The Skeptics Guide to Emergency Medicine

Guest Skeptic: Dr. Dan Lane has a Masters in Health Services Research at the University of Calgary, a Doctor of Philosophy in Clinical Epidemiology from the University of Toronto and is currently a medical student at the University of Calgary. Dan is naturally a contrarian, he strives to understand first principles of conventions in medical research in order to identify and challenge poor practices that have become dogma. He is passionate about statistics and epidemiology and wants to share that passion by making these topics more practical and approachable for clinicians. Believing the key to proper interpretation of medical research does not begin with memorizing some arbitrary threshold for statistical significance, Dan hopes to contribute to the SGEM through sharing an understanding of what story the numbers are actually telling about the data. Dan has no funding whatsoever, and no associations with industry. He is currently a medical student at the University of Calgary. Dan has some pet peeves when it comes to statistics there used and critical appraisals. We will do some more in depth SGEM Xtras on each of these issues. Thomas Bayes Absolute vs. Relative Estimates Effect Estimates and Not P-Values All Models are Wrong Predication vs. Classification Bayes No Frequentists The purpose of this SGEM Xtra, beside to introduce a new SGEM faculty member, is also to announce we are adding a new segment to the SGEM. It is going to be called Statistically Significant. We want to make the SGEM even better and address some of the criticisms from the ClinEpi world about clinicians trying to do critical appraisal. In order to do that we now have a Dr. Dan Lane PhD who will be commenting on each the SGEM episodes. The first instalment of Statistically Significant segment will be on this weeks’ SGEMHOP looking at troponin testing in the elderly patients presenting with non-specific complaints (SGEM#280). Let me know what you think of this idea. We have a few more lined up and feedback is always appreciated. Send me an email [email protected] Statistically Significant #280: Sensitivity and Specificity Despite their dogmatic use in the literature, sensitivity and specificity have a number of limitations that are rarely considered or addressed in diagnostic test studies. Sensitivity and Specificity are crude metrics, meaning they only look at the effect of a single measure and a single outcome. As crude measures they fail to incorporate any other information into their estimates, including potential confounders for the relationship between the test result and the outcome. In this particular study, age is part of the primary objective for the study (geriatric patients) but is also a confounder of the relationship between troponin level (which may increase with age) and acute coronary syndrome risk (also increases with age). When confounders like age are present, crude measures will be influenced based on the prevalence of confounders in each the groups – for example, if there were more older patients in the troponin positive group, the estimates for sensitivity may be inflated. Another limitation of sensitivity and specificity is they require a test result be classified as positive or negative. This is problematic when the real measure is a continuous measure, such as troponin. In the current study the test was considered “positive” if the troponin level was above the 99th percentiles for that enzyme. But this arbitrarily treats patients above or below the 99th percentile as homogeneous groups, meaning the statistics consider everyone above the threshold to be the same, and everyone below the threshold to be the same. Consider a patient with a troponin right below the threshold and another patient right above the threshold – surely these patients are almost identical in terms of their risk for having ACS. But by inserting an arbitrary break into the measure, the statistics will treat them as different resulting in more misclassifications simply because a threshold for positive or negative was selected. Instead of these binary classifications, researchers could focus directly on the patient’s risk of the outcome. This can be represented using probabilities and a smooth curve that shows the probability of ACS based on the exact troponin value. Using simple statistical models, these probability estimates can be adjusted for confounders, like age, and provide easily interpretable probability estimates for the entire range of troponins – no classification required! References: Amrhein, Greenland and McShare. Scientists rise up against statistical significance. Nature 2019 Reginal Nuzzo. STATISTICAL ERRORS. P values, the ‘gold standard’ of statistical validity, are not as reliable as many scientists assume. Nature 2014 Fatovich and Phillips. The probability of probability and research truths. AEM 2017 Greenland et al. Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations. EJE 2016 Guggenmo

