Clinica Chimica Acta 456 (2016) 8992

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Clinica Chimica Acta

journal homepage: www.elsevier.com/locate/clinchim

The clinical utility of CK-MB measurement in patients suspected of acute

coronary syndrome
Jaehyup Kim, Ibrahim A. Hashim
a
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
b
Department of Pathology, Parkland Memorial Hospital, Dallas, TX 75390, USA

a r t i c l e i n f o a b s t r a c t

Article history: Background: This study aims to assess the clinical utility of CK-MB measurement in patients suspected of acute
Received 19 November 2015 coronary syndrome (ACS).
Received in revised form 24 February 2016 Methods: All CK-MB and troponin T measurements performed b 1 h apart during the study period were obtained
Accepted 29 February 2016 and analyzed for concordance. A total of 1214 cases with discordant biomarkers results were found. Retrospec-
Available online 2 March 2016
tive review of electronic health records (EHRs) was performed to assess the clinical impact, if any, of the discor-
dant biomarkers results.
Keywords:
Creatine kinase
Results: In 401 cases, CK-MB concentrations were increased whereas troponin T concentrations were negative at
Troponin b 0.01 ng/ml. In this group, clinical interpretations included, rhabdomyolysis, demand ischemia, and drug intox-
Acute coronary syndrome ication. No additional investigations for ACS were conducted in this group. Among the remaining 813 cases, tro-
ponin T concentrations were increased in the presence of a normal CK-MB result. In this group, the discordant
normal CK-MB lowered suspicion for ACS in only 22 cases (2.7%). Most common interpretations for isolated pos-
itive troponin were demand ischemia and impaired renal function. In most cases, discordant CK-MB results were
not considered a signicant nding.
Conclusions: In the setting of suspected ACS, CK-MB has limited clinical impact when contemporary troponin
assay results are available.
2016 Elsevier B.V. All rights reserved.

1. Introduction the population of interest should have troponin concentrations below

Cardiac biomarkers play a critical role in the initial screening and di-
agnosis of acute coronary syndrome (ACS) particularly in patients with
non-ST elevation myocardial infarction (NSTEMI). Creatine kinase iso-
form MB (CK-MB) has been the cornerstone of initial screening of pa-
tients with suspected ACS, however, troponins T and I became the
preferred screening test for ACS without ST elevation due to their higher
analytical sensitivity and specicity compared with CK-MB [14]. The
joint guidelines from the American College of Cardiologists (ACC) and
the American Heart Association (AHA) published in 2000 reect this
change that was later substantiated in a number of studies [57]. Tropo-
nin assays have since much improved in their analytical sensitivity and
specicity, leading to improved diagnostic and prognostic value shown
in several studies [8,9].
Contemporary troponin assays or high-sensitivity troponin assays
are characterized by improved analytical sensitivity with greater degree
of precision. According to consensus opinion, these assays should have
coefcient of variance b10% at the 99th percentile value of population
of interest [10,11]. Additionally, N50% of healthy individuals within
Corresponding author.
E-mail address: Ibrahim.Hashim@utsouthwestern.edu (I.A. Hashim).
99th percentile value but remain above the limit of detection [10,11].
With improvements in troponin assay, the most recent guideline
from AHA/ACC published in 2014 states that with the advent use of con-
temporary troponin assays, CK-MB measurements do not provide addi-
tional value for the diagnosis of ACS (Class III, Level of evidence A) [12].
However, despite current evidence recommending the use of tropo-
nin as the sole biomarker in patients suspected of ACS, CK-MB testing
remains widely used in the clinical assessment. While older guidelines
listed both troponin and CK-MB as acceptable biomarkers in the diagno-
sis of ACS, high-sensitivity troponin assays rendered the clinical signi-
cance of CK-MB assay questionable at best.
Unfortunately, information regarding the qualitative changes in
high-sensitivity troponin assay may not be readily available to clini-
cians, leading to reluctance in eliminating CK-MB testing in suspected
ACS cases. Given currently available data, CK-MB testing is unlikely to
add signicant information and may increase the cost of medical care.
Moreover, the discrepancy between troponin and CK-MB can lead to
confusion in the interpretation of biomarker results, leading to less
than optimal patient care.
In this study, we sought to assess the clinical utility of CK-MB assay
results in patients with suspected ACS when used in conjunction with
available high-sensitivity troponin T assay. Retrospective EHR review

