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Clinical Chemistry 50:2

333338 (2004)

Proteomics and
Protein Markers

Rates of Positive Cardiac Troponin I and Creatine


Kinase MB Mass among Patients Hospitalized for
Suspected Acute Coronary Syndromes
Joseph C. Lin,1 Fred S. Apple,3* MaryAnn M. Murakami,3 and Russell V. Luepker2*
Background: Cardiac troponin I (cTnI) is a more specific
and sensitive biomarker than creatine kinase MB
(CKMB) for detection of myocardial damage. We report
the prevalence of positive cTnI and CKMB mass among
patients hospitalized with suspected acute coronary
syndrome (ACS) and the potential impact of use of
different reference cutoffs, particularly those proposed
by European Society of Cardiology/American College of
Cardiology (ESC/ACC) consensus guidelines, on rates of
diagnosis of acute myocardial infarction (AMI).
Methods: We analyzed 1719 consecutive patients with
suspected ACS admitted to an urban acute care hospital
over a 6-month period. Patients (>18 years of age) had at
least two separate sets of plasma biomarkers (cTnI and
CKMB) measured more than 1224 h after admission to
determine the potential rates of AMI based on different
biomarker cutoff concentrations.
Results: The prevalence of cTnI-positive cases ranged
from 10.6%, based on a cutoff of twice the ROC curve
(cTnI <1.2 g/L), to 25.0%, using the ESC/ACC-recommended 99th percentile cutoff (cTnI <0.1 g/L). The
prevalence of CKMB-positive cases ranged from 10.4%,
with the cutoff of twice the ROC curve (CKMB <10.0
g/L) to 21.7%, with the 99th percentile cutoff (CKMB
<3.9 g/L). Use of the 10% CV cutoff (cTnI <0.3 g/L
and CKMB <3.9 g/L) instead of the ROC cutoff produced a 26% increase in all cTnI-positive cases. Use of

the 99th percentile reference cutoff instead of the ROC


curve-derived cutoff produced an 85% increase in all
cTnI-positive cases. A substantial proportion of the
increase in total cTnI-positive cases was derived from
cTnI-positive/CKMB-negative cases: 71 (4.1%), 73
(4.2%), 98 (5.7%), and 209 (12.2%) of cTnI-positive cases
were CKMB-negative, as determined by the twice the
ROC, ROC, 10% CV, and 99th percentile reference
cutoffs, respectively. At the 99th percentile cutoffs, 8.8%
of cases were CKMB-positive/cTnI-negative.
Conclusions: Use of lower reference cutoffs for plasma
biomarkers, as recommended by ESC/ACC guidelines,
markedly increases the rates of cTnI-positive cases overall. A substantial proportion of the increase in total
cTnI-positive cases was derived from the creation of
additional cTnI-positive/CKMB-negative cases. CKMBpositive/cTnI-negative cases are likely false positive for
myocardial injury.
2004 American Association for Clinical Chemistry

Consensus guidelines from the American Heart Association, American College of Cardiology (ACC),4 and European Society of Cardiology (ESC) have endorsed the use
of serum or plasma cardiac troponins for the diagnosis of
acute myocardial infarction (AMI) (1 4 ). Revised criteria
predicated on cardiac troponins are based on their improved sensitivity and specificity over creatine kinase MB
(CKMB) (59 ) and their prognostic usefulness in patients
with acute coronary syndromes (ACS) (10 13 ). In the US,
there are numerous commercial cardiac troponin I (cTnI)
and T (cTnT) assays for the diagnosis of AMI, all with
various operating characteristics (14 ). However, hospitals
and emergency departments currently do not observe
uniform cutoff values for interpreting cardiac troponin assays, even for the same assay. Since the adoption of the

