Early and late mortality in hospitalised patients with raised cardiac troponin T
- Peter Sze Chai Wong1,
- Julia Dawn Jones1,
- Reza Ashrafi1,
- Omer Khanzada1,
- Upul Wickramarachchi1,
- Touran Heidi Keen1,
- Derek Richard Robinson2
- 1Aintree Cardiac Centre, University Hospital Aintree, Liverpool, UK
- 2Department of Mathematics, School of Mathematical and Physical Sciences, University of Sussex, Brighton, UK
- Correspondence to Dr Peter Sze Chai Wong, Aintree Cardiac Centre, University Hospital Aintree, Liverpool, Merseyside L9 7AL, UK;
- Received 22 September 2011
- Accepted 25 March 2012
- Published Online First 27 April 2012
Aims Cardiac troponins are measured in acute coronary syndrome (ACS) and other conditions. The authors investigate the prognostic significance of cardiac troponin T (TnT) test and comorbid medical conditions.
Methods Consecutive patients admitted to the Aintree University Hospital, Liverpool, between 2 January 2004 and 29 February 2004 who had TnT measurement were included. Patients were separated into normal (<0.01 μg/l) or raised TnT levels (≥0.01 μg/l), and further categorised into: (1) normal TnT with unstable angina; (2) normal TnT with non-ACS; (3) raised TnT with ACS; and (4) raised TnT with non-ACS. Cox regression was used to identify prognostic variables, and logrank test to compare 7-year survival.
Results Of 1021 patients, 313 had raised TnT (195 ACS, 118 non-ACS) and 708 normal TnT (80 ACS, 628 non-ACS). Age (HR 1.06; 95% CI 1.05 to 1.07), congestive cardiac failure (HR 1.37; 95% CI 1.11 to 1.69), cerebrovascular disease (HR 1.37; 95% CI 1.10 to 1.71), chronic obstructive airway disease (HR 1.44; 95% CI 1.19 to 1.75), liver disease (HR 4.16; 95% CI 2.37 to 7.31), renal disease (HR 1.83; 95% CI 1.27 to 2.64), tumour (HR 1.39; 95% CI 1.07 to 1.79), lymphoma (HR 4.81; 95% CI 2.07 to 11.16), metastatic cancer (HR 3.55; 95% CI 2.32 to 5.45) and a higher Charlson's comorbidity score (HR 1.20, 95% CI 1.13 to 1.26) were adverse predictors. Both raised TnT with ACS (HR 1.92, 95% CI 1.54 to 2.39) and raised TnT with non-ACS (HR 2.37, 95% CI 1.87 to 3.00) were associated with worse survival. Raised TnT with non-ACS had a worse survival than raised TnT with ACS (p=0.001).
Conclusion Hospitalised patients with raised TnT levels from any cause predicted a higher mortality than normal TnT, with worst survival in those without an obvious ACS.
- Troponin T
- acute coronary syndrome
- non-acute coronary syndrome
- adult cardiology
- valvular heart disease
Measurement of cardiac troponins enable clinicians to diagnose, risk stratify and manage patients with acute coronary syndrome (ACS).1 2 Beside diagnosing ACS, cardiac troponins have been shown to predict short- and medium-term mortality in patients with non-ST segment elevation ACS, and ST segment elevation myocardial infarction (MI).3–5 More recently, elevated cardiac troponin levels are increasingly recognised in non-ACS cardiac and other non-cardiac conditions.6 7
In our daily practice, serum cardiac troponin tests are being requested by hospital clinicians in a wide variety of clinical circumstances. We have previously reported higher inhospital mortality among hospitalised patients with elevated cardiac troponin T (TnT) levels than with normal TnT level.8 Patients with elevated cardiac TnT levels and non-ACS conditions had higher inhospital as well as 6-month mortality than ACS with elevated TnT levels. Moreover, we found an increasing level of comorbidity was associated with higher 6-month mortality in patients with ACS and raised TnT levels.9
Patient cohort and hospital profile
These patients were admitted to our secondary care hospital equipped with an accident and emergency unit and were diagnosed of having ACS and other non-ACS conditions after reviewing their clinical information and TnT results. Aintree University Hospital served approximately 330 000 residents in the northern part of Liverpool City and the adjoining Meresyside area.
