European Journal of Internal Medicine 25 (2014) 739–744
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Troponin T in acute heart failure: Clinical implications and prognosis in the Spanish National Registry on Heart Failure María Esther Guisado Espartero ⁎, Prado Salamanca-Bautista, Oscar Aramburu-Bodas, Jose L. Arias-Jimenez, Francesc Formiga, Bernardino Roca-Villanueva, Jose M. Cerqueiro-Gonzalez, Meliton F. Davila-Ramos, Marta Sanchez-Marteles, Manuel Montero-Perez-Barquero Department of Internal Medicine, Hospital Infanta Margarita, Avenida Góngora s/n, CP: 14940 Cabra, Córdoba, Spain
a r t i c l e
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Article history: Received 2 March 2014 Received in revised form 17 August 2014 Accepted 20 August 2014 Available online 6 September 2014 Keywords: Heart failure Troponin T Prognosis
a b s t r a c t Background: Elevated troponin in heart failure has been associated with worse prognosis, but there are differences in the design and results of published studies. Our objective was to determine the association of troponin T with mortality and readmissions in patients with acute heart failure in clinical practice conditions. Methods: We included patients from the RICA registry who were hospitalized for acute heart failure. They were classified into 3 groups according to troponin T levels: normal, intermediate and high (b 0.02, 0.02–0.049 and ≥0.05 ng/mL, respectively). Survival was studied by Kaplan–Meier curves and the association of variables was tested by Cox regression analysis. Results: A total of 406 patients was included. Average age was 76.9 (76.0–77.7) years. Hypertensive heart disease was the most common etiology. Left ventricular ejection fraction was b 45% in 22.1% of the patients. The group with elevated troponin T had higher proportions of women, systolic dysfunction, renal failure and anemia, a lower body mass index and longer hospital stay. At one year, patients with elevated troponin T had higher mortality than patients with normal troponin (35.5 vs. 13.9%, p b 0.001). The composite event (mortality and readmissions) was also more frequent (51.6 vs. 30.9%, p b 0.001), but there were no differences in readmissions alone. Troponin T ≥0.02 ng/mL was independently associated with mortality. Conclusions: Elevated troponin T levels are common in patients with heart failure in clinical practice and are associated with increased mortality and events after one year of follow-up. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Congestive heart failure (HF) is a public health problem due to growing incidence and prevalence, high mortality and morbidity and elevated hospitalization costs [1]. Several biochemical markers are useful in the diagnosis, prognosis and monitoring of the treatment effect in HF. One of these, troponin, not only proves to be an excellent early marker for cardiac injury in acute coronary syndromes, but also allows detection of minor myocardial damage in HF [2,3]. Several studies have shown that mild or persistent elevation of cardiac troponin levels in patients with HF implied worse prognosis and was associated with an increased risk of death [3–13]. However, previously published results are discordant due to heterogeneous populations (mostly patients with reduced left ventricular
Abbreviations: HF, heart failure; TnT, troponin T; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; eGFR, estimated glomerular filtration rate; NTproBNP, N-terminal pro-B-type natriuretic peptide. ⁎ Tel.: +34 957021370; fax: +34 957 021 322. E-mail address: [email protected] (M.E. Guisado Espartero).
ejection fraction [LVEF]), different endpoints and varying clinical situations. In clinical practice, symptomatic patients with HF and preserved LVEF are presenting more frequently but available data are limited and the characteristics of these patients differ from those of patients with reduced LVEF [14,15]. The aim of this study was to analyze whether patients seen in Internal Medicine clinical practice settings with HF and elevated troponin had worse prognosis and increased risk of death or readmission for HF. 2. Material and methods 2.1. Patients Patient data were collected from the Spanish National Registry on Heart Failure (RICA), supported by the Heart Failure Working Group of the Spanish Society of Internal Medicine (SEMI-IC). This registry is a multicenter, prospective, cohort study that began in February 2008 and is still ongoing. It includes patients over 50 years of age presenting with a first episode of HF or decompensation of already identified
http://dx.doi.org/10.1016/j.ejim.2014.08.005 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
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chronic HF and preserved or reduced LVEF, according to the criteria of the European Society of Cardiology, admitted to Internal Medicine units of 52 Spanish public and private hospitals. The RICA registry has been described in previous publications [16–18]. For this study, only patients over 50 years of age with HF and available troponin T (TnT) were included. Other exclusion criteria were HF due to pulmonary hypertension, hospitalization for unstable angina or acute coronary syndrome, death during index hospitalization, inability to participate in the study or anticipated follow-up of less than one year. The investigation conformed to the principles outlined in the Declaration of Helsinki. The study protocol was approved by the Ethical Committee of the University Hospital “Reina Sofía”, Cordoba (Spain), and all patients provided informed consent. Confidentiality was maintained according to law.
2.2. Objectives of the study and follow-up Primary endpoint was death after one year of admission. Secondary endpoints examined the association of troponin with readmission due to worsening HF and a composite endpoint of death or readmission because of worsening HF. Hospital stay in days for the index admission was also evaluated. Total cohort and subgroups, according to preserved or reduced LVEF, were analyzed. Preserved LVEF was defined as at least 45%. Follow-up consisted of two visits scheduled at 3 months and one year.
2.3. Variables Data were collected at the time of enrollment, including demographic data, comorbidities, body mass index, New York Heart Association (NYHA) functional class and HF etiology. LVEF was determined by 2D echocardiography. Biochemical variables (hemoglobin, urea, sodium, potassium, creatinine, TnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were obtained at the time of hospital admission. Anemia was defined using the World Health Organization criteria: hemoglobin b12 g/dL in women and b13 g/dL in men. The estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation (MDRD-4). The pooled population was divided into three troponin groups: normal TnT (b0.02 ng/mL); intermediate TnT (0.02–0.049 ng/mL) and elevated TnT (≥0.05 ng/mL). Although TnT levels were not determined centrally, the cutoff points used by the laboratories were similar in all centers.
2.4. Statistical methods Continuous variables were expressed as mean (95% confidence interval) and categorical variables as frequencies and percentages. Continuous variables were compared using a non-parametric test (Kruskal Wallis H test) and ANOVA test after rank transformation of data and the Bonferroni post-hoc for pairwise comparisons. Categorical variables were compared with the Chi-square test and after the Tukey test to examine differences between groups. One-year mortality and readmission for worsening HF were evaluated using the Kaplan–Meier method. Univariate analysis to evaluate hazard ratios (HRs) were performed using Cox proportional hazards models. A multivariable analysis was then conducted using the Cox regression model adjusted for variables with a p-value of b0.1 in the univariate analysis. Moreover, a binary logistic regression by mortality, readmission and composite event was performed to study confounding variables. A p-value of less than 0.05 was considered statistically significant. All analyses were performed with the Statistical Package for the Social Sciences (SPSS) program (version 15.0).
