88

Journal of The Association of Physicians of India Vol. 64 February 2016

DRUG CORNER

Acenocoumarol: A Review of Anticoagulant

Efficacy and Safety
Abhijit Trailokya1, JS Hiremath2, JPS Sawhney3, YK Mishra4, Vivek Kanhere5, R Srinivasa6,
Mangesh Tiwaskar7

Pharmacokinetics

Abstract
Anticoagulant treatment is required for the treatment and prevention
of thromboembolic disorders. Vitamin K antagonists are commonly
used oral anticoagulants worldwide. Acenocoumarol is mono-coumarin
derivative with racemic mixture of R (+) and S (-) enantiomers. Efficacy
and safety of acenocoumarol has been evaluated in atrial fibrillation,
cardiac valve replacement, after myocardial infarction, treatment of deep
vein thrombosis, after major surgeries and after critical illness requiring
prolonged hospitalization. Acenocoumarol is effective and safe in all age
groups. It offers an advantage over warfarin in terms of better stability of
anti-coagulant effect. Due to its economic advantage acenocoumarol may
be suitable oral anticoagulant for long term use in countries like India.

Introduction

nticoagulant treatment is
indicated for the treatment
and prevention of recurrent
thromboembolic disorders.1 Vitamin
K antagonists are widely used
oral anticoagulants worldwide. 2,3
Vi t a m i n K a n t a g o n i s t s a c t b y
inhibition ofvitaminKepoxide
reductase and are often used for
long-term anticoagulation. 3 The
benefits of oral anticoagulants
h a ve b e e n c l e a r l y e s t a b l i s h e d
in well-designed clinical trials.
Coumarinpreparationsare
commonly used vitamin K
antagonists in clinical practice. 4
Warfarin, phenprocoumon and
acenocoumarol, the mono-coumarin

Fig. 1: Structure of acenocoumarol

derivatives are racemic mixtures of

R (+) and S (-) enantiomers.
Acenocoumarol is structurally
different from warfarin. The
difference is characterized by
nitrogroup in para position of
the phenyl ring (Figure 1). (R+)
acenocoumarol is more potent
anticoagulant compared to S (-)
acenocoumarol. 5
Acenocoumarol inhibits
reduction of vitamin K preventing
carboxylation of glutamic acid
residues of vitamin K dependent
clotting factors, an important
step in the process of clotting.
The mechanism of action of
acenocoumarol is depicted in
Figure 2.

Acenocoumarol is rapidly
absorbed from the gastrointestinal
tract resulting in peak concentration
(Cmax) of 0.3 (0.05) mcg/ml in 2-3
hours. Acenocoumarol is highly
bound to serum proteins; only 1.52%
is free in the plasma. The mean AUC
and half-life of acenocoumarol
are 3.9 (0.7) mcg ml/hr and 10.9
(1.5) hours respectively. After
the oral administration, maximum
effect of rise in prothrombin time
i s s e e n b e t we e n 2 4 - 3 0 h o u r s . 6
The CYP2C9 isoenzyme is
most important enzyme for the
clearance ofwarfarin while its
role in acenocoumarol clearance is
less. 3 Acenocoumarol is excreted
rapidly. 7
A comparative study (n=103)
showed that warfarindoes not
provide better performance than
acenocoumarolin terms of PT level
within therapeutic range (62% vs
59%; p=0.4). 8 Acenocoumarol has
been criticized for risk of factor
VII fluctuations because of shorter
half-life. The study conducted
by Barcellona and colleagues has
clearly shown that it is not true.
The results revealed higher factor
VII levels with both drugs 24 hours
afteradministrationcompared
to 16 hours after administration.

