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Articles |
1
Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115.
2
Department of Laboratory Medicine, Children’s Hospital,
Boston, MA 02115.
3
Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115.
a Address correspondence to this author at: Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. Fax 617-975-0990; e-mail damorrow{at}bics.bwh.harvard.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: We examined the efficacy of three cTnI assays for predicting death, myocardial infarction (MI), or the composite of death, MI, or urgent revascularization at 43 days among patients with non-ST-elevation acute coronary syndromes enrolled in the Thrombolysis In Myocardial Infarction (TIMI) 11B study.
Results: Six hundred eighty-one patients with serum samples
obtained at baseline and/or 12–24 h had cTnI determined using all
three assays. Baseline cTnI was 
0.1 µg/L for 368, 395, and 418
patients with the Bayer Immuno 1TM, ACS:180®,
and Dimension® RxL assays, respectively. Correlation
coefficients for the RxL with the ACS:180 and Bayer Immuno 1 results
were 0.89 (P = 0.0001) and 0.87
(P = 0.0001), with a coefficient of 0.92
(P = 0.0001) for the ACS:180 and Bayer Immuno 1
assays. Patients with cTnI 0.1 µg/L were at increased risk for
death or MI by 43 days (relative risk, 2.2–3.0; P
<0.0006), regardless of the assay used. This prognostic capacity
persisted among those with creatine kinase MB isoenzyme concentrations
within the reference interval. Moreover, cTnI was the strongest
multivariate predictor of death, MI, or urgent revascularization with
adjusted odds ratios of 2.1–2.9 (P <0.0006).
Conclusion: This study demonstrates the prognostic efficacy of three independently developed cTnI assays at a threshold of 0.1 µg/L for the prediction of adverse clinical outcomes among patients with non-ST-elevation acute coronary syndromes.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Multiple assays for cTnI have been approved by the Food and Drug Administration for clinical use and are available commercially. Furthermore, conformational changes in cTnI as it circulates as free, binary, or ternary complexes with troponins C and T (8)(15), and differences in the susceptibility of specific protein epitopes to degradation (8)(16) may variably alter the immunoreactivity of sites targeted by different immunoassay systems. Given that the impact of these factors is heterogeneous across individual assays, reported results for the same sample may vary up to 20-fold between the different analytical methods (8). This phenomenon is reflected in the diversity of decision limits used in clinical studies, as well as diagnostic thresholds offered by manufacturers.
This variability in decision limits may be a source of confusion for clinicians reviewing the clinical literature or moving between institutions that use different assays. However, until analytic methods for cTnI determination are better standardized, specific thresholds established for individual assays should not be generalized, and the clinical efficacy of each cTnI assay at a given decision limit should be established in well-conducted clinical studies (17). To provide a guide for clinical use, we thus sought to evaluate the performance of three commercially available cTnI assays for risk assessment in a cohort of patients with non-ST-elevation acute coronary syndromes participating in a contemporary clinical trial.
In its "Standards of Laboratory Practice: Recommendations for the Use
of Cardiac Markers" (18), the National Academy of Clinical
Biochemistry (NACB) has stated that detection of any myocardial injury
with a specific cardiac marker such as cTnI is clinically important and
warrants the incorporation of a low abnormal decision limit for the
optimum use of such markers in acute coronary syndromes. The NACB
expert committee has further recommended that this lower decision limit
for cardiac troponin assays be guided by the 97.5th percentile among
healthy controls or the minimum detectable concentration (MDC) when all
healthy individuals tested have cTnI concentrations below the detection
limit (18). We previously demonstrated the adverse prognosis
associated with increases in cTnI above 0.4 µg/L (MDC for the
Stratus® II assay, Dade Behring) among patients
with non-ST-elevation acute coronary syndromes in the Thrombolysis In
Myocardial Infarction (TIMI) IIIB clinical trial (9).
