Background:

A majority of patients presenting with chest pain do not present with ST Elevation on initial ECG. In these patients, cardiac biomarkers play a major role in diagnosing myocardial infarction.

The assay of choice since the late 1990’s has been the Troponin assay, which can take 3-4 hours to rise to detectable levels. These traditional troponin assays are only 70-85% sensitive, requiring serial sampling of troponin at 3-6 hours, which prolongs stay and may lead to ED overcrowding. (1)

The high sensitivity troponin was recently approved for use in the United States by the FDA, in the form of 2 assays, the Troponin I test and the Troponin T test.  These assays are able to detect troponin levels in at least 50% of healthy individuals.  They are also quite precise with around 10% variation. By lowering the cutoff of a positive troponin assay, you get a higher sensitivity.   Unfortunately, this will also increase the number of false positives., with previous studies showing the false positive rate to be 50%.(2)Despite this limitation, its high negative predictive value and negative likelihood ratio can potentially make it useful in ruling out disease..

We analyzed 3 papers describing probable strategies incorporating HS-T in risk stratification of chest pain.

Reference 1: The Use of Very Low Concentrations of High-sensitivity Troponin T to Rule Out Acute Myocardial Infarction Using a Single Blood Test.(3)

Study Design: Prospective observational cohort study

Rule out strategy: Single high sensitivity troponin T on admission below the limit of detection (LOD 5ng/L) with negative EKG

Results valid?: Yes. This is an appropriate study design and population for the test in question. The results are in agreement with multiple smaller retrospective studies using high sensitivity troponin showing >99% NPV.

Results?:  37% of patients with no EKG ischemia and concentration of high sensitivity troponin below the level of detection could be safely discharged (NPV=99.6%) with a low expected MACE rate of 1.3% (1 death, 3 revascularizations). This could expand to 50% of patients if include age <65yo.

Key limitations: Original study funded by Roche, the maker of high sensitivity troponin test. Also, the reported rate of 1.3% major cardiac events within 30 days did not include revascularizations performed on initial hospitalization which would increase MACE rate to 3.4%, though this is a subjective measure.

Bottom line:  A single concentration of high sensitivity troponin on admission below the limit of detection combined with negative EKG can allow the rapid, safe exclusion of myocardial infarction in 37% of patients.

Reference 2: The HEART score with high-sensitive troponin T at presentation: ruling out patients with chest pain in the emergency room.(4)

Study Design: single center retrospective observational study

Rule-Out Strategy: HEART score (<3) incorporating HS-T and changes to EKG criteria.

Modified HEART Score:

 

Are the Results Valid? Yes, with limitations. The modified HEART score was not used to stratify patients, as this score was calculated retrospectively. There was no blind comparison with an independent gold standard, as there was no control. Two variables were changed from the original HEART score, so it would be hard to directly compare the effect of high-sensitivity troponins.

Results: 512 (37%) patients with a modified HEART score of less than or equal to 3 had no occurrences of a major adverse cardiac event at 30 and 180 days.  With a HEART score threshold of 3, the sensitivity and negative predictive value of this rule out test were 100%,.

Key Limitations: This was a retrospective single center study involving mostly Caucasian patients.  Thus, there was no real control and generalization of results can be difficult.

Bottom Line: A modified version of the Heart Score using high-sensitivity troponin was able to retrospectively stratify patients complaining of chest pain at a single center into low, intermediate, and high-risk categories. None of the low risk (MHS </= 3) patients went on to have a MACE within 180 days, giving this test a sensitivity of 100%, and allowing it to be an effective rule out test for low risk chest pain in the ED.

Reference 3: Multicenter Evaluation of a 0-Hour/1-Hour Algorithm in the Diagnosis of Myocardial Infarction with High-Sensitivity Cardiac Troponin T. (5)

Study Design: Prospective observational cohort study

Rule out strategy: High-sensitivity Troponin-T at zero hours and one hour <12ng/L and ΔTroponin <3ng/L

Results valid?: Yes. The study was applied to an appropriate patient population with multicenter study design. Overall findings (sensitivity, NPV) correlate well with similar studies.

