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Articles |
1
Departments of Pathology and
2
Medical and Research Technology, University of Maryland School of Medicine, Baltimore, MD 21201.
3
Department of Pathology and Laboratory Medicine,
Hartford Hospital, Hartford CT 06102.
4
University of Tennessee Medical Center at Knoxville,
Dynacare-Tennessee, Knoxville, TN 37920.
5
Department of Laboratory Medicine and Pathology,
Hennepin County Medical Center and University of Minnesota School of
Medicine, Minneapolis, MN 55415.
6
Ischemia Technologies, Denver, CO 80221.
a Address correspondence to this author at: Clinical Pathology, University of Maryland Medical Center, 22 South Greene St., Baltimore, MD 21201. Fax 410-328-5880; e-mail
rchriste{at}umaryland.edu.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: We enrolled 256 acute coronary syndrome patients at four medical centers. Blood specimens were collected at presentation and then 6–24 h later. The dichotomous decision limit and performance characteristics of the ACB Test for predicting troponin-positive or -negative status 6 h-24 h later were determined using ROC curve analysis. Results for 32 patients could not be used because the time of onset of ischemia appeared to have been >3 h before presentation or was uncertain. The reference interval was determined by parametric analysis to estimate the upper 95th percentile of a reference population (n = 109) of ostensibly healthy individuals.
Results: Increased cTnI was found in 35 of 224 patients. The ROC curve area for the ACB Test was 0.78 [95% confidence interval (CI), 0.70–0.86]. At the optimum decision point of 75 units/mL, the sensitivity and specificity of the ACB Test were 83% (95% CI, 66–93%) and 69% (95% CI, 62–76%). The negative predictive value was 96% (95% CI, 91–98%), and the positive predictive value was 33% (95% CI, 24–44%). The within-run CV of the ACB Test was 7.3%. Results for the reference population were normally distributed; the one-sided parametric 95th percentile was 80.2 units/mL.
Conclusions: This exploratory study suggests that the ACB Test has high negative predictive value and sensitivity in the presentation sample for predicting troponin-negative or -positive results 6–24 h later.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The release of currently used myocardial markers into the circulation is believed to require tissue necrosis, whereas the assessment of cardiac ischemia before or in the absence of cell death is frequently an important component of clinical decision-making in the suspected acute coronary syndrome patient (1). The diagnostic performance of commonly used ischemia/coronary artery disease tests must be viewed as imperfect. For example, serial or continuous monitoring electrocardiogram recordings often are used to detect evolving changes of ischemia at rest (1), but the diagnostic benefit has not been confirmed, nor have large randomized studies in appropriate clinical settings been performed. Rest photon emission computed tomography has been reported as a safe and effective tool for assessing acute ischemia (9), but its sensitivity is limited by the requirement that the contrast agent be injected during active chest pain (1). With regard to biochemical markers of ischemia, initial data for glycogen phosphorylase-BB were encouraging (10), but these results have not been confirmed. A sensitive biochemical marker of ischemia would be clinically useful (2)(11)(12), and currently no such marker exists.
Recently, a novel biochemical test has been developed based on the binding between serum albumin and the transition metal cobalt. This test, termed the Albumin Cobalt Binding (ACBTM) Test (Ischemia Technologies, Inc., Denver, CO) is based on observations that the binding of Co(II) is reduced in serum from acute coronary syndrome patients (13)(14). This decreased binding reflects changes to the NH2 terminus of albumin, the binding site for the transition metals Co(II), Cu(II), and Ni(II) (13)(14)(15). Conditions that can alter albumin’s N-terminal region, and therefore albumin cobalt binding, can occur within minutes of an ischemic event via induced endothelial and extracellular hypoxia, acidosis, free radical injury, and sodium and calcium pump disruptions (16)(17)(18)(19). This effect on albumin could be detectable up to 6 h after the ischemic event (16)(17)(18)(19). The ACB Test may be a very early indicator of myocardial ischemia before necrosis.
