Apple, Fred S.

Abstract Background We determined whether circulating cardiac troponin I–cardiac troponin T–troponin C (ITC) complex containing long-form cardiac troponin T (long-T ITC) complex and ratios of high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) could differentiate myocardial infarction (MI) from chronic and acute non-MI myocardial injuries in patients with suspected acute coronary syndrome. Methods We measured long-T ITC complex, hs-cTnI, and hs-cTnT (Mindray) at 0- and 2-h in consecutive patients enrolled in the Mindray hs-cTnI Assay Analytical and Clinical Evaluation for the Diagnosis and RIsk Assessment of Myocardial InfarctIon (MERITnI) trial. Results Among the 882 subjects studied (median 3.0 h presentation), 47 had acute MI (5.3%), 116 had acute non-MI myocardial injury, and 90 had chronic myocardial injury. At 0 and 2 h, areas under the curve (AUC) significantly differentiated acute MI from chronic myocardial injury for long-T ITC complex (0.72 and 0.81, respectively; P = 0.0082) but not acute non-MI myocardial injury (AUC, 0.65 and 0.69, respectively; P = 0.23). 0 and 2 h AUCs for long-T ITC complex/hs-cTnT and hs-cTnI/hs-cTnT ratios also significantly differentiated acute MI from chronic myocardial injury (AUC, 0.79 and 0.86, respectively) and acute non-MI myocardial injury (AUC, 0.68 and 0.71, respectively). There was no biomarker concentration or ratio value discrimination between type 1 and type 2 MIs. Conclusions Long-T ITC concentrations and long-T ITC complex/hs-cTnT and hs-cTnI/hs-cTnT ratios may clinically assist in differentiating acute MI from non-MI myocardial injuries when evaluating patients with suspected acute coronary syndrome. ClinicalTrials.gov Registration Number: NCT05853042.

ABSTRACT BACKGROUND Point-of-care (POC) high-sensitivity cardiac troponin (hs-cTn) testing has the potential to expedite decision-making and reduce emergency department (ED) length of stay for patients presenting with possible myocardial infarction (MI) by ensuring that results are consistently available when looked for by clinicians. We assessed the real-life effectiveness and safety of implementing POC hs-cTn testing in the ED. METHODS We conducted a pragmatic, stepped-wedge cluster randomized trial. The control arm was usual care with an accelerated diagnostic pathway utilizing a single-sample rule-out step with a central laboratory hs-cTn assay. The intervention arm used the same pathway with a POC hs-cTnI. The primary effectiveness outcome was ED length of stay assessed using a generalized linear mixed model, and the safety outcome was 30-day MI or cardiac death. RESULTS Six sites participated with 59,980 ED presentations (44,747 individuals, 61±19 years, 49.5% female) from February 2023 to January 2025, in which 31,392 presentations were during the intervention arm. After adjustment for co-variates associated with length of stay, the intervention reduced length of stay by 13% (95% confidence intervals [CI], 9 to 16%. P<0.001), corresponding to a reduction of 47 minutes (95%CI, 33 to 61 minutes) from a mean length of stay in the control arm of 376 minutes. The 30-day MI or cardiac death rate was similar in the control and intervention arms (0.39% and 0.39% respectively, P=0.54). CONCLUSIONS Implementation of whole-blood hs-cTnI testing at the POC into an accelerated diagnostic pathway was safe and reduced length of stay in the ED compared with laboratory testing. (Australia New Zealand Clinical Trials Registry ACTRN12619001189112) Clinical Perspective What is new? Point-of-care troponin assays with good precision have become available and received regulatory approval as high-sensitivity assays. A pragmatic stepped-wedge cluster randomized trial implementing the validated Siemens VTLi high-sensitivity point-of-care assay into 6 emergency departments investigating ∼60,000 patients, was conducted to ascertain if the rapid turnaround time reduced lengths of stay. Introduction of the VTLi high-sensitivity point-of-care assay into clinical pathways reduced emergency department lengths of stay by an average 13% (47 minutes) without compromising safety. What are the clinical implications? Early decision-making using a point-of-care high-sensitivity troponin assay within a structured clinical pathway was safe. Faster turnaround means troponin results are consistently available when clinicians first seek them. This can facilitate earlier decisions and reduce patient length of stay.

