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Observational Study
. 2025 May 20;14(10):e040468.
doi: 10.1161/JAHA.124.040468. Epub 2025 May 13.

Possible Misdiagnosis of Myocardial Infarction Using Regulatory-Approved and Close-to-Bioequivalent Upper Limits of Normal for Cardiac Troponin

Karin Wildi  1   2   3 , Maria Rubini Gimenez  1   4 , Jasper Boeddinghaus  1   2   5 , Thomas Nestelberger  1   2 , Pedro Lopez-Ayala  1   2 , Luca Koechlin  1   2   6 , Mareike Gerstenberger  1   2 , Naomi Carter  1 , Paolo Bima  1   2   7 , Jonas Glaeser  1   2 , Carlos Spagnuolo  1   2   7 , Oscar Miró  2   8 , F Javier Martín-Sánchez  2   9 , Michael Christ  10 , Dagmar I Keller  11 , Danielle M Gualandro  1   2 , Damian Kawecki  2   12 , Katharina Rentsch  13 , Felix Mahfoud  1 , Christian Mueller  1   2 ; APACE Investigators †
Collaborators, Affiliations
Observational Study

Possible Misdiagnosis of Myocardial Infarction Using Regulatory-Approved and Close-to-Bioequivalent Upper Limits of Normal for Cardiac Troponin

Karin Wildi et al. J Am Heart Assoc. .

Abstract

Background: Possible misdiagnosis of acute myocardial infarction (AMI) may occur due to inappropriate upper limit of normal (ULN) for cardiac troponin and has the potential to harm patients. In this observational international multicenter study, we aimed to assess to what extent the novel hs-cTn-assays are affected.

Methods: A total of 6646 patients presenting with suspected AMI to the emergency department were enrolled. All level pairs (n=18 732) of 4 widely used high-sensitivity cardiac troponin T/I (hs-cTnT/I) assays using (1) the regulatory-approved uniform and sex-specific clinical ULN and (2) mathematically derived close-to-bioequivalent ULNs were assessed. The primary outcome was the quantification of the incidence of inconsistencies in the diagnosis of AMI. Inconsistency was defined as hs-cTnT/I concentration above the recommended ULN in one but not the other assay: for example, hs-cTnT-Elecsys+/hs-cTnI-Architect- or hs-cTnT-Elecsys-/hs-cTnI-Architect+.

Results: AMI was the adjudicated diagnosis in 1422 patients (21.4%). When the regulatory-approved uniform ULN was used, the rate of inconsistent AMI diagnoses was 17.6% (Elecsys/Architect), 18.8% (Elecsys/Centaur), 14.2% (Elecsys/Access), 4.9% (Architect/Centaur), 8.3% (Architect/Access), and 7.4% (Access/Centaur), respectively. Overall, diagnostic mismatches were not decreased, but in fact increased using regulatory-approved sex-specific ULNs. In women as compared with men, they were 23.8% versus 17.6% (Elecsys/Architect), 30.1% versus 19.1% (Elecsys/Centaur), 23.2% versus 15% (Elecsys/Access), 7.2% versus 4.5% (Architect/Centaur), 8.3% versus 8.7% (Architect/Access) and 7.8% versus 8.2% (Access/Centaur), respectively. Using close-to-bioequivalent ULNs reduced inconsistencies by 15% to 20% (P<0.001). Findings were confirmed in a sensitivity analysis among all level pairs with final diagnosis of AMI (mismatches in 7.3%-20.5%).

Conclusions: Current regulatory-approved uniform and sex-specific ULNs for hs-cTnT/I result in discordances in binary assay results, possibly impacting the diagnosis of AMI. A regulatory process that defines bioequivalent ULNs could reduce inconsistencies significantly.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00470587.

Keywords: high‐sensitivity cardiac troponin T and I; misdiagnosis of acute myocardial infarction; upper limit of normal clinical decision values.

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Conflict of interest statement

Dr Wildi has received research funding from the Prince Charles Hospital Foundation, the Wesley Medical Research Foundation, the Swiss National Foundation, and the University of Basel, all outside the submitted work. In addition, she received a PhD scholarship from the University of Queensland, Brisbane, Australia. Dr Rubini Gimenez reports research grants from the Swiss Heart Foundation and Swiss National Foundation (P400PM_180828) and speakers' honoraria from Roche, Ortho Clinical Diagnostics, Quidel, and Siemens. Dr Boeddinghaus has received research grants from the University of Basel and the Division of Internal Medicine, the Swiss National Science Foundation; is supported by an Edinburgh Doctoral College Scholarship; and received speaker honoraria from Siemens, Roche Diagnostics, Ortho Clinical Diagnostics, and Quidel Corporation, outside the submitted work. Dr Nestelberger has received speaker honoraria from Beckman Coulter, outside the submitted work. Dr Lopez‐Ayala has received research grants from the Swiss Heart Foundation (FF20079 and FF21103) and speaker's honoraria from Quidel, paid to the institution, outside the submitted work. Dr Koechlin received a research grant from the Swiss Heart Foundation, the University of Basel, the Swiss Academy of Medical Sciences, and the Gottfried and Julia Bangerter‐Rhyner Foundation, as well as the “Freiwillige Akademische Gesellschaft Basel,” and speaker honoraria from Roche Diagnostics, Siemens, and Abbott outside the submitted work. Dr Mueller has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, Innosuisse, the University of Basel, the University Hospital Basel, Abbott, Beckman Coulter, Biomerieux, Idorsia, Ortho Cinical Diagnostics, Quidel, Roche, Siemens, Singulex, SpinChip, Upstream, and Sphingotec, as well as speaker honoraria/consulting honoraria from Acon, Amgen, Astra Zeneca, Boehringer Ingelheim, Bayer, BMS, Idorsia, Novartis, Novo Nordisk, Osler, Roche, Sanofi, and SpinChip, outside of the submitted work. The remaining authors have no disclosures to report.

