Download Myocardial Infarction by a Simple

The Control of Dicumarol Therapy in
Myocardial Infarction by a Simple
Blood Prothrombin Test
By
BENJAMIN MANCHESTER,
M.D.,
AND
BORIS RABKIN,
M.D.
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Effective anticoagulant therapy is dependent upon adequate and reliable blood prothrombin deter
minations. The initiation of such therapy usually requires hospitalization. The currently available
blood prothrombin tests require special laboratory facilities and trained personnel. The authors of
this report present the results of Dicumarol in myocardial infarction and a simple blood prothrombin
test for the control of such anticoagulant therapy. The test has been employed for more than eight
years. The method has proved to be simple, accurate, and practical, and has made anticoagulants
possible for patients at home as well as in the hospital.
plasma-dilution prothrombin time exponents
each have their own followers. Finally, it is
observed that the one-stage prothrombin time
measures a complex made up chiefly of proconvertin and prothrombin.
Disagreement exists as to whether the prothrombin time should be expressed in seconds
or per cent, as an index, or as the expression of
a hyperbolic curve. The types of thromboacplastin, the variability of thromboplastic
uniform
a
tivity, the inlability to standardize
thromboplastin have also presented problems
which required study.
The added cost to the patient has been
stressed. The requirement of trained technical
personnel and adequate laboratory facilities
VALUE of Dicumarol and heparin
THE
of thromboembolic
in the
prevention
complications seems well
disease and its
established.1-6 However, the indication for anticoagulant therapy in coronary occlusion with
myocardial infarction has been challenged.7-9
The reduction in mortality because of Dicumarol is doubted; the need for anticoagulants
by "good risk" patients is questioned. The
hazard of bleeding or the development of subintimal hemorrhage and resultant extension
of coronary occlusion have been offered as
deterrants to the use of Dicumarol alone or
with heparin.
Some observers have emphasized the difficulty of maintaining adequate, safe, theraof
peutic prothrombin levels. The difficulty
has
test
the
accurately performing prothrombin
not been overlooked. The one-stage method is
too simple and the two-stage method too comdeplicated. The Quick prothrombin timewhile
found
is
some,
by
termination
adequate
others prefer a "modification" of the Quick
prothrombin test. The whole-plasma and the
have been considered to make the use of anticoagulants in the home difficult or even im-
practicable.
the inpsychologic factors, including
the
psychic
conveniences to the patient and
trauma produced by repeated venepunctures,
have not been slighted.
Despite these hazards and objections, we
have treated individuals with acute myocardial
infarction with Dicumarol alone or with
home and in the hospital.
heparin, in the
Since 1946, a total of 300 subjects with one or
more myocardial infarcts have been studied.
One hundred fifty without anticoagulants
served as controls; the other 150 received
Dicumarol and heparin. Both groups otherwise
followed the same regimen and medication.
The
From the George Washington University School of
Medicine, Department of Medicine, and the George
Washington University Medical Service, District of
Columbia General Hospital, Washington, D. C.
Presented before the Scientific Sessions of the
Twenty-Sixth Annual Meeting of the American Heart
Association, Atlantic City, N. J., April 11, 1953. reThis research was made possible through a
search grant-in-aid from the Washington Heart Association.
691
Ci,·c·ulalion, .rolume S, i.ovember 19j.
692
CONTROL OF DICUMAROL THERAPY IN MYOCARDIAL INFARCTION
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BENJAMIN MANCHESTER AND BORIS RABKIN
Moreover, owing to inadequate laboratory
facilities, lack of laboratory technicians and
our awareness of the inaccuracy, variability,
multiplicity and preferability of prothrombin
methods, we employed a simple capillary blood
prothrombin test, a modification of the ZiffrenSmith whole blood prothrombin test.10 The
test was modified to a micromethod for bedside
use; a procedure so simple that it can be
performed by a completely inexperienced but
conscientious, interested person. Two to three
minutes are required to obtain a prothrombin
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time.
