Context Cardiac troponins have become the ‘gold standard’ for diagnosing myocardial infarction. Elevation of cardiac troponins is noted in patients with chronic stable heart failure, but comparative prognostic value of different assay types is not established.
Objective To perform a systematic review for investigating the prognostic value of the different types of cardiac troponins (including low and high sensitivity) in chronic stable heart failure.
Data sources Search of three databases, PubMed, The Cochrane Library and Web of Science, was made in April 2012.
Study selection All studies which provided information on prognosis based upon the baseline cardiac troponin elevation in chronic stable heart failure were included. Limits applied were adults, humans and English language.
Data extraction Two authors individually reviewed all studies and extracted data on patient and study characteristics along with primary and secondary outcomes.
Results 16 of the 365 papers from three databases were finally included for data analysis. Elevated baseline cardiac troponin in patients with chronic stable heart failure was associated with a high risk of mortality (HR 2.85; 95% CI 2.02 to 4.03) and combined adverse cardiovascular outcome (HR 2.38; 95% CI 1.63 to 3.49). Although high-sensitivity assay detected cardiac troponin in higher proportion of patients compared with low-sensitivity assay, there was no statistically significant difference among both groups (p=0.54).
Conclusions Elevated baseline cardiac troponin level identified chronic stable heart failure patients who are at a higher risk of mortality and combined adverse cardiovascular outcomes. There was no statistically significant difference between high- and low-sensitivity cardiac troponins.
- Heart Failure
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Cardiac troponins are highly specific and sensitive markers of myocardial necrosis. The role of cardiac troponins in myocardial infarction is well established and is now essential for diagnosing myocardial infarction.1 Elevation in cardiac troponin level is noted in multiple other cardiac and non-cardiac conditions including acute pulmonary embolism, myocarditis and renal failure.2 Elevated cardiac troponin level has been a marker of poor prognosis in most of these clinical conditions.3 ,4
Heart failure is a chronic and progressive clinical condition and its pathophysiology has evolved dramatically over the last 2 decades. Brain natriuretic peptide (BNP) and N-terminal proBNP are the most commonly used biomarkers in heart failure.5 But elevated cardiac troponin levels have been noted in patients with acute decompensated heart failure,6 and also in patients with chronic stable heart failure.7 The cause of cardiac troponin elevation in patients with heart failure is not fully elucidated. One of the concepts for cardiac troponin elevation involves ongoing apoptosis and myocardial necrosis,8 while impaired renal clearance or pinocytosis may also contribute.9
There are three types of troponins: C, I and T. Troponin I and T are specific to the heart, while troponin C can be expressed in skeletal muscle.10 Low-sensitivity cardiac troponins are currently used as the ‘gold standard’ for detecting myocardial injury. Recent advancements in analytical performance of commercial assays have moved the lower limits of detection of cardiac troponins to much lower ranges. In particular, ‘high-sensitivity cardiac troponin’ assays can measure concentrations >10-fold lower than the lower limit of low-sensitivity cardiac troponins.11 Several studies have demonstrated the potential for quantifying cardiac troponin as prognostic indicator of heart failure, particularly in the acute decompensated states. Nevertheless, there are not many studies which compared high- and low-sensitivity cardiac troponins in prognostication of chronic stable heart failure. We therefore perform a systematic review and meta-analysis to investigate the prognostic value of cardiac troponin measurement in chronic systolic heart failure, with particular emphasis on comparing high- with low-sensitivity assays and between cardiac troponin T and troponin I assays.
Selection of studies
We searched PubMed, The Cochrane Library and the Web of Science in April 2012. Search criteria included the terms ‘Troponin’ and ‘Heart failure’. The search was limited to ‘humans’, ‘adults’ and ‘English’ language. We did not create a formal review protocol. We have included observational studies which evaluated patients with chronic stable heart failure if they provide baseline troponin values. Studies which included patients with both systolic and diastolic heart failure were included. Included studies investigated different types of troponins including high-/low-sensitivity troponins and troponin I/T. Studies evaluating acute decompensated heart failure or those measured troponin during heart failure hospitalisation were excluded. Also, studies not providing outcomes based on troponin values were excluded.
