SGEM#354: Everybody Walk the Dinosaur and Not Take the MSU

Date: December 21st, 2021 Guest Skeptic: Dr. Howard “Howie” Mell began his career as a firefighter / paramedic in Chicago. He became double board certified in Emergency Medicine (EM) and Emergency Medical Services (EMS). Howie also has a Master of Public Health. Reference: Grotta JC et al. Prospective, multicenter, controlled trial of mobile stroke units. NEJM 2021 Case: The Mayor of your community consults you as an expert in public health, EMS and as an EM physician on whether they should purchase a mobile stroke unit (MSU) ambulance. Background: No one who has listened to the SGEM will be surprised we are covering another paper looking at stroke. We have often discussed the use of thrombolysis for acute ischemic stroke (AIS) with or without endovascular therapy (EVT). However, the SGEM has also looked at secondary stroke prevention on previous episodes (SGEM#24, SGEM#303). The SGEM has looked at pre-hospital stroke care using early administration of nitroglycerin by paramedics to see if it would improve neurologic outcome in patients with a presumed acute stroke (SGEM#269). The results from the RIGHT-2 trial reported no statistical difference in functional outcome as measured by the modified Rankin Scale (mRS) score at 90 days. The SGEM bottom line was that very early application of transdermal nitroglycerin by paramedics in the pre-hospital setting cannot be recommended at this time in patients with a suspected stroke. Mobile Stroke Unit The issue of having a MSU has also been discussed on  SGEM#330. A systematic review and meta-analysis which included seven randomized controlled trials and four observational studies including 21,297 patients was critically appraised.  The primary outcomes reported better neurologic outcome at seven days but not at one day post treatment by a MSU compared to conventional care (Fatima et al Int J Stroke 2020). The SGEM bottom line from that episode was we cannot recommend the use of MSU based on the available evidence. Clinical Question: Should mobile stroke units be purchased and deployed in your community? Reference: Grotta JC et al. Prospective, multicenter, controlled trial of mobile stroke units. NEJM 2021 Population: Patients calling EMS with a history and physical/neurological examination consistent with acute stroke who is last seen normal (LSN) possibly within 4 hours and 30 minutes and who had no definite tPA exclusions per guidelines, prior to CT scan or baseline labs. Daytime hours and mostly weekdays. Intervention: Care by a mobile stroke unit (MSU) Comparison: Care by traditional EMS referred to as standard management (SM) Outcome: Primary Outcome: Score on the utility-weighted modified Rankin scale (uw-mRS) at 90 days in patients who were adjudicated to be eligible to receive tPA on the basis of subsequent blinded review Secondary Outcomes: There were twelve secondary endpoints in their final protocol listed in hierarchical sequence of importance Agreement between on-board vascular neurologists (VN) and the remote VN Exploratory cost-effectiveness analysis (CEA) Outcomes comparing patients found eligible for tPA on MSU weeks compared to patients on SM weeks Ordinal (shift) analysis of mRS at 90 days, and Proportion of patients achieving 90 day mRS 0,1 vs 2-6 30% improvement from baseline to 24hr NIHSS Outcomes comparing all patients treated with tPA (whether or not adjudicated as tPA eligible) on MSU weeks compared to patients on SM weeks. Uw-mRS at 90 days Ordinal (shift) analysis of mRS at 90 days, and Proportion of patients achieving 90 day mRS 0,1 vs 2-630% Improvement from baseline to 24hr NIHSS Outcomes of those treated within 60 min LSN compared to those treated from 61 to 270 minutes Change in uw-mRS from baseline at 90 days Ordinal shift analysis of MRS at 90 days Proportion of patients achieving 90 day mRS 0,1 vs 2-6 30% improvement from baseline to 24hr NIHSS Outcomes all patients treated with IAT (separate analyses for those adjudicated as tPA eligible, all tPA treated, or all IAT with or without tPA) on MSU weeks compared to patients on SM weeks. Uw-mRS at 90 days Ordinal (shift) analysis of mRS at 90 days, and Proportion of patients achieving 90 day mRS 0,1 vs 2-6 30% improvement from baseline to 24hr NIHSS The time from LSN to tPA treatment on all patients treated within 4.5 hours of LSN on MSU weeks compared to similarly eligible patients on SM weeks Proportion of patients treated within 60 minutes of LSN on MSU weeks vs SM weeks. The time from LSN and from ED arrival to start of endovascular procedure on MSU vs SM weeks Proportion of all tPA-eligible patients having EVT on MSU vs SM weeks The