Application of a more recent generation of this assay (RxL
Dimension® troponin I; Dade Behring) in a
similar cohort of patients from TIMI 11B has shown that cTnI is a
robust predictor of poor early clinical outcomes at a threshold of 0.1
µg/L (19). We now extend our analysis of this population
with a simultaneous evaluation of the analytic and prognostic
performance of three current generation cTnI assays at a decision limit
equal to the 97.5th percentile for healthy controls or MDC (cTnI 0.1
µg/L) with respect to 43-day outcomes among patients with unstable
angina and NQMI enrolled in TIMI 11B.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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blood sampling and measurement of serum markers
The serum marker protocol specified that upon enrollment and
12–24 h later venous blood samples be drawn and serum stored at
-20 °C or colder at the enrolling site until shipped to the Core
Laboratory at Children’s Hospital Medical Center (Boston, MA) where
samples were then stored at -80 °C. Samples were thawed and
separated into several aliquots. cTnI was measured using the
Dimension® RxL cTnI assay (21) (Dade Behring) at Brigham &
Women’s Hospital (Boston, MA). cTnI was subsequently measured in the
Core Laboratory using the ACS:180®
Chemiluminescence cTnI Immunoassay (22) (Bayer Diagnostics,
Tarrytown, NY) and Bayer Immuno 1TM cTnI
Immunoassay (23) (Bayer Diagnostics) in aliquots having
undergone one additional freeze-thaw cycle.
dimension RxL cTnI ASSAY
The cTnI (TROP) method for the Dimension RxL system is a
colorimetric one-step sandwich immunoassay. The day-to-day precision of
this assay in our laboratory (Brigham and Women’s Hospital) at cTnI
concentrations of 0.57, 2.58, and 12.22 µg/L was reflected by CVs of
8.8%, 3.1%, and 1.5%, respectively. At a concentration of 0.1
µg/L, the SD was 0.027 µg/L, and the MDC was 0.04 µg/L. The
97.5th percentile for 197 healthy blood donors tested in our laboratory
was 0.1 µg/L. A threshold of 1.5 µg/L is suggested by the
manufacturer as consistent with acute myocardial infarction (AMI).
acs:180 cTnI ASSAY
The ACS:180 assay for cTnI is an automated system utilizing a
two-site sandwich immunoassay and direct chemiluminometric technology.
The day-to-day precision of this assay in the Core Laboratory at cTnI
concentrations of 1.1, 16.1, and 34.1 µg/L was reflected by CVs of
8.3%, 9.4%, and 8.7%, respectively. Data from the manufacturer show
a CV of 13% at 0.1 µg/L. The MDC was determined as 2 SD above the
mean signal for 37 replicate measurements of the zero calibrator in the
Core laboratory and was 0.1 µg/L. A diagnostic cutoff for AMI of 1.5
µg/L is suggested by the manufacturer. The 97.5th percentile among
158 healthy controls was given as <0.1 µg/L in data provided to us
by the manufacturer.
bayer immuno 1 cTnI ASSAY
The Bayer Immuno 1 system assay for cTnI is a heterogeneous
sandwich magnetic separation assay utilizing mouse monoclonal anti-cTnI
and goat polyclonal anti-troponin I antibodies. The day-to-day
reproducibility of this assay in the Core Laboratory at cTnI
concentrations of 0.2, 1.7, 7.1, and 49.9 µg/L was reflected by CVs
of 11%, 4.9%, 2.8%, and 2.8%, respectively. The MDC was 0.1 µg/L.
cTnI concentrations 0.9 µg/L with this assay have been observed by
the manufacturer to be indicative of AMI. The 97.5th percentile among
158 healthy controls was below the MDC for this assay in data provided
to us by the manufacturer.
clinical definitions
The diagnosis of the presenting ischemic syndrome for
patients enrolled in TIMI 11B was made by the site investigator on the
basis of WHO criteria for AMI, using serial measurements of CK/CKMB as
defined in the TIMI 11B protocol (20) and collected on the
Initial Hospitalization Case Report Form. A MI was considered to be
present at enrollment if any of the following criteria were met:
(a) CKMB above the ULN and 3% of total CK in samples
obtained at baseline or 
8 h after enrollment; (b) CKMB
was increased in the 16-h sample, and no ischemic discomfort >30 min
had occurred between study entry and the 16-h sample; (c)
total CK more than two times the ULN (if CKMB measurements
unavailable); (d) ECGs obtained at 8 or 16 h after
enrollment revealed new Q waves (>0.03 s) in two or more contiguous
leads (20). Patients presenting with an ischemic syndrome
without AMI by these criteria were diagnosed with unstable angina. The
definition of the clinical endpoint of MI for TIMI 11B was restricted
to new AMI occurring after the qualifying ischemic event and required
either new diagnostic Q waves or left bundle branch block not present
on the enrollment ECG or criteria for enzyme evidence of new infarction
(20). An increase of CKMB to above the ULN and at least 50%
over the prior value, or (if CKMB unavailable) re-elevation of total CK
more than two times the ULN and 25% of the previous value were
sufficient to meet enzymatic criteria for new AMI. For subjects within
24 h of coronary angioplasty or surgical coronary bypass grafting,
total CK or CKMB were required to be 50% of the prior value as well
as three and five times the ULN, respectively (20).
