1542
Analysis of Creatine Kinase, CK-MB,
Myoglobin, and Troponin T Time-Activit
Curves for Early Assessment of Coronary Artery
Reperfusion After Intravenous Thrombolysis
Markus Zabel, MD; Stefan H. Hohnloser, MD; Wolfgang Koster, MD; Martina Prinz, MD;
Wolfgang Kasper, MD; and Hanjorg Just, MD
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Background. Thrombolysis has become the standard therapeutic approach in patients with acute
myocardial infarction. To identify patients who may benefit from early invasive procedures, reliable
noninvasive assessment of success or failure of thrombolytic therapy is mandatory.
Methods and Results. In a prospective study in 63 consecutive patients undergoing thrombolysis for their
first myocardial infarction, serial measurements of creatine kinase (CK), its isoenzyme CK-MB,
myoglobin, and troponin T were done to determine their value for noninvasive prediction of coronary
artery patency. Blood samples were drawn every 15 minutes during the first 90 minutes, every 30 minutes
during the first 4 hours, every 4 hours during the first 24 hours, and every 8 hours during the first 72
hours. The perfusion status of the infarct-related artery was assessed angiographically 90 minutes after
initiation of thrombolysis. For each marker, time to its peak concentration and its early initial slope (start
of thrombolysis to 90 minutes thereafter) were determined. Areas under receiver operator characteristic
(ROC) curves were 0.83, 0.76, 0.82, and 0.80 for maxima of CK, CK-MB, myoglobin, and troponin T,
respectively (p=NS by univariate Z test). The corresponding values for early slopes of CK, CK-MB,
myoglobin, and troponin T were 0.79, 0.82, 0.89, and 0.80 (p =0.23 for comparison between myoglobin and
CK-MB;p=0.07 between myoglobin and CK). Sensitivity, specificity, and positive and negative predictive
values regarding noninvasive prediction of coronary artery patency after 90 minutes were 80%o, 82%, 95%,
and 61% for time to CK maximum; 91%, 77%, 91%, and 77% for time to myoglobin maximum; 87%, 71%,
89%o, and 67% for early CK slope; and 94%, 88%, 94%, and 82% for myoglobin slope, respectively. When
myoglobin slope was assessed together with other clinical reperfusion markers (resolution of chest pain
or ST segment elevation, occurrence of reperfusion arrhythmias) by logistic regression analysis, only the
myoglobin slope was an independent predictor of coronary artery patency (p<0.0001).
Conclusions. With regard to noninvasive prediction of coronary artery patency after thrombolytic
therapy, measurement of the early initial slopes of the serum markers within only 90 minutes after the
initiation of therapy is as accurate as the determination of the time to their peak concentration. Compared
with the other markers examined, myoglobin appears to have advantages because of its earlier rise,
yielding a better negative predictive value and a higher area under the ROC curve for determination of its
early initial slopes. (Circulation 1993;87:1542-1550)
KEY WORDs * myocardial infarction, acute * thrombolysis * reperfusion
T he value of coronary artery reperfusion by means
of intravenous thrombolysis in patients with
evolving myocardial infarction has been rigorously evaluated.'-4 An impressive improvement in survival rates has been demonstrated in patients with
successful reopening of the infarct-related artery. In
addition, left ventricular function has been shown to be
superior in patients treated with thrombolysis compared
with placebo-treated patients.5 It is evident from both
From the University Hospital, Department of Cardiology and
Department of Clinical Chemistry (W.K.), Freiburg, Germany.
Supported by a grant from the Deutsche Gesellschaft fur Herzund Kreislaufforschung, Bad Nauheim, Germany (M.Z.).