In this paper, we report the 7-year all cause mortality and the long-term prognostic effect of comorbid medical conditions in the same cohort of patients where clinicians have requested a TnT test (fourth generation assay) during the index event.
Methods have been described elsewhere.8 9 Briefly, consecutive patients who were admitted to a university teaching hospital between 5 January 2004 and 29 February 2004 who had one or more TnT measurement were included. The original study protocol was prospectively written and approved by the local Sefton Local Research Ethics Committee. The present follow-up study consisted of the same cohort of patients and aimed to extend the all cause mortality observation to 7 years. TnT test was requested by the admitting clinicians when the diagnosis of ACS was suspected, and their decision to measure TnT was not influenced by the study.
Patient identification and catergorisation into four clinical diagnostic groups
Patients were identified prospectively by reviewing the daily hospital admissions list and the list of TnT results. TnT level was routinely measured at 12 h from onset of symptoms in accordance with a hospital-wide policy, by the fourth generation Elecsys troponin T electrochemiluminescence immunoassay ‘ECLIA’ with the Roche Elecsys 2010 analyser (F. Hoffmann-La Roche Ltd, Basel, Switzerland). Patients were separated into those with normal (<0.01 μg/l) or raised TnT levels (≥0.01 μg/l), and further categorised into four groups: (1) normal TnT with unstable angina; (2) normal TnT with non-ACS; (3) raised TnT with ACS; and (4) raised TnT with non-ACS, respectively.
Assessment of primary clinical diagnosis and patient follow-up
Data were abstracted from the medical records and the universal definition of acute MI was used to confirm the presence of MI.10
Universal definition of acute myocardial infarction
Acute myocardial infarction can be confirmed in an appropriate clinical setting, with a rise and/or fall pattern of cardiac troponins of which at least one value is above the normal reference, and also with one or more of the following clinical features:
New electrocardiographic changes of ischaemia (ST-T changes, left bundle branch block or development of Q wave).
New regional wall abnormality on echocardiography or another imaging modality showing new loss of viable myocardium.
The primary clinical diagnosis was determined after reviewing clinical details and TnT results. The diagnosis of a non-ACS condition required two clinicians to confirm the same diagnosis by an independent review. Any disagreement in the diagnosis required a further review by the principal investigator (PW). Survival status for all patients was tracked by the hospital electronic patient record using a semiautomatic computerised data link with the general practice computer systems. Patient demographics and National Health Service number were used to authenticate patient information. The final check was conducted on 27 March 2011, thus accruing full 7-year data.
Charlson's comorbidity score
Comorbid data were collected according to Charlson's method11 (online Appendix A). Charlson's comorbidity score was a weighted index which summed up the individual score according to the presence or absence of 19 prespecified medical conditions. A higher score indicated the presence of a greater number of serious medical conditions.
Data were statistically analysed using the χ2 and Fisher's exact probability test (two-tailed) for comparing categorical variables, and Student t test for comparing group means. Cox proportional hazards regression was first used to investigate individual variables which may affect 7-year mortality. By choosing variables with p<0.1 and using backward elimination, a multivariable Cox regression model was constructed. Significant comorbid medical conditions and clinical variables which affected 7-year mortality were shown in HR with 95% CI. Survival analysis was performed using the Kaplan–Meier method in each of the four TnT groups, and compared with the expected average number of deaths from a reference population in the English Life Table 2000–2002 using subject-years method.12 Survival analysis was focused on patients surviving 30 days or longer. Furthermore, logrank test was used to compare the survival experience among the four TnT groups. Statistical tests were carried out using IBM SPSS Statistics V.18.0.0 (IBM Corporation).
