Critical difference between serial measurements of CK-MB masstodetect

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					Clinical Chemistry 43:2
338-343 (1997)                                                                                                    Enzymes and Protein

Critical difference between serial measurements of
    CK-MB mass to detect myocardial damage
                   Robbert J. de Winter,1* Rudolph W. Koster,1 Jan P. van Straalen,2
                     Jozef P.M.C. Gorgels,2 Frans J. Hoek,2 and Gerard T. Sanders2

To assess the critical difference in serial measurements                          12% [5], and as many as 50% of patients with AMI may
of CK-MBmass and the ability of this critical difference                          initially come to emergency departments with nondiag-
to detect myocardial damage, we studied 110 patients in                           nostic ECGs [6]. Therefore, the diagnosis of myocardial
whom an acute myocardial infarction (AMI) had been                                damage in patients with chest pain may rely on the
ruled out. Blood samples were drawn at 3, 4, 5, 6, 7, 8, 12,                      measurement of biochemical markers.
16, 20, and 24 h after onset of symptoms. With a critical                             New assays for early markers such as myoglobin,
difference of 72.6%, an increase of >2.0 g/L between                              troponin T, and creatine kinase isoenzyme MB mass
two CK-MBmass measurements was determined to be                                   (CK-MBmass) are highly sensitive for the diagnosis of AMI
significant. Twenty-three of the non-AMI patients had                             [1, 4, 7–9]. In addition, however, these assays can detect
an increase in CK-MBmass >2.0 g/L, but five of these                              small amounts of marker release from the damaged
did not have an abnormal concentration of troponin T                              myocardium, and the changes in marker values below the
(i.e., not >0.1 g/L). Also among the 110 non-AMI                                  predetermined cutoff value for AMI may also be of
patients, 22 did have an abnormal troponin T value, 18                            diagnostic and prognostic importance [10 –13]. This so-
of whom (82%) also had CK-MBmass increased by >2.0                                called minor myocardial damage is currently defined as
  g/L. In 20 of the 23 patients with an increase in                               an increased concentration of troponin T ( 0.1 g/L) and
CK-MBmass >2.0 g/L, this increase was detected from                               an increase and decrease of CK-MBmass concentrations
the values for two samples collected at 5 and 12 h after
                                                                                  that remain below the discriminating limit for AMI
onset of symptoms. In conclusion, using the critical
                                                                                  [11, 14, 15].
difference for CK-MBmass defined as an increase >2.0
                                                                                      The question is, How large an increase of CK-MBmass
  g/L detected myocardial damage in patients without
                                                                                  can be considered abnormal? To answer this, one must
                                                                                  first determine the normal variation between serial mea-
                                                                                  surements in a reference population (of chest pain pa-
INDEXING TERMS:       variation, source of      •   creatine kinase    •
                                                                                  tients) in samples collected at relevant timepoints.
isoenzymes     •   troponin T
                                                                                  Changes that exceed this normal variation between serial
In patients presenting with chest pain at the emergency                           measurements—“significant changes,” or the “critical dif-
room, early confirmation or exclusion of the presence of                          ference,” or the “reference change”—will depend on the
acute myocardial infarction (AMI) is essential for cost-                          biological, analytical, and preanalytical variation of the
effective triage and timely treatment of these patients                           biochemical marker under study [16, 17]. To our knowl-
[1– 4].3 However, electrocardiograms (ECGs) can be mis-                           edge, the critical difference for CK-MBmass in patients
leading in 8% of all AMIs and indeterminate in another                            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
    Academic Medical Center, Departments of 1 Cardiology and 2 Clinical
                                                                                  onset of symptoms. We also measured troponin T in the
Chemistry, University of Amsterdam, The Netherlands.
    *Address correspondence to this author, at: Department of Cardiology,         patients and compared the ability of that analyte to detect
Suite G3-231, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam.         myocardial damage with the detection based on a change
Fax 31-20-6915687.                                                                in CK-MBmass greater than this critical difference. The
      Nonstandard abbreviations: AMI, acute myocardial infarction; CK-MB,
creatine kinase MB isoenzyme; and CD, critical difference.                        optimal timing for drawing blood samples within these
    Received February 26, 1996; revised and accepted October 4, 1996.             first 24 h to detect myocardial damage was also assessed.

