Update on global conversion to high sensitivity cardiac troponin assays

The evolution of cardiac troponin (cTn) measurement to high sensitivity assays

The introduction of cTn measurement into the routine clinical laboratory repertoire has led to a profound shift in the role of cardiac biomarker testing. Originally used for retrospective diagnosis, cardiac biomarkers in their current incarnation of high sensitivity cardiac troponin (hs cTn) for measurement of cardiac troponin T (hs cTnT) and cardiac troponin I (hs cTnI) are now recommended by national guideline agencies (1) and professional societies (2). Measurement of cTn is now the “gold standard” test for the diagnosis of myocardial infarction (MI) and has replaced all other cardiac biomarkers (3). The reasons for the transformation are twofold and interlinked. First, the measurement of cTn either as cardiac troponin T (cTnT) or cardiac troponin I (cTnI) was shown to detect prognostically significant myocardial damage, missed MI, in patients considered to have unstable angina by conventional “cardiac enzyme” measurement (4,5). Second, the evidence of the superiority of cTnT and cTnI measurement led to the redefinition of MI in terms of cTn measurement (6).

Uptake of high sensitivity troponin assays

hs cTn assays are defined by two criteria. First, the ability to measure with an imprecision of less than 10% at the 99^th percentile of a reference population. Second, they are able to produce numeric values in at least 50% or more of the reference population, both male and female (7,8). The evolution of cTn assays from the first versions, which were relatively insensitive, to the current versions has been iterative, they did not spring fully formed like Athena from Zeus. Two factors have driven the development of hs cTn assays. First, there is the natural tendency of manufacturers to develop and improve assays. This is nicely illustrated by the conversion of the first to second generation cTnT assay which showed a problem of cardio specificity due to choice of antibodies in the presence of extreme elevation of skeletal troponin T (9). Second, the redefinition of MI mandated an analytical performance that was not met by any of the assays on the market at the time the guideline was produced (6). The first hs cTn assay introduced was the Roche diagnostics cTnT assay (Roche Diagnostics, Switzerland). The performance uplift was quite significant with the limit of detection of the assay moving from (in nanograms) 30 to 3 ng/L. A similar trend for cTnI assays has occurred, although here the shift in performance has not been quite as dramatic. The majority of the existing cTnI assays provided acceptable analytical performance characteristics. There is now an hs cTn assay available from all of the major diagnostics companies. The major problem to date has been regulatory approval with assays available in Europe and Worldwide long before clearance by the US Food and Drug administration (FDA). Clearance of hs cTnT occurred only in January 2017 and the first hs cTnI assay (Abbott) only in 2020.

Uptake of cardiac troponin testing and the use of hs cTn has been monitored over time by a series of European surveys, the CARdiac MARker Guideline Uptake in Europe (CARMARGUE) project of the European Federation of Laboratory Medicine (formerly the European Society of Laboratory Medicine) (10-14). This project undertook a regular internet-based questionnaire survey performed after publication of guidelines and recommendations from clinical and laboratory societies worldwide. A consistent finding was the rapid adoption of cTn measurement and its use as the preferred biomarker. This has been accompanied by a decline in other biomarkers offered with aspartate transaminase (AST) and lactate dehydrogenase (LDH). In the most recent survey, no laboratories reported using AST and LDH as part of their routine cardiac profile. Creatine kinase especially measurement of the MB isoenzyme (CK-MB) remains in routine clinical use although there is little evidence to support this (15). The usual reason expressed for retaining CK-MB is clinician preference. An international telephone survey performed in 2016 found the same trend with cardiac troponin being used as the preferred marker (16). At this point, hs cTn assays were available worldwide but not in the US with on average approximately 50% conversion from conventional sensitive to high sensitivity assays. A comparative survey in the United Kingdom performed in 2014 (when high sensitivity assays were available although not from all manufacturers) found a 60% conversion to high sensitivity assays. Most recently, this has increased to 88% (17). Currently in Europe, there is almost complete transition to high sensitivity assays (14) with laboratories either currently using or intending to use hs cTn (14). Interestingly, where diagnostic facilities are using point of care testing (POCT), which is not high sensitivity, they are shifting to an hs laboratory assay. Internationally, there has been a change to hs cTn. Currently, manufacturer’s offer both a conventional sensitive and hs cTn assay but with the universal intention of phasing out the conventional sensitive assay entirely (personal communication). The stage of completeness in phasing out the conventional sensitive assay depends on the regulatory status and the timing of introduction of the hs cTn assay from any given manufacturer. Early introduction and approval has produced almost 100% transition to hs cTn. In Europe, only hs cTnT is currently sold whereas in the US laboratories are still transitioning. A further complication may be that laboratories are in the process of changing instrumentation and may delay introduction of the high sensitivity assay until the instrument change has occurred. Use of non-high sensitivity assays is now largely confined to countries where there is a current lack of regulatory approval of a high sensitivity assay or where there has been a significant delay in introduction. Here, retention of a conventional sensitive is only prior to conversion to high sensitivity. It is expected that over the course of the next 5 years only high sensitivity assays will be in use internationally.

