Biomarkers in the triage of chest pain: are we making progress?

Abstract

Biomarkers in MedicineVol. 10, No. 4 EditorialFree AccessBiomarkers in the triage of chest pain: are we making progress?Johannes Tobias Neumann, Nils Arne Sörensen & Dirk WestermannJohannes Tobias Neumann General & Interventional Cardiology, University Heart Center Hamburg, Hamburg, GermanySearch for more papers by this author, Nils Arne Sörensen General & Interventional Cardiology, University Heart Center Hamburg, Hamburg, GermanySearch for more papers by this author & Dirk Westermann*Author for correspondence: E-mail Address: d.westermann@uke.de General & Interventional Cardiology, University Heart Center Hamburg, Hamburg, GermanySearch for more papers by this authorPublished Online:22 Mar 2016https://doi.org/10.2217/bmm.16.7AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: acute myocardial infarctionchest paindiagnosisrule-outtroponinFirst draft submitted: 4 February 2016; Accepted for publication: 8 February 2016; Published online: 22 March 2016Triaging acute coronary syndrome: the clinical settingPatients with acute onset chest pain frequently present at the emergency department (ED). These patients can make up to 10% of all patients in the ED utilizing scarce medical resources [1]. Importantly, only around 20% have a final diagnosis of acute myocardial infarction (AMI). Therefore, a rapid rule-out of AMI is urgently needed to limit the overuse of the ED. Furthermore, these patients will be discharged immediately and therefore future cardiovascular risk should be minimal to reduce forthcoming events. This translates into a need for the highest safety margin possible for any rule-out algorithm. On the other hand, the early identification and treatment of AMI-patients is also important, as early treatment improves outcomes for acute coronary syndrome patients [2]. Whether this treatment might be medical or interventional therapy has to be clarified by the clinical setting, but it would be optimal if future diagnostic strategies could differentiate between patients in need of percutaneous coronary interventions and those who are best managed medically. Therefore, there is an unmet need for differentiating between AMI patients caused by either plague rupture that needs percutaneous coronary interventions or other noncoronary forms of myocardial damage.Current diagnostic algorithmsCardiac troponin is released during myocardial injury and is well established in acute cardiac care. Current European Society of Cardiology (ESC) guidelines recommend a troponin-based algorithm with serial measurement after 3 h to rule-out or rule-in AMI [3]. The diagnostic cut-off concentration is recommended at the assay-specific 99th percentile. This approach has been shown to be safe and cost-effective in the ED [4–6]. The use of more sensitive troponin assays enables the detection of lower troponin-concentrations, which can be measured in up to 96% of the general population [7,8]. Using high-sensitivity troponin-assays, a much lower cut-off concentration has been suggested to enable a rapid rule-out or rule-in after only 1 or 2 h [9,10]. In the ADAPT trial a serial measurement of high-sensitivity troponin I (hs-TnI) after 2 h showed a low rate of major adverse cardiac events after 30 days, when combined with a normal ECG and a negative TIMI-score [10]. The APACE cohort showed in 1811 patients, that a hs-TnI based algorithm after 1 h had a high negative predictive value (NPV) of 99.6% [9]. Importantly the suggested cut-off concentration was only 5 ng/L combined with an absolute change of 2 ng/L after 1 h. The rule-in of AMI was suggested for individuals with an absolute hs-TnI increase of 6 ng/L. This resulted in a positive predictive value of 74% and included most of the AMI patients. In the recently presented BACC cohort, the NPV was 99.8% for a cut-off concentration of 6 ng/L after 1 h for the final diagnosis of NSTEMI type 1. This approach was noninferior compared with a 3-h approach [11]. These concentrations are much lower, as compared of the assay-specific 99th percentile at 27 ng/L.An alternative rule-out approach has been investigated using only a single troponin measurement. A negative high-sensitivity troponin T (hs-TnT below 5 ng/L) in combination with a normal ECG showed a high NPV of 99.8% for AMI in a large population of 14,636 individuals in the ED [12]. A recently published study by Shah et al. investigated the more sensitive hs-TnI in 6304 patients with suspected AMI [13]. The immediate discharge of patients with a hs-TnI below 5 ng/L resulted in a 99.6% NPV. Importantly the NPV was much lower for early-presenters that had symptom onset only 2 h prior to presentation. The 2015 ESC guidelines already represent the approach of a single hs-TnI measurement or a rapid algorithm after only 1 h [3]. In summary, individuals with a very low troponin concentration, using a high-sensitivity assay, have a low risk of cardiovascular events. This is also represented in the general population, where a low hs-TnI was associated with a low rate of long-term cardiovascular events [8].Besides high-sensitivity troponin, various other biomarkers have been investigated to triage AMI-patients. The heart-type fatty acid binding protein (htFABP) and copeptin have been the most promising. HtFABP is a cytoplasmatic protein from the myocardial cell that shows an early increase after myocardial injury, but failed to increase the accuracy of AMI-diagnosis when added to high-sensitivity troponin [14]. Copeptin is a stabile fragment of vasopressin, which is released in acute stress and showed an increase rapidly after AMI [15]. When combined with high-sensitivity troponin, the accuracy of rule-out might be slightly improved in low-risk individuals and the duration of stay in the ED shortened. Nevertheless these biomarkers did not yet substantially improve the diagnostic algorithms in the ED.Conclusion & future perspectiveThe major progress in the triage of patients with suspected AMI has been the application of more sensitive troponin assays. The use of much lower cut-off concentrations allows rapid risk stratification at baseline or after 1 h. This concept translates into rapid rule-out of most ED patients (∼50%) and rule-in of AMI patients (∼15%) that can receive immediate treatment [11]. Importantly, patients with elevated, but stable troponin concentrations have an increased cardiovascular risk and should be handled carefully. These individuals should be further observed, receive serial troponin testing and might need further investigation for other causes of symptoms or stress testing to rule-out unstable angina. Importantly, this field is still plagued by limited data and controlled approaches are clearly needed to overcome bias of cohort or register studies. Therefore, randomized clinical trials are paramount and now on their way to be initiated.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Nawar EW, Niska RW, Xu J. National Hospital Ambulatory Medical Care Survey: 2005 emergency department summary. Adv. Data (386), 1–32 (2007).Medline, Google Scholar2 Mehta SR, Granger CB, Boden WE et al. Early versus delayed invasive intervention in acute coronary syndromes. N. Engl. J. 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High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study. Lancet 386(10012), 2481–2488 (2015).Crossref, Medline, CAS, Google Scholar14 Reiter M, Twerenbold R, Reichlin T et al. Heart-type fatty acid-binding protein in the early diagnosis of acute myocardial infarction. Heart 99(10), 708–714 (2013).Crossref, Medline, CAS, Google Scholar15 Mockel M, Searle J, Hamm C et al. Early discharge using single cardiac troponin and copeptin testing in patients with suspected acute coronary syndrome (ACS): a randomized, controlled clinical process study. Eur. Heart J. 36(6), 369–376 (2015).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByA Biomarker Model to Distinguish Types of Myocardial Infarction and InjuryJournal of the American College of Cardiology, Vol. 78, No. 8Rapid and safe discharge from the emergency department: A single troponin to exclude acute myocardial infarction8 January 2018 | Emergency Medicine Australasia, Vol. 30, No. 4 Vol. 10, No. 4 Follow us on social media for the latest updates Metrics History Published online 22 March 2016 Published in print April 2016 Information© Future Medicine LtdKeywordsacute myocardial infarctionchest paindiagnosisrule-outtroponinFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download