3. Results 3.1. Baseline characteristics of patients The study cohort included 406 patients. Patients from the RICA Registry with TnT measured at admission were similar to those without TnT determinations in terms of epidemiology, etiology of HF, NYHA class, anemia and degree of renal dysfunction. However, in patients with reduced LVEF, TnT was determined more frequently (71.8% vs. 65.3%; p = 0.02) (Table 1). Baseline characteristics of the total cohort and of the three TnT groups are presented in Table 2. The mean age of the total cohort was 76.9 (76.0–77.7) years, and 171 (42.1%) were males. A third of the patients had reduced LVEF. Hypertensive heart disease (42.6%) was the most frequent etiology. Mean TnT at admission was 0.09 (0.07–0.12) ng/mL and 60% of patients had TnT above normal limits. The group with elevated TnT (30.5%) had a greater proportion of women, reduced LVEF, anemia, worse renal function and lower BMI, in addition to being older. 3.2. Endpoints and follow-up After 1 year of follow-up, 98 patients (24.1%) died and 97 (23.9%) were readmitted because of worsening HF. One hundred and sixty-six (166) patients (40.9%) had the composite event of death or readmission for HF. Intermediate or elevated TnT was more common in patients who died and in those from the composite event group (p ≤ 0.001). Patients with elevated TnT had also more readmissions but this did not reach statistical significance (Table 3). Fig. 1 shows the survival curves by troponin groups. Patients with intermediate or elevated TnT were associated with poorer prognosis with greater mortality and more composite events. The univariate Cox proportional hazard analysis to predict mortality and composite event showed that intermediate or elevated TnT was associated with the highest risk for both endpoints. TnT did not reach statistical significance when readmissions alone were considered. After multivariate Cox analysis, TnT ≥ 0.02 ng/mL was an independent predictor of mortality (Table 4). NYHA III–IV, eGFR b 60 mL/min/1.73 m2 and preserved LVEF were independent predictors of readmission for worsening HF (Table 5). NYHA III–IV, eGFR b 60 mL/min/1.73 m2 and anemia were independent predictors of the composite endpoint, but TnT was not (Table 6). A binary logistic regression by mortality, readmission and composite event was performed with age, female sex, BMI N 25 kg/m2, ischemic Table 1 Characteristics of patients with and without troponin determined at admission.
Age (years) Female HF etiology —Hypertension —Ischemic —Valvular NYHA III–IV LVEF b 45% Dyslipidemia Diabetes Hypertension eGFR b 60 mL/min/1.73 m2 Ischemic heart disease Previous HF Anemia
Patients with TnT values (n = 406)
Patients without TnT values (n = 842)
p-Value
76.9 (76.0–77.7) 235 (57.9)
76.4 (75.7–77.0) 439 (52.1)
0.28 0.06 0.72
173 (42.6) 101 (24.9) 74 (18.2) 200 (49.3) 121 (32.1) 184 (45.3) 207 (51.0) 344 (84.7) 241 (59.4) 89 (21.9) 309 (75.2) 227 (55.9)
336 (39.9) 211 (25.1) 154 (18.3) 461 (54.8) 223 (26.5) 406 (48.2) 363 (43.1) 712 (84.6) 491 (58.3) 182 (21.6) 595 (70.7) 481 (57.1)
0.15 0.02 0.34 0.01 0.94 0.85 0.98 0.10 0.69
Data are expressed as mean (95% confidence interval) for continuous variables and as frequencies (percentages) for categorical variables. TnT: troponin T; HF: heart failure; NYHA: New York Heart Association class; LVEF: left ventricular ejection fraction; eGFR: estimated glomerular filtration rate.
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Table 2 Characteristics of patients categorized by troponin groups: elevated (TnT ≥ 0.05 ng/mL), intermediate (TnT: 0.02–0.049 ng/mL) and normal (TnT b 0.02 ng/mL). Total (n = 406) Age (years) BMI (kg/m2) Female HF etiology: —Hypertension —Ischemic —Valvular NYHA III–IV LVEF b 45% LVEF Days of hospitalization Smoker Dyslipidemia Diabetes Hypertension eGFR b 60 mL/min/1.73 m2 Atrial fibrillation Ischemic heart disease Previous stroke/TIA COPD Peripheral arterial disease Previous HF Anemia Hemoglobin (g/dL) Potassium (mEq/L) Sodium (mEq/L) Urea (mg/dL) Creatinine (mg/dL) eGFR (MDRD-4) (mL/min/1.73 m2) NT-proBNP (pg/mL)
Normal TnT (n = 165)
Intermediate TnT (n = 117)
76.9 (76.0–77.7) 29.4 (28.8–30.0) 235 (57.9)
75.6 (74.3–77.0) 30.6 (29.6–31.6) 110 (66.7)
77.3 (75.8–78.9) 28.9 (27.7–30.0) 61 (52.1)
173 (42.6) 101 (24.9) 74 (18.2) 200 (49.3) 121 (32.1) 50.3 (48.8–51.8) 11.0 (10.1–11.9) 29 (7.1) 184 (45.3) 207 (51.0) 344 (84.7) 241 (59.4) 236 (58.1) 89 (21.9) 49 (12.1) 122 (30.0) 50 (12.3) 309 (75.2) 227 (55.9) 12.0 (11.7–12.2) 4.3 (4.2–4.4) 139.3 (138.9–139.8) 70.1 (66.5–73.8) 1.4 (1.3–1.4) 56.9 (54.3–59.5) 5761 (4932–6590)
78 (47.3) 27 (16.4) 37 (22.4) 79 (47.9) 27 (17.5) 54.5 (52.6–56.5) 9.1 (8.2–10.0) 7 (4.2) 75 (45.5) 81 (49.1) 136 (82.4) 76 (46.1) 100 (60.6) 27 (16.4) 20 (12.1) 45 (27.3) 13 (7.9) 117 (72.2) 78 (47.3) 12.2 (11.9–12.6) 4.3 (4.2–4.4) 139.4 (138.6–140.2) 60.3 (54.9–65.7) 1.1 (1.1–1.2) 65.6 (61.1–70.1) 3795 (2849–4741)
45 (38.5) 34 (29.1) 21 (17.9) 60 (51.3) 46 (43.4) 47.1 (44.0–50.3) 10.5 (9.0–12.0) 8 (6.8) 47 (40.2) 62 (53.0) 104 (88.9) 74 (63.2) 69 (59.0) 27 (23.1) 10 (8.5) 34 (29.1) 18 (15.4) 82 (73.9) 69 (59.0) 11.8 (11.4–12.2) 4.3 (4.2–4.5) 139.6 (138.8–140.4) 73.3 (66.7–79.8) 1.3 (1.2–1.4) 55.4 (51.0–60.0) 5315 (4132–6498)
Elevated TnT (n = 124) 78.1 (76.5–79.7) 28.3 (27.4–29.2) 64 (51.6) 50 (40.3) 40 (32.3) 16 (12.9) 61 (49.2) 48 (41.0) 47.7 (45.0–50.3) 14.0 (12.0–16.0) 14 (11.3) 62 (50.0) 64 (51.6) 104 (83.9) 91 (73.4) 67 (54.0) 35 (28.2) 19 (15.3) 43 (34.7) 19 (15.3) 110 (79.7) 80 (64.5) 11.7 (11.3–12.1) 4.3 (4.2–4.4) 138.9 (138.1–139.7) 80.1 (73.2–87.0) 1.7 (1.5–1.9) 46.8 (43.0–50.5) 9237 (7118–11357)
p-Value 0.03c 0.01c 0.01a,c 0.27
0.85 b0.001a,c b0.001ª,c b0.001c 0.07 0.31 0.80 0.31 b0.001a,c 0.52 0.05 0.27 0.38 0.08 0.30 0.01c 0.02c 0.99 0.39 b0.001a,c b0.001a,b,c b0.001a,b,c b0.001a,b,c
Data are expressed as mean (95% confidence interval) for continuous variables and as frequencies (percentages) for categorical variables. TnT: troponin T; BMI: body-mass index; NYHA: New York Heart Association class; COPD: chronic obstructive pulmonary disease; TIA: transient ischemic attack; HF: heart failure; LVEF: left ventricular ejection fraction; eGFR: estimated glomerular filtration rate; MDRD-4: Modification of Diet in Renal Disease; NT-proBNP: N-terminal pro-brain natriuretic peptide. a p b 0.05 for comparison between normal TnT and intermediate TnT. b p b 0.05 for comparison between intermediate TnT and elevated TnT. c p b 0.05 for comparison between normal TnT and elevated TnT.