1
Division of Cardiology, Department of Medicine, University of Minnesota Medical School, and 2 Division of Epidemiology, School of Public Health,
University of Minnesota, Minneapolis, MN.
3
Department of Laboratory Medicine and Pathology, Hennepin County
Medical Center and University of Minnesota Medical School, Minneapolis,
MN.
*Address correspondence to these authors: Russell V. Luepker, Division of
Epidemiology, School of Public Health, University of Minnesota, 1300 South
Second St., Suite 300, Minneapolis, MN 55455 (fax 612-624-0315; e-mail
luepker@epi.umn.edu); or Fred S. Apple, Hennepin County Medical Center,
Clinical Laboratories P4-Lab, 701 Park Ave., Minneapolis MN 55415 (fax
612-904-4229; e-mail fred.apple@co.hennepin.mn.us).
Received August 29, 2003; accepted November 20, 2003.
Previously published online at DOI: 10.1373/clinchem.2003.026708

4
Nonstandard abbreviations: ACC, American College of Cardiology; ESC,
European Society of Cardiology; AMI, acute myocardial infarction; CKMB,
creatine kinase MB; ACS, acute coronary syndrome; and cTnI and cTnT,
cardiac troponin I and T, respectively.

333

1469 (85.5%)
1348 (78.4%)
1248 (72.6%)
1137 (66.1%)
112 (6.5%)
159 (9.2%)
195 (11.3%)
221 (12.9%)
71 (4.1%)
73 (4.2%)
98 (5.7%)
209 (12.2%)
Cutoffs are defined in the text.
a

183 (10.6%)
232 (13.5%)
293 (17.0%)
430 (25.0%)
cTnI 1.2 g/L; CKMB 10.0 g/L
cTnI 0.6 g/L; CKMB 5.0 g/L
cTnI 0.3 g/L; CKMB 3.9 g/L
cTnI 0.1 g/L; CKMB 3.9 g/L
Twice the ROC
ROC
10% CV
99th percentile

179 (10.4%)
298 (17.3%)
373 (21.7%)
373 (21.7%)

cTnI()/CKMB(),
n (%)
cTnI()/CKMB(),
n (%)
cTnI()/CKMB(),
n (%)
Total CKMB(),
n (%)
Total cTnI(),
n (%)
Cutoff concentrations

Table 1. Cardiac biomarker results for 1719 consecutive hospital patients admitted for suspected ACS.

Materials and Methods


Hennepin County Medical Center, a 400-bed urban teaching hospital that provides acute care for the city of
Minneapolis, MN, was the site of enrollment of patients
with symptoms suggestive of ACS, after Institutional
Review Board approval. From September 16, 2001,
through March 28, 2002, we enrolled 1719 unselected
consecutive patients who were being prospectively evaluated for AMI. Enrollment included patients presenting
with chest pain as well as other clinical features considered indicative of ACS. Final discharge clinical diagnoses
and electrocardiograms were not obtained. Waste blood
specimens collected from all 1719 patients were used for
analysis of cTnI and CKMB. As part of an Institutional
Review Board-approved substudy to address clinical outcomes and risk assessment, chart reviews allowed preliminary observations to be made about the presence or
absence of skeletal muscle injury in the cTnI-negative/
CKMB-positive group.
cTnI and CKMB mass were measured (Dade-Behring
Dimension RxL) in heparinized plasma specimens obtained from each patient at admission and serially at 4, 8,
12, and 24 h after admission (8 ). Maximum concentrations
for each assay obtained over the 24-h period were used for
analysis. A minimum of two serial samplings, with at
least one obtained at 12 h after presentation, was required.
For cTnI the manufacturers stated detection limit is 0.04
g/L. The ROC curve medical decision cutoff value for
AMI was 0.6 g/L (20 ). The 99th percentile of a
reference population was 0.1 g/L (21 ). The total imprecision cutoff representing a 10% CV was 0.3 g/L
(22 ). In addition, total imprecision was 8.5% at 0.6 g/L
and 13% at 0.15 g/L. For CKMB, the manufacturers
stated detection limit is 0.5 g/L, with a (total imprecision) 10% CV at 3.9 g/L as determined in our laboratory. The ROC curve medical decision cutoff value for
AMI was 5.0 g/L (23 ), and the 99th percentile of a
reference population was 3.9 g/L (21 ). Because the
lowest concentration for CKMB that demonstrates a CV
10% was below the 99th percentile, the same cutoff
concentration (3.9 g/L) was used for both limits.
Differences in mean maximum cTnI and CKMB concentrations between cTnI-positive/CKMB-positive and
cTnI-positive/CKMB-negative cases were compared by
Student t-test (two-sided). Throughout the study, a P
value 0.05 was considered significant. All statistical