The purpose of this report is to describe a
.simple blood prothrombin test and to present
the results of Dicumarol therapy regulated by
this method.
MATERIALS AND METHODS
The 300 patients studied were under direct
supervision of the authors either at home or in the
hospital. Alternate cases in the first 224 patients
received conventional therapy and constitute the
"control" group, while the others received Di-
cumarol, alone or with heparin, in addition to conventional therapy and represent the anticoagulant
group. The remaining 76 patients were selected according to the day first observed. Those first ex-
amined on the odd calendar date received anticoagulants while those seen on the even calendar
*date were placed in the control group. In addition
to the clinical and laboratory findings, electrocardiographic confirmation of myocardial infarction
was required for inclusion in the study.
Most of the patients were seen within 72 hours
-of the onset of their illness. Seventy-five subjects
were seen one week after the onset of the acute
coronary occlusion; 37 were in the control and 38
were in the anticoagulant group. All patients who
died within the first 24 hours were not included in
the present report.
A comparison of the patients in the two groups
with regard to age, sex, previous infarction and
severity of the present attack according to "good"
and "poor" risk1' are shown in table 1. The ages
ranged from 31 to 81 years with a mean age of
58.5 for the anticoagulant and 61 for the control
group. Forty-two and 48 per cent were 61 years
old or over in the anticoagulant and control groups,
respectively. Sixteen per cent in the treated group
and 19.4 per cent in the control group were females.
A history of one or more previous myocardial
infarctions was noted in 28 per cent in the anticoagulant group and in 23 per cent of the control
group.
In the
anticoagulant group 72 per cent received
heparin and Dicumarol and 28 per cent received
Dicumarol alone. The initial dose of Dicumarol
was 200 to 300 mg. and thereafter 100 mg. daily
until the prothrombin level was in the therapeutic
range. For those who received heparin the prothrombin test was made three to four hours after
the last dose or when the clotting time was normal.
Daily prothrombin determinations were performed
during the first 30 days, then repeated at weekly
intervals for six or more weeks.
TECHNIC
The bedside method is a modified Ziffren-Smith
prothrombin test. Two hemoglobin pipets, a concave slide, stop watch, physiologic saline solution
and thromboplastin are the required materials.
(See fig. 1.) The thromboplastin is prepared from
acetone-desiccated rabbit brain as recommended
by Quick.12 To 4 cc. of physiologic saline solution
TABLE 1.-Composition of Total Group: 300 Cases
of Coronary Occlusion with Myocardial Infarction
Surviving First Day of Illness
Control
Anticoagulant
No. of Cases............ 150
Av. Age ............... 58.5
Males ................. 126 (84%)
With Previous Infarct... 42 (28%)
Good Risks............. 33 (22%)
Poor Risks ............ 117 (78%)
Heparin and Dicumarol. 108 (72%)
Dicumarol Alone....... 42 (28%)
150
61
121
(6%)
(12%)
26
42
Thromboembolic Complications.............
Mortality...............
9
18
34
47
103
(80.6%)
(23%)
(31%)
(69%)
0
0
(17.3%)
(28%)
693
FIG. 1
694
CONTROL OF DICUMAROL THERAPY IN MYOCARDIAL INFARCTION
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0.15 Gm. of dried powdered rabbit brain is added.
The mixture is then incubated for 20 minutes at
40 C.
Twenty cu. mm. of thromboplastin warmed to
37 C. are placed on a warm dry slide, and an equal
amount of free-flowing capillary blood, obtained
by a simple needle puncture of a finger, is added.