Date: January 16th, 2020 Reference: Troponin Testing and Coronary Syndrome in Geriatric Patients With Nonspecific Complaints: Are We Overtesting? AEM January 2020 Guest Skeptics: Dr. James VandenBerg: James has a master’s degree in clinical investigation from Washington University in St. Louis, and is currently the Chief Resident at Detroit Receiving Hospital. Dr. Andrew Huang: Andy is the Chief Resident at Sinai-Grace Hospital. Case: As the resident, you have just finished seeing a 78-year-old male who has been brought in by his family over the holidays. The triage nurse has put the reason for the visit as “multiple complaints”. Despite spending 30 minutes in the room, you still are not sure exactly why the patient is here. Your attending says that if you take a good geriatric history that you can always determine what’s going on. However, 15 minutes later your attending leaves the room defeated. The patient’s complaints are just so nonspecific. The attending ends up ordering the “geriatrogram” – ticking off every blood test on the form, including the troponin. You turn to the attending and ask, “do you really think this could be acute coronary syndrome (ACS)?” Background: Patients 65 years and older account for about 15% of emergency department visits in the United States. Their presentations are often complicated as they present with nonspecific symptoms, and there is often obscuring co-morbid conditions, polypharmacy, and cognitive/functional impairment. Nonspecific symptoms in the elderly usually yield a broad differential and there are no recommended diagnostic algorithms, leading to extensive testing. ACS is usually amongst this differential, as cardiovascular disease is a leading cause of morbidity and mortality in this population. Additionally, the elderly population with ACS more commonly presents without chest pain compared to younger patients (up to 20% of elderly patients with MI present with “weakness” as part of their chief complaint). While cardiovascular disease is the leading cause of mortality and morbidity in the elderly, the frequency of ACS amongst this population presenting with nonspecific symptoms is unknown. Clinical Question: What is the frequency of ACS in elderly patients presenting to the ED with nonspecific complaints, and what is the utility of troponin testing in this population? Reference: Wang et al. Troponin Testing and Coronary Syndrome in Geriatric Patients With Nonspecific Complaints: Are We Overtesting? AEM January 2020 Population: Patients aged 65 years and older presenting to the emergency department with nonspecific chief complaints who underwent troponin testing. “Nonspecific” was designed a priori as including weak or weakness, dizzy or dizziness, fatigue, lethargy, altered mental status, light-headedness, medical problem, examination requested, failure to thrive, or “multiple complaints.” Exclusions: If they had a focal chief complaint (ex. focal pain, injury complaint, shortness of breath, vomiting, diaphoresis, syncope, fever, cough, focal neurologic deficit)or fever of at least 38C at triage. Investigation: Troponin testing Comparison: None Outcomes: There were multiple outcomes of interest: The proportion of patients with nonspecific complaints who underwent troponin testing. The proportion of such patients who had elevated troponin. The proportion of patients with ACS at the index visit or within 30 days. The utility of troponin testing to diagnose or exclude ACS. The frequency of other causes of troponin elevation in this population. Dr. Alfred Wang This is a LIVE episode of an SGEMHOP which means we have the lead author on the show. Dr. Alfred Wang is an emergency medicine physician at Indiana University in Indianapolis, IN. With the help from a dedicated team of physician-peers and mentor, Dr. Wang was able to complete this research project. Authors’ Conclusions: “While consideration for ACS is prudent in selected elderly patients with nonspecific complaints, ACS was rare and no patients received reperfusion therapy. Given the false-positive rate in our study, our results may not support routine troponin testing for ACS in this population.” Quality Checklist for A Chart Review: There is a quality check list for ED studies that was published by Gilbert et al in Annals of EM 1996. It had eight items. The list was updated and expanded by Dr. Andrew Worster from BEEM to include 12 items. The authors of this retrospective chart review did a great job and 11 out of 12 answers were yes. The only “no” was that they did not have a management plan described for missing data in the publication. Abstract Training: Were the abstractors trained before the data collection? Yes Case Selection Criteria: Were the inclusion and exclusion criteria for case selection defined? Yes Variable Definition: Were the variables defined? Yes Abstraction Forms: Did the abstractors use data abstraction forms? Yes Performance Monitored: Was the abstractors’ performance monitored? Yes Bin

