High-sensitivity cardiac troponin: do think twice, it’s not all right

AbstractA questionable scientific approach to measuring at low concentrations and inappropriate censoring of results below certain cut-offs have resulted in the dichotomous classification of troponin assays based on their so-called analytical sensitivity. The definition of “high-sensitivity” cardiac troponin is flawed. Evidence suggests that its apparent diagnostic superiority may be explained by the censoring of data. In the evaluation of the detection and quantification capabilities of analytical methods we recommend alignment with International Union of Pure and Applied Chemistry (IUPAC) guidelines, including reporting of all results. This will allow the objective evaluation of the diagnostic performance of troponin assays and will render the current troponin assay classification and nomenclature obsolete.

Download Full-text

Disagreement between Cardiac Troponin Tests Yielding a Higher Incidence of Myocardial Injury in the Emergency Setting

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8030031 ◽

2021 ◽

Vol 8 (3) ◽

pp. 31

Author(s):

Peter A. Kavsak ◽

Shawn E. Mondoux ◽

Janet Martin ◽

Mark K. Hewitt ◽

Lorna Clark ◽

...

Keyword(s):

Cardiac Troponin ◽

Myocardial Injury ◽

Ethylenediaminetetraacetic Acid ◽

High Sensitivity ◽

Clinical Diagnostics ◽

Emergency Setting ◽

Analytical Sensitivity ◽

Edta Plasma ◽

Ortho Clinical Diagnostics

Differences in patient classification of myocardial injury between high-sensitivity cardiac troponin (hs-cTn) assays have largely been attributed to assay design and analytical sensitivity aspects. Our objective was to compare Ortho Clinical Diagnostics’ (OCD) hs-cTnI assay to OCD’s contemporary/conventional assay (cTnI ES) and another hs-cTnI assay (Abbott hs-cTnI) in samples obtained from different emergency departments (EDs). Two different sample types were evaluated (lithium heparin and ethylenediaminetetraacetic acid (EDTA) plasma) in a non-selected ED population (study 1, n = 469 samples) and in patients for which ED physicians ordered cardiac troponin testing (study 2, n = 1147 samples), from five different EDs. The incidence of injury in study 1 was higher with the OCD hs-cTnI assay (30.9%; 95% CI: 26.9 to 35.2) compared to that of the Abbott hs-cTnI (17.3%; 95% CI: 14.1 to 21.0) and the OCD cTnI ES (15.4%; 95% CI: 12.4 to 18.9) assays, with repeat testing identifying 4.8% (95% CI: 3.0 to 7.5) of the OCD hs-cTnI results with poor reproducibility. In study 2, 4.6% (95% CI: 3.5 to 6.0) of the results were not reported for the OCD hs-cTnI assay (i.e., poor reproducibility) with 12.7% (95%CI: 8.7 to 17.8) of the OCD hs-cTnI results positive for injury being negative for injury with the Abbott hs-cTnI assay. In summary, the OCD hs-cTnI assay yields higher rates of biochemical injury with a higher rate of poor reproducible results in different ED populations.

Download Full-text

Abstract 19710: Causes for Increased Cardiac Troponin I Using Gender-Specific 99th Percentiles From a High Sensitivity Assay in a US Population

Circulation ◽

10.1161/circ.130.suppl_2.19710 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Yader Sandoval ◽

Stephen W Smith ◽

Karen M Schulz ◽

MaryAnn M Murakami ◽

Fred S Apple

Keyword(s):

