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Clinical interpretation of high sensitivity troponin T
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www.elsevier.es/medicinaclinica
Review
Clinical interpretation of high sensitivity troponin T夽 Aitor Alquézar Arbé a,∗ , Miguel Santaló Bel a , Alessandro Sionis b a b
Servicio de Urgencias, Hospital de Sant Pau, Barcelona, Spain Unidad Coronaria, Hospital de Sant Pau, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 27 September 2014 Accepted 13 November 2014 Available online xxx Keywords: Chest pain Acute coronary syndrome Acute myocardial infarction without ST elevation High sensitivity cardiac troponin T
a b s t r a c t Determination of cardiac troponin (cTn) is necessary for the diagnosis of acute myocardial infarction without ST segment elevation. However Tnc can be released in other clinical situations. The development of high-sensitive cTn T assays (hs-cTnT) improves the management of patients with suspected acute coronary syndrome. Here, we provide an overview of the diverse causes of hs-cTnT elevation and recommend strategies for the clinical interpretation of the test result. ˜ S.L.U. All rights reserved. © 2014 Elsevier Espana,
Interpretación clínica de la determinación de troponina T de elevada sensibilidad r e s u m e n Palabras clave: Dolor torácico Síndrome coronario agudo Infarto de miocardio sin elevación del segmento ST Troponina T cardíaca de elevada sensibilidad
La determinación de troponina cardíaca (Tnc) es necesaria para el diagnóstico del infarto de miocardio sin elevación del segmento ST, pero existen otras situaciones clínicas donde se observan valores aumentados. El desarrollo de los nuevos inmunoanálisis para determinar Tnc T, denominados de elevada sensibilidad (TnTc-es), han supuesto un avance en el tratamiento de los pacientes con sospecha de síndrome coronario agudo. En este trabajo se revisan brevemente las diferentes causas de elevación de TnTc-es, así como los factores determinantes para su correcta interpretación, enfatizando en el contexto clínico del paciente. ˜ S.L.U. Todos los derechos reservados. © 2014 Elsevier Espana,
Acute coronary syndrome Acute coronary syndrome (ACS) is the most common clinical manifestation of ischaemic cardiomyopathy. Ischaemic cardiomyopathy is among the leading causes of morbidity and mortality in Spain.1 ACS is a group of different clinical manifestations related to acute myocardial ischaemia, which are unstable angina, myocardial infarction (MI) and sudden death.2 The physiopathological background common to the vast majority of cases of ACS is atheromatous plaque rupture. This class of
夽 Please cite this article as: Alquézar Arbé A, Santaló Bel M, Sionis A. Interpretación clínica de la determinación de troponina T de elevada sensibilidad. Med Clin (Barc). 2016. http://dx.doi.org/10.1016/j.medcli.2014.11.004 ∗ Corresponding author. E-mail address: [email protected] (A. Alquézar Arbé).
infarction is called type 1 MI.3 However, there are situations that involve an imbalance between circulatory supply and myocardial demand. This circumstance normally occurs when there is a stable atherosclerotic plaque that significantly decreases the arterial lumen, causing a situation of hypotension, anaemia, infection or tachyarrhythmia that decreases the oxygen supply to cardiac muscle cells. This is the aetiopathogenesis of type 2 MI.3 ACS generally presents as non-traumatic chest pain. Nontraumatic chest pain represents approximately 5% of all emergency department (ED) visits, and is the second most common reason for visiting.4 A substantial proportion of patients with chest pain do not have ACS.5 Often, these patients are admitted to the ED to perform serial monitoring of biomarkers, an electrocardiogram (ECG) and, in certain cases, function tests of induction of myocardial ischaemia.6 This strategy, though safe, is inefficient and promotes ED overcrowding. On the other hand, it has been estimated that up to 2% of patients with ACS are discharged with an incorrect diagnosis.7
˜ S.L.U. All rights reserved. 2387-0206/© 2014 Elsevier Espana,
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The patient’s clinical history, ECG and biomarkers of myocardial injury are essential for an early diagnosis, prognosis and selection of treatment for ACS.8 Biomarkers are mainly valuable in cases of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and cases in which the ECG cannot be interpreted.9 In accordance with the third universal definition of myocardial infarction,3 the diagnosis of MI is based on observation of evolutionary increases/decreases in the determination of biochemical markers. Observing evolutionary changes involves performing serial determinations. In the case of cardiac troponin (cTn), this should be done 3–6 h after the first determination, with at least one determination greater than the 99th percentile of the reference population (p99). This observation should be accompanied by an appropriate clinical context, appropriate symptoms or other consistent findings in the ECG, imaging tests or autopsy.
Cardiac troponin in acute coronary syndrome At present, cTn is the biomarker of choice to be determined in the diagnosis of MI, and additional determination of other markers such as, for example, creatine kinase, is not advised.3 Unlike other markers, cTn is a cardiac structural protein, and therefore a biomarker curve rather than an enzyme curve should be referred to. It has 3 subunits: T, I and C. Immunoassays have been designed to detect 2 of these–T and I–in plasma. Evaluation of the diagnostic usefulness of a biomarker of myocardial necrosis varies according to its intended use. A rule-in diagnosis of non-ST segment elevation myocardial infarction (NSTEMI) should be rapid and precise. For this purpose, high diagnostic sensitivity is required. However, sensitivity should be accompanied by reliability in ruling out NSTEMI. A good diagnostic test should offer a good combination of both characteristics; to this end, the cut-off points used for diagnosis may be modified to increase sensitivity or specificity. The use of the p99 as a criterion to identify MI means that a percentage of false positives of 1% is acceptable in clinical practice.10 In the context of NSTEMI, the cost of a false negative, that is to say, undiagnosed NSTEMI, is assumed to be greater than the cost of doing additional tests on false positives,11 and therefore the diagnostic sensitivity of tests for its diagnosis is prioritised. Despite the existing broad consensus on the role of cTn in identifying MI, several factors contribute to creating confusion on the use of the biomarker:
1. The presence of various cTn immunoassays on the market with different levels in the p99. This occurs both when cTnT is compared with cTnI and when different methods for cTnI are compared with each other. 2. The fact that some laboratories report different clinical decision points classified as “normal”, “indeterminate” or “suggestive” of myocardial injury. Currently, if cTn is measured with highsensitivity methods (hs-cTn), there should be no “positive”, “negative” or “indeterminate” results; instead, there should be results greater than or less than the p99. 3. The indiscriminate use of cTn in broad populations with very different probabilities of having ACS. Levels of cTn are extremely specific to myocardial injury; however, myocardial injury is not at all unique to ACS. Therefore, clinical guidelines stress that cTn levels should be interpreted in relation to the patient’s signs and symptoms. As a result, elevated cTn levels in patients with sepsis, hypertensive crises, pulmonary embolisms, etc. are indicative of myocardial injury, but not of MI, and should not be used to indicate treatments specific to ACS.