                                               Clinical Chemistry 43, No. 2, 1997                                                    339

               Materials and Methods                              where      indicates the 50th, 75th, or 90th percentile, as
subjects and samples                                              needed.
All consecutive patients with chest pain were seen at the            Usually, the critical difference is reported for the me-
Cardiac Emergency Room, a facility that is equipped with          dian CV, with a probability of 95%, giving a z-value of
continuous ECG monitoring of patients remaining under             1.96. The preanalytical variation for the measurement of
observation for a maximum of 24 h. Patients with chest            CK-MB is small [17] and can thus be neglected; therefore,
pain suggestive of myocardial ischemia who presented              CVt is assumed to consist of only the biological variation
within 5 h after the onset of symptoms were eligible for          (CVb) and the analytical variation (CVa). Once the analyt-
the study. Exclusion criteria were AMI, severe skeletal           ical variation is known, the biological variation can be
muscle damage or trauma, cardiac resuscitation, and               calculated, given that CVt2 CVb2 CVa2.
inability or refusal to give informed consent. The protocol          If the probability of false alarm (the probability that a
                                                                  difference between two measurements is interpreted as
was approved by the Medical Ethics Committee of our
                                                                  indicative of myocardial damage when in fact it is not) is
                                                                  set at values from 0.5 to 0.01, probability curves [16] can
   The final diagnosis of AMI was established at hospital
                                                                  be plotted for the CK-MBmass change for CVs for the 50th,
discharge, based on the patient’s clinical history and
                                                                  75th, and 90th percentiles.
symptoms, ECG abnormalities, and a typical increase and
decrease in the CK-MBmass curve with the peak exceeding           analytical variation
15 g/L (considering the results from all timepoints).             The precision, or total reproducibility, was calculated
Patients fulfilling these criteria for AMI were excluded          from the within-run, between-run, and day-to-day varia-
from the study. The physicians making the diagnosis               tion as described in NCCLS EP5-T2 [18]. We determined
were unaware of the troponin T results. Some patients             these values for four concentration ranges by using
(n 17) showed CK-MBmass gradually increasing to 7.5               EVAL-KIT Software (CKCHL, Tilburg, The Netherlands).
  g/L but not exceeding 15 g/L; they were included in
the calculation of the critical difference (see Discussion).      statistical analysis
   Blood samples were drawn with an indwelling intra-             The change in CK-MBmass between 5 and 12 h or between
venous catheter at 3, 4, 5, 6, 7, 8, 12, 16, 20, and 24 h after   6 and 16 h after the onset of symptoms was calculated for
the onset of symptoms. Blood was collected in 10-mL               each patient and reported as means       SD. Differences
heparin-coated evacuated collection tubes. The samples            were analyzed with the Wilcoxon matched-pairs sign
were centrifuged twice at 1500g for 10 min and the cells          rank test. P 0.05 was considered statistically significant.
were discarded; the plasma remaining was aliquoted and
stored at 20 °C until further analysis.                                                               Results
                                                                  Of the 231 patients eligible for the study, 121 patients
laboratory analysis                                               were finally diagnosed as having AMI and were excluded
CK-MBmass was measured with the immunochemical                    from the analysis. Therefore, 110 patients without AMI
method implemented on the ACS:180 analyzer (CIBA                  formed the study group: 70 men and 40 women, median
Corning, Houten, The Netherlands). The detection limit            age 64 years (range 38 – 88). This combination of gender
was 0.65 g/L and assay linearity extended from 0 to 500           and age is representative for a population presenting with
  g/L. Calibrators were supplied by the manufacturer.             chest pain at the emergency room. The time of presenta-
The upper reference limit was 7.5 g/L, and the cutoff             tion of these patients (hours after onset of symptoms,
                                                                  expressed in 6-h periods of 24-h clock time) was 23
value for AMI was 15.0 g/L.
                                                                  between 0000 and 0600, 32 between 0600 and 1200, 34
   Troponin T was measured with an ELISA (cat. no.
                                                                  between 1200 and 1800, and 21 between 1800 and 2400 h.
1289055) on an ES300 analyzer (all from Boehringer
                                                                     The CVs and resulting CD values are summarized in
Mannheim, Mannheim, Germany); calibrators were sup-
                                                                  Table 1. The 50th percentile CV was 16.5%, the 75th per-
plied by the manufacturer. The upper reference limit was          centile CV 26.2%, and the 90th percentile CV 48.8%. The
0.1 g/L, and the linearity range of this determination
was 0 –15 g/L.
                                                                  Table 1. CVs and corresponding CDs of CK-MBmass for 110
critical difference                                                                 patients without AMI.
For each patient the mean value for CK-MBmass and the                                                        CV, %                  CD, %a
total coefficient of variation (CVt) was calculated from the      Mean SD                               21.4    18.3
results from all timepoints. The critical difference (CD)         Range                                   2.9–79.8
was calculated from the 50th, 75th, and 90th percentiles          50th percentile                           16.5                     45.7
                                                                  75th percentile                           26.2                     72.6
[17] of the CVt values, as follows:
                                                                  90th percentile                           48.8                    135.2
                                                                        Calculated from the CVs at the corresponding percentiles.
                 CD      z     2      (CV 2)
340                     de Winter et al.: Critical difference in CK-MB mass measurements in myocardial damage

