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Articles |
1
Academic Medical Center, Departments of Cardiology and
2
Clinical Chemistry, University of Amsterdam, The Netherlands.
a Address correspondence to this author, at: Department of Cardiology, Suite G3-231, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam. Fax 31-20-6915687.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Key Words: indexing terms: variation, source of • creatine kinase • isoenzymes • troponin T
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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New assays for early markers such as myoglobin, troponin T, and creatine kinase isoenzyme MB mass (CK-MBmass) are highly sensitive for the diagnosis of AMI (1)(4)(7)(8)(9). In addition, however, these assays can detect small amounts of marker release from the damaged myocardium, and the changes in marker values below the predetermined cutoff value for AMI may also be of diagnostic and prognostic importance (10)(11)(12)(13). This so-called minor myocardial damage is currently defined as an increased concentration of troponin T (>0.1 µg/L) and an increase and decrease of CK-MBmass concentrations that remain below the discriminating limit for AMI (11)(14)(15).
The question is, How large an increase of CK-MBmass can be considered abnormal? To answer this, one must first determine the normal variation between serial measurements in a reference population (of chest pain patients) in samples collected at relevant timepoints. Changes that exceed this normal variation between serial measurements—"significant changes," or the "critical difference," or the "reference change"—will depend on the biological, analytical, and preanalytical variation of the biochemical marker under study (16)(17). To our knowledge, the critical difference for CK-MBmass in patients presenting with chest pain but without AMI has not been studied. Therefore, we undertook to assess the critical difference for serial measurements of CK-MBmass in such patients, using frequent sampling in the first 24 h after the onset of symptoms. We also measured troponin T in the patients and compared the ability of that analyte to detect myocardial damage with the detection based on a change in CK-MBmass greater than this critical difference. The optimal timing for drawing blood samples within these first 24 h to detect myocardial damage was also assessed.
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Materials and Methods |
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The final diagnosis of AMI was established at hospital discharge, based on the patient's clinical history and symptoms, ECG abnormalities, and a typical increase and decrease in the CK-MBmass curve with the peak exceeding 15 µg/L (considering the results from all timepoints). Patients fulfilling these criteria for AMI were excluded from the study. The physicians making the diagnosis were unaware of the troponin T results. Some patients (n = 17) showed CK-MBmass gradually increasing to >7.5 µg/L but not exceeding 15 µg/L; they were included in the calculation of the critical difference (see Discussion).
Blood samples were drawn with an indwelling intravenous catheter at 3, 4, 5, 6, 7, 8, 12, 16, 20, and 24 h after the onset of symptoms. Blood was collected in 10-mL heparin-coated evacuated collection tubes. The samples were centrifuged twice at 1500g for 10 min and the cells were discarded; the plasma remaining was aliquoted and stored at -20 °C until further analysis.
laboratory analysis
CK-MBmass was measured with the immunochemical
method implemented on the ACS:180 analyzer (CIBA Corning, Houten, The
Netherlands). The detection limit was 0.65 µg/L and assay linearity
extended from 0 to 500 µg/L. Calibrators were supplied by the
manufacturer. The upper reference limit was 7.5 µg/L, and the cutoff
value for AMI was 15.0 µg/L.
Troponin T was measured with an ELISA (cat. no. 1289055) on an ES300 analyzer (all from Boehringer Mannheim, Mannheim, Germany); calibrators were supplied by the manufacturer. The upper reference limit was 0.1 µg/L, and the linearity range of this determination was 0–15 µg/L.
critical difference
For each patient the mean value for CK-MBmass and
the total coefficient of variation (CVt) was calculated
from the results from all timepoints. The critical difference (CD) was
calculated from the 50th, 75th, and 90th percentiles (17)
of the CVt values, as follows:
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indicates the 50th, 75th, or 90th percentile, as needed. Usually, the critical difference is reported for the median CV, with a probability of 95%, giving a z-value of 1.96. The preanalytical variation for the measurement of CK-MB is small (17) and can thus be neglected; therefore, CVt is assumed to consist of only the biological variation (CVb) and the analytical variation (CVa). Once the analytical variation is known, the biological variation can be calculated, given that CVt2 = CVb2 + CVa2.
