658591

research-article2016
ACC0010.1177/2048872616658591European Heart Journal: Acute Cardiovascular CareSandoval et al.

EUROPEAN
SOCIETY OF
Review CARDIOLOGY ®

European Heart Journal: Acute Cardiovascular Care

High-sensitivity cardiac troponin 2018, Vol. 7(2) 120­–128

© The European Society of Cardiology 2016
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DOI: 10.1177/2048872616658591
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Yader Sandoval1,2, Fred S Apple3 and Stephen W Smith4

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Abstract
The term unstable angina has been conventionally applied to patients with myocardial ischemia without myocardial
necrosis. However, while the clinical context has remained constant over time, the biomarkers of myocardial injury and
acute myocardial infarction have evolved. High-sensitivity cardiac troponin assays have several key analytical differences
from prior cardiac troponin assay generations, which may alter the diagnosis and frequency of unstable angina, as well
as affect our understanding of previously developed risk stratification strategies. This document reviews the current
challenges in regards to unstable angina when using high-sensitivity cardiac troponin I and T assays.

Keywords
Unstable angina, acute coronary syndrome, myocardial infarction, cardiac troponin, high-sensitivity cardiac troponin

Received 13 April 2016; accepted 17 June 2016

Unstable angina (UA) is a clinical syndrome occurring
between stable angina and acute myocardial infarction
(AMI).1 Historically, various terms have been used to
describe this clinical syndrome, including impending coro-
nary occlusion, acute coronary insufficiency, intermediate
coronary syndrome, coronary failure, status anginosus, pre-
infarction angina, or crescendo angina.2–4 In 1989, in order
to facilitate communication, to improve decision-making
regarding both diagnostic tests and therapies, to provide a
basis for assessing clinical outcomes, and to ease the inclu-
sion of patients in clinical trials, a clinical classification of
UA was proposed.5 This classification, based on the prem-
ise of excluding AMI using serum enzymes (e.g. negative
creatine kinase MB (CKMB)), classified patients according
to severity, clinical circumstances, presence or absence of
electrocardiographic (ECG) changes, and the onset of
symptoms in relation to anti-ischemic therapy (Table 1).5,6
From a biomarker perspective, the term UA has been
CKMB were used as indicators of myonecrosis in order to
distinguish patients with AMI from those with UA.9
Subsequently, first-generation cardiac troponin (cTn) I and
T assays were operationalized as more sensitive biomarkers
of myocardial injury and AMI, replacing CKMB.
Measurement of cTn was shown to have a prognostic value,
with associated increasing risk with increasing cTn concen-
trations.9,10 The implementation of cTn assays led to the
identification of UA patients, as defined by negative
CKMB, but who also had increased cTn levels and obtained
more benefit from specific therapies than did patients with
negative cTn; these therapies include glycoprotein IIb/IIIa
1Divisionof Cardiology, Department of Medicine, Hennepin County
Medical Center, Minneapolis, MN, USA
2Minneapolis Heart Institute, Abbott-Northwestern Hospital,

conventionally applied to patients with myocardial ischemia Minneapolis, MN, USA

that does not result in myocardial necrosis. To support the
diagnosis of UA, studies dating back several decades
emphasized the need to document the absence of increased
3Department of Laboratory Medicine and Pathology, Hennepin
County Medical Center and University of Minnesota, Minneapolis,
MN, USA
4Department of Emergency Medicine, Hennepin County Medical Center

biomarker levels.3,7 While the clinical context has remained
constant over time, the biomarkers of myocardial injury
and AMI have evolved,8 leading to changes in the clinical
diagnosis, management, and risk stratification of patients
with UA. Initially, cardiac biomarkers such as total CK and
and University of Minnesota, Minneapolis, MN, USA
Corresponding author:
Yader Sandoval, Hennepin County Medical Center, 701 Park Avenue,
Orange Building 5th Floor, Minneapolis, MN 55415, USA.
Email: yader.sandoval@hcmed.org
Sandoval et al. 121