The significant advantage of hs cTn assays over conventional sensitive assays is the ability to measure cTn at very low levels, values in the lowest quartile of the reference population and typically in the lower centile with very high reproducibility on repeat measurement. This is referred to as the ability to measure with high sensitivity and low imprecision. These analytical characteristics have resulted in the development of a number of accelerated predictive and diagnostic pathways, described in detail later in this issue, based on measurement of cTn using a high sensitivity method on admission and 1, 2 or 3 hours from admission. Utilisation of these strategies has however significantly lagged behind the uptake of hs-cTn measurement (14,16).

Utilization of high sensitivity troponin measurements in routine clinical practice—the reality challenges

Ever since troponin testing was introduced there has been a chronic problem of over requesting (18,19). The high degree of cardio specificity of cTn measurements means that there has been a tendency to use measurement as a general rule out test for any form of cardiac injury. This is a double-edged sword as non-specific requesting may in fact delay appropriate care (20). There is no doubt that troponin elevations outside the acute coronary syndrome (ACS) population carry prognostic significance (21). There is therefore some logic to the concept of using troponin measurement when diagnosis is uncertain to exclude myocardial injury. The advent of hs cTn measurement has increased the prevalence of troponin elevations outside the ACS population. Indeed, it is now the case that more troponin elevations are due to type 2/ischemic myocardial injury than to type 1 (classical) MI (22). The problem is that only a minority of patients presenting to the emergency department (ED) have a final diagnosis that includes ischemic heart disease. Typically, in a low-risk chest pain population presenting to the ED 9% have a final diagnosis of MI and 8% angina (23). The problems of a large number of patients who do not have the ischemic heart disease but have troponin elevations has been considered in the fourth redefinition of MI. The introduction of a classification recognizing myocardial injury distinct from MI acknowledges the problems of elevation in a wide spectrum of clinical conditions (3). One approach to this problem is closer liaison between clinical and laboratory staff to more closely define requesting protocols. This must be accompanied by regular audits cycles and reporting back of the results.

A significant problem is that clinicians do not adhere to current recommendations for diagnosis and show a high variability in choice of diagnostic cut-offs (13) and protocols (17,24,25). In the most recent audit of requesting practice at St. George’s Hospital (26) over a 4-month period, 4,869/7,352 requests (66%) were for a single troponin of which 2,664 (36%) were in the range 3–50 ng/L (cTnT) which should, according to protocol, have undergone serial testing. The use of rapid diagnostic algorithms is predicated by appropriate sample timings. A 0–3-hour repeat testing protocol was in use at the time, but the timing of the second sample was variable with a median of 3 hours but an interquartile range of 2.2–3.9 hours. Similar problems with sample timings were seen on switching to a 0–2-hour repeat testing protocol where a repeat sample taken at 3 hours from hospital admission was used for the final diagnostic classification (27). Sample timings of the 2 hours sample showed a median time interval between first and second sample (anticipated 2 hours) of 2.2 hours (interquartile range 1.8–2.7 hours) and between the second and third samples (anticipated 1 hour) the median interval was 1.2 hours (interquartile range 0.9–1.9 hours). According to the protocol, the second sample should have been taken at 2 hours from hospital admission and the third at 3 hours from hospital admission. A recently reported audit of introduction of a 0–1-hour protocol provides almost identical data (28) and reflects the difference between reported academic studies and the reality of real world utilisation of such strategies.

