Abstract
Coumarin derivatives such as acenocoumarol, phenprocoumon and warfarin are frequently used for the prevention of stroke and systemic embolism in patients with atrial fibrillation or for the treatment of venous thromboembolism. These oral anticoagulants have a narrow therapeutic range and a large variability in dose requirement among patients. A subtherapeutic
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dose is related to therapy failure and thereby leads to an increased risk of stroke, deep venous thrombosis or systemic embolism, while a supratherapeutic dose leads to an increased risk of bleeding. Personalised dosing using genetic information is expected to help physicians to prescribe the required dose from the start of the therapy and thereby increase the efficacy and safety of the treatment. It is important to assess the cost-effectiveness of pharmacogenetic-guided coumarin dosing, because this information is used by payers such as health insurers to make decisions about reimbursement. The aim of this thesis was to study genetic and other determinants that explain the variability in response to coumarin derivatives. We also aimed to study the economic consequences of different options (personalised medicine or using new oral anticoagulant drugs) to improve anticoagulant therapy. Genetic variation influences the risk of over- or underanticoagulation, especially in the first month. Concomitant medication use can influence the required coumarin dose and users of omeprazole or esomeprazole require a lower coumarin dose. Next to prescribing the correct dose to a patient, it is important that a patient is compliant with this dose. On average, coumarin users had a positive attitude towards their treatment and the compliance is therefore expected to be high. Pharmacogenetic-guided dosing of coumarin derivatives has the possibility to improve anticoagulant therapy in a cost-effective way. The large uncertainty in the results made it impossible to conclude whether or not pharmacogenetic-guided dosing should be implemented. When the results of ongoing large clinical trials such as the EU-PACT trial are available, the cost-effectiveness can be assessed more accurately. The setting in which the management of the treatment takes place (specialised anticoagulation clinics, general practitioner or hospital settings) varies between countries. The percentage time spent in the target range, which is a measure for quality of anticoagulation, also varies considerably between the countries. It is therefore important to perform country specific cost-effectiveness analyses. In a country specific cost-effectiveness analyses on the new oral anticoagulants (NOACs) versus coumarin derivatives in The Netherlands and in the United Kingdom we showed that dabigatran and apixaban could be considered cost-effective in both countries. Rivaroxaban was considered as cost-effective in The United Kingdom, but not in The Netherlands. In conclusion: Pharmacogenetic-guided dosing of coumarin derivatives could be used to improve the therapy for patients with atrial fibrillation or venous thromboembolism. NOACs were also shown to be promising alternatives to coumarin derivatives. The results of the cost-effectiveness studies in this thesis underline the importance of country specific cost-effectiveness analysis when looking at the economic consequences of improving oral anticoagulant therapy
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