Troponin: the basis of decision-making in suspected acute coronary syndromes and beyond

Download the Issue @ a Glance podcast Subscribe to the EHJ Podcast The evaluation of patients presenting to the emergency department with suspected acute coronary syndrome remains a clinical challenge.1 The traditional assessment includes clinical risk assessment based on history, symptoms, cardiovascular risk factors with serial ECGs, and, more recently, measurements of cardiac troponin and other biomarkers.2 Troponins are much more specific for myocardial necrosis than previously used biomarkers and have moved to centre stage in decision-making in patients presenting with acute chest pain. The newest generation of troponin assays are markedly more sensitive and are thought to provide more rapid and more reliable information on the optimal management of such patients. Besides biomarkers, novel imaging modalities, in particular coronary computed tomography,3 are increasingly used in the assessment of patients presenting with acute chest pain. Indeed, in spite of the increasing use of high sensitive troponin assays, a considerable number of patients with acute coronary syndrome are missed and are exposed to an increased risk of death. Thus, the second review article ‘Highly sensitive troponin and coronary computed tomography angiography in the evaluation of suspected acute coronary syndrome in the emergency department’ by Maros Ferencik and colleagues from the Oregon Health and Science University in Portland, Oregon in the USA is a timely update on the combined use of highly sensitive troponin and coronary computed tomography in the rapid and efficient evaluation of such patients.4 The authors again remind us of the fact that highly sensitive troponin increases the sensitivity for detection of myocardial infarction and decreases time to diagnosis, but often decreases the specificity, especially when used as a dichotomous variable, rather than a continuous variable. Thus, coronary computed tomography represents a complementary and rapid diagnostic tool that decreases the time to diagnosis and discharge.5 However, coronary computed tomography may lead to more invasive procedures and radiation exposure. Therefore, Maros Ferencik and colleagues outline the opportunities for the combined use of highly sensitive troponin and coronary computed tomography angiography that may result in increased efficiency, decreased need for imaging, lower cost, and decreased radiation dose. Troponin release in patients with acute coronary syndromes may also be used a a surrogate endpoint6 in phase II trials aiming to evaluate novel treatment strategies. Indeed, the amount of troponin released reflects infarct size and predicts clinical outcome. Unstable plaques are considered the culprit lesions in acute coronary syndromes.7 Inflammation induced, among others, by cholesterol crystals8 is the triggering event in this context, and hence cytokines such as interleukin-69,10 which contribute to atherosclerotic plaque vulnerability are considered novel therapeutic targets.11 In a first paper entitled ‘Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase II trial’, Ola Kleveland and colleagues from St. Olavs Hospital in Trondheim, Norway investigated whether the interleukin-6 receptor antagonist tocilizumab would attenuate inflammation, and in turn reduce troponin release in non-ST-elevation myocardial infarction.12 In a double-blind, placebo-controlled trial, 117 patients with non-ST-elevation myocardial infarction were randomized at a median of 2 days after symptom onset to receive placebo or tocilizumab as a single dose prior to coronary angiography. The median area under the curve for high sensitivity C-reactive protein during hospitalization was 2.1 times higher in the placebo than in the tocilizumab group. Also, the median area under the curve for high sensitivity troponin T during hospitalization was 1.5 times higher in the placebo compared with the tocilizumab group. The differences between the two treatment groups were observed mainly in patients included <2 days from symptom onset, but also in those undergoing percutaneous coronary intervention. No safety issues were detected during 6 months of follow-up. Thus, tocilizumab attenuated the inflammatory response and primarily percutaneous coronary intervention-related troponin T release in non-ST-elevation myocardial infarction. These intriguing findings are put into perspective in a thought-provoking Editorial by Filippo Crea from the Universita Catolica del Santo Cuore in Rome, Italy.13 In a second clinical research manuscript entitled ‘Consequences of implementing a cardiac troponin assay with improved sensitivity at Swedish coronary care units: an analysis from the SWEDEHEART registry’, Kai M. Eggers and colleagues from Uppsala University in Sweden assessed the clinical