Rapid rule out of acute myocardial infarction: novel biomarker-based strategies

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1 653229ACC / European Heart Journal: Acute Cardiovascular CareMueller et al. research-article2016 Original scientific paper Rapid rule out of acute myocardial infarction: novel biomarker-based strategies EUROPEAN SOCIETY OF CARDIOLOGY European Heart Journal: Acute Cardiovascular Care 2017, Vol. 6(3) The European Society of Cardiology 2016 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: journals.sagepub.com/home/acc Christian Mueller 1, Evangelos Giannitsis 2, Martin Möckel 3, Kurt Huber 4, Johannes Mair 5, Mario Plebani 6, Kristian Thygesen 7, Allan S Jaffe 8 and Bertil Lindahl 9 ; the Biomarker Study Group of the ESC Acute Cardiovascular Care Association Keywords Acute myocardial infarction, diagnosis, rule out Date received: 10 May 2016; accepted: 15 May 2016 Introduction Millions of patients present with symptoms of possible acute myocardial infarction (AMI) each year. 1 3 The majority do not have AMI. Thus, the expeditious evaluation of such patients is important. Delays in ruling out AMI may interfere with the detection of other underlying diseases and contribute to emergency department (ED) crowding and its associated medical and economic problems. 1 3 Detailed clinical assessments including chest pain characteristics, ECG and blood tests to measure the concentration of cardiac troponin (ctn) T or I form the cornerstones for the diagnosis of AMI. 1 5 If the clinical setting is compatible with myocardial ischaemia, a dynamic elevation of ctn above the 99th percentile upper reference limit is diagnostic of AMI. 2 4 In patients with AMI, ctn concentrations rise rapidly after symptom onset and remain elevated for many days. 2 8 Recent advances in ctn assays now allow for sensitive detection of myocardial injury. 9 The high sensitivity cardiac troponin (hs-ctn) assays allow for the development of rapid rule-out strategies by increasing diagnostic accuracy at presentation, reducing the troponin-blind interval and allowing the time interval to the second measurement of hs-ctn to be shortened, which may result in substantial reductions in the time to decision and/or diagnosis. 1 7,10 21 The aim of this review is to provide a condensed summary of the key characteristics and performance measures of six novel and validated rule-out strategies, which will allow cardiologists, ED physicians and laboratory specialists to select the algorithm that best suits their local needs. These strategies are applied after the initial ECG has ruled out ST-segment elevation AMI. 8 Their performance measures are summarised in Table ,10 21,22 The 2015 European Society of Cardiology (ESC) guidelines recommend the use of the hs-ctn 3-h algorithm, 2,8 the hs-ctn 1-h algorithm, and the single blood draw approach using very low blood concentrations of hs-ctn in patients presenting at least 3 h after chest pain onset (see below). 8 It is important to note that the exact metrics of each of these algorithms (e.g. proportion eligible for rule out and negative predictive value; NPV) applied in a specific setting depend 1 Department of Cardiology and Cardiovascular Research Institute Basel, University Hospital Basel, Switzerland 2 Medizinische Klinik III, University Heidelberg, Germany 3 Division of Emergency Medicine and Department of Cardiology, Charite, Universitätsmedizin Berlin, Germany 4 3rd Department of Medicine, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Austria 5 Department of Internal Medicine III Cardiology and Angiology, Innsbruck Medical University, Austria 6 Department of Laboratory Medicine, University Hospital Padova, Italy 7 Department of Cardiology, Aarhus University Hospital, Denmark 8 Mayo Clinic and Medical School, USA 9 Department of Medical Sciences, Uppsala University and Uppsala Clinical Research Center, Sweden The first two authors contributed equally and should be considered first author. Corresponding author: Bertil Lindahl, UCR, University Hospital, SE Uppsala, Sweden. bertil.lindahl@ucr.uu.se