heart disease, previous HF, anemia, LVEF b 45%, NYHA III–IV, eGFR b 60 mL/min/1.73 m2, NT-proBNP N 3264 pg/mL and TnT ≥ 0.02 ng/ml (data not shown). This analysis reveals a positive trend between elevated troponin and mortality (p = 0.07) or composite event (p = 0.09). 3.3. Subgroup analysis In the subgroup analysis, patients with preserved LVEF and intermediate or elevated TnT had significantly higher mortality and composite endpoint (33.3 vs. 15.7% and 55.8 vs. 34.6%, respectively), but not HF readmissions (33.3 vs. 23.6%, p = 0.08). Patients with reduced LVEF and intermediate or elevated TnT had more frequent mortality and composite endpoint, but statistical significance was not reached (28.7 vs. 11.7%, p = 0.06 y 36.2 vs. 22.2%, p = 0.17, respectively). In the subgroup with preserved LVEF, divided by the 3 TnT levels, there were significant differences in anemia, creatinine, moderate to severe renal Table 3 One-year mortality. HF readmission and composite endpoint categorized by troponin groups: elevated (TnT ≥ 0.05 ng/mL), intermediate (TnT: 0.02–0.049 ng/mL) and normal (TnT b 0.02 ng/mL). All Mortality HF readmission Composite endpoint
Normal TnT
98 (24.1) 23 (13.9) 97 (23.9) 35 (21.2) 166 (40.9) 51 (30.9)
Intermediate TnT
Elevated TnT
p-Valuea
31 (26.5) 27 (23.1) 51 (43.6)
44 (35.5) 35 (28.2) 64 (51.6)
b0.001b,c 0.37 b0.001b,c
Data are expressed as frequencies (percentages). HF: heart failure; TnT: troponin. a Chi-square test. b p b 0.05 for comparison between normal TnT and intermediate TnT. c p b 0.05 for comparison between normal TnT and elevated TnT.
failure, days of hospitalization and NT-proBNP; the findings were similar to the total cohort, but unlike the total cohort, there were also differences in age and hemoglobin, but not in sex or body mass index. In patients with reduced LVEF, the only differences were days of hospitalization and NT-proBNP. In the comparison of subgroups according to renal function, patients with eGFR b 60 mL/min/1.73 m2 and intermediate-high TnT had more deaths than those with eGFR ≥ 60 mL/min/1.73 m2, but not combined event or readmissions for HF. 4. Discussion There are few studies evaluating TnT in HF in Spain. The recently published TROPICA study (Troponin in Acute Heart Failure) investigated the prognostic value of troponin in patients with acute heart failure from Spanish Emergency Departments [19] and another study compared the prognostic significance of high-sensitivity cardiac troponin and sensitive-contemporary troponin I in an outpatient HF population in Spain [20]. In our study, the first point of interest is the high percentage (59.4%) of patients with TnT ≥ 0.02 ng/mL, the upper cutoff point for normality; this is similar to other studies in decompensated HF [13,21–23]. Furthermore, 30.5% of our patients had elevated levels (≥ 0.05 ng/mL); this result was similar to the 31% reported in the TROPICA study [19]. However, in the ADHERE study, this percentage, at 6.2%, was much lower, even though patients with acute coronary syndrome or inhospital mortality were not excluded, as was the case in the present study. This important difference could be due to the characteristics of the ADHERE population (younger, better renal function and less arterial hypertension) and also because troponin was considered high if TnT was ≥0.1 ng/mL or troponin I ≥1 ng/mL [8].
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Fig. 1. Kaplan–Meier analysis of one-year mortality (A) and mortality/HF readmission (B), by TnT groups.
Secondly, in our cohort, TnT has prognostic value in patients with HF. According to previous studies, elevated TnT provides important short and long-term prognostic information in both acute and chronic HF. However, variability in the populations studied (stable or decompensated HF, systolic or diastolic dysfunction), different types of troponin measured, diverse endpoints and the consideration of other events (total or cardiovascular mortality, readmission for worsening HF, acute coronary syndromes or renal failure) do not allow generalized conclusions to be drawn. The prognostic value of TnT has been analyzed in studies such as TROPICA, ADHERE and PROTECT. In the Spanish multicenter TROPICA study with 806 patients, troponin positivity in patients with HF was independently associated with greater in-hospital and 30-day mortality
but not with a greater rate of reconsultation during the following 30 days [19]. Also, in the ADHERE study, a positive cardiac troponin test was independently associated with higher in-hospital mortality [8]. In the PROTECT study, levels of cardiac TnT N 0.03 ng/mL were confirmed to be an independent predictor of the composite endpoint of cardiovascular/renal rehospitalization or death at 60 days; TnT N 0.01 ng/mL was only predictor on univariate analysis [13]. Finally, Braga et al. also reported that elevated troponin was associated with a higher risk of death and cardiovascular hospitalizations at 30, 180 and 365 days [24]. In our study, slightly increased levels of TnT (≥0.02 ng/mL) were independently associated with a greater risk of total mortality but not with readmission for HF. It is possible that a larger sample size is required to appreciate differences in readmissions or that the characteristics of our patients (older and with high prevalence of preserved LVEF) may make our cohort dissimilar from those of other studies [25]. Moreover, our group of patients with elevated TnT had higher mortality or HF readmissions than the group with intermediate TnT, as observed in other studies, where higher troponin implies increased risk [6,23,26]. Our patients with intermediate or elevated TnT had significantly lower LVEF (and therefore a higher percentage of patients with reduced LVEF) than those with normal TnT, a finding also in line with previous studies [4,6,24,26]. Perna et al. and Felker et al. observed that these differences were not statistically significant [9,22]. It is remarkable that 67.9% of our patients had preserved LVEF, since most studies where the prognostic value of troponin is analyzed mostly include patients with reduced LVEF [6] and series of preserved LVEF are usually small [27]. After subgroup analysis, patients with preserved LVEF and elevated TnT had significantly higher mortality and composite event. In patients with reduced LVEF, differences were not significant, probably because it was a small subgroup and because of the exclusion of patients with acute coronary syndrome and those who died during hospitalization. Furthermore, once LVEF is low, the risk of dying is so high that TnT modifies it only slightly. In previous studies of patients with preserved LVEF, mortality and HF readmissions were significantly higher in the patients with increased TnT [21,27]. However, in the study reported by Kutsuzawa, TnT did not predict cardiovascular events in patients with preserved LVEF, probably because the sample was small [28]. Troponin is known to increase in the presence of renal failure. In this study, patients with lower eGFR had significantly higher values of TnT. Thus, renal function could have been a confounding factor, especially when variables related to renal failure, such as anemia, are also significant. However, the Cox analysis showed that the prognostic value of TnT was independent of renal function and anemia. These findings are consistent with other studies in renal failure where troponin had also an independent prognostic value [29,30].
Table 4 Cox proportional hazards model: one-year mortality. Univariate
Multivariate
Variable
HR (95% CI)
p-Value
HR (95% CI)
p-Value
Age Sex (female vs. male) BMI N 25 kg/m2 Ischemic heart disease Previous HF Anemia LVEF b 45% NYHA III–IV eGFR b 60 mL/min/1.73 m2 Troponin T ≥ 0.02 ng/mL NT-proBNP N 3264 pg/mL
1.04 (1.02–1.07) 0.77 (0.52–1.15) 0.56 (0.37–0.84) 1.26 (0.80–1.98) 1.24 (0.76–2.01) 2.07 (1.34–3.19) 1.02 (0.66–1.57) 1.78 (1.19–2.67) 2.08 (1.33–3.26) 2.52 (1.58–4.01) 2.27 (1.39–3.71)
0.001 0.21 0.01 0.34 0.39 0.001 0.95 0.01 0.001 b0.001 0.001
1.03 (1.00–1.06)
0.06
0.75 (0.45–1.23)
0.25
1.43 (0.86–2.38)
0.17
1.26 (0.79–2.02) 1.27 (0.73–2.21) 1.91 (1.09–3.32) 1.53 (0.90–2.59)
0.33 0.40 0.02 0.11
HR: hazard ratio; 95% CI: 95% confidence interval; HF: heart failure; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association class; eGFR: estimated glomerular filtration rate; NT-proBNP: N-terminal pro-brain natriuretic peptide. HR value shows group comparison Yes vs. No, unless otherwise indicated.