Address for correspondence: Stefan H. Hohnloser, MD, University Hospital, Department of Cardiology, Hugstetter Str. 55,
7800 Freiburg, FRG.
Received June 15, 1992; revision accepted January 14, 1993.
laboratory and clinical studies that the benefits of
thrombolytic therapy are conferred by restoration of
patency of the infarct-related artery.6-9 Recently, Abbottsmith and coworkers10 have reported that salvage
angioplasty after failed thrombolysis improves outcome
in these patients. Thus, invasive means are valuable in
selected patients to establish coronary artery patency.11,2 Rescue thrombolysis with readministration of
the same or a different thrombolytic agent may also
have a role after failed initial thrombolytic therapy.13
On the other hand, acute routine angiography in all
patients receiving thrombolytic therapy for acute infarction is unnecessary and may eventually cause harm to
some.14-16 Hence, reliable methods other than angiography are needed to detect coronary reperfusion early
during the hospital course. In previous studies, the
normalization of ST segment elevation in the surface
Zabel et al Serum Markers for Prediction of Reperfusion
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ECG,17-21 the occurrence of reperfusion arrhythmias,19,22-24 the resolution of infarct-related chest
pain,25,26 and various cardiac enzymes have been used
for this purpose. For example, a short time to peak
creatine kinase (CK)27 or CK-MB concentration28,29 has
been proposed as an indicator of reperfusion. More
recently, new serum markers such as myoglobin,28'30
CK-MB isoforms,31 and the specific cardiac antigen
troponin T32 have become available and have been
examined in small groups of patients with acute myocardial infarction. Up to now, however, the value of
these new reperfusion markers has not been vigorously
evaluated, and they have not been compared with each
other in a reasonably large cohort of patients undergoing thrombolysis. The aims of the present prospective
study, therefore, were 1) to develop simple indexes for
success or failure of reperfusion therapy according to
the initial CK and CK-MB time-activity curves and 2)
to evaluate whether new reperfusion markers such as
myoglobin and troponin T yield a higher diagnostic
accuracy in prediction of thrombolysis-induced reopening of the infarct-related artery compared with conventional serum markers. Particular attention was paid to
the question of whether analysis of early increases in
enzyme or protein concentrations (within 120 minutes
after start of thrombolysis) is as accurate regarding
prediction of coronary artery patency as the determination of the time to their peak concentration, since this
would be of marked clinical utility.
Methods
Patient Population
Sixty-three consecutive patients with acute myocardial infarction treated with thrombolysis were studied
prospectively between May 1990 and October 1991.
Patients with typical chest pain of .30 minutes' duration, unresponsive to nitrates, and with ECG ST segment elevation of .0.1 mV in at least two limb leads or
>0.2 mV in at least two precordial (V) leads were
eligible for the study. Patients with cardiogenic shock
were excluded. Thrombolytic therapy had to be initiated
within 6 hours after onset of symptoms. The thrombolytic agent used was prourokinase in 32 patients combined with recombinant tissue plasminogen activator
(rt-PA) in 20 patients and anisoylated plasminogen
streptokinase activator complex (APSAC) in 31 patients. After thrombolysis, all patients received a bolus
of 7,500 to 10,000 units of heparin followed by a
continuous infusion of 1.250 units/hr for the next 72-96
hours (partial thromboplastin time adjusted to two
times the upper normal). All patients gave their informed consent to the study. The usual exclusion criteria for thrombolysis were applied.
Coronary Angiography
Coronary angiography was performed within 90 minutes after onset of thrombolytic therapy and repeated 24
hours later. The angiographic findings were assessed
according to the Thrombolysis in Myocardial Infarction
(TIMI) criteria for reperfusion.4 For this purpose, the
first injection of contrast was taken as the patency
assessment. TIMI grades 2 and 3 were defined as
coronary artery patency. For statistical analysis, early
1543
patency within the first 90 minutes was considered
successful coronary artery opening.
Serum Markers
Blood samples (10 mL) were taken before initiation
of thrombolysis, every 15 minutes for the first 90 minutes after start of therapy, every 30 minutes for the first
4 hours, every 4 hours up to 24 hours, and every 8 hours
up to 72 hours. The samples were stored at room
temperature to allow clotting and frozen at -20°C after
centrifugation until analysis. Samples were analyzed by
investigators who were unaware of the angiographic
results. Plasma total CK activity was assayed according
to the method of Rosalki.33 The mass of the CK-MB
isoenzyme was determined by means of a rapid fluorometric enzyme immunoassay based on a two-site sandwich immunoassay methodology (Baxter Stratus, Miami, Fla.).34 Units are given in nanograms per milliliter.