2 Mueller et al. 219 Table 1. Summary of rapid rule-out algorithms. 3-h ESC 2-h ADP 2-h algorithm 1-h algorithm ctn + copeptin <LOD/very low Negative predictive value for AMI %* %** % % % 96 99% with hs-ctn Effectiveness Characteristics** If using hs-ctn T If using hs-ctn I and GRACE <140 and pain-free and GRACE <140 and pain-free Feasibility ++ requires GRACE score Challenges Pain onset often difficult to quantify Independent validation in large multicentre studies Validation in an openlabel RCT Rule out possible with a single blood draw and ECG OK and TIMI 1 and ECG OK and TIMI 1 ++ requires TIMI score and 2 h delta <4 Hs-cTn I <6 and 2 h delta <2 Hs-cTn T <12 (0 h) and 1 h delta <3 Hs-cTn I <5 and 1 h delta <2 and Copeptin <10 and copeptin < requires second biomarker, which currently can only be measured on separate analyser Cut-off levels are assay specific Cut-off levels are assay specific # + ## + for chest pain onset >6 h Additional advantages Already used clinically Also provides guidance for rule in % Hs-cTn T <5 Hs-cTn I < Cut-off levels are assay specific + + for chest pain onset >3 h Also provides guidance for rule in Effectiveness is quantified by the percentage of consecutive chest pain patients eligible for this rule-out strategy: + 20%, ++ 40%, %, Hs-cTn concentrations are shown in ng/l, copeptin in pmol/l. Four algorithms require two measurements of hs-ctn: In three of them (3-h algorithm, 2-h ADP, 2-h algorithm) the criteria for the maximum hs-ctn blood concentration allowed for safe rule out had to be met at both time points. In the publications of the 1-h algorithm, the criteria had to be met only at presentation. Delta changes apply in both directions: increase and decrease. Both would suggest the presence of acute disease, e.g. AMI. *Wildi K, personal communication (manuscript in revision). ** For major adverse cardiac events (death, AMI, major arrhythmias). Characteristics are provided for the hs-ctn T (Roche Diagnostics) and hs-ctn I (Abbott Diagnostics). Cut-off levels differ for other hs-ctn assays. # Open label + small single centre study not powered for safety. ## Open label + using a conventional ctn assay in the majority of patients. AMI: acute myocardial infarction; LOD: lower limit of detection; ctn: cardiac troponin; hs: high sensitivity; ADP: accelerated diagnostic protocol; GRACE: global registry of acute coronary events; TIMI: thrombolysis in myocardial infarction; ESC: European Society of Cardiology; RCT: randomised controlled trial.

3 220 European Heart Journal: Acute Cardiovascular Care 6(3) on the local prevalence of AMI; for example, a lower prevalence of AMI will increase the NPV and vice versa. In addition, the individual decision values are assay specific. Accordingly, the algorithms of other hs-ctn I assays, which are in development, will have different decision values due to a lack of assay harmonisation. ESC 3-h algorithm Patients are ruled out if concentrations of hs-ctn remain in the normal range at presentation and at 3 h, and if the patient is pain-free and has a low risk global registry of acute coronary events (GRACE) score of below In patients presenting more than 6 h after chest pain onset, a hs-ctn value below the 99th percentile upper reference level at presentation is considered sufficient. 8 We would advise some caution applying the 6-h limit for a single blood draw given the challenges determining the symptom onset in clinical practice. 2-h Advanced diagnostic protocol and 2-h algorithm Two strategies allow for rule out of AMI with sensitive ctn assays performed at zero and 2 h. The 2-h advanced diagnostic protocol combines a low thrombolysis in myocardial infarction (TIMI) score ( 1) with the ECG and ctn at presentation and 2 h and allows the safe rule out in up to 40% of patients Another 2-h algorithm exclusively uses hs-ctn data and achieves a comparable NPV by taking into account absolute concentration changes within 2 h. 3 Absolute changes (increase or decrease) seem to be the best metric to differentiate acute cardiac injury including AMI from other causes of chest pain. 3 5 The strategy allows rapid rule out of AMI in up to 60% of patients, including patients with mild ECG abnormalities. 3 1-h Algorithm The 1-h algorithm is based on information provided by the hs-ctn concentrations. It is based on the same concepts as the 2-h algorithm. 3 5 This strategy allows the rapid rule out of AMI in up to 60% of chest pain patients. It is important to note that the cut-off levels and deltas are assay specific. 