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Table 5 Cox proportional hazards model: one-year HF readmission. Univariate
Multivariate
Variable
HR (95% CI)
p-Value
Age Sex (female vs. male) BMI N 25 kg/m2 Ischemic heart disease Previous HF Anemia LVEF b 45% NYHA III–IV eGFR b 60 mL/min/1.73 m2 Troponin T ≥ 0.02 ng/mL NT-proBNP N 3264 pg/mL
1.01 (0.98–1.03) 1.14 (0.76–1.71) 1.34 (0.832–2.16) 1.41 (0.91–2.20) 1.65 (0.98–2.78) 1.41 (0.94–2.13) 0.49 (0.29–0.83) 1.77 (1.18–2.67) 2.29 (1.44–3.63) 1.25 (0.83–1.89) 1.25 (0.78–2.02)
0.59 0.54 0.23 0.13 0.06 0.10 0.01 0.01 b0.001 0.29 0.36
HR (95% CI)
p-Value
1.26 (0.74–2.16) 1.40 (0.90–2.15) 0.49 (0.29–0.83) 1.63 (1.06–2.51) 1.88 (1.15–3.08) 1.13 (0.72–1.77)
0.40 0.16 0.01 0.03 0.01 0.59
HR: hazard ratio; 95% CI: 95% confidence interval; HF: heart failure; NYHA: New York Heart Association class; eGFR: estimated glomerular filtration rate; NT-proBNP: N-terminal pro-brain natriuretic peptide. HR value shows group comparison Yes vs. No, unless otherwise indicated.
In view of our results, the evaluation of troponin in patients with acute HF should be considered for early identification of patients with poor prognosis, to improve the risk stratification (in TROPICA study only 35% of patients had troponin measured [19]) and monitoring of the treatment effect. Several issues remain to be clarified: if highsensitivity troponin has greater power of discrimination or prognostic value than conventional troponin (which seems highly probable [20]), if it plays a different role in ischemic or non-ischemic etiology, the value of serial measurements and the determination of the cutoff point after which troponin provides more prognostic information.
4.1. Study limitations Our study has several potential limitations. Firstly, patients with TnT levels might be significantly different from the general population of HF patients. We analyzed baseline characteristics of patients with TnT measured and these were not different from those without TnT. Secondly, TnT was not determined centrally and there may be some variability in the cutoff values that define it as positive, depending on the analytical method. In this case, the problem could be minimized by standardizing values in the different laboratories. A single determination of TnT was made at the time of hospital admission, so the usefulness of serial measurements could not be assessed. In addition, patients who died during hospitalization were not included, so the prognostic value of troponin in relation to in-hospital mortality was not studied and the prevalence of elevated troponin may be underestimated. Total mortality was analyzed, but not mortality due to heart failure. Finally, conventional troponin was measured instead of high-sensitivity troponin, which may lead to an underestimation of the prognostic value of troponin in HF.
5. Learning points • Elevated troponin is associated with poorer prognosis in patients hospitalized for HF. • Patients with preserved LVEF or eGFR b 60 mL/min/1.73 m2 and elevated troponin have higher mortality. 6. Conclusions In conclusion, TnT is higher than normal in a large percentage of patients with acute HF, indicating the presence of myocardial damage. Furthermore, TnT is a good and independent predictor of one-year mortality, especially in patients with preserved LVEF. Conflicts of interest The authors state that they have no conflicts of interest. Acknowledgments We gratefully acknowledge all investigators participating in the RICA Registry. This project was possible thanks to an unrestricted educational scholarship granted by Laboratorios Menarini. We would like to thank the RICA Registry Coordinating Center “S&H Medical Science Service” for their quality control, data management, logistic and administrative support. Appendix A RICA Registry members: Anarte L, Aramburu O, Arévalo JC, Arias JL, Bettencourt P, Carrera M, Ceresuela LM, Cerqueiro JM, Conde A, Dávila MF, Díez-Manglano J,
Table 6 Cox proportional hazards model: one-year composite endpoint (mortality/HF readmission). Univariate
Multivariate
Variable
HR (95% CI)
p-Value
HR (95% CI)
p-Value
Age Sex (female vs. male) BMI N 25 kg/m2 Ischemic heart disease Previous HF Anemia LVEF b 45% NYHA III–IV eGFR b 60 mL/min/1.73 m2 Troponin T ≥ 0.02 ng/mL NT-proBNP N 3264 pg/mL
1.03 (1.01–1.05) 1.02 (0.75–1.39) 0.73 (0.53–1.01) 1.34 (0.95–1.90) 1.37 (0.94–1.99) 1.74 (1.27–2.40) 0.69 (0.48–0.99) 1.82 (1.34–2.49) 2.26 (1.60–3.19) 1.77 (1.27–2.46) 1.48 (1.03–2.12)
0.001 0.88 0.06 0.09 0.10 0.001 0.05 b0.001 b0.001 0.001 0.03
1.02 (1.00–1.05)
0.06
0.87 (0.57–1.33) 1.24 (0.78–1.96) 0.92 (0.56–1.53) 1.53 (1.01–2.34) 0.65 (0.40–1.04) 1.64 (1.11–2.42) 1.61 (1.02–2.54) 1.36 (0.89–2.08) 1.01 (0.66–1.53)
0.53 0.36 0.75 0.05 0.07 0.01 0.04 0.16 0.96
HR: hazard ratio; 95% CI: 95% confidence interval; HF: heart failure; NYHA: New York Heart Association class; eGFR: estimated glomerular filtration rate; NT-proBNP: N-terminal pro-brain natriuretic peptide. HR value shows group comparison Yes vs. No, unless otherwise indicated.