The slide is tilted gently back and forth until a
coagulum is formed. The time in seconds is the prothrombin time. The "total clotting time" for capillary blood is 15 to 18 seconds, with a standard
deviation of 2.5 seconds. A normal blood prothrombin time on a control is always taken before
it is determined on a patient. The therapeutic
level is maintained at twice the normal (36 to 40
seconds). When the prothrombin time is expressed
as a percentage of the normal the therapeutic level
was maintained between 40 and 60 per cent. The
equation for this determination is
Prot
index
hrombi --
normal prothrombin time
patient's prothrombin time
"poor risk" category. Patients without the
above signs or symptoms were classified as
"good risks." The grouping was made on the
clinical examination excluding the electrocardiographic and other laboratory data.
The total mortality in the control group was
42, or 28 per cent, and in the anticoagulant
group, 18 or 12 per cent (table 1). Clinical
thromboembolic phenomena occurred in 26,
or 17.3 per cent and in nine, or 6 per cent, in
the control and anticoagulant groups, re-
spectively.
Among the 47 good-risks in the control
group, the mortality was six, or 12.8 per cent.
Among the 33 good risks in the anticoagulant
group there were three deaths, or 9.1 per cent.
Thromboembolism occurred in two of the
or 4.2 per cent. Embolism was fatal
in both of these cases. Death occurred 14 and
18 days, respectively, after the onset of illness
and during otherwise uneventful convalescence.
In the anticoagulant group thromboembolism
also occurred in two patients, but the patients
recovered from this complication.
The mortality in the 103 poor risks in the
control group was 36, or 35 per cent, whereas
in the anticoagulant group of 117 there were
15 deaths of 12.8 per cent. Thromboembolic
complications in these poor risks showed a
corresponding contrast. They occurred in 24,
or 23.3 per cent, of the control group and in
only seven, or 5.9 per cent, of the anticoagulant
group. Death due to pulmonary embolism
occurred 12 times among poor risks in the
control group and once in the anticoagulant
group. Pulmonary embolism in the remaining
cases of both groups complicated by thromboembolism was the precipitating cause of
severe congestive heart failure.
In poor risks with two or more myocardial
good risks,
A comparison of this method with the Quick
and Link-Shapiro blood prothrombin tests is shown
in table 2. It compares favorably with the LinkShapiro method. The values expressed in per cent
in the Quick blood prothrombin test are based on
a hyperbolic dilution curve. When the bedside prothrombin test, expressed in per cent, is 60 to 40,
this corresponds to Quick prothrombin time expressed as 30 to 10 per cent, respectively. The
bedside prothrombin test is discussed in greater
detail in another report to be published.13
RESULTS
The subjects in both groups were classified
with regard to prognosis according to the
criteria of Russek and his co-workers" as
"good risk" and "poor risk" patients. Those
who had previous myocardial infarction,
angina pectoris, intractable pain, severe shock,
cardiomegaly, congestive heart failure, auricular fibrillation or other serious arrhythmia,
previous pulmonary embolism, or other states
predisposing to thrombosis, were placed in the
TABLE 3.-Mortality Rate and Incidence of Thromboembolic Complications in Control and Anticoagulant Groups
No. of Cases
Control
Good Risk
.......................
Poor Risk.........................
Total
*
...........................
Fatal.
Mortality
Anticoag.
Control
47
103
117
6
36
(12.8%)
150
150
42
(28%)
33
(35%)
t Recovered.
Embolism
Anticoag.
3
15
15
(9.1%)
(12.8%)
(12%)
Control
2
24
26
(4.2%)*
(23.5%)
(17.3%)
Anticoag.
2
7
9
(6.0%)t
(5.9%)
(6.0%)
BENJAMIN MANCHESTER AND BORIS RABKIN
TABLE 4.-Mortality Rate and Incidence of Thromboembolic Complications in Patients with Previous
Infarction
Mortality
No. of
of
No.
Cases
Anticoag.
Control
.
42
36
.
...............
Embolism
No.
%
No.