Raised TnT versus normal TnT level
Of 1021 patients, 313 had a raised TnT level (≥0.01 μg/l) and 708 normal TnT level (<0.01 μg/l) (table 1). Patients with a raised TnT level were older by a mean age of 8.5 years (74.1 vs 65.6 years; p<0.001) and had more pre-existing comorbid medical conditions as evidenced by a higher Charlson's score (p=0.021) than those with a normal TnT level. Of these medical conditions, patients with a raised TnT level were more likely to have a history of hypertension, MI, diabetes mellitus, cerebrovascular disease, renal disease and dementia, and were less likely to have prior coronary revascularisation or angina. Inhospital (25.2% vs 3.0%) and posthospital discharge to 1-year all cause mortality (18.3% vs 9.4%) were significantly higher in patients with raised TnT levels than those with normal TnT level (p<0.001). After the first year, the mortality rates in the raised TnT group remained higher than the normal TnT group (post 1-year to 7-year mortality 44.1% vs 34.2%; p=0.016). Total 7-year cumulative mortality was significantly higher in patients with raised TnT than normal TnT level (68.4% vs 42.4%; p<0.001).
ACS and non-ACS, with raised or normal TnT level
Of 746 non-ACS, patients with raised TnT levels were older by a decade and with higher Charlson's comorbidity score than those with normal TnT level (table 2). A history of MI, cerebrovascular disease, moderate/severe renal or liver disease, diabetes mellitus, and dementia were more frequent in non-ACS with raised TnT levels. The primary diagnoses for 628 patients with non-ACS and normal TnT are illustrated in online appendix B. Of 708 patients with a normal TnT level, a history of hypertension, angina, MI and coronary revascularisation were more common in those with unstable angina whereas tumour was more commonly found in non-ACS. Among 275 ACS, patients with raised TnT levels were older and more likely to have diabetes mellitus than those with normal TnT level. On the other hand, a history of hypertension, angina, MI, congestive cardiac failure and coronary revascularisation was more common in ACS with normal TnT than raised TnT. We have previously reported the clinical characteristics and primary diagnosis in patients with raised TnT levels.8
Multivariable analysis for factors affecting survival
By using a multivariable Cox proportional hazards model, we identified increasing age (HR 1.06; 95% CI 1.05 to 1.07), congestive cardiac failure (HR 1.37; 95% CI 1.11 to 1.69), cerebrovascular disease (HR 1.37; 95% CI 1.10 to 1.71), chronic obstructive airway disease (HR 1.44; 95% CI 1.19 to 1.75), moderate/severe liver disease (HR 4.16; 95% CI 2.37 to 7.31), moderate/severe renal disease (HR 1.83; 95% CI 1.27 to 2.64), any tumour (HR 1.39; 95% CI 1.07 to 1.79), lymphoma (HR 4.81; 95% CI 2.07 to 11.16) and metastatic cancer (HR 3.55; 95% CI 2.32 to 5.45) as adverse predictors (table 3). A history of hypertension was associated with a better survival (HR 0.79; 95% CI 0.66 to 0.95). Both raised TnT with ACS (HR 1.92, 95% CI 1.54 to 2.39; p<0.001) and raised TnT with non-ACS (HR 2.37, 95% CI 1.87 to 3.00; p<0.001) were associated with a poorer survival. A separate analysis was performed including Charlson's score and all comorbid conditions, and a higher Charlson's score was associated with worse survival (HR 1.20, 95% CI 1.13 to 1.26; p<0.001).
Kaplan–Meier survival analysis and comparison of survival experience
The survival of patients having normal TnT with unstable angina, normal TnT with non-ACS, raised TnT with ACS and raised TnT with non-ACS were compared individually with the English Life Table survival taking into account age and sex difference in each group (figure 1A–D). Survival was worse in all groups compared with the reference population and was significantly different in normal TnT with non-ACS, raised TnT with ACS and raised TnT with non-ACS groups (p<0.001).
Survival was compared among the four TnT groups (figure 1E). Between the two normal TnT groups, survival was worse in patients with non-ACS than ACS (p=0.016). Both raised TnT with ACS (p<0.001) and raised TnT with non-ACS (p<0.001) had a worse survival than those with normal TnT. Furthermore, raised TnT with non-ACS had a significantly worse survival than raised TnT with ACS (p=0.001). Kaplan–Meier survival curves showed that the steepest fall in survival among the two raised TnT groups occurring during index hospital admission and within the first year, thereafter with similar declining rates of survival among the four TnT groups.