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[16] Pérez-Calvo JI, Montero-Pérez-Barquero M, Camafort-Babkowski M, ContheGutiérrez P, Formiga F, Aramburu-Bodas O, et al. Influence of admission blood pressure on mortality in patients with acute decompensated heart failure. Q J Med 2011; 104:325–33. [17] Trullàs JC, Formiga F, Montero M, Conde A, Casado J, Carrasco FJ, et al. Paradoja de la obesidad en la insuficiencia cardiaca. Resultados del Registro RICA. Med Clin (Barc) 2011;137:671–7. [18] Conde-Martel A, Formiga F, Pérez-Bocanegra C, Armengou-Arxé A, Muela-Molinero A, Sánchez-Sánchez C, et al. Clinical characteristics and one-year survival in heart failure patients more than 85 years of age compared with younger. Eur J Intern Med 2013;24:339–45. [19] Jacob J, Martín-Sánchez F, Herrero P, Miró O, Llorens P. Valor pronóstico de la troponina en pacientes con insuficiencia cardíaca aguda atendidos en los Servicios de Urgencias hospitalarios españoles: estudio TROPICA (TROPonina en Insuficiencia Cardiaca Aguda). Med Clin (Barc) 2013;140:145–51. [20] De Antonio M, Lupón J, Galán A, Vila J, Zamora E, Urrutia A, et al. Head-to-head comparison of high-sensitivity troponin T and sensitive-contemporary troponin I regarding heart failure risk stratification. Clin Chim Acta 2013;426:18–24. [21] Perna E, Apromonte N, Cimbaro J, Di Tano G, Macin S, Feola M, et al. Minor myocardial damage is a prevalent condition in patients with acute heart failure syndromes and preserved systolic function with long-term prognostic implications. A report from the CIAST-HF (collaborative italo-argentinean study on cardiac troponin T in heart failure) study. J Card Fail 2012;18:822–30. [22] Felker GM, Hasselblad V, Tang WH, Hernández AF, Amstrong PW, Fonarow GC, et al. Troponin I in acute decompensated heart failure: insights from the ASCEND-HF study. Eur J Heart Fail 2012;14:1257–64. [23] Pascual-Figal DA, Casas T, Ordoñez-Llanos J, Manzano-Fernández S, Bonaque JC, Boronat M, et al. Highly sensitive troponin T for risk stratification of acutely destabilized heart failure. Am Heart J 2012;163:1002–10. [24] Braga J, Tu J, Austin P, Chong A, You J, Farkouh M, et al. Outcomes and care of patients with acute heart failure syndromes and cardiac troponin elevation. Circ Heart Fail 2013;6:193–202. [25] Nagarajan V, Hernández AV, Tang WH. Prognostic value of cardiac troponin in chronic stable heart failure: a systematic review. Heart 2012;98:1778–86. [26] Latini R, Masson S, Anand IS, Missov E, Carlson M, Vago T, et al. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation 2007;116:1242–9. [27] Macin SM, Perna ER, Cimbaro JP, Augier N, Riera JL, Cialzeta J, et al. Increased levels of cardiac troponin-T in outpatients with heart failure and preserved systolic function are related to adverse clinical findings and outcome. Coron Artery Dis 2006;17: 685–91. [28] Kutsuzawa D, Arimoto T, Watanabe T, Shishido T, Miyamoto T, Miyashita T, et al. Ongoing myocardial damage in patients with heart failure and preserved ejection fraction. J Cardiol 2012;60:454–61. [29] Buhaescu I, Izzedine H, Covic A. Cardiac troponins in renal failure — time for an optimistic consensus? Int J Clin Pract 2005;59:1317–25. [30] Abbas NA, John RI, Webb MC, Kempson ME, Potter AN, Price CP, et al. Cardiac troponins and renal function in nondialysis patients with chronic kidney disease. Clin Chem 2005;51:2059–66.
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Troponin T in acute heart failure: Clinical implications and prognosis in the Spanish National Registry on Heart Failure María Esther Guisado Espartero ⁎, Prado Salamanca-Bautista, Oscar Aramburu-Bodas, Jose L. Arias-Jimenez, Francesc Formiga, Bernardino Roca-Villanueva, Jose M. Cerqueiro-Gonzalez, Meliton F. Davila-Ramos, Marta Sanchez-Marteles, Manuel Montero-Perez-Barquero Department of Internal Medicine, Hospital Infanta Margarita, Avenida Góngora s/n, CP: 14940 Cabra, Córdoba, Spain
a r t i c l e
i n f o
Article history: Received 2 March 2014 Received in revised form 17 August 2014 Accepted 20 August 2014 Available online 6 September 2014 Keywords: Heart failure Troponin T Prognosis
a b s t r a c t Background: Elevated troponin in heart failure has been associated with worse prognosis, but there are differences in the design and results of published studies. Our objective was to determine the association of troponin T with mortality and readmissions in patients with acute heart failure in clinical practice conditions. Methods: We included patients from the RICA registry who were hospitalized for acute heart failure. They were classified into 3 groups according to troponin T levels: normal, intermediate and high (b 0.02, 0.02–0.049 and ≥0.05 ng/mL, respectively). Survival was studied by Kaplan–Meier curves and the association of variables was tested by Cox regression analysis. Results: A total of 406 patients was included. Average age was 76.9 (76.0–77.7) years. Hypertensive heart disease was the most common etiology. Left ventricular ejection fraction was b 45% in 22.1% of the patients. The group with elevated troponin T had higher proportions of women, systolic dysfunction, renal failure and anemia, a lower body mass index and longer hospital stay. At one year, patients with elevated troponin T had higher mortality than patients with normal troponin (35.5 vs. 13.9%, p b 0.001). The composite event (mortality and readmissions) was also more frequent (51.6 vs. 30.9%, p b 0.001), but there were no differences in readmissions alone. Troponin T ≥0.02 ng/mL was independently associated with mortality. Conclusions: Elevated troponin T levels are common in patients with heart failure in clinical practice and are associated with increased mortality and events after one year of follow-up. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Congestive heart failure (HF) is a public health problem due to growing incidence and prevalence, high mortality and morbidity and elevated hospitalization costs [1]. Several biochemical markers are useful in the diagnosis, prognosis and monitoring of the treatment effect in HF. One of these, troponin, not only proves to be an excellent early marker for cardiac injury in acute coronary syndromes, but also allows detection of minor myocardial damage in HF [2,3]. Several studies have shown that mild or persistent elevation of cardiac troponin levels in patients with HF implied worse prognosis and was associated with an increased risk of death [3–13]. However, previously published results are discordant due to heterogeneous populations (mostly patients with reduced left ventricular
Abbreviations: HF, heart failure; TnT, troponin T; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; eGFR, estimated glomerular filtration rate; NTproBNP, N-terminal pro-B-type natriuretic peptide. ⁎ Tel.: +34 957021370; fax: +34 957 021 322. E-mail address: [email protected] (M.E. Guisado Espartero).
ejection fraction [LVEF]), different endpoints and varying clinical situations. In clinical practice, symptomatic patients with HF and preserved LVEF are presenting more frequently but available data are limited and the characteristics of these patients differ from those of patients with reduced LVEF [14,15]. The aim of this study was to analyze whether patients seen in Internal Medicine clinical practice settings with HF and elevated troponin had worse prognosis and increased risk of death or readmission for HF. 2. Material and methods 2.1. Patients Patient data were collected from the Spanish National Registry on Heart Failure (RICA), supported by the Heart Failure Working Group of the Spanish Society of Internal Medicine (SEMI-IC). This registry is a multicenter, prospective, cohort study that began in February 2008 and is still ongoing. It includes patients over 50 years of age presenting with a first episode of HF or decompensation of already identified
http://dx.doi.org/10.1016/j.ejim.2014.08.005 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
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chronic HF and preserved or reduced LVEF, according to the criteria of the European Society of Cardiology, admitted to Internal Medicine units of 52 Spanish public and private hospitals. The RICA registry has been described in previous publications [16–18]. For this study, only patients over 50 years of age with HF and available troponin T (TnT) were included. Other exclusion criteria were HF due to pulmonary hypertension, hospitalization for unstable angina or acute coronary syndrome, death during index hospitalization, inability to participate in the study or anticipated follow-up of less than one year. The investigation conformed to the principles outlined in the Declaration of Helsinki. The study protocol was approved by the Ethical Committee of the University Hospital “Reina Sofía”, Cordoba (Spain), and all patients provided informed consent. Confidentiality was maintained according to law.
2.2. Objectives of the study and follow-up Primary endpoint was death after one year of admission. Secondary endpoints examined the association of troponin with readmission due to worsening HF and a composite endpoint of death or readmission because of worsening HF. Hospital stay in days for the index admission was also evaluated. Total cohort and subgroups, according to preserved or reduced LVEF, were analyzed. Preserved LVEF was defined as at least 45%. Follow-up consisted of two visits scheduled at 3 months and one year.
2.3. Variables Data were collected at the time of enrollment, including demographic data, comorbidities, body mass index, New York Heart Association (NYHA) functional class and HF etiology. LVEF was determined by 2D echocardiography. Biochemical variables (hemoglobin, urea, sodium, potassium, creatinine, TnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were obtained at the time of hospital admission. Anemia was defined using the World Health Organization criteria: hemoglobin b12 g/dL in women and b13 g/dL in men. The estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation (MDRD-4). The pooled population was divided into three troponin groups: normal TnT (b0.02 ng/mL); intermediate TnT (0.02–0.049 ng/mL) and elevated TnT (≥0.05 ng/mL). Although TnT levels were not determined centrally, the cutoff points used by the laboratories were similar in all centers.