Participants were determined to have recurrent ischemia requiring
urgent revascularization if they suffered either recurrent angina that
prompted the performance of coronary revascularization during the same
hospitalization, or an episode of unstable angina after discharge that
led to repeat hospitalization and coronary intervention. All clinical
endpoints in TIMI 11B, including recurrent ischemia requiring urgent
revascularization, were adjudicated by an independent Clinical
Endpoints Committee incorporating a detailed review of relevant ECG
tracings, serum marker data, angiographic findings, and a narrative
summary.
statistical analysis
Statistical comparisons of baseline characteristics and clinical
outcomes were performed using the 
2 or Fisher
exact test for dichotomous variables and either the Wilcoxon rank-sum
or two-sample t-test for continuous variables. Agreement
between cardiac troponin results in the present substudy was evaluated
both as a continuous variable using a Spearman rank test and a Deming
regression analysis (24), as well as a dichotomous variable
utilizing a 
statistic or McNemar’s test for paired data. Analyses
were performed using baseline determinations of cTnI alone, as well as
results from the first 24 h after enrollment. Multivariate
analyses were performed using a logistic regression model incorporating
recognized cardiovascular risk factors (age, gender, history of
coronary artery disease, diabetes, hypertension, and smoking status),
ST depression, and congestive heart failure on presentation. Data
analyses were performed using SAS statistical software (Ver. 6.12; SAS
Institute). All statistical comparisons were two-tailed, and
P <0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) with a profile indicative of severe unstable ischemic heart
disease, and notable for ST-segment deviation on >70% of presenting
ECGs. Patients with increased cTnI (any of the three assays) were more
likely to be male and to have ECG abnormalities, especially ST
depression (0.5 mm or more), at presentation. They were less likely to
report a history of prior angina.
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cTnI RESULTS
In this high-risk population of patients with unstable angina or
NQMI, baseline cTnI values were abnormal (0.1 µg/L) for 368 (58%),
395 (62%), and 418 (66%) of patients with the Bayer Immuno 1,
ACS:180, and Dimension RxL assays, respectively. Among those patients
with unstable angina and available baseline samples (n = 322), the
number of individuals with increased baseline cTnI with the Bayer
Immuno 1, ACS:180, and Dimension RxL assays were 102 (32%), 119
(37%), and 148 (46%), respectively.
Strong positive correlation was evident between cTnI results from each
of the three assays. Spearman correlation coefficients for the
Dimension RxL with the ACS:180 and Bayer Immuno 1 assay baseline
measurements were 0.89 (P = 0.0001) and 0.87
(P = 0.0001), respectively, with a correlation
coefficient of 0.92 (P = 0.0001) for the ACS:180 and
Bayer Immuno 1 cTnI results. Regression lines for these relationships
are shown in Fig. 1
. Agreement between categorical (positive/negative) baseline
cTnI results was good to excellent (25) for the Dimension
RxL and Bayer Immuno 1 ( = 0.66), Dimension RxL and ACS:180
( = 0.73), and the ACS:180 and Bayer Immuno 1 ( = 0.78)
assays.
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clinical outcomes
Among the 681 patients with cTnI measurements, there were 30
deaths (4.4%) by 43 days. Fifty-three patients (7.8%) suffered a MI
after the qualifying index event, and 86 (12.6%) had recurrent
ischemia requiring urgent revascularization by 43 days. Final diagnoses
for the presenting symptoms made by the site investigators on the basis
of WHO criteria using CK/CKMB results were unstable angina for 50.7%
and NQMI for 42.4%, with <7% of participants being diagnosed with
Q-wave MI or non-cardiac chest pain.
Individuals with an increased cTnI as determined with each of the three
assays were at significantly increased risk for adverse clinical events
by 43 days, including a two- to threefold higher risk of suffering
death or MI (Table 2
). Similar risk relationships were evident when only the
baseline samples were used for prognostic assessment (Fig. 2
). Furthermore, among the subgroup of patients with unstable
angina, increased cTnI was a potent predictor of adverse outcomes
including death, MI, and the composite primary endpoint of death, MI,
or urgent revascularization by 43 days (Fig. 3
).