Our cohort of hospitalised patients with ACS and a wide variety of other medical conditions had a higher mortality than the reference population. Both raised TnT with and without ACS were associated with higher mortality than the normal TnT cohorts, with raised TnT and non-ACS having the highest mortality. Mortality in both raised TnT with and without ACS was the highest during index hospital admission and the first 12 months.
Raised TnT levels in our patients were likely the result of myocardial necrosis occurring in ACS and other non-ACS conditions. The levels of TnT elevation were related to the extent of myocardial necrosis and were previously found to predict mortality in both ACS and non-ACS patients at 6 months.9 Among our two raised TnT groups, the acute insult from a non-ACS condition together with additional myocardial damage as detected by the elevated TnT levels could explain the higher mortality when compared with myocardial damage from ACS alone. In addition, these patients with non-ACS had more serious comorbid medical conditions than ACS.9 The presence of myocardial damage in our non-ACS patients could have been precipitated and exacerbated by having underlying coronary artery disease, although it was also recognised that patients with raised TnT levels may not necessarily have significant angiographic coronary disease.13 There were other possible mechanisms causing release of cardiac troponins from myocytes in different clinical circumstances.6 7 Among our two normal TnT groups, non-ACS patients had a worse outcome than ACS. This difference in outcome could possibly be explained by a higher prevalence of malignancy in non-ACS patients (tumour, leukaemia, lymphoma, metastatic solid tumour 15.0% vs 5.0%, p=0.015) and better treatment in the ACS group regarding coronary revascularisation and hypertension (PCI and/or CABG 36.3% vs 7.3%, p<0.001; hypertension 72.5% vs 39.0%, p<0.001).
The recent introduction of high sensitivity TnT assay (fifth generation) has improved our precision in detecting low troponin concentration down to 3 ng/l, with 99th percentile value of 13.5 ng/l determined in the reference population.14 All our patients with raised TnT levels were likely to remain elevated above normal reference if tested by the newer high sensitivity TnT assay. This high sensitivity TnT assay would enable a greater number of patients with acute MI to be identified, as compared with fourth generation TnT assay. The recent proposal of serial troponin testing using a new criterion of ≥20% relative change (rise and fall pattern, or vice versa)15 would also identify a greater number of patients with MI, although this change in TnT pattern could occur in other non-ACS conditions. It is likely that serial troponin testing using high sensitivity assays will increase the diagnosis of all types of ‘biomarker’ MI, and particularly type 2 MI among patients who were hospitalised with other non-ACS conditions. These patients were likely to have acute decompensating medical conditions which could cause a fluctuating pattern in their troponin level, thus potentially leading to a diagnosis of type 2 MI pending on the presence and interpretation of symptoms, electrocardiographic changes or cardiac wall motion abnormalities. We have previously shown in a different hospitalised cohort that type 1 MI had a better 1-year survival than type 2 MI (33.8% vs 65.0%; p=0.011).16 Despite the continuing evolution of guidelines in the diagnosis of MI and promising new treatments for type 1 MI, management of type 2 MI lacks consensus guidelines and clinical trial evidence, and has been left at the discretion of individual clinicians.17 Recent advances in cardiac MRI could increase the accuracy of diagnosing MI in patients with raised TnT levels and non-conclusive symptoms or electrocardiographic changes.18
Our cohort included patients who were suspected of having ACS, and with one or more TnT blood result. We did not include patients who may have a raised TnT level due to other comorbid medical conditions in whom TnT blood test had not been requested by the admitting clinician. Patients with increased comorbidity were known to have a worse prognosis irrespective of their TnT level.9 Moreover, the presence of excess or serious comorbid medical conditions could have influenced the attending clinician's decision in measuring TnT. This may explain the higher risk of death in our cohort when compared with the reference population. Our results were based on the fourth generation TnT assay. It was envisaged that all our patients with raised TnT levels would remain elevated above normal reference if tested by the newer high sensitivity TnT assay.14 Our conclusion remained unchanged regarding the ability of fourth generation TnT test in predicting early and late mortality among patients with or without an obvious MI. It would be interesting to explore the prognostic relationship of the lower TnT levels made possible by the newer high sensitivity TnT assay. We have limited our analysis to comorbid medical conditions and the final clinical diagnostic categories of normal TnT with unstable angina, normal TnT with non-ACS, raised TnT with ACS and raised TnT with non-ACS conditions. Additional clinical features or newer biomarkers may add important survival information in these high risk patients with a wide range of medical conditions.19 20 Our mortality data were obtained using hospital details and also a hospital approved and secured external computer network linkage which received regular updated information from general practices. The fidelity of this information linkage system was not fully evaluated, although we were confident about the confirmed cases of death.
