EDITORIAL
European Heart Journal (2012) 33, 944–946
doi:10.1093/eurheartj/ehs009
Sensitive cardiac troponin assays: sense
and sensibility
Torbjørn Omland 1,2*
1
K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; and 2Division of Medicine, Akershus
University Hospital, Lørenskog, Norway
Online publish-ahead-of-print 16 February 2012
This editorial refers to ‘Early diagnosis of acute myocardial infarction in patients with pre-existing coronary
artery disease using more sensitive cardiac troponin
assays’†, by M. Reiter et al., on page 988
Is analytical improvement
mirrored in clinical advantages?
To meet the criteria defined in the universal definition of acute
myocardial infarction (AMI), sensitive assays for cardiac troponins
I and T have recently been introduced into clinical medicine.
Such assays are commonly understood to have a detection limit
,99th percentile of a reference population and a total imprecision
at the 99th percentile ≤10%.1 The analytical performance of these
assays, i.e. the detection limit and imprecision profile, is clearly
improved compared with previous generation assays.1 Among clinicians, however, there has been scepticism as to whether use of
more sensitive assays represents a clinically significant improvement.2 Initial clinical studies of patients with acute chest pain and
suspected acute coronary syndromes (ACS) demonstrated that
sensitive assays provide enhanced diagnostic accuracy, particularly
in patients with a short duration from symptom onset to hospital
admission.3,4 Thus, the principal advantage of the sensitive assays is,
not surprisingly given their name, the enhanced sensitivity to identify troponin elevation in early presenters. The enhanced sensitivity
comes at a cost, however, i.e. decreased specificity. This decreased
specificity has raised concerns among both emergency room physicians and cardiologists who fear that an increased rate of patients
with troponin elevation of causes other than ACS will complicate
triage in the emergency room and lead to overdiagnosis of AMI.
Moreover, there are concerns that use of sensitive troponin
assays with reduced specificity will lead to an increasing number
of requests for cardiological assessment of patients with an elevated troponin test result from other departments. It has also
been argued that the problem of decreased specificity has been
underestimated because published studies, in particular those
from specialized chest pain units or invasive centres, may not accurately reflect the patients seen in the emergency rooms of
general hospitals, where older patients with complex comorbidities and higher troponin levels are frequently seen.
Troponin levels in patients with
stable coronary artery disease
Studies using sensitive assays have demonstrated that cardiac troponins are frequently found circulating and elevated in a substantial
number of patients with a wide range of conditions other than
ACS. These conditions are commonly observed in the emergency
room, and include heart failure,5 chronic obstructive pulmonary
disease,6 and sepsis.7 Moreover, the great majority of patients
with stable coronary artery disease (CAD) have detectable levels
of cardiac troponin T, and .10% of such patients have levels
above the 99th percentile of a reference population.8 As a
history of CAD is common in patients presenting with acute
chest pain, and the pre-test probability of AMI in these patients
is high, it is important to establish the performance of sensitive
cardiac troponin assays for diagnosing AMI and ACS in this
patient group. Thus, the recent study of Reiter and co-workers9
addresses a number of pertinent questions that are highly relevant
for both emergency room physicians and cardiologists alike.
Diagnosing myocardial infarction
in patients with prior coronary
artery disease
The results reported by Reiter and colleagues are based on the
Advantageous Predictors of Acute Coronary Syndrome Evaluation
(APACE) study, an ongoing, multicentre prospective observational
study of patients presenting in the emergency room with chest
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Division of Medicine, Akershus University Hospital, NO-1478 Lørenskog, Norway. Tel: +47 40107050, Fax: +47 67968860,
Email: [email protected]
†
doi:10.1093/eurheartj/ehr376.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: [email protected]
945
Editorial
Figure 1 Release of cardiac troponins in patients with acute myocardial infarction (AMI): impact of previous coronary artery disease (CAD)
on diagnostic performance. Modified from Wu et al. with permission.12
pain suggestive of AMI. The primary results of the trial on the diagnostic performance of sensitive troponin assays were published in
2009.4 In the current report, the diagnostic and prognostic accuracy of a conventional fourth-generation cardiac troponin T assay
was compared with those of a sensitive assay for cardiac troponin
T and two sensitive assays for cardiac troponin I. Complete data
for all four assays were available from 1098 patients.
As expected, the incidence of AMI was significantly higher in
patients with a history of CAD than in those without such a
history. Confirming results in stable CAD, the authors found that
in patients without a final diagnosis of AMI, a diagnosis of prior
CAD was associated with higher median levels of cardiac troponins. The optimal diagnostic decision limits, according to receiver
operating characteristics analysis, were correspondingly higher in
patients with prior CAD (e.g. cardiac troponin T 30 ng/L vs.
20 ng/L in those with and without prior CAD). Importantly, in
patients with CAD, sensitive assays performed significantly better
than the fourth-generation cardiac troponin T assay, and there
were no significant differences in the overall diagnostic performance between the different sensitive assays.
Does the diagnostic accuracy
of troponin T and I differ?
A surprising observation in the study of Reiter and colleagues was
the finding that there were marked differences between the rates
of elevated cardiac troponin levels between the different assays.
Thus, 40% of patients without a final diagnosis of AMI but with a
history of CAD had elevated levels with the sensitive cardiac
troponin T assay, whereas the rates for cardiac troponin I elevation
were substantially lower, i.e. 15% and 13% for the two assays evaluated. The rate of troponin elevation at baseline with the sensitive
assays was substantially lower in those patients without a history of
CAD, but the pattern was similar, with a higher prevalence of
cardiac troponin T than cardiac troponin I elevation (18% vs. 9%
and 7%). Not unexpectedly, given the higher levels of cardiac
troponins in patients with stable CAD, the assay specificity was
lower for patients with prior CAD than those without. The
lower specificity was particularly pronounced for the sensitive
cardiac troponin T assay. Whether this pattern is based on real
pathobiological differences between troponin T and I or whether
it reflects differences between the reference groups of the
various assays, remains unclear. One strategy to address this question would be the use of an identical reference population for the
different assays evaluated. Given the relatively strong effects of age
and gender on circulating troponin levels in the population,10 and
the fact that current decision limits are based on younger populations than those patients typically presenting in the emergency
room with acute chest pain, the use of age-dependent decision
limits is likely to enhance diagnostic specificity, and probably
overall diagnostic accuracy.
Making sense of sensitive
troponin assays
The question many clinicians currently are asking is how best to
incorporate sensitive troponin assays in clinical practice. Existing
data clearly suggest that these assays provide a superior means
for early identification of patients with AMI, making other early
markers of myocardial injury redundant.4 By obtaining the
second troponin sample earlier than previously recommended,
e.g. after 2 h rather than after 6 h, the diagnostic process can
be speeded up.11 Using the absolute rather than a relative increase in troponin levels also appears to enhance diagnostic performance.11 Increased awareness of alternative causes of chronic,
low-grade troponin elevation, as well as thorough assessment of
the pre-test probability of AMI, history, and clinical symptoms
and signs, will be increasingly important for the correct interpretation of cardiac troponin test results. From this perspective, the
article by Reiter and colleagues on the impact of prior CAD on
diagnostic accuracy represents an important, new piece in the
946
puzzle of making sense of sensitive troponin assay test results in
patients with acute chest pain.
Conflict of interest: T.O. has received research support and
speaker honoraria from Roche Diagnostics and Abbott
Laboratories.
Editorial
7.
8.
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