Myocardial Ischemia ◽

Cardiac Troponin ◽

Myocardial Injury ◽

Troponin I ◽

Plaque Rupture ◽

High Sensitivity ◽

The United States ◽

Universal Definition ◽

Definition Of ◽

Gender Specific

Introduction: High-sensitivity cardiac troponin (hs-cTn) assays have not yet been FDA cleared for clinical use in the United States (US). Pending expected approval of hs-cTn assays, which will use gender-specific cutoffs (GSC), it is relevant to recognize the causes of cTn increases using hs-cTnI assays in a US population. Our purpose was to describe the frequency of distinct etiologies of hs-cTnI assay increases using GSC. Methods: Retrospective study of 310 patients with serial hs-cTnI (Abbott ARCHITECT, 99th percentiles: F:16 ng/L; M:34 ng/L) measurements. Patients with an increased hs-cTnI were adjudicated into categories according to the 3rd Universal Definition of MI. Categories included, A: primary myocardial ischemia (i.e. plaque rupture); B: injury secondary to supply/demand imbalance; C: injury not related to myocardial ischemia (i.e. cardiac contusion, ablation, shock, surgery); D: multifactorial or indeterminate myocardial injury (i.e. heart failure, critically ill, pulmonary HTN, sepsis, stroke, renal failure, pulmonary embolism); E: Unknown. Results: 127 (41%) had an increased hs-cTnI above the GSC 99th percentile, whereas 183 (59%) had a normal hs-cTnI. The most common causes of hs-cTnI increases were: a) multifactorial or indeterminate injury - 43% among all patients and 52% in males, and b) supply/demand imbalance - 39% in women (Table). Injury related to primary myocardial ischemia was present in 10% (n=13). Females had more injury related to supply/demand ischemia than males (39% vs. 18%, p=0.01), whereas males had more multifactorial or indeterminate injury (52% vs. 33%, p=0.05). Conclusions: Most increased hs-cTnI values were explained by non-plaque rupture conditions. Males tended to have hs-cTnI increases due to multifactorial/indeterminate causes, whereas in women supply/demand imbalance was the most common etiology. Investigations are needed to better understand if etiologies of myocardial injury have gender differences.

Download Full-text

Global Adoption of High-Sensitivity Cardiac Troponins and the Universal Definition of Myocardial Infarction

Clinical Chemistry ◽

10.1373/clinchem.2018.298059 ◽

2019 ◽

Vol 65 (3) ◽

pp. 484-489 ◽

Cited By ~ 21

Author(s):

Atul Anand ◽

Anoop S V Shah ◽

Agim Beshiri ◽

Allan S Jaffe ◽

Nicholas L Mills

Keyword(s):

Myocardial Infarction ◽

Cardiac Troponin ◽

Clinical Pathways ◽

High Sensitivity ◽

Diagnosis And Management ◽

Coronary Syndrome ◽

Diagnostic Threshold ◽

Serial Sampling ◽

Universal Definition ◽

Definition Of

Abstract BACKGROUND The universal definition of myocardial infarction (UDMI) standardizes the approach to the diagnosis and management of myocardial infarction. High-sensitivity cardiac troponin testing is recommended because these assays have improved precision at low concentrations, but concerns over specificity may have limited their implementation. METHODS We undertook a global survey of 1902 medical centers in 23 countries evenly distributed across 5 continents to assess adoption of key recommendations from the UDMI. Respondents involved in the diagnosis and management of patients with suspected acute coronary syndrome completed a structured telephone questionnaire detailing the primary biomarker, diagnostic thresholds, and clinical pathways used to identify myocardial infarction. RESULTS Cardiac troponin was the primary diagnostic biomarker at 96% of surveyed sites. Only 41% of centers had adopted high-sensitivity assays, with wide variation from 7% in North America to 60% in Europe. Sites using high-sensitivity troponin more frequently used serial sampling pathways (91% vs 78%) and the 99th percentile diagnostic threshold (74% vs 66%) than sites using previous-generation assays. Furthermore, high-sensitivity institutions more often used earlier serial sampling (≤3 h) and accelerated diagnostic pathways. Fewer than 1 in 5 high-sensitivity sites had adopted sex-specific thresholds (18%). CONCLUSIONS There has been global progress toward the recommendations of the UDMI, particularly in the use of the 99th percentile diagnostic threshold and serial sampling. However, high-sensitivity assays are still used by a minority of sites, and sex-specific thresholds by even fewer. Additional efforts are required to improve risk stratification and diagnosis of patients with myocardial infarction.

