IJCA-18413; No of Pages 6 International Journal of Cardiology xxx (2014) xxx–xxx

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

High-sensitivity cardiac troponin for risk prediction in patients with and without coronary heart disease☆,☆☆ Willibald Hochholzer ⁎,1, Christian M. Valina 1, Christian Stratz, Michael Amann, Daniel Schlittenhardt, Heinz Joachim Büttner, Dietmar Trenk, Franz-Josef Neumann Universitaets-Herzzentrum Freiburg · Bad Krozingen, Klinik für Kardiologie und Angiologie II, Suedring 15, 79189 Bad Krozingen, Germany

a r t i c l e

i n f o

Article history: Received 20 December 2013 Received in revised form 30 May 2014 Accepted 26 July 2014 Available online xxxx Keywords: Troponin Risk prediction Mortality Coronary heart disease Prognosis

a b s t r a c t Background: In stable patients with unknown coronary anatomy, higher levels of cardiac troponin are associated with an increased risk of cardiovascular events. It was supposed that this association might be explained by the ability of cardiac troponin to detect minor myocardial necrosis which might be caused by subclinical coronary atherosclerosis. Thus, this analysis tested if the predictive value of high-sensitivity troponin T (hsTnT) in stable patients is dependent of the presence or absence of angiographically documented coronary heart disease. Methods: Stable patients undergoing elective coronary angiography were enrolled (n = 2046). HsTnT was determined before diagnostic procedures. The patients were followed for up to seven years. Primary endpoint was all-cause mortality or non-fatal myocardial infarction. All endpoints were adjudicated by independent physicians. Results were adjusted to a clinical model including independent clinical predictors of the primary endpoint. Results: Out of the 2046 patients enrolled, 1236 (60%) had a diagnosis of obstructive coronary heart disease. HsTnT predicted independently the primary endpoint (adjusted HR 1.33, 95%-CI 1.21–1.46, P b 0.001). The use of hsTnT in addition to the clinical model significantly improved discrimination (c-statistic: 0.751 to 0.773, P b 0.001) as well as reclassification of the primary endpoint (NRI = 0.362, P b 0.001). This significant improvement persisted across various subsets and was independent of the presence of clinically detectable coronary heart disease and other variables. Conclusion: The use of hsTnT in addition to clinical variables significantly improves discrimination and reclassification of patients with respect to all-cause mortality or non-fatal myocardial infarction irrespective of the presence of clinically detectable coronary heart disease. Clinical Trial Registration: ClinicalTrials.gov (Identifier: NCT00457236). © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Cardiac troponin is an established marker of cardiac necrosis with unchallenged myocardial tissue specificity, and has a large body of evidence for therapeutic decision-making in the setting of acute coronary syndromes (ACS) [1–3]. Recently, novel cardiac troponin assays have been introduced with improved sensitivity. These high-sensitivity assays allow for the first time the detection of troponin levels in 25–80% of subjects from stable populations depending

☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ☆☆ Grant support: This work was supported by Roche Diagnostics by provision of laboratory kits for high-sensitivity troponin T. ⁎ Corresponding author. Tel.: +49 7633 4020; fax: +49 7633 4022489. E-mail address: [email protected] (W. Hochholzer). 1 Both authors have contributed equally to this manuscript.

on clinical background and assay used [4–6]. In stable patients with unknown coronary anatomy, higher levels of cardiac troponin are associated with an increased risk of cardiovascular events as demonstrated by recent analyses of large cohorts [5–7]. This association may be explained by the ability of cardiac troponin to reveal subclinical and thus yet undiagnosed coronary atherosclerosis since higher levels of cardiac troponin are seen in patients with established coronary heart disease (CHD) [5,6,8,9]. It is currently unclear, however, whether this is the sole mechanism for the association between cardiac troponin and cardiovascular risk in stable patients with unknown coronary anatomy. In this setting, cardiac troponin may also reflect other subclinical cardiac and non-cardiac pathologies and thus may predict outcome even in patients in whom coronary artery disease is excluded by coronary angiography. We, therefore, sought to test the hypothesis that the predictive value of highsensitivity cardiac troponin (hsTnT) in stable patients is independent of the presence or absence of angiographically documented CHD.