The main objective of this study was to describe the performance characteristics of the ACB Test in suspected acute coronary syndrome patients who presented to a medical institution early after the onset of ischemic events. There is no "gold standard" for accurately assessing myocardial ischemia; therefore, we used cTnI in samples collected 6–24 h later in the course of care as a surrogate for cardiac ischemia at presentation. Using this strategy, we examined the ability of the ACB Test result for samples collected at presentation to predict a cardiac troponin-positive result in the subsequent 6–24 h timeframe, which reflects myocardial injury caused by ischemia, or a cardiac troponin-negative outcome 6–12 h after presentation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The protocol for this study was approved by each site’s local
Institutional Review Board.
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reference control subjects
A single serum or plasma specimen collected from 109 apparently
healthy individuals (55 men and 54 women; age range, 20–85 years) was
utilized to determine the 95th percentile of a control reference
population for the ACB Test.
study subjects
As indicated in Fig. 1
, 256 patients were recruited for this study in the 5-month
period between January and June 2000. All patients arrived at the
Emergency Department at participating centers within 3 h of
clinical signs and symptoms of acute coronary syndrome, as determined
by medical record review. All enrolled patients had blood collected
within 1 h of arrival, hereafter referred to as
"presentation", and at least one other specimen collected between 6
and 24 h later. The ACB Test and a cTnI assay were performed for
each presentation sample; all enrolled patients had a negative cTnI
result for this early sample, as classified by the cutoffs listed in
Table 1
. cTnI testing was also performed for all samples from the 6–24
h timeframe.
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The design of this study required knowledge of the timeframe and nature
of acute cardiac ischemia with as much confidence as possible. For this
reason, 32 of the 256 patients enrolled were excluded from analysis
because of uncertainties surrounding their clinical event. Of these 32
patients, 8 were excluded because MI may have occurred >3 h before
presentation, as indicated by increased values of other biochemical
markers, including myoglobin and/or cTnT at the time of admission.
Sixteen other patients were excluded because of uncertainty in that
their cTnI results did not match other biochemical marker data in the
6–24 h timeframe. In the remaining 8 of these 32 patients (Fig. 1
),
ACB Test results were negative at presentation, but cTnI results were
positive 12–24 h later. Categorization was indeterminate because no
specimen was available in the 6–12 h timeframe to determine whether
ischemia and MI had occurred by the time of presentation, in which case
the negative ACB Test would be classified as falsely negative, or at a
time after presentation, in which case the negative ACB Test result
would be classified as a true negative. The study population comprised
the remaining 224 patients included in data analysis.
specimen collection
Blood was collected in red-top or green-top Vacutainer Tubes,
containing no anticoagulant or containing lithium heparin,
respectively. Specimens were routinely centrifuged within 2 h of
collection for 10 min at 1000g, and serum or heparinized
plasma was harvested. Specimens were stored at 2–8 °C for a maximum
of 2 weeks; if a delay in testing was anticipated, samples were frozen
at -20 °C or colder within 96 h. Frozen samples were mixed
thoroughly after thawing and recentrifuged before analysis. Specimens
handled in this way showed no significant loss of recovery (data on
file). Repeat freeze-thaw cycles were avoided.
cTnI assays
The assays used at individual sites are listed in Table 1
. The
characteristics of the Abbott AxSYM cTnI system (Abbott Diagnostics
Inc., Abbott Park, IL) (20), the Dimension RxL cTnI system
(Dade-Behring, Inc, Glasgow, DE) (21), and the Vitros ECi
cTnI (Ortho Clinical Diagnostics, Raritan, NJ) (22) have
been reported previously. The typical imprecision (CV) of each
troponin assay was <8% at the cutoffs listed in Table 1
.
Patients were considered troponin positive if any sample collected
during the 6–24 h period exceeded the institutional cutoff listed in
Table 1
.
sample preparation for the acb test
Serum or heparinized plasma (500 µL) was added to a centrifuge
tube containing 0.45 g of CaCl2. Without
premixing, the sample and
CaCl2 were centrifuged for 10 min at
1000–1200g. After centrifugation, 300 µL of the resulting
supernatant was transferred to a COBAS MIRA or FARA sample cup (Roche
Diagnostics), taking care not to resuspend the
CaCl2. This pretreatment procedure was performed
to remove chelators used as preservatives that might be present in
samples from patients receiving intravenous medications.
acb test
All measurements were performed using either the COBAS MIRA or
FARA instrument systems (Roche Diagnostics); Table 1
lists the
instrument system used at each site. Maintenance and operation of
instruments were performed in accordance with the manufacturer’s
specifications.
