Evaluation of the analytical and clinical performance of a high-sensitivity troponin I point-of-care assay in the Mersey Acute Coronary Syndrome Rule Out Study (MACROS-2).

OBJECTIVES: The objective of this study is to evaluate the analytical and diagnostic performance of a high-sensitivity point-of-care (POC) cardiac troponin I assay, the Quidel TriageTrue™ (QuidelOrtho Inc, San Diego, USA), compared to central laboratory testing (CLT) in accelerated diagnostic protocols (ADP) in real time in a clinical environment. METHODS: In a nested sub-study of a pragmatic randomised control trial, consecutive patients with suspected acute coronary syndrome (ACS) and chest pain <12 h duration were randomised to the ESC 0/1 and 0/3-h ADP. Subjects underwent sampling for Quidel TriageTrue POC hs-TnI whole blood and plasma, CLT hs-TnT Roche Elecsys and a validated, NICE approved CLT High sensitivity cardiac troponin I (hs-TnI) (Siemens Attellica) at each time point. Assay imprecision was assessed by repeat analysis of whole blood samples at three levels (low, near 10 % CV 5-10 ng/L, medium, approximating 99th percentile 15-25 ng/L and high, 3-5 times the 99th percentile, 60-100 ng/L). Final diagnosis was adjudicated at 6 weeks by Roche hs-TnT using the 4th universal definition of myocardial infarction (MI). RESULTS: A total of 1,157 patients consented and had both investigational POC whole blood and plasma and central lab hs-cTn available. The median age was 59, 47.2 % were female and 15 % had suffered a previous MI. Assay imprecision of whole blood POC TriageTrue revealed 10 % CV at 8.6 ng/L (>50 % lower than 99th percentile [20.5 ng/L]) and a 20 % CV at 1.2 ng/L. Receiver operator characteristics (ROC) curves were computed for each assay against adjudicated index type 1 MI to study clinical performance. At all-time points there were excellent performance for whole blood POC TriageTrue: area under the curve (AUC) 0.97 [95 % CI 0.94-098], 0.98 [95 % CI 0.97-1.00] and 0.95 [95 % CI 0.92-0.98] at time 0, 1 and 3 h respectively. There was statistical equivalence for performance of whole blood and plasma POC TriageTrue hs-TnI and laboratory Siemens Atellica hs-TnI. CONCLUSIONS: The whole blood POC TriageTrue hs-TnI assay demonstrates imprecision levels consistent with high sensitivity characteristics and has a clinical performance equivalent to an established, validated and NICE approved laboratory Siemens Atellica hs-TnI.

Safety and feasibility of triage and rapid discharge of patients with chest pain from emergency room: A pragmatic, randomized noninferiority control trial of the European Society of Cardiology (ESC) 0 to 1 hour pathway vs conventional 0 to 3 hour accelerated diagnostic protocol.

Patients presenting with chest pain represent a significant proportion of Emergency Department (ED) attendances but only a minority, typically 10%, have a final diagnosis of myocardial infarction (MI). Prompt discharge of patients without MI will alleviate ED overcrowding as well as improve patient satisfaction and reduce exposure to risk of hospital acquired infections such as Covid 19. The measurement of cardiac troponin (cTn) by a high sensitivity method is recommended by the National Institute for health and Care Excellence (NICE) for rapid categorization of patients presenting with chest pain. Strategies proposed include measurement on admission and 1 hour from admission (ESC 0-1-hour pathway, the recent guideline approved pathway which has not been implemented widely), and measurement on admission and 3 hours from admission (0-3-hour pathway, which is conventional and widely adopted). The primary objective of this study is twofold: firstly, to assess the safety, feasibility, and impact of implementing the ESC (European Society of Cardiology) 0 to 1-hour pathway in clinical practice by reference to the more established ESC 0 to 3-hour protocol. The principal outcome measure will be the safety of the ESC 0 to 1-hour protocol. However, there are concerns that the time from sample draw to result availability (typically around 60 minutes) will impact on the feasibility of the ESC 0 to 1-hour pathway. Secondly, therefore, our goal is to evaluate whether measurement of high sensitivity troponin by a bedside analyzer (point of care testing, POCT), which will produce results in 15 minutes is a feasible alternative to laboratory testing. We will compare the results produced by POCT with the laboratory results in the context of the ESC 0 to 1 hour and 0 to 3-hour pathway, as a nested controlled study in the context of a randomized controlled trial. (clinicaltrials.gov: NCT05322395).