http://dx.doi.org/10.1016/j.ijcard.2014.07.094 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Hochholzer W, et al, High-sensitivity cardiac troponin for risk prediction in patients with and without coronary heart disease, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.094

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W. Hochholzer et al. / International Journal of Cardiology xxx (2014) xxx–xxx

2. Methods

3. Results

2.1. Study population

3.1. Study population

This study represents a secondary analysis as prespecified by protocol of the prospective observational EXCELSIOR trial (Impact of Extent of Clopidogrel-Induced Platelet Inhibition during Elective Stent Implantation on Clinical Event Rate; ClinicalTrials.gov Identifier: NCT00457236) [10,11]. In brief, patients with stable angina pectoris and suspected obstructive CHD scheduled for elective cardiac catheterization were eligible for the study. The primary analysis investigated the impact of on-clopidogrel platelet function on the clinical outcome of patients undergoing coronary intervention. Major exclusion criteria were acute myocardial infarction (MI) with a rise and fall of cardiac troponin as defined by current guidelines [12], signs of ischemia at rest, more than mild valvular heart disease, chronic oral anticoagulation, thienopyridine pretreatment, active cancer, hemodialysis, and hemodynamic instability. All patients underwent full cardiovascular assessment including ECG, echocardiography, and coronary angiography. From 2003 to 2004, 2053 patients were enrolled in this study. Blood samples for biomarker testing were missing from 7 patients leaving 2046 individuals. All patients gave written informed consent. The study was approved by the ethics committee of the University of Freiburg, Germany. Results of coronary angiography regarding vessels of more than 1.5 mm in diameter were divided into four groups according to grade of stenosis: b20%: no or only very minor visible coronary changes; 20–49%: minimal coronary changes; 50–74%: intermediate coronary obstruction; and ≥75% (or left main disease ≥50%): hemodynamically relevant coronary obstruction.

Seven out of 2053 enrolled patients were excluded due to missing blood samples for biomarker testing leaving 2046 individuals for the present analysis. Baseline characteristics of the cohort are shown in Table 1. Patients that reached the primary endpoint were older and more often male, had a higher proportion of established cardiovascular risk factors and coronary atherosclerosis, had a higher mean risk score, lower mean hemoglobin, glomerular filtration rate, and LDL cholesterol levels, and higher plasma levels of hsTnT. A hemodynamically relevant obstructive CHD was diagnosed in 1236 (60%) of these patients. A five-year follow-up was available in 94% of patients. During a median follow-up of 69 months (interquartile range: 64–75 months), the combined primary endpoint of all-cause mortality or non-fatal MI occurred in 325 patients. A fatal event was recorded in 240 patients, 151 of these deaths were classified as cardiovascular. A non-fatal MI was diagnosed in 111 patients, out of these, 30 events were adjudicated as ST-segment elevation MI. 3.2. Cox regression analyses

2.2. Clinical endpoints To obtain a complete follow-up, all patients were contacted in written form and asked to fill in a standardized questionnaire on a regular basis up to seven years after enrolment. In case of no response, a second letter was sent to the patient or the primary physician. Source documents were obtained for all events if available. All analyzed endpoints were adjudicated by two independent cardiologists who had access to all available medical records and entered their diagnosis into a secured data base. An automated algorithm for comparison of results sent all potential endpoints with diagnostic disagreement for review and adjudication to a third cardiologist. MI was defined and coded according to the Universal Definition of Myocardial Infarction [12]. The primary endpoint of the present analysis was the composite of all-cause mortality and non-fatal MI. Key secondary outcomes were the single of all-cause mortality and non-fatal MI as well as the composite of cardiovascular mortality and non-fatal MI excluding MI of type 2 (infarction related to myocardial oxygen supplies and demand).