Download Full-text

Prognostic Performance of a High-Sensitivity Cardiac Troponin I Assay in Patients with Non–ST-Elevation Acute Coronary Syndrome

Clinical Chemistry ◽

10.1373/clinchem.2013.206441 ◽

2014 ◽

Vol 60 (1) ◽

pp. 158-164 ◽

Cited By ~ 58

Author(s):

Erin A Bohula May ◽

Marc P Bonaca ◽

Petr Jarolim ◽

Elliott M Antman ◽

Eugene Braunwald ◽

...

Keyword(s):

Cardiac Troponin ◽

Troponin I ◽

High Sensitivity ◽

Cardiovascular Death ◽

Cardiac Troponin I ◽

Fourth Generation ◽

Prognostic Performance ◽

Coronary Syndrome ◽

Low Concentrations ◽

Increased Risk

Abstract BACKGROUND High-sensitivity assays for cardiac troponin enable more precise measurement of very low concentrations and improved diagnostic accuracy. However, the prognostic value of these measurements, particularly at low concentrations, is less well defined. METHODS We evaluated the prognostic performance of a new high-sensitivity cardiac troponin I (hs-cTnI) assay (Abbott ARCHITECT) compared with the commercial fourth generation cTnT assay in 4695 patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS) from the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in NSTE-ACS) and SEPIA-ACS1-TIMI 42 (Otamixaban for the Treatment of Patients with NSTE-ACS) trials. The primary endpoint was cardiovascular death or new myocardial infarction (MI) at 30 days. Baseline cardiac troponin was categorized at the 99th percentile reference limit (26 ng/L for hs-cTnI; 10 ng/L for cTnT) and at sex-specific 99th percentiles for hs-cTnI. RESULTS All patients at baseline had detectable hs-cTnI compared with 94.5% with detectable cTnT. With adjustment for all other elements of the TIMI risk score, patients with hs-cTnI ≥99th percentile had a 3.7-fold higher adjusted risk of cardiovascular death or MI at 30 days relative to patients with hs-cTnI <99th percentile (9.7% vs 3.0%; odds ratio, 3.7; 95% CI, 2.3–5.7; P < 0.001). Similarly, when stratified by categories of hs-cTnI, very low concentrations demonstrated a graded association with cardiovascular death or MI (P-trend < 0.001). Use of sex-specific cutpoints did not improve prognostic performance. Patients with negative fourth generation cTnT (<10 ng/L) but hs-cTnI ≥26 ng/L were at increased risk of cardiovascular death/MI compared to those with hs-cTnI <26 ng/L (9.2% vs 2.9%, P = 0.002). CONCLUSIONS Application of this hs-cTnI assay identified a clinically relevant higher risk of recurrent events among patients with NSTE-ACS, even at very low troponin concentrations.

Download Full-text

Global Adoption of High-Sensitivity Cardiac Troponins and the Universal Definition of Myocardial Infarction

10.1101/371138 ◽

2018 ◽

Cited By ~ 1

Author(s):

Atul Anand ◽

Anoop SV Shah ◽

Agim Beshiri ◽

Allan S Jaffe ◽

Nicholas L Mills

Keyword(s):