In the ACB Test method, 95 µL of a patient’s sample and 5 µL of Co(II), in the form of cobalt chloride, are incubated in the instrument cuvette for 5 min. During incubation, the Co(II) (final concentration, 0.58 mmol/L) binds to the NH2 terminus of unaltered albumin in the sample; albumin for which the NH2 terminus is altered as a result of ischemic processes binds the added Co(II) to a far lesser extent (13)(14). After incubation, 25 µL of dithiothreitol is added to the mixture. Dithiothreitol (final concentration, 1.67 mmol/L) forms a colored complex with Co(II) that is not bound at the NH2 terminus of albumin, and this complex can be measured spectrophotometrically at 500 nm. The ACB Test results were obtained from a calibration curve produced using five calibrators with assigned ACB Test values of 6–186 units/mL. The ACB Test was designed so that all samples are measured in duplicate, with the higher reading being the result of the assay.
reproducibility
The imprecision (CV) of the ACB Test was calculated from
the duplicate results for each sample at each test site.
categorization criteria of the acb test results
A flow chart showing the categorization of patients in the study
is shown in Fig. 1
. If the ACB Test was equal to or above the cutoff
from ROC curve analysis, then the result was positive; otherwise the
test result was negative. True-positive results occurred when the ACB
Test was positive and the cTnI result for the subsequent 6–24 h
sample(s) was also positive. A true-negative result occurred when the
ACB Test was negative and the cTnI result was also negative for the
next sample(s) collected within the subsequent 6 to 12 h. A
false-positive result occurred when the ACB Test was positive but the
cTnI results for samples collected in the subsequent 6–24 h were
negative. A false-negative result occurred when the ACB Test was
negative and the cTnI result within the subsequent 6–12 h was
positive.
statistical methods
ROC curve analysis and calculation of the area under the curve was
done for the ACB Test in the 224 patients included in the study
population according to the method of Hanley and McNeil
(23). The optimum cutoff for the ACB Test was selected from
the ROC analysis to minimize the number of false-positive and
false-negative results in this study population. This optimum cutoff
was used to dichotomously classify each patient as ACB Test positive or
ACB Test negative. Diagnostic sensitivity, specificity, positive
predictive value (PPV), and negative predictive value (NPV) were
calculated to determine the ability of the dichotomous ACB Test value
at presentation to predict a later positive or negative troponin value
at 6–24 h after presentation. The exact 95% confidence intervals
(95% CIs) were calculated using binomial distribution statistics.
Goodness of fit to a gaussian distribution for the ACB Test
results for the control reference population was evaluated using the
2 method. The upper 95th percentile ACB Test
value for apparently healthy individuals was calculated using
parametric statistics. The Wilcoxon rank test was used to compare the
ACB Test values between the cTnI-positive and cTnI-negative patients.
P <0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Table 1
also shows that the CVs for the ACB Test at each site were similar
(mean CV, 7.3%; range, 6.0–8.7%).
The ACB Test values for the control reference population are shown in
Fig. 2
. These data were normally distributed
(2 = 0.693; P = 0.9946).
Values for the control reference population (n = 109) were
25.7–84.5 units/mL (mean, 58.7 units/mL; median, 59.5 units/mL). The
upper 95th percentile was 80.2 units/mL.
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The baseline characteristics of the enrolled and excluded subjects are
displayed in Table 2
. ACB Test results for the 224 acute coronary syndrome patients
are shown in Fig. 3
. The top panel of Fig. 3
displays the distribution of the ACB
Test results that were used to plot the ROC curve shown in the bottom
panel of Fig. 3
. Differences in the ACB Test results between the
cTnI-positive and -negative patients (Fig. 3
, top panel) were highly
significant (P <0.00001). The area under the ROC curve
(Fig. 3
, bottom panel) was 0.78 (95% CI, 0.70–0.86). The optimum
decision point for the ACB Test was determined to be 75 units/mL, and
this decision limit was used in subsequent analyses.
