Oral anticoagulation

A brief review of acenocoumarol

Chronology
1921 - Epidemic of a serious hemorrhagic disease of cattle is reported
in USA.
1924 - Frank Schofield found that cattle bleed within 15 days of
ingestion of the plant sweet clover.
1940 - Karl Link identifies natural coumarins, found to get oxidized in
the plant to form the anticoagulant substance that later became better
known as dicoumarol.
1941 - Mayo Clinic first reports the success of the use of dicoumarol in
the prophylaxis of deep vein thrombosis following surgery.
1953 - Development of Nicoumalone/acenocoumarol by Ciba Geigy
1955,1956 - Reports of the use of nicoumalone appear from Europe and
America
Atrial fibrillation
Atrial fibrillation (AF) is one of the most commonly encountered
tachyarrhythmia in clinical practice.
AF affects 5% of people older than 65 years and nearly 10% of those
over 80 years of age.
AF is an independent predictor of mortality, and contributes to
substantial morbidity and mortality from stroke, thromboembolism,
and heart failure, adversely affects quality of life and is a condition of
increasing clinical and economic importance in an increasingly aging
population.
The presence of atrial fibrillation without any valve disease increases
the risk of stroke and thromboembolism by five times.
Lip GYH, Boos CJ. Heart 2006;92:155161
Atrial fibrillation
Patients with atrial fibrillation and valvular heart disease have a
substantially greater risk of stroke and other thromboembolic events.
AF increases the risk of stroke four- to fivefold across all age groups,
accounting for 1015% of all ischaemic strokes and nearly a quarter of
strokes in people aged more than 80 years.
Mitral valve stenosis is a substantial risk for stroke and
thromboembolism. Events may occur in 920% of patients, of which
upto 75% may have cerebral emboli.
The risk of thromboembolism is increased by 37 times in patients with
mitral stenosis in sinus rhythm who develop atrial fibrillation.
Kalra L, Lip GYH. Heart 2007;93:3944
Antithrombotics in AF
Antithrombotic prophylaxis is essential for patients with atrial
fibrillation at risk of cerebral stroke.
Introduction and monitoring of prolonged anticoagulation may be
considered more important for patients than taking a decision about
the conversion of atrial fibrillation to a normal sinus rhythm.
Prolonged oral anticoagulation with proper INR control decreases the
risk of a cerebral stroke by 2/3 times, and prevents permanent
disability among patients with atrial fibrillation.

Vitamin K antagonists of the coumarin type are widely used oral
anticoagulants.
Rewiuk K, Bednarz S et al. Cardiology Journal 2007, 14(1):4449
Venous Thromboembolism (VTE)
Is a potentially fatal disease, consisting of Deep Vein Thrombosis (DVT)
and Pulmonary Embolism (PE).
May occur in more than 50% of patients undergoing surgical
procedures, particularly those involving the hip and knee; and 10% to
40% of patients who undergo abdominal or thoracic operations.
DVT occurs less frequently in the upper extremity than in the lower
extremity, initial aim of treatment of DVT is prevention of thrombus
extension and PE.
The need for systemic thromboprophylaxis, especially in surgical
patients is based on the high prevalence of postoperative DVT and PE,
the frequent silent presentation of VTE and the potential for major
adverse events.
Clinical efficacy studies with acenocoumarol have shown the drug to be
effective in the prophylaxis of DVT.
Parakh R, Kakkar VV,et al. JAPI 2007; 55:49-70
Commercially available coumarins
Worldwide there are different coumarin derivatives available.
The coumarins most frequently used are warfarin, acenocoumarol and
phenprocoumon.
In patients with nonvalvular atrial fibrillation oral anticoagulation with
the vitamin K antagonists acenocoumarol and warfarin reduce the risk
of stroke by more than 60%.
Van Leeuwen Y, Rosendaal FR, et al. Thromb Res. 2008;123(2):225-30
Mechanism of Action of Oral
Anticoagulants
Coagulation factors II, VII, IX and X and the anticoagulant proteins C
and S are synthesized mainly in the liver and are biologically inactive
unless carboxylated .
Carboxylation is directly coupled to the oxidation of vitamin K to its
corresponding vitamin K epoxide or oxidized vitamin K.
For the continued synthesis of activated clotting factors, vitamin K
must be regenerated from the biologically inactive epoxide by vitamin K
epoxide reductase .
Acenocoumarol and the coumarin anticoagulants are structurally
similar to vitamin K and competitively inhibit the enzyme vitamin K-
epoxide reductase.
These drugs exert their anticoagulant action by preventing the
regeneration of reduced vitamin K by interfering with action of vitamin
K epoxide reductase.
Ansell J et al. Chest 2008;133;160S-198S
Mechanism of Action of Oral Anticoagulants
Acenocoumarol/Nicoumalone
Earlier approved BAN (British Approved Name) is Nicoumalone, while
the now approved rINN (recommended International Non-Proprietary
Name) is Acenocoumarol.
Acenocoumarol's rapid onset of action and 15- to 20-hour duration of
effect are great advantages in its clinical use.
In a clinical study, at the end of 43 hours, 94 per cent of patients
receiving acenoacoumarol were in the therapeutic range.
The dose required to maintain a therapeutic level varies greatly from
patient to patient.
Limited experience suggests that it is a more nearly ideal anticoagulant
than any of the commonly used coumarin derivatives.
Acenocoumarol/Nicoumalone
Found to be well tolerated when administered orally.
Data suggests that it will induce a therapeutic prothrombin level in
most patients 36 hours after the initial dose.
When given in a single daily dose, a therapeutic effect is easily
maintained.
Rapidly excreted, elimination of 1 dose usually results in a prompt
return of the prothrombin time toward normal.
Vitamin K1 in relatively small dosage counteracts its effect within a few
hours.
The dosage is relatively constant in a given patient but, as with all
anticoagulants, may vary with changes in the clinical condition of the
patient.
Pharmacologic properties
Rapid Onset of Action: The increase in prothrombin time reaches a
maximum after 36-48 hours after the administration of
acenocoumarol.
Stability: Patients receiving acenocoumarol were found to maintain
their prothrombin time within the accepted therapeutic levels (10-30%
of normal) 91% of the time.
Rapid Reversal of Action: Prothrombin time is reported to return
towards normalcy (32-80%) in about 24-hours. It is reported that the
prothrombin time normalizes within 36-48 hours.
Metabolites: Studies have shown that the anticoagulant activity of
acenocoumarol resides in the drug per se and not in its metabolites.
Administration
Mismetti et al., documented that the anticoagulant activity of
acenocoumarol does not show fluctuations when the drug is
administered once daily.
Acenocoumarol is to be administered as a single dose daily.
Pharmacokinetics
Absorption
Following oral administration, acenocoumarol is rapidly absorbed; at least
60% of the administered dose is systemically available.
Peak plasma concentrations are achieved within 1 to 3 hours after a single
dose of 10 mg.

