The uncertainty principle states, there is a limit to the precision with which the position and momentum of any subatomic particle can be measured. Their location and velocity can only be described in degrees of probability, rather than with the certainties we are accustomed to. This nanoscopic world cannot be predicted by classical physics nor understood using the anecdotal experiences of everyday life. What, you may ask, does this have to do with the practice of Emergency Medicine? Although some would argue that Schrodinger and his cat would have made wonderful Emergency Physicians, until now Emergency Medicine and Quantum Mechanics have occupied their own mutually separate sectors of space. With the arrival of high-sensitivity troponin assays and the uncertainty that comes with interpreting their results, these independent circles may have come closer to intercepting then we ever would have anticipated.
Ideally during an acute myocardial infarction, serum levels of cardiac-specific troponin rise incrementally. We utilize this predicted rise and its high specificity to confirm our suspicion of myocardial necrosis. More recently, as the troponin assays have become more sensitive they have been utilized to further risk stratify chest pain patients at low risk for ACS (9). Given the delayed fashion of troponin's release into the blood stream, a single troponin is not sensitive enough to effectively rule out ACS (2), and thus emergency providers have taken to measuring troponin levels in a serial fashion. Traditional recommendations state providers should allow at least 3-6 hours between measurements to ensure identification of patients who are early in their presentation (6). The hope of those who are supporters of the high-sensitivity assays is that these tests will be able to identify patients earlier in their disease process and reduce time required between serial measurements leading to faster, more accurate dispositions.
The difficulty with the increasing sensitivity of troponin assay is two-fold. First, the newest generation of assays can now detect troponin levels in well over 50% of the general population (1). In fact, in an article published in NEJM in 2009 by Reichlin et al, the Roche high sensitivity troponin assay, at its limit of detection (LOD) found 87% of the cohort to have measurable troponin levels (2). This baseline troponinemia makes differentiating ACS from baseline noise a difficult proposition. The standard concept of utilizing the 99th percentile, or the troponin level below which 99% of a healthy cohort will fall, is only moderately more effective. In this same trial, using the 99th percentile, Reichlin et al raised the specificity of the assay to 80% but at the cost of missing 5% of the acute myocardial infarctions (2). To better distinguish this baseline troponin levels from the disease state in question, a delta troponin approach has been proposed (4). The delta troponin strategy asserts that rather than using an absolute threshold from which to base your decisions on, trending the changes in the troponin level with serial troponin measurements may be a more accurate method of differentiating ACS from this baseline troponinemia. Given that the high-sensitivty assays are capable of measuring levels of troponin exponentially smaller than our standard assays, they seem to be the ideal tool for the delta strategy.
Unfortunately things are not so simple. The second concern with the use of the high-sensitivity troponin is the inherent imprecision of the assays themselves. All assays, both standard and high-sensitivity, will demonstrate a certain degree of test-retest variability. At high values of serum troponin, this variability is inconsequential but at the very low levels with which we are attempting to trend incremental changes, this imprecision becomes increasingly more important (7). The 10% coefficient of variation is a measurement attempting to quantify this variability. This is the serum troponin level below which the variability of the assay is greater than 10%. Simply put, it is the level at which the imprecision of the assay becomes clinically significant (6). The accuracy of assays in which the level of the 99th percentile is below that of the 10% coefficient of variation will suffer (2).Similarly as you attempt to measure smaller absolute changes in troponin between serial measurements, this imprecision will undermine your efforts (3).
These flaws are illustrated nicely in an article published in Circulation in 2011, in which Reichlin et al attempt to validate the delta troponin strategy. The authors compare the absolute and relative changes of two troponin assays at 1 and 2 hours after presentation to the “gold standard“ of the diagnoses of myocardial infarction made by 2 cardiologists using standard troponin assays drawn at six and nine hours after presentation. Using an absolute change of 0.007 micrograms/L at 2 hours after presentation, the hs-TnT assay had a sensitivity of 89% and a specificity of 93%. In the subgroup of patients who presented with initial troponin levels above the 99th percentile, the delta troponin methods produced a sensitivity and specificity of 90% and 87% respectively. In the subgroup who presented with an initial troponin level below the 99th percentile, the delta troponin provided a negative predictive value of 100%. Unfortunately in this group a positive delta troponin meant very little, providing a positive predictive value of only 22%. Compared to the diagnostic characteristics of a single troponin measurement taken at presentation (sensitivity of 95% ,specificity of 80%, NPV of 99% and PPV of 50%), very little is gained from this delta troponin strategy (2).