cTnI()/CKMB(),
n (%)

cardiac troponin standard in clinical practice, some reports


have shown that the increased sensitivity and specificity of
cTnI and cTnT may yield substantially higher rates of AMI
diagnoses (1519 ). This is primarily attributable to the creation of additional AMI diagnoses from cases that test
positive for cTnI or cTnT but negative for CKMB. In this
study we evaluate the potential effects of use of various cTnI
cutoff concentrations on the rates of AMI diagnosis in a large
patient cohort with suspected ACS.

67 (3.9%)
139 (8.1%)
178 (10.4%)
152 (8.8%)

Lin et al.: cTnI and CKMB in Suspected ACS

Cutoffa

334

335

0.0001c
0.0001c
0.0001c
Cutoffs are defined in the text.
For cTnI()/CKMB() vs cTnI()/CKMB().
c
For cTnI()/CKMB() vs cTnI()/CKMB().
b

cTnI()/CKMB()

77.6 (53.0102.1)
65.8 (45.486.1)
60.6 (42.578.7)
21.6 (15.727.4)
15.9 (11.720.2)
14.9 (10.319.4)

cTnI()/CKMB()
P

Results

0.0001b
0.0001b
0.0001b
1.8 (1.32.2)
1.1 (0.91.3)
0.6 (0.50.7)

cTnI()/CKMB()

analyses were performed with SAS for Windows software, Ver. 8.02.

22.7 (15.629.9)
18.8 (12.824.7)
16.6 (11.321.9)

cTnI()/CKMB()
Cutoff concentrations

Mean (95% confidence interval), g/L

cTnI 0.6 g/L; CKMB 5.0 g/L


cTnI 0.3 g/L; CKMB 3.9 g/L
cTnI 0.1 g/L; CKMB 3.9 g/L

Cutoff

ROC
10% CV
99th percentile

Mean (95% confidence interval), g/L

CKMB
cTnI

Table 2. Maximum cardiac biomarker concentrations for 1719 consecutive patients admitted for suspected ACS.

