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
Acenocoumarol is rapidly
Anticoagulant treatment is required for the treatment and prevention
absorbed from the gastrointestinal
of thromboembolic disorders. Vitamin K antagonists are commonly
tract resulting in peak concentration
used oral anticoagulants worldwide. Acenocoumarol is mono-coumarin
(Cmax) of 0.3 (±0.05) mcg/ml in 2-3
derivative with racemic mixture of R (+) and S (-) enantiomers. Efficacy
hours. Acenocoumarol is highly
and safety of acenocoumarol has been evaluated in atrial fibrillation,
bound to serum proteins; only 1.52%
cardiac valve replacement, after myocardial infarction, treatment of deep is free in the plasma. The mean AUC
vein thrombosis, after major surgeries and after critical illness requiring and half-life of acenocoumarol
prolonged hospitalization. Acenocoumarol is effective and safe in all age are 3.9 (±0.7) mcg ml/hr and 10.9
groups. It offers an advantage over warfarin in terms of better stability of (±1.5) hours respectively. After
anti-coagulant effect. Due to its economic advantage acenocoumarol may the oral administration, maximum
be suitable oral anticoagulant for long term use in countries like India. 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
Introduction derivatives are racemic mixtures of
clearance of warfarin while its
R (+) and S (-) enantiomers.

A nticoagulant treatment is role in acenocoumarol clearance 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 of vitamin K epoxide
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.
Coumarin preparations are
commonly used vitamin K
antagonists in clinical practice. 4
Warfarin, phenprocoumon and
acenocoumarol, the mono-coumarin
Acenocoumarol is structurally less. 3 Acenocoumarol is excreted
different from warfarin. The
rapidly. 7
difference is characterized by
nitrogroup in para position of A comparative study (n=103)
the phenyl ring (Figure 1). (R+) showed that warfarin does not
acenocoumarol is more potent provide better performance than
anticoagulant compared to S (-) acenocoumarol in terms of PT level
acenocoumarol. 5 within therapeutic range (62% vs
59%; p=0.4). 8 Acenocoumarol has
Acenocoumarol inhibits been criticized for risk of factor
reduction of vitamin K preventing VII fluctuations because of shorter
carboxylation of glutamic acid half-life. The study conducted
residues of vitamin K dependent by Barcellona and colleagues has
clotting factors, an important clearly shown that it is not true.
step in the process of clotting. The results revealed higher factor
The mechanism of action of VII levels with both drugs 24 hours
acenocoumarol is depicted in after administration compared
Figure 2. 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
Fig. 1: Structure of acenocoumarol

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 short half-life
pharmacodynamic activity
of acenocoumarol 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 twice daily doses,
demonstrated that acenocoumarol
can be administered once daily.
Twice-daily use 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
Journal of The Association of Physicians of India ■ Vol. 64 ■ February 2016
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
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
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
90 Journal of The Association of Physicians of India ■ Vol. 64 ■ February 2016

88.20% and cardiac death. In elderly reduced mortality rate in patients

patients on anticoagulants after with CHF class III-IV NYHA
52.90%
primary myocardial infarction were with anticoagulant or antiplatelet
15 days randomized to receive treatment therapy. 21
with placebo or continuation of the
One year
23.50% Atrial Fibrillation
11.80% anticoagulant treatment for two
Antithrombotic prophylaxis is
years. The total two year mortality
essential in patients with atrial
Acenocoumarol Control group
(7.6% vs 13.4%; p = 0.017) and
fibrillation at risk of developing
incidence of recurrent myocardial
Fig. 3: Comparative response c e r e b r a l s t r o k e . 14 I t h a s b e e n
(complete resolution of infarction (5.7% vs15.9%; p = 0.0001)
documented that prolonged oral
thrombus) post MI was significantly less with oral
anticoagulation with proper control
anticoagulant therapy compared
coagulation profile is required of INR significantly reduces the
to placebo. The rate of intracranial
when starting or stopping any risk of cerebral stroke. 24 However
event was less with anticoagulant,
concomitant medicine. 10 outcome also depends on the
but not statistically significant
patient’s cooperation, an important
(5.6% vs 3.1%; p = 0.18). There were
Rapid Onset and Long no fatal extracranial haemorrhages
parameter in long term oral
antithrombotic therapy. 14
Duration of Action with the use of oral anticoagulant. 23
In patients with atrial
Acenocoumarol has rapid onset of Acenocoumarol therapy started
fibrillation acenocoumarol therapy
action 7,13 while the effect lasts for 15 early i.e. preferably within
should be preferred over aspirin
to 20 hours. Acenocoumarol causes five weeks after acute MI is
(dose to provide maximal inhibition
therapeutic hypoprothrombinemia significantly effective in resolution
of platelet function) considering
in most patients after about 36 of left ventricular thrombus. Two-
its benefits. One year follow of
hours of initial dose and almost dimensional echocardiography
patients showed acenocoumarol
all patients in ≤48 hours. The assessed the effects of
lowers D-dimer and prevents and
average maintenance daily dose of acenocoumarol on left ventricular
improves the breakdown of left
acenocoumarol is 5.9 mg. 7 thrombosis after acute MI. A
auricular thrombus formation. It
total of 38 post MI patients with
also lowers the risk of ischemic
Efficacy and Safety l e f t   ve n t r i c u l a r   t h r o m b i we r e
stroke and thromboembolism.
treated with either acenocoumarol
On the other hand, aspirin does
Efficacy and safety of (n=19) and results were compared
n o t r e d u c e D - d i m e r l e ve l s , o r
acenocoumarol has been studied with 19 non-treated patients.
promote breakdown of left
in wide conditions requiring At 1 5 d a y s a n d o n e ye a r p o s t
auricular thrombi. Acenocoumarol
prevention and treatment of treatment (n=17) thrombus was
is superior to aspirin in prevention
thromboembolism including completely resolved in 52.9% and
of ischemic stroke. 25
atrial fibrillation, 14-16 cardiac valve 88.2% patients respectively. In
replacement, 17 after myocardial Non-valvular Atrial Firbillation
control group only two patients
infarction,7 prophylaxis of deep vein had resolution of thrombus at Nonvalvular atrial fibrillation
thrombosis after major surgeries18,19 1 5 d a y s a n d f o u r a t o n e ye a r . is another indication for
and after critical illness leading to Reduction in thrombus size was long-term oral anticoagulation
prolonged hospitalization. 1 The seen in another four patients in treatment because of high risk for
data related to cardiac indications control group. However, thrombus thromboembolic complications. A
for use of acenocoumarol after was unchanged in 52.9% patients in randomized trial (n=117) showed
acute myocardial infarction control group (Figure 3). 20 a ve r a g e I N R va l u e s w i t h b o t h
( M I ) , 20 c h r o n i c h e a r t f a i l u r e , 21 warfarin and acenocoumarol in the
The size of thrombi in patients
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 therapeutic (2-3) range [2.12 (±0.61)
treated with acenocoumarol also
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 2.26 (±0.79) respectively] with
reduced consistently during follow
and cardiac valve replacement 17 is average total weekly dose of 27.89
up.
briefly discussed here. (±12.34) and 20.44 (±9.94) mg
Long-term anticoagulant therapy respectively. 15
After Acute Myocardial Infarction
can reduce mortality rate in chronic
A randomized, multicentre, Kulo and colleagues evaluated
heart failure (CHF). Patient who
double-blind study23 has shown that t he t reat ment quality b et ween
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
in selected elderly patients (n=878), warfarin and acenocoumarol in
or antiplatelet therapy (n=150)
long term oral anticoagulant patients with nonvalvular atrial
had an annual death rate of 4%
therapy after myocardial infarction fibrillation in a one year study. In
compared to 1.2% in patients who
significantly reduces the risk of both groups, all average monthly
received acenocoumarol (n=75)
recurrent myocardial infarction INR values were within therapeutic
or aspirin (n=250), indicating