critical differences calculated with these CVs were CDp50
45.7%, CDp75 72.6%, and CDp90 135.2%, respectively.
    The total reproducibility (analytical variation) of CK-
MBmass determinations at concentrations of 6.4, 9.1, 24.2,
and 93.9 g/L was 3.9%, 2.3%, 5.4%, and 4.5%, respec-
tively. Because the analytical variation of the CK-MBmass
assay in the lower concentration range (i.e., 15 g/L)
averaged 3.1%, the total variation in patients without AMI
mainly consisted of the biological variation (median,
    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
                                                                                      Fig. 2. CVs from 110 non-AMI patients, plotted as a function of mean
mean CK-MBmass value for all of the non-AMI patients
                                                                                      CK-MBmass ( g/L); each point is the mean of samples taken at 10
determined to be 2.7         1.76 g/L, we chose the cutoff                            timepoints during the first 24 h after the onset of chest pain (median
value for the change in CK-MBmass as 2.0 g/L.                                         CV 16.5%).
    For each patient, we plotted the CV and average                                   (F) 87 patients without an increase in CK-MBmass 2.0 g/L. The values for 23
CK-MBmass from all timepoints during the 24 h of blood                                patients with an increase in CK-MBmass 2.0 g/L are indicated separately: (E),
                                                                                      17 patients with myocardial damage (as indicated by increase in CK-MBmass
collection and observation (Fig. 2). Among the 110 pa-                                  2.0 g/L) and peak CK-MB between 7.5 and 15 g/L; (‚), 6 patients with
tients, 23 had an increase in CK-MBmass of 2.0 g/L. Of                                myocardial damage (CK-MBmass increase 2.0 g/L) and peak CK-MB 7.5
these, 17 patients showed an increase and decline in
CK-MBmass concentration, with the peak between 7.5 and
15 g/L; the other 6 had an increase in CK-MBmass of 2.0                                  Of the 22 patients with an abnormal concentration of
  g/L but the peak was 7.5 g/L. Overall, of the 23                                    troponin T, 18 (82%) were identified by an increase in
patients with CK-MBmass increased by 2.0 g/L, 18 also                                 CK-MBmass 2.0 g/L. One of these 22 patients had
had an abnormal concentration of troponin T ( 0.1 g/L)                                moderate renal dysfunction (serum creatinine 159 mol/
but 5 had normal troponin T values. On the other hand, of                             L); all the others—including the 4 patients with an abnor-
the 87 patients with no critical increase in CK-MBmass,                               mal troponin T but no critical increase in CK-MBmass—
only 4 patients had above-normal troponin T; the remain-                              had normal renal function.
ing 83 had normal values for both markers.                                               The increase in CK-MBmass 2.0 g/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 g/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 g/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 g/L; P        0.008) and between 6 and 16 h (from
                                                                                      2.55 1.60 to 2.22 1.56 g/L; P 0.001).

                                                                                      New accurate CK-MBmass assays that are highly precise in
                                                                                      the lower concentration range make it possible to detect
Fig. 1. Probability curves vs the percentage change for an increase in
                                                                                      minute quantities of CK-MB released from the ischemic
CK-MBmass.                                                                            heart. This minor release of CK-MB is expected to result in
Curves depict the “probability of false alarm,” or the probability that an increase   a small increase in plasma CK-MBmass between 3 and 12 h
between two CK-MBmass values is interpreted as indicating release from the            after the onset of ischemia. By definition, an increase in
myocardium when in fact there is no such release. The three curves are drawn for
biological variation of patients with CV values equal to the 50th, 75th, and 90th
                                                                                      CK-MBmass larger than that expected from normal varia-
percentiles of 110 non-AMI patients. x-axis: critical difference, percent.            tion, “the critical difference,” may signify release from the
                                              Clinical Chemistry 43, No. 2, 1997                                          341

