Recently a letter to the editor was sent to us at the EMCRIT Consortium regarding a recent post I had written about the use of high sensitivity (HS) troponin assays for the work up of ACS in the emergency department. Typically, such remarks are posted in the comments section of the individual blog posts, but since the authors invested a great deal of effort we thought we should publish it as its own independent post. It can be read in total here.
This post will serve as a response to the comments and concerns penned by Drs Smith, Limkakeng, and Peacock. While the authors make a fairly compelling argument describing why my opinions are misguided and just plain wrong, the tone of their letter is far from genteel. For example I did not “willfully misrepresent” 5 studies in order to defend my position. I simply stated my general opinion on the data examining the use of HS troponin assays. Stating, “while a number of studies have demonstrated that the introduction of a high-sensitivity assay allowed clinicians to send more patients home from the ED without increasing the number of patients diagnosed with AMI, an equal number have demonstrated the opposite”. I then cited a number of articles, some of which demonstrated early discharge, others showing an increase in positive tests and downstream testing. While Drs Smith, Limkakeng, and Peacock May feel their opinion represents the gold standard, simply disagreeing with their perspective is not equivalent to willful misrepresentation.
In an attempt to avoid further mischaracterization of my intent and continued bickering over the meaning of each individual article I shall endeavor to provide a general oversight and analysis of the data and allow readers to draw their own conclusions.
First let us examine the problem that HS troponin assays are purported to solve. Chest pain in the ED is a fairly common complaint ,and ACS is one of the primary concerns when assessing these patients. We have been taught that our current evaluation strategy is insufficient and misses an unacceptably high number of patients with an MI. Is this true? The paper most often cited to support such a statement was published in the NEJM in 2000 by Pope et al (1). This paper examined 10,689 patients presenting to the Emergency Department with concerns for ACS. Of this large population, only 19 patients with an MI were sent home, for a miss rate of 0.18%. Furthermore, when the authors examined the clinical outcomes of the patients whose MI was initially missed, they did as well as the population who was admitted to the hospital on initial presentation.
During the intervening years, these numbers have not changed. Still today the risk of death or MI following a negative work up in the Emergency Department consisting of an EKG and fourth generation troponin assay is extremely low. Weinstock et al reported on their experience of over 7,000 patients admitted to the hospital following an ED work with negative fourth generation troponins and a non-ischemic EKG. Of the 7266 patients examined, 4 had clinically relevant adverse cardiac events (death, STEMI, ventricular arrhythmias, cardiac/respiratory arrest), and 28 (0.39% [95% CI, 0.26%- 0.56%]) had a final diagnosis of NSTEMI (2). This trial is not unique. Trial after trial has demonstrated that following an ED workup, consisting of an EKG and fourth generation troponin assay, the risk of MI or death is exceptionally low (3). This has been observed as far back as the data examining the utility of stress tests following an ED workup for chest pain (4-8). As an example, Amsterdam et al examined 1000 patients following an ED workup for chest pain, finding only 1 patient (0.1%) experienced an MI in the next 30 days. Meyer et al studied 903 patients following a work up for chest pain, and only 2 (0.2%) experienced an MI with the following 6 months.
The same pattern is present in the data examining the use of CCTA for patients presenting to the ED for chest pain. Hoffman et al (9) looked at 1000 patients randomly assigned to CCTA or standard care. A total of 5 patients (0.5%) experienced an MI within 28 days following ED presentation. Similar numbers are seen throughout the trials examining the use of CCTA(10, 11).
The same risk is seen again and again throughout the literature (12,13). The rate of true patient important outcomes, death or MI, following a negative ED workup is exceptionally low. So low in fact one has to wonder if a more sensitive tool intended to further lower this population’s risk of an MI is likely to cause more harm than benefit.
To answer this, let us examine the test itself. Drs Smith, Limkakeng, and Peacock’s contention is the test is poorly named. In their letter they state,
“I like to call high-sensitivity assays “high-precision” assays because they can accurately quantify low levels of troponin, far below the 99th percentile cutpoint. This means that troponin changes at low levels can be detected in order to rule in or rule out MI earlier by using low thresholds or delta values. Small changes at low values are true changes, not just analytical noise.”
This is factually accurate, but somewhat disingenuous. They are describing the assay’s laboratory diagnostic characteristics or its ability to identify troponin. What we are concerned with as clinicians is the assays clinical diagnostic characteristics, or the ability to correctly identify ACS in patients presenting to the ED. From this perspective, the name high sensitivity (low specificity) troponin is fitting. A meta-analysis by Al-Saleh et al (14) published in CMAJ in 2014 examined 9 studies with a total of 9186 patients. The authors reported the HS troponin assays had a higher sensitivity and lower specificity than the fourth generation assays.