Myocardial Infarction ◽

Cardiac Troponin ◽

High Sensitivity ◽

Diagnosis And Management ◽

Coronary Syndrome ◽

The Third ◽

Diagnostic Threshold ◽

Serial Sampling ◽

Universal Definition ◽

Definition Of

AbstractImportanceThe third Universal Definition of Myocardial Infarction aimed to standardize the approach to the diagnosis and management of myocardial infarction. High-sensitivity cardiac troponin testing was recommended, as these assays have improved precision at low concentrations, but concerns over specificity may have limited implementation.ObjectiveTo determine the global adoption of high-sensitivity cardiac troponin assays and key recommendations from the Universal Definition.Design, Setting and ParticipantsGlobal survey of 1,902 medical centers across 23 countries evenly distributed across all five continents. Included respondents were involved in the diagnosis and management of patients with suspected acute coronary syndrome at their institutions.Main Outcomes and MeasuresStructured questionnaire detailing the primary biomarker used for myocardial infarction, diagnostic thresholds and critical elements of clinical pathways for comparison to the third Universal Definition recommendations.ResultsCardiac troponin was the primary diagnostic biomarker for myocardial infarction at 96% of all sites surveyed. Only 41% of centers had adopted high-sensitivity cardiac troponin assays, with wide variation from 7% in North America to 60% in Europe. Sites using high-sensitivity assays more frequently employed serial sampling pathways (91% vs. 78%) and the 99th percentile diagnostic threshold (74% vs. 66%) when compared to sites using the previous generation of troponin assays. Furthermore, sites using high-sensitivity assays more often used earlier serial sampling (≤3 hours) and accelerated diagnostic pathways. However, fewer than 1 in 5 sites using high-sensitivity assays had adopted sex-specific thresholds (18%).Conclusions and RelevanceProgress has been made in adopting the recommendations of the Universal Definition of Myocardial Infarction, particularly in the use of the 99th percentile diagnostic threshold and serial sampling. However, high-sensitivity assays are used in a minority of sites and sex-specific thresholds in even fewer. These findings highlight regions where additional efforts are required to improve the risk stratification and diagnosis of patients with myocardial infarction.

Download Full-text

Laboratory-related issues in the measurement of cardiac troponins with highly sensitive assays

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2020-0017 ◽

2020 ◽

Vol 58 (11) ◽

pp. 1773-1783

Author(s):

Magdalena Krintus ◽

Mauro Panteghini

Keyword(s):

Cardiac Troponin ◽

Clinical Utility ◽

Laboratory Medicine ◽

Performance Characteristics ◽

Analytical Sensitivity ◽

New Wave ◽

Low Concentrations ◽

Assay Performance ◽

Highly Sensitive ◽

Cardiac Troponins

AbstractA number of assay-related issues can affect the performance of cardiac troponin (cTn) measurement in everyday practice. In this respect, it is vital that all information on cTn assays is known and that the performance characteristics of assays are objectively assessed and adequately described. The advent of the latest generation of more sensitive cTn assays has heralded a new wave of information about low concentrations of cTn in blood. These recent generation assays have improved analytical sensitivity and corresponding performance at low cTn concentrations when compared to their predecessors, providing a convincing goal for laboratory medicine in helping clinicians in the diagnosis of acute myocardial infarction. Crucial to the clinical utility of highly sensitive cTn assays is the laboratorians’ role in closely scrutinizing proposed assays and defining their value in relation to available evidence. Analytical, as well as pre-analytical and post-analytical, aspects must be documented. In this review, we describe what laboratory professionals should know about their cTn assay performance characteristics and the pre-analytical prerequisites for robustness to ensure optimal post-analytical reporting.

Download Full-text

Short- and Long-Term Biological Variation in Cardiac Troponin I Measured with a High-Sensitivity Assay: Implications for Clinical Practice

Clinical Chemistry ◽

10.1373/clinchem.2008.107391 ◽

2009 ◽

Vol 55 (1) ◽

pp. 52-58 ◽

Cited By ~ 180

Author(s):

Alan H B Wu ◽

Quynh Anh Lu ◽

John Todd ◽

Joachim Moecks ◽

Frank Wians

Keyword(s):

