Editorial Board: F. Grosse-Brockhoff, Düsseldorf
· H. Krauss, Freiburg/Br. · R. H. Rosie,
Stuttgart · H. Köbcke, Munich
German Medical Monthly
Editor of the English Language Edition:
G. R. GRAHAM, LONDON
Board of Editorial Consultants: L. Heilmeyer
GEORG THIEME VERLAG – STUTTGART
Vol. XIII Stuttgart, March 1968 No. 3, page 111-116
The Thrombolytic Therapy of Recent Myocardial Infarction 1
Ill. Overall Assessment and Evaluation of Enzyme Studies
P. Körtge, F. Praetorius, B. Schneider, F. Heckner, J. van de Loo, F. A. Pezold,
H. Poliwoda, R. Schmutzler and D. Zekorn
From the First Medical Clinic (Director: Prof. H. Frh. v. Kress),
Free University, Berlin;
Institute of Biometry and Documentation (Director: Prof. B. Schneider),
College of Medicine, Hanover;
Division of Internal Medicine (Head: Prof. F. Heckner),
Zweckverband Hospital, Einbeck;
Medical Clinic and Policlinic (Director: Prof. E. Fritze),
Bergmannsheil Hospitals, Bochum;
Medical Clinic (Director: Prof. R. Gross),
University of Cologne;
Divisions of Internal Medicine and Infectious Diseases
(Director: Prof. F. A. Pezold), Behring City Hospital, Berlin;
Medical University Clinic (Former director: Prof. R. Schoen;
present director: Prof. W. Creutzfeldt), Gottingen;
Medical Clinic (Director: Prof. F. Hartmann),
College of Medicine, Hanover;
Medical University Clinic (Director: Prof. F. Koller),
and the Medical-Scientific Research Division of Farbwerke Hoechst AG,
1 Translated from the Dtsch. med. Wschr. 92 (1967), 1546.
In earlier reports (18, 22) of this investigation
of the treatment of recent myocardial infarction
with streptokinase and anticoagulants, the
mortality, thromboembolic complications, risks of
haemorrhage and electrocardiographic findings
were compared in the two treatment groups. The
risks of treatment were equally small in the two
groups. The mortality rate (2nd-40th days) and the
electrocardiographic changes (ST-elevation, QRS
changes, T-wave inversion, formation of
rudimentary infarcts) were each significantly more
favourable in the group receiving thrombolytic
therapy. The timing of the commencement of
thrombolytic therapy within a twelve-hour period
after the onset of infarction was found to have no
definite effect on the parameters investigated.
The present report deals with the serum enzyme
findings in the two treatment groups.
1. Methods of enzyme estimation. Enzyme activity
was measured with reagent combinations produced by
Boehringer, Mannheim (12, 24). The serum levels of
glutamic-oxalacetic transaminase (GOT) and creatinine
phosphokinase (CPK) activity were measured. Other
enzymes such as GPT and LDH and its isoenzymes
were not estimated in every one of the participating
centres and were therefore excluded from this
assessment. Since the times of collection of the blood
samples reported in Part I sometimes entailed storage of
the samples for up to twelve hours before the tests were
performed, the interpretation of the curves of CPK
results is subject to some reservation.
The problem of the stability of CPK in vitro has
recently been re-emphasized (2, 6, 9, 20, 25). It should
be pointed out, however, that all groups investigated
(streptokinase early, late; anticoagulants alone) were
equally affected by this problem. Serum GOT, on the
other hand, only loses 4 % of its activity after 24 hours
(2, 6). The similarity of behaviour of the two enzyme
curves and the fact that any loss of CPK activity applied
equally to all groups justified the comparative
evaluation of the findings and tended to reduce doubts
about the absolute height of the CPK curves.