Clinical Chemistry 50, No. 2, 2004

The mean (SD) age of the 1719 suspected ACS patients for
these admissions was 58.4 (14.7) years (median, 57.3 years;
range, 18 98 years). Of these patients, 57.1% (n 983)
were male. Whites accounted for the majority of these
admissions, comprising 52.1% of admissions. Blacks, Native Americans, Hispanics, and Asians comprised 30.3%,
7.0%, 3.3%, and 2.3% of admissions, respectively. Other
ethnicities accounted for 5.0% of admissions.
Of the 1719 suspected ACS admissions, 183 (10.6%),
232 (13.5%), 293 (17.0%), and 430 (25.0%) cases were
cTnI-positive, as determined by cutoffs based on twice the
ROC (cTnI 1.2 g/L), the ROC (cTnI 0.6 g/L), 10%
CV (cTnI 0.3 g/L), and the 99th percentile (cTnI 0.1
g/L), respectively (Table 1). Similarly, 179 (10.4%), 298
(17.3%), 373 (21.7%), and 373 (21.7%) were CKMB-positive, as determined by the twice the ROC (CKMB 10.0
g/L), ROC (CKMB 5.0 g/L), 10% CV (CKMB 3.9
g/L), and 99th percentile (CKMB 3.9 g/L) cutoffs,
respectively. Depending on which reference cutoff was
used, 6.512.9% of cases were cTnI-positive/CKMB-positive, whereas 4.112.2% of cases were cTnI-positive/
CKMB-negative. Therefore, compared with the ROC cutoff, the 10% CV cutoff yielded 26% more cTnI-positive
cases overall and 34% more cTnI-positive/CKMB-negative cases. Compared with the ROC cutoff, the 99th
percentile cutoff produced 85% more cTnI-positive cases
overall and 186% more cTnI-positive/CKMB-negative
cases. Furthermore, in the cTnI-positive/CKMB-negative
cases and in the overall cTnI-positive cases, we observed
113% and 47% increases in cases, respectively, between
the 10% CV and the 99th percentile cutoffs.
As reference cutoff concentrations decreased, no consistent pattern was observed in cTnI-negative/CKMBpositive cases, which comprised 3.9%, 8.1%, 10.4%, and
8.8% of all admissions, as determined by the twice the
ROC, ROC, 10% CV, and 99th percentile cutoffs, respectively. Table 1 also shows the total number of positive
cases when a cutoff of twice the ROC was used: 179 cases
(10.4%) were detected for CKMB and 183 cases (10.6%) for
cTnI, with an approximately equal number of cTnI-positive/CKMB-negative (n 71; 4.1%) and cTnI-negative/
CKMB-positive (n 67; 3.9%) cases.
Among cTnI-positive cases, the mean maximum cTnI
concentration for each hospital admission was 12 to 25
times higher (P 0.0001) in CKMB-positive than CKMBnegative cases (Table 2). Distribution analysis of maximum cTnI values by box plots (Fig. 1) demonstrated that
median values for maximum cTnI were substantially
higher among CKMB-positive than CKMB-negative cases:
6.2 vs 1.3 g/L, 3.7 vs 0.8 g/L, and 2.9 vs 0.3 g/L, as
determined by the ROC, 10% CV, and 99th percentile
cutoffs, respectively. Maximum cTnI concentrations for
cTnI-positive/CKMB-positive cases were skewed toward

336

Lin et al.: cTnI and CKMB in Suspected ACS

Fig. 1. Box and whisker plots representing maximum


cTnI concentrations in cTnI-positive/CKMB-negative
and cTnI-positive/CKMB-positive patients.
Boxes represent the 75th percentile, median, and 25th
percentile, respectively. The inset shows the entire range of
the findings.

much higher concentrations compared with those for


cTnI-positive/CKMB-negative cases.

Discussion
This study shows that of the 1719 hospital admissions to
an urban hospital for suspected ACS over a 6-month
period, there was an 17% prevalence [based on the 10%
CV cutoff used in clinical practice by the hospital (14 )] of
cTnI-positive cases. However, depending on which reference cutoff is chosen, this prevalence can be as low as
13.5% (ROC cutoff) to as high as 25% (99th percentile
cutoff; Table 1). Although the majority of these cTnIpositive cases were also CKMB-positive, the prevalence of
cTnI-positive cases that were CKMB-negative accounted
for 4.212.2% of all ACS admissions, which is nearly the
proportion of cTnI-positive/CKMB-positive cases (Table
1). It has been proposed that among ACS patients, troponin-positive/CKMB-negative cases probably represent
non-Q-wave or non-ST-elevation myocardial infarction
diagnosed by cTnI or cTnT that would have been diagnosed as unstable angina by CKMB (3 ). Thus, adoption of
lower biomarker reference limits, such as the 99th percentile cutoff endorsed by the ESC/ACC guideline (1, 2, 4 ),
produces additional cTnI-positive/CKMB-negative cases
that probably represent mild cases of AMI. Therefore,

