The highs and lows of high sensitivity troponin

Troponin elevation is the premier biochemical criterion for the diagnosis of acute myocardial infarction (AMI).1 Current recommendations are to use only troponin assays which are reliable (<10% coefficient of variation) at the decision limit (99th percentile of a normal reference population).1 Many conventional assays do not comply with these recommendations and have to use cut-points higher than the 99th percentile in order to maintain precision levels. Because of this, there has been development of high sensitivity troponin assays to increase the analytical, and thus clinical, sensitivity for detection of myocardial injury; this is achieved by including longer incubation times or signal amplification techniques during analysis of samples.2 Newer assays now comply or are close to complying with the guidelines for precision and have limits of detection that are much lower, those classified specifically as high sensitivity assays can detect very low levels of troponin. However, there is no real consensus on what constitutes a ‘high-sensitivity’ assay. It has been suggested that in addition to a total imprecision of <10% at the 99th percentile, a truly high sensitivity assay should enable detection of measurable troponin in >90–95% of apparently healthy subjects and may involve different cut-points depending on age, sex and ethnicity.3 The use of sensitive assays permits earlier diagnosis of AMI.4-8 Detection of troponin elevations earlier than current recommendations for a second troponin in patients under investigation for acute coronary syndrome (ACS), 6–12 h post-symptom onset,1, 9 should enable a change in hospital chest pain algorithms with more rapid triage to intensive and invasive treatment strategies in those with elevations. It should also allow earlier stress testing in those with normal early troponin values. Findings in studies investigating assays with improved precision show that when the 99th percentile is used, these assays were equivalent to each other but outperform assays previously employed routinely in practice. Some of these assays may have only appeared to have performed less well because decision cut-points used were higher than the 99th percentile, cut-points chosen due to the poor performance of these assays at lower values.5-7, 10, 11 Test performance has been shown to increase with use of serial troponin samples;5, 6, 8, 10 however, higher sensitivity assays are more likely to be increased at baseline in those with AMI4-8, 10 and are more reliable in those presenting early after symptom onset.6 An additional illustration of the increase in clinical sensitivity of these assays is that when higher sensitivity assays are used, an increase in the number of patients with elevations is seen and that at least a proportion of these would be suitable for recategorization from, for example, unstable angina to AMI with recategorization rates of ≥10%.7, 11 However, as yet there is no clear consensus as to how early a negative second troponin is reliable and whether it can indeed accelerate the current recommendations. In addition to AMI due to type 1 myocardial infarction1 due to a primary coronary event such as plaque erosion and/or rupture, fissuring, or dissection, AMI can be secondary to ischaemia due to either increased oxygen demand or decreased supply, for example coronary artery spasm, coronary embolism, anaemia, arrhythmias, hypertension or hypotension. Troponin may therefore be raised in both cardiac (acute coronary artery disease and other conditions) as well as non-cardiac conditions, such as renal failure and sepsis.1 Because of these facts, troponin results must be interpreted within the clinical context in which they are measured, as recommended by World Heart Federation Task Force,12 especially as troponin positive patients are treated more aggressively with potent antiplatelet therapies and early angiography, that is, procedures and treatments which carry risks. Although the temporal and logistical demands of clinical management often require provisional diagnosis of AMI based on a single measurement of troponin >99th percentile, the formal definition requires a rise and/or fall1 although the degree to which troponin must rise or fall is not specified. This approach has been advocated to help distinguish chronic elevations from acute elevations, seen in conditions such as cardiomyopathy and valvular disease.1, 13 In the appropriate acute clinical setting, troponin concentrations greatly in excess of the cut-point concentrations, cardiac troponin becomes almost pathognomonic for AMI. At values around the cut-off, troponin is more likely to signify AMI if serial measurements show increasing values (signifying new onset infarction) or decreasing values (signifying resolving infarction). However, even a changing pattern does not confirm the diagnosis of AMI unless the presentation is suggestive of acute ischaemic heart disease because other acute illnesses such as myocarditis, takotsubo syndrome, pulmonary embolism and sepsis have also been associated with acute cardiac injury. For this reason, an elevated value of cardiac troponin in the absence of clinical evidence of ischaemia should prompt consideration of aetiologies other than plaque rupture.1 The degree to which