Warfarin Sodium: Uses, Preparations
Uses and Administration
Warfarin is a coumarin anticoagulant used in the treatment and prophylaxis of thromboembolic disorders. It acts by depressing the hepatic vitamin Independent synthesis of coagulation factors II (prothrombin), VII, LX, and X, and of the anticoagulant protein C and its cofactor protein S. For an explanation of the coagulation cascade, see Haemostasis and Fibrinolysis. Since warfarin acts indirectly, it has no effect on existing clots. Also as the coagulation factors involved have half-lives ranging from 6 to 60 hours, several hours are required before an effect is observed. A therapeutic effect is usually apparent by 24 hours, but the peak effect may not be achieved until 2 or 3 days after a dose; the overall effect may last for 5 days.
Warfarin is used in the prevention and treatment of venous thromboembolism (deep-vein thrombosis and pulmonary embolism). If an immediate effect on blood coagulation is required, heparin should be given intravenously or subcutaneously to cover the first 2 to 3 days. Warfarin therapy may be begun with, or shortly after, initial heparin treatment. Warfarin is also used for the prevention of systemic thromboembolism and ischaemic stroke in some patients with atrial fibrillation, prosthetic heart valves (see Valvular Heart Disease), or who have suffered a myocardial infarction. It may also have a role in the prevention of myocardial infarction and in the management of stroke or transient ischaemic attacks. Antiplatelet drugs may be given concomitantly.
Some patients may show a hereditary resistance to warfarin. Warfarin is a potent rodenticide although resistance has been reported in rats.
Administration and dosage. Warfarin is equally effective either orally or intravenously, but is usually given orally. Dosage must be determined individually as discussed below under Control of Anticoagulant Therapy. When rapid anticoagulation is required, an initial dose of warfarin sodium 10 mg may be given on the first day, although in many cases an initial dose of 5 mg daily is adequate; initial doses of less than 5 mg daily may be used in elderly patients and in those at increased risk of bleeding (see Precautions, above). Subsequent doses depend on the results of coagulation tests, but maintenance doses usually range from 3 to 9 mg daily. If necessary the same dose may be given by slow intravenous injection. Doses of warfarin sodium should be given at the same time each day. Theoretically, stopping warfarin abruptly may result in rebound hypercoagulability with risk of thrombosis. Therefore some clinicians tail off long-term treatment over several weeks but the need for this is unclear and the British Society for Haematology suggests that treatment may be stopped abruptly. Anticoagulant treatment booklets should be carried by patients.
Warfarin has also been given as the potassium salt; warfarin-deanol has been tried.
Control of oral anticoagulant therapy. Treatment with oral anticoagulants must be monitored to ensure that the dose is providing the required effect on the vitamin-K-dependent clotting factors; too small a dose provides inadequate anticoagulation, too large a dose puts the patient at risk of haemorrhage. This monitoring is commonly carried out by checking the clotting property of the patient’s plasma using a suitable preparation of thromboplastin and a source of calcium. The time taken for the clot to form due to the effect of the thromboplastin preparation on prothrombin is known as the prothrombin time (FT). The prothrombin time ratio (PTR) is the prothrombin time of the patient’s plasma divided by that for a standard plasma sample.
So that there is some consistency in prothrombin time ratios measured at different times or at different laboratories, it is now common practice for the manufacturer or control laboratory to calibrate their batches of thromboplastin against the international reference preparation. This calibration produces an international sensitivity index (ISI) appropriate to that thromboplastin. The laboratory measuring the clotting capacity of a sample of plasma is thus able to convert the prothrombin time ratio to an international normalised ratio (INR) using the sensitivity index through the formula:
INR = PTR
Thus a prothrombin time ratio of 2.0 obtained with a thromboplastin with a declared international sensitivity index of 1.5 would be converted to an international normalised ratio of 2.8. An international normalised ratio is therefore equivalent to a prothrombin time ratio carried out using the primary international reference preparation of thromboplastin.
This method of standardisation has taken over from methods involving use of a standard reagent such as the British or Manchester comparative thromboplastin. Preparations of thromboplastin derived from rabbit brain have superseded or are superseding those from human brain because of the dangers of viral transmission; a recombinant human form is also available.