Date: January 10th, 2020 Reference: Dodick DW et al. Ubrogepant for the Treatment of Migraine. NEJM 2019 Guest Skeptic: Dr. Anand Swaminathan is an Assistant Professor of Emergency Medicine at St. Joseph’s Hospital in Paterson, NJ. He is also the managing editor of EM:RAP and associate editor at REBEL EM. Case: A 23-year-old man with a history of migraines presents with two days of headache, nausea and photo-photophobia typical of his prior migraines. He’s tried a number of medications at home including ibuprofen, acetaminophen, aspirin and sumatriptan without any considerable improvement in symptoms. You start to offer him your standard medications like metoclopramide and haloperidol when he asks about a new drug he heard about called ubrogepant. Background: Migraine headaches are a chronic neurologic disease characterized by throbbing, often unilateral headaches that are often associated with nausea, vomiting, photophobia and phonophobia. It is a common disease and can be severe enough to impede on people’s lives. Headaches themselves are not only a common emergency department presentation but one that is filled with potential dangers. There are a number of causes of headache that are life and limb threatening – subarachnoid hemorrhage (SGEM#201), meningitis, encephalitis, cerebral venous thrombosis, vertebral artery dissection among other things but, most headaches are benign in nature. There is an international classification system of headaches (IHS 2018). The current system classifies them into primary and secondary headaches. An important part of our job as emergency physicians is to differentiate the lethal headache from the benign headache. Though we rarely make a de novo diagnose of migraines in the emergency department, many patients with migraines present to us for symptom management. The pathophysiology of migraines is both complicated and poorly understood but there are a number of potential treatments including NSAIDs, acetaminophen, aspirin, neuroleptics, triptans and even propofol. More recently, calcitonin gene-related peptide antagonists (CGRPs) have emerged as a new potential treatment. The first big study that came out on these drugs was published in the NEJM in 2019 and was entitled Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist for Migraine (Lipton et al). Now, we have a second study published in the NEJM on a related drug, ubrogepant. Clinical Question: Does ubrogepant increase the percentage of patients who were free from pain and absent of the most bothersome migraine-associated symptom at two hours from initial dose in comparison to placebo? Reference: Dodick DW et al. Ubrogepant for the Treatment of Migraine. NEJM 2019 Population: Adult patients (18-75 years of age) with at least a one-year history of migraine with or without aura that met criteria from the International classification of headache disorders and had migraine onset before the age of 50. Patients had to have a history of migraines between 4-72 hours and a history of migraine attacks separated by at least 48 hours of freedom from headache. Additionally, they had to have suffered from two to eight migraines per month over the last three months. Exclusions: Patients with 15 or more headaches/month on average in the previous six months. Hard to distinguish the type of headache. Use of acute migraine treatment on ten or more days in the previous three months. Participated in a trial involving CGRP. Had clinically significant cardiovascular or cerebrovascular disease. History of hepatitis in the last six months or laboratory findings of liver disease (elevated AST, AST, Bilirubin or low serum albumin). Additional Exclusions from ClinicalTrials.gov Has a history of migraine aura with diplopia or impairment of level of consciousness, hemiplegic migraine, or retinal migraine Has a current diagnosis of new persistent daily headache, trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial neuropathy Required hospital treatment of a migraine attack 3 or more times in the previous 6 months Has a chronic non-headache pain condition requiring daily pain medication Has a history of malignancy in the prior 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer Has a history of any prior gastrointestinal conditions (eg, diarrhea syndromes, inflammatory bowel disease) that may affect the absorption or metabolism of investigational product; participants with prior gastric bariatric interventions which have been reversed are not excluded Intervention: Ubrogepant 50 mg or 100 mg Comparison: Placebo Outcomes: Co-Primary Outcome: Freedom from pain at two hours from initial dose of medication. Absence of the most bothersome symptom associated with migraine two hours from initial dose of medication. Secondary Outcomes: Change in severity of headache at two hours, sustained pain relief, sustained freedom from pain, absence of photophobia, absence of