Archives of Cardiovascular Disease (2015) 108, 132—149
Available online at
ScienceDirect
www.sciencedirect.com
REVIEW
High-sensitivity cardiac troponin assays:
Answers to frequently asked questions
Troponine dosée avec un test de haute sensibilité : éléments de réponse aux
questions fréquemment posées
Camille Chenevier-Gobeaux a,∗,
Éric Bonnefoy-Cudraz b, Sandrine Charpentier c,
Monique Dehoux d, Guillaume Lefevre e,
Christophe Meune f,g, Patrick Ray h,i,j , for the SFBC,
SFC, SFMU ‘Troponins’ workgroup
a
Laboratoire de Biochimie, GH Cochin-Broca-Hôtel Dieu, HUPC, Assistance Publique des
Hôpitaux de Paris (AP—HP), 75014 Paris, France
b
Service de Cardiologie, Hôpital Louis-Pradel, Hospices Civils de Lyon, 69002 Lyon, France
c
Service d’Accueil des Urgences, Hôpital Rangueil, CHU de Toulouse, Université Toulouse III —
Paul-Sabatier, INSERM UMR 1027 Équipe 5, 31400 Toulouse, France
d
Laboratoire de Biochimie, Hôpital Bichat-Claude-Bernard, HUPNVS, Assistance Publique des
Hôpitaux de Paris (AP—HP), 75018 Paris, France
e
Laboratoire de Biochimie et Hormonologie, Hôpital Tenon, HUEP, Assistance Publique des
Hôpitaux de Paris (AP—HP), 75020 Paris, France
f
Service de Cardiologie, Hôpital Avicenne, HUPSSD, Assistance Publique des Hôpitaux de Paris
(AP—HP), 93000 Bobigny, France
g
Université Paris 13, 93000 Paris, France
h
Service d’Accueil des Urgences, Hôpital Tenon, HUEP, Assistance Publique des Hôpitaux de
Paris (AP—HP), 75020 Paris, France
i
Université Pierre-et-Marie-Curie, Paris 6, 75013 Paris, France
j
DHU ‘Fighting against ageing and stress’ (FAST), UPMC Paris 6, AP—HP, 75013 Paris, France
Received 7 May 2014; accepted 24 November 2014
Abbreviations: ACS, acute coronary syndrome; AMI, acute myocardial infarction; cTn, cardiac troponin; cTnI, cardiac troponin I; cTnT,
cardiac troponin T; CV, coefficient of variation; ECG, electrocardiogram; ESC, European Society of Cardiology; HAMA, heterophilic human
antimouse antibody; hs-cTn, high-sensitivity cardiac troponin; LBBB, left bundle branch block; LoB, Limit of Blank; LoD, Limit of Detection;
LoQ, Limit of Quantitation; NSTEMI, non-ST-segment elevation myocardial infarction; RCV, reference change value; ROC, receiver operator
curve; SFBC, Société française de biologie clinique; SFC, Société française de cardiologie; SFMU, Société française de médecine d’urgence;
STEMI, ST-segment elevation myocardial infarction; URL, upper reference limit.
∗ Corresponding author at: Laboratoire de Biochimie, GH Cochin-Broca-Hôtel Dieu, UPC, Assistance Publique des Hôpitaux de Paris (AP—HP),
27, rue du Faubourg-Saint-Jacques, 75679 Paris Cedex 14, France.
E-mail address: (C. Chenevier-Gobeaux).
http://dx.doi.org/10.1016/j.acvd.2014.11.001
1875-2136/© 2014 Elsevier Masson SAS. All rights reserved.
© 2021 Elsevier Masson SAS. Tous droits réservés. - Document téléchargé le 27/11/2021 Il est interdit et illégal de diffuser ce document.