%
9
21
21.3
58.3
4
14
9.3
38.8
infarctions treated with Dicumarol the
nosis
better
was
patients. Among
control
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per cent
four
times,
or
58.3
14
subjects,
The
150
followed
died of
as
38.8
per
spectively,
sion of the
after onset
heart
sudden
re-
died
exten-
and in four
the
Of 15
series of
pulmonary embolism,
heart
failure,
to
intravenous
three
to
respiratory
one
morphine,
causes.
complications were noted in
cent of treated patients. The
10.6 per
hemorrhagic manifestations
as
20
the
unexplained death,
or
days,
anticoagulant
to
congestive
Hemorrhagic
20
death
patients
two
undetermined.
was
depression following
and four to unknown
16,
patients
myocardial infarct;
one was due
to
control group of
12
illness;
failure; four died of
of
fatalities in the entire
150,
the
In
follows:
death
of
nine
cent.
of death in
pulmonary embolism;
ruptured hearts 14 and
of congestive
cause
(table 4). Embolization occurred
in 9.9 per cent. In the control
or
causes
were
comparable
42 such
were 21
fatalities,
and
embolism
occurred in
cent,
per
or
prog-
subjects there
of 36
group
the
patients who
nine
died, or
therapy,
anticoagulant
received
21.3
in
than
distributed
were
epistaxis in two, ecchymoses on the
eight, hematuria in four, and hema-
follows:
body
in
temesis
and
hemoptysis
in two. If
epistaxis and ecchymoses,
hemorrhagic
the
one
excludes
incidence
be
of
or
4 per
complications
six,
cent. There were no deaths from hemor-
rhage
in the group treated with
would
anticoagulants.
Hemorrhagic
complications were the cause of
death in two, or 1.33 per cent of the control
group, as a result of ventricular rupture and
cardiac
tamponade.
DISCUSSION
The greatest deterrent to
cumarol therapy is the fact
the
use of Di-
that
a
simple,
695
accurate and inexpensive method for measuring
blood prothrombin activity has not been
available. Methods currently employed require
trained technical personnel and laboratory
facilities. The present report is unique in one
respect; Dicumarol has been given to patients
with coronary thrombosis and infarction in
the home as well as in the hospital. Effective
antithrombotic levels as measured by a simple
blood prothrombin test were maintained without the increased hazard of bleeding.
Whole blood for performing a blood prothrombin test has been employed by many
investigators in the past. A similar method
employing capillary blood was first described
by Quick in 1939.'4 Tocantins15 has employed
whole venous blood for the Ziffren-Smith
prothrombin test in his routine control of
anticoagulant therapy. Bruzelius'6 in Sweden
has used a similar micromethod for Dicumarol
therapy. Several modifications of a similar
type of prothrombin test have been reported.'7-21 So far as is known, the present
report is the first to deal with a large series of
patients with acute myocardial infarction in
which Dicumarol dosage has been controlled
by such a simple blood prothrombin test.
A comparison of this bedside prothrombin
test with current one-stage procedures shows
it to have much in common with the latter.
The term "prothrombin test" for such methods
is a misnomer. Both measure more than prothrombin activity. It has been shown that the
one-stage prothrombin test measures prothrombin, fibrinogen, and accelerator factors.22
The prothrombin time, therefore, is an accelerated "clotting test" and reflects more
than prothrombin concentration.
The present method is not without its
pitfalls. The accuracy and sensitivity of this
test was dependent upon an active and reliable
source of thromboplastin. While normal plasma
yielded the same prothrombin time with
different types of thromboplastin, Dicumarol
plasma behaved differently with various types
of thromboplastin. The results reported here
can only be reproduced if desiccated acetonedehydrated rabbit brain is used as the source
of thromboplastin. The thromboplastin activity may vary with the age, temperature and
696
CONTROL OF DICUMAROL THERAPY IN MYOCARDIAL INFARCTION
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amount employed. A control prothrombin
time must always be determined first on a
normal subject.
The described test has proved a valuable
practical guide to Dicumarol therapy for the
prevention of thromboembolic complications.