60.0%
64.9%
>50% therapeutic INR
values
18.3%
22.8% > 75% therapeutic INR
values
Warfarin 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
Strict anticoagulation therapy is
essential for maintaining patency of
graft after stent 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
artery bypass grafting. 22
After Cardiac Valve Replacement
In patients with cardiac valve
replacement acenocoumarol 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
Journal of The Association of Physicians of India ■ Vol. 64 ■ February 2016
37.60%
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 receive acenocoumarol stabilized
over five days before operation
and continued during second
postoperative week (n=48),
subcutaneous low-dose heparin
(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
receiving acenocoumarol showed
INR in the therapeutic range
(2.0-3.0) in 82.5% patients. Overall
bleeding rate (2.27/100 patients-
year ) and thrombotic event rate
was low (0.2/100 patients-year) was
92 Journal of The Association of Physicians of India ■ Vol. 64 ■ February 2016
22.90%
6.30% 6.10%
Acenocoumarol Heparin
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 in children. Woods A et al
reported long term experience
of acenocoumarol plus aspirin in
31 children (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 patient-
months. 11
Superior Anticoagulant
Stability with
Acenocoumarol
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
with warfarin (W) in 74 patients
with chronic atrial fibrillation.
Table 1: Comparison of acenocoumarol with warfarin
Absorption on oral
administration
Peak concentration
Protein binding
Half-life
Saline Duration of action
Elimination
Dependence on CYP2C9 for
metabolism3
Anticoagulation stability16,29
Availability32
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 (56±26.8% vs 49±22.6%;
p < 0.05) while supratherapeutic
values occurred more commonly
on warfarin compared with
acenocoumarol (28±20% vs 19±19%;
p<0.001). 29
Conversion Factor for
Dose from Warfarin to
Acenocoumarol
The SPORTIF-III substudy
has shown a good correlation
between doses of warfarin and
acenocoumarol. The dose ration
of warfarin to acenocoumarol is
2.18±0.78. 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
Comparison of
Acenocoumarol with
Warfarin
The differential features of
acenocoumarol with warfarin are
given in table 1.
Acenocoumarol monograph
Acenocoumarol Warfarin
Rapid6 Rapid, Complete30
2-3 hours6 Within four hours30
Approximately 99%30 98.48%6
10.9 hours (short)6 Long (30-80 hours) 16
2 days (48 hours)31 2-5 days31
Renal 60% 92% renal; Very little is
Faces 29%31 excreted unchanged30
+ ++
++ +
1, 2 and 4 mg tablets 1, 2, 2.5, 3, 4, 5, 6, 7.5, and 10
mg.
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.
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
4. Better anticoagulation stability
than warfarin 16,,29
5. Rapid reversal of anticoagulant
action with relatively small
amounts of vitamin K 17
Adverse Events
The most serious complication
with oral anticoagulation is
bleeding. An Italian study
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
oral anticoagulation 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

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
Coumarin preparations cause
overall similar haemorrhagic
complications in older or younger
age. 4 The challenges for the use
of vitamin K antagonists include
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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