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ACB Test data for the 32 patients excluded from this study are
displayed in Fig. 4
. These data were not analyzed because of issues described in
Materials and Methods.
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Categorization of the 224 patients is summarized in Fig. 1
. Table 3
displays truth tables for the ACB Test using a cutoff of 
75
units/mL. The data shown yielded a sensitivity for the ACB Test of 83%
(95% CI, 66–93%), a specificity of 69% (95% CI, 62–76%), a PPV
of 33% (95% CI, 24–44%), and a NPV of 96% (95% CI, 91–98%).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ROC curve analysis of the ACB Test results for suspected acute coronary
syndrome patients, all of whom were initially troponin negative at
presentation and either troponin negative or positive at 6–24 h after
presentation, was used to determine the optimum decision limit. At the
optimum cutoff, the sensitivity and specificity were 70–80%, and the
NPV was high at 96% (95% CI, 91–98%). The 75 units/mL optimum
cutoff for the ACB Test derived from ROC curve analysis was lower than
the 80.2 units/mL value representing the upper 95th percentile of the
control reference population included in this study. Although the
difference between the cTnI-positive and -negative groups was highly
significant, the ACB Test values between the groups overlapped (Fig. 3
, top panel). Use of an ACB Test cutoff of 75 units/mL was a balance
between maximizing sensitivity and the tradeoff of increasing
false-positive results. This lowered diagnostic specificity (69%) and
the PPV (33%). Overlap between high-risk (disease) and control
reference (non-disease) populations is not ideal but is also seen with
numerous useful diagnostic laboratory tests, including total
cholesterol, high-sensitivity C-reactive protein, and total creatine
kinase. Additional research is needed to determine the meaning of
positive ACB Test results.
As with any new marker, there were several issues and limitations that require additional research. One caveat is that the diagnostic performance must be viewed as preliminary because it was derived from the same study population that was used to determine the optimum ACB Test decision limit and for calculating diagnostic sensitivity, specificity, PPV, and NPV. These diagnostic parameters need to be confirmed in another group of acute coronary syndrome patients. A second issue is related to the fact that no reference standard for cardiac ischemia currently exists. For this reason, troponin-positive or -negative results 6–24 h after ACB Test performance was the surrogate outcome used for classification. This use of troponin required that the timeframe of acute cardiac ischemia be known with as much confidence as possible, necessitating exclusion of 12.5% of enrolled patients because of uncertainties in their clinical course. A third issue is that unlike troponin, ACB Test measurements do not indicate necrosis; rather, ACB measurements reflect modifications in the NH2 terminus of albumin produced by extracellular hypoxia, acidosis, free radical injury, and sodium and calcium pump disruptions (16)(17)(18)(19). Therefore, ischemia in the absence of necrosis may cause bias toward apparent false-positive ACB data by yielding a positive ACB Test result associated with a negative cTnI. Studies comparing the ACB Test with technologies such as rest and stress nuclear imaging may provide additional interpretive insight.
If these performance characteristics are confirmed, the high NPV of the ACB Test could allow clinicians to more safely and cost-effectively identify low-risk patients at the time of presentation at the Emergency Department. In this way, the ACB Test could have large impact for the estimated 8 million patients who present annually with symptoms suspicious for acute coronary syndromes (1). The ACB test could bring a new dimension to the care of acute coronary syndrome patients and would add substantially to troponin measurements, which have low diagnostic sensitivity (30–50%) in the first hours after presentation (24)(25). This early benefit of the ACB Test is important because the REACT study showed that the median time from onset of symptoms to presentation was only 2.0 h for acute coronary syndrome patients, with only 25% of patients delaying presentation longer than 5.2 h (26). The high sensitivity and NPV demonstrated by ACB Test results for samples collected at the time of presentation at the Emergency Department may substantially reduce delays in patient disposition from the 6–24 h required for reliable troponin-negative classification. Provided that the high NPV can be confirmed, the ACB Test could have an important role, either alone or in combination with markers of necrosis, in greatly reducing the inappropriate admission of low-risk patients.
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Acknowledgments |
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Footnotes |
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References |
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