Myoglobin was determined nephelometrically by a
quantitative latex agglutination test developed from an
earlier-described semiquantitative test (Behring Werke,
Marburg, Germany).35 Assay times are 15-30 minutes.
The test was validated against the commonly used
radioimmunoassay determination of myoglobin30 (Behring Werke; data on file). Troponin T was measured
with a recently developed enzyme immunoassay (Bohringer Mannheim, Germany) that has been described in
detail elsewhere.3236,37 The upper limits of the normal
range were 70 units/L for creatine kinase, 5.6 ng/mL for
CK-MB (mass), 85 ng/mL for myoglobin, and 0.2 ng/mL
for troponin T. For each of these serum markers, time
to peak concentration after start of therapy was calculated. In addition, the slope of each serum marker
within the first 90 minutes was calculated and expressed
in units per liter per hour or nanograms per milliliter
per hour by dividing the difference of the corresponding
values at initiation of therapy and 90 minutes thereafter
by 1.5. In Figure 1, raw data from a patient with
successful reperfusion and from another without reperfusion are shown to illustrate the technique of slope
determinations.
Clinical Reperfusion Markers
Resolution of maximal ST segment elevation was
judged from two surface ECGs taken before and 120
minutes after start of thrombolysis. In addition, Holter
monitoring was started before injection of the thrombolytic agent for assessment of reperfusion arrhythmias
within the first 90 minutes. Accelerated idioventricular
rhythm (AIVR) was defined by a heart rate of < 100
beats per minute, a long coupling interval, a regular
configuration and rate, and termination by sinus escape.
Sinus bradycardia was defined by a heart rate of <55
beats per minute. Patients were also interviewed for the
severity of chest pain on a subjective scale ranging from
0 to 10 before and 90 minutes after thrombolysis.
Statistical Methods
Values are given as mean±+SD. The calculation of
sensitivity, specificity, positive predictive value, and
negative predictive value was performed according to
the formulas described in our previous report.19 A x2
test was used to test the univariate correlation of
noninvasive markers to patency of the infarct artery as
well as differences of numerical parameters between
Circulation Vol 87, No S May 1993
1544
CK (U/ll
3000 - _~
2750
2500
2250
2000
1750
1500
1250
1000 ;
750
500
250
0
t
t
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FIGURE 1. Graphs showing raw data from two
representative patients with (TIMI grade 3) and
without (TIMI grade 0) successful thrombolysisinduced reperfusion. Upper panel: Creatine kinase
(CK) values. Lower panel: Myoglobin (Myo) values.
The two arrows indicate the points of time used for
determination of the early slopes in CK and myoglobin concentration increases (90-minute value minus 0-minute value divided by 1.5).
Minutes after sart of thrombolysis
Myo [nglmq
5500
-
5000.
4500
4000
3500
3000
2500
2000
1500
1000
500 _
Ad
0
30 60
90
120
150
180 210 240
400
800 1200
1 60
2000 2400 2800 3200
Minutes after start of thronmbolysis
Linear regression analysis was performed for
related parameters, and coefficients of correlations
were calculated and tested for significance. The independent correlation of serum and clinical markers to
coronary artery patency was determined by means of
logistic regression analysis with coronary artery patency
as the outcome variable. Markers were entered as
categorical variables (positive or negative) by use of
their respective cutoff values (see below). For statistical
purposes, the following definitions of positive reperfusion markers were applied. According to two previous
studies at our institution,19,38 a maximum of CK activity
within the first 12 hours after start of thrombolysis was
prospectively defined as a positive marker of coronary
artery patency. For the CK slope, a cutoff of 40
units. L`. hr-' was prospectively derived from the report of Lewis et al.39 As reported by Hogg et al17 and a
previous study from our institution,'9 a positive ST
marker was defined as a reduction of ST segment
elevation of 250%. With respect to pain score, a
decrease of at least two points was considered suggestive of reperfusion.26 AIVR19,23 and sinus bradycardia
<55 beats per minute19,22 within the first 90 minutes
(only in patients with inferior infarctions) were prospectively defined as reperfusion arrhythmias. The cutoffs
groups.