median/mean time from LSN to tPA therapy decision on all patients considered for treatment within 4.5 hours of LSN on MSU weeks compared to SM weeks Time between 911 call and onset of etiology-specific BP management on MSU vs SM weeks. Safety Endpoints: Incidence of symptomatic intracranial hemorrhage (sICH) in enrolled tPA treated patients on MSU weeks compared to SM weeks. sICH was defined as any intracranial blood accumulation associated with a clinical deterioration of 4 points of the NIHSS for which the hemorrhage has been identified as the dominating cause of the neurologic deterioration) Mortality up to one year Incidence of stroke mimics and transient ischemic attacks (TIAs) in tPA treated patients on MSU weeks compared to SM weeks. Trial: Prospective cohort study with cluster randomized deployment weeks and blinded assessment of both trial entry and clinical outcomes. Cluster randomization can have both strengths and weaknesses just like any study design. For those less familiar with this methodology Taljaard and Grimshaw wrote a good article the topic in 2014. Authors’ Conclusions: "In patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS." Quality Checklist for Observational Studies: Did the study address a clearly focused issue? Yes Did the authors use an appropriate method to answer their question? No Was the cohort recruited in an acceptable way? No Was the exposure accurately measured to minimize bias? Yes Was the outcome accurately measured to minimize bias? No Have the authors identified all-important confounding factors? No Was the follow up of subjects complete enough? Yes How precise are the results? Unsure Do you believe the results? No Can the results be applied to the local population? No Do the results of this study fit with other available evidence? Yes Did the study have no conflicts of interest. No Key Results: This prospective observational study screened 10,443 patients and enrolled 1,515 patients (58.5% MSU vs 41.5% SM). Fourteen percent overall were not eligible for tPA due to intracranial blood seen on CT scan. Two-thirds in both groups (1,047 total) were decided post-hoc to be eligible for tPA. Of the tPA eligible patients, 97% in the MSU group received tPA compared to 79.5% in the SM group. This results section was a real struggle. It was unclear which primary and secondary outcomes we should highlight in the review. Should it be those published in the NEJM or do we discuss the original ClinicalTrials.gov outcomes, the current ClinicalTrials.gov outcomes or pre-specified published protocol outcomes (Yamal et al Int J Stroke 2018)? At the end of the day, we decided to provide the published primary outcome, mention the secondary outcomes and give a few of the safety outcomes. Key Result: Patients treated with a mobile stroke unit had better 90 day outcomes. Primary Outcome (NEJM): Score on the uw-mRS at 90 days in patients who were adjudicated to be eligible to receive tPA on the basis of subsequent (post-hoc) blinded review 0.72 in the MSU group and 0.66 in the SM group Adjusted Odds Ratio (aOR) ≥0.91, 2.43 (95% CI, 1.75 to 3.36; P<0.001). Secondary Outcomes: Among the patients eligible for tPA, 55.0% in the MSU group and 44.4% in the SM group had a score of 0 or 1 on the mRS at 90 days. Among all enrolled patients, the mean score on the uw-mRS at discharge was 0.57 in the MSU group and 0.51 in the SM group (aOR for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). For more secondary outcomes see the NEJM publication. Safety Endpoints: sICH in ~2% of patients who received tPA in each group and none of the patients considered to be stroke mimics. Mortality at 90 days was 8.9% in the MSU group vs 11.9% SM group. 1. Houston, We Have a Problem: They changed their protocol at least four times over the course of the study. These changes were described in the PDF of their protocol. Sometimes the changes were minor and other times they were major. You can also see how their primary outcomes changed on ClinicalTrials.gov, in their pre-published protocol and through to their published manuscript in the NEJM. We were unable to find the any data in the manuscript or supplemental material on the other three “original” or “current” primary outcomes. This included the kappa value for the agreement between on scene vascular neurologist and remote vascular neurologist, cost effectiveness or the change in uw-mRS from baseline at 90 days. We have reached out to the lead author Dr. Grotta and will update the blog if this information becomes available. UPDATE: The Cohen kappa was published by Wu et al in 2017 with a value of 0.73 which is considered moderate inter rater reliability according to McHugh 2012.