Table 1. The 1989 Braunwald classification of unstable angina.5

Severity Clinical circumstances

A. Secondary UA B. Primary UA C. Post-infarction UA

Develops in the presence of Develops in the absence Develops within 2 weeks
an extracardiac condition that of an extracardiac of acute myocardial
intensifies myocardial ischemia condition infarction
I. New onset of severe angina or IA IB IC
accelerated angina; no rest pain
II. Angina at rest within the past IIA IIB IIC
month, but not within the preceding
48 hours (angina at rest, subacute)

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III. Angina at rest within 48 hours IIIA IIIB IIIC
(angina at rest, acute)

Patients with UA may also be divided into three groups depending on whether angina occurs: (1) in the absence of treatment for chronic stable
angina; (2) during treatment for chronic stable angina; or (3) despite maximal anti-ischemic drug therapy. These three groups may be designated by
subscripts 1, 2, or 3, respectively. Patients with UA may be further divided into those with and without transient ST–T wave changes during pain.
UA: unstable angina.

Table 2.  Principal presentations of unstable angina.20

Categorization Presentation
Rest angina Angina occurring at rest and prolonged, usually >20 minutes
New-onset angina New-onset angina of at least Canadian Class Score (CCS) III severity
Increasing angina Previously diagnosed angina that has become distinctly more frequent, longer in duration, or lower
in threshold (i.e. increased by ⩾1 CCS class to at least CCS III severity)