A raised TnT level in hospitalised patients was a sign of myocardial injury, which could be due to ACS or other non-ACS conditions. Patients with raised TnT levels from whatever cause had higher mortality than normal TnT, particularly during index hospital admission and the first 12 months. The diagnosis of MI should only be made after interpreting cardiac troponin result in conjunction with the clinical presentation. Patients who presented with ischaemic symptoms and a diagnostic pattern of cardiac troponin level had a type 1 ‘classical’ MI. New electrocardiographic changes or regional myocardial wall abnormality would help to confirm the diagnosis, especially if there was uncertainty over symptoms. The diagnosis of type 1 MI, usually the result of atherosclerotic plaque rupture or fissuring, enabled clinicians to apply evidence-based ACS drug treatments and coronary revascularisation. Whereas in type 2 MI, the rise and/or fall pattern of cardiac troponin level could be precipitated by a wide range of non-ACS conditions, irrespective of any pre-existing coronary artery disease. These patients may not have any well-defined ischaemic symptoms, electrocardiographic changes or regional myocardial wall abnormality. Management for these patients should focus on treating the underlying non-ACS conditions. The use of contemporary ACS treatments in type 2 MI was not evidence-based from clinical trials, and the potential risks and benefits of such treatments should be carefully considered in each patient. Experience from other researchers and ours have shown that clinicians should be aware of the prognostic role of TnT blood test, as well as its diagnostic role in MI.
Cardiac troponin T, comorbidity and age were important prognostic factors in predicting survival.
Patients with raised cardiac troponin T with non-acute coronary syndrome conditions had the worst survival.
The risk of death with raised cardiac troponin T levels was the highest during index admission and the first 12 months.
Current research questions
The prognostic role of high sensitivity cardiac troponin T assay should be examined in these patients.
The threshold value as well as different levels of high sensitivity cardiac troponin T which could predict prognosis should be investigated.
▶ Kelley WE, Januzzi JL, Christenson RH. Increases of cardiac troponin in conditions other than acute coronary syndrome and heart failure. Clin Chem 2009;55:2098–112
▶ De Gennaro L, Brunetti ND, Cuculo A, et al. Increased troponin levels in nonischemic cardiac conditions and noncardiac diseases. J Interv Cardiol 2008;21:129–39.
▶ Wong P, Murray S, Ramsewak A, et al. Raised cardiac troponin T levels in patients without acute coronary syndrome. Postgrad Med J 2007;83:200–5
▶ Wong P, Ramsewak A, Murray S, et al. Effects of comorbidity and hospital care on 6-month mortality in patients with elevated cardiac troponin T. Postgrad Med J 2007;83:332–7
▶ Thygesen K, Alpert JS, White HD. Joint ESC/ACCF/AHA/WHF task force for the redefinition of myocardial infarction. Universal definition of myocardial infarction. J Am Coll Cardiol 2007;50:2173–95.
▶ Thygesen K, Mair J, Katus H, et al; the Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. Recommendations for the use of cardiac troponin measurement in acute cardiac care. Eur Heart J 2010;31:2197–206
Competing interests None.
Ethics approval Original study was approved by the local Sefton Local Ethics Committee. Previous communication with Local Ethics chairman suggested that the original study could have been performed as an audit and was also published as a clinical audit.8 Patient management was not changed as a result of the study.
Provenance and peer review Not commissioned; externally peer reviewed.