The current situation may however be transitional as the relative novelty of rapid diagnostic algorithms recedes. Growing clinician confidence with hs cTn assays as well as a growing body of evidence of the validity of the rapid diagnostic algorithms and their endorsement by professional societies is likely to increase their rate of adoption. A further factor may be that hs cTn assays are now becoming available by POCT. POCT has a very rapid turnaround time, typically 15 minutes or less, which will greatly facilitate provision of results within the timing of a decision making framework. Timeliness of results makes rapid diagnostic protocols more attractive. There may also be another factor in that many troponin requests are entirely protocol driven before the physician assesses the patient. POCT with its potential for result availability within the time of the initial consultation might produce more directed testing (29).

Conclusions

At present there is some geographical variation in the utilization of hs cTn measurement. This has been largely driven by regulatory problems which has delayed implementation. However, it is expected that there will be global utilization of high sensitivity assays. The major problem at present is the widespread use of non-specific troponin testing. Currently, utilization of rapid assessment protocols remains low and problematic. It remains a challenge for laboratory professionals and clinicians to formulate strategies that will facilitate the obvious promise of hs cTn assays in the real world and balance appropriate patient selection with the use of rapid diagnostic protocols to confirm or exclude ACS.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Xander van Wijk, Amy Saenger, Steven Meex, and Allan Jaffe) for the series “Cardiac Troponin” published in Journal of Laboratory and Precision Medicine. The article has undergone external peer review.