, High-sensitivity cardiac troponin assays: Answers to frequently asked questions 133
KEYWORDS Summary Cardiac troponin (cTn) assays have quickly gained in analytical sensitivity to
Troponin; become what are termed ‘high-sensitivity cardiac troponin’ (hs-cTn) assays, bringing a flurry of
High-sensitivity; dense yet incomplete literature data. The net result is that cTn assays are not yet standardized
Myocardial and there are still no consensus-built data on how to use and interpret cTn assay results. To
infarction; address these issues, the authors take cues and clues from multiple disciplines to bring responses
Acute coronary to frequently asked questions. In brief, the effective use of hs-cTn hinges on knowing: specific
syndrome; assay characteristics, particularly precision at the 99th percentile of a reference population;
Chest pain factors of variation at the 99th percentile value; and the high-individuality of hs-cTn assays, for
which the notion of individual kinetics is more informative than straight reference to ‘normal’
values. The significance of patterns of change between two assay measurements has not yet
been documented for every hs-cTn assay. Clinicians need to work hand-in-hand with medical
biologists to better understand how to use hs-cTn assays in routine practice.
© 2014 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Résumé L’évolution rapide des méthodes de dosage des troponines cardiaques (cTn) vers
Troponine ; une meilleure sensibilité analytique (cTn de haute sensibilité, ou cTn HS) s’accompagne de
Haute sensibilité ; nombreuses données de la littérature mais encore incomplètes. En l’absence de standardisation
Infarctus du des cTn et de données consensuelles sur l’utilisation et l’interprétation des résultats, les auteurs
myocarde ; de cette revue proposent, à partir d’une revue de la littérature, et de façon multidisciplinaire,
Syndrome coronarien des éléments de réponses aux questions fréquemment posées. En conclusion, le bon usage
aigu ; des cTn HS repose sur la connaissance : des caractéristiques propres de la méthode utilisée,
Douleur thoracique en particulier de la précision obtenue au 99e percentile d’une population de référence ; des
facteurs de variation de la valeur du 99e percentile ; de la forte individualité des dosages de
cTn HS, pour lesquels la notion de cinétique individuelle est plus informative que la simple
référence à des valeurs usuelles. La significativité des variations entre deux dosages, n’est pas
encore documentée pour toutes les méthodes HS. La collaboration entre cliniciens et biologistes
est nécessaire à une meilleure utilisation des troponines au quotidien.
© 2014 Elsevier Masson SAS. Tous droits réservés.
Background ‘Question and Answer’ format to connect with grass-roots
practitioners, and is written to provide clinicians and biol-
International guidelines on myocardial infarction (MI) diag- ogists with the most routine-relevant conclusions possible,
nosis recommend running a cardiac troponin (cTn) assay in including a series of boxes headed ‘In practice/takeaways’,
suspected MI patients unless they present ST-segment ele- which recap the key messages.
vation (suspected lone-event non-ST-segment elevation MI
[NSTEMI]). The need to observe an increase in troponin over
the 99th percentile of a reference population together with
the significant assay-to-assay variation make it necessary to
Terms and definitions
use what are dubbed sensitive or hypersensitive cTn assays.
cTn assays are rapidly gaining in analytical sensitivity. Pub- What does assay sensitivity mean?
lished data on this latest generation of more sensitive assays
are dense, but are still incomplete. Furthermore, cTn assays An assay that qualifies as sensitive or hypersensitive (quali-
are not yet standardized and there are still no consensus- fiers arbitrarily grouped under the term ‘high-sensitivity’ in
built data on how to use and interpret high-sensitivity cTn this paper) is an assay that demonstrates greater analytical
(hs-cTn) assay results. sensitivity and precision than the conventional method it is
Given this context, three French academic societies built on. The word ‘sensitive’ refers to the assay, not to the
— the Société française de médecine d’urgence (SFMU) for biomarker itself.
emergency medicine, the Société française de cardiologie From an analytical standpoint, analytical sensitivity is the
(SFC) for cardiology and the Société française de biologie smallest measurable analyte concentration above the limit
clinique (SFBC) for clinical biology — have joined forces to of detection. Here, sensitivity is determined by the slope of
co-propose an integrated French-language document that, the calibration curve. Higher sensitivity increases the possi-
through a review of the literature, tackles the issue of how bility of getting low variations between two assays, as their
to use troponin assays properly. The document adopts a respective signals will be significantly different (Fig. 1).
© 2021 Elsevier Masson SAS. Tous droits réservés. - Document téléchargé le 27/11/2021 Il est interdit et illégal de diffuser ce document.
, 134 C. Chenevier-Gobeaux et al.
