Warfarin
Warfarin impairs utilisation of vitamin K and thus reduces synthesis of factors II, VII, IX, X and the anticoagulant proteins C and S. Warfarin has no direct effect on coagulation factors present in the blood, so its effects become manifest as they are cleared. Half-lives of factor VII and protein C are 6 to 8 hours, and of factors IX, X and II are 24, 36 and 54 hours respectively, and of protein S is 30 hours. Thus factor VII and protein C levels fall long before those of other coagulation factors. In the first 24 hours a hypercoagulable state secondary to the reduction in protein C can occur. For this reason, and because of the delayed fall of clotting factors, unfractionated heparin (UFH) or low molecular weight heparin (LMWH) therapy should be continued for at least 48 hours after the international normalised ratio (INR) reaches the therapeutic range.
Warfarin is transformed into inactive metabolites and eliminated, with a half-life ranging from 20 to 60 hours.
Adverse effects, precautions and interactions:
Many factors can influence the anticoagulant effect of warfarin, including fluctuations in vitamin K intake, hepatic dysfunction, congestive heart failure, and hypermetabolic states produced by fever or hyperthyroidism. There is also significant potential for drug interactions, which can result in either increased or decreased anticoagulant effects. Caution should be exercised when starting or stopping any drug in combination with warfarin until its effects on INR are known. The duration for close monitoring is influenced by the half-life of the concomitant drug (eg the effects of amiodarone on warfarin clearance and INR can take several weeks to stabilise).
Bleeding is the most important adverse effect. The concomitant use of antiplatelet drugs can also increase the risk of bleeding. Some herbal and complementary medicines (eg fish oil, ginkgo biloba) can also have an antiplatelet effect. Paracetamol is widely used for analgesia in patients on warfarin and is preferred to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) because of the antiplatelet effects and risk of gastrointestinal bleeding associated with these latter drugs. Small occasional doses of paracetamol do not normally affect the anticoagulant effect of warfarin. Larger amounts of paracetamol (2 to 4 g daily) taken for several days may increase the INR. More frequent monitoring is indicated particularly if paracetamol administration coincides with other risk factors (eg febrile illness).
Anticoagulant effects can be reversed within hours with vitamin K, or immediately by replacing clotting factors using fresh frozen plasma or whole blood if transfusion is indicated.
Warfarin is a recognised teratogen, and if given in the first trimester of pregnancy it can cause a fetal warfarin syndrome or warfarin embryopathy characterised by bone stippling and nasal hypoplasia. It can also cause perinatal bleeding in the mother and infant. Other occasional reactions to warfarin include rashes, skin necrosis, fever and cholesterol embolism.
Monitoring and dosing:
Regular monitoring of warfarin is mandatory. This is done using variations of the prothrombin time. The INR standardises results between laboratories by comparison with a World Health Organization standard.
The goal of warfarin loading regimens is to rapidly attain a stable therapeutic INR without over-anticoagulation. In the treatment of deep vein thrombosis, if the time to reach a therapeutic INR is delayed, ongoing UFH or LMWH therapy is required. When warfarin is indicated for prophylaxis rather than therapeutic reasons, there is less need to rapidly attain a therapeutic INR. The INR should be determined before commencing warfarin, and if it is 1.4 or greater then careful consideration must be given before initiating warfarin for any condition. A number of dosage protocols have been developed to facilitate the attainment of a stable therapeutic INR. If local guidelines exist that reflect the local circumstances—for example initiation of warfarin in the elderly—these should be sought to provide assistance. A widely used schedule is 5 mg daily for two days, with the dose thereafter adjusted according to the INR to achieve the required INR. In older patients, those with impaired liver function, and those with congestive heart failure, oral anticoagulation should be started cautiously. The patient's INR should be determined daily or every second day until it has stabilised within the therapeutic range.
Oral anticoagulation with warfarin should preferably be started in conjunction with heparin, as initially warfarin may be associated with a procoagulant state resulting from a rapid reduction in the concentration of protein C, which is also a vitamin K–dependent protein. Heparin should be continued until the INR has been in the therapeutic range for two consecutive days. Patients at a high risk of thrombosis and those with a large atrial thrombus may need longer treatment with heparin.
Patient education is an important part of warfarin management and should be explicitly planned using resources such as anticoagulant booklets. These include information on what to do when starting or stopping new medications (including over-the-counter and complementary medicines), advice about diet and alcohol intake, and columns for the date of each blood test, the INR result, and the recommended daily warfarin dose. It is also important to encourage use of the same brand of warfarin for all dosage strengths.
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