1
Medical Services Division, Abbott Healthcare Private Limited, Mumbai, Maharashtra; 2Director, Cath Lab,
Ruby Hall Clinic, Pune, Maharashtra; 3Sir Ganga Ram Hospital, Delhi; 4Director, Department of Cardiovascular
Surgery, Fortis Escorts Heart Institute & Research Centre, Delhi; 5Consultant Cardiac Surgeon, Chirayu Cardiac
Centre, Bhopal; 6Senior Professor of Neurology and Head, Dept. of Neurology, MS Ramaiah Medical college
and Hospitals, Bangalore, Karnataka; 7Consultant Physician, Asian Heart Institute & Research Centre, Karuna
Hospital, Mumbai, Maharashtra
Received: 18.07.2015; Revised: 22.12.2015; Accepted: 06.01.2016

Journal of The Association of Physicians of India Vol. 64 February 2016

89

three days and if remains above

4, then drug should be stopped. 1
For most of the conditions the INR
target is 2-3 while post-myocardial
infarction patients may need INR
between 3.0 to 4.0.
Based on the genotyping of
polymorphisms specific algorithm
has also been proposed for more
accurate acenocoumarol dosage
prediction. 12

Contraindications

Fig. 2: Mechanism of action of acenocoumarol

Intake of vitamin K affects the level

of factor VII rather than the half-life
of drug. 8
Wa r f a r i n s l o n g e r h a l f - l i f e
of approximately 36 hours
theoretically would provide
more stable anticoagulation.8
Despite the shorthalf-life
pharmacodynamicactivity
ofacenocoumarol is stable after
achieving the steady state. The
results of a clinical trial among
hospitalized patients with deep-vein
thrombosis, who received either
daily dose or twicedailydoses,
demonstrated that acenocoumarol
can be administeredoncedaily.
Twice-dailyuse is not required. 9

Dose
Acenocoumarol is usually
administered as once daily oral
dose1 given at the same time
every day. Because of differing
sensitivity to anticoagulant effect,
regular testing of prothrombin
time (PT)/ international normalized
ratio (INR) is required to adjust
the dosage. In settings of
unavailability of such facility,
use of acenocoumarol should
be avoided. In adult patients,
with normal thromboplastin time,
acenocoumarol should be given
4 mg per day. If the patient is on
heparin, dose may be reduced.
Loading dose is not required if the
PT/INR values are normal. On the
second day, acenocoumarol dose

ranges between 4-8 mg. Therapy

should be started carefully, if initial
thromboplastin time is abnormal.
Older patients or malnourished
people may need lower dose. The
maintenance dose (usually 1-8
mg/day) should be determined on
regular laboratory parameters and
adjusted based on INR estimations.
Tapering of dosage is generally
not required during withdrawal;
however, some high risk patients
may need gradual lowering of the
dose. 10
In children with mechanical
heart valves, acenocoumarol has
been given initially in oral doses
of 0.7-2 milligrams daily (average
1.5 milligram/day) in combination
with aspirin 150 to 500 milligrams
daily (average 250 milligrams/day)
started on the third day of surgery.
Subsequent dose adjustments
are done based on prothrombin
time ratio and activated partial
thromboplastin time. 11
If INR is less than 1.3, 1 mg per
day should be added while for
level between 1.4-2, dose of 0.5
mg should be added. Dose can be
maintained if INR falls between
2.1-3.0. If INR ranges between
3.1-3.5 and 3.6-4, then dose should
be reduced by 0.5 mg and 1 mg
per day respectively. INR should
b e repeat ed aft er one week in
all cases if the dose is altered. If
INR crosses 4, then drug should
be temporarily discontinued for

Acenocoumarol should
not be used in severe renal or
hepatic impairment. It should be
carefully used in mild to moderate
impairment. Acenocoumarol
should not be used in pregnancy,
hypersensitivity to acenocoumarol/
excipients or coumarin derivatives,
and conditions where the risk of
haemorrhage is more than the
potential benefit. 10

Warnings and Precautions

for Use
Missed dose of acenocoumarol
should be taken as early as possible
on the same day; but should not be
doubled to make up the missed dose.
Sometimes quick anticoagulation is
required and in such cases heparin
should be preferably used while
acenocoumarol may be started
s i m u l t a n e o u s l y o r a f t e r wa r d s .
Normal dose of heparin should be
given for minimum four days after
starting acenocoumarol. Heparin
should be continued till INR is in
the target level for minimum two
days. While stopping heparin,
close monitoring of coagulation
profile is recommended. During
major surgery or other procedure
where there is risk of bleeding,
close supervision of coagulation
status is required. Minor surgical
procedures where local hemostatic
precautions and treatment is
possible can be done without high
risk of bleeding. Risks and benefits
should always be considered while
st opping t he t herapy or using
other anticoagulant treatment.
Careful monitoring with repeated