Peer Review File: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-22-64/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-22-64/coif). The series “Cardiac Troponin” was commissioned by the editorial office without any funding or sponsorship. PC is an associate editor of the Journal of Applied Laboratory Medicine (unpaid) and a consultant to the International Federation of Clinical Chemistry Committee on Clinical Applications of Cardiac Biomarkers (unpaid) and on the advisory board of Psyros Diagnostics and has previously advised Radiometer, LumiraDx and Siemens. He also reports honoraria for lectures from Siements Healthineers. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. NICE. Diagnostic Guidance 40 [DG40] Diagnostics Assesment Committee National Institute for Health and Care Excellence. High-sensitivity troponin tests for the early rule out of NSTEMI. Available online: https://www.nice.org.uk/guidance/DG40
2. Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021;42:1289-367. [Crossref] [PubMed]
3. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Eur Heart J 2019;40:237-69. [Crossref] [PubMed]
4. Stubbs P, Collinson P, Moseley D, et al. Prospective study of the role of cardiac troponin T in patients admitted with unstable angina. BMJ 1996;313:262-4. [Crossref] [PubMed]
5. Galvani M, Ottani F, Ferrini D, et al. Prognostic influence of elevated values of cardiac troponin I in patients with unstable angina. Circulation 1997;95:2053-9. [Crossref] [PubMed]
6. Myocardial infarction redefined--a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Eur Heart J 2000;21:1502-13. [Crossref] [PubMed]
7. Apple FS, Collinson PO. Analytical characteristics of high-sensitivity cardiac troponin assays. Clin Chem 2012;58:54-61. [Crossref] [PubMed]
8. Apple FS, Jaffe AS, Collinson P, et al. IFCC educational materials on selected analytical and clinical applications of high sensitivity cardiac troponin assays. Clin Biochem 2015;48:201-3. [Crossref] [PubMed]
9. Collinson PO, Stubbs PJ, Rosalki SB. Cardiac troponin T in renal disease. Clin Chem 1995;41:1671-3. [Crossref] [PubMed]
10. Collinson P, Pulkki K, Suvisaari J, et al. How well do laboratories follow guidelines on cardiac markers? The cardiac marker guideline uptake in Europe study. Clin Chem 2008;54:448-9. [Crossref] [PubMed]
11. Pulkki K, Suvisaari J, Collinson P, et al. A pilot survey of the use and implementation of cardiac markers in acute coronary syndrome and heart failure across Europe. The CARdiac MArker Guideline Uptake in Europe (CARMAGUE) study. Clin Chem Lab Med 2009;47:227-34. [Crossref] [PubMed]
12. Collinson PO, van Dieijen-Visser MP, Pulkki K, et al. Evidence-based laboratory medicine: how well do laboratories follow recommendations and guidelines? The Cardiac Marker Guideline Uptake in Europe (CARMAGUE) study. Clin Chem 2012;58:305-6. [Crossref] [PubMed]
13. Collinson P, Hammerer-Lercher A, Suvisaari J, et al. How Well Do Laboratories Adhere to Recommended Clinical Guidelines for the Management of Myocardial Infarction: The CARdiac MArker Guidelines Uptake in Europe Study (CARMAGUE). Clin Chem 2016;62:1264-71. [Crossref] [PubMed]
14. Collinson P, Suvisaari J, Aakre KM, et al. How Well Do Laboratories Adhere to Recommended Guidelines for Cardiac Biomarkers Management in Europe? The CArdiac MARker Guideline Uptake in Europe (CAMARGUE) Study of the European Federation of Laboratory Medicine Task Group on Cardiac Markers. Clin Chem 2021;67:1144-52. [Crossref] [PubMed]
15. Jaffe AS, Lindahl B, Giannitsis E, et al. ESC Study Group on Cardiac Biomarkers of the Association for Acute CardioVascular Care: A fond farewell at the retirement of CKMB. Eur Heart J 2021;42:2260-4. [Crossref] [PubMed]
16. Anand A, Shah ASV, Beshiri A, et al. Global Adoption of High-Sensitivity Cardiac Troponins and the Universal Definition of Myocardial Infarction. Clin Chem 2019;65:484-9. [Crossref] [PubMed]
17. Thapa S, Wong R, Goodacre S. Implementation of rapid rule out of myocardial infarction using high-sensitivity troponin: cross-sectional survey of English hospitals. Emerg Med J 2020;37:229-31. [Crossref] [PubMed]
18. Gardezi SA. Troponin: think before you request one. BMJ Qual Improv Rep 2015;4:u204560.w3221.
19. Scorgie R, Nicholls GM, Jones P. Association between an educational intervention and a reduction in inappropriate troponin testing in patients presenting to an adult emergency department. Intern Med J 2014;44:1100-8. [Crossref] [PubMed]
20. Buntine PG, Sze S, Aldridge ES. High-sensitivity troponin T use in non-chest pain presentations in the emergency department. Emerg Med Australas 2020;32:864-6. [Crossref] [PubMed]
21. Eggers KM, Jernberg T, Lindahl B. Cardiac Troponin Elevation in Patients Without a Specific Diagnosis. J Am Coll Cardiol 2019;73:1-9. [Crossref] [PubMed]
22. Shah ASV, Sandoval Y, Noaman A, et al. Patient selection for high sensitivity cardiac troponin testing and diagnosis of myocardial infarction: prospective cohort study. BMJ 2017;359:j4788. [Crossref] [PubMed]
23. Collinson P, Gaze D, Goodacre S. Comparison of contemporary troponin assays with the novel biomarkers, heart fatty acid binding protein and copeptin, for the early confirmation or exclusion of myocardial infarction in patients presenting to the emergency department with chest pain. Heart 2014;100:140-5. [Crossref] [PubMed]
24. Howell SJ, Amsterdam EA, Mumma BE, et al. Implementation of High-Sensitivity Cardiac Troponin: Challenges From the International Experience. Crit Pathw Cardiol 2018;17:173-8. [Crossref] [PubMed]
25. Bevins NJ, Chae H, Hubbard JA, et al. Emergency Department Management of Chest Pain With a High-Sensitivity Troponin-Enabled 0/1-Hour Rule-Out Algorithm. Am J Clin Pathol 2022;157:774-80. [Crossref] [PubMed]
26. Collinson PO, Ford S, Krishnanandan S. A-014 Audit of High Sensitivity Cardiac Troponin Requesting Patterns in Routine Clinical Use. AACC Annual Scientific Meeting. 2022. Available online: https://meeting.aacc.org/-/media/Files/Meetings-and-Events/Annual-Meeting/2022/AACC22_AbstractBook_Final.pdf?la=en&hash=B978AA002D9D9DE1E12185BCB2CCB3861302F210
27. Ford S, Krishnanandan S, Collinson P. 1704 Feasibility of implementing a 0–2 troponin algorithm in routine clinical practice. Emerg Med J 2022;39:abstr A985-7.
28. Couch LS, Sinha A, Navin R, et al. Rapid risk stratification of acute coronary syndrome: adoption of an adapted European Society of Cardiology 0/1-hour troponin algorithm in a real-world setting. Eur Heart J Open 2022;2:oeac048.
29. Collinson P, Aakre KM, Saenger A, et al. 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). Clin Chem Lab Med 2023; Epub ahead of print. [Crossref] [PubMed]