Differential diagnosis of increased levels of cardiac troponin There are increased cTn levels in clinical situations other than that of type 1 MI. Increased levels may be chronic or acute and are very normal in day-to-day practice. More than 50% of patients who visit owing to chest pain have high cTn levels. However, the majority of them do not have type 1 MI.12
Chronically increased cardiac troponin Chronically increased cTn is observed in various diseases, both when it is measured by conventional methods and when it is measured by high-sensitivity methods. This elevated cTn characteristically remains stable without subsequent increases or decreases. The most common causes are: - Stable coronary heart disease: Up to 97% of patients with stable coronary heart disease with preserved left ventricular ejection fraction have detectable levels of cTn measured with highsensitivity immunoassays; in 11% of cases, these values exceed the p99. Increased hs-cTn is associated with a poor prognosis with a risk of heart failure and cardiovascular death.13 - Chronic heart failure (CHF): Levels of hs-cTn are detectable in 92% of patients with CHF, and in many cases levels exceed the p99 of reference. As in the previous case, increased highsensitivity cardiac T troponin (hs-cTnT) is associated with increased mortality.14 - Diabetes: These patients have elevated levels of hs-cTn, a circumstance that significantly increases the risk of cardiovascular episodes.15 - Pulmonary hypertension: Elevated hs-cTn levels are detected in approximately 10% of these patients; the increase is associated with increased mortality after 6 months.16 - Kidney failure. It is very normal to detect increased hs-cTn (just as this was detected when cTn was measured with conventional methods) in patients with decreased kidney function.17 In these patients, cTn levels have a proportional inverse relationship to creatinine clearance figures and are associated with greater mortality.18,19 In the case of hs-cTn, elevated levels of hscTn have been shown to be detected in virtually 100% of patients in chronic haemodialysis; these elevated levels are in turn associated with an elevated risk of death after 2 years.20 - Age: Levels of cTn (conventional method) and hs-cTn increase with age. It is normal to see elevated values of cTn (both cTnI and cTnT) in elderly patients (>70 years) without NSTEMI. It is unknown whether these increased cTn values with age are physiological or reflect subclinical disease processes (deterioration of the myocardium and/or kidney function, etc.), but in practice they decrease the specificity of the cTn measure and this makes the values obtained harder to interpret.21 Acute increases not associated with type 1 myocardial infarction In some clinical situations, increases/decreases are observed in serial measures of cTn in the absence of type 1 MI. These signs and symptoms may co-exist in the clinical picture (for example, evolutionary increases in cTn in a patient with stable coronary heart disease who has acute heart failure) and make MI harder to diagnose. The main clinical situations in which this circumstance may occur are21 : - Myopericarditis: cTn values are very variable in these patients, and are associated with the underlying inflammatory process in the myocardium.22 It is not clear whether they are correlated with a poor prognosis.23
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In summary, elevated cTn levels are not synonymous with MI; there are many clinical situations in which elevations in cTn are observed in the absence of MI. High-sensitivity cardiac T troponin Recently, new immunoassays, called high-sensitivity immunoassays, have been introduced in clinical practice to determine cTn. They were developed by modifying some of the characteristics of the test to optimise its diagnostic yield. The designation “high-sensitivity” should be reserved for those immunoassays that are capable of determining the p99 with a coefficient of variation < 10% and that are capable of measuring cTn levels in at least 50% of a healthy population of reference. These are the 2 characteristics that distinguish them from earlier immunoassays.37 hs-cTnT meets these requirements.hs-cTnT
Delay in diagnosis
50 40
Troponin T (ng/l)
- Stress-induced cardiomyopathy (takotsubo cardiomyopathy): cTn values tend to be more modestly elevated than in MI. It is not clear whether they are correlated with a poor prognosis.24 - Pulmonary embolism: It is very normal to detect elevated cTn levels in these patients. These elevated levels are indicative of right ventricular dysfunction and are associated with increased mortality.25 Currently, it is recommended that cTn be determined in these patients for their risk stratification26 and to identify those who could benefit from intravenous fibrinolytic treatment.23 - Tachyarrhythmias: In these situations, increased levels of cTn are commonly observed, even in cases in which there is no associated coronary heart disease. In atrial fibrillation, increased cTn is independently associated with the risk of ischaemic stroke and death of cardiovascular origin.27 - Acute heart failure (AHF): It is also common to find increased cTn levels in AHF; this is related to advanced stages of underlying cardiomyopathy and greater mortality.28,29 - Coronary vasospasm: This may involve acute increases in cTn. It has been reported that 25% of patients with suspected ACS and a normal coronary angiography have elevated cTn levels. Among these patients, 74% have positive provocation tests for coronary spasm.30 - Electric cardioversion/defibrillation: Both manoeuvres may cause modestly increased levels of cTn that are more significant in patients with left ventricular hypertrophy.31 - Non-cardiac surgery: Increased levels of cTn have been reported in 12% of postoperative non-cardiac surgery patients. There is a significant association between maximum cTn value three days after a procedure and mortality after 30 days.32 - Sepsis: Increased cTn is very common in patients with serious sepsis or septic shock; often these are patients without associated coronary heart disease. Their increased cTn doubles their risk of mortality.33 This relationship to mortality has also been reported in patients with other serious diseases admitted to intensive care units. - Cerebrovascular accident: Increased levels of cTn have been observed in ischaemic and haemorrhagic stroke and subarachnoid haemorrhage.34 cTn figures are correlated with the severity of neurological injury and of underlying cardiovascular abnormalities. - Trauma: After direct chest trauma, it is normal to see increased cTn; however, only a minority of patients have cardiovascular complications.35 - Strenuous physical exertion: Increased levels of cTn have been reported in long-distance runners after high-intensity and extended-duration exercises. These increases do not have any clinical implications in the short term, but their long-term clinical significance is unknown.36
3
35
4th G-cTnT; CV≤10%
30 25 20 15 10
99th percentile hs-cTnT; CV≤10%
5 0 0
2
4
6
8
Hours post-start of AMI Fig. 1. Improvement in sensitivity and early diagnosis with high-sensitivity T troponin. CV: coefficient of variation; MI: myocardial infarction; hs-cTn: highsensitivity cardiac T troponin; 4thG-cTn: fourth-generation cardiac T troponin.