4,5,8,14 17 The cut-off values for the 1-h and 2-h algorithms have been established for the commercially available hs-ctnt assay (Roche Diagnostics) 3,5,13,14,16,17 and ARCHITECT High Sensitive STAT Troponin-I assay (Abbott Laboratories). 11,15 In the studies of hs-ctn T the samples were assayed using the Elecsys ,5,13,14,16,17 or Cobas e instruments (Roche Diagnostics). In one additional study the precommercial Dimension Vista 1500 hs-ctn I assay (Siemens Diagnostics) was used. 17 Dual-marker strategy combining ctn and copeptin A dual-marker strategy combining ctn and copeptin (the c-terminal part of the vasopressin prohormone) takes advantages of the reciprocal release kinetics of both biomarkers. 1,6 8 This combination provides incremental diagnostic value as compared to the use of a single conventional ctn concentration, but provides no or only minor incremental value when using hs-ctn assays. 1,6 8 The limitations of this strategy include the complexity of an additional biomarker, low positive predictive value for the combination of an elevated copeptin with a negative ctn, and the need for an additional analyser. Undetectable/very low levels of high-sensitivity ctn at admission Very low plasma concentrations of hs-ctn at presentation have a high NPV for AMI. 8,18 21 Because the lower limit of detection is assay dependent very low concentrations, for example, below the 40% percentile of healthy individuals, may be a preferred metric to identify biological equivalent values. Several large studies have provided consistent results for hs-ctn T and hs-ctn I assays. 8,18 21 Limitations and caveats With these algorithms, several caveats apply: They should only be used in conjunction with all available clinical information including detailed assessments of symptoms, the ECG and other tests to avoid missing other acute life-threatening diseases causing chest pain. Not all patients in whom AMI and other acute lifethreatening disorders are ruled out are necessarily ideal candidates for rapid discharge. For example, patients with unstable angina still might benefit from hospitalisation. Procedures should be in place to ensure appropriate follow-up, which may include additional testing. The number of patients presenting very early (within 1 2 h) has been modest in the studies deriving and validating these algorithms. Therefore, particular caution and additional blood sampling is advised in very early presenters with a high pre-test probability for AMI. Late increases in hs-ctn have been described in small (1%) numbers of patients. 8,10 21 Thus, serial hs-ctn testing should continue if the clinical suspicion remains high or if patients develop a new chest pain episode. The extrapolation to clinical practice of guideline recommendations and evidence from observational

4 Mueller et al. 221 studies in the field of diagnostics have been suboptimal. 8 Therefore, cardiologists, ED physicians and laboratory specialists jointly need to ensure that appropriate medical education is provided before any rapid rule-out algorithm is implemented. These algorithms have been mostly derived and validated in large multicentre diagnostic studies recruiting patients presenting with acute chest pain/ discomfort to the ED with the prevalence of AMI ranging from 10% to 20%. 2 7,10 21 Further studies are necessary when considering the application of these algorithms in settings with other AMI prevalence and in the hospital setting where a variety of insults can lead to ctn release such as critical illness, structural heart disease and the like. Some challenging patient groups were either underrepresented or excluded from previous studies, such as patients on chronic haemodialysis and patients presenting more than 12 h after chest pain onset. Evidence-based guidance regarding the additional testing of the portion of patients that are neither ruled out, nor ruled in, based on the algorithm is limited. The patients left in this observe or grey zone constitute at least 20% of the chest pain population. Pilot studies suggested that further hs-ctn measurements, functional stress imaging and coronary angiography are the key diagnostic modalities. 