PubMed search criteria
The following search criteria was used in PubMed: ‘Troponin’[Mesh] AND ‘Heart Failure’[Mesh] AND (‘humans’[MeSH Terms] AND English [lang] AND ‘adult’ [MeSH Terms]) AND (‘humans’[MeSH Terms] AND English [lang] AND ‘adult’[MeSH Terms]).
The primary outcome was mortality (both all-cause mortality and cardiovascular mortality). Multiple studies have used different combination of outcomes as secondary outcomes. Hence, we used combined adverse cardiovascular outcome (involving heart failure hospitalisation, worsening heart failure, death or transplantation, all-cause mortality, cardiovascular mortality or a combination of secondary outcomes) as our secondary outcome.
One investigator (VN) performed the electronic database search and listed the eligible studies. Study selection was performed initially by a review of title and abstracts. A second investigator (AH) independently reviewed all abstracts. Disagreements were resolved by discussion. For eligible abstracts, full text articles were obtained and reviewed further for eligibility by both authors.
We collected study details including type of study, year of publication, type and sensitivity of cardiac troponin, assay and manufacturer details, and patient details like age, gender and type of heart failure along with the primary and secondary outcomes. We also recorded the cut-off threshold for elevated troponin used for all studies.
Our meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement.12 Primary analysis was performed for the primary outcome, involving all available studies. We also performed sensitivity analysis including all-cause mortality and cardiovascular mortality separately. Subgroup analyses were performed for: a) high- versus low-sensitivity troponin studies and b) cardiac troponin T versus I studies. Heterogeneity among studies was tested with the χ² statistic and quantified with the I2 (low: <25%; moderate: 25%–50%; high: >50%). As we expected, we noted a high level of heterogeneity among studies and hence we used random effects model. The indirect and simple methods by Parmar et al13 were used to calculate logarithms of HRs (i.e. logHR) and their standard errors per study. The inverse variance method was used to combine logHRs. Associations are shown as HR and their 95% CI. Publication bias was evaluated graphically with the funnel plot and tested with the Egger's test. RevMan 5.1 and the meta for package of R 2.12.2 were used for all calculations.
Figure 1 displays the flow diagram for the literature search which identified 209 studies from ‘PubMed’, 58 studies from ‘The Cochrane library’ and 98 studies from ‘Web of Science’. Studies that were available in more than one database were included only once. Studies evaluating acute decompensated heart failure were excluded. Overall, 31 abstracts were considered potentially eligible by both investigators and were retrieved as full text articles. After a review of full text, studies which report a different type of outcome and with no interpretable data were excluded. Also, seven studies were noted to include patients with acute heart failure and were excluded.
Only 16 articles were included for the analysis. Only 12 of these studies reported either all-cause mortality or cardiovascular mortality as one of the outcomes, while the remaining four did not. Hence the analysis for primary outcome included 12 studies. The salient features of all the studies are given in table 1. Six of these studies used low-sensitivity assay and five used high-sensitivity assay while the last one compared both high- and low-sensitivity cardiac troponins. We used the investigators’ definition of cardiac troponin positive and the cut-off values for cardiac troponin in individual studies are provided in table 2, which also includes details about different assays used and the manufacturer name. Five studies used cardiac troponin I, while the remaining seven used cardiac troponin T. The mean age of patients in most studies was between 60 and 75 years. The predominant gender (>50%) in all the studies was male. Overall, high-sensitivity cardiac troponins were noted to be elevated in higher proportion of patients than low-sensitivity patients. The largest study in our meta-analysis is from Latini et al and the proportion of patients in this study with positive high-sensitivity cardiac troponins is 92% compared with 10.4% of patients with positive low-sensitivity cardiac troponins.14 Excluding that study, the mean percentage of positive high-sensitivity cardiac troponins is 63.9% (range 43%–80.4%) and of low-sensitivity cardiac troponins is 31.1% (range 11%–54.2%). Nine studies used all-cause mortality as one of the outcomes while three studies used cardiovascular mortality as one of the outcomes.
Figure 2 graphically depicts our prognostic value of cardiac troponins in predicting our primary outcome (either all-cause or cardiovascular mortality). This forest plot clearly showed that elevated baseline cardiac troponin in patients with chronic stable heart failure is associated with a high risk of mortality (HR 2.85; 95% CI 2.02 to 4.03). HRs varied from 1.19 to 7.32 among different studies. I2 statistic was 88% showing that the studies are highly heterogeneous. Publication bias was evaluated graphically with funnel plot (figure 3) which showed no evidence of publication bias (Egger's test: p=0.2).