Detection Limit ◽

Cardiac Troponin ◽

Troponin I ◽

High Sensitivity ◽

Population Based ◽

Biological Variation ◽

Cardiac Troponin I ◽

Low Concentrations ◽

Short And Long Term

Abstract Background: The improved detection limit and precision in new-generation commercial assays for cardiac troponin I (cTnI) have lowered the 99th-percentile cutoff value, yielding higher frequencies of positive test results. Because serial testing is important in interpreting low concentrations, we evaluated the biological variation of cTnI in both the short (hours) and long (weeks) terms and determined reference change values (RCVs) and the index of individuality (II) for cTnI. Methods: To assess short- and long-term variation, we collected blood from 12 healthy volunteers hourly for 4 h and from 17 healthy individuals once every other week for 8 weeks, measured cTnI with a high-sensitivity assay (detection limit, 0.2 ng/L), and computed analytical, intraindividual, interindividual, and total CVs (CVA, CVI, CVG, and CVT, respectively; CVT = CVA + CVI + CVG) as well as the II. Because of the slight right-skewness of the data, RCVs were calculated with a lognormal approach. Results: Within-day CVA, CVI, and CVG values were 8.3%, 9.7%, and 57%, respectively; the corresponding between-day values were 15%, 14%, and 63%. Within- and between-day IIs were 0.21 and 0.39, respectively. Lognormal within-day RCVs were 46% and −32%, respectively; the corresponding between-day values were 81% and −45%. Conclusions: The low II indicates that population-based reference intervals are less useful for interpreting cTnI values than following serial changes in values in individual patients. This criterion is particularly important for interpreting results from patients who show cTnI increases at low concentrations measured with very high-sensitivity assays, from patients presenting with chest pain (short term), and for evaluating drugs for cardiotoxicity (long term).

Download Full-text

Evaluation of analytical performance of a new high-sensitivity immunoassay for cardiac troponin I

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2017-0387 ◽

2018 ◽

Vol 56 (3) ◽

pp. 492-501 ◽

Cited By ~ 20

Author(s):

Silvia Masotti ◽

Concetta Prontera ◽

Veronica Musetti ◽

Simona Storti ◽

Rudina Ndreu ◽

...

Keyword(s):

Cardiac Troponin ◽

Troponin I ◽

High Sensitivity ◽

Cardiac Troponin I ◽

Analytical Performance ◽

Analytical Sensitivity ◽

Plasma Samples ◽

Serum Samples ◽

Significant Difference ◽

Heparin Plasma

AbstractBackground:The study aim was to evaluate and compare the analytical performance of the new chemiluminescent immunoassay for cardiac troponin I (cTnI), called Access hs-TnI using DxI platform, with those of Access AccuTnI+3 method, and high-sensitivity (hs) cTnI method for ARCHITECT platform.Methods:The limits of blank (LoB), detection (LoD) and quantitation (LoQ) at 10% and 20% CV were evaluated according to international standardized protocols. For the evaluation of analytical performance and comparison of cTnI results, both heparinized plasma samples, collected from healthy subjects and patients with cardiac diseases, and quality control samples distributed in external quality assessment programs were used.Results:LoB, LoD and LoQ at 20% and 10% CV values of the Access hs-cTnI method were 0.6, 1.3, 2.1 and 5.3 ng/L, respectively. Access hs-cTnI method showed analytical performance significantly better than that of Access AccuTnI+3 method and similar results to those of hs ARCHITECT cTnI method. Moreover, the cTnI concentrations measured with Access hs-cTnI method showed close linear regressions with both Access AccuTnI+3 and ARCHITECT hs-cTnI methods, although there were systematic differences between these methods. There was no difference between cTnI values measured by Access hs-cTnI in heparinized plasma and serum samples, whereas there was a significant difference between cTnI values, respectively measured in EDTA and heparin plasma samples.Conclusions:Access hs-cTnI has analytical sensitivity parameters significantly improved compared to Access AccuTnI+3 method and is similar to those of the high-sensitivity method using ARCHITECT platform.

