Editor's Note: Based on Omland T, Pfeffer MA, Solomon SD, et al. Prognostic value of cardiac troponin I measured with a highly sensitive assay in patients with stable coronary artery disease. J Am Coll Cardiol 2013; 61:1240-9.

Background

Cardiac troponins are routinely used in the diagnosis of acute coronary syndromes (ACS) in patients with acute chest pain. Moreover, troponin elevation provides information on risk of adverse events and identifies patients likely to benefit from particular interventions.^1-3 In stable patients, high-sensitivity troponin assays permit the detection of very low levels of troponin in the circulation, including levels that are detectable in most normal people. Thus they offer the potential to identify low levels of occult myocardial injury in different disease states. Despite the seemingly interchangeable use of troponin I (TnI) and troponin T (TnT) in the diagnosis of ACS, recent evidence suggests that high-sensitivity (hs) assays for these troponins may provide different prognostic information and that their release and/or clearance may be governed by differing mechanisms.⁴ Therefore, the study by Omland et al. was conducted to determine the prognostic value of hs-TnI and contrast these results with those obtained from assessment of hs-TnT.

Methods

The article by Omland et al. is a biomarker substudy of the PEACE trial. Briefly, the main objective of the PEACE trial was to assess the efficacy of the ACE inhibitor trandalopril in reducing the composite of cardiovascular (CV) death, nonfatal MI, and need for urgent revascularization in subjects with stable CAD. The trial randomized patients with stable coronary disease without any hospitalizations for unstable angina in the preceding three months from enrollment and with left ventricular (LV) ejection fraction (EF) >40%. Patients with LV wall motion abnormalities or evidence of heart failure were excluded from the PEACE trial. Treatment with trandalopril offered no significant benefit over placebo with respect to the primary endpoint or its components. Subjects with blood samples available to assay hs-TnI and hs-TnT were included in this biomarker substudy. The primary objective was to determine the univariable and multivariable associations of hs-TnI with the composite endpoint of CV death and nonfatal heart failure, as well as with nonfatal acute myocardial infarction (AMI). Also, the incremental prognostic value of including hs-TnI and hs-TnT to regression models was determined.

Results

Overall, there were 8,290 subjects randomized to trandalopril or placebo in the PEACE trial with approximately 44% (n=3,623) of the total trial population included in the assessment of hs-TnI. Among those included, 98.5% of patients had hs-TnI concentrations above the lower limit of detection; moreover, 2.9% had hs-TnI concentrations above the sex-specific 99th percentile of the general population. In contrast, 10.9% of patients had hs-TnT concentrations above the sex-specific 99th percentile of the general population. Notably, increasing quartiles of hs-TnI were only moderately correlated with hs-TnT (r=0.44) and NT-proBNP (r=0.39). In multivariable analysis, there were several factors that were significantly associated with elevated hs-TnI and hs-TnT including older age, sex, BMI, diabetes, and higher NT-proBNP. However, a history of prior MI was only associated with hs-TnI, whereas glomerular filtration rate (GFR) and current smoking status were only significantly associated with hs-TnT.

During median follow up of 5.2 years, 5.6% of patients experienced CV death or first hospitalization for heart failure. In the multivariable Cox model adjusting for age, sex, EF <50%, GFR, smoking, serum cholesterol, prior hypertension, diabetes, MI, percutaneous coronary intervention, arterial claudication, aspirin use, CRP, and NT-proBNP, hs-TnI was a strong predictor of risk of CV death or heart failure (HR 1.34; 95% CI 1.19-1.51; p<0.0001). When including hs-TnT in the model, hs-TnI remained a significant predictor of outcome with an attenuated effect estimate (HR 1.18; 95% CI 1.01-1.36; p=0.033). In analyzing the hs-Tn based on dichotomizing patients according to the sex-specific 99th percentile values, hs-TnI was a more powerful predictor of risk for CV death or heart failure than hs-TnT in multivariate analysis: HR 1.96 (1.40-2.74) and HR 1.43 (1.00-2.05), respectively.

In total, there were 209 hospitalizations for nonfatal AMI. In multivariable analysis adjusting for important predictors, hs-TnI was modestly and significantly associated with risk for nonfatal AMI (HR 1.20; 95% CI 1.04-1.37; p=0.01). In contrast, hs-TnT was not a significant predictor for MI (p=0.714).

For the endpoint of CV death or nonfatal heart failure, the C-index of the multivariable clinical model showed a moderately high level of discrimination at 0.763. Although significant, there was only a small increase in the C-index when including hs-TnI or hs-TnT to the model: 0.777 and 0.774, respectively. However, adding hs-TnI or hs-TnT did not significantly increase discrimination in the model for nonfatal AMI.

Conclusions

Based on the results, the authors conclude that in patients with stable CAD and preserved LV systolic function, hs-TnI and hs-TnT are significantly associated with risk for CV death or heart failure. Elevated concentrations of hs-TnI provide incremental prognostic information to conventional risk markers including NT-proBNP and hs-TnT. Of note, hs-TnI was associated with risk of future AMI, but not hs-TnT, perhaps indicating different pathophysiologic mechanisms governing the release of these highly specific cardiac markers into the circulation.

Commentary/Perspective

It has been almost 20 years since the prognostic importance of elevated serum troponin was demonstrated in patients with ACS.^{5, 6} In the initial updated universal definition of MI, there was an emphasis on using troponin instead of CK-MB as the biomarker of choice when evaluating patients with acute chest pain.⁷ Following these revelations, elevated levels of circulating troponin have also been found to be important markers of adverse outcomes in other disease states, such as chronic heart failure, pulmonary embolism, chronic kidney disease, and atrial fibrillation.^8-11 As newer more sensitive assays have been developed, our ability to quantify lower levels of troponin in the circulation has increased. Accordingly, our understanding and interpretation of such levels must evolve to inform how this prognostic information may be helpful to guide practice.

The featured article shows that there is important prognostic information in quantifying cardiac troponins in the circulation. In this study, the information adds to prediction in a highly statistically significant way. But it only adds modestly to clinical predictors with respect to the ability to discriminate risk and the direct implications for patient care are uncertain. Another important finding of this study is that there appear to be different biologic determinants, and different implications, of TnI and TnT levels in patients with stable coronary artery disease.

As we continue to refine our ability to risk stratify patients with stable coronary disease, the roles of new biomarkers that provide independent prognostic information need to be defined. Along these lines, in order to justify their routine use, not only must biomarkers provide incremental diagnostic and/or prognostic information, but they must also lead to better decision making that improves clinical outcomes.¹² The above article provides a framework for ways to evaluate high-sensitivity assays in CV disease. As suggested by the authors, further understanding the biologic mechanisms determining blood levels of high sensitivity troponin in stable patients may ultimately lead to the identification of novel treatment pathways.

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References

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