If the probability of false alarm (the probability that a difference between two measurements is interpreted as indicative of myocardial damage when in fact it is not) is set at values from 0.5 to 0.01, probability curves (16) can be plotted for the CK-MBmass change for CVs for the 50th, 75th, and 90th percentiles.
analytical variation
The precision, or total reproducibility, was calculated from the
within-run, between-run, and day-to-day variation as described in NCCLS
EP5-T2 (18). We determined these values for four
concentration ranges by using EVAL-KIT Software (CKCHL, Tilburg, The
Netherlands).
statistical analysis
The change in CK-MBmass between 5 and 12 h
or between 6 and 16 h after the onset of symptoms was calculated
for each patient and reported as means ± SD. Differences were
analyzed with the Wilcoxon matched-pairs sign rank test. P
<0.05 was considered statistically significant.
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Results |
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The CVs and resulting CD values are summarized in Table 1
. The 50th percentile CV was 16.5%, the 75th percentile CV
26.2%, and the 90th percentile CV 48.8%. The critical differences
calculated with these CVs were CDp50 = 45.7%,
CDp75 = 72.6%, and CDp90 = 135.2%,
respectively.
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The total reproducibility (analytical variation) of CK-MBmass determinations at concentrations of 6.4, 9.1, 24.2, and 93.9 µg/L was 3.9%, 2.3%, 5.4%, and 4.5%, respectively. Because the analytical variation of the CK-MBmass assay in the lower concentration range (i.e., <15 µg/L) averaged 3.1%, the total variation in patients without AMI mainly consisted of the biological variation (median, 16.2%).
For biological variation of patients equal to the values for
CVp50, CVp75, and CVp90,
separate probability curves ("probabilities of false alarm") can be
drawn (Fig. 1
). The probability is shown on the y-axis, and the
relative difference between two measurements is given on the
x-axis. As can be seen, a >75% change in
CK-MBmass is below P = 0.01 for the
CVp50 curve and is at P = 0.05 for the
CVp75 curve. With this 75% difference, and with the mean
CK-MBmass value for all of the non-AMI patients determined
to be 2.7 ± 1.76 µg/L, we chose the cutoff value for the change
in CK-MBmass as 2.0 µg/L.
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For each patient, we plotted the CV and average
CK-MBmass from all timepoints during the 24 h of
blood collection and observation (Fig. 2
). Among the 110 patients, 23 had an increase in
CK-MBmass of >2.0 µg/L. Of these, 17 patients showed an
increase and decline in CK-MBmass concentration, with the
peak between 7.5 and 15 µg/L; the other 6 had an increase in
CK-MBmass of >2.0 µg/L but the peak was <7.5 µg/L.
Overall, of the 23 patients with CK-MBmass increased by
>2.0 µg/L, 18 also had an abnormal concentration of troponin T
(>0.1 µg/L) but 5 had normal troponin T values. On the other hand,
of the 87 patients with no critical increase in CK-MBmass,
only 4 patients had above-normal troponin T; the remaining 83 had
normal values for both markers.
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Of the 22 patients with an abnormal concentration of troponin T, 18 (82%) were identified by an increase in CK-MBmass >2.0 µg/L. One of these 22 patients had moderate renal dysfunction (serum creatinine 159 µmol/L); all the others—including the 4 patients with an abnormal troponin T but no critical increase in CK-MBmass—had normal renal function.
The increase in CK-MBmass >2.0 µg/L was evident at 8 h after the onset of symptoms in 14 patients and at 12 h in another 6 patients. One patient had a sudden, large (14.3 µg/L) increase in CK-MBmass at 24 h after the onset of symptoms. For two patients, CK-MBmass concentrations were greatest at admission. In the 87 patients without increases in CK-MBmass >2.0 µg/L, the variation in the CK-MBmass values was not random. Although one might expect the CK-MBmass concentrations to remain stable over time in these patients, in fact the CK-MBmass values declined between 5 and 12 h (from 2.45 ± 1.52 to 2.39 ± 1.57 µg/L; P = 0.008) and between 6 and 16 h (from 2.55 ± 1.60 to 2.22 ± 1.56 µg/L; P <0.001).