inhibitors, enoxaparin, and the early invasive strategy of
coronary angiography.11–13
In recent years, analytically improved high-sensitivity
(hs) cTn assays have been increasingly adopted worldwide,
except in the United States (US), where they have not
yet been cleared for clinical use by the Food and Drug
Administration (FDA).14–16 These assays have several key
analytical differences from prior cTn assay generations
(designated as contemporary assays), which may alter the
diagnosis and frequency of UA, as well as affect our under-
standing of previously developed risk stratification strate-
gies for UA, which are based on the dichotomization of
patients into cTn-positive and cTn-negative cohorts.
UA in present major guidelines
In the US, the 2014 American Heart Association (AHA)/
American College of Cardiology (ACC) guidelines differ-
entiate non-ST-elevation myocardial infarction (NSTEMI)
from UA based on the presence or absence of increased cTn
measurements17 and recommend against (class III) the use
of CKMB and myoglobin for the diagnosis of acute coro-
nary syndromes (ACS) if contemporary cTn assays are
available.17 In Europe, where hs-cTn assays are available
and have class I recommendations for distinct 0- to 1-hour
and 0- to 3-hour rule-out protocols, the 2015 European
Society of Cardiology (ESC) Guidelines differentiate
NSTEMI from UA according to the presence of cardiomyo-
cyte necrosis.18 The 2015 ESC guidelines included a short
section addressing UA in the era of hs-cTn assays, in which
UA is defined as myocardial ischemia at rest or minimal
exertion in the absence of cardiomyocyte necrosis.18 The
World Health Organization (WHO) 2008–2009 revision
defines UA as being when there are new or worsening
symptoms of ischemia or changing symptom patterns and
ischemic ECG changes with normal biomarkers.19
In all major guidelines, a consistent definition for UA
exists that relies on a clinical presentation (Table 2)20 con-
sistent with UA and cardiac biomarkers below the deci-
sion limit. If using cTn, this limit refers to concentrations
under the 99th percentile. The ESC/American College of
Cardiology Foundation (ACCF)/AHA and World Heart
Federation have made substantial efforts to clarify the
nomenclature and classification of AMI in the Third
Universal Definition of Myocardial Infarction expert con-
sensus document21; however, UA in the context of hs
assays has not been fully addressed.
Furthermore, recognizing the continuum between UA
and NSTEMI, the 2014 AHA/ACC guidelines endorsed the
term “non-ST-elevation acute coronary syndromes” (NSTE-
ACS), partly because of the challenges in distinguishing UA
from NSTEMI at presentation, with the term NSTE-ACS
being practical as it encompasses both conditions.17
hs-cTn assays
An assay is labeled as hs according to the International
Federation of Clinical Chemistry (IFFC) if: (a) it measures
122 European Heart Journal: Acute Cardiovascular Care 7(2)
Figure 1.  Acute coronary syndromes, acute myocardial infarction, and unstable angina annual rates (including secondary discharge
diagnoses) according to American Heart Association statistics.24–34
cTn concentrations above the limit of detection (LoD) in
⩾50% of healthy subjects; and (b) it has a coefficient of vari-
ation (%CV) of ⩽10% at the 99th percentile.22 In contrast to
contemporary cTn assays, which measure cTn above the
LoD in ⩽35% of healthy subjects and most of which have a
%CV of between 10% and 20%, the ability to measure cTn
above the LoD in ⩾50% of healthy subjects refers to the
capacity of hs assays to detect, measure, and reliably report
very low concentrations below the 99th percentile.15,16,23 hs
assays are more precise at the 99th percentile upper reference
limit (URL), and measure with high precision concentrations
above the LoD of the assay, allowing for clinical reporting.
Challenges for researchers and
clinicians
Since the diagnosis of UA relies on the absence of myocar-
dial necrosis, its incidence depends on the analytical sensi-
tivity of the biomarker. Decades ago, the use of insensitive
enzyme biomarkers contributed to a higher incidence of
UA and a lower incidence of NSTEMI. In contrast, the
implementation of increasingly analytically sensitive cTn
assays has contributed to a higher incidence of NSTEMI
and a lower incidence of UA. In the US, the UA annual
event rate has been reduced by half, as shown in Figure
1.24–34 Taking into account secondary discharge diagnoses
and hospitalizations that received both UA/MI diagnoses,
UA represented 42% of all ACS in 2003, but only 28% of
all ACS in 2010.24,34 The advent of more sensitive cTn
assays for myocardial injury has contributed to the reclas-
sification of UA into AMI; however, other factors are