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 &gt;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

Introduction Clinical assessment in emergency departments (EDs) for possible acute myocardial infarction (AMI) requires at least one cardiac troponin (cTn) blood test. The turn-around time from blood draw to posting results in the clinical portal for central laboratory analysers is ~1–2 hours. New generation, high-sensitivity, point-of-care cardiac troponin I (POC-cTnI) assays use whole blood on a bedside (or near bedside) analyser that provides a rapid (8 min) result. This may expedite clinical decision-making and reduce length of stay. Our purpose is to determine if utilisation of a POC-cTnI testing reduces ED length of stay. We also aim to establish an optimised implementation process for the amended clinical pathway. Methods and analysis This quality improvement initiative has a pragmatic multihospital stepped-wedge cross-sectional cluster randomised design. Consecutive patients presenting to the ED with symptoms suggestive of possible AMI and having a cTn test will be included. Clusters (comprising one or two hospitals each) will change from their usual-care pathway to an amended pathway using POC-cTnI—the ‘intervention’. The dates of change will be randomised. Changes occur at 1 month intervals, with a minimum 2 month ‘run-in’ period. The intervention pathway will use a POC-cTnI measurement as an alternate to the laboratory-based cTn measurement. Clinical decision-making steps and logic will otherwise remain unchanged. The POC-cTnI is the Siemens (Erlangen Germany) Atellica VTLi high-sensitivity cTnI assay. The primary outcome is ED length of stay. The safety outcome is cardiac death or AMI within 30 days for patients discharged directly from the ED. Ethics and dissemination Ethics approval has been granted by the New Zealand Southern Health and Disability Ethics Committee, reference 21/STH/9. Results will be published in a peer-reviewed journal. Lay and academic presentations will be made. Māori-specific results will be disseminated to Māori stakeholders. Trial registration number ACTRN12619001189112.

This study aimed to evaluate and compare the performance of three anti-S and one anti-N assays that were available to the project in detecting antibody levels after three commonly used SARS-CoV-2 vaccines (Pfizer, Moderna, and Johnson & Johnson). It also aimed to assess the association of age, sex, race, ethnicity, vaccine timing, and vaccine side effects on antibody levels in a cohort of 827 individuals. In September 2021, 698 vaccinated individuals donated blood samples as part of the Association for Diagnostics & Laboratory Medicine (ADLM) COVID-19 Immunity Study. These individuals also participated in a comprehensive survey covering demographic information, vaccination status, and associated side effects. Additionally, 305 age- and gender-matched samples were obtained from the ADLM 2015 sample bank as pre-COVID-19-negative samples. All these samples underwent antibody level analysis using three anti-S assays, namely Beckman Access SARS-CoV-2 IgG (Beckman assay), Ortho Clinical Diagnostics VITROS Anti-SARS-CoV-2 IgG (Ortho assay), Siemens ADVIA Centaur SARS-CoV-2 IgG (Siemens assay), and one anti-N antibody assay: Bio-Rad Platelia SARS-CoV-2 Total Ab assay (BioRad assay). A total of 827 samples (580 COVID-19 samples and 247 pre-COVID-19 samples) received results for all four assays and underwent further analysis. Beckman, Ortho, and Siemens anti-S assays showed an overall sensitivity of 99.5%, 97.6%, and 96.9%, and specificity of 90%, 100%, and 99.6%, respectively. All three assays indicated 100% sensitivity for individuals who received the Moderna vaccine and boosters, and over 99% sensitivity for the Pfizer vaccine. Sensitivities varied from 70.4% (Siemens), 81.5% (Ortho), and 96.3% (Beckman) for individuals who received the Johnson & Johnson vaccine. BioRad anti-N assays demonstrated 46.2% sensitivity and 99.25% specificity based on results from individuals with self-reported infection. The highest median anti-S antibody levels were measured in individuals who received the Moderna vaccine, followed by Pfizer and then Johnson & Johnson vaccines. Higher anti-S antibody levels were significantly associated with younger age and closer proximity to the last vaccine dose but were not associated with gender, race, or ethnicity. Participants with higher anti-S levels experienced significantly more side effects as well as more severe side effects (e.g., muscle pain, chills, fever, and moderate limitations) (p < 0.05). Anti-N antibody levels only indicated a significant correlation with headache. This study indicated performance variations among different anti-S assays, both among themselves and when analyzing individuals with different SARS-CoV-2 vaccines. Caution should be exercised when conducting large-scale studies to ensure that the same platform and/or assays are used for the most effective interpretation of the data.

Abstract In 2021, the Association for Diagnostics & Laboratory Medicine (ADLM) (formerly the American Association for Clinical Chemistry [AACC]) developed a scientific study that aimed to contribute to the understanding of SARS-CoV-2 immunity during the evolving course of the pandemic. This study was led by a group of expert member volunteers and resulted in survey data from 975 individuals and blood collection from 698 of those participants. This paper describes the formulation and execution of this large-scale scientific study, encompassing best practices and insights gained throughout the endeavor.