Precision, LoD and LoQ vary from cTn assay to cTn assay,
so they need to be verified by the laboratories and, if
appropriate, communicated to the clinicians, to optimize
the results interpretation process. Within the laboratory
competency accreditation framework (standard ISO 15189),
the analytical characteristics of hs-cTn assays are to be
verified as stipulated in document SH-GTA 04 (see ‘What pre-
cautions does the laboratory need to take when transitioning
to a hs-cTn assay?’).
In practice/takeaways
• The analytical precision of an assay is given by the
CV at a given analyte concentration.
• Analytical characteristics (sensitivity, precision, LoD,
LoQ) are assay specific.
Figure 1. Graphical comparison of the sensitivity of two assays.
Assay B sensitivity is higher than assay A sensitivity; it is easier to
detect a small difference of concentration between two measures What is an hs-cTn assay and are all hs-cTn
(black arrow) with assay B because the difference between observed assays essentially similar?
signals is higher for assay B (blue arrow) than for assay A (turquoise
blue arrow). An hs-cTn assay possesses better sensitivity and better ana-
lytical precision than the ‘conventional’ assay it is built on.
High-sensitivity assays offer 4-fold to 10-fold greater ana-
In other words, a method’s sensitivity is also its ability to
lytical sensitivity than conventional methods.
precisely and reliably differentiate between two different
Apple and Collinson short-listed two basic criteria for
concentrations.
defining whether a cTn assay is ‘highly sensitive’: precision
of a reference population; and proportion of measurable
In practice/takeaways concentrations in healthy individuals above the assay’s LoD
• The word ‘sensitive’ refers to the assay, not to the [2]. For an assay to qualify as’ high-sensitivity’, it has to
biomarker itself. demonstrate ≤ 10% total imprecision at the 99th percentile
• Analytical sensitivity is the smallest difference in value and be able to quantitate at least 50% of healthy indi-
concentration measurable by the assay. viduals [2].
cTn assays — whether high-sensitivity or conventional —
are still not standardized at this time. Standardization
efforts are hampered by a combination of factors, chiefly
the heterogeneity of the circulating cTn forms that the
assays can recognize, post-translational modifications to cTn
What does analytical precision mean? isoforms and immunoassay response modifications tied to
interferences and autoantibodies.
The analytical precision of an assay is an evaluation of the Compounding the issue, results do not directly corre-
degree of dispersion in serial test results on a single sample; late from technique to technique. In theory, the assays are
it is expressed as the analytical coefficient of variation (CV) equimolar, which means they should identically recognize all
of the assay, where CV = mean/standard deviation × 100, circulating forms. In practice, however, the distribution of
given as a percentage (%). Analytical precision splits into circulating cTn forms in a given patient at a given time can
a repeatability strand (intraseries precision) and a repro- vary, thus producing different responses in different assays.
ducibility strand (interseries precision). Consequently, the results given by different assays are not
A measurement method’s lower-range limits are defined directly transposable from test to test.
by: the Limit of Blank (LoB; the concentration below which The net result is that each assay method has its own char-
95% of results are expected to be found when replicates acteristics and its own cut-off thresholds (Table 1) [3—5].
[n > 60] of a sample containing no analyte [i.e. a biomarker- Consequently, it is vital that a patient’s cTn concentra-
free sample] are measured); the Limit of Detection (LoD; the tions are monitored with the same assay. The high-sensitivity
lowest detectable analyte concentration likely to be reliably assays add to a long list of conventional cTn assays. In most
distinguished from the LoB; it is determined based on the cases, the high-sensitivity method has replaced the conven-
LoB and the standard deviation of replicates of a sample tional assay (e.g. fourth-generation cTnT [cardiac troponin
containing a low, but non-zero, biomarker concentration); T] upgraded to hs-cTnT at Roche Diagnostics, ARCHITECT
the Limit of Quantitation (LoQ; the smallest value obtained cTnI [cardiac troponin I] upgraded to ARCHITECT hs-cTnI
at a predefined CV). In the specific subfield of cTn, and for at Abbott, etc.). The analytical modifications integrated in
conventional assay methods, 10% CV is the analytical limit high-sensitivity assays are patent protected and are rarely
adopted for MI diagnosis [1]. published.
© 2021 Elsevier Masson SAS. Tous droits réservés. - Document téléchargé le 27/11/2021 Il est interdit et illégal de diffuser ce document.