Thus you are left in perpetual uncertainty. Unsure if the low level of troponin is the early rise associated with myocardial necrosis or a baseline troponinemia present in so many patients. Likewise you are equally uncertain if the change in levels at 2-hours is further confirmation of infarction or simply due to the random imprecision of the assay itself. In a recently published article by Pretorius et al, these authors have turned to statistical modeling in an attempt to resolve this ambiguity (5). The reference change value (RCV) is a mathematical concept contrived to combat this variability. It is a calculation that takes into account this analytical imprecision, the estimates of within-subject biological variation and calculates the amount of change above which is not likely to be due to chance alone (8). Pretorius et al have attempted to apply this concept to the delta troponin strategy (5). Using the RCV the authors calculate a z-score and propose a threshold of 1.96 above which the delta troponin measurements should be considered positive. This is the level that corresponds to a p-value of 0.05 or a 5% probability that the change in troponin level was due to chance. This strategy of course speaks to the more nerdy among us but how well does it perform clinically?
Using a prospectively gathered cohort of Emergency Department chest pain patients, Pretorius et al retrospectively applied their z-score, comparing it’s performance to absolute and relative change of the 2-hour troponin assay levels. As a tool to rule in myocardial infarction the z-score method outperformed both the absolute and relative changes methods. Among the three high-sensitivity assays examined, the z-score's specificity was found to be 94%, 97%, and 98% respectively, each one outperforming their absolute and relative change counterparts. Unfortunately when using the z-score, the sensitivities of each assay (79%, 77%, and 69% respectively) suffered. Interestingly most of the AMI patients, which the z-score missed, had initial troponin levels well above the diagnostic threshold of the 99th percentile and would probably have not required a second troponin value to confirm the diagnosis. Of note, this was a retrospective application of this statistical method and it will have to be tested prospectively on a novel cohort before it can be applied clinically. In addition, its performance was evaluated in an undifferentiated chest pain population. Where the z-score may potentially provide benefit is in the clinically ambiguous patients.
The most obvious question is how clinically relevant is any of this? The major weakness of all these trials is that each of the various assays and techniques which were evaluated, were done so in a vacuum. What is important to the Emergency Physician is not how these high-sensitivity assays perform in isolation but how much they add to our clinically evaluation and EKG findings. The majority of the ACS cases will be identified by clinical exam and EKG. When these factors are taken into consideration, the troponin assay provide very little additional diagnostic utility. Than et al utilized the strategy of clinical risk stratification in combination with EKG and serial troponin measurements in 2-hours increments (9). In doing so, the authors identified 99.7% of 30-day major adverse cardiac events (MACEs). Taken together TIMI risk score and EKG identified 98.3% of these events without the help of the troponin assay. The added value of the standard assay was minimal. When a high-sensitivity troponin assay was applied to the same cohort it added no statistical or clinically relevant diagnostic utility (10).
Up to this point, the benefits that high-sensitivity assays provide has been abstract in nature. As far back as the publication of Dr. Hector Pope's trial in NEJM, Emergency Physicians were accurately identifying the large majority of ACS patients. These physicians ultimately missed 19 out 10,689 patients (11). To improve on this performance would be a Herculean task. Increasing the sensitivity of our troponin assays does not seem to be the answer. Using minute changes in troponin values to guide our treatment is fraught with uncertainty. These changes are equally likely to be due to random chance as they are to be caused by true myocardial necrosis. Like the subatomic particle, discrete troponin values and their respective momentum can only by reported in varying degrees of uncertainty. After all, physicist Werner Heisenberg wrote when describing the uncertainty principle, In the sharp formulation of the law of causality– “if we know the present exactly, we can calculate the future”-it is not the conclusion that is wrong but the premise.
1. Lippi G, Cervellin G. Do we really need high-sensitivity troponin immunoassays in the emergency department? Maybe not. Clin Chem Lab Med. 2014 Feb 1;52(2):205-12.
2. Reichlin et al. et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med. 2009;361(9): 858-867.
3. Mueller M, Biener M, Vafaie M, et al. Absolute and relative kinetic changes of high-sensitivity cardiac troponin T in acute coronary syndrome and in patients with increased troponin in the absence of acute coronary syndrome. Clin Chem 2012; 58: 209–218.
4. Reichlin et al. Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction. Circulation. 2011 Jul 12;124(2):136-45.
5.Pretorius et al. Towards a consistent definition of a significant delta troponin with z-scores: a way out of chaos? Eur Heart J Acute Cardiovasc Care. 2013 Dec 17.
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7. Panteghini et al. Evaluation of Imprecision for Cardiac Troponin Assays at Low-Range Concentrations. Clinical Chemistry. February 2004 vol. 50 no. 2 327-332
8. Fraser, CG. Reference change values. Clin Chem Lab Med. 2011 Sep 30;50(5):807-12.
9. Than et al. 2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial. J Am Coll Cardiol. 2012 Jun 5;59(23):2091-8
10. Cullen et al. Validation of High-Sensitivity Troponin I in a 2-Hour Diagnostic Strategy to Assess 30-Day Outcomes in Emergency Department Patients With Possible Acute Coronary Syndrome. J Am Coll Cardiol, Volume 62, Issue 14, 1 October 2013, Pages 1242-1249
11. Pope et al. Missed Diagnoses of Acute Cardiac Ischemia in the Emergency Department. N Engl J Med 2000; 342:1163-1170 April 20, 2000