One of our predetermined subgroup analyses was to compare the prognostic value of high- and low-sensitivity cardiac troponins. Although the point estimate of HRs was higher in high-sensitivity cardiac troponin group (HR 3.19; 95% CI 1.66 to 6.15) than low-sensitivity cardiac troponin group (HR 2.55; 95% CI 1.91 to 3.40), suggesting a higher risk of mortality, there was no statistically significant difference among both groups (p=0.54) (figure 4). The pooled analysis of these studies also showed similar results with two types of troponin; elevated cardiac troponin T level (HR 2.92; 95% CI 1.88 to 4.53) was associated with a higher risk of mortality when compared with cardiac troponin I based on point estimates (HR 2.64; 95% CI 1.83 to 3.79), but again there was no statistically significant difference between both groups (p=0.73) (figure 5).
Cumulative meta-analysis (figure 6) based on the year of publication showed progressive increase in HRs after 2007. This correlated with the year when the first high-sensitivity cardiac troponin study included in our analysis was published. But there was always a significant association between cardiac troponin and mortality. We have also provided the sensitivity analysis for all-cause mortality and cardiovascular mortality (figures 7 and 8). Elevated baseline cardiac troponin level seems to be strongly associated with all-cause mortality (HR 2.72; 95% CI 1.84 to 4.02) and cardiovascular mortality (HR 3.15; 95% CI 1.81 to 5.51). From the pooled analysis, elevated baseline troponin level was significantly associated with our secondary outcome, combined adverse cardiovascular outcome (HR 2.38; 95% CI 1.63 to 3.49) (figure 9). There was significant heterogeneity (I2=84%) in the magnitude of effect sizes, although there was a consistent positive relationship between cardiac troponin and combined adverse cardiovascular outcome.
This main findings of this systematic review are as follows: 1) Elevated baseline troponin level has very good prognostic value in chronic stable heart failure and was associated with all-cause mortality, cardiovascular mortality and combined adverse cardiovascular outcome irrespective of the type or sensitivity of the troponin. 2) High-sensitivity troponins are elevated in a higher proportion of patients with chronic stable heart failure. Nevertheless, based on our analysis, there was no statistically significant difference between high- and low-sensitivity cardiac troponins although the point estimate of the HRs was higher in high-sensitivity cardiac troponins. 3). Furthermore, there was no statistically significant difference between two types of cardiac troponins, cardiac troponin T and I, although again the point estimate of HRs was slightly higher in cardiac troponin T group.
The cause of cardiac troponin release in patients with chronic heart failure is unclear. The basic concept behind cardiac troponin release is irreversible cardiomyocyte damage, although the potential for reversible damage as a cause of cardiac troponin is under debate.15 Demand–supply mismatch of oxygen at cellular level may be a cause of troponin release. This could explain the reason for cardiac troponin elevation in septic shock, severe hypotension and tachyarrhythmias.16 This oxygen demand–supply mismatch could cause reversible or permanent damage to cardiomyocytes, thereby causing troponin release. Another non-thrombotic cause of cardiac troponin release would be myocardial stress,17 potentially due to subendocardial ischaemia or directly due to myocyte damage. Meanwhile, accelerated apoptosis leading to progressive loss of cardiomyocytes and cardiac troponin release18 may likely promote progression of heart failure. Impaired renal function could also be a cause of elevated cardiac troponin levels.
Elevated cardiac troponin level has been noted to be associated with poor prognosis in heart failure and in many other cardiac and non-cardiac diseases. Elevated cardiac troponin level is rare in general population in the absence of cardiac or renal diseases.19 High-sensitivity troponin is also noted to be associated with increased risk of all-cause mortality.20 A higher proportion of patients with acute decompensated heart failure were found to have elevated cardiac troponin levels when compared with chronic stable heart failure.21 In our analysis, all the included studies showed significant association of cardiac troponin with prognosis. Association in two studies was not significant, but the CIs were large, suggesting relatively small sample sizes. Our study confirmed the association of cardiac troponin with mortality which was shown earlier in multiple small studies. It is also important to note that our studies have been published over a decade during which heart failure management has changed significantly. But irrespective of available heart failure therapies, troponin predicts mortality and this is shown on the cumulative meta-analysis based on the year of publication (figure 6). Also, only few studies blinded the test results to the physicians and hence there is a chance that positive troponins results could have influenced treatment.