Available online at
ScienceDirect
www.sciencedirect.com
REVIEW
High-sensitivity cardiac troponin assays:
Answers to frequently asked questions
Troponine dosée avec un test de haute sensibilité : éléments de réponse aux
questions fréquemment posées
Camille Chenevier-Gobeaux a,∗,
Éric Bonnefoy-Cudraz b, Sandrine Charpentier c,
Monique Dehoux d, Guillaume Lefevre e,
Christophe Meune f,g, Patrick Ray h,i,j , for the SFBC,
SFC, SFMU ‘Troponins’ workgroup
a
Laboratoire de Biochimie, GH Cochin-Broca-Hôtel Dieu, HUPC, Assistance Publique des
Hôpitaux de Paris (AP—HP), 75014 Paris, France
b
Service de Cardiologie, Hôpital Louis-Pradel, Hospices Civils de Lyon, 69002 Lyon, France
c
Service d’Accueil des Urgences, Hôpital Rangueil, CHU de Toulouse, Université Toulouse III —
Paul-Sabatier, INSERM UMR 1027 Équipe 5, 31400 Toulouse, France
d
Laboratoire de Biochimie, Hôpital Bichat-Claude-Bernard, HUPNVS, Assistance Publique des
Hôpitaux de Paris (AP—HP), 75018 Paris, France
e
Laboratoire de Biochimie et Hormonologie, Hôpital Tenon, HUEP, Assistance Publique des
Hôpitaux de Paris (AP—HP), 75020 Paris, France
f
Service de Cardiologie, Hôpital Avicenne, HUPSSD, Assistance Publique des Hôpitaux de Paris
(AP—HP), 93000 Bobigny, France
g
Université Paris 13, 93000 Paris, France
h
Service d’Accueil des Urgences, Hôpital Tenon, HUEP, Assistance Publique des Hôpitaux de
Paris (AP—HP), 75020 Paris, France
i
Université Pierre-et-Marie-Curie, Paris 6, 75013 Paris, France
j
DHU ‘Fighting against ageing and stress’ (FAST), UPMC Paris 6, AP—HP, 75013 Paris, France
Received 7 May 2014; accepted 24 November 2014
Abbreviations: ACS, acute coronary syndrome; AMI, acute myocardial infarction; cTn, cardiac troponin; cTnI, cardiac troponin I; cTnT,
cardiac troponin T; CV, coefficient of variation; ECG, electrocardiogram; ESC, European Society of Cardiology; HAMA, heterophilic human
antimouse antibody; hs-cTn, high-sensitivity cardiac troponin; LBBB, left bundle branch block; LoB, Limit of Blank; LoD, Limit of Detection;
LoQ, Limit of Quantitation; NSTEMI, non-ST-segment elevation myocardial infarction; RCV, reference change value; ROC, receiver operator
curve; SFBC, Société française de biologie clinique; SFC, Société française de cardiologie; SFMU, Société française de médecine d’urgence;
STEMI, ST-segment elevation myocardial infarction; URL, upper reference limit.
∗ Corresponding author at: Laboratoire de Biochimie, GH Cochin-Broca-Hôtel Dieu, UPC, Assistance Publique des Hôpitaux de Paris (AP—HP),
27, rue du Faubourg-Saint-Jacques, 75679 Paris Cedex 14, France.
E-mail address: (C. Chenevier-Gobeaux).
http://dx.doi.org/10.1016/j.acvd.2014.11.001
1875-2136/© 2014 Elsevier Masson SAS. All rights reserved.
© 2021 Elsevier Masson SAS. Tous droits réservés. - Document téléchargé le 27/11/2021 Il est interdit et illégal de diffuser ce document.