Tab. 1. Numbers, sex distribution and mean ages of
patients studied in Parts I - III of this report. a = all
patients (Part I), b = ECG studies (Part II), c = enzyme
studies (Part III). m = male; f = female
Streptokinase Anticoagulants alone
a 297 261
Number (n) b 134 100
c 94 24
a 235 (79.1 %) 215 (82.3 %)
m b 116 (86.5 %) 86 (86.0 %)
c 83 (88.3 %) 18 (75.0 %)
a 62 (20.9 %) 46 (17.7 %)
f b 18 (13.5 %) 14 (14.0 %)
c 11 (11.7 %) 6 (25.0 %)
Age of patients (years):
a 57.8 58.1
m + f b 58.0 60.8
c 57.8 62.0
a 56.9 57.2
m b 56.9 60.4
c 57.5 61.2 (51-77)
a 61.6 62.4
f b 61.9 62.9
c 61.4 64.2 (54-73)
2. Choice of patients. Table I lists the patients
studied in Parts I-III of this investigation according to
method of treatment, study group, sex and age. In the
group of patients treated with anticoagulants alone there
were only 24 with sufficiently detailed enzyme studies.
The group was thus too small as an adequate control
group for comparison with the streptokinase-treated
group. Our interpretation was therefore confined to a
comparison of enzyme activity in relation to the time of
commencement of thrombolytic therapy between the
early group (within three hours of infarction) and the
late group (between three and twelve hours of
For this purpose the course of enzyme activities in
94 patients treated with streptokinase was available. The
age and sex distribution of these 94 patients was similar
to those of other treatment groups. They comprised 54
patients whose treatment commenced within three hours
of infarction ("streptokinase early") and 40 patients
whose treatment commenced from three hours to within
twelve hours after infarction ("streptokinase late"). The
mean ages of the two groups were 57.5 and 59.1 years
respectively. The site of infarction did not affect the
enzyme studies (4, 17). Re-infarction was not
To qualify for admission to the study programme
patients had to have at least two sets of enzyme estimations
during the first 24 hours after infarction. The
reduction in the total numbers of patients to 94 was
mainly due to the fact that the majority of patients did
not meet this requirement. Moreover, patients with
"rudimentary" infarcts, which were considered as a
special group in Part II, were omitted in the present
evaluation on account of their small numbers. As the
selection of patients in these circumstances could not be
held to be biased in favour of good risk patients, the
publication of the results of enzyme studies appeared
justified. Considerations involved in the interpretation
of enzyme kinetics in myocardial infarction also
appeared to be of general interest.
Altogether 838 enzyme estimations were assessed
(GOT: 534; CPK: 304). In a pilot study of patients
treated with streptokinase (n = 36) at one of the participating
centres, the mean levels of enzyme activity at
various points of time were calculated and a curve was
constructed (16) by geometric means (19). This showed
a higher level of enzyme activity in the ascending
portion of the curve in the "streptokinase early"
treatment group. The differences were significant
during the third to fourth hours (CPK) and the fifth to
sixth hours (GOT). In order to define these differences
more precisely the total material from the six
participating centres was analysed with the aid of an
electronic calculator at the Institute of Biometry and
Statistics of the College of Medicine at Hanover; this,
amongst other things, permitted the accurate calculation
of means for the individual treatment groups without the
need to segregate single values into time class intervals.
3. Method of interpretation. The purpose of the
evaluation was to define measures of the height of
serum enzyme activity in relation to time after
myocardial infarction. These parameters were chosen to
describe the course of the curves adequately and at the
same time to permit comparison of the curves in various
treatment groups so that the effect of treatment could be
A study of the course of experimental enzyme
curves showed that this resembled the mathematical
y = A ⋅
( e − e )
In this formula y represents enzyme activity, t the time
(after the onset of infarction), and A1, k1, and k2 are the
indices of size describing the form of the curve. Of
these indices k1 describes the descending limb of the
curve, k2 the ascending limb and A the height of the
peak of the curve.