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In a regression model including clinical risk factors (age, gender,
history of coronary artery disease, diabetes, hypertension, and smoking
status) as well as ST-segment depression on the qualifying ECG and
evidence of congestive heart failure on admission, the prognostic
capacity of baseline values of cTnI persisted after adjustment for
these clinical variables (Table 3
). Moreover, regardless of the assay used, baseline cTnI was the
strongest prognostic indicator even after controlling for other
recognized predictors of cardiovascular risk (adjusted odds ratios of
2.2–2.9; P <0.0006).
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Of those individuals who suffered an adverse clinical event (death, MI, or urgent revascularization), baseline categorical results (positive/negative) differed between the ACS:180 and Dimension RxL for 13 (9.8%), of whom 10 had positive results with the Dimension RxL and negative with the ACS:180 (P = 0.05, McNemar’s test). Similarly, there were discordant results between the Dimension RxL and Bayer Immuno 1 assays for 16 patients, 15 of whom had positive results with the Dimension RxL (P = 0.001, McNemar’s test).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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0.1 µg/L (97.5th percentile of healthy controls
or MDC) as determined with each of these assays are predictive of
higher risk for adverse clinical outcomes by 43 days, including death,
MI, or recurrent ischemia prompting urgent revascularization. Moreover,
we found that the robust prognostic capacity of these three cTnI assays
persists after adjustment for multiple important clinical risk
indicators, including ST-segment deviation. This prognostic utility is
evident for each of these commercially available assays in spite of
analytic variability characterized in this report. The targeting of different protein epitopes by the unique anti-cTnI antibody components of each of the available cTnI immunoassay systems is responsible for much of the variation in the signal detected by these assays (26). Notably, disparity in the signal is influenced not only by diversity of the epitopes recognized but also by interaction between the locations of these protein regions and the actions of proteolytic enzymes causing degradation at both the COOH and NH2 termini of cTnI (26)(27). In addition, conformational changes resulting from the association of cTnI with troponins C and T in binary and ternary complexes may have differing effects on the accessibility of individual epitopes (8). As such, the establishment of a reference material based on a single cTnI complex type, (e.g., binary cTnIC), may allow calibration of individual assays with respect to a primary standard but will not eradicate all of the variation between assays that incorporate different antibodies (8)(28).
Although clinicians and clinical chemists must be cognizant of the intermethod variability and the current lack of standardization for cTnI assays, these factors do not obviate the clinical utility of cTnI as a prognostic marker, as evident in this report of data from TIMI 11B. However, one must be cautious about generalization of thresholds established for a specific assay. Until adequate cTnI standardization is possible, an evidence-based approach requiring investigation of individual thresholds for each available assay appears warranted (17).
Several large clinical studies have demonstrated the utility of cTnI
for risk stratification in various settings. Among patients with
non-ST-elevation acute coronary syndromes enrolled in TIMI III,
increased cTnI (0.4 µg/L) was associated with increased mortality
at 6 weeks after presentation (9). In addition, the
GUSTO-IIa Investigators observed that among 770 individuals with acute
coronary syndromes that included ST-elevation MI, cTnI
concentrations 1.5 µg/L (Stratus II; Dade Behring) at
enrollment identified those at higher risk for death by 30
days (7). Furthermore, the TRIM investigators
demonstrated that cTnI concentrations 2.0 µg/L (Opus;
Behring Diagnostics) were associated with higher 30-day
mortality among 516 patients with unstable angina (11). Now
the increased sensitivity of current generation cTnI assays has enabled
the evaluation of new lower decision limits for risk stratification. In
our current study, we demonstrated the clinical efficacy of the
Dimension RxL, ACS:180, and Bayer Immuno 1 cTnI assays at a decision
threshold of 0.1 µg/L (97.5th percentile of healthy controls or MDC
for each of the assays evaluated) for risk assessment among patients
presenting with non-ST-elevation acute coronary syndromes.
study limitations
The preferred method for determining the optimal prognostic
threshold for clinical use of the cardiac troponins has been a subject
of some debate. However, the current standard offered by the NACB
Standards of Laboratory Practice as a Class I recommendation is that
the low abnormal decision limit be "established for each marker on a
population of healthy individuals, using the 97.5th percentile (one
tail) of results" (18). Thus, we used this standard
embraced by the NACB Expert Committee on the Use of Cardiac Markers in
Coronary Artery Diseases in defining the predetermined decision limits
for this substudy. Although the utility of ROC curves for selection of
clinically optimal prognostic cut-points is not universally accepted,
we retrospectively constructed ROC curves for each of the troponin
assays (Fig. 4
), lending additional support for the thresholds used in this
study.