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Journal of The Association of Physicians of India Vol. 64 February 2016

88.20%

52.90%
15 days
One year
23.50%
11.80%

Acenocoumarol

Control group

Fig. 3: Comparative response

(complete resolution of
thrombus) post MI

coagulation profile is required

when starting or stopping any
concomitant medicine. 10

Rapid Onset and Long

Duration of Action
Acenocoumarol has rapid onset of
action 7,13 while the effect lasts for 15
to 20 hours. Acenocoumarol causes
therapeutic hypoprothrombinemia
in most patients after about 36
hours of initial dose and almost
all patients in 48 hours. The
average maintenance daily dose of
acenocoumarol is 5.9 mg. 7

Efficacy and Safety

Efficacy and safety of
acenocoumarol has been studied
in wide conditions requiring
prevention and treatment of
thromboembolism including
atrial fibrillation, 14-16 cardiac valve
replacement, 17 after myocardial
infarction,7 prophylaxis of deep vein
thrombosis after major surgeries18,19
and after critical illness leading to
prolonged hospitalization. 1 The
data related to cardiac indications
for use of acenocoumarol after
acute myocardial infarction
( M I ) , 20 c h r o n i c h e a r t f a i l u r e , 21
a t r i a l f i b r i l l a t i o n , 14-16 s t e n t i n g
a f t e r c a r d i a c b y p a s s s u r g e r y 22
and cardiac valve replacement 17 is
briefly discussed here.
After Acute Myocardial Infarction

A randomized, multicentre,
double-blind study23 has shown that
in selected elderly patients (n=878),
long term oral anticoagulant
therapy after myocardial infarction
significantly reduces the risk of
recurrent myocardial infarction

and cardiac death. In elderly

patients on anticoagulants after
primary myocardial infarction were
randomized to receive treatment
with placebo or continuation of the
anticoagulant treatment for two
years. The total two year mortality
(7.6% vs 13.4%; p = 0.017) and
incidence of recurrent myocardial
infarction (5.7% vs15.9%; p = 0.0001)
was significantly less with oral
anticoagulant therapy compared
to placebo. The rate of intracranial
event was less with anticoagulant,
but not statistically significant
(5.6% vs 3.1%; p = 0.18). There were
no fatal extracranial haemorrhages
with the use of oral anticoagulant. 23
Acenocoumarol therapy started
early i.e. preferably within
five weeksafteracuteMI is
significantly effective in resolution
of left ventricularthrombus. Twodimensional echocardiography
assessed the effects of
acenocoumarol on left ventricular
thrombosis afteracuteMI. A
total of 38 post MI patients with
l e f t ve n t r i c u l a r t h r o m b i we r e
treated with either acenocoumarol
(n=19) and results were compared
with 19 non-treated patients.
At 1 5 d a y s a n d o n e ye a r p o s t
treatment (n=17) thrombus was
completely resolved in 52.9% and
88.2% patients respectively. In
control group only two patients
had resolution of thrombus at
1 5 d a y s a n d f o u r a t o n e ye a r .
Reduction in thrombus size was
seen in another four patients in
control group. However, thrombus
was unchanged in 52.9% patients in
control group (Figure 3). 20
The size of thrombi in patients
treated with acenocoumarol also
reduced consistently during follow
up.
Long-term anticoagulant therapy
can reduce mortality rate in chronic
heart failure (CHF). Patient who
d i d n o t r e c e i ve a n t i c o a g u l a n t
or antiplatelet therapy (n=150)
had an annual death rate of 4%
compared to 1.2% in patients who
received acenocoumarol (n=75)
or aspirin (n=250), indicating

reduced mortality rate in patients

with CHF class III-IV NYHA
with anticoagulant or antiplatelet
therapy. 21
Atrial Fibrillation