Implementation of high sensitivity troponin into routine clinical practice - results of the extended CARdiac MArkers guideline uptake in Europe group (CARMAGUE) survey.

BACKGROUND: Measurement of cardiac troponin (cTn) by a high sensitivity method is now the recommended strategy for the detection of myocardial injury. An international survey was undertaken to assess how this has been implemented. METHODS: A questionnaire based around 14 domains on cardiac biomarkers was distributed electronically with the aid of professional societies accessed by a web link within the invitation. Results were returned electronically then extracted into a relational database for analysis. RESULTS: Responses were obtained from 663 laboratories across 76 countries ranging from 1 to 69 largest country. The majority of responses (79.6%) came from the European area. Responses were grouped into broad geographic areas for analysis. Most responses came from hospitals providing a local and regional service of which the majority provided angioplasty. cTn measurement was the dominant biomarker. The majority of laboratories include creatine kinase (CK) in their cardiac profile and approximately 50% also offer the MB isoenzyme of CK. The majority of laboratories (91.9%) measure cTn by a high sensitivity method. Sex specific reference ranges were typically implemented for cardiac troponin I but not for cardiac troponin T. The preferred unit of measurement was nanograms/L. A structured decision-making pathway utilising high sensitivity cTn measurement was used by 83.3% of laboratories who responded. Single sample rule out is common but the majority used serial sampling strategy based on measurement on admission and three hours. CONCLUSIONS: Measurement of cTn by a high sensitivity method is now well established internationally, the use of rapid diagnostic protocols lags behind.

The multidimensional value of natriuretic peptides in heart failure, integrating laboratory and clinical aspects.

Natriuretic peptides (NP) play an essential role in heart failure (HF) regulation, and their measurement has improved diagnostic and prognostic accuracy. Clinical symptoms and objective measurements, such as NP levels, should be included in the HF definition to render it more reliable and consistent among observers, hospitals, and healthcare systems. BNP and NT-proBNP are reasonable surrogates for cardiac disease, and their measurement is critical to early diagnosis and risk stratification of HF patients. NPs should be measured in all patients presenting with dyspnea or other symptoms suggestive of HF to facilitate early diagnosis and risk stratification. Both BNP and NT-proBNP are currently used for guided HF management and display comparable diagnostic and prognostic accuracy. Standardized cutoffs for each NP assay are essential for data comparison. The value of NP testing is recognized at various levels, including patient empowerment and education, analytical and operational issues, clinical HF management, and cost-effectiveness.

Lower Limits for Reporting High-Sensitivity Cardiac Troponin Assays and Impact of Analytical Performance on Patient Misclassification.

BACKGROUND: Cardiac troponin measurements are indispensable for the diagnosis of myocardial infarction and provide useful information for long-term risk prediction of cardiovascular disease. Accelerated diagnostic pathways prevent unnecessary hospital admission, but require reporting cardiac troponin concentrations at low concentrations that are sometimes below the limit of quantification. Whether analytical imprecision at these concentrations contributes to misclassification of patients is debated. CONTENT: The International Federation of Clinical Chemistry Committee on Clinical Application of Cardiac Bio-Markers (IFCC C-CB) provides evidence-based educational statements on analytical and clinical aspects of cardiac biomarkers. This mini-review discusses how the reporting of low concentrations of cardiac troponins impacts on whether or not assays are classified as high-sensitivity and how analytical performance at low concentrations influences the utility of troponins in accelerated diagnostic pathways. Practical suggestions are made for laboratories regarding analytical quality assessment of cardiac troponin results at low cutoffs, with a particular focus on accelerated diagnostic pathways. The review also discusses how future use of cardiac troponins for long-term prediction or management of cardiovascular disease may require improvements in analytical quality. SUMMARY: Clinical guidelines recommend using cardiac troponin concentrations as low as the limit of detection of the assay to guide patient care. Laboratories, manufacturers, researchers, and external quality assessment providers should extend analytical performance monitoring of cardiac troponin assays to include the concentration ranges applicable in these pathways.