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Although cTnI concentrations above the MDC or 97.5th percentile were predictive of adverse clinical outcomes with each of the assays evaluated in this study, differences in analytic and clinical performance were detected and underscore the difficulties in generalizing clinical cut-points in the absence of adequate standardization for cTnI assay methods. It bears emphasizing that the prognostic decision limits utilized for each assay were selected independently and that although they converged on a common result, these data should not be extrapolated to other assays not evaluated in the clinical setting. Furthermore, this study was designed as a concurrent prognostic evaluation of three assays in current clinical use rather than as a direct method comparison and thus may be extrapolated to the latter only with limitations because testing conditions between methods were subject to minor variations. For example, as noted in Materials and Methods, the aliquots used for the ACS:180 and Bayer Immuno 1 cTnI determinations had undergone one additional freeze-thaw (-80 °C) cycle. Although data from the manufacturers demonstrating the stability of cTnI measurements with the ACS:180 and Bayer Immuno 1 assays across multiple freeze-thaw cycles (B. Bluestein, Bayer Diagnostics, Tarrytown, NY, personal communication) render it unlikely that this factor contributed significantly to variation between these and the Dimension RxL assay, we cannot exclude an impact. However, even allowing for this possibility, cTnI as determined with each of these assays was a strong predictor of outcomes.
Finally, one must maintain some caution in extrapolating our data using a low abnormal prognostic decision limit among patients with a high-risk clinical profile and unstable ischemic heart disease to a more heterogeneous population of patients presenting with chest pain syndromes. However, it is interesting to note that using a point-of-care device (Spectral Diagnostics) with a similar low range detection limit of 0.1 µg/L, Hamm et al. (29) found that a positive cTnI among patients presenting to an emergency department with chest pain was associated with higher risk for cardiac death or nonfatal MI over a follow-up of 30 days.
In conclusion, cTnI is a highly specific and sensitive marker of myocardial necrosis with documented utility for risk assessment in unstable coronary disease. Analytic variability between multiple available assays requires that specific decision limits proposed for clinical use be evaluated for each assay in well-conducted clinical studies. Our report responds to this mandate, demonstrating the clinical efficacy of three current generation commercially available cTnI assays at a threshold of 0.1 µg/L for risk stratification in non-ST-elevation acute coronary syndromes.
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Acknowledgments |
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Footnotes |
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References |
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The following articles in journals at HighWire Press have cited this article:
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NACB WRITING GROUP MEMBERS, D. A. Morrow, C. P. Cannon, R. L. Jesse, L. K. Newby, J. Ravkilde, A. B. Storrow, A. H.B. Wu, R. H. Christenson, NACB COMMITTEE MEMBERS, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes Clin. Chem., April 1, 2007; 53(4): 552 - 574. [Full Text] [PDF]
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J. A. de Lemos, D. A. Morrow, C. M. Gibson, S. A. Murphy, M. S. Sabatine, N. Rifai, C. H. McCabe, E. M. Antman, C. P. Cannon, and E. Braunwald The prognostic value of serum myoglobin in patients with non-ST-segment elevation acute coronary syndromes: Results from the TIMI 11B and TACTICS-TIMI 18 studies J. Am. Coll. Cardiol., July 17, 2002; 40(2): 238 - 244. [Abstract] [Full Text] [PDF]
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G. C. Wong, D. A. Morrow, S. Murphy, N. Kraimer, R. Pai, D. James, D. H. Robertson, L. A. Demopoulos, P. DiBattiste, C. P. Cannon, et al. Elevations in Troponin T and I Are Associated With Abnormal Tissue Level Perfusion: A TACTICS-TIMI 18 Substudy Circulation, July 9, 2002; 106(2): 202 - 207. [Abstract] [Full Text] [PDF]
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D. Uettwiller-Geiger, A. H.B. Wu, F. S. Apple, A. W. Jevans, P. Venge, M. D. Olson, C. Darte, D. L. Woodrum, S. Roberts, and S. Chan Multicenter Evaluation of an Automated Assay for Troponin I Clin. Chem., June 1, 2002; 48(6): 869 - 876. [Abstract] [Full Text] [PDF]
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D. A. Colantonio, W. Pickett, R. J. Brison, C. E. Collier, and J. E. Van Eyk Detection of Cardiac Troponin I Early after Onset of Chest Pain in Six Patients Clin. Chem., April 1, 2002; 48(4): 668 - 671. [Full Text] [PDF]
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