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Discussion |
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We determined the critical difference for CK-MBmass to be 2.0 µg/L on the basis of our CD75 of 72.6%, which was very similar to the CD90 in healthy individuals determined by Costongs et al. (17). Using this critical difference, we were able to identify 18 of 22 patients (82%) who had an abnormal concentration of serum troponin T.
The mean ± SD CV (21.4% ± 18.3%) we found in the non-AMI
patients was in the range of that reported (32.5%) for CK-MB activity
in selected patients in a retrospective study (19). The
median variation for CK-MBmass we determined, 16.5%,
resulting in a critical difference of 45.7%, was just slightly above
the value Costongs et al. reported for healthy subjects, 40.1%
(17). The CVP90 of 48.8% in our study results
in a critical difference of 135.2%, which is higher than that reported
for healthy subjects (72%) (17); however, as seen in Fig. 2
, most patients with a CV >40% had an average CK-MBmass
<2 µg/L. The one patient with a CV of 80% had a
CK-MBmass of ~4 µg/L; at 24 h, the
CK-MBmass suddenly rose to 14.3 µg/L, suggesting a new
episode of ischemia but without symptoms.
In comparison with healthy individuals, higher CVs also could be
expected in a group of chest pain patients that included patients with
a peak CK-MBmass >7.5 but <15 µg/L. This is in
part a problem of the "gold standard" for AMI, because a group of
patients for whom AMI is ruled out will include patients with a small
increase and peak for CK-MBmass below the cutoff value for
AMI. Calculating the critical difference in a reference population of
chest pain patients in whom an AMI has been ruled out and subsequently
excluding patients with a minor increase in CK-MBmass leads
to circular reasoning, because the definition of "a minor increase"
follows from the determination of the critical difference. However, if
we assume that the majority of the patients determined not to have AMI
do not have myocardial damage, then taking the median or 75th
percentile value of the CVs from this group of patients will result in
a critical difference that is not much influenced by the higher CVs of
the patients with a peak CK-MBmass between 7.5 and 15.0
µg/L (Fig. 2
).
Using the probability curves in Fig. 1
, one can link the percentage
change between two measurements with the probability that the observed
change is the result of "normal" or "reference" variation. The
level of certainty required for excluding myocardial damage may depend
on the clinical situation of the individual patient. Therefore,
probability curves such as those in Fig. 1
may aid clinicians in
decision- making.
In the 87 patients without an increase in CK-MB >2.0 µg/L, most showed a slight but statistically significant decline in CK-MB values between 5 and 12 h or between 6 and 16 h after the onset of symptoms. This is not an effect of diurnal variation, because the onset of symptoms was evenly distributed over the day (see Results). Instead, this decline may show a "regression to the mean" effect, because patients with a large increase in CK-MB have been excluded; or perhaps it reflects the effects of hospitalization, in that CK-MB released from skeletal muscle during normal activity before admission (and the corresponding concentrations in plasma) decreases when patients are in bed during evaluation in the hospital; or more-effective clearance of CK-MB may be the cause. In 20 of 23 patients whose CK-MBmass increased >2.0 µg/L, the increase became evident between 5 and 12 h after the onset of symptoms. This implies that, for many patients, CK-MBmass determinations in two samples taken 5 and 12 h after the onset of symptoms will help clinicians decide what patient management is called for.
Use of 2.0 µg/L to indicate a significant increase in CK-MBmasswas suggested previously by Pettersson et al. (20), using a different CK-MBmass assay (Tandem ICON QSR CK-MB; Hybritech, San Diego, CA)—although they did not arrive at this value with the concept of the critical difference. In that study, unstable angina patients with a significant increase in CK-MBmass >2.0 µg/L (n = 14) had a higher mortality after 2 and 4 years than did patients without such an increase (n = 20).