Results?:  63.4% of patients fell into the rule-out category and were safe for discharge (NPV=99.1). There were only 7 false-negatives in the rule-out group of >800 patients and only 1 received percutaneous coronary intervention.

Key limitations: ΔTroponin (in the positive or negative direction) can be due to ischemia or due to variance of the test itself. A sizeable (22.5%) portion of patients still fall into an indeterminate category that need further evaluation prior to potential discharge. Two tests must be spaced one-hour apart, resulting in slightly longer ED stays compared to a single troponin algorithm. EKG findings were not included to aid in decision making.

Bottom line:  A Δtroponin algorithm at 0- and 1-hour allows for the exclusion of AMI in nearly two-thirds of ED patients presenting with chest pain.

Comparison of different risk stratification strategies

Single HsT as a rule out:

A meta-analysis (6) of this strategy showed a pooled sensitivity of 97.4%. The miss rate is 2.6%.  Likely, a single test without input from ECG/ history/ risk factors will miss an unacceptable number of acute MI’s.

Combining HsT with a Clinical Prediction Score

A number of trials has investigated incorporating the HS-T into various risk prediction scores. One recent trial compared 5 risk scores with HS-T(7) In this study, there was a very low prevalence of disease (8%). Use of risk prediction scores all performed similarly. This study showed that by using a prediction score, one may potentially be able to rule out >30% of patients and keep NPV >99.5%. Our review of the modified HEART score as detailed above shows that this method can safely rule out 37% of patients with a NPV and sensitivity of 100%.

Utilizing a clinical prediction score with the HS-T has the benefit of applying a tool we already use (The HEART score), with a new test. The added benefit is that there is no need for serial sampling. However, this only allows for the safe discharge of – 30-40% of patients, which is quite low. When compared to the initial validation of the Heart score (8), it identified a similar proportion of low risk individuals (36.4%) with a superior NPV and – LR. If you were previously using the HEART score, using the HS-T will conceivably allow you to discharge patients 3 hours earlier than previously without any detriments to the quality of your test.

HST plus ECG:

One of the arguments against using risk prediction scores is that the data behind using history and risk factors is sparse. Many studies have shown the poor predictive value of history. (9) Other atypical symptoms also do not helpfully rule out disease. Cardiac risk factors have been shown to be poor predictors of ACS in patients over 40 (10)The benefit of removing these aspects from the risk prediction tool is that it makes the calculation more standardized and generalizable by taking out any subjective nature. This has been studied in a retrospective study which had a sensitivity of 100%. (11) The large, multi-center prospective study by Body that was reviewed shows that using the limit of detection (LOD) and ECG can safely risk stratify 37% of patients with a NPV of 99.6%. This performs similarly to the HEART score algorithm, but requires a lower cutoff for troponin values. One benefit of the HEART score algorithm is that it allows variability in HS-T levels.

Serial HsT 0/1 hr (delta HsT):

Another potential strategy is serial enzyme testing at 0-1 hours.   The reviewed article from Annals of Emergency Medicine was able to rule out 63.4% of patients with a NPV 99.1% and a Sensitivity 96.7%.  (5)Another recent article compared 4 strategies and found this strategy to be able to safely rule out 52% of patients with a sensitivity of 98.4% .(12)

The issues of using serial sampling is that, while these tests are precise, they all have a coefficient of variance of 10%. It is hard to know if a rise in troponin is due to ischemia, or the limits of the test. A higher delta Troponin helps eliminate this issue, but will still capture a significant number of false positives.  These two papers revealed that a high (>50%) percentage of patients could be safely ruled out using this approach; however, both papers had a lower sensitivity and negative predictive value than ideal, as using the HEART score with 2 traditional troponin tests achieves a higher negative predictive value at only the expense of 3 hours of waiting between clinical samples.