improves early diagnosis of MI compared to cTnT measured with conventional methods for various reasons (Fig. 1): - An elevated hs-cTnT value at the time of admission has greater diagnostic sensitivity for MI, especially if the determination is made within the first 2 h of the onset of symptoms.38 - The first determination of hs-cTnT rules out a diagnosis of NSTEMI in some patients.39 - The use of hs-cTnT decreases the wait time before making the second determination to 3 h from the first determination, instead of the 6–9 h that were recommended for cTn.40 - hs-cTnT identifies 22% of NSTEMIs that were diagnosed as unstable angina using cTnT. This group of small-size NSTEMIs that are only identified by cTnT has an elevated risk of mortality (16% at 30 months).41 The improved sensitivity and negative predictive value obtained with hs-cTnT, however, is associated with decreased specificity and positive predictive value.42 In practice, this results in increased numbers of patients with hs-cTnT levels greater than the reference p99.43 In the general population, 2% of individuals are observed to have moderately elevated hs-cTnT levels, greater than the p99.44 In the population that goes in to EDs, this proportion is more elevated,45 since these patients have many of the above-mentioned causes of chronically elevated cTn levels. As a result, in the majority of suspected cases, NSTEMI cannot be ruled in or ruled out by means of a single laboratory determination, except when hs-cTnT is undetectable (<3 ng/l) after 3 or more hours of evolution of the symptoms indicative of angina – this rules out NSTEMI39 – or the initial value is very elevated, in which case the probability of NSTEMI is very high. Evolutionary increases or decreases in high-sensitivity cardiac T troponin (delta value) For NSTEMI to be diagnosed, cTn must be measured in at least 2 serial samples over time. This will allow the kinetics of increase or decrease, called a delta value, () to be detected. As mentioned, kinetics will distinguish between acute cTn increases (this is the case of NSTEMI) and chronic increases (these may show levels greater than the p99, but do not show evolutionary changes). Successive definitions of MI have recommended the use of the value of cTn, but without making it clear whether this should be expressed in relative or absolute terms or what its optimal magnitude should be. Optimal delta value There is no consensus on the optimal value. Currently, there is a tendency to use the relative value ≥ 20% proposed by some
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Table 1 Studies that showed the best diagnostic yield of the absolute delta value. Author
Trial
Time
criterion
Yield (AUC)
p
False negative
Reichlin et al.47 , n = 836
hs-cTnT (Roche)
0–2 h
7 ng/l 30% 20 ng/l 117% 9.2 ng/l 20% 30 ng/l NA 7 ng/l 30%
0.95 0.76 0.95 0.72 0.90 0.75 0.90 0.79 0.95 0.75 0.97 0.75 0.96 0.75 NA
<0.01 <0.01
10% 7%
<0.01
10%
<0.01
23%
<0.01 <0.01 <0.01
NA
NA
0.93 0.75 0.93 0.78
<0.01
12% 26% NA
cTnT (Siemens) Mueller et al.48 , n = 784
hs-cTnT (Roche)
0–<6 h
Cullen et al.49 , n = 874
cTnI (Beckman Coulter AccuTnl)
0–2 h
hs-cTnT (Roche)
0–2 h
50
Irfan et al. , n = 830
hs-TnT (Beckman Coulter) hs-cTnI (Siemens) 51
Bjurman et al.
hs-cTnT (Roche)
0–6 h
Wildi et al.52 , n = 943
hs-cTnI (Beckman Coulter)
0–2 h
9 ng/l 20% 11 ng/l 86% 6 ng/l 82%
hs-cTnI (Siemens)
<0.01
AUC: area under the curve; criterion: delta criterion used to diagnose myocardial infarction; false negative: percentage of false negatives with the exclusive application of the criterion used; NA: not available; cTnI: conventional cardiac troponin I; hs-cTnI: high-sensitivity cardiac troponin I; cTnT: conventional cardiac troponin T; hs-cTnT: high-sensitivity cardiac troponin T.