Implementation of the European Society of Cardiology 0/3-hour accelerated diagnostic protocol, using high sensitive troponin T: a clinical practice evaluation of safety and effectiveness involving 3003 patients with suspected acute coronary syndrome.

BACKGROUND: There have been relatively few studies detailing the real-world effectiveness and safety of accelerated diagnostic protocols (ADP), using high sensitivity cardiac troponin (hs-cTn). OBJECTIVE: To analyse the safety and effectiveness of early emergency department (ED) discharge following implementation of the European Society of Cardiology (ESC) 0/3-hour ADP for suspected acute coronary syndromes (ACS). METHOD: We prospectively studied 2 cohorts of consecutive suspected ACS presentations to ED before (n=1642) and after (n=1376, 2 centres) implementation of the ESC 0/3-hour ADP incorporating limit of detection rule out. Safety was defined by MACE (major adverse cardiac events) inclusive of type 1 myocardial infarction (MI) in patients discharged from ED, and clinical effectiveness by percentage ED discharge. Continuous variables and categorical data were evaluated by independent t-test and χ2 test, respectively. Time-to-event data were analysed as survival data and converted to Kaplan-Meier curves for interpretation. RESULTS: In the preimplementation period, there was a higher prevalence of MI. Discharge from ED increased by >100% (from 27.1% to 56.5% of the cohort) with no safety signal (MACE rate 4/444 (0.9%) vs 4/769 (0.52%), p=0.430 for the 2011 and 2018 cohort, respectively). This correlated with a marked reduction in length of stay overall but a more modest reduction for those discharged from ED (6 hours 10 min vs 5 hours 25 min, p<0.001) for the 2011 and 2018 cohort, respectively. There were improvements in presentation to blood draw (163-90 min, p<0.001). Time from presentation to first ECG actually increased (16.2 vs 31.2 min, p<0.001). Analysis of hs-cTn values and ECGs revealed a maximum ED discharge rate of 69%, by applying the 0/3-hour protocol, implying potential for increasing safe ED discharge. CONCLUSIONS: Implementation of an ADP with hs-cTn is safe and effective for early rule-out and discharge of suspected ACS but require considerable resources and education to optimise maximal patient flow.

Aiming toWards Evidence baSed inTerpretation of Cardiac biOmarkers in patients pResenting with chest pain using Point of Care Testing (WESTCOR-POC): study design.

OBJECTIVES: Patients presenting with symptoms suggestive of acute coronary syndrome (ACS) contribute to a high workload and overcrowding in the Emergency Department (ED). Accelerated diagnostic protocols for non-ST-elevation myocardial infarction have proved challenging to implement. One obstacle is the turnaround time for analyzing high-sensitivity cardiac troponin (hs-cTn). In the WESTCOR-POC study (Clinical Trials number NCT05354804) we aim to evaluate safety and efficiency of a 0/1 h hs-cTn algorithm utilizing a hs-cTnI point of care (POC) instrument in comparison to central laboratory hs-cTnT measurements. DESIGN: This is a prospective single-center randomized clinical trial aiming to include 1500 patients admitted to the ED with symptoms suggestive of ACS. Patients will receive standard investigations following the European Society of Cardiology 0/1h protocols for centralized hs-cTnT measurements or the intervention using a 0/1h POC hs-cTnI algorithm. Primary end-points are 1) Safety; death, myocardial infarction or acute revascularization within 30 days 2) Efficiency; length of stay in the ED, 3) Cost- effectiveness; total episode cost, 4) Patient satisfaction, 5) Patient symptom burden and 6) Patients quality of life. Secondary outcomes are 12-months death, myocardial infarction or acute revascularization, percentage discharged after 3 and 6 h, total length of hospital stay and all costs related to hospital contact within 12 months. CONCLUSION: Results from this study may facilitate implementation of POC hs-cTn testing assays and accelerated diagnostic protocols in EDs, and may serve as a valuable resource for guiding future investigations for the use of POC high sensitivity troponin assays in outpatient clinics and prehospital settings.

