Aakre, Kristin M.

Abstract Background The clinical use and interpretation of cardiac troponins (cTn) in pediatric patients is heterogeneous. Content This review is based on an appraisal and synthesis of the available literature and discussions between International Federation of Clinical Chemistry and Laboratory Medicine Committee on Clinical Application of Cardiac Biomarkers members and pediatricians, cardiologists, emergency department physicians, and laboratorians. It aims to summarize current knowledge and best practices related to cTn measurements in pediatric patients, including which percentile should be applicable as the upper reference limit, and the influence of age, sex, and physiology on circulating concentrations. Preanalytical and analytical precautions, and a consensus on optimal interpretation of the reported results are discussed. Summary Current studies report high cTn concentrations in healthy infants and newborns. The nadir is reached at 1–3 years at which time concentrations gradually increase, reaching adult levels through puberty. The incidence of myocardial injury is reported to be low and dependent on whether the 97.5th or 99th percentile is chosen as the upper reference limit. The main clinical indication for testing appears to be suspicion of myo/pericarditis or traumatic chest injury. On occasion, cTn is measured in cases of possible heart failure and/or myocardial ischemia. There is heterogeneity among the limited clinical studies published. Most of the data are retrospective, and the current suggestions for clinical practice are thus largely based on expert opinion. More research is needed regarding all aspects of cTn testing in children, and suggestions for future research are included at the end of this review.

Abstract A challenge in the implementation of rapid risk-stratification algorithms for patients with suspected acute coronary syndrome is the turnaround time for cardiac troponin (cTn) from blood sampling to reporting of results. Measurement of cTn in whole blood using point of care (POC) offers a solution. There is lack of consensus on how these instruments should be assessed and deployed when implemented into routine practice. A pragmatic strategy is needed to balance the requirement for appropriate evaluation, validation and local verification of POC high sensitivity (hs) cTn assays whilst avoiding unnecessary duplication of previously conducted work using central laboratory assays. The International Federation of Clinical Chemistry and Laboratory Medicine Committee on Clinical Application of Cardiac Bio-Markers (IFCC C-CB) has developed an educational document to provide practical suggestions as to how hs-cTn POC assays may be implemented in acute health care settings and networks. The objective of this document is to provide a pragmatic framework for implementation of such systems. The article describes the validation and verification procedures and outlines what should be the responsibility of the manufacturers and provides recommendations on how a local verification may be undertaken before instruments are implemented into routine clinical practice.

Abstract Background This study simulates how assay-specific bias influences the diagnostic performance of 0/1-h accelerated diagnostic protocols (ADPs) for 3 different high-sensitivity cardiac troponin (hs-cTn) assays. Methods We included 1493 patients presenting with chest pain. hs-cTnT (Roche Diagnostics), hs-cTnI from Abbott Diagnostics (hs-cTnI-A), and Siemens Healthineers (hs-cTnI-S) were measured at admission. The absolute total error observed in a state-of-the-art EQA study were added to the admission concentrations, producing 6 new variables being adjusted for maximum possible bias (if analytical variation is 0) (+biasmean, +biasmax95%CI, +biasmin95%CI, −biasmean, −biasmax95%CI, −biasmin95%CI). The influence of this “worst-case scenario” bias was compared after calculating sensitivity, specificity, negative and positive predictive values, and rule-out proportion for 30-day myocardial infarction or death for the observed and bias-adjusted hs-cTn concentrations. Results For 0-h rule-out, hs-cTnI-S and hs-cTnT had a sensitivity of >99.0%, compared to 97.7% for hs-cTnI-A. After adding the bias, sensitivity was unchanged for hs-cTnI-S (99.5%), but lower for hs-cTnT (95.5%), and hs-cTnI-A (96.2%). For the 0-/1-h algorithm, adding bias reduced sensitivity to 95.5% for hs-cTnT, while both hs-cTnI algorithms were unchanged (100.0%). Rule-out proportions for 0 h ranged from 0% to 60.0% for hs-cTnT, 28.2%–62.7% for hs-cTnI-A, and 3.5%–35.5% for hs-cTnI-S. For the 0-/1-h algorithm, ranges were 57.7%–75.8% (hs-cTnT), 52.8%–67.5% (hs-cTnI-A), and 45.7%–61.2% (hs-cTnI-S), Conclusion Analytical bias of hs-cTn assays affects the clinical rule-out rate of the 0/1-h ADPs more than the diagnostic sensitivity. Bias may have a greater influence on the proportion of patients requiring hospital admission and may contribute to the heterogeneity of the reported rule-out rates of current ADPs. ClinicalTrials.gov Registration Number: NCT02620202

Abstract Background Several guidelines groups have made recommendations about how to use natriuretic peptides (NPs) to screen patients with diabetes for incipient heart failure. This group is at risk for undetected and stage B heart failure, where structural heart disease is present despite the absence of clinical signs and symptoms. These recommendations are based on trial data that suggest there are therapeutic options to benefit these patients. Content These guidelines do not adequately account for the marked analytic differences between NP assays nor their high degree of biological and analytical variability. Thus, without additional data and guidance, these recommendations could lead to excessive testing for some groups but might disadvantage others. In addition, these issues could lead to difficulties in the interpretation of values. Accordingly, the Committee on Clinical Applications of Cardiac Bio Markers of the International Federation of Clinical Chemistry has developed a consensus educational document to describe these difficulties and define areas where additional data are needed. Clinicians should be cognizant of differences in the assays for NPs, the high degree of variability of values, differences in sex and ethnicity and the need to factor in a variety of clinical and treatment variables in interpreting NP values. Summary These suggestions for diabetes eventually will include others at high risk. They will require close attention to the issues involved in measuring and interpreting NP values.