serial troponin measurements should differ (‘delta’) has not been explicitly defined. A delta of greater than both the biological and analytical variability of an assay is deemed the most appropriate as measurements above these levels would mean that any differences between two readings in the same patient are pathological. Wu showed this to be an increase of 46% or decrease of 32% from the previous measurement for a high sensitivity troponin I assay,14 and Vasile et al. 84% for short-term changes (0–4 h) of a high sensitivity troponin T assay;15 however, these calculations have been made in healthy populations with biological levels of troponin (by definition having troponin values within the normal range 99% of the time). The National Academy of Clinical Biochemistry has recommended the use of a ≥20% delta in sensitive, but not specifically high sensitivity, assays16 in patients with pathological levels of troponin (i.e. those with troponin ≥99th percentile). This should be above imprecision levels for all troponin assays for values ≥99th percentile if the troponin assay is compliant with current guidelines for having a ≤10% coefficient of variation at this level. Others have attempted to calculate the optimum delta by use of receiver operating characteristic curve analysis but this method is highly influenced by the population in which it is being calculated and has been anywhere between 30% and 243%.7, 8 It is likely that it will be impossible to distinguish between a rising pattern indicative of acute cardiac injury from biological and analytical variation if only minor to modest changes in serial results with a high sensitivity troponin occur. The optimum timing of troponin measurements over which to calculate a delta has also not been explicitly determined. Another limitation to the use of a delta to increase specificity for AMI is that the sensitivity is reduced with reductions in AMI diagnoses of at least 15% when using a delta of >20%.7, 13 The poor outcome in those with missed AMI/ACS is well documented17 and would be a grave concern if a strict delta criterion was adhered to. In addition to the fact that the analytical and biological variation will be different for each individual assay, the baseline circulating concentration of troponin is individual to each patient.15 A patient, whose natural troponin concentration is quite low, may suffer micro-infarction (by pathological definition), but troponin levels might still fall below the 99th percentile. Likewise, by definition, 1% of a healthy population have natural circulating levels ≥99th percentile. These levels are likely to be only marginally elevated above the 99th percentile, the levels at which high sensitivity assays are more sensitive in detecting. Hence, it can be envisaged that when using more sensitive assays, differentiating between troponin increases due to non-ischaemic causes, those with higher baseline circulating levels of troponin and those with true AMI will be more difficult. It is possible that single values of sensitive troponins ≥99th percentile, in a clinical context consistent with ACS, will perform well and largely obviate the need to await a rising or falling pattern. However, as a rise or fall in troponin is required by current definition to make the diagnosis of AMI,1 more research is required to ascertain whether formal delta calculations are required and if so, the optimum magnitude and timing for such calculations. Higher values of cardiac troponin have been shown in numerous studies to be predictive of adverse cardiac events in the short and long term8, 18-21 post-ACS even when only minor increments in troponin above decisions cut-points including the 99th percentile have been used.10 In addition to this, those with elevations in troponin have been shown to benefit from low molecular weight heparin, glycoprotein llbllla inhibitors in patients with refractory angina and in patients undergoing percutaneous intervention, antiplatelet therapy, 24–48 h of telemetry, angiography as the preferred investigation and revascularization and such treatments are recommended in the American College of Cardiology/American Heart Association guidelines for patients with unstable angina/non-ST-elevation myocardial infarction.9 Several studies comparing higher sensitivity assays with contemporary troponin assays for prognostic utility have shown only modest differences in the short term,5, 8 likely because the signal for short-term events is usually larger increases in troponin. Long-term outcomes are influenced by any elevation in troponin and therefore, the higher sensitivity assays have clear superiority in the long term.18-20 However, there is a graded relationship between the magnitude of troponin elevation and prognosis.21 Given the evidence that patient outcomes are positively influenced by troponin results, distinguishing whether instituting high sensitivity assays into clinical practice will improve outcomes further is vital, but has yet to be investigated. This is a worrying phenomenon when procedures and treatments, which carry risks, are instigated in response to troponin elevations (elevations more likely to have a non-coronary cause in high sensitivity assays than in conventional assays) and when such assays are already available and in use in many centres.