On the assumption of a 3-compartment model for
myocardial infarction (4), k1 may be taken as the
"elimination rate" of the enzyme from the blood serum
which is regarded as the distribution, k2 as the "infusion
rate" of the enzyme from the site of infarction into the
blood serum, and A as a measure of the total enzyme
activity liberated and hence proportional to the size of
the infarcted area as a whole. It must be obvious that
this interpretation is based on a greatly simplified
hypothetical model which only reflects an approximate
outline of the major relationships. The model cannot
take into account the finer points of this complicated
biological process. Great discrimination must therefore
be exercised in any interpretation of the parameters.
Notwithstanding this reservation, the descriptive
significance of the parameters A, k1 and k2 may be used
to describe and compare the course of the various
curves. In this context their application and
interpretation can be subjected to exact statistical
criteria. An objective basis for comparison is thus
The mathematical and biometric bases of this model
will be the subject of a separate report (Schneider and
colleagues: in preparation).
The method of least squares was used for purposes
of calculation (statistical evaluation) of the parameters
A, k1 and k2 from the observed points on the curves;
according to this the curves are constructed in such a
way that the sum of the squares of the deviations
between the points measured and the points on the
curves are as small as possible.
For reasons stated earlier, interpretation could not be
applied to each patient individually. Patients were
therefore grouped according to types of treatment
received. The curves of the patients in the
"streptokinase early" group and of patients in the
"streptokinase late" group were compared by the
method of least squares. This proved difficult because
of the wide scatter of values within each group and the
lack of any tendency to form smooth curves. This was
regarded as being due to individual differences between
the enzyme concentration curves of individual patients.
The result of this was that the scatter of points actually
measured about the calculated curve varied between
166 and 299 %.
In the classification of various patients into
treatment groups, the calculated parameters no longer
have any individual biological significance. Rather, they
should be regarded as a sort of "mean value" reflecting
something like the enzyme concentration over the
course of time of a group as a whole. This explains why
the peaks of the curves are substantially below the
peaks of the levels found in individual patients.
On the other hand, it may be expected that the height
and form of the curves will characterize the behaviour
of the enzymes in the various treatment groups. The
statistical evaluation of our results rests on this
The course of the curves of enzyme activity of
GOT and CPK is illustrated in Figs. 1-3. Both enzymes
showed distinct differences in the ascending
Fig. 1. Levels of enzyme activities of GOT and CPK
in patients receiving early and late treatment of recent
myocardial infarcts with streptokinase (SK).
Fig. 2. Serum GOT activity during the first 48 hours after
the onset of infarction in patients receiving streptokinase
(SK). The constant k. is a measure of the steepness of
the rise in serum enzyme activity.
Fig. 3. Serum CPK activity during the first 48 hours after
the onset of infarction in patients receiving streptokinase
(SK). The constant k,, is a measure of the steepness of
the rise in serum enzyme activity.
limb of the curves between patients treated with
streptokinase early and those treated late. The
peaks of enzyme activity were also reached at
different points of time: the peak of CPK occurred
5.1 hours and the peak for GOT 4.3 hours earlier in
the patients who received early streptokinase
therapy. The differences in the heights of the peaks
were not significant: 2.7 mU/ml. for GOT and 0.63
mU/ml. for CPK.
Table 11 shows the parameters of the calculated
In addition to the peak, the constant k2 is important
in the interpretation. This constant exercises
its greatest influence over the ascending limb of
the curve of enzyme activity (first few hours after
the onset of infarction) and is to some extent a
measure of the steepness of rise in enzyme
activity. k2 was found to be greater for both
enzymes in the early streptokinase treatment group
than in the late group. This was interpreted as
evidence of a steeper rise in enzyme activity with
early streptokinase therapy (Figs. 2-3).
A statistical test could not be applied to the
parameters obtained since the parameters did not
follow a linear function and their distribution could
not be defined accurately. The results were
nevertheless statistically relevant since they were
obtained by the objective procedure of the method
of least squares. They thus possess practically all
the optimal statistical properties and, in particular,
they are true to expectation in that the mean of the
actual values coincides with the expected values,
and are efficient in the sense that they exhibit
minimal variance. These factors provided the
statistical basis for the interpretation of the results
The prevention of myocardial necrosis by
instant thrombolysis must be a very rare event in
coronary artery thrombosis. It must be assumed
that this optimal result of therapy is virtually
unattainable in practice and in fact cannot be
Tab. II. Parameters of the calculated curves * where E = the normal mean (6).