2.3. Laboratory procedures Blood samples for biomarker testing were collected after enrolment into serum tubes and before coronary angiography. Within 1 h, samples were carefully processed and frozen at − 80 °C until assayed in a blinded fashion in the central laboratory. Highsensitivity troponin T (hsTnT) was measured with a sandwich enzyme electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany) using lot number 153401 that is not affected by the recently detected shift in the low end measuring range. This assay has a limit of blank of 3 ng/L, a 99th-percentile of a healthy population cut-off point of 14 ng/L, and a coefficient of variation of less than 10% at 13 ng/L [13]. Creatinine clearance was estimated with the use of the Cockcroft–Gault formula.

2.4. Statistics For this analysis, the screening cohort of EXCELSIOR including all patients with and without coronary intervention was used. In general, discrete variables are reported as counts (percentages) and continuous variables as mean ± standard deviation. NonGaussian continuous variables identified by Kolmogorov–Smirnov test were described as median (interquartile range). For discrete variables, we tested differences between groups with the χ2-test or Fisher exact test when expected cell sizes were less than 5. We used the two-tailed t-test to compare continuous variables, or the Mann–Whitney U test for non-Gaussian variables. In the 2-sided test, a P value b 0.05 was regarded as significant. Cox proportional hazards models were used to calculate hazard ratios (HR) with associated 95%-confidence intervals (CIs). Results of hsTnT were entered log-transformed given their non-parametric distribution. For certain analyses, hsTnT levels were grouped into computer generated bins with a width of N1 ng/L of hsTnT and a target bin size of more than 100 patients. To assess sensitivity, specificity, and c-statistic of risk scores and hsTnT, receiver operating characteristic curves were constructed. The method described by DeLong was used for comparison of c-statistics (area under the receiver operating characteristic curve). Calibration was determined by Hosmer–Lemeshow testing. To evaluate the improvement of the model by adding hsTnT, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated using the algorithms developed by Frank Harrell (based on Pencina's method) [14]. Statistical analyses were run in R, Version 2.10.1 (R Development Core Team, Vienna, Austria).

The clinical model used for adjustment is shown in Table 2. Independent predictors for death or non-fatal MI during follow-up were identified by COX regression analysis with backwards step-wise exclusion. This model showed a good calibration for the primary endpoint (Hosmer–Lemeshow P = 0.41). Quite unusually, hypercholesterolemia was associated in this model with reduced risk. However, further analyses demonstrated that patients with this risk factor had a significantly lower incidence of diabetes, active smoking, and reduced left ventricular function, which might explain this finding. HsTnT independently predicted the primary endpoint (unadjusted HR 1.62, 95%-CI 1.51–1.71, P b 0.001; adjusted HR 1.29, 95%-CI 1.17– 1.42, P b 0.001; Supplementary Fig. A) as well as the single endpoints (death: adjusted HR 1.41, 95%-CI 1.27–1.56, P b 0.001; MI: adjusted HR 1.23, 95%-CI 1.04–1.46, P = 0.02). No significant interactions of hsTnT and important baseline characteristics (age, sex, body mass index, diabetes, renal function, left ventricular function) were found with respect to the primary endpoint (PInteract. N 0.26). Only the results of the coronary angiography performed after cardiac troponin testing showed a significant interaction with hsTnT for prediction of death or non-fatal MI (PInteract. = 0.009) — however, hsTnT persisted as independent predictor of death or non-fatal MI in all subgroups of this variable (adjusted HR for no CAD [b20% obstruction]: 4.35, 95%-CI 1.07–17.71, P = 0.04; minimal CAD [20–49% obstruction]: 1.92, 95%CI 1.26–2.94, P = 0.002; intermediate CAD [50–74% obstruction]: 1.13, 95%-CI 1.02–1.23, P = 0.03; obstructive CAD [≥75% obstruction or left main disease ≥50%]: 1.31, 95%-CI 1.18–1.45, P b 0.001). Kaplan–Meier graphs for the primary endpoint according to these four subgroups are shown in Supplementary Fig. B. Increasing levels of hsTnT were not only associated with increasing mortality but also with an increasing incidence for non-fatal MI (Table 3 and Fig. 1). This increase was already seen for levels of hsTnT slightly above the limit of detection but far below the 99th-percentile of a healthy population. After adjustment for the clinical model, this clear association prevailed for mortality but was damped for non-fatal MI (Fig. 1). Calibration of hsTnT was acceptable (Hosmer–Lemeshow P = 0.06) for death or non-fatal MI as well as for the single endpoints mortality (Hosmer–Lemeshow P = 0.06) and non-fatal MI (Hosmer– Lemeshow P = 0.83). 3.3. Discrimination and reclassification analyses HsTnT showed a good discrimination for death or non-fatal MI (c-statistic = 0.727), mainly driven by the discrimination for

