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;92:155–161

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 10–15% 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 9–20% of patients, of which upto 75% may have cerebral emboli.

The risk of thromboembolism is increased by 3–7 times in patients with mitral stenosis in sinus rhythm who develop atrial fibrillation.

Kalra L, Lip GYH. Heart 2007;93:39–44

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):44–49

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.

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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).

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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 K1 (phytomenadione) may antagonise the inhibitory effect of Acenocoumarol within 3 to 5 hours.

In cases of moderate haemorrhage, 2 to 5 mg Vitamin K1 should be given orally; in severe haemorrhage, 5 to 10mg Vitamin K1 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 K1 should not be given by intramuscular injection.

Doses of Vitamin K1 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

Warfarin’s 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 2–3.

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.

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