http://dx.doi.org/10.1016/j.cca.2016.02.030
0009-8981/ 2016 Elsevier B.V. All rights reserved.
90 J. Kim, I.A. Hashim / Clinica Chimica Acta 456 (2016) 8992
was performed to determine if CK-MB results added any clinically valu-
able information and inuenced clinical decision-making.
2. Materials and methods
2.1. Study design
This is a retrospective review of electronic health record of patients
suspected of ACS and who have undergone both troponin T and CK-
MB testing during the same admission period. To reduce the effect of
temporal changes, we selected cases with measurement of troponin T
and CK-MB performed b 1 h apart (Fig. 1). Additionally, we disregarded
repetitive measurements performed within one week of admission.
However, if measurements were performed N 1 week apart, they were
considered part of a separate event and were included in the review.
For cases with discrepant troponin T and CK-MB results, clinical inter-
pretations were collected following EHR review. The study population
was from Parkland Memorial Hospital between August 2014 and
January 2015. This study was approved by the institutional review
board of the University of Texas Southwestern Medical Center, Dallas,
TX.
2.2. Participants
Patients suspected of ACS and who have been tested for both CK-MB
and troponin T during the same admission event between August 2014
and January 2015 were included into the study. Patients with discrepant
Fig. 1. Study inclusion criteria. CK-MB and troponin measurements performed within 1 h were reviewed for concordance. Repeat measurements were excluded if within less than 1 week.
Final cases with discrepant CK-MB and troponin measurement were selected for electronic health record review.
CM-MB and troponin T results were included for nal analysis and addi-
tional EHR review for clinical interpretation within 3 days of availability
of discrepant CK-MB and troponin T results.
2.3. Assay systems
Both CK-MB and troponin T measurements were performed using
the COBAS Immunoassay analyzer (Roche Diagnostics). Analysis was
according to the manufacturer's protocol. Troponin T concentrations
N0.01 ng/ml (99th percentile among general population) were
interpreted as positive troponin, whereas, CK-MB index N3 and or abso-
lute value N3 ng/ml in females or 5 ng/ml in males (which is the 97.5th
percentile among general population), was interpreted as positive CK-
MB. Gender specic reference intervals for CK-MB are obtained from
the manufacturer (Roche) and veried by the clinical laboratory.
3. Results
A total of 8980 CK-MB and 26,041 troponin T measurements were
performed during the study period. Cases were screened for discrepan-
cy between CK-MB and troponin results as depicted in Fig. 1. Patients
with discrepant biomarker results were identied for EHR review. Brief-
ly, CK-MB measurements were matched with troponin measurements
performed b 1 h apart (76.2% of these cases were performed on the
same sample). Repeat measurements within 1 week were excluded
from the study, but if measurements were N1 week apart, this was
regarded as a separate case and were included in the analysis. Finally,
 J. Kim, I.A. Hashim / Clinica Chimica Acta 456 (2016) 8992 91

cases (59.2%) with isolated troponin T increase with normal CK-MB

result did not result in additional intervention or new clinical
interpretation.