2.4. Statistical methods Continuous variables were expressed as mean (95% confidence interval) and categorical variables as frequencies and percentages. Continuous variables were compared using a non-parametric test (Kruskal Wallis H test) and ANOVA test after rank transformation of data and the Bonferroni post-hoc for pairwise comparisons. Categorical variables were compared with the Chi-square test and after the Tukey test to examine differences between groups. One-year mortality and readmission for worsening HF were evaluated using the Kaplan–Meier method. Univariate analysis to evaluate hazard ratios (HRs) were performed using Cox proportional hazards models. A multivariable analysis was then conducted using the Cox regression model adjusted for variables with a p-value of b0.1 in the univariate analysis. Moreover, a binary logistic regression by mortality, readmission and composite event was performed to study confounding variables. A p-value of less than 0.05 was considered statistically significant. All analyses were performed with the Statistical Package for the Social Sciences (SPSS) program (version 15.0).
3. Results 3.1. Baseline characteristics of patients The study cohort included 406 patients. Patients from the RICA Registry with TnT measured at admission were similar to those without TnT determinations in terms of epidemiology, etiology of HF, NYHA class, anemia and degree of renal dysfunction. However, in patients with reduced LVEF, TnT was determined more frequently (71.8% vs. 65.3%; p = 0.02) (Table 1). Baseline characteristics of the total cohort and of the three TnT groups are presented in Table 2. The mean age of the total cohort was 76.9 (76.0–77.7) years, and 171 (42.1%) were males. A third of the patients had reduced LVEF. Hypertensive heart disease (42.6%) was the most frequent etiology. Mean TnT at admission was 0.09 (0.07–0.12) ng/mL and 60% of patients had TnT above normal limits. The group with elevated TnT (30.5%) had a greater proportion of women, reduced LVEF, anemia, worse renal function and lower BMI, in addition to being older. 3.2. Endpoints and follow-up After 1 year of follow-up, 98 patients (24.1%) died and 97 (23.9%) were readmitted because of worsening HF. One hundred and sixty-six (166) patients (40.9%) had the composite event of death or readmission for HF. Intermediate or elevated TnT was more common in patients who died and in those from the composite event group (p ≤ 0.001). Patients with elevated TnT had also more readmissions but this did not reach statistical significance (Table 3). Fig. 1 shows the survival curves by troponin groups. Patients with intermediate or elevated TnT were associated with poorer prognosis with greater mortality and more composite events. The univariate Cox proportional hazard analysis to predict mortality and composite event showed that intermediate or elevated TnT was associated with the highest risk for both endpoints. TnT did not reach statistical significance when readmissions alone were considered. After multivariate Cox analysis, TnT ≥ 0.02 ng/mL was an independent predictor of mortality (Table 4). NYHA III–IV, eGFR b 60 mL/min/1.73 m2 and preserved LVEF were independent predictors of readmission for worsening HF (Table 5). NYHA III–IV, eGFR b 60 mL/min/1.73 m2 and anemia were independent predictors of the composite endpoint, but TnT was not (Table 6). A binary logistic regression by mortality, readmission and composite event was performed with age, female sex, BMI N 25 kg/m2, ischemic Table 1 Characteristics of patients with and without troponin determined at admission.
Age (years) Female HF etiology —Hypertension —Ischemic —Valvular NYHA III–IV LVEF b 45% Dyslipidemia Diabetes Hypertension eGFR b 60 mL/min/1.73 m2 Ischemic heart disease Previous HF Anemia
Patients with TnT values (n = 406)
Patients without TnT values (n = 842)
p-Value
76.9 (76.0–77.7) 235 (57.9)
76.4 (75.7–77.0) 439 (52.1)
0.28 0.06 0.72
173 (42.6) 101 (24.9) 74 (18.2) 200 (49.3) 121 (32.1) 184 (45.3) 207 (51.0) 344 (84.7) 241 (59.4) 89 (21.9) 309 (75.2) 227 (55.9)
336 (39.9) 211 (25.1) 154 (18.3) 461 (54.8) 223 (26.5) 406 (48.2) 363 (43.1) 712 (84.6) 491 (58.3) 182 (21.6) 595 (70.7) 481 (57.1)
0.15 0.02 0.34 0.01 0.94 0.85 0.98 0.10 0.69
Data are expressed as mean (95% confidence interval) for continuous variables and as frequencies (percentages) for categorical variables. TnT: troponin T; HF: heart failure; NYHA: New York Heart Association class; LVEF: left ventricular ejection fraction; eGFR: estimated glomerular filtration rate.
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Table 2 Characteristics of patients categorized by troponin groups: elevated (TnT ≥ 0.05 ng/mL), intermediate (TnT: 0.02–0.049 ng/mL) and normal (TnT b 0.02 ng/mL). Total (n = 406) Age (years) BMI (kg/m2) Female HF etiology: —Hypertension —Ischemic —Valvular NYHA III–IV LVEF b 45% LVEF Days of hospitalization Smoker Dyslipidemia Diabetes Hypertension eGFR b 60 mL/min/1.73 m2 Atrial fibrillation Ischemic heart disease Previous stroke/TIA COPD Peripheral arterial disease Previous HF Anemia Hemoglobin (g/dL) Potassium (mEq/L) Sodium (mEq/L) Urea (mg/dL) Creatinine (mg/dL) eGFR (MDRD-4) (mL/min/1.73 m2) NT-proBNP (pg/mL)
Normal TnT (n = 165)
Intermediate TnT (n = 117)
76.9 (76.0–77.7) 29.4 (28.8–30.0) 235 (57.9)
75.6 (74.3–77.0) 30.6 (29.6–31.6) 110 (66.7)
77.3 (75.8–78.9) 28.9 (27.7–30.0) 61 (52.1)
173 (42.6) 101 (24.9) 74 (18.2) 200 (49.3) 121 (32.1) 50.3 (48.8–51.8) 11.0 (10.1–11.9) 29 (7.1) 184 (45.3) 207 (51.0) 344 (84.7) 241 (59.4) 236 (58.1) 89 (21.9) 49 (12.1) 122 (30.0) 50 (12.3) 309 (75.2) 227 (55.9) 12.0 (11.7–12.2) 4.3 (4.2–4.4) 139.3 (138.9–139.8) 70.1 (66.5–73.8) 1.4 (1.3–1.4) 56.9 (54.3–59.5) 5761 (4932–6590)
78 (47.3) 27 (16.4) 37 (22.4) 79 (47.9) 27 (17.5) 54.5 (52.6–56.5) 9.1 (8.2–10.0) 7 (4.2) 75 (45.5) 81 (49.1) 136 (82.4) 76 (46.1) 100 (60.6) 27 (16.4) 20 (12.1) 45 (27.3) 13 (7.9) 117 (72.2) 78 (47.3) 12.2 (11.9–12.6) 4.3 (4.2–4.4) 139.4 (138.6–140.2) 60.3 (54.9–65.7) 1.1 (1.1–1.2) 65.6 (61.1–70.1) 3795 (2849–4741)
45 (38.5) 34 (29.1) 21 (17.9) 60 (51.3) 46 (43.4) 47.1 (44.0–50.3) 10.5 (9.0–12.0) 8 (6.8) 47 (40.2) 62 (53.0) 104 (88.9) 74 (63.2) 69 (59.0) 27 (23.1) 10 (8.5) 34 (29.1) 18 (15.4) 82 (73.9) 69 (59.0) 11.8 (11.4–12.2) 4.3 (4.2–4.5) 139.6 (138.8–140.4) 73.3 (66.7–79.8) 1.3 (1.2–1.4) 55.4 (51.0–60.0) 5315 (4132–6498)
Elevated TnT (n = 124) 78.1 (76.5–79.7) 28.3 (27.4–29.2) 64 (51.6) 50 (40.3) 40 (32.3) 16 (12.9) 61 (49.2) 48 (41.0) 47.7 (45.0–50.3) 14.0 (12.0–16.0) 14 (11.3) 62 (50.0) 64 (51.6) 104 (83.9) 91 (73.4) 67 (54.0) 35 (28.2) 19 (15.3) 43 (34.7) 19 (15.3) 110 (79.7) 80 (64.5) 11.7 (11.3–12.1) 4.3 (4.2–4.4) 138.9 (138.1–139.7) 80.1 (73.2–87.0) 1.7 (1.5–1.9) 46.8 (43.0–50.5) 9237 (7118–11357)
p-Value 0.03c 0.01c 0.01a,c 0.27
0.85 b0.001a,c b0.001ª,c b0.001c 0.07 0.31 0.80 0.31 b0.001a,c 0.52 0.05 0.27 0.38 0.08 0.30 0.01c 0.02c 0.99 0.39 b0.001a,c b0.001a,b,c b0.001a,b,c b0.001a,b,c
Data are expressed as mean (95% confidence interval) for continuous variables and as frequencies (percentages) for categorical variables. TnT: troponin T; BMI: body-mass index; NYHA: New York Heart Association class; COPD: chronic obstructive pulmonary disease; TIA: transient ischemic attack; HF: heart failure; LVEF: left ventricular ejection fraction; eGFR: estimated glomerular filtration rate; MDRD-4: Modification of Diet in Renal Disease; NT-proBNP: N-terminal pro-brain natriuretic peptide. a p b 0.05 for comparison between normal TnT and intermediate TnT. b p b 0.05 for comparison between intermediate TnT and elevated TnT. c p b 0.05 for comparison between normal TnT and elevated TnT.