Please cite this article as: Hochholzer W, et al, High-sensitivity cardiac troponin for risk prediction in patients with and without coronary heart disease, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.094

W. Hochholzer et al. / International Journal of Cardiology xxx (2014) xxx–xxx Table 1 Baseline characteristics. Death or non-fatal myocardial infarction during follow-up

Age (years) Male Active smoker Arterial hypertension Hypercholesterolemia Diabetes mellitus Body mass index (kg/m2) Hemoglobin (g/dL) LDL cholesterol (mmol/L) Glomerular filtration rate (mL/min) High-sensitivity troponin T (ng/L) Medication on admission Aspirin β-Blockers ACE inhibitors Nitrates Statins Previous balloon angioplasty Previous CABG Previous myocardial infarction Left ventricular ejection fraction ≥55% 40–54% 30–39% b30% CCS Angina class III or IV NYHA class III or IV Coronary angiography result None (b20% obstruction) Minimal (20–49% obstruction) Intermediate (50–74% obstruction) Obstructive (≥75% obstruction)a Extent of coronary heart disease 1-vessel disease 2-vessel disease 3-vessel disease Coronary stent implantation Coronary artery bypass surgery

P

Yes

No

n = 325

n = 1721

70 ± 8 254 (78.2%) 33 (10.2%) 286 (88.0%) 284 (87.4%) 116 (35.7%) 27.4 ± 3.7 14.1 ± 1.2 3.2 ± 1.0 73 ± 24 10.9 (5.5–21.2)

64 ± 10 1134 (65.9%) 206 (12.0%) 1328 (77.2%) 1497 (87.0%) 322 (18.7%) 27.8 ± 4.0 14.4 ± 1.4 3.4 ± 1.0 82 ± 21 4.7 (3.0–8.2)

b0.001 b0.001 0.35 b0.001 0.84 b0.001 0.08 b0.001 0.002 b0.001 b0.001

324 (99.7%) 224 (68.9%) 175 (53.8%) 116 (35.7%) 180 (55.4%) 120 (36.9%) 64 (19.7%) 109 (33.5%)

1718 (99.8%) 1138 (66.1%) 719 (41.8%) 408 (23.7%) 860 (50.0%) 503 (29.2%) 161 (9.4%) 335 (19.5%)

0.62 0.33 b0.001 b0.001 0.07 0.006 b0.001 b0.001 b0.001

156 (48.0%) 86 (26.5%) 61 (18.8%) 22 (6.8%) 103 (31.7%) 74 (22.8%)

1231 (71.5%) 336 (19.5%) 126 (7.3%) 28 (1.6%) 377 (21.9%) 167 (9.7%)

6 (1.8%) 31 (9.5%) 24 (7.4%) 264 (81.2%)