4. Discussion

Detection of myocardial injury in a timely manner is challenging but

Fig. 2. Number of cases where CK-MB test result changed management plan or affected
diagnosis. Change in management plan or diagnosis was determined by reviewing
medical chart within 3 days of test performance. If CK-MB result was listed as reason for
ruling out ACS or performing additional workup for ACS, the test was included in the
Change category. Percentage was calculated within respective group (CKMB negative,
troponin positive or CKMB positive, troponin negative).
a total of 1214 cases with discordant CK-MB and troponin T results were
identied for inclusion into the EHR review study. Out of the 1214 cases,
401 cases had increased CK-MB (either absolute concentration of
CK-MB or CK-MB index) with normal troponin T concentrations, where-
as 813 cases had increased troponin T concentrations with normal
CK-MB concentrations and CK-MB index. Detailed EHR review of each
of the 1214 cases was conducted to assess interpretation of cardiac bio-
marker measurements made by the clinicians within 3 days of tests
requests.
In cases with isolated elevation of CK-MB without high troponin
concentrations, none resulted in further workup for ACS. Among cases
with normal CK-MB and increased troponin T, CK-MB result affected
clinical decision in only 22 of the 813 cases (2.7%) (Fig. 2). Common in-
terpretation for isolated CK-MB elevation included rhabdomyolysis
(4.0%), demand ischemia (3.7%), drug intoxication (2.2%), impaired
renal function (1.0%) and stable angina (0.7%) (Table 1). However,
most of the cases (86.8%) did not have any interpretation or annotation
with respect to the increased CK-MB concentrations.
Among the 813 cases with increased troponin T without concomi-
tant CK-MB elevation, 68 cases (8.4%) were interpreted as having ACS
while demand ischemia was cited as the most likely cause in 113 of
the cases (13.9%) (Fig. 3). Other common interpretations for isolated
troponin T elevation included impaired renal function (10.7%), conges-
tive heart failure (5.5%) and cardiac intervention (1.1%). Most of the
its importance cannot be overemphasized given the high prevalence
of ACS and associated morbidity and mortality. The use of cardiac
biomarkers is an invaluable tool when investigating patients
suspected of ACS. CK-MB measurement began to gain attention as a
biomarker for myocardial damage in 1970s [13,14]. However, with
the availability of troponin assays in 2000s, troponin has become
the biomarker of choice. In 2014 joint guidelines from American
Heart Association (AHA) and American College of Cardiologists
(ACC) considered the value of CK-MB not to be high enough to warrant
testing if contemporary troponin assay is available [12]. However, the
use of CK-MB testing is still widespread in suspected ACS cases despite
the current guidelines.
The result from current study shows that the use of CK-MB results in
the setting of ACS did not impact clinical decision-making in the major-
ity of cases analyzed. Negative CK-MB results helped rule out ACS in
only 2.7% of cases with isolated troponin increase while none of the
cases with isolated CK-MB elevation lead to further ACS workup. Over-
all, CK-MB results failed to contribute much in identifying suspected
ACS cases and not performing CK-MB test is unlikely to lead to signi-
cant increase in false negative results.
According to the College of American Pathologist (CAP) participants
survey results (20132015), total number of testing platforms used for
CK-MB assay was about 3000 while that of troponin was 3600 (troponin
T and troponin I combined) [15]. Interestingly, for the past 2 years, num-
ber of troponin participants has been on the rise while the number of
laboratories offering CK-MB has been declining [15]. It must be men-
tioned that this information does not provide denite data regarding
assay volume or associated patient population and labs using multiple
testing platforms can skew result. However, it would be appropriate
to assume that troponin assay is at least as commonly available or
even more widely available than CK-MB and the use of troponin in the
setting of suspected ACS would not provide logistical challenges to
many medical centers.
While the current study is limited by the fact that it is based on
electronic health record review at a single medical center and that test
ordering behavior and test interpretation practice may not be generaliz-
able, it is notable that our review of large number of medical records
conrmed practice guideline proposed by AHA/ACC that CK-MB test is
of limited clinical value in the diagnosis/management of ACS. Also inter-
esting is the fact that while CK-MB is commonly ordered along with tro-
ponin, it is rarely interpreted, which again cast doubt on the usefulness
of CK-MB measurement in the setting of suspected ACS.