Background: In the emergency setting, many diagnostic pathways incorporate change in high-sensitivity cardiac troponin (hs-cTn) concentrations (i.e., the delta) to classify patients as low-risk (rule-out) or high-risk (rule-in) for possible myocardial infarction (MI). However, the impact of analytical variation on the delta for correct classification is unknown, especially at concentrations below and around the 99th percentile. Our objective was to assess the impact of delta variation for correct risk classification across the European Society of Cardiology (ESC 0/1 h and 0/2 h), the High-STEACS, and the common change criteria (3C) pathways. Methods: A yearlong accuracy study for hs-cTnT was performed where laboratories across Canada tested three patient-based samples (level 1 target value = 6 ng/L, level 2 target value = 9 ng/L, level 3 target value = 12 ng/L) monthly across 41 different analyzers. The assigned low-delta between levels 1 and 2 was 3 ng/L (i.e., 9 − 6 = 3 ng/L) and the assigned high-delta between levels 1 and 3 was 6 ng/L (i.e., 12 − 6 = 6 ng/L). The low- and high-deltas for each analyzer were determined monthly from the measured values, with the difference calculated from the assigned deltas. The obtained deltas were then assessed via the different pathways on correct classification (i.e., percent correct with 95% confidence intervals, CI) and using non-parametric analyses. Results: The median (interquartile range) difference between the measured versus assigned low-delta (n = 436) and high-delta (n = 439) was −1 ng/L (−1 to 0). The correct classification differed among the pathways. The ESC 0/1 h pathway yielded the lowest percentage of correct classification at 35.3% (95% CI: 30.8 to 40.0) for the low-delta and 90.0% (95% CI: 86.8 to 92.6) for the high-delta. The 3C and ESC 0/2 h pathways yielded higher and equivalent estimates on correct classification: 95.2% (95% CI: 92.7 to 97.0) for the low-delta and 98.2% (95% CI: 96.4 to 99.2) for the high-delta. The High-STEACS pathway yielded 99.5% (95% CI: 98.4 to 99.9) of correct classifications for the high-delta but only 36.2% (95% CI: 31.7 to 40.9) for the low-delta. Conclusions: Analytical variation will impact risk classification for MI when using hs-cTn deltas alone per the pathways. The 3C and ESC 0/2 h pathways have <5% misclassification when using deltas for hs-cTnT in this dataset. Additional studies with different hs-cTnI assays at concentrations below and near the 99th percentile are warranted to confirm these findings.

Abstract The International Federation of Clinical Chemistry Committee on Clinical Applications of Cardiac Biomarkers (IFCC C-CB) provides educational documents to facilitate the interpretation and use of cardiac biomarkers in clinical laboratories and practice. Our aim is to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay. Measurements of cardiac troponin (cTn) have a prominent place in the clinical work-up of patients with suspected acute coronary syndrome. It is therefore important that clinical laboratories know how to recognize and assess analytical issues. Two emerging analytical issues resulting in falsely high cTn concentrations, often several fold higher than the upper reference limit (URL), are antibody-mediated assay interference due to long-lived cTn-antibody complexes, called macrotroponin, and crosslinking antibodies that are frequently referred to as heterophilic antibodies. We provide an overview of antibody-mediated cTn assay interference and provide recommendations on how to confirm the interference and interpret the results.

Abstract The International Federation of Clinical Chemistry and Laboarator Medicine (IFCC) Committee on Clinical Applications of Cardiac Bio-Markers (C-CB) has provided evidence-based educational resources to aid and improve the understanding of important analytical and clinical aspects of cardiac biomarkers. The present IFCC C-CB educational report focuses on recommendations for appropriate use, analytical performance, and gaps in clinical studies related to the use of cardiac troponin (cTn) by point of care (POC) measurement, often referred to as a point of care testing (POCT). The use of high-sensitivity (hs)-cTn POC devices in accelerated diagnostic protocols used in emergency departments or outpatient clinics investigating acute coronary syndrome has the potential for improved efficacy, reduction of length of stay and reduced costs in the health care system. POCT workflow integration includes location of the instrument, assignment of collection and testing responsibility to (non-lab) staff, instrument maintenance, in-service and recurrent training, quality control, proficiency assessments, discrepant result trapping, and troubleshooting and inventory management.

Abstract The International Federation of Clinical Chemistry Committee on Clinical Application of Cardiac Bio-Markers provides evidence-based educational documents to facilitate uniform interpretation and utilization of cardiac biomarkers in clinical laboratories and practice. The committee’s goals are to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay in clinical practice. Measurement of high-sensitivity cardiac troponin (hs-cTn) assays is a cornerstone in the clinical evaluation of patients with symptoms and/or signs of acute cardiac ischemia. To define myocardial infarction, the Universal Definition of Myocardial Infarction requires patients who manifest with features suggestive of acute myocardial ischemia to have at least one cTn concentration above the sex-specific 99th percentile upper reference limit (URL) for hs-cTn assays and a dynamic pattern of cTn concentrations to fulfill the diagnostic criteria for MI. This special report provides an overview of how hs-cTn 99th percentile URLs should be established, including recommendations about prescreening and the number of individuals required in the reference cohort, how statistical analysis should be conducted, optimal preanalytical and analytical protocols, and analytical/biological interferences or confounds that can affect accurate determination of the 99th percentile URLs. This document also provides guidance and solutions to many of the issues posed.