experts.46 However, since the development of high-sensitivity methods to measure cTn, there are 2 clinical situations in which the use of an absolute value would have a better diagnostic yield than that of a relative value. In the case of hs-cTnT, this would involve: - Patients without MI whose serial determinations have levels close to that of the p99; in these cases, a small change in levels may involve an elevated percentage change and cause a false positive for MI. - Patients with evolved MI (when the hs-cTnT release curve is found to be in a stable area) may have elevated serial hs-cTnT levels, but only small percentage changes, giving rise to a false-negative diagnosis of MI. Various studies have shown a better yield for an absolute value47–52 (Table 1). These studies compared different intervals of time between determinations (0–1 h, 0–2 h, 0–3 h, 0–6 h). Taken together, an interval of 2 h after the first determination was the one that obtained the best diagnostic yield, although one study obtained this 6 h after the first determination.48 Although the majority of studies had elevated diagnostic yields (AUC > 0.900), all of them had a proportion of patients in whom MI had not been diagnosed using this criterion exclusively. Studies have recommended optimising the yield of the absolute value based on other determinants, such as hs-cTn value in the first determination,47 time from the onset of symptoms up to the first determination49 and characteristics of the population cared for.48 However, despite the potentially improved diagnostic yield for MI that they offer, these strategies are hard to implement in clinical practice, especially in the ED, where patients in whom they should be applied are most commonly cared for. Interpretation of the delta value Regardless of whether an absolute or percentage value is used, there are various circumstances to be taken into account to properly define and interpret the value:
-
-
-
-
-
and specificity. A low value will offer elevated sensitivity and low specificity. No MI will remain undiagnosed, but there will be many false positive diagnoses. This strategy is valid for an emergency doctor, but uncomfortable for cardiology specialists, as they prioritise specificity to diagnose NSTEMI and optimise a patient’s clinical approach.45 Each hs-cTn immunoassay should be validated for its best absolute and percentage value.53 The value should be analysed based on the time between the onset of symptoms and the first determination. In cases of short times of evolution, the established criterion is more likely to be met, but patients with MI who seek treatment late may have low levels owing to starting from very elevated hs-cTn levels.51 The interval of time between determinations used to evaluate the value must be uniform because it has not been fully demonstrated that cTn release after MI remains constant over time.45 However, there are data that show constant release in the first few hours of evolution of MI.50 It is advisable to evaluate the value systematically in all patients and clinical circumstances. The value should be calculated in patients with an unequivocal diagnosis of MI or non-MI. Some studies that evaluated the optimal hs-cTnT value were based on MI diagnosed with conventional cTn that did not identify small-size MI and, therefore, distorted the diagnostic specificity of hs-cTnT,54 or alternatively, on MI diagnosed by any hs-cTnT value greater than the p99, but without changes in kinetics.51 The presence of a value does not distinguish between type 1 and type 2 MI.53 The presence of a value is not at all specific to MI, since it may be seen in other acute clinical situations (for example, pulmonary embolism, myocarditis and sepsis). The value diagnostic of MI may be established to be different from the value of other causes of cardiac injury, but this theory has not been demonstrated. Persistently high levels of any hs-cTn are associated with a poor prognosis, even if a significant value is not observed.51
Conclusions - Studies that identified the best value47–52 were based on analysis of receiver operating characteristic curves. This statistical approach grants the same weight to both diagnostic sensitivity
Availability of hs-cTn measurement improves the diagnostic strategy for patients with chest pain in the ED.
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1. hs-cTnT allows MI to be ruled out earlier in the majority of patients who visit the emergency department owing to chest pain. 2. Increased hs-cTnT levels may not be due to MI, but patients who have them have an elevated risk of short- and long-term complications; the cause of the increased levels should be identified and, if possible, treated specifically. 3. Finally, it is essential to interpret hs-cTnT levels together with the signs and symptoms and the ECG.
Conflict of interest Aitor Alquézar Arbé received training grants for minor sums from Roche Diagnostics that were not conditional on the contents of this article. Miguel Santaló Bel and Alessandro Sionís have no conflicts of interest.
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ACCF 2012 expert consensus document on practical clinical considerations in the interpretation of troponin elevations: a report of the American College of Cardiology Foundation task force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2012;60:2427–63. 24. Guzón Illescas O, Alonso Blas C. Miocardiopatía inducida por estrés o síndrome de Takotsubo. Emergencias. 2013;25:292–300. 25. Guijarro Merino R. Papel de los biomarcadores cardíacos en la estratificación del riesgo de tromboembolia pulmonar. Med Clin (Barc). 2009;13:221–3. 26. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al., Authors/Task Force Members. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) Endorsed by the European Respiratory Society (ERS). Eur Heart J. 2014;35:3033–73, http://dx.doi.org/10.1093/eurheartj/ehu283. 27. Hijazi Z, Wallentin L, Siegbahn A, Andersson U, Alexander JH, Atar D, et al. Highsensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin. J Am Coll Cardiol. 2014;63:52–61. 28. Peacock WF 4th, de Marco T, Fonarow GC, Diercks D, Wynne J, Apple FS, et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med. 2008;358:2117–26. 29. Jacob J, Martín-Sanchez FJ, Herrero P, Miró O, Pere Llorens P. Valor pronóstico de la troponina en pacientes con insuficiencia cardiaca aguda atendidos en los ˜ estudio TROPICA (TROPonina en Servicios de Urgencias hospitalarios espanoles: Insuficiencia Cardiaca Aguda). Med Clin (Barc). 2013;140:145–51. 30. Wang CH, Kuo LT, Hung MJ, Cherng WJ. Coronary vasospasm as a possible cause of elevated cardiac troponin I in patients with acute coronary syndrome and insignificant coronary artery disease. Am Heart J. 2002;144:275–81. 31. Piechota W, Gielerak G, Ryczek R, Kazmierczak A, Bejm J, Piechota W. Cardiac troponin I after external electrical cardioversion for atrial fibrillation as a marker of myocardial injury – a preliminary report. Kardiol Pol. 2007;65:664–9, discussion 670–1. 32. Devereaux PJ, Chan MT, Alonso-Coello P, Walsh M, Berwanger O, Villar JC, et al., Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) Study Investigators. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012;307:2295–304. 33. Bessiere F, Khenifer S, Dubourg J, Durieu I, Lega JC. Prognostic value of troponins in sepsis: a meta-analysis. Intensive Care Med. 2013;39:1181–9. 34. Naidech AM, Kreiter KT, Janjua N, Ostapkovich ND, Parra A, Commichau C, et al. Cardiac troponin elevation, cardiovascular morbidity, and outcome after subarachnoid hemorrhage. Circulation. 2005;112:2851–6. 35. Velmahos GC, Karaiskakis M, Salim A, Toutouzas KG, Murray J, Asensio J, et al. Normal electrocardiography and serum troponin I levels preclude the presence of clinically significant blunt cardiac injury. J Trauma. 2003;54:45–50. 36. Neumayr G, Gaenzer H, Pfister R, Sturm W, Schwarzacher SP, Eibl G, et al. Plasma levels of cardiac troponin I after prolonged strenuous endurance exercise. Am J Cardiol. 2001;87:369–71. A10. 37. Jaffe AS, Ordonez-Llanos J. High-sensitivity cardiac troponin: from theory to clinical practice. Rev Esp Cardiol (Engl Ed). 2013;66:687–91. 38. Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med. 2009;361:858–67. 39. Rubini Giménez M, Hoeller R, Reichlin T, Zellweger C, Twerenbold R, Reiter M, et al. Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin. Int J Cardiol. 2013;168:3896–901. 40. Biener M, Mueller M, Vafaie M, Keller T, Blankenberg S, White HD, et al. Comparison of a 3-hour versus a 6-hour sampling-protocol using high-sensitivity cardiac troponin T for rule-out and rule-in of non-STEMI in an unselected emergency department population. Int J Cardiol. 2013;167:1134–40. 41. Reichlin T, Twerenbold R, Reiter M, Steuer S, Bassetti S, Balmelli C, et al. Introduction of high-sensitivity troponin assays: impact on myocardial infarction incidence and prognosis. Am J Med. 2012;125:1205–13, e1. 42. Keller T, Zeller T, Ojeda F, Tzikas S, Lillpopp L, Sinning C, et al. Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction. JAMA. 2011;30:2684–93. 43. Rubini M, López B, Rubini S, Mueller C. Biomarcadores en el paciente con dolor torácico: pasado, presente y futuro. Emergencias. 2014;26:221–6. 44. De Lemos JA, Drazner MH, Omland T, Ayers CR, Khera A, Rohatgi A, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA. 2010;304:2503–12.