Table 1
List of interpretations for patients with discordant CK-MB and troponin T results. Some patients in CKMB negative, troponin positive group have multiple interpretations listed in the chart,
leading to sum of percentage N100%. Cases with acute kidney injury or chronic kidney disease have been combined into impaired renal function group (PCI: percutaneous coronary in-
tervention, CABG: coronary artery bypass graft, CPR: Cardio-Pulmonary Resuscitation).

CKMB positive, troponin negative Cases Percentage CKMB negative, troponin positive Cases Percentage

Total 401 100.0 Total 813 100.0

Rhabdomyolysis 16 4.0 Demand ischemia 113 13.9
Demand ischemia 15 3.7 Impaired renal function 87 10.7
Drug intoxication 9 2.2 ACS 68 8.4
Impaired renal function 4 1.0 Congestive heart failure 45 5.5
Stable angina 3 0.7 Cardiac intervention (e.g. PCI, CABG, CPR) 9 1.1
Cardiac intervention (e.g. PCI, CABG, CPR) 1 0.2 Drug intoxication 6 0.7
Post ACS 1 0.2 Post ACS 4 0.5
Congestive heart failure 1 0.2 Aortic dissection 3 0.4
Stable angina 3 0.4
Miscellaneous 3 0.7 Miscellaneous 13 1.6
No interpretation 348 86.8 No interpretation 481 59.2
92 J. Kim, I.A. Hashim / Clinica Chimica Acta 456 (2016) 8992
Fig. 3. Prevalence of acute coronary syndrome and demand ischemia among patients with
discrepant CK-MB and troponin T. Tests with interpretations suggesting demand ischemia
or new/recent onset ACS have been counted for each group.
Another point of potential concern is that current study analysis
included multiple assay results from the same patient in some
cases. This could confound calculation of true clinical signicance
of CK-MB but given the possibility that patients may develop new
episodes of ACS during the course of clinical care, including all of
the available assay results in the analysis was deemed preferable.
Furthermore, in many patients, interpretation relied on recent
trends from serial measurements, again supporting the inclusion of
multiple assay results from single patient into analysis.
While this study failed to nd supporting evidence for the use of CK-
MB, it must be mentioned that among patients undergoing percutane-
ous coronary intervention (PCI) or coronary artery bypass graft
(CABG), the use of CK-MB is still recommended for screening of new
ACS episode. Most studies have supported CK-MB elevation N 10 times
the upper limit of normal within population of interest as signs of clin-
ically relevant post PCI ischemic events but troponin is not generally
recommended due to high analytical sensitivity [16]. However, It was
reported that peak troponin values of 20 times the diagnostic concen-
tration has similar predictive value to CK-MB when N3 times the diag-
nostic concentration [17], which roughly translates into 1:7 ratio
between CK-MB and troponin concentrations. Extrapolation of this
would be troponin concentration N70 times the upper limit would
have similar predictive value with CK-MB increase N 10 times. However,
the clinical signicance of this stipulation has not been tested enough
and uncertainties remain regarding the appropriate role of troponin in
the setting of post PCI or post CABG. Since this study focused on the
management of patients with suspected ACS, not on those receiving in-
tervention, the role of CK-MB in the setting of coronary intervention
cannot be determined based on the result from current study. One inter-
esting observation from current study is that several patients have un-
dergone troponin measurement after receiving PCI or CABG despite
the lack of guideline supporting the use of troponin. This might be due
to the practice of ordering both CK-MB and troponin regardless of clin-
ical presentation, pointing to the need for improved and targeted test
usage based on clinical evidence.
In conclusion, considering the role of cardiac marker as screening
test, CK-MB measurement appears to have very limited clinical utility
in patients with suspected ACS when contemporary troponin assay is
available. While further study might be necessary to clarify the role of
CK-MB in certain clinical situations such as those receiving coronary in-
tervention, the use of CK-MB as an initial screening test for patient with
suspected ACS should be avoided when high-sensitivity troponin assay
is available.
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