295 (17.1%) 315 (18.3%) 139 (8.1%) 972 (56.5%)

50 (15.4%) 74 (22.8%) 167 (51.4%) 162 (49.8%) 18 (5.5%)

347 (20.2%) 343 (19.9%) 477 (27.7%) 640 (37.2%) 72 (4.2%)

b0.001 b0.001 b0.001

b0.001

b0.001 0.28

Data are expressed as mean value + SD (for high-sensitivity troponin T: median and quartiles) or number of patients (percentage). P by one-way ANOVA, Mann Whitney U, or χ2 test. a Or left main disease ≥50%.

mortality (c-statistic = 0.759) which was higher than for non-fatal MI (c-statistic = 0.644). The use of hsTnT in addition to the clinical model significantly improved discrimination (c-statistic from 0.751 to 0.773, P b 0.001) as well as reclassification of death or non-fatal MI (NRI = 0.362, 95%-CI 0.243–0.481, P b 0.001; IDI = 0.017, P b 0.001). This improvement of NRI and IDI was similar for patients with and without obstructive coronary heart disease (Fig. 2). The significant improvement in reclassification persisted also across multiple subgroups as shown in Fig. 3. The use of hsTnT also improved the reclassification of mortality (c-statistic from 0.770 to 0.795; NRI = 0.409, 95%-CI 0.274–0.543, P b 0.001; IDI = 0.018, P b 0.001) and non-fatal MI as single endpoint (c-statistic from 0.731 to 0.738; NRI = 0.194, 95%-CI 0.003– 0.386, P = 0.04; IDI = 0.004, P = 0.02).

3.4. Sensitivity analyses Since cardiac troponin might be mainly a marker for cardiovascular mortality, a sensitivity analysis excluding the 89 non-cardiovascular out of 240 fatal events was performed showing similar results as for all-cause mortality (adjusted HR for cardiovascular mortality: 1.34,

3

95%-CI 1.16–1.53, P b 0.001; discrimination for cardiovascular mortality: c-statistic = 0.727; improvement of discrimination: c-statistic from 0.748 to 0.770, P b 0.001; reclassification of cardiovascular mortality: NRI = 0.324, 95%-CI 0.207–0.442, P b 0.001; IDI = 0.005, P b 0.001). The corresponding analysis for the 89 non-cardiovascular fatal events provided similar findings (adjusted HR for non-cardiovascular mortality: 1.39, 95%-CI 1.15–1.67, P b 0.001; discrimination for non-cardiovascular mortality: c-statistic = 0.707; improvement of discrimination: c-statistic from 0.748 to 0.765, P b 0.001; reclassification of non-cardiovascular mortality: NRI = 0.212, 95%-CI 0.092– 0.336, P b 0.001; IDI = 0.003, P b 0.001). Four out of 111 non-fatal MIs (3.6%) were adjudicated as secondary MI not resulting from coronary obstruction (type 2 according to Universal Definition of MI). Sensitivity analyses excluding these four events showed consistent results. To evaluate if hsTnT is a short-term and/or long-term predictor of death or non-fatal MI, landmark analyses were created indicating that hsTnT predicts both short- and long-term outcome (landmark ≤ 30 days following troponin testing: unadjusted HR 1.73, 95%-CI 1.27–2.35, P = 0.001; adjusted HR 1.48, 95%-CI 0.95–2.28, P = 0.08; landmark N 30 days: unadjusted HR 1.62, 95%-CI 1.50–1.74, P b 0.001; adjusted HR 1.28, 95%-CI 1.16–1.41, P b 0.001). When analyzing only patients with hsTnT at admission of ≤14 ng/L, hsTnT still independently predicted the primary endpoint (unadjusted HR 1.81, 95%-CI 1.48–2.22, P b 0.001; adjusted HR 1.42, 95%-CI 1.14– 1.76, P = 0.001). 4. Discussion The results of the present analysis demonstrate that cardiac troponin can predict risk even in patients with no or only minimal coronary obstruction. This prognostic value also remained constant irrespective of left ventricular function, cardiovascular risk, age, or other risk factors. Cardiovascular risk prediction is a major cornerstone for therapy stratification in stable subjects. If patients are already diagnosed with diabetes or have an established CHD, they are considered to be already at high risk [15]. For all other stable subjects in primary prevention, the use of risk scores such as the Framingham Risk Score [16,17] and the SCORE [15,18] are recommended for therapy stratification by American and European guidelines. Apart from clinical risk scores, multiple biomarkers such as C-reactive protein or cardiac troponin and other tests have been proposed for cardiovascular risk prediction in stable subjects [5–7,19–22]. Several mechanisms have been supposed leading to the predictive value for cardiovascular events such as the detection of inflammatory processes. However, the early increase in cardiovascular event rates in subjects identified to be at higher risk by biomarkers and scores suggest that the predictive value might be based on the detection of significant cardiac pathologies that are undiagnosed so far. This theory is supported by data linking levels of biomarkers and in particular levels of cardiac troponin to the extent of different cardiac pathologies such as coronary plaque burden [5,6,8,9,23]. However, if the predictive value of biomarkers (and risk scores as well) is based on the identification of patients with non-significant cardiac disease that develop subsequent cardiovascular events, it is uncertain if risk scores or cardiac specific biomarkers still apply if ischemic or structural heart disease is excluded since the risk for subsequent cardiovascular events might be lower than in subjects in whom structural heart disease is not ruled out. The present analysis focused on stable patients with full cardiac assessment including ECG, echocardiography and coronary angiography. The use of hsTnT in addition to a specifically for this cohorts developed risk model significantly improved risk prediction. This finding was irrespective of coronary status, left ventricular function, or other clinical factors. After the introduction of high-sensitivity cardiac troponin assays into clinical routine, this finding is of particular interest, since significant proportions of stable patients present in different