Peak of curve
Time (hours) Height (mU/ml.)
GOT Streptokinase late
y = A⋅
( e − e )
CPK Streptokinase late
** Relative scatter of measured values about the calculated curve.
practice and in fact it cannot be demonstrated by
means of the methods available at the present time.
The rudimentary infarcts discussed in Part II (18)
of this report characteristically showed an
elevation in enzyme activity, but were excluded
from the analysis of enzyme activity because they
were not transmural infarcts. Since both optimal
possibilities (absence of necrosis, rudimentary
infarct) were excluded, only the findings in fully
developed myocardial infarcts will be discussed.
The following results were obtained:
1. The height of the peak of the curves was not
significantly different in the early and late
streptokinase treatment groups.
2. The curves of both enzymes (GOT, CPK)
showed a steeper rise in patients treated with
streptokinase early. With early treatment the peak
was thus attained more rapidly.
In Part I of this report (22) discussion of the
effects of thrombolytic therapy dealt with the
following possibilities: the re-opening of vessels
occluded by thrombus; the prevention of spread of
thrombosis to neighbouring vessels or its effective
treatment; and the restoration of the circulation in
the border zone adjoining the area of necrosis.
From these considerations the following
interpretations might be placed on the course of
a) According to current concepts it is assumed
that the total quantity of enzymes leaving a
myocardial infarct is proportional to the bulk of the
tissue destroyed (15, 21). The peak of the curve of
enzyme activity in the serum is regarded as
representative of the total enzyme release. Against
this is the fact that the influx of GOT into the
blood has a half-time of 42 hours (4) whereas the
peak of enzyme activity is attained much earlier.
At the time of the peak of the curve the rate of
influx of the enzyme into the blood is greater than
the rate of efflux of enzyme from the blood. After
the peak of the curve the "diffusion phase" first
predominates, that is, the distribution of the
enzyme throughout the vascular and extravascular
space (first exponential fall) (10). After this the
further fall in enzyme activity ("elimination
phase") (10) to normal levels - until equilibrium is
restored - is determined only by the turnover rate
The assumption that the peak of enzyme
activity corresponds to the total quantity of
enzymes and hence to the size of the infarct can
really only be used for the comparison of series in
which the conditions for the loss of enzymes from
the infarcted area are constant as, for instance, in
infarcts of the same size due to permanent ligation
of a branch of the coronary artery. This is evident
from the model devised by Brüdigam and
colleagues (4) in which the peak of the curve was
shown to be equally affected by the total quantity
and the velocity constants of the influx and of the
It is especially important for the circulatory
conditions through the area to be identical for
groups under comparison (10). This condition
cannot be fulfilled during the course of therapy
designed to improve the circulation through the
area by re-opening vessels. The re-opening of a
vessel supplying the region of the infarct could be
expected to result in the more rapid appearance of
the liberated enzymes in the general circulation
(5). This would result not only in an earlier
attainment of the peak but also in a greater height
of the peak itself since the injection of enzymes in
animal experiments has shown that an influx of
enzymes of this order cannot be compensated for
so rapidly by enzyme distribution and elimination.
Accordingly, in two groups of patients with
myocardial infarcts of similar size receiving
thrombolytic therapy, the more rapidly the vessels
were re-opened the sooner the peak of enzyme
activity would be attained and the higher it would
be. In these circumstances a higher peak, if
attained earlier, would not signify a larger area of
) If it were assumed that the vessels in the
necrotic region remained patent at least during the
early phases of the process of infarction, the rate of
enzyme outflow would be dependent on the rate of
flow through the large afferent vessels (5). Other
factors which would affect the mechanism of
distribution of enzymes throughout the extracellular
tissue space and the entry of enzymes into
the plasma are not known at present (10).