for the time to peak CK-MB, myoglobin, and troponin T
retrospectively defined at 10, 3, and 15 hours after
start of thrombolysis, respectively, since no previously
described cutoff values were available from the literature. Accordingly, the cutoffs for the absolute rise of
each marker over the first 90 minutes of therapy were
chosen as 10, 150, and 0.2 ng* mL-'* hr-' for CK-MB,
myoglobin, and troponin T, respectively. To allow comparison with the CK data, these numbers were chosen to
represent similarly good but not optimal cutoffs. Since
potential bias concerning the choice of a single cutoff
cannot be excluded (even if prospectively defined),
sensitivity and specificity data are represented over the
entire cutoff range in the applicable figure (Figure 2).
Furthermore, receiver operator characteristic (ROC)
curve analysis as an objective means for determination
of the utility of the various markers for noninvasive
prediction of coronary artery patency was applied. The
major advantage of this technique is provided by its
independence of definitions of cutoff values. This statistical method was initially developed in the field of
signal detection theory and provides a powerful tool to
assess the predictive quality of a given test.40-42 With
this technique, sensitivity (true positives) is plotted
against 1-specificity (true negatives) for the possible
were
Zabel et al Serum Markers for Prediction of Reperfusion
CKMB maximum [cutoff In hi
CK maximum [cutoff in hi
lolp
4~
*w~
lone
lvv-
*-^
a^^-
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so
80
60
60
40
40
20
20
0
100
200
300
r
_
000
400
1545
600
700
800
40
20
M
CK slope 0-90 min [cutoff In U/l/hi
-
-
-
426 100
12
14
80
120
140
60
100
160
CKMB slope 0-90 min [cutoff in ng/mil/hl
100
[%]
D
m
m
%
80
60
40
20'ff
--
n
4
10
6
12
14
H
v
0
10
Myoglobin maximum [cutoff in hi
20
30
40
60
Do-0
600
1000
Myoglobin
'-
1600
slope
sensitivity
2000
2600
70
60
Troponin T maximum Icutoff in hi
3000
3600
0
Icutoff in ng/mil/hl
---rf
2
4
6
8
10
12
14
Troponin T slope Icutoff in ng/ml/hl
--&
+ specificity
sensitivity
+ specificity
FIGURE 2. Graphs. PanelsA: Sensitivity and specificityforprediction of coronary artery patency at various cutoffpoints for time
to creatine kinase (CK) maximum and of CK slopes for the first 90 minutes after initiation of thrombolysis. Panels B: CK-MB
maximum
and slope. Panels C: Myoglobin maximum and slope. Panels D: Troponin T maximum and slope.
range of cutoff points of a specific marker.40-42 The area
under the ROC curve represents a single number for
the predictive quality of the test, with a maximum of 1.0
representing an ideal test (100% accuracy) compared
with an area of 0.5 indicating that the test is no better
than chance.40-42 Thus, ROC curve analysis yields a
single value for each marker evaluated. To compare the
different areas under the ROC curves of several markers (i.e., to compare the predictive quality of tests), a
univariate Z-test has been described in detail by Hanley
and McNeil.41 Significance was considered at a value of
pS0.05.
1546
Circulation Vol 87, No S May 1993
TABLE 1. Sensitivity, Specificity, Positive and Negative Predictive Values, Univariate x2, and Area of ROC Curve
for Noninvasive Prediction of Coronary Patency by Means of Peak and Slope Analysis of Various Serum Markers
Negative
Positive
Area under
predictive
predictive
Specificity
Sensitivity
ROC curve
value (%)
value (%)
(%)
(%)
Marker
X2
18.5
0.83
61
95
82
80
Time to CK maximum
17.4
0.79
87
71
67
89
CK slope
Time to CK-MB
8.5
0.76
52
86
78
65
maximum
71
15.5
0.79
63
85
96
CK-MB slope
Time to myoglobin
25.6
0.82
77
77
91
91
maximum
94
88
94
82
36.7
0.89
Myoglobin slope
Time to troponin T
74
71
8.6
0.80
50
87
maximum
80
65
9.7
0.80
55
93
Troponin T slope
ROC, receiver operator characteristics; CK, creatine kinase.