At the same time it was possible to detect
hypoprothrombinemia and to prevent hemorrhagic complications. The usefulness of the
simple blood prothrombin test which we have
employed for the control of Dicumarol therapy
is reflected in the therapeutic efficacy and
safety noted in this series. The results compare
favorably with the reports of other investigators using other prothrombin tests.
Those who challenge the value of anticoagulant therapy have suggested that the
favorable results noted in the literature may
be due primarily to the added attention given
to all patients who have received anticoagulant
drugs. Every effort was made in the study to
follow an identical medical regimen and provide
the same attention to the patients in both
groups.
It has been postulated that in addition to
prevention of thromboembolic complication,
anticoagulants prevent congestive failure,
ventricular fibrillation and cardiac asystole
by the prevention of intravascular coronary
thrombosis. Gilbert and Nalefski23 have suggested that the favorable results observed from
Dicumarol were due primarily to an increase in
coronary blood flow. Gilchrist24 believed that
in addition to the reduction in thromboembolism, anticoagulants had a favorable
influence on the associated shock syndrome.
The collective statistics from the proponents
of anticoagulant therapy have been critically
probed for defects and inaccuracies. Those
who challenge the value of anticoagulant
therapy emphasize the comparable low incidence of mortality in good risks not treated
with anticoagulants. The occasional thromboembolic complication would have little influence on the over-all mortality rate and hence
would justify their view. However rare, this
complication did occur and proved fatal to
two in our control group. While the increased
mortality from such a complication was only
4.2 per cent, hardly significant statistically,
the unpredictability of such a complication in a
good risk increased the responsibility of avoiding a preventable fatality from thromboembolism. To a family, the survival of such a
patient assumes greater importance than any
significant statistical figure. These observations
are in agreement with Wright's25 earlier
admonitions.
One critic has agreed that anticoagulants
are indicated in the poor risk. The mortality
in the control group was 35 per cent as against
12.3 per cent in the anticoagulant group.
Death was nearly three times more frequent
in the control group. Thromboembolic complications showed a decrease in the anticoagulant group. The prognosis in the poor risk
group with two or more myocardial infarctions
treated with Dicumarol was better than in the
comparable control group. The mortality
was reduced from 58.3 per cent to 21.3 per
cent, and embolization from 38.8 to 9.3 per
cent. These results have afforded an increased
sense of security and a more favorable prognosis. It was not vitiated by either anxiety or
fear of hemorrhage. The results of this study
indicate that the advantages of Dicumarol
therapy were greater than all the disadvantages
reported to date.
The hazard of hemorrhage was nevertheless
present. Without careful clinical observation,
attention to detail, and an awareness of
idiosyncracies, many medicaments are dangerous and even fatal. The incidence of hemorrhagic complications was low and compares
well with previous reports. Frequent prothrombin determinations made it possible to detect
levels of hypoprothrombinemia before hemorrhagic complications developed. The withdrawal of Dicumarol and administration of
vitamin K, orally or parenterally, was always
effective in stopping these manifestations. It
was unnecessary to hospitalize the patient or
to administer blood. Bleeding usually ceased
within 6 to 10 days. There were no deaths
from this cause.
SUMMARY
The control of Dicumarol therapy in acute
myocardial infarction by a simple capillary
blood prothrombin test has proved convenient,
BENJAMIN MANCHESTER AND BORIS RABKIN
practical and economical. It was possible to
administer anticoagulant therapy to 150
patients with myocardial infarction at home
and in the hospital. An additional 150 subjects
who did not receive anticoagulants served as
controls. Except for Dicumarol, alone or with
heparin, both groups followed the same regimen
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and received the same medication.
Mortality in the anticoagulant group was
12 per cent; in the control group it was 28
per cent. Among 33 subjects in the "good risk"
group treated with Dicumarol, there were
three deaths (9.1 per cent); while in 47 of the
good risks in the control group, the mortality
rate was six (12.8 per cent). The mortality
among 117 cases of the "poor risk" anticoagulant group was 15 (12.8 per cent). Among
the poor risks of the control group of 103 cases,
there were 36 deaths (35 per cent).