Please cite this article as: Hochholzer W, et al, High-sensitivity cardiac troponin for risk prediction in patients with and without coronary heart disease, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.094

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W. Hochholzer et al. / International Journal of Cardiology xxx (2014) xxx–xxx

Table 2 Cox regression model for death or non-fatal MI during follow-up. Whole model

Age (per decade) Male Active smoker Arterial hypertension Hypercholesterolemia Diabetes mellitus Body mass index (kg/m2) Hemoglobin (g/dL) LDL cholesterol (mmol/L) Glomerular filtration rate (mL/min) High-sensitivity troponin T (ng/L) Medication on admission Aspirin β-Blockers ACE inhibitors Nitrates Statins Previous balloon angioplasty Previous CABG Previous myocardial infarction Left ventricular ejection fraction (compared to ≥55%) 40–54% 30–39% b30% CCS angina class III or IV NYHA class III or IV Coronary angiography result (compared to no obstruction [b20%]) Minimal (20–49%) Intermediate (50–74%) Obstructive (≥75%a) Extent of coronary heart disease (compared to no vessel disease) 1-vessel disease 2-vessel disease 3-vessel disease Coronary stent implantation Coronary artery bypass surgery

Final model

HR

95%-CI

P

HR

95%-CI

P

1.49 1.34 1.34 1.45 0.75 1.63 0.96 0.97 0.99 1.00 1.25

(1.27–1.76) (0.98–1.82) (0.90–2.02) (1.01–2.08) (0.51–1.09) (1.26–2.11) (0.93–0.99) (0.88–1.07) (0.87–1.13) (0.99–1.00) (1.12–1.40)

b0.001 0.07 0.15 0.04 0.13 b0.001 0.007 0.53 0.89 0.30 b0.001

1.49

(1.30–1.71)

b0.001

1.48 0.70 1.58 0.96

(1.05–2.09) (0.50–0.98) (1.24–2.01) (0.93–0.99)

