra episode. Dr. Garg saw some tweets about the NINDS trial and sent me his recent publication. I asked him to come on the SGEM and discuss the original NINDS trial, some of the reanalyses and share his analysis of the NINDS data. One of the criticisms of Emergency Medicine physicians who have done FOAMed post publication reviews of the stroke literature like Dr. Justin Morgenstern, Dr. Ryan Radecki, Dr. Anand Swaminathan and Dr. Salim Razaie, is that we are not neurologists and specifically not stroke neurologists. While this is true, we are part of the team that diagnose and treat acute stroke patients. The SGEM tries to include a wide variety of clinicians in this knowledge translation project. Great emergency care takes a team from the prehospital setting, emergency department, inpatient and outpatient all working together. That is why we have had paramedics, nurses, physiotherapists, pharmacists and a wide spectrum of physician specialists on the SGEM. However, until now have we not had a neurologist on the SGEM who has a specialized interest in stroke neurology and published on thrombolysis as a guest skeptic. Dr. Garg sent me his analysis of the NINDS trial that he wrote with his co-author Dr. Steffen Mickenautsch. This new peer reviewed publication is the basis of this SGEM Xtra episode. The NINDS trial was published back in 1995 and we did a structured critical appraisal of the classic paper with Dr. Anand Swaminathan on SGEM#70.  I was a resident at the time of publication and Dr. Garg was only eight years old. Dr. Garg was asked a series of questions. You can listen to his responses on the SGEM podcast. Thoughts on the NINDS Trial and Some of the Reanalyses Dr. Ravi Garg Any general thoughts about NINDS trial? One concern about the NINDS trial was the baseline differences in NIHSS score. This resulted in multiple reanalyzes attempting to control for these factors. NINDS commissioned an independent committee to investigate if any of these imbalances invalidated the entire trial. This committee’s findings supported the use of tPA in less than three hours (Ingall et al 2004). What are your thoughts on this commissioned report? Another reanalysis was done by Kwiatkowski et al 2005 that also confirmed that the baseline imbalance in the NINDS trial did not account for the better outcome of tPA-treated patients. Any brief comments on this reanalysis? Hoffman and Schrieger stirred things up a bit with their graphic reanalysis of the NINDS trial using the NIHSS score. They published their findings in Annals of EM 2009. The results questioned the effect of tPA for acute ischemic stroke in patients treated within three hours. The graphs created in the publication also failed to support the "time-is-brain" hypothesis. There are some criticisms of this graphic reanalysis. What are your thoughts on this contrarian view? Saver et al responded to Hoffman and Schrieger’s graphic reanalysis in Academic Emergency Medicine 2010. They pointed out number concerns with the publications. Did Saver and colleagues make some sound arguments? Ravi Garg and Steffen Mickenautsch BMC June 2022 The title of your paper is Risk of selection bias assessment in the NINDS rt-PA stroke study. It was published in BMC Medical Research Methodology, June 2022. With all the other reanalyses, what motivated you to do this another reanalysis of the NINDS trial? You were able to get patient level data for this review. Why is that important? What tool did you use to assess the NINDS trial for risk of selection bias?