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Results
paper. Four patients had to be defibrillated within the
first hours because of the occurrence of ventricular
fibrillation, and one other patient had femoral bleeding
consequent to angiography. Since the overall predictive
value of the markers examined was not significantly
influenced by the data of these five patients, they were
included in the analysis.
Clinical Data
Sixty-three consecutive patients were included in the
protocol. There were 54 men and nine women with a
mean age of 59±11 years (range, 33-81 years). Twentyeight patients suffered from anterior and 35 from inferior myocardial infarction. Angiography revealed the
left anterior descending coronary artery in 26, the right
coronary artery in 32, and the circumflex artery in five
patients as the corresponding infarct-related artery.
The time interval from onset of chest pain to start of
thrombolysis averaged 190±112 minutes. In 46 patients
(73%), angiography revealed TIMI grade 2 or 3 reperfusion of the infarct-related vessel at 90 minutes. In the
remaining 17 patients, the infarct-related artery was
found to be occluded (TIMI grade 0 or 1). Late
reperfusion of the infarct vessel between 90 minutes and
24 hours occurred in 10 patients, whereas two patients
had reocclusion within this time frame. Among the 17
patients with an occluded vessel on the first coronary
angiogram, late reperfusion (within 24 hours) did not
Analysis of CK
The mean peak CK value was 1,041±686 units/L for
patients with a patent versus 942±758 units/L for patients with an occluded infarct artery (p=NS). Time to
peak concentration averaged 9.0±6.2 hours in patients
with versus 17.1±6.4 hours for patients without coronary artery patency (p<0.001). Sensitivity and specificity for prediction of vessel patency at the chosen cutoff
were 80% and 82%, respectively, and they were comparable for a range of cutoffs between 10 and 15 hours
(Figure 2, Table 1). This resulted in a high area under
the ROC curve of 0.83 and a univariate x2 of 18.5
(Figure 3). For the initial CK slope between 0 and 90
minutes after start of therapy, sensitivity and specificity
were almost comparable at 87% and 71%, respectively
(Figure 1 and Table 1). Accordingly, ROC curve area
significantly influence the time elapsed to peak concentrations of the various serum markers. Thus, these
patients are referred to as one group throughout the
Slopes 0 - 90 min
Time to Peak
100
60
0
60
.0
*~~~~~~~~~~.A
C KMB(mass)
Myogiobin
40
40
20
20
00
0
*Troponin
04
20
40
60
1-Specificity 1%1
80
100
0
20
40
60
80
T
100
1-Specificity l[l
FIGURE 3. Receiver operator characteristic (ROC) curves for noninvasive prediction of coronary artery patency by means ofpeak
and slope measurements of creatine kinase (CK), CK-MB, myoglobin, and troponin T (n=63).
1547
Zabel et al Serum Markers for Prediction of Reperfusion
and x2 were slightly lower, at 0.79 and 17.4 (Table 1).
The optimal range of cutoffs was between 40 and 80
units * - hr-t (Figure 2). An inverse correlation was
found between CK slope and maximum (r= -0.40,
p<O.0Ol).
Downloaded from http://circ.ahajournals.org/ by guest on September 30, 2016
Analysis of CK-MB Mass
Peak CK-MB averaged 216±151 ng/mL for patients
with a patent versus 167±130 units/L for patients with
an occluded infarct artery (p=NS). Time to peak was
similar to that of CK and averaged 7.5±4.1 hours in
patients with versus 12.0±5.3 hours for patients without
coronary artery patency (p=0.004). Sensitivity and
specificity for prediction of vessel patency at the chosen
cutoff of 10 hours were 78% and 65% for CK-MB
maximum, respectively. The best range of cutoffs was
8.5-12 hours. For the slope of CK-MB, the range of
acceptable cutoffs was 15-20 ng . mL` * hr-1 (Figure 2
and Table 1). ROC curve analysis disclosed values of
0.76 for CK-MB maximum and 0.79 for CK-MB slope.