The potential harms associated with this decrease in specificity is illustrated clearly in the Shah et al paper, discussed extensively in a previous blog post. The 17% of patients who had an elevation in HS troponin, but not in standard troponin, underwent more interventions and medical management, without any reduction in patient centered outcomes. As with any overly sensitive test, when applied to a population with a very low risk of the disease in question there is a potential to expose patients to harm, in the form of overdiagnosis and overtreatment.
Do HS troponins identify MIs or death at a greater frequency than the standard troponin assays? As best as we can tell the answer is no. Neither the RCT by Shah et al (15) or Chew et al (16) found the use of HS troponins reduced the rate of MI or death. And how could they, the risk of MI or death following a negative ED work up is so low, it would be next to impossible to further reduce a patient’s risk. Drs Smith, Limkakeng, and Peacock state that HS troponins have the potential for identifying more patients who require urgent caths, and stents that will prevent downstream MIs. Much has been written on the utility of revascularization as a clinical endpoint. For a fantastic review written by Dr. Justin Morgenstern see this post. In short, if the HS troponin assays identified a subset of patients who would benefit from urgent revascularization we would have observed a decrease in the rate of MI over the follow up period. This was not observed in either of the trials in question. In fact, if HS troponin assays led to an increase in PCI without a change in the rate of death or MI, then it is likely these interventions were clinically unnecessary.
If HS troponin assays do not decrease the rates of death or MI, can they at least assist in ED flow? Can we discharge patients faster or more frequently then with our current diagnostic? Drs Smith, Limkakeng, and Peacock cite a number articles stating this is the case,
His (That’s me) response ignores a decade of research detailing how high-sensitivity assays can beneficially impact ED patients. There are many systematic reviews, meta-analyses, and prospective randomized trials from dozens of countries and tens of thousands of patients on use of high-sensitivity troponin for safe rapid ED discharge (just for example, Zhelev Z,et al. BMJ. 2015 Jan 20;350:h15. Than MP, et al. Circ 2018; 137 (4): 354-63, Twerenbold R, et al. Eur Heart J. 2016 Nov 21;37(44):3324-3332) The literature is replete with data showing how proper implementation of high-sensitivity troponin can avoid increased workups and downstream testing, while at the same time decreasing ED length of stay and costs.
They are not wrong. There is a large quantity of data stating that you can send patients home directly from the ED without further diagnostic work ups following a negative HS troponin value. They failed to add the data suggests you can send these patients home directly from the ED even without the use of HS troponin assays.
Shah et al found no difference in the primary outcome, or the difference in the rate of death or MI at 1-year, but did find that patients in the HS troponin group had a higher rate of left heart catheterization and medical therapy than those in the standard fourth generation group. Chew et al also found no difference in the rate of MI or death at 30-days. They not find a difference in the number of patients who were discharged directly from the ED, 45% vs. 33%, p<0.001. As pointed out by Drs Smith, Limkakeng, and Peacock, this demonstrates the potential clinical value of HS troponin. Under the right circumstances more patients can be discharged directly home from the Emergency Department and undergo less follow up testing. But if HS assays do not identify patients who will experience death or MI that would have been otherwise missed by the standard generation assay, their ability to discharge patients home is based simply on clinician comfort. 91% of the patients in the control group had a negative troponin at 3-hours. One could argue that the vast majority of these patients could be discharged from the ED without further work up as their risk of an adverse event is exquisitely low and admission to the hospital for further testing is unlikely to add benefit. And so we are asked to weigh the added sensitivity on the front end and the small amount of time saved in the subset of patients that have initial undetectable HS troponin values vs the potential increase in downstream testing that will inevitably occur when you apply a more sensitive test to a cohort with a low incidence of the disease in question. If you are in a practice environment that is likely to admit the vast majority of chest pain patients, the addition of HS troponin may help reduce admissions and testing. But if you work in an environment that can institute policies that encourage early discharge and outpatient follow up in patients following a negative ED work up then you are likely to achieve the same results.
In the end, this discussion is likely to matter very little. We will all be using HS assays soon enough whether we like them or not. Whether this will change practice for the better is yet to be demonstrated. My fear is even with the best protocols, the broad use of HS troponin assays will structurally change the diagnosis of MI. More people will be diagnosed with MIs, which means more people will become patients. More patients will undergo invasive and non-invasive therapies and will be exposed to medical treatments. It is likely a good portion of these patients will not benefit from excess interventions and testing, experiencing only the harms associated with such interventions.
