Effectiveness of Different Cutoff Points of High-Sensitivity
Troponin T to Diagnose Myocardial Infarction
Stella Maris Macin, Luciana Nacke, Josefina Blanchet, Gabriela Reyes,
Rodrigo Zoni, Eduardo Roque Perna Instituto de Cardiología de Corrientes "Juan F Cabral". (3400) Corrientes, Argentina. E-mail
Recibido 21-MAR-2014 – ACEPTADO 05-MAYO-2014. The authors declare not having conflicts of interest
Rev Fed Arg Cardiol. 2014; 43(3): 141-145
Introduction: With the advent of high-sensitivity cardiac troponin T (hs-cTnT) has improved the diagnosis of myocardial infarction, increasing the number of patients with this diagnosis. However, there are more and more individuals with biomarker elevation of this outside the context of acute myocardial infarction (AMI). This study aimed to evaluate the usefulness of hs-cTnTlevel for diagnosis of AMI in patients hospitalized in the coronary care unit. Methods: Prospective study of 148 patients admitted to the Institute of Cardiology and Corrientes between 30/Apr/2013 and 01/Nov/2012 in hs-cTnTwho requested within 6h admission and 3 – 12 h after the first determination. Absolute (AD) and percentage Delta (PD) between the two measurements was calculated. Results: The mean age was 64 + 12 years. Infarction was diagnosed in 59.5 % (group 1) and excluded in 40.5 % (group 2). hs-cTnTaverage in admittance in both groups was 2113 + 5432 ng / L, and 63 + 160 ng / L (p <0.001 ) respectively. The area under the ROC curve hs-cTnTfor the diagnosis of AMI at admission was 0.84, and a cutoff point of 38ng / L had a sensitivity of 80% and specificity of 72%. The AD was 702 + 30 3704 +163 ng / L (p = 0.03), and +873 % to 1456 PD 112 + 698 (p = 0.02) in the two groups respectively. Conclusions: This study shows that the value of hs-cTnTin admission was more useful than the changes in their values for the diagnosis of AMI. Due to their low specificity, cutoff points greater than the recommended 99 percentile are required.
Cardiac troponins play an essential role to establish the diagnosis and to stratify the risk in acute coronary syndromes (ACS), and they allow differentiating between acute myocardial infarction (AMI) and unstable angina . They play a key role in muscle contraction and as a result of their release before the myocardial impairment; they have become the main diagnostic indicator of myocardial impairment, as well as the prognostic predictor in patients with acute coronary syndromes [2-5].
In year 2000, clinical trials with high sensitivity and specificity troponin, originated a change in the consensus to define infarction, considering them as the new gold standard .
In the clinical context of an acute coronary syndrome, the existence of a test with a high capacity of exclusion (negative predictive value) and accurate diagnosis (positive predictive value) holds a great value. The negative predictive value for infarction as the only test during admittance is >95%. If a second sample is included within the first 3 h after appearance, the sensibility for infarction is close to 100% .
In regard to the high values of high-sensitivity cardiac troponin T (hs-cTnT), there is no consensus about the cutoff point for the diagnosis of infarction, and a remarkable number of false positives are observed. Moreover, the reasonable doubt that it may be an infarction before a given patient with positive hs-cTnT generates an increase in the number of coronary angiographies, some of them unnecessary [8, 9].
To keep the specificity in the diagnosis of infarction, it is necessary to differentiate a chronic troponin elevation from an acute one. So, the extent of change from the initial value gains relevance to differentiate between acute and chronic myocardial impairment. It is being debated what should be considered a relevant change in regard to the basal concentration. Mainly in the cases of concentration close to the limit, since they are not specific to myocardial disease since they are elevated in other pathologies that are not necessarily acute coronary syndrome, the change should exceed the natural biological variation and has to be defined for each test .
The objective of this study was to evaluate the usefulness of the different levels of hs-cTnT for the diagnosis of AMI in in-hospital patients in the coronary unit.
Patients admitted in the Instituto de Cardiología de Corrientes, from November 1, 2012 to April 30, 2013, with a diagnosis of acute coronary syndrome, in whom hs-cTnT was measured within 6 h of admittance.
Age older than 18 years.
The patients should give their informed consent.
Patients in whom the measurement of hs-cTnT could not be made.
Prospective, observational, single-center study.
hs-cTnT was analyzed at admittance (within 6 h) and 3-12 h after the first determination. Absolute delta and percentage delta were estimated between both determinations.