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involved, including changes in reimbursements polices and
greater care of patients in same-day chest pain units.24,34,35
D’Souza et al. recently assessed the proportions of each
component of ACS in an unselected population using a
contemporary cTnI assay and reported that 516 of 3762
patients had ACS, amongst which UA represented only 7%
(n = 37) (67% NSTEMI and 26% STEMI).36
While there has been a general expectation that the
adoption of hs assays may lead to the extinction of UA,37 it
needs to be recognized that: (a) each cTn assay, including
hs assays, is unique; and (b) studies comparing less analyti-
cally sensitive to more analytically sensitive assays should
be interpreted with caution. For example, Reichlin and col-
leagues studied the impact of introducing hs-cTnT on the
incidence of AMI.38 In their study, cTnT levels at presenta-
tion were above the 99th percentile in 22% of all patients,
in contrast to 36% using the hs-cTnT assay.38 The use of
hs-cTnT for adjudication resulted in an increase in the inci-
dence of AMI from 18% to 22% (from 198 to 242 events),
and the increase in AMI resulted in a reciprocal decrease in
the incidence of UA from 13% to 11% (from 151 to 122
events).38 This observation led to the concept that the adop-
tion of all hs-cTn assays would lead to a significant increase
in the proportion of patients with values above the 99th
percentile, as well as an increased incidence of AMI.23
Conversely, in the UTROPIA study (NCT02060760), in
which patients presenting to the emergency department had
simultaneous measurement of both a sensitive contempo-
rary cTnI and a hs-cTnI assays (both Abbott ARCHITECT),
no difference was observed in the overall proportion of
patients with increased cTnI concentrations above the 99th
Sandoval et al. 123
percentile (31% contemporary cTnI versus 26% hs-cTnI,
p = 0.09).39 The extent of new cTn increases will depend on
the analytical sensitivity of both the contemporary assay in
use and the high-sensitivity assay to be implemented; that
is to say, when transitioning from CKMB and early cTn
assays to novel hs-cTn assays, a marked increase in positiv-
ity rate (values >99th percentile) with a decrease in the inci-
dence of UA may be observed, whereas when transitioning
from sensitive contemporary cTn to hs-cTn assays, the
change may be attenuated or absent.
Using hs-cTn assays, there will be some patients in
whom the clinical diagnosis is UA, but who have chronic,
but stable (without a rise and/or fall), increased cTn values
above the 99th percentile due to such conditions as end-
stage renal disease or structural heart disease.15 This is an
important issue that has been ignored in the literature, as
highlighted by the International Federation of Clinical
Chemistry (IFCC) in their 2015 educational document
regarding hs-cTn assays.15 The detection of increased cTn
by hs assays in, for example, patients with chronic condi-
tions but without acute myocardial injury, is likely due to
the improved analytical sensitivity of hs assays, and such
patients may have chronic, stable increases of cTn.
In patients with stable, chronic heart failure and left
ventricular ejection fraction under 40%, the hs-cTnT
assay (LoD 1 ng/L, 99th percentile 12 ng/L) was shown to
have values above the 99th percentile in 50% (2032 of
4053) of patients without AMI, in contrast to 10% using
the contemporary cTnT assay.40 In a similar analysis
exploring the hs-cTnT assay (LoD 3 ng/L, 99th percentile
13.5 ng/L) in patients with chronic heart failure, based on
data from two large clinical trials including the Valsartan
Heart Failure Trial (Val-HeFT) and Gruppo Italiano per lo
Studio della Sopravvivenza nell’Insufficienza Cardiaca –
Heart Failure (GISSI-HF) trial, baseline values were
above the 99th percentile in 47.1% and 64% of patients
without AMI, respectively.41 In the PARAMOUNT clini-
cal trial examining patients with heart failure and pre-
served ejection fraction, hs-cTnT was above the 99th
percentile (14 ng/L) in 55% of patients.42 These studies
also highlight the heterogeneity observed in the upper ref-
erence limit of cTnT. Contrary to cTnI assays, which have
numerous manufacturers and will likely never be stand-
ardized,43 Roche Diagnostics has had the patent rights to
the cTnT assay and thus has been the only manufacturer
marketing it.16 There are two current generations of cTnT
in the marketplace: the fourth generation and the fifth
generation; the latter is marketed by Roche as the hs-cTnT
assay. Roche did have a calibration problem with their hs-
cTnT assay in 2011–2012, which led to a bias around and
below their 99th percentile.44 The fourth-generation and
the fifth-generation (hs-cTnT) assays are not harmonized;
this, along with the calibration correction that occurred in