heart disease, previous HF, anemia, LVEF b 45%, NYHA III–IV, eGFR b 60 mL/min/1.73 m2, NT-proBNP N 3264 pg/mL and TnT ≥ 0.02 ng/ml (data not shown). This analysis reveals a positive trend between elevated troponin and mortality (p = 0.07) or composite event (p = 0.09). 3.3. Subgroup analysis In the subgroup analysis, patients with preserved LVEF and intermediate or elevated TnT had significantly higher mortality and composite endpoint (33.3 vs. 15.7% and 55.8 vs. 34.6%, respectively), but not HF readmissions (33.3 vs. 23.6%, p = 0.08). Patients with reduced LVEF and intermediate or elevated TnT had more frequent mortality and composite endpoint, but statistical significance was not reached (28.7 vs. 11.7%, p = 0.06 y 36.2 vs. 22.2%, p = 0.17, respectively). In the subgroup with preserved LVEF, divided by the 3 TnT levels, there were significant differences in anemia, creatinine, moderate to severe renal Table 3 One-year mortality. HF readmission and composite endpoint categorized by troponin groups: elevated (TnT ≥ 0.05 ng/mL), intermediate (TnT: 0.02–0.049 ng/mL) and normal (TnT b 0.02 ng/mL). All Mortality HF readmission Composite endpoint
Normal TnT
98 (24.1) 23 (13.9) 97 (23.9) 35 (21.2) 166 (40.9) 51 (30.9)
Intermediate TnT
Elevated TnT
p-Valuea
31 (26.5) 27 (23.1) 51 (43.6)
44 (35.5) 35 (28.2) 64 (51.6)
b0.001b,c 0.37 b0.001b,c
Data are expressed as frequencies (percentages). HF: heart failure; TnT: troponin. a Chi-square test. b p b 0.05 for comparison between normal TnT and intermediate TnT. c p b 0.05 for comparison between normal TnT and elevated TnT.
failure, days of hospitalization and NT-proBNP; the findings were similar to the total cohort, but unlike the total cohort, there were also differences in age and hemoglobin, but not in sex or body mass index. In patients with reduced LVEF, the only differences were days of hospitalization and NT-proBNP. In the comparison of subgroups according to renal function, patients with eGFR b 60 mL/min/1.73 m2 and intermediate-high TnT had more deaths than those with eGFR ≥ 60 mL/min/1.73 m2, but not combined event or readmissions for HF. 4. Discussion There are few studies evaluating TnT in HF in Spain. The recently published TROPICA study (Troponin in Acute Heart Failure) investigated the prognostic value of troponin in patients with acute heart failure from Spanish Emergency Departments [19] and another study compared the prognostic significance of high-sensitivity cardiac troponin and sensitive-contemporary troponin I in an outpatient HF population in Spain [20]. In our study, the first point of interest is the high percentage (59.4%) of patients with TnT ≥ 0.02 ng/mL, the upper cutoff point for normality; this is similar to other studies in decompensated HF [13,21–23]. Furthermore, 30.5% of our patients had elevated levels (≥ 0.05 ng/mL); this result was similar to the 31% reported in the TROPICA study [19]. However, in the ADHERE study, this percentage, at 6.2%, was much lower, even though patients with acute coronary syndrome or inhospital mortality were not excluded, as was the case in the present study. This important difference could be due to the characteristics of the ADHERE population (younger, better renal function and less arterial hypertension) and also because troponin was considered high if TnT was ≥0.1 ng/mL or troponin I ≥1 ng/mL [8].
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Fig. 1. Kaplan–Meier analysis of one-year mortality (A) and mortality/HF readmission (B), by TnT groups.
Secondly, in our cohort, TnT has prognostic value in patients with HF. According to previous studies, elevated TnT provides important short and long-term prognostic information in both acute and chronic HF. However, variability in the populations studied (stable or decompensated HF, systolic or diastolic dysfunction), different types of troponin measured, diverse endpoints and the consideration of other events (total or cardiovascular mortality, readmission for worsening HF, acute coronary syndromes or renal failure) do not allow generalized conclusions to be drawn. The prognostic value of TnT has been analyzed in studies such as TROPICA, ADHERE and PROTECT. In the Spanish multicenter TROPICA study with 806 patients, troponin positivity in patients with HF was independently associated with greater in-hospital and 30-day mortality
but not with a greater rate of reconsultation during the following 30 days [19]. Also, in the ADHERE study, a positive cardiac troponin test was independently associated with higher in-hospital mortality [8]. In the PROTECT study, levels of cardiac TnT N 0.03 ng/mL were confirmed to be an independent predictor of the composite endpoint of cardiovascular/renal rehospitalization or death at 60 days; TnT N 0.01 ng/mL was only predictor on univariate analysis [13]. Finally, Braga et al. also reported that elevated troponin was associated with a higher risk of death and cardiovascular hospitalizations at 30, 180 and 365 days [24]. In our study, slightly increased levels of TnT (≥0.02 ng/mL) were independently associated with a greater risk of total mortality but not with readmission for HF. It is possible that a larger sample size is required to appreciate differences in readmissions or that the characteristics of our patients (older and with high prevalence of preserved LVEF) may make our cohort dissimilar from those of other studies [25]. Moreover, our group of patients with elevated TnT had higher mortality or HF readmissions than the group with intermediate TnT, as observed in other studies, where higher troponin implies increased risk [6,23,26]. Our patients with intermediate or elevated TnT had significantly lower LVEF (and therefore a higher percentage of patients with reduced LVEF) than those with normal TnT, a finding also in line with previous studies [4,6,24,26]. Perna et al. and Felker et al. observed that these differences were not statistically significant [9,22]. It is remarkable that 67.9% of our patients had preserved LVEF, since most studies where the prognostic value of troponin is analyzed mostly include patients with reduced LVEF [6] and series of preserved LVEF are usually small [27]. After subgroup analysis, patients with preserved LVEF and elevated TnT had significantly higher mortality and composite event. In patients with reduced LVEF, differences were not significant, probably because it was a small subgroup and because of the exclusion of patients with acute coronary syndrome and those who died during hospitalization. Furthermore, once LVEF is low, the risk of dying is so high that TnT modifies it only slightly. In previous studies of patients with preserved LVEF, mortality and HF readmissions were significantly higher in the patients with increased TnT [21,27]. However, in the study reported by Kutsuzawa, TnT did not predict cardiovascular events in patients with preserved LVEF, probably because the sample was small [28]. Troponin is known to increase in the presence of renal failure. In this study, patients with lower eGFR had significantly higher values of TnT. Thus, renal function could have been a confounding factor, especially when variables related to renal failure, such as anemia, are also significant. However, the Cox analysis showed that the prognostic value of TnT was independent of renal function and anemia. These findings are consistent with other studies in renal failure where troponin had also an independent prognostic value [29,30].