myocardium. Therefore, in the continuous spectrum of             decline in CK-MB values between 5 and 12 h or between
changes in serial CK-MBmass measurements in chest pain           6 and 16 h after the onset of symptoms. This is not an
patients, the cutoff value for AMI forms the upper limit         effect of diurnal variation, because the onset of symptoms
and the critical difference forms the lower limit of CK-         was evenly distributed over the day (see Results). Instead,
MBmass changes indicative of myocardial damage in pa-            this decline may show a “regression to the mean” effect,
tients for whom AMI has been ruled out.                          because patients with a large increase in CK-MB have
   We determined the critical difference for CK-MBmass to        been excluded; or perhaps it reflects the effects of hospi-
be 2.0 g/L on the basis of our CD75 of 72.6%, which was          talization, in that CK-MB released from skeletal muscle
very similar to the CD90 in healthy individuals deter-           during normal activity before admission (and the corre-
mined by Costongs et al. [17]. Using this critical differ-       sponding concentrations in plasma) decreases when pa-
ence, we were able to identify 18 of 22 patients (82%) who       tients are in bed during evaluation in the hospital; or
had an abnormal concentration of serum troponin T.               more-effective clearance of CK-MB may be the cause. In
   The mean      SD CV (21.4%      18.3%) we found in the        20 of 23 patients whose CK-MBmass increased 2.0 g/L,
non-AMI patients was in the range of that reported               the increase became evident between 5 and 12 h after the
(32.5%) for CK-MB activity in selected patients in a             onset of symptoms. This implies that, for many patients,
retrospective study [19]. The median variation for CK-           CK-MBmass determinations in two samples taken 5 and
MBmass we determined, 16.5%, resulting in a critical             12 h after the onset of symptoms will help clinicians
difference of 45.7%, was just slightly above the value           decide what patient management is called for.
Costongs et al. reported for healthy subjects, 40.1% [17].           Use of 2.0 g/L to indicate a significant increase in
The CVP90 of 48.8% in our study results in a critical            CK-MBmass was suggested previously by Pettersson et al.
difference of 135.2%, which is higher than that reported         [20], using a different CK-MBmass assay (Tandem ICON
for healthy subjects (72%) [17]; however, as seen in Fig. 2,     QSR CK-MB; Hybritech, San Diego, CA)—although they
most patients with a CV 40% had an average CK-MBmass             did not arrive at this value with the concept of the critical
  2 g/L. The one patient with a CV of 80% had a                  difference. In that study, unstable angina patients with a
CK-MBmass of 4 g/L; at 24 h, the CK-MBmass suddenly              significant increase in CK-MBmass 2.0 g/L (n 14) had
rose to 14.3 g/L, suggesting a new episode of ischemia           a higher mortality after 2 and 4 years than did patients
but without symptoms.                                            without such an increase (n 20).
   In comparison with healthy individuals, higher CVs                The prognostic implications of minor myocardial dam-
also could be expected in a group of chest pain patients         age, as detected with CK-MBmass or with troponin T and
that included patients with a peak CK-MBmass 7.5 but             troponin I, have recently been discussed in several other
  15 g/L. This is in part a problem of the “gold stan-           reports [10 –13, 21]. In our previous study [13], using a
dard” for AMI, because a group of patients for whom              cutoff value of 7.5 g/L CK-MBmass for minor myocardial
AMI is ruled out will include patients with a small              damage, we were unable to demonstrate independent
increase and peak for CK-MBmass below the cutoff value           prognostic information for CK-MBmass in comparison
for AMI. Calculating the critical difference in a reference      with increased troponin T. Ravkilde et al. [12], using a
population of chest pain patients in whom an AMI has             cutoff of 6.0 g/L for CK-MBmass with another assay
been ruled out and subsequently excluding patients with          (Novoclone; Dako, Copenhagen, Denmark), found similar
a minor increase in CK-MBmass leads to circular reasoning,       independent prognostic information for CK-MBmass and
because the definition of “a minor increase” follows from        troponin T but saw no additional prognostic information
the determination of the critical difference. However, if        once the ECG ST-T changes were considered. However,
we assume that the majority of the patients determined           they did not perform an analysis of CK-MBmass changes
not to have AMI do not have myocardial damage, then                6.0 g/L. We identified 6 patients in the present study
taking the median or 75th percentile value of the CVs            with increased CK-MBmass 2.0 g/L and peak CK-
from this group of patients will result in a critical differ-    MBmass 7.5 g/L whose troponin T had increased to
ence that is not much influenced by the higher CVs of the          0.1 g/L. If the release of CK-MB and troponin T is the
patients with a peak CK-MBmass between 7.5 and 15.0              result of the same process in the myocardium, namely,
  g/L (Fig. 2).                                                  cardiac myocyte necrosis, looking at the CK-MBmass re-
   Using the probability curves in Fig. 1, one can link the      lease curve “with a magnifying glass” may detect myo-
percentage change between two measurements with the              cardial damage as well as an increased troponin T does in
probability that the observed change is the result of            patients who have a clear time of onset of symptoms and
“normal” or “reference” variation. The level of certainty        a timely admission to the emergency room. Three of the
required for excluding myocardial damage may depend              four patients in our study with increased troponin T and
on the clinical situation of the individual patient. There-      “normal” CK-MB values had above-normal troponin T on
fore, probability curves such as those in Fig. 1 may aid         admission, suggesting an episode of ischemia/necrosis
clinicians in decision- making.                                  before the one that motivated the patient to seek medical
   In the 87 patients without an increase in CK-MB 2.0           attention. For a long enough interval, the CK-MBmass on
  g/L, most showed a slight but statistically significant        admission probably had already returned to normal val-
342              de Winter et al.: Critical difference in CK-MB mass measurements in myocardial damage

ues. Although impaired renal function may cause falsely                                      References
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