, High-sensitivity cardiac troponin assays: Answers to frequently asked questions 133
KEYWORDS Summary Cardiac troponin (cTn) assays have quickly gained in analytical sensitivity to
Troponin; become what are termed ‘high-sensitivity cardiac troponin’ (hs-cTn) assays, bringing a flurry of
High-sensitivity; dense yet incomplete literature data. The net result is that cTn assays are not yet standardized
Myocardial and there are still no consensus-built data on how to use and interpret cTn assay results. To
infarction; address these issues, the authors take cues and clues from multiple disciplines to bring responses
Acute coronary to frequently asked questions. In brief, the effective use of hs-cTn hinges on knowing: specific
syndrome; assay characteristics, particularly precision at the 99th percentile of a reference population;
Chest pain factors of variation at the 99th percentile value; and the high-individuality of hs-cTn assays, for
which the notion of individual kinetics is more informative than straight reference to ‘normal’
values. The significance of patterns of change between two assay measurements has not yet
been documented for every hs-cTn assay. Clinicians need to work hand-in-hand with medical
biologists to better understand how to use hs-cTn assays in routine practice.
© 2014 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Résumé L’évolution rapide des méthodes de dosage des troponines cardiaques (cTn) vers
Troponine ; une meilleure sensibilité analytique (cTn de haute sensibilité, ou cTn HS) s’accompagne de
Haute sensibilité ; nombreuses données de la littérature mais encore incomplètes. En l’absence de standardisation
Infarctus du des cTn et de données consensuelles sur l’utilisation et l’interprétation des résultats, les auteurs
myocarde ; de cette revue proposent, à partir d’une revue de la littérature, et de façon multidisciplinaire,
Syndrome coronarien des éléments de réponses aux questions fréquemment posées. En conclusion, le bon usage
aigu ; des cTn HS repose sur la connaissance : des caractéristiques propres de la méthode utilisée,
Douleur thoracique en particulier de la précision obtenue au 99e percentile d’une population de référence ; des
facteurs de variation de la valeur du 99e percentile ; de la forte individualité des dosages de
cTn HS, pour lesquels la notion de cinétique individuelle est plus informative que la simple
référence à des valeurs usuelles. La significativité des variations entre deux dosages, n’est pas
encore documentée pour toutes les méthodes HS. La collaboration entre cliniciens et biologistes
est nécessaire à une meilleure utilisation des troponines au quotidien.
© 2014 Elsevier Masson SAS. Tous droits réservés.
Background ‘Question and Answer’ format to connect with grass-roots
practitioners, and is written to provide clinicians and biol-
International guidelines on myocardial infarction (MI) diag- ogists with the most routine-relevant conclusions possible,
nosis recommend running a cardiac troponin (cTn) assay in including a series of boxes headed ‘In practice/takeaways’,
suspected MI patients unless they present ST-segment ele- which recap the key messages.
vation (suspected lone-event non-ST-segment elevation MI
[NSTEMI]). The need to observe an increase in troponin over
the 99th percentile of a reference population together with
the significant assay-to-assay variation make it necessary to
Terms and definitions
use what are dubbed sensitive or hypersensitive cTn assays.
cTn assays are rapidly gaining in analytical sensitivity. Pub- What does assay sensitivity mean?
lished data on this latest generation of more sensitive assays
are dense, but are still incomplete. Furthermore, cTn assays An assay that qualifies as sensitive or hypersensitive (quali-
are not yet standardized and there are still no consensus- fiers arbitrarily grouped under the term ‘high-sensitivity’ in
built data on how to use and interpret high-sensitivity cTn this paper) is an assay that demonstrates greater analytical
(hs-cTn) assay results. sensitivity and precision than the conventional method it is
Given this context, three French academic societies built on. The word ‘sensitive’ refers to the assay, not to the
— the Société française de médecine d’urgence (SFMU) for biomarker itself.
emergency medicine, the Société française de cardiologie From an analytical standpoint, analytical sensitivity is the
(SFC) for cardiology and the Société française de biologie smallest measurable analyte concentration above the limit
clinique (SFBC) for clinical biology — have joined forces to of detection. Here, sensitivity is determined by the slope of
co-propose an integrated French-language document that, the calibration curve. Higher sensitivity increases the possi-
through a review of the literature, tackles the issue of how bility of getting low variations between two assays, as their
to use troponin assays properly. The document adopts a respective signals will be significantly different (Fig. 1).
© 2021 Elsevier Masson SAS. Tous droits réservés. - Document téléchargé le 27/11/2021 Il est interdit et illégal de diffuser ce document.
, 134 C. Chenevier-Gobeaux et al.