Finally, the authors argue that my lack of research experience in this area makes me unable to effectively criticize this research. Respectfully, I disagree. In contrast to Drs Smith, Limkakeng, and Peacock I have no intellectual or financial conflicts of interests in regards to this topic. If HS troponin assays eventually demonstrate their clinical superiority, then I will use them with minimal objection. As with many of my posts, these were written to stimulate thought and discussion. By that standard they have been fairly successful. With that in mind we thank Drs Smith, Limkakeng, and Peacock for their thoughtful letter and take their concerns under advisement and eagerly await the results of further trials examining the utility of HS troponin to continue this discussion.
- Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med. 2000;342(16):1163-70.
- Weinstock MB, Weingart S, Orth F, et al. Risk for Clinically Relevant Adverse Cardiac Events in Patients With Chest Pain at Hospital Admission. JAMA Intern Med. 2015;175(7):1207–1212.
- Foy AJ, Liu G, Davidson WR, Sciamanna C, Leslie DL. Comparative Effectiveness of Diagnostic Testing Strategies in Emergency Department Patients With Chest Pain: An Analysis of Downstream Testing, Interventions, and Outcomes. JAMA Intern Med. 2015;175(3):428–436.
- Gomez, M., J. Anderson, L. Karagounis, et al. (1996). “An emergency department-based protocol for rapidly ruling out myocardial ischemia reduces hospital time and expense: results of a randomized study (ROMIO).” Journal of the American College of Cardiology 28(1): 25-33.2
- Amsterdam, E. A., J. D. Kirk, D. B. Diercks, et al. (2002). “Immediate exercise testing to evaluate low-risk patients presenting to the emergency department with chest pain.” Journal of the American College of Cardiology 40(2): 251-6.1
- Meyer, M., R. Mooney and A. Sekera (2006). “A critical pathway for patients with acute chest pain and low risk for short-term adverse cardiac events: role of outpatient stress testing.” Annals of Emergency Medicine 47(5): 435e1-3.4
- Manini, A. F., A. T. McAfee, V. E. Noble, et al. (2010). “Prognostic value of the Duke treadmill score for emergency department patients with chest pain.” The Journal of Emergency Medicine 39(2): 135-43.3
- Scheuermeyer, F., G. Innes, E. Grafstein, et al. (2012). “Safety and Efficiency of a Chest Pain Diagnostic Algorithm With Selective Outpatient Stress Testing for Emergency Department Patients With Potential Ischemic Chest Pain.” Annals of Emergency Medicine.59(4):256.64.5
- Hoffmann U, Truong QA, Schoenfeld DA, et al. Coronary CT angiography versus standard evaluation in acute chest pain. The New England journal of medicine. 2012; 367(4):299-308.
- Litt HI, Gatsonis C, Snyder B, et al. CT angiography for safe discharge of patients with possible acute coronary syndromes. The New England journal of medicine. 2012; 366(15):1393-403.
- deFilippi CR, Rosanio S, Tocchi M, et al. Randomized comparison of a strategy of predischarge coronary angiography versus exercise testing in low-risk patients in a chest pain unit: in-hospital and long-term outcomes. Journal of the American College of Cardiology. 2001;
- Backus BE, Six AJ, Kelder JC, et al. A prospective validation of the HEART score for chest pain patients at the emergency department. International journal of cardiology. 2013; 168(3):2153-8.
- Poldervaart JM, Reitsma JB, Backus BE, et al. Effect of Using the HEART Score in Patients With Chest Pain in the Emergency Department: A Stepped-Wedge, Cluster Randomized Trial. Annals of internal medicine. 2017; 166(10):689-697.
- Al-Saleh A, Alazzoni A, Al Shalash S, Ye C, Mbuagbaw L, Thabane L, Jolly SS. Performance of the high-sensitivity troponin assay in diagnosing acute myocardial infarction: systematic review and meta-analysis. CMAJ Open 2014; 2(3): E199-E207
- Shah A, Anand A, Strachan F, et al. High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial. Lancet. August 2018.
- Chew DP, Lambrakis K, Blyth A, et al. A Randomized Trial of a 1-Hour Troponin T Protocol in Suspected Acute Coronary Syndromes: The Rapid Assessment of Possible ACS In the Emergency Department with High Sensitivity Troponin T (RAPID-TnT) Study. Circulation. 2019;
University of Georgetown
Resuscitation and Critical Care Fellowship Graduate