consequences of the implementation of high sensitivity assays in a retrospective register-based study involving 37 710 coronary care unit admissions of the SWEDEHEART registry.14 They compared case mix, diagnostic and therapeutic procedures, and 1-year all-cause mortality 1 year prior to (i.e. period 1) and 1 year after (i.e. period 2) the implementation of a cardiac troponin assay with improved sensitivity. During study period 2, more at-risk patients were admitted and more patients had cardiac troponin levels above the cut-off. Cardiac troponin levels above this cut-off exhibited stronger associations with mortality risk in study period 2, with an adjusted hazard ratio of 4.45 compared with period 1 with an adjusted hazard ratio of 2.43. While there was no multivariable-adjusted increase in the use of diagnostic procedures, significant trends towards more differentiated treatment depending on the cause of cardiac troponin elevation, i.e. acute coronary syndromes or non-acute coronary syndrome, were noted. Thus, in the real world, implementation of a cardiac troponin assay with improved sensitivity was associated with an increase in the number of patients who, due to their cardiac troponin status, were identified as suitable for beneficial therapies. Notably, there was no increase in inappropriate hospital resource utilization. As such, cardiac troponin assays with high sensitivity improve the clinical management of patients with suspected acute coronary syndrome, a message that is further discussed in an comprehensive Editorial by Héctor Bueno from the Hospital General Universitario Gregorio Marañón in Madrid, Spain.15 Importantly, troponin may not only be useful in patients with chest pain, but appears to provide an important tool for future risk prediction. In a meta-analysis entitled ‘Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE Consortium’, Stefan Blankenberg from the Universitätsklinikum Hamburg in Germany evaluated the distribution of troponin I concentrations in population cohorts across Europe and their predictive value beyond the ESC SCORE (Figure 1).16 Based on BiomarCaRE, the biomarkers for Cardiovascular Risk Assessment in Europe project, they analysed individual level data from 10 prospective population-based studies including 74 738 participants. They investigated the value of adding troponin I levels to conventional risk factors for prediction of cardiovascular disease by calculating measures of discrimination (C-index) and net reclassification improvement as well as the clinical implication of statin therapy based on the troponin concentration in 12 956 individuals free of cardiovascular disease in the JUPITER study. Troponin I remained an independent predictor with a hazard ratio of 1.37 for cardiovascular mortality, 1.23 for cardiovascular disease, and 1.24 for total mortality. The addition of troponin I information to a prognostic model for cardiovascular death constructed of ESC SCORE variables increased the C-index discrimination measure by 0.007 and yielded a net reclassification improvement of 0.048, whereas the addition to prognostic models for cardiovascular disease and total mortality led to lesser C-index discrimination and net reclassification improvement. In individuals with >6 ng/L troponin I, a concentration near the upper quintile, rosuvastatin resulted in higher absolute risk reduction compared with in individuals with <6 ng/L troponin I. The authors conclude that in individuals free of cardiovascular disease, the addition of troponin I to variables of an established risk score improves prediction of cardiovascular death and cardiovascular disease. The manuscript is accompanied by an Editorial by Hugo A. Katus from the University Hospital in Heidelberg, Germany.17 Hazard ratios according to fifths of the troponin I distribution in the study population. The troponin I quintiles, computed in the overall population via linear quantile mixed models, are 2.5, 2.8, 5.4, and 5.9 ng/L. The hazard ratios come from Cox models adjusted for variables of the ESC SCORE (cardiovascular mortality, total mortality) and ACC/AHA score (cardiovascular disease). Age was used as the time scale. The models were stratified by sex and cohort. ns stands for non-significant (P ≥ 0.05), *0.01 ≤ P < 0.05, **0.001 ≤ P < 0.01, ***0.0001 ≤ P < 0.001, and ****P < 0.0001. (From Blankenberg S, Salomaa V, Makarova N, Ojeda F, Wild P, Lackner KJ, Jørgensen T, Thorand B, Peters A, Nauck M, Petersmann A, Vartiainen E, Veronesi G, Brambilla P, Costanzo S, Iacoviello L, Linden G, Yarnell J, Patterson CC, Everett BM, Ridker PM, Kontto J, Schnabel RB, Koenig W, Kee F, Zeller T, Kuulasmaa K; BiomarCaRE Investigators. Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium. See pages 2428–2437). The editors hope that this issue of the European Heart Journal will capture the interest of its readers.