|Home | About | Journals | Submit | Contact Us | Français|
High-sensitivity cardiac troponin T (hs-cTnT) is widely used for the diagnosis of acute myocardial infarction (AMI). The current cut-off value of 0.014 ng/mL was determined based on the 99th percentile of a normal reference population; however, little data exist regarding the appropriate cut-off value in the elderly (≥75 years). Accordingly, we aimed to investigate the accuracy of the current cut-off value in an elderly population.
We assessed 355 consecutive patients (mean age =66.7±16.1 years, male =210) whose hs-cTnT levels were measured at Kanazawa University Hospital from January 2014 to July 2015. Twenty-six patients were eventually diagnosed with AMI. Hs-cTnT was measured during a visit to the emergency or outpatient department. Receiver operating characteristic (ROC) curves were assessed to determine the appropriate cut-off levels, yielding the maximum sensitivity and specificity while dividing the subjects into two groups according to ages (≥75 or ≤74 years).
The appropriate overall cut-off value was 0.038, the sensitivity and specificity of which were 85% and 89%, respectively, with an area under the ROC curve (AUC) of 0.945 overall. The conventional cut-off value (99th percentile: 0.014 ng/mL) provided low specificity, particularly in the elderly or those with renal dysfunction. In contrast, a calculated appropriate cut-off provided higher sensitivity with significantly larger c-statistics in the elderly (0.940 vs. 0.629, p<0.001).
When measuring hs-cTnT, careful assessments are needed in elderly subjects.
Acute myocardial infarction (AMI) is caused by acute ischemia to the myocardium, resulting from numerous factors, with one example being coronary artery stenosis. AMI is an acute disease with a high mortality rate, causing death and disability worldwide (1). A timely diagnosis of AMI is crucial as the initiation of early, effective, evidence-based medical management, including early revascularization, is essential for the best outcome (2,3). Recently, more sensitive cardiac troponin (cTn) assays have been developed with a limit of detection below the 99th percentile of healthy reference populations, thus improving precision in clinical practice (4-6). However, their clinical utility in the elderly has been questioned (7), which is also the case for renal dysfunction with elevated baseline cTnT levels (8). According to the universal definition of AMI, the 99th percentile could be an acceptable reference value for diagnosis (9); however, in practice, reference values required for optimal clinical decision making at presentation may differ. We therefore aimed to examine the diagnostic performance of high-sensitivity cTnT (hs-cTnT) assays and to identify the appropriate cut-off levels for the early diagnosis of AMI in the elderly.
We investigated patients referred to the emergency and outpatient departments at Kanazawa University Hospital from January 2014 to July 2015. We assessed 355 consecutive patients who were measured their hs-cTnT levels for any reasons. Patients who suffered out-of-hospital cardiac arrest were excluded. The elderly were defined as those over 75 years of age.
The diagnosis of AMI was based on the criteria from the following organizations: Joint European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, and World Heart Federation Task Force definition (10). AMI was indicated in the presence of at least one of the following features, including: symptoms of ischemia, new ST-T changes or development of pathologic Q waves in electrocardiography (ECG), evidence of further loss of viable myocardium, or regional wall motion abnormalities in imaging findings. AMI was defined as clinical evidence of ischemia with an increase or decrease in the troponin levels.
The hs-cTnT analyses were performed using the Elecsys 2010 system (Roche Diagnostics) with a limit of detection of 2 ng/L, a 99th-percentile cut-off point of 14 ng/L, and a coefficient of variation of less than 10 at 13 ng/L (11). We used the hs-cTnT levels measured at the earliest timing after the onset, and none of the patients were assessed earlier than one hour after the onset.
Hypertension was defined as a systolic blood pressure ≥140 mmHg, a diastolic blood pressure ≥90 mmHg, or the use of antihypertensive medication. Diabetes was defined using the guidelines of the Japan Diabetes Society (12), or in the case of patient use of diabetes medication. The plasma levels of low-density lipoprotein (LDL) cholesterol ≥160 mg/dL, plasma triglycerides <200 mg/dL, or the use of lipid-lowering agents indicated hypercholesterolemia. Stage 3 chronic kidney disease (CKD) or greater denoted impaired kidney function. Coronary artery disease (CAD) was defined by the presence of angina pectoris, myocardial infarction, or severe stenotic region(s) in the coronary artery, identified either by an angiogram or by computed tomography.
Continuous variables are presented as the mean ± standard deviation (SD); categorical variables are presented as numbers and percentages. Continuous and categorical variables were compared using the Mann-Whitney test and the Pearson χ2 test, respectively. Receiver operating characteristic (ROC) curves were constructed to assess the sensitivity and specificity of cTn measurements and to compare their ability to diagnose AMI. Logistic regression was used to combine the cTn levels at presentation with early changes in the cTn levels. A comparison of the areas under the ROC curves (AUC) was performed as recommended by DeLong et al. (13). The appropriate cut-off values were determined by the point furthest from the bisector of the ROC curve. All hypothesis testing was two-tailed, and p values of 0.05 were considered to be statistically significant. All statistical analyses were performed with R statistical software program.
The hs-cTnT levels of 355 consecutively enrolled patients were measured at presentation; 128 (36%) were over 75 years old. The elderly differed from those under 75 years of age in several baseline characteristics (see Table 1). Among the total subjects, 26 patients fulfilled the criteria of AMI, of whom, 8 were over 75 years old. As expected, the prevalence of hypertension (85% vs. 53%, p<0.001), diabetes (36% vs. 21%, p<0.001), prior coronary artery disease (29% vs. 13%, p<0.001), prior coronary artery bypass grafting (CABG) (9% vs. 2%, p<0.001), impaired kidney function (27% vs. 10%, p<0.001), previous stroke (20% vs. 8%, p<0.001), and estimated glomerular filtration (eGFR) <60 (54% vs. 24%, p<0.001) were significantly larger in the elderly than those under 75 years of age. Furthermore, the eGFR levels in the elderly were lower than those under 75 years old (58.89 mL/min/1.73 m2 vs. 78.94 mL/min/1.73 m2, p<0.001).
