Special RepoRt

Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon, are commonly prescribed as oral anticoagulants for the treatment of thromboembolic disorders. Therapy with coumarin derivatives is most effective when the international normalized ratio (INR) is kept within a narrow range. Prescribing of these drugs is difficult because of their narrow therapeutic window and the wide interindividual variability in dose requirement; coumarin deriva tive dosages can vary by a factor 10 among patients [1,2]. For these reasons, it is of difficult to predict anticoagulation response to a standard dosing regimen, as this is the case with the current dosing algorithms used for the initiation of anticoagulation therapy. Consequently, treatment is often either subtherapeutic (due to underdosing) or supratherapeutic (due to overdosing), placing the patient at risk of (recurrent) thrombosis or hemorrhage, respectively, which can be life-threatening [3,4]. Because of the uncertainty in anticoagulation response, patients on coumarin derivative therapy require careful monitoring [1,4,5]. Anticoagulation response to coumarin derivatives is influenced by a number of clinical, environmental and genetic factors. It has been established that factors such as concurrent drug therapy, co-morbidity, age, sex, BMI, smoking and dietary vitamin K intake influence coumarin derivative dose requirements [6–10]. Polymorphisms in the CYP2C9 and VKORC1 genes, encoding for the metabolizing enzyme cytochrome P450 2C9 (CYP2C9) and the target enzyme vitamin K epoxide reductase (VKOR) respectively, together account for about 40% of the variability in coumarin derivative maintenance dose requirements [11,12]. Several studies have demonstrated that patients with allelic variants in the CYP2C9 and VKORC1 genes require lower coumarin derivatives doses than those with wild-type alleles [13–17]. This exposes them to a greater risk of over-anticoagulation and hemorrhage, particularly during initiation of therapy. Polymorphisms in other genes, for example, the CYP4F2 gene, have only a nominal effect on the coumarin derivate dose [18,19]. The recognition that genetic factors influence coumarin derivative dose requirements and thus may predispose to serious and life threatening hemorrhage has highlighted the inadequacy of the currently used dosing regimens. To date, several studies have quantified the contribution of the CYP2C9 and VKORC1 genes in coumarin derivative dose requirement and put forward pharmacogenetic-based dosing equations [10,12,20–25]. However, these equations (mainly developed for warfarin) are based on data derived from patients on stable maintenance therapy and are therefore unsuitable for those The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogeneticguided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.