High-sensitivity cardiac troponin assays detect troponin at a much lower level when compared with low-sensitivity assays. Six of our studies used low-sensitivity cardiac troponin, while five studies used high sensitivity and one study compared both high and low-sensitivity cardiac troponin. As mentioned in the results, the largest study in our analysis from Latini et al14 showed a very high proportion of patients with positive high-sensitivity cardiac troponin compared with low-sensitivity cardiac troponin (92% vs 10.4%). Such a large difference has not been observed in any of the other trials. The cause of this discrepancy is unclear. This could be due to difference in assays or cut-offs used in the study. But, overall, a higher proportion of chronic heart failure patients are noted to have elevated high-sensitivity cardiac troponin than low-sensitivity cardiac troponin (mean percentage is 63.9% vs 31.1%). Most of the studies using high-sensitivity cardiac troponins had higher HR, thereby stronger association with mortality when compared with low-sensitivity cardiac troponins. This could be due to difference in patient population between studies examining high- and low-sensitivity cardiac troponins. Latini et al14 examined the prognostic strength of both high- and low-sensitivity cardiac troponins in the same group of patients. This study showed a weaker association of high-sensitivity cardiac troponins with mortality than low-sensitivity cardiac troponins. A very high proportion (92%) of patients had detectable high-sensitivity troponin in this study and they used the median level as cut-off level to make two equal groups, which makes the interpretation difficult. It would be good to look at patients with negative low-sensitivity troponins and positive high-sensitivity troponins in future trials. Similar results were not noted in any other study. This could also be attributed to the hypothesis that when larger proportion of patients are identified as ‘positive’ using high-sensitivity cardiac troponins and hence deemed ‘high risk’, the HR can be more diminished. The sensitivity and specificity vary depending upon the cut-off level used and an appropriate balance between them needs to be addressed in future studies. But, overall, in our analysis including 12 studies, there was no statistically significant difference between high- and low-sensitivity cardiac troponins due to a significant overlap in confidence intervals between the two groups. When more studies are published using high-sensitivity cardiac troponins, the answer will become clearer. There were few studies which used serial cardiac troponin measurement to predict prognosis. Out of these studies, we have included only the prognostic significance of baseline troponin level in our analysis.
In addition to mortality, we have used combined adverse cardiovascular outcomes as our secondary outcome, as this cumulative endpoint is defined differently in different studies. In our analysis, cardiac troponins are associated with increased risk of combined adverse cardiovascular outcomes. By combining different outcomes into a single secondary outcome, we have shown that the prognostic value of cardiac troponin exists irrespective of the type of outcome studied.
There are multiple limitations to our study. Most of the studies in our meta-analysis are prospective studies, but most of them are not randomised trials. The assays and cut-off levels used in different studies are extremely different which makes the interpretation really difficult. This may make one to hesitate to make generalised assumptions from this analysis, but different assays and different cut-offs in different hospitals are the norm even in the real world. Nevertheless, our study clearly demonstrated the prognostic value of different type of cardiac troponins in chronic stable heart failure. There are multiple prognostic scores in heart failure like heart failure survival score22 and Seattle heart failure model,23 but most of them do not use cardiac troponin as a predictor in the model. With this analysis, the role of baseline cardiac troponin in prognostication of heart is very clear and we expect to see newer scores using cardiac troponin as a predictor in models soon. Nevertheless, it is conceivable that cardiac troponins may some day be tested even as a biomarker in guiding management strategies. For example, the decision to start a therapeutic agent may be based on detectable cardiac troponin and to monitor treatment response following intensification of medical therapy. Until then, the potential for cardiac troponin testing as prognostication purposes is justified.
Elevated single-point cardiac troponin measurement identifies chronic stable heart failure patients who are at a high risk of mortality and combined adverse cardiovascular outcomes. Cardiac troponin is already established as the gold standard in diagnosing myocardial infarction. These findings confirm cardiac troponin as a prognostic biomarker in the setting of heart failure. Nevertheless, in our analysis, there was no statistically significant difference between high- and low-sensitivity cardiac troponins or between subtypes of cardiac troponins measured.
Contributors All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; WHWT has previously received research grant support from Abbott Laboratories within the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.
Funding This research received no specific funding.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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