A- The final diagnosis of infarction was based on the 3rd universal definition of infarction, requiring an increase or decrease in the values of cardiac biomarkers with at least one value above the 99th percentile of the upper limit of reference and with at least one of the following: ischemia symptoms, new significant changes in the ST-T segment, or new His bundle left branch, appearance of pathological Q waves in ECG, tests by image of new loss of viable myocardium or new regional anomalies in the wall motion, identification of intracoronary thrombus in angiography or autopsy . High-sensitivity troponin was determined by the electrochemiluminescence immunoassay method and the value used as reference limit was 14 ng/L.
B- The delta of hs-cTnT was determined as the change in value between the first measurement and the second, both in percentage values and in absolute values.
Statistical Analysis A database with the SPSS software 18.0 was made, including the information of the patients (clinical characteristics, risk factors, complications, lab data and supplementary studies).
The population was divided into two groups according to the presence or absence of AMI, and the hs-cTnT values obtained in both groups were compared, both in the first and the second measurement.
The qualitative variables were expressed in percentage, and compared through the chi-squared test.
The quantitative variables were expressed in averages with their standard deviations and analyzed by the T test, or with the non-parametric test as corresponding.
The differences were considered as statistically significant when p<0.05. The data obtained were analyzed by the SPSS 18.0 software.
There were 148 patients included; the average age was 64±12 years. 68% were males, 27% were diabetic, and 28% had renal failure. AMI was diagnosed in 59.5% (group 1), and the rest constituted group 2. The population characteristics are listed in Table 1.
Table 1. Basal characteristics in both groups
63,1 + 12
65,8 + 14
AMI: acute myocardial infarction
hs-cTnT levels atadmission and its modifications
The patients in group 1 (with AMI) had greater average values of hs-cTnT in admission, average of 2113±5432 ng/L, and median of 362 ng/L (interquartile interval 25-75 of 60-1969 ng/L) against 63±160 ng/L, and 21 ng/L (interquartile interval 25-75 of 8-50 ng/L) of group 2 (without AMI) (p<0.001).
The values of the second measurement of hs-cTnT were also greater in group 1 (2354±4058 ng/L compared with 108±230 ng/L) (p<0.001).
The area below the ROC curve of hs-cTnT at admission for the diagnosis of AMI was 0.84; and the best cutoff point was 38 ng/L, with a sensitivity of 80% and a specificity of 72%.
The absolute delta was 702±3704 ng/L in patients of group 1 and of 30±163 ng/L (p 0.03) in group 2.
The percentage delta was 1456±873% in comparison to 112±698% in both groups respectively (p=0.02).
The area below the ROC curve for the absolute delta was 0.66 and for percentage delta it was 0.67, with a cutoff point of 76 ng/L and 13% respectively. The diagnostic usefulness of the different measurements is listed in Table 2.
Table 2. Measurements of hs-cTnT and its usefulness for the diagnosis of infarction
ABC: Area below the curve. Se: Sensitivity. Sp: Specificity.
hs-cTnT: high-sensitivity cardiac troponin T
The area below the ROC curve of the first hs-cTnT was statistically higher than the absolute delta (p<0.0001) and the percentage delta (p<0.0001) (Figure 1).
Figure 1. Areas below the ROC curve of the different measurements of high-sensitivity cardiac troponin T (hs-cTnT) for the diagnosis of acute myocardial infarction.
TROPONIN: value of hs-cTnT at admission; ABS DELTA: absolute delta of hs-cTnT; PER DELTA: percentage delta of hs-cTnT.
This paper shows the value of hs-cTnT at admission was of greater usefulness than the changes in its values for the diagnosis of AMI. Due to its low specificity cutoff points higher than the 99th percentile recommended are required.
In spite of the new advancements in high-sensitivity troponin to detect infarction, there is a controversy as to the absolute values, of increase and decrease of hs-cTnT that should be considered for its diagnosis [11-13]. The studies with hs-cTnT increased the diagnostic sensibility (reclassifying 25% of unstable angina in infarctions) but leading to a lower diagnostic specificity [14,15], since they are not specific to CAD and have been identified in patients with different diseases associated to myocardial injury, such as heart failure, chronic renal failure, chronic CAD, hypotension, sepsis, myocarditis, toxicity by anthracyclines, stroke, pulmonary thromboembolism, acute pulmonary edema, among others [16-22]. These troponin elevations in patients with diseases other than ACS, indicate the presence of cardiac lesion, by ischemic cause or not, and they also predict an adverse evolution in these patients .
Troponin cutoff points to diagnose and rule out infarction.