Download Full-text

Concordance, Variance, and Outliers in 4 Contemporary Cardiac Troponin Assays: Implications for Harmonization

Clinical Chemistry ◽

10.1373/clinchem.2011.175059 ◽

2012 ◽

Vol 58 (1) ◽

pp. 274-283 ◽

Cited By ~ 33

Author(s):

Jacobus P J Ungerer ◽

Louise Marquart ◽

Peter K O'Rourke ◽

Urs Wilgen ◽

Carel J Pretorius

Keyword(s):

Myocardial Infarction ◽

Cardiac Troponin ◽

Troponin I ◽

Troponin T ◽

Analytical Imprecision ◽

Universal Definition ◽

Definition Of ◽

Abbott Architect ◽

Roche Cobas

Abstract BACKGROUND Data to standardize and harmonize the differences between cardiac troponin assays are needed to support their universal status in diagnosis of myocardial infarction. We characterized the variation between methods, the comparability of the 99th-percentile cutoff thresholds, and the occurrence of outliers in 4 cardiac troponin assays. METHODS Cardiac troponin was measured in duplicate in 2358 patient samples on 4 platforms: Abbott Architect i2000SR, Beckman Coulter Access2, Roche Cobas e601, and Siemens ADVIA Centaur XP. RESULTS The observed total variances between the 3 cardiac troponin I (cTnI) methods and between the cTnI and cardiac troponin T (cTnT) methods were larger than expected from the analytical imprecision (3.0%–3.7%). The between-method variations of 26% between cTnI assays and 127% between cTnI and cTnT assays were the dominant contributors to total variances. The misclassification of results according to the 99th percentile was 3%–4% between cTnI assays and 15%–17% between cTnI and cTnT. The Roche cTnT assay identified 49% more samples as positive than the Abbott cTnI. Outliers between methods were detected in 1 patient (0.06%) with Abbott, 8 (0.45%) with Beckman Coulter, 10 (0.56%) with Roche, and 3 (0.17%) with Siemens. CONCLUSIONS The universal definition of myocardial infarction should not depend on the choice of analyte or analyzer, and the between- and within-method differences described here need to be considered in the application of cardiac troponin in this respect. The variation between methods that cannot be explained by analytical imprecision and the discordant classification of results according to the respective 99th percentiles should be addressed.

Download Full-text

Analytical Characteristics of High-Sensitivity Cardiac Troponin Assays

Clinical Chemistry ◽

10.1373/clinchem.2011.165795 ◽

2012 ◽

Vol 58 (1) ◽

pp. 54-61 ◽

Cited By ~ 542

Author(s):

Fred S Apple ◽

Paul O Collinson ◽

Keyword(s):

Clinical Practice ◽

Cardiac Troponin ◽

Myocardial Injury ◽

High Sensitivity ◽

Clinical Database ◽

Coronary Syndrome ◽

Low Concentrations ◽

Reference Limits ◽

Unified View ◽

Cardiac Troponins

Abstract BACKGROUND Cardiac troponins I (cTnI) and T (cTnT) have received international endorsement as the standard biomarkers for detection of myocardial injury, for risk stratification in patients suspected of acute coronary syndrome, and for the diagnosis of myocardial infarction. An evidence-based clinical database is growing rapidly for high-sensitivity (hs) troponin assays. Thus, clarifications of the analytical principles for the immunoassays used in clinical practice are important. CONTENT The purpose of this mini-review is (a) to provide a background for the biochemistry of cTnT and cTnI and (b) to address the following analytical questions for both hs cTnI and cTnT assays: (i) How does an assay become designated hs? (ii) How does one realistically define healthy (normal) reference populations for determining the 99th percentile? (iii) What is the usual biological variation of these analytes? (iv) What assay imprecision characteristics are acceptable? (v) Will standardization of cardiac troponin assays be attainable? SUMMARY This review raises important points regarding cTnI and cTnT assays and their reference limits and specifically addresses hs assays used to measure low concentrations (nanograms per liter or picograms per milliliter). Recommendations are made to help clarify the nomenclature. The review also identifies further challenges for the evolving science of cardiac troponin measurement. It is hoped that with the introduction of these concepts, both laboratorians and clinicians can develop a more unified view of how these assays are used worldwide in clinical practice.

Download Full-text