In patients treated with streptokinase the GOT
and CPK levels rose more rapidly when treatment
was started earlier, that is, within three hours of the
onset of infarction. The peak of the enzyme curves
was also attained earlier.
From the foregoing discussion it might be
expected that the earlier peaks in the patients
receiving early streptokinase therapy would also
have been higher. This proved not to be so. The
differences of 2.7 mU/ml. for GOT and 0.6 mU/
ml. for CPK were small and not significant. It
could be argued that since the patients treated with
streptokinase early should have had not only
steeper rises but also higher peaks in enzyme
activity than those treated late if the infarcts were
of equal size in the two groups, the fact that they
did not have higher peaks could suggest that the
total quantity of enzymes and thus the average size
of the infarct was perhaps actually smaller in the
early treatment group.
An effect of streptokinase on the elimination
phase (from say the 4th to the 7th days) of the
enzymes is not to be expected since elimination
depends not on further happenings in the infarcted
area but on protein turnover rates (1, 10). In this
phase the curves of the early and late treatment
groups no longer showed any differences (Fig. 1).
In an investigation comparing streptokinase with
urokinase, Lippschutz and colleagues (14) found an
inverse correlation between the peak of enzyme activity
and the time required for enzyme levels to return to
normal: higher peaks led to a more rapid fall in the level
of enzyme activity. This finding is in line with the
interpretation we have discussed. A more rapid rise in
enzyme activity during streptokinase therapy was also
observed by Benda (3). Fletcher (8) obtained similar
curves for GOT activity. According to the in-vitro
investigations of Fletcher (7) there was no suggestion
that streptokinase influenced these enzymes directly.
Signs of Recanalization
According to the animal experiments of Hort
and colleagues (11), compared with permanent
occlusion, rapid re-opening of an occluded
coronary vessel produced a more rapid and more
extensive connective tissue reaction and scar
formation. The more rapid rise in CPK and GOT in
the serum of patients treated with streptokinase
early who attained the same peak level of enzyme
activity could be interpreted as being due to the
re-opening of a vessel occluded by thrombus.
From the findings we have presented that we are
not in a position to discuss in which particular
patients recanalization occurred or whether the
recanalization was complete. The possibility of
recanalization was mentioned also in Part II of this
report dealing with the electrocardiographic course
of myocardial infarction under thrombolytic
therapy (rapid onset of the so-called "regression
phenomena": regression of ST-elevation; reduction
of QRS changes; appearance and disappearance of
Another consequence of rapid recanalization of
thrombotically occluded vessels could be an earlier
delineation of the necrotic area (11, 13), if it can be
assumed that not all the fibres have been subjected
to irreversible anoxic damage simultaneously
(incomplete occlusions; border areas). Two
findings in our material tend to support such an
effect: the relatively increased incidence of
rudimentary infarcts, that is infarcts which remain
small in the electrocardiogram, during
streptokinase therapy; and the presence of earlier
but not higher peaks of enzyme activity in patients
receiving early streptokinase therapy.
Treatment of an infarct with streptokinase involves
the patient in little risk. The nature and frequency of
the complications are acceptable in such a condition as
myocardial infarction. In no case was death due to
streptokinase and in only one patient was it necessary
to discontinue streptokinase therapy because of
haemorrhage in this case from a previously unsuspected
carcinoma of the stomach. Attention is drawn to
the most frequently encountered complication, because
it is usually avoidable: on six occasions bleeding
developed from the puncture sites after intramuscular
Overall Results and Conclusions
The purpose of this cooperative study from six
medical centres was to conduct a clinical and
therapeutic trial of the effects of thrombolytic
therapy with streptokinase in myocardial
infarction. The mortality, incidence of complications,
electrocardiographic findings and serum
enzyme curves were compared in numerically
large treatment groups of patients receiving
streptokinase and anticoagulant therapy.