The appropriate cut-off values were determined based on the ROC curve for diagnosis of AMI (Fig. 1--3,3, Table 2). Based on the ROC curve analysis, the optimal cut-off value of hs-cTnT was 0.038 ng/mL, and sensitivity and specificity were 85% and 89%, respectively, with an overall AUC of 0.945 (Fig. 1). When we divided the subjects into two groups based on age, the optimal cut-off value of hs-cTnT for the AMI diagnosis in the elderly was 0.07 ng/mL, the sensitivity and specificity of which were 84% and 88%, respectively, with an AUC of 0.94; whereas, the optimal cut-off value of hs-cTnT in patients under 75 years was 0.02 ng/mL, the sensitivity and specificity of which were 76% and 100%, respectively, with an AUC of 0.95 (Fig. 2). When we compared the AUCs between the conventional cut-off value (0.014 ng/mL) and the values determined for each age group by ROC curve, the AUC in the elderly group was significantly larger than that of the conventional cut-off value (0.94 vs.0.629, p<0.001, Table 2). On the contrary, the difference in AUCs between ROC curve and conventional cut-off values in patients under 75 years was much smaller, although statistically significant (0.95 vs. 0.849, p<0.001, Table 2).
Similar trends were observed for the renal function; the optimal cut-off value of hs-cTnT for AMI diagnosis in the group with eGFR <60 mL/min/1.73 m2 was 0.239 ng/mL, the sensitivity and specificity of which were 95% and 80%, respectively, with an AUC of 0.899; whereas, the optimal cut-off value of hs-cTnT was 0.07 ng/mL in patients with a normal renal function, the sensitivity and specificity of which were 98% and 81%, respectively, with an AUC of 0.959 (Fig. 3). When we compared the AUCs between the conventional cut-off value (0.014 ng/mL) and the values determined for each renal function group by the ROC curve, the AUC in the group with eGFR <60 mL/min/1.73 m2 was significantly larger than that of the conventional cut-off value (0.899 vs. 0.615, p<0.001, Table 2). Conversely, the difference in AUCs determined by the ROC curve and those of conventional cut-off values was much smaller, although they were statistically significant (0.959 vs. 0.845, p<0.001, Table 2).
In this retrospective study, we investigated the diagnostic performance of hs-cTnT for the early diagnosis of AMI in the elderly. We found that the conventional cut-off value (99th percentile: 0.014 ng/mL) provided low specificity, particularly in the elderly or those with renal dysfunction.
The hs-cTnT assay is currently widely used in the global clinical setting for the diagnosis of AMI. In addition to its usage for making a diagnosis, there are a number of studies showing the prognostic value of the hs-cTnT levels, in addition to significant associations with other established biomarkers in different types of cardiac diseases (14-18). Determining the cut-off values is vitally important for any disease. In the case of hs-cTnT, the currently accepted cut-off value (0.014 ng/mL) was determined according to the 99th percentile of a healthy reference population. However, recent clinical studies have suggested that this value might not be appropriate in some specific individuals, such as in patients with renal dysfunction. In addition, a separate study demonstrated that the optimal cut-off value may also be different in the elderly. Determining the optimal cut-off values for these two groups is therefore quite important because both situations are apparent risk factors of AMI. In the current study, we demonstrate that the optimal cut-off values for renal patients and the elderly should be different from the conventional one in the Japanese population.
Another aspect we observed in this study was the complexity when the patient suffers from heart failure. The most frequent cause of false positive of hs-cTnT was heart failure (Table 3). It is not surprising that pressure and/or volume overload could lead to a mild elevation of the hs-cTnT as reported elsewhere (19). Accordingly, careful attention should be paid in such a situation.
The limitations associated with this study include its retrospective nature and observational analysis at a single center. However, it uses one of the largest sample sizes to investigate the diagnostic value of hs-cTnT in the Japanese population. In addition, our findings were consistent with previous studies. A further limitation of this study was lack of any data regarding the timing of measurements which could affect the values. However, at least one hour had passed since the onset in all of the patients in this study, thus, a significant elevation should be observed if the patients truly suffered AMI at that point. In addition, we assessed the initial hs-cTnT value, not the peak hs-cTnT values, which potentially undervalues the power of hs-cTnT. However, the initial assessment is the most important, since the judgement at that point should directly affect the prognosis of the patient. Related to this point, we also acknowledged the fact that sensitivity using conventional cut-off value was 100%, suggesting that the timing after the onset of all of our patients with MI might have been sufficient. A further study investigating the patients with a very acute phase (within oue hour after the onset) would be needed. In addition, most of the patients with AMI (nineteen out of twenty-six) were ST-elevation MI (STEMI), where the information for hs-cTnT is not necessarily needed for the diagnosis of AMI. Accordingly, a further study investigating a sufficient number of patients with non-STEMI could more fully elucidate the clinical usefulness of hs-cTnT. Finally, we could not evaluate whether or not an older age is an independent predictor of the elevated hs-cTnT. Further studies are therefore needed to elucidate this point using a sufficient number of study samples.
In summary, these data suggest that the conventional cut-off value (99th percentile: 0.014 ng/mL) provides low specificity in the elderly in addition to those with renal dysfunction. When measuring hs-cTnT, careful assessments are therefore needed in the elderly.
The authors state that they have no Conflict of Interest (COI).
We express our special thanks to Kazuko Honda and Takako Ohbayashi (staff of Kanazawa University)