Control of warfarin therapy.

Warfarin has been established as the oral anticoagulant of choice for many years. It is preferred to other coumarin-type drugs because of its greater reliability in clinical practice, and it benefits many thousands of patients each year. Nonetheless, it is not without hazard and there must be very few doctors who have not experienced difficulties in controlling a patient's coagulation state. Warfarin is indicated for prophylaxis of thrombi in patients with existing thrombi, such as deep venous thrombosis (DVT) or pulmonary embolism, or in those at high risk, such as atrial fibrillation, prolonged bed-rest, post-surgery.' The degree of anticoagulation required depends upon the condition being treated.2 Prophylaxis for non-hip surgery requires an international normalized ratio (INR) of 2-2.5, hip surgery and treatment of DVT, pulmonary embolus or transient ischaemic attacks 2.0-3.0 and recurrent thrombosis, valvular or arterial disease 3.0-4.5. The standardization of assay procedures is vital but has been well covered elsewhere.3 Many minor surgical proce dures can be adequately covered by the use of subcutaneous heparin and warfarin is in any case contraindicated in the first and third trimesters of pregnancy because of the high rate of fetal malformation and bleeding. It is also contraindicated in patients with bleeding diatheses, peptic ulceration, severe hypertension or endocarditis, although the presence of an artificial valve may over-ride the last contra-indication. In rare cases of allergy or intrinsic resistance to warfarin, phenindione can be used, as may intravenous or subcutaneous heparin. The choice ofan initial dose, and its conversion to a maintenance dose, is hampered by the delay in response (1-2 days), the wide variation between individuals and the lack of a close relationship between serum warfarin concentration and response. Several authors have published predictive schedules for dosing based on INR measurements in the first 2 days of treatment,'6 but these have proved to be of only limited benefit and the most common method is still to 'try it and see'. In an otherwise healthy adult, a typical regime would call for 9-10 mg daily for 3 days and then adjust the dose according to INR.6 Patients with thyrotoxicosis, liver impairment, heart failure, preexisting high INR, or low body-weight should all be given lower doses (say, 9,6,6 mg) as should those over 80 years. Careful control in an anticoagulant clinic is essential to good management and this can be achieved by practised doctors, nurses or pharmacists.7 Patient compliance is a major determinant of success, as are the numerous potential interactions with food and drugs. Some clinics try to improve compliance by using only one strength of warfarin tablet, thus simplifying the dosage instructions and reducing the risk of incorrect doses. Interactions may be divided into those that affect absorption, those that affect metabolism, those that affect protein-binding and those that affect coagulation directly or cause bleeding. Only the most important examples are given here, there are several good texts which may be consulted for details of others.8-" Absorption takes 2-4 hours, with a peak serum level at about 2 hours, and is generally faster after food. It is probably unaffected by antacids, despite some in vitro evidence to the contrary, but may be decreased by the use oflaxatives. Cholestyramine resin or liquid paraffin can have variable effects on clotting because of effects on both warfarin and vitamin K. Special diets containing large amounts of vitamin K, or even a high intake of green vegetables, such as broccoli, can alter coagulation. Patients should be counselled to take their warfarin at the same time each day (the evening is usually convenient because it is easier to make dosage adjustments in the clinic with immediate effect) and either with or without food, but not sometimes with and sometimes without. To avoid problems associated with tablets sticking in the oesophagus, patients should swallow their tablets with a drink of water whilst standing or sitting upright.'2 Problems that may occur include oesophageal ulceration, a well-known complication for some other drugs but recently reported for the first time for warfarin by Loft et al.'3 An unexpected difficulty caused by a pharyngeal pouch is reported by Ong and Slater in this issue'4 and serves to illustrate the great vigilance