Mills, Nicholas L

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 Background High-sensitivity cardiac troponin (hs-cTn) assays are recommended for the diagnosis of acute myocardial infarction. Here, we characterize the analytical performance of a next-generation hs-cTn assay, Elecsys® Troponin T hs Gen 6 (Roche Diagnostics International). Methods Surplus lithium-heparin plasma or serum samples from patients or healthy volunteers were run on Cobas® e 801, e 402, and Pro analyzers. Limits of blank (LoB), limits of detection (LoD), and limits of quantitation (LoQ) were determined according to CLSI EP17-A2, with target values of 1.0 and 1.5 ng/L for LoB/LoD and 3.0 ng/L (10% CV) and 1.5 ng/L (20% CV) for LoQ, respectively. Precision was measured, per CLSI EP17-A2, using 3 QC samples (approximately 4, 30, and 220 ng/L), 12 native samples, and 3 reagent lots. Linearity, per CLSI EP06-Ed2, was determined by diluting samples with cardiac troponin T (cTnT) concentration above the measuring range with a low/blank sample. Interference (per Glick) with endogenous and assay components at 5 cTnT concentrations was assessed. Results Measured values for LoB, LoD, and LoQ at 10% and 20% CV were 0.1 to 0.7 ng/L, 0.3 to 1.4 ng/L, 1.0 to 2.9 ng/L, and 0.4 to 1.2 ng/L, respectively. Repeatability CVs were 1.0 to 5.8% for mean cTnT concentrations of 2.6 to 9230 ng/L in lithium-heparin plasma. High precision was shown across lots, and linearity was observed across the measuring range (1.5 to 9500 ng/L, all Pearson's r = 1.00). No interferences were observed, specified up to ≤1000 mg/dL hemoglobin, ≤50 mg/dL [≤855 µmol/L] icterus/bilirubin, and ≤1200 ng/mL biotin. Conclusions The analytical performance characterization of the assay demonstrated high sensitivity, high precision at the low end and across the measuring range, and resistance to interference.

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 Measurement of cardiac troponin (cTn) using high-sensitivity assays is recommended for the diagnosis of myocardial infarction. We determined sex-specific and uniform 99th percentile upper reference limits (URLs) using the new Elecsys® Troponin T high-sensitivity Gen 6 assay in a global, healthy reference range cohort. Methods Lithium-heparin plasma and serum samples were prospectively collected from apparently healthy individuals aged ≥20 years across 34 global sites in the United States, Europe, China, and Japan. cTnT was measured using the Troponin T high-sensitivity Gen 6 assay on the Cobas® e 801 analyzer. Exclusion criteria were defined according to the 2022 IFCC guidance. Uniform and sex-specific 99th percentile URLs and nonparametric 95% CIs were determined in plasma and serum separately and combined. Results The final study population comprised 4147 participants (52.5% female) with a median (25th–75th percentiles) age of 48.0 (33.0–59.0) years; 45.8%, 47.9%, 5.2%, and 1.1% were White, Asian, Black, and other/unknown, respectively. For sample matrices combined (n = 8294), 81.0% and 99.2% of cTnT values were above the limit of detection in females and males, respectively. Sex-specific 99th percentile URLs (95% CI) were 18 (16–23) ng/L for females and 32 (28–35) ng/L for males; the uniform 99th percentile URL was 27 (24–31) ng/L. URLs were comparable in plasma and serum samples. Conclusions This study determined sex-specific and uniform 99th percentile URLs for the Troponin T high-sensitivity Gen 6 assay that were comparable irrespective of the matrix used in a large, global, healthy reference population.

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

Abstract Aims Type 2 myocardial infarction due to myocardial oxygen supply–demand imbalance is associated with poor outcomes. There are no guidelines to inform care for these patients. The consensus on the assessment and management of type 2 myocardial infarction is gained. Methods and results An international e-Delphi study including experts in type 2 myocardial infarction identified through systematic review was conducted. Participants were asked to describe their approach to (i) definition and diagnosis, (ii) risk stratification, (iii) assessment of coronary artery disease and cardiac function, (iv) specialty management, (v) treatment and secondary prevention, and (vi) communication and rehabilitation. Statements generated in round one were circulated, with consensus defined a priori as ≥70% agreement on a 5-point Likert scale. Where no consensus was reached, statements were amended and recirculated for a final round. The response rate was 56% (38/68), 54% (37/68), and 72% (49/68) in the first, second, and third rounds, respectively. Following the first round, 67 unique statements were generated across six domains. Overall, consensus was achieved on 64% (43/67) of statements. Consensus was achieved for 42% (5/12) of statements on the diagnosis of type 2 myocardial infarction, 75% (3/4) on risk stratification, 50% (9/18) on the assessment of coronary artery disease and cardiac function, 60% (6/10), on specialty management, 100% (9/9) on treatment and secondary prevention, and 79% (11/15) on communication and rehabilitation. Conclusion Consensus was obtained across a number of domains for the assessment and management of patients with type 2 myocardial infarction. However, there was limited agreement amongst experts on the diagnostic criteria, which may benefit from refinement.

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.

Abstract New technologies enabling access to high-sensitivity cardiac troponin (hs-cTn) assays at the point of care (POC) are available for routine use. POC technology can accelerate cardiac troponin testing within the hospital setting and support testing in other healthcare environments. Pre-analytical and analytical issues unique to POC testing are discussed. The opportunities and the evidence needed to support the routine use of hs-cTn POC assays in clinical care are outlined. Based on recent developments, the potential impact of hs-cTn at the POC in multiple clinical settings is described, and a roadmap of the steps required for successful implementation is provided.