The prognostic implications of minor myocardial damage, as detected with CK-MBmass or with troponin T and troponin I, have recently been discussed in several other reports (10)(11)(12)(13)(21). In our previous study (13), using a cutoff value of 7.5 µg/L CK-MBmass for minor myocardial damage, we were unable to demonstrate independent prognostic information for CK-MBmass in comparison with increased troponin T. Ravkilde et al. (12), using a cutoff of 6.0 µg/L for CK-MBmass with another assay (Novoclone; Dako, Copenhagen, Denmark), found similar independent prognostic information for CK-MBmass and troponin T but saw no additional prognostic information once the ECG ST-T changes were considered. However, they did not perform an analysis of CK-MBmass changes <6.0 µg/L. We identified 6 patients in the present study with increased CK-MBmass >2.0 µg/L and peak CK-MBmass <7.5 µg/L whose troponin T had increased to >0.1 µg/L. If the release of CK-MB and troponin T is the result of the same process in the myocardium, namely, cardiac myocyte necrosis, looking at the CK-MBmass release curve "with a magnifying glass" may detect myocardial damage as well as an increased troponin T does in patients who have a clear time of onset of symptoms and a timely admission to the emergency room. Three of the four patients in our study with increased troponin T and "normal" CK-MB values had above-normal troponin T on admission, suggesting an episode of ischemia/necrosis before the one that motivated the patient to seek medical attention. For a long enough interval, the CK-MBmass on admission probably had already returned to normal values. Although impaired renal function may cause falsely positive troponin T results (22), all four of the troponin T-positive/CK-MB-negative patients had normal renal function, as did all but one of the other patients with an above-normal troponin T.
Among the potential limitations of this study is the high prevalence of patients with an AMI (123 of 231) in comparison with the prevalence in other studies. However, our patients presented at a cardiac emergency room and not at a general emergency room or first aid department. Also, because the patients had to present within 5 h after the onset of symptoms, patients with a more gradual or "stuttering" onset of chest pain were excluded. Finally, the study protocol, with all the timed samples, may have biased the attending physicians in preferably including patients whose symptoms had a well-defined onset, who are more likely to have AMI. How this possible bias in patient selection might affect the magnitude of the critical difference is as yet unclear.
We used time of onset of symptoms and not the time of admission as a reference, because time of admission has no biological meaning for studying appearance of markers of ischemia. However, the time of onset of symptoms can be difficult or impossible to establish in some patients, and the time of onset of symptoms may not be the time of onset of necrosis. Indeed, in patients with a less precise time of onset of symptoms or with repeated episodes, a marker that stays increased longer (e.g., troponin T) may better identify patients with myocardial damage in whom CK-MBmass has returned to normal values. Given budgetary restraints and the fact that only one specific cardiac marker is available in most hospitals, it may be worthwhile to extract as much information as possible from serial samples by measuring just one marker. Whether a change in the management of non-AMI patients based of the detection of myocardial damage with CK-MBmass or troponin T will improve the outcome in these patients has not yet been shown in a prospective study.
In conclusion, for patients with chest pain but without AMI, a difference between two CK-MBmass measurements >2.0 µg/L provides evidence of myocardial damage. Using this cutoff value, we identified 23 of 110 non-AMI patients as having myocardial damage. Of the 22 patients with an increased troponin T, 18 (82%) also had an increase in CK-MBmass >2.0 µg/L. In our study, 20 of 23 patients with increased CK-MBmass were detected from the values for two serial samples collected at 5 and 12 h after the onset of symptoms.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The following articles in journals at HighWire Press have cited this article:
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  R Bholasingh, R J de Winter, J C Fischer, R W Koster, R J G Peters, and G T Sanders Safe discharge from the cardiac emergency room with a rapid rule-out myocardial infarction protocol using serial CK-MBmass Heart, February 1, 2001; 85(2): 143 - 148. [Abstract] [Full Text]
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), 17
patients with myocardial damage (as indicated by increase in
CK-MBmass >2.0 µg/L) and peak CK-MB between 7.5 and 15
µg/L; (
), 6 patients with myocardial damage (CK-MBmass
increase >2.0 µg/L) and peak CK-MB <7.5 µg/L.