Analysis of Myoglobin
Myoglobin peaked after 2.1±2.8 hours in patients
with successful (peak value, 2,361±1,824 ng/mL) compared with 4.9±4.2 hours (p<0.02) in patients with
failed reperfusion (peak value, 1,037±1,137 ng/mL,
p=0.001). Sensitivity was 91% together with a specificity of 77% at the predefined cutoff of 3 hours. For the
myoglobin slope, a sensitivity of 94% and specificity of
88% at the preselected cutoff of 150 ng. mL- . hr-1
were obtained (Figure 2). ROC curve area was comparable to the other markers for myoglobin maximum at
0.82; however, the univariate X2 value was highest of all
maxima with 25.6. Myoglobin slope revealed the highest
ROC curve area and univariate x2 value of all studied
markers (ROC, 0.89; X2=36.7) (Figure 3, Table 1).
There was an inverse correlation between myoglobin
slope and maximum (r=-0.35,p<0.01).
Analysis of Troponin T
Troponin T peaked after 11.6±9.3 hours in patients
with successful reperfusion (peak value, 23.6±18.8 ng/
mL) compared with 20.3±14.4 hours (p=0.03) in patients without reperfusion (peak value, 10.1±6.3 ng/mL;
p<0.001). Sensitivity and specificity were 74% and 71%,
respectively, at the preselected cutoff of 15 hours, with
a narrow range of favorable cutoffs between 14 and 16
hours (Figure 2). This range was also narrow for the
analysis of troponin T slopes, for which sensitivity was
80% at a specificity of only 65% for the predefined
cutoff of 0.2 ng * mL- * hr-1. ROC curve areas were 0.80
for both maximum and slope analysis of troponin T
(Figure 3, Table 1). Univariate X2 values were low, with
8.6 for troponin maximum and 9.7 for troponin slope.
Comparison of Serodiagnostic Markers
The ROC curves of the four serum markers were
plotted to compare the value of each serum marker
regarding noninvasive prediction of reperfusion. Analysis of time to peak concentration revealed similar
values for all four markers evaluated. Comparison of
early slopes demonstrated the highest ROC area for
analysis of myoglobin (Figure 3, Table 1). The difference in ROC areas between myoglobin and CK was
close to significance (p=O0.07), whereas the difference in
25r
E
E
20 F
x
X
a
.0
0
2
15k
r * 0.59
p c 0.001
y * 0.28x - 0.33
0
10F
O
F
6
0
01
~~~~~~~~-0
~~
E-
0
5
0
0
:11
~
O
on
15
10
20
E80
2
E
I.E
E1
25
30
366
25
30
35
0
T70
B0
r * 0.59
p 0.001
950
y *0.95x +3.3
40
A
c
CL
0
so~
30-
111
2
0
-._
20
11
~~~~~
0
-~~~~~~~~~
10
d
10n
0
5
20
16
10
Time to CK maximum Ih]
FIGURE 4. Upper panel: Plot of time to creatine kinase (CK)
maximum vs. time to myoglobin maximum. Lower panel: Plot
of time to CK maximum versus time to troponin T maximum.
CK-MB slope was not significant (p=0.23). As demonstrated in Figure 4, regression analysis disclosed a
significant correlation between time to myoglobin and
CK maximum and between time to troponin T and CK
maximum (r=0.59 for both correlations). With respect
to the time-activity curves, analyses of CK, CK-MB,
and troponin T were comparable, revealing pathological
findings in approximately 60-65% of patients at 60
minutes and in 90% at 120 minutes after the initiation
of thrombolysis (Figure 5). The release of myoglobin,
however, occurred significantly earlier, resulting in abnormal findings in 77% of patients as early as 30
120
60
Imin after
CK
-C- GKMB
thrombolyasil
-* Troponin T
Myoglobin
FIGURE 5. Graph showing percentage of patients (pts) with
abnormal values of various serum markers according to time
from initiation of thrombolysis (*p<0.05 between myoglobin
and creatine kinase [CK]-MB for 0-60 minutes and between
myoglobin and CK for 90 and 120 minutes; **p<0.01
between myoglobin and CKfor 0-60 minutes).