2012, partially accounts for differences in the upper refer-
ence limit concentrations that have been published.
Similarly, in patients with valvular heart disease, cTn
increases above the 99th percentile may be observed. By
measuring cTn with a hs-cTnI assay (Abbott; 99th percen-
tile 26 ng/L) in stable patients with aortic stenosis, Chin
et al. demonstrated that 7.6–8.1% of patients had concen-
trations above the 99th percentile.45
Finally, in patients with advanced renal disease, cTn
measurements above the 99th percentile are also common.
deFilippi and colleagues studied both a prototype hs-cTnI
(Siemens Dimension Vista; 99th percentile 9 ng/L) and the
hs-cTnT (Roche; 99th percentile 14 ng/L) assays among
patients with stable chronic kidney disease (CKD) (n = 148),
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defined as those not requiring renal replacement therapy
who had a reduction in estimated glomerular filtration rate
of ⩽60 mL/min−1 × (1.73 m2)−1 based on the simplified
Modification of Diet in Renal Disease formula (excluding
stage 5 CKD, dialysis or kidney transplant), and demon-
strated that 38% and 68% of patients had values above the
99th percentile of the two respective assays.46 In stable
patients with stage 5 CKD undergoing either hemodialysis
or peritoneal dialysis (n = 55), Fahim et al. reported that
90% of patients had hs-cTnT concentrations above the 99th
percentile (14 ng/L).47 In a stable hemodialysis population,
50–90% of hs-cTnT concentrations were above the 99th
percentile, compared to <25% for the hs-cTnI assay.48,49
The ability to detect stable cTn patterns above the 99th
percentile using hs assays in numerous scenarios that
are not consistent with AMI creates a potential cohort of
patients who have chronic myocardial injury that may not
have a rise and/or fall that is consistent with AMI (acute
on chronic myocardial injury), but have a clinical context
that is consistent with UA. As we increasingly encounter
patients with myocardial injury due to other chronic condi-
tions, we must realize that in the right clinical context,
patients with increased cTn, but in the absence of new
dynamic cTn changes, can be diagnosed with UA. Based
on these concepts, a revised classification system is pro-
posed in Figure 2.
Conceptually, stable, chronic myocardial injury occurs in
the context of concomitant chronic comorbidities, such as
CKD, end-stage renal disease, or chronic congestive heart
failure, which lead to chronic cTn increases above the 99th
percentile without evidence of overt myocardial ischemia.
Stable, chronic myocardial injury may best be diagnosed if
cTn results were obtained in a non-emergent clinical setting,
such as in a clinic. From an analytical perspective, when
using hs-cTn assays, assay-specific delta change values will
need to be established with two serial cTn measurements
over a 1–2-hour period in order to improve the clinical spec-
ificity for differentiating stable, chronic myocardial injury
from an acute, evolving myocardial injury.
Among patients presenting with possible ischemic
symptoms, clinicians should obtain a detailed clinical his-
tory and examination, 12-lead ECG, serial hs-cTn measure-
ments, and assess the pre-test probability of having an ACS.
124 European Heart Journal: Acute Cardiovascular Care 7(2)
Figure 2.  Updated decision tree for patients presenting with possible ischemic symptoms in the absence of ST-segment elevation
using hs-cTn assays.
ACS: acute coronary syndrome; AMI: acute myocardial infarction; ECG: electrocardiogram; hs-cTn: high-sensitivity cardiac troponin; NSTEMI: non-
ST-segment elevation myocardial infarction; UA: unstable angina.
For diagnostic purposes, it should be emphasized that while
rule-out strategies using hs-cTn measurements have been
shown to have very high negative predictive values (NPVs)
and/or diagnostic sensitivities for AMI, such strategies do
not exclude UA.50–52 For example, using the hs-cTnT assay
(LoD 5 ng/L, 99th percentile 14 ng/L), Thelin et al. showed
that if the concentration on admission was under the LoD,
the NPV and diagnostic sensitivity for NSTEMI were 100%
and 100%, whereas for UA, they were 94% and 73%,
respectively.52
Patients with a typical history of UA and serial hs-cTn
under the 99th percentile, usually with other objective sup-
porting evidence, will have classic UA as traditionally
defined, while patients with chronic myocardial injury (hs-
cTn above the 99th percentile) without a significant rise
and/or fall but with a typical UA history may also be diag-
nosed as having UA (Figure 2).
Based on this paradigm shift, clinicians and researchers
should consider the issues described below:
1. Based on the challenges described above, studies
may differ in how they define/adjudicate UA,
emphasizing the need for consensus.