Antithrombotic prophylaxis is
essential in patients with atrial
fibrillation at risk of developing
c e r e b r a l s t r o k e . 14 I t h a s b e e n
documented that prolonged oral
anticoagulation with proper control
of INR significantly reduces the
risk of cerebral stroke. 24 However
outcome also depends on the
patients cooperation, an important
parameter in long term oral
antithrombotic therapy. 14
In patients withatrial
fibrillationacenocoumarol therapy
should be preferred over aspirin
(dose to provide maximal inhibition
ofplateletfunction) considering
its benefits. One year follow of
patients showed acenocoumarol
lowers D-dimer and prevents and
improves the breakdown of left
auricular thrombus formation. It
also lowers the risk of ischemic
stroke and thromboembolism.
On the other hand, aspirindoes
n o t r e d u c e D - d i m e r l e ve l s , o r
promote breakdown of left
auricular thrombi. Acenocoumarol
is superior to aspirin in prevention
of ischemic stroke. 25
Non-valvular Atrial Firbillation

Nonvalvular atrial fibrillation

is another indication for
long-term oral anticoagulation
treatment because of high risk for
thromboembolic complications. A
randomized trial (n=117) showed
a ve r a g e I N R va l u e s w i t h b o t h
warfarin and acenocoumarol in the
therapeutic (2-3) range [2.12 (0.61)
and 2.26 (0.79) respectively] with
average total weekly dose of 27.89
(12.34) and 20.44 (9.94) mg
respectively. 15
Kulo and colleagues evaluated
t he t reat ment quality b et ween
warfarin and acenocoumarol in
patients with nonvalvular atrial
fibrillation in a one year study. In
both groups, all average monthly
INR values were within therapeutic

Journal of The Association of Physicians of India Vol. 64 February 2016

37.60%

64.9%

60.0%

>50% therapeutic INR

values
18.3%

Warfarin

22.8%

> 75% therapeutic INR

values

Acenocoumarol

Fig. 4: Comparative effect on INR

range (2.0-3.0) without differences

in the quality of treatment. More
than 50% (P = 0.721) as well as
>75% (P = 0.714) therapeutic INR
values were similar in both groups
(Figure 4).
Significantly better stability
defined as period during which
therapeutic INR values were
stable (P = 0.0002) was seen with
acenocoumarol compared to
warfarin treatment (Figure 5). 16
After Cardiac Stenting

Strictanticoagulation therapy is
essential for maintaining patencyof
graft afterstent implantation as
shown by analysis of 46 stents (n=
24) in 35 lesions. In these patients
activated partial thromboplastin
time was maintained at 2-3 times
control level by giving intravenous
heparin till thrombotest values
we r e r e d u c e d 5 - 1 0 % b y u s i n g
acenocoumarol. Adequate
anticoagulation was observed in
all except two patients who were
successfully treated with coronary
arterybypassgrafting. 22
After Cardiac Valve Replacement

In patients with cardiac valve

replacementacenocoumarol plus
aspirin (330 mg) and dipyridamole
(75 mg) twice daily INR of 2-3 is safer
and also provides good protection
against thromboembolism
compared to INR of 3-4.5. 17
Prophylaxis and Treatment of Deep
Vein Thrombosis

A total of 101 patients

undergoing total hip replacement
were studied in a prospective study.
The patients were randomized to
receive treatment with either of
the two regimens; acenocoumarol
3 mg once day started four days
before surgery or on the day of

35.70%

Warfarin

Acenocoumarol

Fig. 5: Percentage time of INR

values in therapeutic range

the surgery; Acenocoumarol 3

mg was started on preoperatively
with dose adjustment to yield
an INR of 1.5-1.6 during surgery
and thereafter 2.1. There was no
difference between two groups in
the incidence of proximal localized
deep venous thrombosis (11/51 vs
12/50). No cases of postoperative
hemorrhagic complications or
fatal pulmonaryembolism occurred
during the study. 18
In another study patients
with more than 40 years of age
undergoing major gynaecological
surgery (n=145) were randomized
to receiveacenocoumarol stabilized
over five days before operation
and continued during second
postoperative week (n=48),
subcutaneouslow-doseheparin
(n=49)or subcutaneous saline
(n=48). The incidence of DVT
e v a l u a t e d b y 125I - f i b r i n o g e n
scanning was almost similar to
heparin (Figure 6). The incidence
of haemorrhage was similar in all
groups. 19
A small study from India
evaluated the safety and efficacy of
acenocoumarol in DVT prophylaxis
among 39 critically ill patients who
were treated with low molecular
weight heparin and acenocoumarol
2 mg for five days. The dose was
adjusted to maintain INR of 2-3.
Once therapeutic level of INR was
achieved, heparin was stopped
a n d o n l y a c e n o c o u m a r o l wa s
continued. These patients needed
prolonged mechanical ventilation
with mean duration of 38.57 (9.23)
days. During the mean duration
of intensive care unit (ICU) stay
of 47.73 (16.22) days. During
ICU stay or three months after, no