1. The mortality during the first 24 hours was
the same in the two groups (5.38 % streptokinase;
5.36 % anticoagulants only). On the other hand,
the infarct mortality rate from the second to the
40th days was significantly lower in the streptokinase
group (8.7 %) than in the anticoagulant
group (16.1 %). The net result was a lower total
mortality (up to the 40th day) of 14.1 % (streptokinase)
compared with 21.7 % (anticoagulants
alone). There was no significant difference in the
incidence of cardiac rupture (2.7 % for streptokinase;
3.4 % for anticoagulants). Complications occurred
in 3.7 % of patients during streptokinase
therapy (among 558 patients; see Part I of this
2. On electrocardiography a significantly larger
number of patients belonging to the streptokinase
group showed rapid regression of ST-elevation,
changes in the QRS complex and T-wave
inversion. The proportion of rudimentary infarcts
was higher in the streptokinase treated group. At
the end of the 50-day observation period these
phenomena were again found in a higher
percentage of streptokinase patients. Rudimentary
infarcts were more frequently demonstrated in the
streptokinase group (among 234 patients; see Part
11 of this report ).
3. During streptokinase therapy a more rapid
rise in CPK and GOT activity occurred when
treatment was started during the first three hours
after infarction than when it was started later (3-12
hours). With early streptokinase therapy the peaks
of CPK and GOT activity were attained earlier.
There was no significant difference between the
heights of the peaks of the two streptokinase
treated groups. Statistical comparison with the
control group was omitted because of inadequate
numbers of estimations (among 94 patients; see
Part III of this report).
Strict randomization of treatment groups in the
present series was not attained. It was possible,
however, to show that there was no bias in selection
with regard to degree of severity in the various groups.
The findings of the present investigation have
confirmed the effect of thrombolytic therapy on
the course of recent myocardial infarction. The fall
in mortality rate from 21.7 % to 14.1 % suggests
that this effect may be significant for the patient.
In view of the statistically proved therapeutic
effect of streptokinase therapy in recent
myocardial infarction as assessed by various
methods of investigation (overall statistics,
electrocardiograms, enzymes) it seems reasonable
to suggest that patients with recent myocardial
infarction presenting within twelve hours of the
onset of the classical clinical features of infarction
should receive thrombolytic therapy, provided no
known contraindications to this exist.
A co-operative study was undertaken at six
medical centres to assess the effect of thrombolytic
therapy on the course of recent myocardial infarcts
in comparison with anticoagulant therapy alone.
The drop in mortality rate from 21.7 % to 14.1 %,
the more rapid regression of ECG changes and the
more rapid rise in serum enzyme activity were
evidence of the favourable effect of thrombolytic
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(Authors' addresses: Privatdozent Dr. P. Körtge; Dr. F.
Praetorius, I. Medizinische Universitätsklinik im Städtischen
Krankenhaus Westend, 1 Berlin 19, Spandauer
Damm 130; Prof. Dr. B. Schneider, Institut für Biometrie
und Dokumentation der Medizinischen Hochschule, 3
Hannover, Bischofsholer Damm 15; Prof. Dr. F, Heckner,
Innere Abteilung des Zweckverband-Krankenhauses
Einbeck, 3352 Einbeck, Deinerlindenweg; Dr. J. van de
Loo, Medizinische Universitätsklinik, 5 Köln-Lindenthal,
Lindenburg; Prof. Dr. F. A. Pezold, Städtisches Behring-
Krankenhaus, 1 Berlin-Zehlendorf, Gimpelsteig 3-5;
Privatdozent Dr. H. Poliwoda, Medizinische Klinik der
Medizinischen Hochschule Hannover im Krankenhaus
Oststadt, 3 Hannover, Podbielskistr. 380; Privatdozent
Dr. R. Schmutzler, Medizinische Universitätsklinik,
Bürgerspital, CH-4000 Basle; Dr. D. Zekorn, Medizinisch-Wissenschaftliche
Abteilung der Farbwerke
HoechstAG, 623 Frankfurt(M)-Hoechst,Germany)
The original text (Part I-III) in „Deutsche Medizinische