2. Due to the improved analytical sensitivity provided
by hs-cTn assays, the incidence of cTn-negative UA
has decreased and a reclassification of UA into
NSTEMI has occurred.
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3. Similarly, improved cTn assay analytical sensitiv-
ity has allowed for the detection of patients with
chronic myocardial injury, which by definition have
relatively stable chronic increases above the 99th
percentile over time. In a clinical setting consistent
with acute myocardial ischemia, these patients may
have acute on chronic myocardial injury, as demon-
strated by a dynamic rise and/or fall in cTn, and
be diagnosed with AMI. Alternatively, in the right
circumstances, they may have a stable increased
cTn pattern on serial measurements and may be
diagnosed with UA.
4. It is often challenging to determine whether a
patient has a stable, increased cTn pattern due to
chronic myocardial injury versus a late AMI pres-
entation, in which the rise and/or fall in cTn hypo-
thetically occurred prior to presentation, and
consequently there is a cTn plateau across serial
measurements.53
5. Pending consensus on how investigators define and
adjudicate UA, studies will be needed in order to
assess the contemporary epidemiology and risk of
UA and AMI using hs-cTn assays.
6. Each hs-cTnI and hs-cTnT assay has unique ana-
lytical characteristics (Figure 3), including a dis-
tinct assay-specific ability to measure values above
the LoD and the 99th percentile in stable patients.
Sandoval et al. 125
Figure 3.  Comparison of both 99th percentile values (blue circles) and percentage measurable concentrations (red boxes) in
a presumably healthy population for 19 cTn assays (high sensitivity, sensitive-contemporary, and point-of-care cTn assays) (with
permission from reference 22).
Therefore, the incidence rates of UA and AMI will
be dependent on the assay that is utilized.
7. With earlier-generation cTn assays, cTn-positive/
CKMB-negative patients were identified as benefit-
ting more than cTn-negative/CKMB-negative
patients from specific medical therapies/interven-
tions.11–13 Since hs-cTn assays allow for the detec-
tion of values above the 99th percentile in a
significant proportion of patients without acute
events (i.e. chronic myocardial injury), novel risk
stratification strategies (e.g. additional imaging,
novel biomarkers, etc.) and outcomes studies may
be necessary.
8. As the total imprecision (%CV) of cTn assays
improves, cTn concentration changes may be fol-
lowed at very low concentrations. Whether patients
with possible ischemic symptoms with dynamic
serial changes under the 99th percentile represent a
higher-risk cohort compared to patients with a sta-
ble pattern is uncertain.
9. Rule-out strategies using hs-cTn assays have
focused on ruling out AMI, not UA. Hence, UA
remains a clinical diagnosis.
10. As hs-cTn assays become increasingly used for pri-
mary and secondary prevention and are measured in
the outpatient clinic, awareness of cTn concentra-
tions in the stable outpatient setting will facilitate
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the evaluation of increased cTn measurements in
the emergency department, particularly when dif-
ferentiating chronic myocardial injury from a pos-
sible late AMI presentation.
Conclusion
In contrast to contemporary cTn assays, hs-cTn assays
have been shown to be both analytically and clinically
superior. hs-cTnI and hs-cTnT assays are more precise at
low concentrations, particularly at the 99th percentile
URL, and have been shown to expedite both the ruling in
and ruling out of AMI, hence reducing hospital costs and
overcrowding. As the analytical sensitivity of cTn assays
improves, a paradigm shift will occur in our understanding
of UA, such that patients with chronic myocardial injury
will be increasingly encountered for whom, in the right
clinical context, either AMI or UA may be diagnosed
depending on the presence or absence of new dynamic cTn
changes.
Conflict of interest
Yader Sandoval: no financial relationships. Non-salaried advisor,
Roche Clinical Diagnostics: non-financial support for a Roche
scientific meeting.
Stephen W Smith: consultant: Alere, Siemens. Advisor: Roche.
Fred S Apple:
126 European Heart Journal: Acute Cardiovascular Care 7(2)
-  Consultant: Phillips Health Incubator
-  Board of Directors: HyTest Ltd
-  Honorarium: Abbott POC Advisory Group
- Research through Minneapolis Medical Research Foundation
(MMRF), not salaried: Abbott Diagnostics, Roche Diagnostics,
Siemens Healthcare, Alere, Ortho-Clinical Diagnostics,
Trinity, Nanomix, Becton Dickinson
-  Other: associate editor of Clinical Chemistry.
Funding
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.
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