Unstable angina in the context of high-sensitive troponins: Still a marker of high risk? A comparison of outcomes with adjudicated type 1 myocardial infarction.

BACKGROUND: Unstable angina (UA), considered historically a marker of high risk, has rarely been studied in the high sensitive troponin era. We sought to characterise this population and determine short- and medium-term outcomes for UA and compared this to both patients with musculoskeletal chest pain and adjudicated type 1 MI (NSTEMI). METHOD: We conducted a post-hoc analysis of 2 prospective cohort studies of suspected acute coronary syndrome in 2 hospitals in the northwest of England. (n = 3018) We used a dedicated symptom score to diagnose unstable angina. Type 1 MI (NSTEMI) was diagnosed by independent physician adjudication according to 3rd universal definition of MI. Follow-up was 100% complete for all patients to 1 year. RESULTS: 185 (6.1%) and 249 (8.3%) were adjudicated as suffering from UA and NSTEMI respectively. We restricted our analysis of UA to 158 (5.2%) patients with UA with high sensitive troponin T (Roche Elecsys) ≤14 ng/L (≤99th percentile). Compared to the NSTEMI population, the UA cohort were younger (59 vs 74, p < 0.002), had a lower incidence of hypertension (56.3% vs 69.1%, p = 0.009), had significantly lower composite risk scores and had fewer ECG abnormalities (ST depression >1 mm, 5.1% vs 15.6%, p = 0.001, T wave flattened, biphasic or inverted 24.1% vs 47.8%, p < 0.0001). Subsequent Type 1 MI to 30 days and 1 year in the UA cohort was 1.9% and 1.9% respectively compared to 0.8% and 2.4% in the index type 1 MI (NSTEMI cohort) respectively. However, compared to patients presenting with musculoskeletal chest pain (n = 468) there was a significantly greater incidence of subsequent MI and coronary revascularisation in patients with unstable angina. All cause death at 30 days and 1 year was 0.0% and 0.6% (n = 1) for UA patients and 2.8% (n = 7) and 16.1% (n = 40) for the NSTEMI cohort respectively. CONCLUSION: UA, defined objectively by a symptom score and absence of myocyte necrosis, is still prevalent as an entity, with a risk of subsequent MI and urgent or emergency coronary revascularisation. However, mortality is >10-fold lower when compared to NSTEMI, indicating a less severe pathology in terms of atherosclerosis or plaque burden, and implying the need for a different management strategy to that of NSTEMI.

Single Troponin Measurement to Rule Out Myocardial Infarction: JACC Review Topic of the Week.

The term "single-sample rule-out" refers to the ability of very low concentrations of high-sensitivity cardiac troponin (hs-cTn) on presentation to exclude acute myocardial infarction with high clinical sensitivity and negative predictive value. Observational and randomized studies have confirmed this ability. Some guidelines endorse use of a concentration of hs-cTn at the assay's limit of detection, while other studies have validated the use of higher concentrations, allowing this approach to identify a greater proportion of patients at low risk. In most studies, at least 30% of patients can be triaged with this approach. The concentration of hs-cTn varies according to the assay used and sometimes how regulations permit reporting. It is clear that patients need to be at least 2 hours from the onset of symptoms being evaluated. Caution is warranted, particularly with older patients, women, and patients with underlying cardiac comorbidities.

Troponin in early presenters to rule out myocardial infarction.