91

patient developed complication

related to acenocoumarol
treatment. No patient developed
deep vein thrombosis during
ICU stay as evaluated by
symptoms or Doppler. The cost
of acenocoumarol including the
cost of INR monitoring was only
330 Indian rupees for thirty day
therapy. Acenocoumarol can be a
good alternative for prevention of
DVT in critically ill patients. 1
Treatment of Symptomatic Venous
Thromboembolism

A r a n d o m i z e d , c o m p a r a t i ve
study among 4289 patients
with symptomatic venous
thromboembolism who received
three month treatment with one
of the four oral anticoagulants
(warfarin, acenocoumarol,
phenprocoumon or fluindione)
started within 72 hours of episode
with dose adjustment to achieve
a target INR of 2.0-3.0 showed
lower incidence of recurrent
venous thromboembolism with
acenocoumarol compared to
wa r f a r i n ( 2 . 5 % v s 4 . 6 % ) w i t h
similar safety. 26 Warfarin resistance
defined as dose requirements of >70
mg weekly to maintain target INR
level could be another indication
for use of acenocoumarol. At the
moment, this indication is not
studied in well designed clinical
trials, but found useful in a case
report. 27

Long Term Use

A Spanish study documented
ten year experience with use of
acenocoumarol in ambulatory
patients. The most common
indication for the use of
acenocoumarol in this cohort was
atrial fibrillation. A total of 73%
patients received acenocoumarol for
atrial fibrillation. Analysis of 1,086
patients with median age of 74 years
receivingacenocoumarolshowed
INR in the therapeutic range
(2.0-3.0) in 82.5% patients. Overall
bleeding rate (2.27/100patientsyear ) and thrombotic event rate
was low (0.2/100patients-year) was

92

Journal of The Association of Physicians of India Vol. 64 February 2016

22.90%

6.30%

6.10%

Acenocoumarol

Heparin

Saline

Fig. 6: Incidence of DVT on

prophylaxis

low. Acenocoumarol can be safely

used in elderly. The analysis of
Spanish cohort showed age and is
not associated with higher risk of
bleeding. 28
Cost is a concern for long
term therapy with any disease
especially in countries like
India. Acenocoumarol can be an
economic option for long term
anti-coagulant therapy. According
to an Indian study, the cost of
acenocoumarol including the cost
of INR monitoring is about 330
Indian rupees for one month. 1

Acenocoumarol in
Children
Anticoagulant treatment with
acenocoumarol is not difficult
even inchildren. Woods A et al
reported long term experience
of acenocoumarol plus aspirin in
31children (5 months-16 years) with
cardiac valve replacement (mitral
n=20; aortic and mitral-aortic n=4
each; tricuspid n=3) followed up
for 1336 months. With adequate
anticoagulation, the embolism was
seen in 0.74/1000 patient-months.
Close to 94% patients did not have
thromboembolism up to 96 months
of follow-up. The incidence of
minor and major haemorrhage was
1.49/1000 and 0.74/1000 patientmonths. 11

Table 1: Comparison of acenocoumarol with warfarin

Absorption on oral
administration
Peak concentration
Protein binding
Half-life
Duration of action
Elimination
Dependence on CYP2C9 for
metabolism3
Anticoagulation stability16,29
Availability32

Acenocoumarol
Rapid6

Warfarin
Rapid, Complete30

2-3 hours6
Approximately 99%30
10.9 hours (short)6
2 days (48 hours)31
Renal 60%
Faces 29%31
+

Within four hours30

98.48%6
Long (30-80 hours) 16
2-5 days31
92% renal; Very little is
excreted unchanged30
++

++
1, 2 and 4 mg tablets

+
1, 2, 2.5, 3, 4, 5, 6, 7.5, and 10
mg.