Distribution
Over 98% of acenocoumarol is protein-bound, mainly to albumin.

Metabolism
Acenocoumarol is extensively metabolized, although the metabolites appear
to be pharmacologically inactive in man.

Elimination
The elimination half-life of acenocoumarol from the plasma is 8 to 11 hours,
29% is excreted in the feces and 60% in the urine.
http://www.medicines.org.uk/EMC/medicine/129/SPC/Sinthrome+Tablets+1mg
Dose and administration
A starting dose of 4 mg/day on Day 1 is generally recommended, with 4
to 8mg being administered on Day 2.
Initial dosages of 6mg and 4mg acenocoumarol on days 1 and 2
respectively(6-4 dosage rgimen) or 6,4, and 2mg on days 1,2,and 3
respectively (6-4-2 dosage regimen) have been used.
The first INR is determined on day 3 (6-4 dosage regimen) or day 4 (6-
4-2 dosage regimen).
Subsequently, determination of optimal maintenance dosage can take 3
or 4 weeks with INR control taking place on a weekly basis.
van Geest-Daalderop J, et al. J Thrombosis and Thrombolysis 2003;15(3):197-203
Dose and administration
Depending on the individual, the maintenance dose generally lies
between 1 to 8mg daily.
This varies from patient to patient and must be determined on the basis
of regular laboratory estimations of the patient's blood coagulation
time.
Adjustment of the maintenance dose can only be made by monitoring
the international normalised ratio (INR) at regular intervals, ensuring
that the dosage remains within the therapeutic range.
Goodman and Gilman's the pharmacological basis of therapeutics. 12th Ed, Page 865
Dosing algorithm
Notaridis G et al. Rev Med Suisse. 2010;6(235):292, 294-7
If a patient shows any sign of bleeding, the next dose of anticoagulant
should be withheld and the plasma thromboplastin measured.

If bleeding is minor or self-limited, therapy may be continued after
adjusting the dosage and/or correcting the reason for the altered
response.




Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological
Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990., p. 1320


Overdose / Toxicity
Clinical manifestations of overdosage are unlikely with large single
doses, but more likely following prolonged use of daily doses exceeding
those required therapeutically.






http://www.medicines.org.uk/emc/medicine/129/SPC/


Treatment:
The necessity, or desirability of the treatment by gastric lavage in
addition to the activated charcoal and cholestyramine administration is
controversial. The benefits of these treatments should be balanced
against the risk of bleeding in each patient.

For patients who have not previously received anticoagulants, arriving
within 1 hour of ingestion, who are not obtunded, comatose or
convulsing, and show no signs of bleeding from any source, then drug
absorption may be reduced by gastric lavage. (However, note that
gastric lavage may provoke bleeding).



http://www.medicines.org.uk/emc/medicine/129#OVERDOSE


This may then be followed by the administration of activated charcoal.
It should also be noted that vitamin-K mediated reversal of
anticoagulation may be dangerous for patients who require constant
anticoagulation such as those with prosthetic heart valves.
Colestyramine may markedly enhance the drug's elimination by
inhibiting the enterohepatic circulation.
A temporary reduction of the dose of Acenocoumarol is often sufficient
to control slight bleeding.



http://www.medicines.org.uk/emc/medicine/129#OVERDOSE
Emergency and supportive measures:
In emergency situations of severe haemorrhage, clotting factors can be
returned to normal by administering fresh whole blood or fresh frozen
plasma, complex concentrate or recombinant factor VIIa supplemented
with vitamin K1.