lower biomarker reference cutoffs will contribute to increased rates of AMI diagnoses (1719 ). Any increases in
cTnI or CKMB above the different cutoff concentrations
were considered indicative of a MI. We acknowledge that
in clinical practice, careful review of the clinical data
would be prospectively included in the context of minor
biomarker increases before diagnoses were determined.
Determination of clinical outcomes was not part of this
study design, but the clinical significance of lowering the
MI cutoff to the 99th percentile has been supported by
studies that have demonstrated added risk stratification
for adverse outcomes at cardiac troponin concentrations
above the 99th percentile but below both the 10% CV and
the ROC curve cutoffs (12, 13, 24 ). In the current study,
this would have included an additional 137 patients (47%
increase) between the 99th percentile and 10% CV cutoffs
and an additional 61 patients (26% increase) between the
10% CV and ROC cutoffs, with an overall increase of 85%
between the ROC and 99th percentile cutoffs.
On the basis of the 99th percentile cutoffs, the prevalence of CKMB-positive cases among ACS patients in our
hospital was 21.7%. However, only 40% of these were
cTnI-positive. These cases should be considered representative of AMI. The specificity of cTnI for diagnosis of AMI
has been established as superior to that of CKMB

Clinical Chemistry 50, No. 2, 2004

(23, 25, 26 ). As such, 60% of the cases that were CKMBpositive in our study may be considered false positives for
AMI. Preliminary analysis of these CKMB-positive/cTnInegative cases suggests that they can be explained by the
presence of trauma, rhabdomyolysis, generalized seizures, myopathies, and other mechanisms of injury to
skeletal muscle that cause increases in CKMB in the
absence of myocardial damage (4 6, 26 ). Supporting our
categorization of these cases as false positive for myocardial injury, there is no literature to our knowledge that has
demonstrated a MI case that shows increased CKMB with
a normal cardiac troponin.
When only a single, maximum CKMB concentration is
used as a diagnostic biomarker for MI detection in the
clinical setting, for epidemiology trending, or for clinical
trial enrollment or endpoint criteria, caution is suggested
regarding the potential of false-positive CKMB results as
being indicative of and interpreted as myocardial injury.
Although not part of the current study design, trending
rising and falling CKMB patterns would likely assist in
distinguishing true-positive CKMB increases from falsepositive CKMB increases. Interestingly, when twice the
ROC cutoff concentrations for both CKMB and cTnI were
used, as are commonly used in clinical or epidemiology
trials, an approximately equal number of cTnI-positive/
CKMB-positive cases were identified overall, with no
difference found when the alternative biomarker was negative (Table 1). This observation again demonstrates how
event rates can be confounded based on biomarker cutoffs
that are used for study enrollment or endpoint criteria.
ESC/ACC consensus guidelines (1, 2 ), in agreement
with the IFCC (27 ), have specifically proposed that the
upper reference limit of normal for cardiac troponin measurements should be the 99th percentile of a reference
control group. Furthermore, it has been agreed on that all
cardiac troponin assays should meet a total imprecision of
10% CV at the 99th percentile. Therefore, in the clinical
setting of myocardial ischemia, any increase of cTnI or cTnT
during the first 24 h after the index event is considered an
appropriate criterion for the diagnosis of AMI (1 4, 27 ). In
the current study, serial sampling over 1224 h after admission was used to determine the maximum cTnI or CKMB
concentrations and, thus, to determine the rate of MI. Therefore, whether the patient was triaged as an inpatient or
outpatient would not impact the overall findings of our
study. Current commercial assays, however, cannot attain
the 10% CV imposed by standard requirements for precision (14 ). This shortcoming probably contributes to the lack
of uniformity among hospitals and emergency departments
in their adoption of reference cutoffs for the various commercially available cTnI and cTnT assays used to diagnose
AMI. It has been proposed that until 10% CV can be
attained at the 99th percentile reference limit, the lowest
concentration that produces a CV of 10% should be adopted
as the diagnostic cutoff (14, 25 ). Our study has demonstrated that adopting a 99th percentile reference cutoff for
cTnI, in compliance with the current ESC/ACC guideline,