Treatment was started with

warfarin and changed to
acenocoumarol. The patients
were followed for three months
on warfarin and acenocoumarol
each. The percentage of patients
with INR in therapeutic range
( 2 - 3 ) wa s s i g n i f i c a n t l y h i g h e r
with acenocoumarol compared to
warfarin (5626.8% vs 4922.6%;
p < 0.05) while supratherapeutic
values occurred more commonly
on warfarin compared with
acenocoumarol (2820% vs 1919%;
p<0.001). 29

has been described in the Indian

Pharmacopoeia.33 Various strengths
of acenocoumarol tablets from
0.5-6 mg are available in India
for prophylaxis and treatment of
thromboembolic disorders.

Conversion Factor for

Dose from Warfarin to
Acenocoumarol

4. Better anticoagulation stability

than warfarin 16,,29

The SPORTIF-III substudy

has shown a good correlation
between doses of warfarin and
acenocoumarol. The dose ration
of warfarin to acenocoumarol is
2.180.78. 29
In another study the transition
factor between acenocoumarol and
warfarin is shown to be 1.85. The
transition factor helps to calculate
the maintenance dose when patient
is required to be switch from
acenocoumarol to warfarin. 2

Superior Anticoagulant
Stability with
Acenocoumarol

Comparison of
Acenocoumarol with
Warfarin

In the SPORTIF-III substudy

a c e n o c o u m a r o l wa s c o m p a r e d
withwarfarin(W) in 74 patients
with chronic atrial fibrillation.

The differential features of

acenocoumarol with warfarin are
given in table 1.
Acenocoumarol monograph

Overall Advantages
1. Rapid onset of action 7,13
2. T h e e f f e c t l a s t s f o r 1 5 - 2 0 hours. 7
3. Less dependence on CYP2C9
for metabolism compared to
warfarin 3

5. Rapid reversal of anticoagulant

action with relatively small
amounts of vitamin K 17

Adverse Events
The most serious complication
withoralanticoagulation is
bleeding. AnItalianstudy
involving 2745 patients (warfarin
64%, acenocoumarol 36%) with
follow up of 267 days had
bleeding complication rate of 7.6
per 100 patient-years of which
0.25 per 100 patient-years were
fatal. These results show that
oralanticoagulation is safer with
proper monitoring. 34
Acenocoumarol is well tolerated
when given orally. The risk of
bleeding is significantly high in
patients with INR more than five.
The risk of bleeding could be
higher in patients in patients
with mechanical prostheses and

Journal of The Association of Physicians of India Vol. 64 February 2016

drug interaction. The other risk

factors for bleeding are history
of intercurrent disease in the last
month, and non-compliance. 35
Cases of hematuria have been
r e p o r t e d w h e n a c e n o c ou ma r ol
was used for acute myocardial
infarction which resolved after
vitamin K 1 administration. 7
Coumarinpreparationscause
overall similar haemorrhagic
complications in older or younger
age. 4 The challenges for the use
of vitaminKantagonistsinclude
narrow therapeutic index and
unpredictable dose-response
pattern.3 Vitamin K1 given orally can
antagonise effect of acenocoumarol
within three to five hours and may
be required in case of moderate
to severe haemorrhage. Higher
dose of vitamin K 1(usually more
than 5 mg) can lead to resistance
to anticoagulant effects. In
life-threatening haemorrhagic
c o n d i t i o n s , i n t r a ve n o u s b l o o d
transfusion or recombinant factor
VIIa may also be required. 10

Summary
Anticoagulation is indicated for
the treatment and prevention of
various recurrent thromboembolic
disorders including atrial
fibrillation, after cardiac valve
replacement and for prophylaxis
of DVT in critically ill patients.
Acenocoumarol is a good alternative
for long term anticoagulation
because of its rapid onset of action
and long duration of action. Despite
short half-life acenocoumarol
provides stable anticoagulant
effect. Its long term safety has
been well established. Vitamin
K 1 in small dosage when used to
counter the effect provides results
in few hours.

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Azim A, Baronia AK, Rao PB, et al. Safety

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Van Leeuwen Y, Rosendaal FR, van der Meer FJ.

The relationship between maintenance dosages

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Ufer M. Comparative pharmacokinetics of vitamin

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Taberner DA, Poller L, Burslem RW, Jones JB.

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Tramarin R, Pozzoli M, Febo O, et al. Two

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