Thromboembolic complications developed
in nine (6 per cent) of the treated patients as
against 26 (17.3 per cent) in the control group.
Death due to pulmonary embolism occurred
in one subject (0.66 per cent) in the treated
group and in 12 (8 per cent) in the control
group. Two of the deaths in the latter group
occurred among the good risks. The prognosis
in the poor risk group with two or more myocardial infarctions treated with Dicumarol
was better than among poor risks of the control
group.
Hemorrhagic complications were noted in
16 (10.6 per cent) of the treated and in two
(1.33 per cent) of the control group.
The advantages of Dicumarol therapy,
properly administered, were greater than all
the disadvantages reported to date.
The value of the simple blood prothrombin
test employed for the control of Dicumarol
therapy is reflected in the therapeutic efficacy
and safety noted in this series. It compares
favorably with the reports of other investigators using other prothrombin tests.
SUMARIO ESPAROL
El control de la terapia de Dicumarol en el
infarto del miocardio agudo por medio de una
prueba sencilla de protrombina capilar sanguinea ha probado ser conveniente, practico y
economico. Fu6 posible administrar terapia
697
anticoagulante a 150 pacientes con infartos del
miocardio en su hogar y en el hospital. Unos
150 casos adicionales que no recibieron anticoagulantes sirvieron de controles. Excepto por
Dicumarol, solo o con heparina, ambos grupos
siguieron el mismo regimen y recibieron el
mismo medicamento.
La mortalidad en el grupo a que se les administr6 anticoagulante fu6 de 12 por ciento; en
el grupo control fu6 28 por ciento. Entre 33
sujetos en el grupo "buen riesgo" tratados con
Dicumarol, ocurri.eron
tres muertes (9.1 por
ciento); mientras que en 47 de los buenos riesgos
en el grupo control, la mortalidad fue de seis
(12.8 por ciento). La mortalidad entre 117 casos
de los riesgos pobres en el grupo tratado con
anticoagulante fun 15 (12.8 por ciento). Entre
los riesgos pobres en el grupo control de 103
casos, hibieron 36 muertes (35 por ciento).
Complicaciones tromboembolicas se desarrollaron en nueve (6 por ciento) de los pacientes
tratados en contraste a 26 (17.3 por ciento) del
grupo control.
Muerte debida a embolismo pulmonar ocurri6 en un sujeto (0.66 por ciento) en el grupo
con anticoagulante y en 12 (8 por ciento) del
grupo control. Dos de las muertes en este
uiltimo grupo ocurrieron entre los buenos riesgos. El prognostico en el grupo de riesgo pobre
con dos o mas infartos del miocardio tratados
con Dicumarol fu6 mejor que en el grupo de
pobres riesgos en el grupo control.
Complicaciones hemorragicas fueron observadas en 16 (10.6 por ciento) de los tratados y en
dos (1.33 por ciento) del grupo control. Las
ventajas de la terapia con Dicumarol propiamente administrada, fueron mayores que todas
las desventajas informadas hasta la fecha.
El valor de la prueba sencilla de protrombina
sanguinea empleada en el control de la terapia
con Dicumarol se refleja en la eficacia terap6utica y la inocuidad notada en esta serie. Compara favorablemente con los informes de otros
investigadores usando otras pruebas de protrombina.
ACKNOWLEDGMENTS
The authors wish to express their gratitude to
Dr. Irving S. Wright for his encouragement, kindness and helpful advice during the past eight years
of this project.
698
CONTROL OF DICUMAI(OL THERAPY IN MY( )(ARI)IAL
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The Control of Dicumarol Therapy in Myocardial Infarction by a Simple Blood
Prothrombin Test
BENJAMIN MANCHESTER and BORIS RABKIN
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Circulation. 1954;10:691-698
doi: 10.1161/01.CIR.10.5.691
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