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45. Korley FK, Jaffe AS. Preparing the United States for high-sensitivity cardiac troponin assays. J Am Coll Cardiol. 2013;61:1753–8. 46. Wu AH, Jaffe AS. The clinical need for high-sensitivity cardiac troponin assays for acute coronary syndromes and the role for serial testing. Am Heart J. 2008;155:208–14. 47. Reichlin T, Irfan A, Twerenbold R, Reiter M, Hochholzer W, Burkhalter H, et al. Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction. Circulation. 2011;124:136–45. 48. Mueller M, Biener M, Vafaie M, Doerr S, Keller T, Blankenberg S, 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;58:209–18. 49. Cullen L, Parsonage WA, Greenslade J, Lamanna A, Hammett CJ, Than M, et al. Delta troponin for the early diagnosis of AMI in emergency patients with chest pain. Int J Cardiol. 2013;168:2602–8.
50. Irfan A, Reichlin T, Twerenbold R, Meister M, Moehring B, Wildi K, et al. Early diagnosis of myocardial infarction using absolute and relative changes in cardiac troponin concentrations. Am J Med. 2013;126:781–8, e2. 51. Bjurman C, Larsson M, Johanson P, Petzold M, Lindahl B, Fu ML, et al. Small changes in troponin T levels are common in patients with non-ST-segment elevation myocardial infarction and are linked to higher mortality. J Am Coll Cardiol. 2013;62:1231–8. 52. Wildi K, Reichlin T, Twerenbold R, Mader F, Zellweger C, Moehring B, et al. Serial changes in high-sensitivity cardiac troponin I in the early diagnosis of acute myocardial infarction. Int J Cardiol. 2013;168:4103–10. 53. Apple FS, Morrow DA. Delta cardiac troponin values in practice: are we ready to move absolutely forward to clinical routine? Clin Chem. 2012;58:8–10. 54. Santalo M, Martin A, Velilla J, Povar J, Temboury F, Balaguer J, et al. Using highsensitivity troponin T: the importance of the proper gold standard. Am J Med. 2013;126:709–17.
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www.elsevier.es/medicinaclinica
Review
Clinical interpretation of high sensitivity troponin T夽 Aitor Alquézar Arbé a,∗ , Miguel Santaló Bel a , Alessandro Sionis b a b
Servicio de Urgencias, Hospital de Sant Pau, Barcelona, Spain Unidad Coronaria, Hospital de Sant Pau, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 27 September 2014 Accepted 13 November 2014 Available online xxx Keywords: Chest pain Acute coronary syndrome Acute myocardial infarction without ST elevation High sensitivity cardiac troponin T
a b s t r a c t Determination of cardiac troponin (cTn) is necessary for the diagnosis of acute myocardial infarction without ST segment elevation. However Tnc can be released in other clinical situations. The development of high-sensitive cTn T assays (hs-cTnT) improves the management of patients with suspected acute coronary syndrome. Here, we provide an overview of the diverse causes of hs-cTnT elevation and recommend strategies for the clinical interpretation of the test result. ˜ S.L.U. All rights reserved. © 2014 Elsevier Espana,
Interpretación clínica de la determinación de troponina T de elevada sensibilidad r e s u m e n Palabras clave: Dolor torácico Síndrome coronario agudo Infarto de miocardio sin elevación del segmento ST Troponina T cardíaca de elevada sensibilidad
La determinación de troponina cardíaca (Tnc) es necesaria para el diagnóstico del infarto de miocardio sin elevación del segmento ST, pero existen otras situaciones clínicas donde se observan valores aumentados. El desarrollo de los nuevos inmunoanálisis para determinar Tnc T, denominados de elevada sensibilidad (TnTc-es), han supuesto un avance en el tratamiento de los pacientes con sospecha de síndrome coronario agudo. En este trabajo se revisan brevemente las diferentes causas de elevación de TnTc-es, así como los factores determinantes para su correcta interpretación, enfatizando en el contexto clínico del paciente. ˜ S.L.U. Todos los derechos reservados. © 2014 Elsevier Espana,
Acute coronary syndrome Acute coronary syndrome (ACS) is the most common clinical manifestation of ischaemic cardiomyopathy. Ischaemic cardiomyopathy is among the leading causes of morbidity and mortality in Spain.1 ACS is a group of different clinical manifestations related to acute myocardial ischaemia, which are unstable angina, myocardial infarction (MI) and sudden death.2 The physiopathological background common to the vast majority of cases of ACS is atheromatous plaque rupture. This class of
夽 Please cite this article as: Alquézar Arbé A, Santaló Bel M, Sionis A. Interpretación clínica de la determinación de troponina T de elevada sensibilidad. Med Clin (Barc). 2016. http://dx.doi.org/10.1016/j.medcli.2014.11.004 ∗ Corresponding author. E-mail address: [email protected] (A. Alquézar Arbé).