0.03 0.04 b0.001 0.01

1.29

(1.17–1.42)

b0.001

0.78 0.92 1.13 1.12 0.83 0.97 1.19 1.06

(0.10–6.20) (0.71–1.20) (0.89–1.45) (0.87–1.43) (0.64–1.10) (0.74–1.27) (0.86–1.65) (0.78–1.41)

0.82 0.52 0.30 0.37 0.17 0.82 0.29 0.71

1.20 1.55 2.10 0.99 1.59

(0.88–1.64) (1.07–2.30) (1.22–3.66) (0.76–1.28) (1.17–2.14)

0.26 0.02 0.01 0.91 0.003

1.39 1.88 2.68

(1.06–1.82) (1.36–2.58) (1.63–4.35)

0.02 b0.001 b0.001

1.55

(1.17–2.05)

0.002

4.37 4.33 5.77

(1.66–11.49) (1.40–13.37) (1.86–17.89)

0.003 0.011 0.002

3.75 3.96 6.32

(1.56–9.02) (1.60–9.80) (2.77–14.44)

1.00 1.13 1.32 1.01 0.89

(0.51–1.98) (0.55–2.34) (0.64–2.72) (0.76–1.35) (0.51–1.58)

1.00 0.74 0.46 0.93 0.69

0.003 0.003 b0.001

Independent predictors for death or non-fatal MI during follow-up were identified by COX regression analysis with backwards step-wise exclusion. a Or left main disease ≥50%.

cardiovascular and non-cardiovascular settings with detectable levels of cardiac troponin of uncertain clinical significance so far [1–3]. Apart from full cardiac assessment in all patients and analysis of multiple subgroups, further important features of the present analysis are the long-term follow-up with all endpoints adjudicated by independent reviewers, and the uniform treatment of all patients. The reasons for the finding that clinical risk prediction with hsTnT appears to work independently of a clinically detectable underlying cardiovascular disease remain a matter of further research, similar as the independent prediction of non-cardiovascular events. Potential explanations are the detection of other non-cardiac pathologies associated with increased levels of cardiac troponin that might boost the risk Table 3 Incidence of death or myocardial infarction during long-term follow-up. High-sensitivity troponin T

b3.0 ng/L 3.0–4.9 ng/L 5.0–6.9 ng/L 7.0–8.9 ng/L 9.0–10.9 ng/L 11.0–13.9 ng/L 14.0–17.9 ng/L 18.0–29.9 ng/L ≥30.0 ng/L

n

624 361 272 222 139 113 95 119 101

Death

MI

Death or MI

n

%

n

%

n

%

23 20 23 23 15 20 29 47 40

3.7% 5.5% 8.5% 10.4% 10.8% 17.7% 30.5% 39.5% 39.6%

19 11 16 14 7 10 7 17 10

3.0% 3.0% 5.9% 6.3% 5.0% 8.8% 7.4% 14.3% 9.9%

41 29 37 35 21 28 32 60 42

6.6% 8.0% 13.6% 15.8% 15.1% 24.8% 33.7% 50.4% 41.6%

for cardiovascular events such as chronic obstructive pulmonary disease or other pulmonary diseases and the detection of cardiac pathologies not detectable by imaging techniques so far [24,25]. Further data suggest the detection of other pathophysiological and not cardiacspecific mechanisms such as cytokine mediated apoptosis or inflammation which might increase event rate in many ways [26,27]. Another important finding of the present analysis was that the risk for the combined as well as for the single endpoints increased already at very low troponin levels far below the 99th-percentile of a healthy population. Similar results were also seen in other large cohorts of stable patients with either established CHD or predominantly without known vascular disease [5,6,22]. This extents the previous findings with less sensitive troponin assays [28] and indicates that even with current high-sensitivity assays almost all detectable levels of cardiac troponin are associated with increased risk, even if these levels are far below the detection limits of previous assays and below what is considered within the range of a healthy population with current assays. Similar to what was described for hsTnT in other stable populations [5,6], hsTnT was detectable in ~70% of patients in the present analysis. Thus, an elevated hsTnT escorted the majority of patients undergoing cardiovascular assessment. The reason for this elevation is a matter of ongoing discussion and might represent cardiomyocyte turnover [1]. Cardiac troponin testing has certain advantages compared to other approaches of cardiovascular risk prediction given its wide availability, short testing time, the experience of most physicians with this test, and its myocardial tissue specificity [1,2]. Recent studies evaluated