Recommended target values or ranges of international normalised ratio for patients receiving anticoagulant treatment or cover for various conditions or procedures are given by the British Society for Haematology in the UK and the American College of Chest Physicians.
An INR within 0.5 units of the target value in the UK is generally considered satisfactory. In the United States of America (USA) it is recommended that the INR be maintained at the mid-level of the range. An INR less than 2.0 generally represents inadequate anti-coagulation and an INR above 4.5 represents greater risk of haemorrhage.
Measurements should be carried out before treatment and then daily or on alternate days in the early stages of treatment. Once the dose has been established and the patient well stabilised the measurement can be made at greater but regular intervals, for example every 8 weeks; allowances should be made for any events that might influence the activity of the anticoagulant. Self-monitoring may be appropriate in some patients.
Administration and dosage. Algorithms and guidelines have been developed for beginning anticoagulant therapy, based on the method of Fennerty et al. Although a loading dose of 10 mg daily for 2 days (depending on the INR) has been widely used, lower doses may be more appropriate, especially in hospitalised patients at greater risk of overantic oagulation. Studies comparing warfarin loading doses of 5 and 10 mg found that for both groups a therapeutic INR in the range of 2.0 to 3.0 was reached in most patients by day 5 of treatment. Although a study of outpatients with venous thromboembolism found that a therapeutic INR was achieved 1.4 days sooner with the larger loading dose, the nomogram used was not designed for inpatients.
In situations where rapid anticoagulation is not necessary, loading doses may not be required and treatment should begin with the estimated maintenance dose. Studies have found that the maintenance dose decreases with age and is lower in women than in men, and lower initial doses are therefore recommended in the elderly. Regimens that have been suggested include warfarin in a dose of 4 mg daily for 3 days, then adjusted according to the INR, or, for patients requiring anticoagulation prophylaxis, 2 mg daily for 2 weeks followed by weekly adjustment using an algorithm until the target INR is reached.
Administration in infants and children. Increasing numbers of infants and children are receiving anticoagulants for prophylaxis and treatment of thromboembolism. Doses of warfarin and therapeutic INR ranges have been adapted from adult therapy but cohort studies of paediatric patients have found that warfarin requirements may be affected by a number of factors including age, and the use of infant formulas supplemented with vitamin K. Recommendations for the use of oral anticoagulants in children have been published.
Catheters and cannulas. For mention of the use of oral anticoagulants to prevent thrombosis in patients with indwelling infusion devices, see Heparin Sodium.
Connective tissue and muscular disorders. Warfarin has been proposed to treat subcutaneous calcium deposition (calcinosis cutis) in patients with dermatomyositis, but its value is disputed, see Polymyositis and Dermatomyositis.
Preparations
British Pharmacopoeia, 2008: Warfarin Tablet;
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Warfarin Sodium for Injection; Warfarin Sodium Tablets.
Proprietary Preparations
Argentina: Circuvit; Coumadin;
Australia: Coumadin; Marevan;
Belgium: Marevan;
Brazil: Coumadin; Marevan;
Canada: Coumadin;
Chile: Coumadin;
Czech Republic: Lawarin;
Denmark: Marevan;
Finland: Marevan;
France: Coumadine;
Germany; Coumadin;
Greece: Marevan; Panwarfin;
Hungary: Marfarin;
India: Uniwarfin; Warf;
Ireland: Warfant;
Israel: Coumadin;
Italy: Coumadin;
Malaysia: Coumadin; Orfarin;
Mexico: Coumadin;
Norway: Marevan;
New Zealand: Coumadin; Marevan;
Philippines: Coumadin;
Portugal: Varfine;
Russia: Warfarex;
South Africa: Coumadin †;
Singapore: Coumadin; Marevan; Orfarin;
Spain: Aldocumar; Tedicumar;
Sweden: Waran;
Thailand: Befarin; Fargem; Maforan; Orfarin;
Turkey: Coumadin; Orfarin;
United Kingdom (UK): Marevan;
United States of America (US and USA): Coumadin; Jantoven;
Venezuela: Anasmol; Coumadin; Cumar
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