Precision, LoD and LoQ vary from cTn assay to cTn assay,
so they need to be verified by the laboratories and, if
appropriate, communicated to the clinicians, to optimize
the results interpretation process. Within the laboratory
competency accreditation framework (standard ISO 15189),
the analytical characteristics of hs-cTn assays are to be
verified as stipulated in document SH-GTA 04 (see ‘What pre-
cautions does the laboratory need to take when transitioning
to a hs-cTn assay?’).
In practice/takeaways
• The analytical precision of an assay is given by the
CV at a given analyte concentration.
• Analytical characteristics (sensitivity, precision, LoD,
LoQ) are assay specific.
Figure 1. Graphical comparison of the sensitivity of two assays.
Assay B sensitivity is higher than assay A sensitivity; it is easier to
detect a small difference of concentration between two measures What is an hs-cTn assay and are all hs-cTn
(black arrow) with assay B because the difference between observed assays essentially similar?
signals is higher for assay B (blue arrow) than for assay A (turquoise
blue arrow). An hs-cTn assay possesses better sensitivity and better ana-
lytical precision than the ‘conventional’ assay it is built on.
High-sensitivity assays offer 4-fold to 10-fold greater ana-
In other words, a method’s sensitivity is also its ability to
lytical sensitivity than conventional methods.
precisely and reliably differentiate between two different
Apple and Collinson short-listed two basic criteria for
concentrations.
defining whether a cTn assay is ‘highly sensitive’: precision
of a reference population; and proportion of measurable
In practice/takeaways concentrations in healthy individuals above the assay’s LoD
• The word ‘sensitive’ refers to the assay, not to the [2]. For an assay to qualify as’ high-sensitivity’, it has to
biomarker itself. demonstrate ≤ 10% total imprecision at the 99th percentile
• Analytical sensitivity is the smallest difference in value and be able to quantitate at least 50% of healthy indi-
concentration measurable by the assay. viduals [2].
cTn assays — whether high-sensitivity or conventional —
are still not standardized at this time. Standardization
efforts are hampered by a combination of factors, chiefly
the heterogeneity of the circulating cTn forms that the
assays can recognize, post-translational modifications to cTn
What does analytical precision mean? isoforms and immunoassay response modifications tied to
interferences and autoantibodies.
The analytical precision of an assay is an evaluation of the Compounding the issue, results do not directly corre-
degree of dispersion in serial test results on a single sample; late from technique to technique. In theory, the assays are
it is expressed as the analytical coefficient of variation (CV) equimolar, which means they should identically recognize all
of the assay, where CV = mean/standard deviation × 100, circulating forms. In practice, however, the distribution of
given as a percentage (%). Analytical precision splits into circulating cTn forms in a given patient at a given time can
a repeatability strand (intraseries precision) and a repro- vary, thus producing different responses in different assays.
ducibility strand (interseries precision). Consequently, the results given by different assays are not
A measurement method’s lower-range limits are defined directly transposable from test to test.
by: the Limit of Blank (LoB; the concentration below which The net result is that each assay method has its own char-
95% of results are expected to be found when replicates acteristics and its own cut-off thresholds (Table 1) [3—5].
[n > 60] of a sample containing no analyte [i.e. a biomarker- Consequently, it is vital that a patient’s cTn concentra-
free sample] are measured); the Limit of Detection (LoD; the tions are monitored with the same assay. The high-sensitivity
lowest detectable analyte concentration likely to be reliably assays add to a long list of conventional cTn assays. In most
distinguished from the LoB; it is determined based on the cases, the high-sensitivity method has replaced the conven-
LoB and the standard deviation of replicates of a sample tional assay (e.g. fourth-generation cTnT [cardiac troponin
containing a low, but non-zero, biomarker concentration); T] upgraded to hs-cTnT at Roche Diagnostics, ARCHITECT
the Limit of Quantitation (LoQ; the smallest value obtained cTnI [cardiac troponin I] upgraded to ARCHITECT hs-cTnI
at a predefined CV). In the specific subfield of cTn, and for at Abbott, etc.). The analytical modifications integrated in
conventional assay methods, 10% CV is the analytical limit high-sensitivity assays are patent protected and are rarely
adopted for MI diagnosis [1]. published.
© 2021 Elsevier Masson SAS. Tous droits réservés. - Document téléchargé le 27/11/2021 Il est interdit et illégal de diffuser ce document.