Author Contributions: Drs Wildi, Rubini Gimenez, Lopez Ayala, and Mueller had full access to the data of the study and take full responsibility for its integrity and data analysis.

Figures

Figure 1
Figure 1. Performance of the ULN as approved by regulatory bodies and as recommended by the manufacturers in receiver operating characteristics curves.
A, Uniform; (B) sex‐specific women; (C) sex‐specific men; (D) mathematically derived close‐to‐bioequivalent ULN in all patients. All assay units in ng/L. Elecsys: hs‐cTnT–Elecsys (Roche); Architect: hs‐cTnI–Architect (Abbott); Centaur: hs‐cTnI–Centaur (Siemens); Access: hs‐cTnI–Access (Beckman); CDV indicates clinical decision value; and ULN, upper limit of normal.
Figure 2
Figure 2. Distribution of level pairs of the different hs‐cTnT/I assays in quadrants according to regulatory‐approved and manufacturer‐recommended uniform ULN for all level pairs independently of final diagnosis.
All assay units in ng/L. Elecsys: hs‐cTnT–Elecsys (Roche); Architect: hs‐cTnI–Architect (Abbott); Centaur: hs‐cTnI–Centaur (Siemens); Access: hs‐cTnI–Access (Beckman); r: correlation coefficient. hs‐cTnT/I indicates high‐sensitivity cardiac troponin T/I; and ULN, upper limit of normal.
Figure 3
Figure 3. Distribution of level pairs of the different hs‐cTnT/I assays in quadrants according to regulatory‐approved and manufacturer‐recommended sex‐specific ULN for all level pairs independently of final diagnosis in (A) women and (B) men.
All assay units in ng/L. Elecsys: hs‐cTnT–Elecsys (Roche); Architect: hs‐cTnI–Architect (Abbott); Centaur: hs‐cTnI–Centaur (Siemens); Access: hs‐cTnI–Access (Beckman); r: correlation coefficients. hs‐cTnT/I indicates high‐sensitivity cardiac troponin T/I; and ULN, upper limit of normal.
Figure 4
Figure 4. Distribution of level pairs of the different hs‐cTnT/I assays in quadrants according to close‐to‐bioequivalent ULNs for all level pairs in all patients.
All assay units in ng/L. Elecsys: hs‐cTnT–Elecsys (Roche); Architect: hs‐cTnI–Architect (Abbott); Centaur: hs‐cTnI–Centaur (Siemens); Access: hs‐cTnI–Access (Beckman); and ULN: upper limit of normal.
See this image and copyright information in PMC

References

    1. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD, Corbett S, Chettibi M, Hayrapetyan H. Fourth universal definition of myocardial infarction (2018). Circulation. 2018;138:618–651. doi: 10.1161/CIR.0000000000000617 - DOI - PubMed
    1. Collet JP, Thiele H, Barbato E, Barthélémy O, Bauersachs J, Bhatt DL, Dendale P, Dorobantu M, Edvardsen T, Folliguet T, et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST‐segment elevation. Eur Heart J. 2021;42:1289–1367. doi: 10.1093/eurheartj/ehaa575 - DOI - PubMed
    1. Gulati M, Levy PD, Mukherjee D, Amsterdam E, Bhatt DL, Birtcher KK, Blankstein R, Boyd J, Bullock‐Palmer RP, Conejo T, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of CHEST pain. Circulation. 2021;144:e368–e454. doi: 10.1161/CIR.0000000000001029 - DOI - PubMed
    1. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli‐Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST‐segment elevation. Eur Heart J. 2018;39:119–177. doi: 10.1093/eurheartj/ehx393 - DOI - PubMed
    1. Wildi K, Gimenez MR, Twerenbold R, Reichlin T, Jaeger C, Heinzelmann A, Arnold C, Nelles B, Druey S, Haaf P, et al. Misdiagnosis of myocardial infarction related to limitations of the current regulatory approach to define clinical decision values for cardiac troponin. Circulation. 2015;131:2032–2040. doi: 10.1161/CIRCULATIONAHA.114.014129 - DOI - PMC - PubMed

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