23 There is concern about whether the assays have adequate precision to make some of the distinctions in the change criteria or in the very low concentration range proposed. In addition, the accuracy of specific high sensitivity reagents may vary modestly depending on the analyser that is used. 24 Some of these studies do not describe follow-up evaluations, which could be critical in redressing any errors that occur acutely and in ensuring a good prognosis. Safe clinical application of these algorithms requires regular quality controls of the hs-ctn assay in use, including verification that the calibration curve satisfies the established quality specifications. 25 The diagnostic studies deriving and validating these algorithms required patient informed consent. This state-of-the-art element of clinical research may introduce an invariable selection bias. Furthermore, most of the biomarker studies are done on frozen samples at a core laboratory, which may introduce another source of bias. The process of freezing, thawing and re-spinning the samples might change the measured concentrations of troponin. 26 In addition, there may be a publication bias as positive studies are more likely to be published than negative studies. Accordingly, additional real-life data applying these algorithms in routine clinical care will be important. Summary: critical clinical concepts Accelerated hs-ctn-based algorithms allow for faster and reliable rule out of AMI in a large proportion of patients with suspicion of AMI. Exclusion of AMI with these algorithms does not exclude the possibility of unstable angina or other serious diseases. The hs-ctn-based algorithms should always be used in conjunction with all available clinical information including the ECG and, for example, by the concomitant use of a validated clinical risk score. Caution is advised with these strategies for those who are early presenters and/or have a high pre-test probability of AMI. Patients discharged with rule-out AMI should be offered a proper and timely outpatient follow-up. Conflict of interest Dr Mair reports grants from Philips Health Care Incubator and lecture honorarium from Roche Diagnostics; and has received consulting fees from Philips Health Care Incubator (Eindhoven, The Nederlands). Dr Plebani has received speaker/consulting honoraria and/or travel support from Abbott Diagnostics, Roche Diagnostics, Siemens Healthcare and Becton-Dickinson. Dr Mueller reports research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the Cardiovascular Research Foundation Basel, Abbott, Astra Zeneca, Beckman Coulter, Biomerieux, BRAHMS, Roche, Siemens, Singulex, Sphingotec and the University Hospital Basel, as well as speaker/consulting honoraria and/or travel support from Abbott, ALERE, Astra Zeneca, Bayer, BG Medicine, Biomerieux, BMS, BRAHMS, Cardiorentis, Daiichi Sankyo, Eli-Lilly, Novartis, Roche, Siemens and Singulex. Dr Jaffe consults outside the submitted work for most of the major diagnostic companies including Beckman-Coulter, Abbott, Alere, Roche, Radiometer, ET Healthcare, Diadexus, Lpath, Siemens, Novartis and theheart.org. Dr Lindahl has received consulting fees from Roche Diagnostics, biomérieux Clinical Diagnostics, Philips Healthcare, ThermoFischer and Fiomi Diagnostics; and has received a research grant from biomérieux Clinical Diagnostics and Fiomi Diagnostics. Dr Möckel reports grants and personal fees from BRAHMS, Roche Diagnostics, Novartis and Radiometer and personal fees from AstraZeneca outside the submitted work. Dr Giannitsis reports grants and personal fees from Roche Diagnostics, AstraZeneca, BayerVital and personal fees from Brahms outside the submitted work. Dr Thygesen reports personal fees from Roche Diagnostics and Siemens Healthcare outside the submitted work.

5 222 European Heart Journal: Acute Cardiovascular Care 6(3) Dr Huber has received speaker/consulting fees from AstraZeneca, Bayer, BMS, BRAHMS, Daiichi Sanky, Lilly and The Medicines Company. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References 1. Möckel M, Searle J, Hamm C, et al. Early discharge using single cardiac troponin and copeptin testing in patients with suspected ACS: a randomized, controlled clinical process study. Eur Heart J 2015; 36: Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009; 361: Reichlin T, Cullen L, Parsonage WA, et al. Two-hour algorithm for triage toward rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Am J Med 2015; 128: Reichlin T, Irfan A, Twerenbold R, et al. 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