337

may yield substantial increases in AMI diagnoses. Replacing


the ROC with 99th percentile reference cutoff would increase cTnI-positive cases by 85%. A more modest but
substantial increase of 26% in cTnI-positive cases would
result if the ROC cutoff is replaced with the 10% CV cutoff.
Our study has shown that depending on which reference cutoff is used, substantially different rates of AMI
may be attained, largely as a result of the inclusion of
additional cTnI-positive cases that are CKMB-negative.
The 99th percentile cutoff, compared with the ROC cutoff,
produced an 85% increase in cTnI-positive cases, with
69% of this increase derived from cases that are cTnIpositive/CKMB-negative. These cTnI-positive/CKMBnegative cases increased by 186% when the reference limit
was decreased from the ROC to the 99th percentile cutoff.
These data are consistent with results of previous studies,
which have shown that cardiac troponin assays yield
higher rates of AMI compared with CKMB because of the
classification of additional troponin-positive/CKMB-negative cases (15, 16 ). Our data underscore the importance
of choosing appropriate reference cutoffs for AMI diagnosis because they can potentially have profound effects
on the AMI rates that result. The cTnI assay used in the
current study (Dade-Behring Dimension) represents a
second-generation assay with good low-end analytical
precision characteristics (23 ). However, because different
cardiac troponin assays display variable imprecision at
the low concentration limit, the findings of our study
should not be translated to other assays without confirmation (14 ). However, we anticipate similar trends of
increasing numbers of increased MI rates based on increased cardiac troponin findings for all cardiac troponin
assays compared with CKMB (28 ).
In this study we do not present actual clinically diagnosed AMIs, but biomarker diagnoses, with special attention given to the prevalence of positive cTnI among
suspected ACS admissions. This may perhaps be the main
limitation of our study because cTnI can become positive
in any pathologic condition that causes myocardial damage, such as myocarditis and severe pulmonary thromboembolism, and not be truly representative of AMI (4
6, 26 ). Nevertheless, because our aim was to illustrate
how use of different reference cutoffs can produce markedly varied rates of AMI, our study using a large patient
cohort presents rates of positive cTnI among suspected
ACS patients to serve as estimates of biomarker-positive
AMI. It should be re-emphasized, however, that increases
in cardiac troponins specifically detect the presence of
myocardial injury and that these increases, in the clinical
setting of cardiac ischemia, define AMI (1 4, 25 ).
In summary, we have shown that use of lower reference
cutoffs for plasma cardiac troponin, as recommended by
ESC/ACC and American Heart Association/ACC guidelines, markedly increases the rates of cTnI-positive hospitalizations for suspected ACS. A substantial proportion of
the increase in these cTnI-positive cases was derived from

338

Lin et al.: cTnI and CKMB in Suspected ACS

an increased number of cTnI-positive/CKMB-negative


cases. These findings serve to suggest that implementing
these guidelines for adopting lower biomarker reference
cutoffs may substantially increase rates of diagnosis of
AMI. Furthermore, we demonstrate a high false-positive
rate for AMI among CKMB-positive cases: approximately
one-half of them were cTnI-negative. Thus we recommend caution when only CKMB is used as a diagnostic
criterion. These findings could have an overall impact
regarding patient management, therapeutic decisions in
the assessment of risk in ACS patients, in medical reimbursement, in clinical trial outcomes, and in epidemiologic surveys for rates of detection of AMI.
This research was supported by Grant HL-65755 from the
National Institute of Neurological Disorders and Stroke (to
R.V.L.) and Grants HL-65293 (to R.V.L.) and HL-65293 (to
F.S.A.) from the National Heart, Lung, and Blood Institute.

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