infarction is called type 1 MI.3 However, there are situations that involve an imbalance between circulatory supply and myocardial demand. This circumstance normally occurs when there is a stable atherosclerotic plaque that significantly decreases the arterial lumen, causing a situation of hypotension, anaemia, infection or tachyarrhythmia that decreases the oxygen supply to cardiac muscle cells. This is the aetiopathogenesis of type 2 MI.3 ACS generally presents as non-traumatic chest pain. Nontraumatic chest pain represents approximately 5% of all emergency department (ED) visits, and is the second most common reason for visiting.4 A substantial proportion of patients with chest pain do not have ACS.5 Often, these patients are admitted to the ED to perform serial monitoring of biomarkers, an electrocardiogram (ECG) and, in certain cases, function tests of induction of myocardial ischaemia.6 This strategy, though safe, is inefficient and promotes ED overcrowding. On the other hand, it has been estimated that up to 2% of patients with ACS are discharged with an incorrect diagnosis.7
˜ S.L.U. All rights reserved. 2387-0206/© 2014 Elsevier Espana,
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The patient’s clinical history, ECG and biomarkers of myocardial injury are essential for an early diagnosis, prognosis and selection of treatment for ACS.8 Biomarkers are mainly valuable in cases of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and cases in which the ECG cannot be interpreted.9 In accordance with the third universal definition of myocardial infarction,3 the diagnosis of MI is based on observation of evolutionary increases/decreases in the determination of biochemical markers. Observing evolutionary changes involves performing serial determinations. In the case of cardiac troponin (cTn), this should be done 3–6 h after the first determination, with at least one determination greater than the 99th percentile of the reference population (p99). This observation should be accompanied by an appropriate clinical context, appropriate symptoms or other consistent findings in the ECG, imaging tests or autopsy.
Cardiac troponin in acute coronary syndrome At present, cTn is the biomarker of choice to be determined in the diagnosis of MI, and additional determination of other markers such as, for example, creatine kinase, is not advised.3 Unlike other markers, cTn is a cardiac structural protein, and therefore a biomarker curve rather than an enzyme curve should be referred to. It has 3 subunits: T, I and C. Immunoassays have been designed to detect 2 of these–T and I–in plasma. Evaluation of the diagnostic usefulness of a biomarker of myocardial necrosis varies according to its intended use. A rule-in diagnosis of non-ST segment elevation myocardial infarction (NSTEMI) should be rapid and precise. For this purpose, high diagnostic sensitivity is required. However, sensitivity should be accompanied by reliability in ruling out NSTEMI. A good diagnostic test should offer a good combination of both characteristics; to this end, the cut-off points used for diagnosis may be modified to increase sensitivity or specificity. The use of the p99 as a criterion to identify MI means that a percentage of false positives of 1% is acceptable in clinical practice.10 In the context of NSTEMI, the cost of a false negative, that is to say, undiagnosed NSTEMI, is assumed to be greater than the cost of doing additional tests on false positives,11 and therefore the diagnostic sensitivity of tests for its diagnosis is prioritised. Despite the existing broad consensus on the role of cTn in identifying MI, several factors contribute to creating confusion on the use of the biomarker:
1. The presence of various cTn immunoassays on the market with different levels in the p99. This occurs both when cTnT is compared with cTnI and when different methods for cTnI are compared with each other. 2. The fact that some laboratories report different clinical decision points classified as “normal”, “indeterminate” or “suggestive” of myocardial injury. Currently, if cTn is measured with highsensitivity methods (hs-cTn), there should be no “positive”, “negative” or “indeterminate” results; instead, there should be results greater than or less than the p99. 3. The indiscriminate use of cTn in broad populations with very different probabilities of having ACS. Levels of cTn are extremely specific to myocardial injury; however, myocardial injury is not at all unique to ACS. Therefore, clinical guidelines stress that cTn levels should be interpreted in relation to the patient’s signs and symptoms. As a result, elevated cTn levels in patients with sepsis, hypertensive crises, pulmonary embolisms, etc. are indicative of myocardial injury, but not of MI, and should not be used to indicate treatments specific to ACS.
Differential diagnosis of increased levels of cardiac troponin There are increased cTn levels in clinical situations other than that of type 1 MI. Increased levels may be chronic or acute and are very normal in day-to-day practice. More than 50% of patients who visit owing to chest pain have high cTn levels. However, the majority of them do not have type 1 MI.12
Chronically increased cardiac troponin Chronically increased cTn is observed in various diseases, both when it is measured by conventional methods and when it is measured by high-sensitivity methods. This elevated cTn characteristically remains stable without subsequent increases or decreases. The most common causes are: - Stable coronary heart disease: Up to 97% of patients with stable coronary heart disease with preserved left ventricular ejection fraction have detectable levels of cTn measured with highsensitivity immunoassays; in 11% of cases, these values exceed the p99. Increased hs-cTn is associated with a poor prognosis with a risk of heart failure and cardiovascular death.13 - Chronic heart failure (CHF): Levels of hs-cTn are detectable in 92% of patients with CHF, and in many cases levels exceed the p99 of reference. As in the previous case, increased highsensitivity cardiac T troponin (hs-cTnT) is associated with increased mortality.14 - Diabetes: These patients have elevated levels of hs-cTn, a circumstance that significantly increases the risk of cardiovascular episodes.15 - Pulmonary hypertension: Elevated hs-cTn levels are detected in approximately 10% of these patients; the increase is associated with increased mortality after 6 months.16 - Kidney failure. It is very normal to detect increased hs-cTn (just as this was detected when cTn was measured with conventional methods) in patients with decreased kidney function.17 In these patients, cTn levels have a proportional inverse relationship to creatinine clearance figures and are associated with greater mortality.18,19 In the case of hs-cTn, elevated levels of hscTn have been shown to be detected in virtually 100% of patients in chronic haemodialysis; these elevated levels are in turn associated with an elevated risk of death after 2 years.20 - Age: Levels of cTn (conventional method) and hs-cTn increase with age. It is normal to see elevated values of cTn (both cTnI and cTnT) in elderly patients (>70 years) without NSTEMI. It is unknown whether these increased cTn values with age are physiological or reflect subclinical disease processes (deterioration of the myocardium and/or kidney function, etc.), but in practice they decrease the specificity of the cTn measure and this makes the values obtained harder to interpret.21 Acute increases not associated with type 1 myocardial infarction In some clinical situations, increases/decreases are observed in serial measures of cTn in the absence of type 1 MI. These signs and symptoms may co-exist in the clinical picture (for example, evolutionary increases in cTn in a patient with stable coronary heart disease who has acute heart failure) and make MI harder to diagnose. The main clinical situations in which this circumstance may occur are21 : - Myopericarditis: cTn values are very variable in these patients, and are associated with the underlying inflammatory process in the myocardium.22 It is not clear whether they are correlated with a poor prognosis.23