Table 4 Cox proportional hazards model: one-year mortality. Univariate
Multivariate
Variable
HR (95% CI)
p-Value
HR (95% CI)
p-Value
Age Sex (female vs. male) BMI N 25 kg/m2 Ischemic heart disease Previous HF Anemia LVEF b 45% NYHA III–IV eGFR b 60 mL/min/1.73 m2 Troponin T ≥ 0.02 ng/mL NT-proBNP N 3264 pg/mL
1.04 (1.02–1.07) 0.77 (0.52–1.15) 0.56 (0.37–0.84) 1.26 (0.80–1.98) 1.24 (0.76–2.01) 2.07 (1.34–3.19) 1.02 (0.66–1.57) 1.78 (1.19–2.67) 2.08 (1.33–3.26) 2.52 (1.58–4.01) 2.27 (1.39–3.71)
0.001 0.21 0.01 0.34 0.39 0.001 0.95 0.01 0.001 b0.001 0.001
1.03 (1.00–1.06)
0.06
0.75 (0.45–1.23)
0.25
1.43 (0.86–2.38)
0.17
1.26 (0.79–2.02) 1.27 (0.73–2.21) 1.91 (1.09–3.32) 1.53 (0.90–2.59)
0.33 0.40 0.02 0.11
HR: hazard ratio; 95% CI: 95% confidence interval; HF: heart failure; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association class; eGFR: estimated glomerular filtration rate; NT-proBNP: N-terminal pro-brain natriuretic peptide. HR value shows group comparison Yes vs. No, unless otherwise indicated.
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Table 5 Cox proportional hazards model: one-year HF readmission. Univariate
Multivariate
Variable
HR (95% CI)
p-Value
Age Sex (female vs. male) BMI N 25 kg/m2 Ischemic heart disease Previous HF Anemia LVEF b 45% NYHA III–IV eGFR b 60 mL/min/1.73 m2 Troponin T ≥ 0.02 ng/mL NT-proBNP N 3264 pg/mL
1.01 (0.98–1.03) 1.14 (0.76–1.71) 1.34 (0.832–2.16) 1.41 (0.91–2.20) 1.65 (0.98–2.78) 1.41 (0.94–2.13) 0.49 (0.29–0.83) 1.77 (1.18–2.67) 2.29 (1.44–3.63) 1.25 (0.83–1.89) 1.25 (0.78–2.02)
0.59 0.54 0.23 0.13 0.06 0.10 0.01 0.01 b0.001 0.29 0.36
HR (95% CI)
p-Value
1.26 (0.74–2.16) 1.40 (0.90–2.15) 0.49 (0.29–0.83) 1.63 (1.06–2.51) 1.88 (1.15–3.08) 1.13 (0.72–1.77)
0.40 0.16 0.01 0.03 0.01 0.59
HR: hazard ratio; 95% CI: 95% confidence interval; HF: heart failure; NYHA: New York Heart Association class; eGFR: estimated glomerular filtration rate; NT-proBNP: N-terminal pro-brain natriuretic peptide. HR value shows group comparison Yes vs. No, unless otherwise indicated.
In view of our results, the evaluation of troponin in patients with acute HF should be considered for early identification of patients with poor prognosis, to improve the risk stratification (in TROPICA study only 35% of patients had troponin measured [19]) and monitoring of the treatment effect. Several issues remain to be clarified: if highsensitivity troponin has greater power of discrimination or prognostic value than conventional troponin (which seems highly probable [20]), if it plays a different role in ischemic or non-ischemic etiology, the value of serial measurements and the determination of the cutoff point after which troponin provides more prognostic information.
4.1. Study limitations Our study has several potential limitations. Firstly, patients with TnT levels might be significantly different from the general population of HF patients. We analyzed baseline characteristics of patients with TnT measured and these were not different from those without TnT. Secondly, TnT was not determined centrally and there may be some variability in the cutoff values that define it as positive, depending on the analytical method. In this case, the problem could be minimized by standardizing values in the different laboratories. A single determination of TnT was made at the time of hospital admission, so the usefulness of serial measurements could not be assessed. In addition, patients who died during hospitalization were not included, so the prognostic value of troponin in relation to in-hospital mortality was not studied and the prevalence of elevated troponin may be underestimated. Total mortality was analyzed, but not mortality due to heart failure. Finally, conventional troponin was measured instead of high-sensitivity troponin, which may lead to an underestimation of the prognostic value of troponin in HF.
5. Learning points • Elevated troponin is associated with poorer prognosis in patients hospitalized for HF. • Patients with preserved LVEF or eGFR b 60 mL/min/1.73 m2 and elevated troponin have higher mortality. 6. Conclusions In conclusion, TnT is higher than normal in a large percentage of patients with acute HF, indicating the presence of myocardial damage. Furthermore, TnT is a good and independent predictor of one-year mortality, especially in patients with preserved LVEF. Conflicts of interest The authors state that they have no conflicts of interest. Acknowledgments We gratefully acknowledge all investigators participating in the RICA Registry. This project was possible thanks to an unrestricted educational scholarship granted by Laboratorios Menarini. We would like to thank the RICA Registry Coordinating Center “S&H Medical Science Service” for their quality control, data management, logistic and administrative support. Appendix A RICA Registry members: Anarte L, Aramburu O, Arévalo JC, Arias JL, Bettencourt P, Carrera M, Ceresuela LM, Cerqueiro JM, Conde A, Dávila MF, Díez-Manglano J,
Table 6 Cox proportional hazards model: one-year composite endpoint (mortality/HF readmission). Univariate
Multivariate
Variable
HR (95% CI)
p-Value
HR (95% CI)
p-Value
Age Sex (female vs. male) BMI N 25 kg/m2 Ischemic heart disease Previous HF Anemia LVEF b 45% NYHA III–IV eGFR b 60 mL/min/1.73 m2 Troponin T ≥ 0.02 ng/mL NT-proBNP N 3264 pg/mL
1.03 (1.01–1.05) 1.02 (0.75–1.39) 0.73 (0.53–1.01) 1.34 (0.95–1.90) 1.37 (0.94–1.99) 1.74 (1.27–2.40) 0.69 (0.48–0.99) 1.82 (1.34–2.49) 2.26 (1.60–3.19) 1.77 (1.27–2.46) 1.48 (1.03–2.12)
0.001 0.88 0.06 0.09 0.10 0.001 0.05 b0.001 b0.001 0.001 0.03
1.02 (1.00–1.05)
0.06
0.87 (0.57–1.33) 1.24 (0.78–1.96) 0.92 (0.56–1.53) 1.53 (1.01–2.34) 0.65 (0.40–1.04) 1.64 (1.11–2.42) 1.61 (1.02–2.54) 1.36 (0.89–2.08) 1.01 (0.66–1.53)
0.53 0.36 0.75 0.05 0.07 0.01 0.04 0.16 0.96
HR: hazard ratio; 95% CI: 95% confidence interval; HF: heart failure; NYHA: New York Heart Association class; eGFR: estimated glomerular filtration rate; NT-proBNP: N-terminal pro-brain natriuretic peptide. HR value shows group comparison Yes vs. No, unless otherwise indicated.
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