1548
Circulation Vol 87, No S May 1993
TABLE 2. Sensitivity, Specificity, Positive and Negative Predictive Values, Univariate x2, and Area Under the ROC
Curve for Noninvasive Prediction of Coronary Patency by Means of Clinical Markers
Negative
Positive
Area under
predictive
predictive
Specificity
Sensitivity
ROC curve
value (%)
value (%)
(%)
(%)
Marker
X2
41
96
...
94
8.4
50
Reperfusion arrhythmias
0.74
9.7
42
83
71
76
ST segment reduction
0.67
2.7*
47
79
41
83
Reduction in pain score
ROC, receiver operator characteristics. See text for details.
*p=NS.
minutes and 91% at 60 minutes after start of therapy
(Figure 5).
Comparison With Other Clinical
Reperfusion Markers
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Table 2 demonstrates that resolution of ST segment
elevation and the occurrence of reperfusion arrhythmias were also predictors of coronary artery patency.
The calculated x2 values indicate that both markers
were comparable to those serum markers with the
lowest predictive values for coronary artery patency
(Tables 1 and 2). ROC curve analysis for ST segment
resolution resulted in an area under the ROC curve of
0.74 (versus 0.79 for CK slope, p=NS; versus 0.89 for
myoglobin slope, p<0.02). Because of the lack of variable cutoffs with respect to reperfusion arrhythmias,
ROC curve analysis cannot be performed for this
marker. The chest pain score did not yield statistically
significant prediction of the reperfusion status (Table
2). When myoglobin slope was assessed together with
other clinical markers by means of logistic regression
analysis, only the myoglobin slope was an independent
predictor of coronary artery patency (p<0.0001). The
probability values for the other markers examined were
0.10 for the occurrence of reperfusion arrhythmias, 0.13
for ST segment resolution, and 0.28 for resolution of
chest pain.
Discussion
The present study indicates that noninvasive prediction of coronary artery patency after thrombolytic therapy in patients with acute myocardial infarction is
possible by assessment of time-activity curves of serum
markers. Of particular clinical importance is the observation that analysis of the initial slopes of activity curves
over the first 90 minutes after initiation of thrombolysis
yields the same and for myoglobin even better predictive
accuracy than the determination of the time to peak
concentration of each marker. Decision making as to
further invasive procedures can be improved by use of
analysis of these early slopes in a substantial proportion
of patients. This allows early mechanical interventions
such as salvage angioplasty in selected individuals in
whom the infarct-related artery remains occluded after
thrombolysis. It has been demonstrated that these patients benefit from invasive interventions,11,12 whereas
routine coronary angiography is unnecessary and may
even be harmful to some individuals.14-'6
In previous studies from our institution as well as
from others, a short time to peak CK or CK-MB
concentration has been proposed as an indicator of
successful thrombolysis-induced coronary artery reperfusion.19'27-29 Only two studies so far have aimed to
examine the usefulness of the initial slopes of timeactivity curves of the two serum markers CK and
CK-MB concerning assessment of coronary artery patency.29'39 These investigators found that a rapid increase in CK and CK-MB concentrations closely reflected angiographic documentation of reperfusion.
However, ROC characteristics were not reported.
Other newly developed serum markers such as CK-MB
isoforms31 or the specific cardiac antigen troponin T32
have also been examined with respect to their utility as
indicators of coronary reperfusion. Puleo and Perryman31 analyzed peaks of MB2/MB, subform ratios in 33
patients undergoing thrombolysis and found this ratio
helpful for assessment of coronary artery patency within
2 hours after start of therapy. However, their study
appears to be limited by the small number of patients
undergoing thrombolytic therapy and by the fact that
coronary angiography was performed as late as 5 days
after thrombolysis. Katus et a132 studied the value of the
new cardiac antigen troponin T in 57 patients and
showed that troponin T peaks significantly earlier if the
infarct-related artery is successfully reperfused. However, cutoff values and initial slopes were not specifically
assessed in this study.