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In summary, elevated cTn levels are not synonymous with MI; there are many clinical situations in which elevations in cTn are observed in the absence of MI. High-sensitivity cardiac T troponin Recently, new immunoassays, called high-sensitivity immunoassays, have been introduced in clinical practice to determine cTn. They were developed by modifying some of the characteristics of the test to optimise its diagnostic yield. The designation “high-sensitivity” should be reserved for those immunoassays that are capable of determining the p99 with a coefficient of variation < 10% and that are capable of measuring cTn levels in at least 50% of a healthy population of reference. These are the 2 characteristics that distinguish them from earlier immunoassays.37 hs-cTnT meets these requirements.hs-cTnT
Delay in diagnosis
50 40
Troponin T (ng/l)
- Stress-induced cardiomyopathy (takotsubo cardiomyopathy): cTn values tend to be more modestly elevated than in MI. It is not clear whether they are correlated with a poor prognosis.24 - Pulmonary embolism: It is very normal to detect elevated cTn levels in these patients. These elevated levels are indicative of right ventricular dysfunction and are associated with increased mortality.25 Currently, it is recommended that cTn be determined in these patients for their risk stratification26 and to identify those who could benefit from intravenous fibrinolytic treatment.23 - Tachyarrhythmias: In these situations, increased levels of cTn are commonly observed, even in cases in which there is no associated coronary heart disease. In atrial fibrillation, increased cTn is independently associated with the risk of ischaemic stroke and death of cardiovascular origin.27 - Acute heart failure (AHF): It is also common to find increased cTn levels in AHF; this is related to advanced stages of underlying cardiomyopathy and greater mortality.28,29 - Coronary vasospasm: This may involve acute increases in cTn. It has been reported that 25% of patients with suspected ACS and a normal coronary angiography have elevated cTn levels. Among these patients, 74% have positive provocation tests for coronary spasm.30 - Electric cardioversion/defibrillation: Both manoeuvres may cause modestly increased levels of cTn that are more significant in patients with left ventricular hypertrophy.31 - Non-cardiac surgery: Increased levels of cTn have been reported in 12% of postoperative non-cardiac surgery patients. There is a significant association between maximum cTn value three days after a procedure and mortality after 30 days.32 - Sepsis: Increased cTn is very common in patients with serious sepsis or septic shock; often these are patients without associated coronary heart disease. Their increased cTn doubles their risk of mortality.33 This relationship to mortality has also been reported in patients with other serious diseases admitted to intensive care units. - Cerebrovascular accident: Increased levels of cTn have been observed in ischaemic and haemorrhagic stroke and subarachnoid haemorrhage.34 cTn figures are correlated with the severity of neurological injury and of underlying cardiovascular abnormalities. - Trauma: After direct chest trauma, it is normal to see increased cTn; however, only a minority of patients have cardiovascular complications.35 - Strenuous physical exertion: Increased levels of cTn have been reported in long-distance runners after high-intensity and extended-duration exercises. These increases do not have any clinical implications in the short term, but their long-term clinical significance is unknown.36
3
35
4th G-cTnT; CV≤10%
30 25 20 15 10
99th percentile hs-cTnT; CV≤10%
5 0 0
2
4
6
8
Hours post-start of AMI Fig. 1. Improvement in sensitivity and early diagnosis with high-sensitivity T troponin. CV: coefficient of variation; MI: myocardial infarction; hs-cTn: highsensitivity cardiac T troponin; 4thG-cTn: fourth-generation cardiac T troponin.
improves early diagnosis of MI compared to cTnT measured with conventional methods for various reasons (Fig. 1): - An elevated hs-cTnT value at the time of admission has greater diagnostic sensitivity for MI, especially if the determination is made within the first 2 h of the onset of symptoms.38 - The first determination of hs-cTnT rules out a diagnosis of NSTEMI in some patients.39 - The use of hs-cTnT decreases the wait time before making the second determination to 3 h from the first determination, instead of the 6–9 h that were recommended for cTn.40 - hs-cTnT identifies 22% of NSTEMIs that were diagnosed as unstable angina using cTnT. This group of small-size NSTEMIs that are only identified by cTnT has an elevated risk of mortality (16% at 30 months).41 The improved sensitivity and negative predictive value obtained with hs-cTnT, however, is associated with decreased specificity and positive predictive value.42 In practice, this results in increased numbers of patients with hs-cTnT levels greater than the reference p99.43 In the general population, 2% of individuals are observed to have moderately elevated hs-cTnT levels, greater than the p99.44 In the population that goes in to EDs, this proportion is more elevated,45 since these patients have many of the above-mentioned causes of chronically elevated cTn levels. As a result, in the majority of suspected cases, NSTEMI cannot be ruled in or ruled out by means of a single laboratory determination, except when hs-cTnT is undetectable (<3 ng/l) after 3 or more hours of evolution of the symptoms indicative of angina – this rules out NSTEMI39 – or the initial value is very elevated, in which case the probability of NSTEMI is very high. Evolutionary increases or decreases in high-sensitivity cardiac T troponin (delta value) For NSTEMI to be diagnosed, cTn must be measured in at least 2 serial samples over time. This will allow the kinetics of increase or decrease, called a delta value, () to be detected. As mentioned, kinetics will distinguish between acute cTn increases (this is the case of NSTEMI) and chronic increases (these may show levels greater than the p99, but do not show evolutionary changes). Successive definitions of MI have recommended the use of the value of cTn, but without making it clear whether this should be expressed in relative or absolute terms or what its optimal magnitude should be. Optimal delta value There is no consensus on the optimal value. Currently, there is a tendency to use the relative value ≥ 20% proposed by some
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Table 1 Studies that showed the best diagnostic yield of the absolute delta value. Author
Trial
Time
criterion
Yield (AUC)
p
False negative
Reichlin et al.47 , n = 836
hs-cTnT (Roche)
0–2 h
7 ng/l 30% 20 ng/l 117% 9.2 ng/l 20% 30 ng/l NA 7 ng/l 30%
0.95 0.76 0.95 0.72 0.90 0.75 0.90 0.79 0.95 0.75 0.97 0.75 0.96 0.75 NA
<0.01 <0.01
10% 7%
<0.01
10%
<0.01
23%
<0.01 <0.01 <0.01
NA
NA
0.93 0.75 0.93 0.78
<0.01
12% 26% NA
cTnT (Siemens) Mueller et al.48 , n = 784
hs-cTnT (Roche)
0–<6 h
Cullen et al.49 , n = 874
cTnI (Beckman Coulter AccuTnl)
0–2 h
hs-cTnT (Roche)
0–2 h
50
Irfan et al. , n = 830
hs-TnT (Beckman Coulter) hs-cTnI (Siemens) 51
Bjurman et al.