Our work showed that the values of hs-cTnT at admission had a higher diagnostic accuracy in comparison to the relative and absolute changes obtained in the second measurement; however, due to its low specificity, cutoff points greater than the 99th percentile recommended are required.
When determining the area below the ROC curve of hs-cTnT at admission for the diagnosis of infarction, the best cutoff point was 38 ng/L, with a sensibility of 80% and a specificity of 72%.
This cutoff point was greater than that recommended in the guidelines of the universal definition of infarction , so we consider that this should be reviewed to improve the usefulness of these new tools in clinical practice, and thus rule out the other causes of elevation of this biomarker. That is to say, the greater the level of hs-cTnT in the presentation, the greater the predictive value for its diagnosis.
Reiter et al  showed that hs-cTnT also had a high diagnostic accuracy in patients with chronic CAD. It is usual to find minimum elevations in these patients, and the optimal cutoff levels for the diagnosis of infarction in them tend to be higher.
On the other hand, although there were statistically significant differences in the values of hs-cTnT at admission and in their changes between the patients with and without infarction, only the first value detected was considered useful in the final diagnosis of infarction. This finding suggests that hs-cTnT release could be linear in the early stage of acute myocardial infarction .
Troponin delta for the diagnosis of infarction
MacRae et al , showed in a cohort of 258 patients with suspicion of ACS, the usefulness of a delta of 20%. Fabregat Andrés et al , in a study of 78 patients had similar findings. Recent studies suggest that this cutoff point for troponin delta should be greater[28,29]. A study of Keller T et al, showed that a relatively elevated change (250%) seemed to provide more specificity . On the other hand, Apple et al , evaluated the usefulness of a delta ≥10%, ≥20% and ≥30% and observed that the delta ≥30% improved the specificity and the evaluation of cardiovascular risk. Giannitsis et al , compared the changes in hs-cTnTconcentration within 3 hours of admission between patients without diagnosis of infarction and those with diagnosis of unstable angina that presented initially with negative troponin, showing that a delta ≥117% increased the clinical specificity for the diagnosis of infarction.
So, the diagnostic information obtained from the hs-cTnT levels found in the patients with acute chest pain in the ER is critical [31,32], with the reference values optimized to prevent false positives.
It is important to differentiate between persistent elevations in cardiovascular diseases that evolve with continuous subclinical myocytic degeneration, with the typical release with a curve of increase and decrease that occurs in acute coronary syndrome .
In this paper, in spite of the percentage change between the measurements having low sensibility and specificity, the results were better in regard to those obtained with the absolute change. A percentage change of 13% had a sensibility of 60% and a specificity of 76%, while with absolute delta of 76 ng/L, a sensibility of 46% and specificity of 30% were obtained.
As infarction is not the only cause of myocardial impairment, it is important to consider the absolute level, as well as the subsequent changes of hs-cTnT for a differential diagnosis in the etiology of myocardial impairment .
This study showed that with the use of state-of-the-art biomarkers, the diagnostic sensibility increases at the expense of a decrease in specificity. In patients with high levels of hs-cTnT it is important to assess the clinical context and the possible causes of elevation of this biomarker different from infarction, to prevent the unnecessary admission of patients . It is important to make a pre-test assessment of CAD before obtaining the values of hs-cTnT, and later integrate the values obtained during the clinical evaluation. Many of them don’t have a dynamic pattern (they present persistent elevation of hs-cTnT) and they could be evaluated as outpatients. Those with a dynamic pattern in the lab, require the admission into the intensive care unit . Different prevalent pathologies may evolve with hs-cTnT elevation, as heart failure, chronic renal failure, chronic CAD, hypotension, sepsis, pulmonary embolism, acute respiratory failure, myocarditis, among other causes , and often patients with these entities denote a significant increase of hs-cTnT, so we have to consider the differential diagnosis in each clinical scenario.
Using troponin delta is useful in patients with mildly elevated values, since the elevation in time is usually big in acute events, and minimal changes (<20%) are little useful . If the elevation is 50-60%, it is lilkely an acute event . If delta is lower, one should take medical criteria as basis. If the basal value of troponin is increased, a delta greater than 20% is considered representative. And finally, the normal biological variation should be considered, and argue that a significant delta should exceed this value.
The main limitation of the study was the small number of patients admitted and the fact that it was made in a single center.
With the use of state-of-the-art biomarkers, the diagnostic sensibility of infarction increases at the expense of a decrease in specificity. In this study, the value of hs-cTnT at admission was of greater usefulness than the changes in its values for the diagnosis of infarction, but due to its low specificity, cutoff points greater than the 99th percentile recommended are required.
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