Antidote:
Vitamin K
1
(phytomenadione) may antagonise the inhibitory effect of
Acenocoumarol within 3 to 5 hours.

In cases of moderate haemorrhage, 2 to 5 mg Vitamin K
1
should be
given orally; in severe haemorrhage, 5 to 10mg Vitamin K
1
should be
injected very slowly (at a rate less than 1mg/min) intravenously.

Additional doses (up to a maximum dose of 40mg daily) should be
given at 4-hour intervals. Vitamin K
1
should not be given by
intramuscular injection.

Doses of Vitamin K
1
in excess of 5mg can cause resistance to further
anticoagulant therapy for several days.
If an anticoagulant is required, heparin may be used temporarily,
although oral anticoagulant therapy should be resumed at the same
time and heparin withdrawn once the therapeutic range has been
reached.
In the case of life-threatening haemorrhage, intravenous transfusions
of fresh frozen plasma or whole blood, complex concentrate or
recombinant factor VIIa supplemented with vitamin K1 can abolish the
effects of Acenocoumarol .


http://www.medicines.org.uk/emc/medicine/129/SPC/



Clinical evidence
Acenocoumarol in the treatment of DVT
4289 patients with symptomatic venous
thromboembolism were randomly allocated to receive
one oral anticoagulant within 72 hours of the episode
warfarin, acenocoumarol, phenprocoumon or fluindione.
The dose was adjusted to achieve a target INR of 2.0-3.0
and the treatment was continued for 3 months.
Clinical assessment: The 3-month incidence of
recurrent venous thromboembolism and of major
bleeding.
Results: The incidence of recurrent venous
thromboembolism was lower with acenocoumarol,
phenprocoumon and fluindione compared to warfarin.
The safety of the 4 drugs was comparable.
Lensing AWA, Hematology Meeting Reports 2008; 2(1): 11-12
Limitations of Warfarin
Warfarins narrow therapeutic index makes it difficult to
maintain patients within a defined anticoagulation range.
An analysis of 6454 patients with atrial fibrillation taking
warfarin showed that for almost 50% of the time,
the INR was outside the target range of 23.
Individual dosage requirements vary widely between and
within individuals.
In other studies investigating the use of acenocoumarol
and warfarin in atrial fibrillation, it has been seen that
the stability of anticoagulant action of
acenocoumarol was better than warfarin.
Pirmohamed M, Br J Clin Pharmacol, 2006; 65(5): 509-511 , Lengyel M. Orv Hetil. 2004;145(52):2619-21.
120 patients who met inclusion criteria were randomised in two
parallel groups of 60 patients.
Routinely measured International normalised ratio (INR) values
were the basic parameter for individual quality and stability
assessment.
Average, monthly INR values were in therapeutic range (2.0-3.0) in
both therapeutic groups. There were no significant differences
either in the number of therapeutic INR values per patient or in
individual quality of treatment: >50% therapeutic INR values
(60.0% vs. 64.9%, P = 0.721) and >75% therapeutic INR values
(18.3% vs. 22.8%, P = 0.714) in the warfarin and acenocoumarol
group, respectively.
Significantly better stability was determined for
acenocoumarol as compared with warfarin treatment in
terms of a longer period of the total observed time during
which therapeutic INR values were stable (37.6% vs.
35.7%, P = 0.0002).
Warfarin vs acenocoumarol in AF
Kuo A et al. Med Glas Ljek komore Zenicko-doboj kantona. 2011;8(1):9-14
Switching from warfarin to acenocoumarol
van Leeuwen Y et al., Thromb Res. 2008;123(2):225-30
When transitioning a patient from warfarin to acenocoumarol, the
warfarin dose should be calculated by a transition factor of 0.53.
For example in a patient receiving 6mg warfarin (6 x 0.53 =
approximately 3mg of acenocoumarol).
Summary
Clinical use of oral anticoagulants has come a long way since
their discovery over 60 years ago.
Despite the development of several new oral anticoagulants,
the place of coumarin anticoagulants remains unchallenged.
Their efficacy has been established beyond doubt and they
have long years of clinical experience.
Amongst the coumarins, acenocoumarol offers rapid onset
and offset of action and well documented efficacy and safety.
Acenocoumarol has been shown to be superior to warfarin in
maintaining INR stability within therapeutic range and in
efficacy.
The availability of dosing algorithms based on INR and the
transition algorithm for switch over from one coumarin to
another will enable a greater ease of use of this valuable drug
in clinical practice.



THANK YOU