Please cite this article as: Hochholzer W, et al, High-sensitivity cardiac troponin for risk prediction in patients with and without coronary heart disease, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.094

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Fig. 1. Unadjusted and adjusted Cox regressions models. MI, myocardial infarction. CI, confidence interval. Adjusted for model shown in Table 2.

different approaches such as C-reactive protein, brain natriuretic peptides, coronary artery calcium scoring, or carotid intima-media thickness measurements for improvement of discrimination and reclassification of risk scores [19,21,29,30]. However, results from more than 246,000 subjects suggest that assessment of C-reactive protein can improve prediction of cardiovascular events but this improvement appears to be very limited with an increase in c-statistics of less than 1% [20]. The major limitation of imaging studies is the limited availability, potential variability in results depending on used technique or experience of investigator, and the potential of harm (e.g., radiation

exposure). Thus, cardiac troponin might be the optimal additional test to improve discrimination of established clinical scores.

4.1. Limitations This analysis enrolled only patients scheduled for elective coronary angiography which received to a considerable proportion already medications affecting lipid levels or arterial hypertension. Thus, it cannot be excluded that this has affected the prognostic value of risk prediction.

Fig. 2. Prognostic performance and reclassification improvement by high-sensitivity troponin T for death or non-fatal MI in patients with and without obstructive coronary heart disease. *Coronary heart disease: result of angiography during index hospitalization. P-value of NRI and IDI b 0.01.

Please cite this article as: Hochholzer W, et al, High-sensitivity cardiac troponin for risk prediction in patients with and without coronary heart disease, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.094

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W. Hochholzer et al. / International Journal of Cardiology xxx (2014) xxx–xxx

References

Fig. 3. Reclassification improvement by high-sensitivity troponin T for death or non-fatal MI in various subgroups. *Cardiovascular risk estimated by the SCORE [18]. †P-value of NRI and IDI b 0.05 except for subgroups “age b 60 years” (NRI: P = 0.08; IDI: P = 0.11) and “NYHA class III/IV” (NRI: P = 0.01; IDI: P = 0.08). GFR, glomerular filtration rate. LV-EF, left ventricular ejection fraction.

Even if only stable patients with full cardiac assessment and without any known acute conditions were enrolled into the present analysis, it cannot be excluded that elevations in hsTnT were in part caused by underlying undiagnosed diseases. 5. Conclusion The use of hsTnT in addition to clinical risk prediction significantly improves discrimination and reclassification of patients with respect to all-cause mortality or non-fatal myocardial infarction as well as cardiovascular and non-cardiovascular mortality to a clinically meaningful extent irrespective of the presence of clinically detectable coronary heart disease or other variables. The findings of the present analysis might help to establish cardiac troponin as valuable marker for patients outside the setting of ACS and may help guide therapeutic decisions for primary prevention. However, further prospective trials are needed to confirm these data and clarify the clinical significance. Conflicts of interest Dr. Trenk reports receiving consulting and lecture fees from Eli Lilly, Daiichi Sankyo, AstraZeneca, Bayer Vital, Bristol Myers Squibb, Boehringer Ingelheim KG, and Merck Sharp & Dohme. All other authors report no conflict of interests. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2014.07.094.

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Please cite this article as: Hochholzer W, et al, High-sensitivity cardiac troponin for risk prediction in patients with and without coronary heart disease, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.094