Warfarin

Warfarin’s clinical use as an anticoagulant dates back to 1954.41 Warfarin, acenocoumarol and dicoumarol interfere with all the coagulation factors that depend on vitamin K.40,42 So, vitamin K antagonists reduce levels of several coagulation factors (II [prothrombin], VII, IV and X) and thrombotic factors (protein C, S and Z).40,42 This diversity of action, combined with marked variations in warfarin metabolism, makes predicting the articulatory effect of a dose of warfarin difficult.40,42

Using warfarin to maintain an international normalised ratio (INR) target range of two to three reduces the risk of recurrent stroke by 64% in AF patients (from 23% to 9%).7 In a study that followed patients for five years after experiencing an AF-related stroke, warfarin reduced mortality by 60%.23 Warfarin remains the anticoagulant of choice for AF related to metallic prosthetic heart valves and mitral stenosis, and for patients with non-valvular AF and severe renal dysfunction.34 

Warfarin can, however, prove difficult to use clinically. For instance, the INR needs to remain within the target range. An INR more than three is associated with an increased risk of haemorrhage. An INR less than two is associated with an increased risk of thrombotic events. But maintaining patients in the target INR range of two to three is often difficult: AF patients taking warfarin may be outside the target range for almost 50–65% of the time.40,41 Two-thirds of the remainder have INRs below two predisposing to thromboembolism. A third are above three, increasing the risk of haemorrhage.40

Numerous factors potentially influence warfarin metabolism, including drug- and food-interactions, alcohol intake and genetic polymorphisms. As a result, individual warfarin doses vary widely between patients and within the same person, ranging from 0.5 mg/day to more than 20 mg/day.41 So, people taking warfarin require frequent monitoring and adherence can be poor.43

Warfarin’s side effects

Warfarin commonly causes bleeding: the rates of major and fatal bleeding are 7.2 and 1.3 per 100 patient years respectively.41 The absolute risk of developing warfarin-related intracranial haemorrhage is small compared with the benefits arising from avoiding strokes. Nevertheless, the risk of major bleeding complications more than double in patients with poor INR control, especially those older than 75 years.11 Warfarin’s other side-effects include skin necrosis, hair loss and even venous limb gangrene.41


Warfarin’s pharmacokinetics can also make the drug difficult to use in clinical practice. Warfarin, for example, has a slow onset of action.34 Furthermore, the biologically inactive clotting factors need to degrade before normal coagulation returns, which can take several days. As a result, warfarin’s half-life is approximately 40 hours.40

The next section details direct oral anticoagulants


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