The race for higher sensitivity troponins, but for what prize?

This editorial refers to ‘Consequences of implementing a cardiac troponin assay with improved sensitivity at Swedish coronary care units: an analysis from the SWEDEHEART registry’†, by K.M. Egger et al., on page 2417. Cardiac troponins play a central role in the diagnosis of acute myocardial infarction (AMI) and the management of non-ST-segment elevation acute coronary syndromes (NSTEACS). The third universal definition bases the diagnosis of AMI on the ‘detection of a rise and/or fall of cardiac biomarker values (preferably cardiac troponin) with at least one value above the 99th percentile upper reference limit’.1 The European Society of Cardiology (ESC) guidelines for the management of NSTEACS recommend an urgent invasive strategy, i.e. within 24 h, in patients with high-risk criteria, including those with a rise or fall in cardiac troponin compatible with MI.2 The early and accurate diagnosis of AMI is a key function of emergency departments. Delayed diagnosis may result in substandard initiation of AMI treatments, inadequate rule out of alternative diagnoses, and the failure to discharge very low risk patients—each being associated with the potential for increased costs and adverse clinical outcomes. Moreover, ‘negative’ cardiac troponin values may lead to patients with ACS who have small, but measureable, cardiac damage being inappropriately discharged from hospital. Such imperfections in ACS diagnostics triggered a race to develop higher sensitivity cardiac troponin assays, which allow the detection of minimal circulating cardiac troponin concentrations in shorter periods of time. Consequent to the development of higher sensitivity cardiac troponin assays, their introduction has been very successful; reducing the troponin-blind period of AMI to a minimum and allowing fast and safe decision-making.3,4 Presently, higher sensitivity cardiac troponin assays have been adopted by a large number of hospitals and healthcare systems. The underlying premise is that a shift to using higher sensitivity troponins leads to more diagnoses of AMI more expeditiously, a reduction in the rate of diagnosis of unstable angina, earlier (and, eventually, more frequent) use of coronary angiography, and, if compliant with guidelines recommendations, a decline in adverse clinical outcomes. There is, however, concern that widespread implementation of higher sensitivity troponins may lead to the identification of lower risk patients that would not offer a net clinical and financial gain for health systems. That is to say, by virtue of lowering the threshold for the diagnosis of AMI, there would be a greater requirement for specialist cardiology input, more frequent use of an invasive strategy, and the potential for diagnostic errors with associated inappropriate use of therapies and iatrogenic complications. The use of the 99th percentage of values measured in a healthy population as the cut-off for the diagnosis of AMI with higher sensitivity cardiac troponin assays, as recommended by the universal definition of MI,1 has led to the identification of an increasing number of patients who have detectable levels of cardiac troponin in a number of other settings, such as acute heart failure, pulmonary embolism, atrial fibrillation, and stable coronary artery disease. Each scenario has prognostic application, but unclear implications for clinical management. In fact, a sizeable proportion of patients who attend emergency departments have higher sensitivity cardiac troponin values greater than the 99th percentile in the absence of AMI.5 There is no question that cardiac troponins are useful tools for the diagnosis of AMI, but it is also true that there is a risk of interpreting elevated levels of cardiac troponin as AMI regardless of the clinical presentation. In this regard, it should be emphasized that the correct use and interpretation of high sensitivity cardiac troponin assays is an important clinical skill that must not be taken for granted (Figure 1). Integrative use of high sensitivity troponins and interpretation of results in different clinical scenarios. ECG, electrocardiogram; ESC, European Society of Cardiology; hs, high sensitivity; NSTEACS, non-ST-segment elevation acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction; Tn, troponin. A question relating to the rapid, system-wide implementation of the use of higher sensitivity troponins is: what is the evidence for clinical benefit across a health service? Among the limited studies investigating the impact of implementing higher sensitivity cardiac troponin assays, few have described a reduction in mortality, but rather an increase in the rate of AMI diagnoses,6 with only weak evidence to suggest that higher sensitivity cardiac troponin testing may provide a cost-effective approach to early rule-out of AMI.7 Eggers and colleagues report in this issue of the journal the results of a retrospective analysis of the SWEDEHEART registry during a time when there was system-wide change by way of national adoption of higher sensitivity cardiac troponin assays.8 This ‘natural experiment’ is the first to evaluate the impact of lowering the threshold for the diagnosis of AMI on the use of guideline-indicated treatments for the management of NSTEACS and mortality at a system level. Across 47 hospitals in Sweden between 2009 and 2012 and >30 000 patients with suspected NSTEACS, the authors describe an increase in the cases of ACS and a fall in non-acute coronary syndrome diagnoses after higher sensitivity cardiac troponin assay implementation. After adoption, the use of antiplatelet agents, angiotensin-converting enzyme (ACE) inhibitors, statins, echocardiography, coronary angiography, and intervention increased. In particular, a higher sensitivity cardiac troponin assay identified higher risk patients with NSTEACS, who appropriately received guideline-indicated treatments. Yet, the authors failed to show a decline in the rates of death consequent to enhanced diagnosis and application of evidence-based treatments. Several aspects of these results are of note. When guideline-indicated treatments for AMI are clearly associated with improved outcomes,9 why did the authors fail to provide evidence for a decline in mortality in AMI patients? One possible explanation is that the greater co-morbidity burden observed in the latter years may have accelerated mortality rates which were not fully accounted for in the survival models (especially when non-cardiovascular disease is the predominant cause of death following percutaneous coronary intervention and significantly affects survival estimates).10 However, a significantly lower adjusted mortality was observed in NSTEACS patients with cardiac troponin levels below the AMI cut-off, as well as in non-ACS patients. In addition, the authors noted that after case mix adjustment there was no increase in the use of diagnostic procedures, which is surprising when more at-risk patients were hospitalized and the prognostic impact of a raised cardiac troponin was greater with the higher sensitivity assay. Finally, and contrary to what would be expected, the introduction of higher sensitivity cardiac troponin was associated with an increase in the rate hospitalization for unstable angina and non-acute coronary syndrome. As such, the Swedish experience, together with other findings, raises the question of whether the rapid adoption of higher sensitivity cardiac troponin assays is occurring as a result of clear clinical evidence in its favour. Certainly, a retrospective evaluation of the Swedish system-wide implementation has revealed encouraging results, but leaves many important questions unanswered. A critical achievement for the application of higher sensitive troponins will be robust evidence for its association with lower mortality rates from AMI in addition to its proven ability to enable the efficient diagnosis of those with and to rule out those without AMI. Clearly, the impact of the use of high sensitivity troponins in improving prognosis from patients with suspected ACS remains a field for research. Conflict of interest: none declared.