To the best of our knowledge, the present study is the
first to compare the serum markers CK, CK-MB, myoglobin, and troponin T systematically regarding their
value for noninvasive prediction of reperfusion. Of all
markers examined, myoglobin appears to exhibit several
advantages that make this protein particularly suitable
for early noninvasive prediction of patency of the infarct-related vessel. First, comparison of the ROC curve
characteristics revealed that analysis of the initial myoglobin concentration increase allows the best overall
prediction of success or failure of thrombolytic therapy
of all studied markers for analysis of both time to peak
and early slopes. Although the differences between the
ROC areas were small, the difference between myoglobin and CK approached significance (p=0.07), indicating potential clinical importance. Furthermore, the
highest univariate X2 values were also obtained for both
myoglobin slope and time to peak concentration. This
also resulted in high sensitivity and positive predictive
value for prediction of coronary artery patency. Additionally, the negative predictive value and specificity,
which reflect identification of patients with occluded
vessels, were quite high at 82% and 88%, respectively,
numbers that are not reached by the other markers
examined. Second, as already mentioned, quantitative
nephelometric analysis of myoglobin, which has been
validated against the radioimmunoassay used by Ellis et
al,30 provides laboratory results after a short turnover
time of only 15-30 minutes. Furthermore, an even more
Zabel et al Serum Markers for Prediction of Reperfusion
Downloaded from http://circ.ahajournals.org/ by guest on September 30, 2016
rapid assay using turbidimetry has recently been introduced into clinical practice.4344 Third, myoglobin concentration exhibited the earliest rise of all serum markers examined after initiation of therapy. Although the
purpose of the present investigation was not to examine
the accuracy of serum markers with respect to diagnosis
of myocardial infarction but rather the efficacy of
thrombolysis, this protein may offer an additional diagnostic advantage. The usefulness of myoglobin for noninvasive prediction of infarct-artery patency has recently been confirmed by other investigators.45
However, Clemmensen and coworkers45 reported no
comparison with other serodiagnostic markers in their
study. In the present investigation, CK maximum and
CK-MB maximum yielded relatively good diagnostic
information regarding coronary artery patency as well.
However, compared with the time elapsed to reach peak
myoglobin levels, it took four to five times as long to
reach maximal concentrations of these enzymes. This
time frame would therefore significantly reduce the
chances to salvage jeopardized myocardium by means of
invasive procedures. It has been shown previously that
combined analysis of noninvasive markers (i.e., peak
CK, resolution of ST segment elevation, occurrence of
reperfusion arrhythmias) can improve assessment of
success or failure of thrombolytic therapy.19 In the
present study, other clinical reperfusion markers did not
add significantly to the predictive power of myoglobin
slope analysis, indicating the particular strength of this
marker.
According to the results of the present study, troponin T offers no advantages for noninvasive prediction of
coronary reperfusion in patients undergoing thrombolysis (Table 1). However, troponin T analysis was helpful
in the four patients suffering from ventricular fibrillation. In these patients, CK values were distorted by the
enzyme release from skeletal muscles caused by the
defibrillation shock, whereas troponin T levels were not
affected because of the high specificity of this marker
for myocardial tissue.36
Clinical Implications
The present study demonstrates that analysis of the
early initial rise of several serum markers is as accurate
as determination of the time elapsed to reach their peak
concentration with respect to noninvasive prediction of
success or failure of thrombolysis in patients with acute
infarction. This allows early noninvasive prediction of
coronary artery patency in the majority of patients
within the first 2 hours after initiation of thrombolytic
therapy. These time limits allow for measures such as
rescue angioplasty that aim to salvage myocardium.
Early slope analysis of myoglobin appears to be superior
to the other serum markers examined and, in addition,
exhibits the most rapid concentration increase of all
markers evaluated.
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M Zabel, S H Hohnloser, W Köster, M Prinz, W Kasper and H Just
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Circulation. 1993;87:1542-1550
doi: 10.1161/01.CIR.87.5.1542
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