hs-cTnT (Roche)
0–6 h
Wildi et al.52 , n = 943
hs-cTnI (Beckman Coulter)
0–2 h
9 ng/l 20% 11 ng/l 86% 6 ng/l 82%
hs-cTnI (Siemens)
<0.01
AUC: area under the curve; criterion: delta criterion used to diagnose myocardial infarction; false negative: percentage of false negatives with the exclusive application of the criterion used; NA: not available; cTnI: conventional cardiac troponin I; hs-cTnI: high-sensitivity cardiac troponin I; cTnT: conventional cardiac troponin T; hs-cTnT: high-sensitivity cardiac troponin T.
experts.46 However, since the development of high-sensitivity methods to measure cTn, there are 2 clinical situations in which the use of an absolute value would have a better diagnostic yield than that of a relative value. In the case of hs-cTnT, this would involve: - Patients without MI whose serial determinations have levels close to that of the p99; in these cases, a small change in levels may involve an elevated percentage change and cause a false positive for MI. - Patients with evolved MI (when the hs-cTnT release curve is found to be in a stable area) may have elevated serial hs-cTnT levels, but only small percentage changes, giving rise to a false-negative diagnosis of MI. Various studies have shown a better yield for an absolute value47–52 (Table 1). These studies compared different intervals of time between determinations (0–1 h, 0–2 h, 0–3 h, 0–6 h). Taken together, an interval of 2 h after the first determination was the one that obtained the best diagnostic yield, although one study obtained this 6 h after the first determination.48 Although the majority of studies had elevated diagnostic yields (AUC > 0.900), all of them had a proportion of patients in whom MI had not been diagnosed using this criterion exclusively. Studies have recommended optimising the yield of the absolute value based on other determinants, such as hs-cTn value in the first determination,47 time from the onset of symptoms up to the first determination49 and characteristics of the population cared for.48 However, despite the potentially improved diagnostic yield for MI that they offer, these strategies are hard to implement in clinical practice, especially in the ED, where patients in whom they should be applied are most commonly cared for. Interpretation of the delta value Regardless of whether an absolute or percentage value is used, there are various circumstances to be taken into account to properly define and interpret the value:
-
-
-
-
-
and specificity. A low value will offer elevated sensitivity and low specificity. No MI will remain undiagnosed, but there will be many false positive diagnoses. This strategy is valid for an emergency doctor, but uncomfortable for cardiology specialists, as they prioritise specificity to diagnose NSTEMI and optimise a patient’s clinical approach.45 Each hs-cTn immunoassay should be validated for its best absolute and percentage value.53 The value should be analysed based on the time between the onset of symptoms and the first determination. In cases of short times of evolution, the established criterion is more likely to be met, but patients with MI who seek treatment late may have low levels owing to starting from very elevated hs-cTn levels.51 The interval of time between determinations used to evaluate the value must be uniform because it has not been fully demonstrated that cTn release after MI remains constant over time.45 However, there are data that show constant release in the first few hours of evolution of MI.50 It is advisable to evaluate the value systematically in all patients and clinical circumstances. The value should be calculated in patients with an unequivocal diagnosis of MI or non-MI. Some studies that evaluated the optimal hs-cTnT value were based on MI diagnosed with conventional cTn that did not identify small-size MI and, therefore, distorted the diagnostic specificity of hs-cTnT,54 or alternatively, on MI diagnosed by any hs-cTnT value greater than the p99, but without changes in kinetics.51 The presence of a value does not distinguish between type 1 and type 2 MI.53 The presence of a value is not at all specific to MI, since it may be seen in other acute clinical situations (for example, pulmonary embolism, myocarditis and sepsis). The value diagnostic of MI may be established to be different from the value of other causes of cardiac injury, but this theory has not been demonstrated. Persistently high levels of any hs-cTn are associated with a poor prognosis, even if a significant value is not observed.51
Conclusions - Studies that identified the best value47–52 were based on analysis of receiver operating characteristic curves. This statistical approach grants the same weight to both diagnostic sensitivity
Availability of hs-cTn measurement improves the diagnostic strategy for patients with chest pain in the ED.
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1. hs-cTnT allows MI to be ruled out earlier in the majority of patients who visit the emergency department owing to chest pain. 2. Increased hs-cTnT levels may not be due to MI, but patients who have them have an elevated risk of short- and long-term complications; the cause of the increased levels should be identified and, if possible, treated specifically. 3. Finally, it is essential to interpret hs-cTnT levels together with the signs and symptoms and the ECG.
Conflict of interest Aitor Alquézar Arbé received training grants for minor sums from Roche Diagnostics that were not conditional on the contents of this article. Miguel Santaló Bel and Alessandro Sionís have no conflicts of interest.
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