Overall Summary:

Overall, all three rule-out algorithms utilizing high-sensitivity troponin are valid and demonstrate very high sensitivity and negative predictive values. However, each of the papers have limitations as outlined above including relatively low specificity. Compared to a single troponin plus EKG or a single troponin plus clinical decision tool (HEART score), a Δ1-hour strategy allows for the greatest percentage of patients to be discharged from the ED while only increasing length-of-stay by the one hour between each lab test. This Δtroponin algorithm placed nearly two-thirds of patients into the rule-out category, approximately double the other two algorithms. One concern for the Δtroponin algorithm is the lower NPV and sensitivity.  While not formally studied in the above articles, utilization of EKG findings (as is done in all emergency departments) and possibly a clinical decision tool such as the HEART score in conjunction with a 0- and 1-hour Δtroponin algorithm may result in even higher sensitivity and NPV.

The choice on which strategy to utilize is complex, and should be made with consideration of the unique patient population in your department. All 3 strategies are safe to use, if incorporated in a standardized fashion throughout your Emergency Department.

Authors: Alexander Beyer, MD, Andrew Adan, MD, John Joseph, MD, Mohammad Khan, MD.

Faculty Reviewer: Brendan Munzer, MD

References:

  1. Keller T, Zeller T, Peetz D, Tzikas S, Roth A, Czyz E, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med. 2009;361(9):868-77.
  2. Body R, Carley S, McDowell G, Jaffe AS, France M, Cruickshank K, et al. Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a high-sensitivity assay. J Am Coll Cardiol. 2011;58(13):1332-9.
  3. Body R, Mueller C, Giannitsis E, Christ M, Ordonez-Llanos J, de Filippi CR, et al. The Use of Very Low Concentrations of High-sensitivity Troponin T to Rule Out Acute Myocardial Infarction Using a Single Blood Test. Acad Emerg Med. 2016;23(9):1004-13.
  4. Santi L, Farina G, Gramenzi A, Trevisani F, Baccini M, Bernardi M, et al. The HEART score with high-sensitive troponin T at presentation: ruling out patients with chest pain in the emergency room. Intern Emerg Med. 2017;12(3):357-64.
  5. Mueller C, Giannitsis E, Christ M, Ordonez-Llanos J, deFilippi C, McCord J, et al. Multicenter Evaluation of a 0-Hour/1-Hour Algorithm in the Diagnosis of Myocardial Infarction With High-Sensitivity Cardiac Troponin T. Ann Emerg Med. 2016;68(1):76-87.e4.
  6. Zhelev Z, Hyde C, Youngman E, Rogers M, Fleming S, Slade T, et al. Diagnostic accuracy of single baseline measurement of Elecsys Troponin T high-sensitive assay for diagnosis of acute myocardial infarction in emergency department: systematic review and meta-analysis. Bmj. 2015;350:h15.
  7. Carlton EW, Khattab A, Greaves K. Identifying Patients Suitable for Discharge After a Single-Presentation High-Sensitivity Troponin Result: A Comparison of Five Established Risk Scores and Two High-Sensitivity Assays. Ann Emerg Med. 2015;66(6):635-45.e1.
  8. Backus BE, Six AJ, Kelder JC, Bosschaert MA, Mast EG, Mosterd A, et al. A prospective validation of the HEART score for chest pain patients at the emergency department. Int J Cardiol. 2013;168(3):2153-8.
  9. Swap CJ, Nagurney JT. Value and limitations of chest pain history in the evaluation of patients with suspected acute coronary syndromes. Jama. 2005;294(20):2623-9.
  10. Han JH, Lindsell CJ, Storrow AB, Luber S, Hoekstra JW, Hollander JE, et al. The role of cardiac risk factor burden in diagnosing acute coronary syndromes in the emergency department setting. Ann Emerg Med. 2007;49(2):145-52, 52.e1.
  11. Bandstein N, Ljung R, Johansson M, Holzmann MJ. Undetectable high-sensitivity cardiac troponin T level in the emergency department and risk of myocardial infarction. J Am Coll Cardiol. 2014;63(23):2569-78.
  12. Boeddinghaus J, Nestelberger T, Twerenbold R, Wildi K, Badertscher P, Cupa J, et al. Direct Comparison of 4 Very Early Rule-Out Strategies for Acute Myocardial Infarction Using High-Sensitivity Cardiac Troponin I. Circulation. 2017;135(17):1597-611.

 

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Alex Beyer, MD

EM Resident Class of 2019

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