AIMS: Whether a single cardiac troponin measurement can safely rule out myocardial infarction in patients presenting within a few hours of symptom onset is uncertain. The study aim was to assess the performance of troponin in early presenters. METHODS AND RESULTS: In patients with possible myocardial infarction, the diagnostic performance of a single measurement of high-sensitivity cardiac troponin I at presentation was evaluated and externally validated in those tested ≤3, 4-12, and >12 h from symptom onset. The limit-of-detection (2 ng/L), rule-out (5 ng/L), and sex-specific 99th centile (16 ng/L in women; 34 ng/L in men) thresholds were compared. In 41 103 consecutive patients [60 (17) years, 46% women], 12 595 (31%) presented within 3 h, and 3728 (9%) had myocardial infarction. In those presenting ≤3 h, a threshold of 2 ng/L had greater sensitivity and negative predictive value [99.4% (95% confidence interval 99.2%-99.5%) and 99.7% (99.6%-99.8%)] compared with 5 ng/L [96.5% (96.2%-96.8%) and 99.3% (99.1%-99.4%)]. In those presenting ≥3 h, the sensitivity and negative predictive value were similar for both thresholds. The sensitivity of the 99th centile was low in early and late presenters at 71.4% (70.6%-72.2%) and 92.5% (92.0%-93.0%), respectively. Findings were consistent in an external validation cohort of 7088 patients. CONCLUSION: In early presenters, a single measurement of high-sensitivity cardiac troponin I below the limit of detection may facilitate the safe rule out of myocardial infarction. The 99th centile should not be used to rule out myocardial infarction at presentation even in those presenting later following symptom onset.

Antibody-mediated interferences affecting cardiac troponin assays: recommendations from the IFCC Committee on Clinical Applications of Cardiac Biomarkers.

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.

Cardiac troponin measurement at the point of care: educational recommendations on analytical and clinical aspects by the IFCC Committee on Clinical Applications of Cardiac Bio-Markers (IFCC C-CB).

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.

Rapid diagnostic strategies using high sensitivity troponin assays: what is the evidence and how should they be implemented?

The introduction of high sensitivity measurement of cardiac troponin T (hs cTnT) and cardiac troponin I (hs cTnI) has given the laboratory the ability to measure very low levels of cardiac troponin. The limit of detection of these assays is well below the 99th percentile. These low levels can also be measured with small values of imprecision. A range of algorithms combining presentation measurement with repeat sample intervals of as little as one to 2 hours have been developed. These are able to predict with acceptable accuracy the diagnosis that would be achieved with continued repeat sampling out to six to 12 hours from presentation. In this article, we review the evidence for the diagnostic accuracy of these approaches and the practical aspects of implementation into routine clinical practice.

High-Sensitivity Cardiac Troponin and the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guidelines for the Evaluation and Diagnosis of Acute Chest Pain.

The 2021 American Heart Association/American College of Cardiology/American Society of Echocardiography/American College of Chest Physicians/Society for Academic Emergency Medicine/Society of Cardiovascular Computed Tomography/Society for Cardiovascular Magnetic Resonance guidelines for the evaluation and diagnosis of acute chest pain make important recommendations that include the recognition of high-sensitivity cardiac troponin (hs-cTn) as the preferred biomarker, endorsement of 99th percentile upper reference limits to define myocardial injury, and the use of clinical decision pathways, as well as acknowledgment of the uniqueness of women and other patient subsets. Details on how to integrate hs-cTn into clinical practice are less extensively addressed. Clinicians should be aware of some of the analytical aspects related to hs-cTn assays regarding the limit of detection and the limit of quantitation and how they are used clinically, especially for the single sample strategy to rule out acute myocardial infarction. Likewise, it is important for clinicians to understand issues related to the derivation of the 99th percentile upper reference limit; the value of sex-specific 99th percentile upper reference limits; how to use changing concentrations (deltas) to facilitate diagnosis and risk stratification of patients with suspected acute coronary syndrome, including the differentiation of acute from chronic myocardial injury; and how to best integrate the use of hs-cTn with clinical decision pathways. With the use of hs-cTn, conditions such as type 2 myocardial infarction become more common, whereas others such as unstable angina become less frequent but still occur. Sections relating to these issues are included.