Personalized oral anticoagulant treatment: dosing algorithms, drug interactions and economic aspects

In this thesis we aimed to further explore the relevance of dosing algorithms for VKAs compared to standard dosing and how these algorithms perform in different age groups. We also aimed to evaluate the influence of drug interactions on the safety of DOACs in daily clinical practice and whether health care practitioners take into account drug interactions when deciding on the prescribed dose of DOACs. We also study the cost-effectiveness of a variety of clinical and genotype-guided dosing algorithms for VKAs versus DOACs. In Chapter 2, a study is presented in which we compared the anticoagulant effect of dosing algorithms for acenocoumarol and phenprocoumon including clinical patient characteristics with standard care in the Netherlands. Chapter 3 describes a study in which we compared the effect of genotype-guided dosing of acenocoumarol or phenprocoumon in younger and older patients. Chapter 4 of this thesis focuses on the influence of drug interactions on the safety of DOACs. We conducted a case control study in the UK Clinical Practice Research Datalink to investigate the association between concurrent use of potential pharmacokinetic or pharmacodynamic interacting drugs and major bleeding among DOAC users. In Chapter 5, we describe the frequency of adjustments of DOAC treatment including dose adjustment, discontinuation of use, and switching to a VKA when interacting drugs were concomitantly used. In Chapter 6, we assessed the cost-effectiveness of DOACs versus different clinical and genotype-guided dosing algorithms for acenocoumarol and phenprocoumon as well as standard care in Dutch patients with atrial fibrillation. Finally, in Chapter 7, we summarize our main findings and discuss them in a broader perspective, discuss strengths and limitations and present recommendations for daily practice and further research. Our studies contribute to the knowledge on factors that influence the benefit risk of those oral anticoagulants and thereby will contribute to the safe use of these medicines in daily practice. Furthermore, our cost-effectiveness analysis showed that DOACs are an acceptable alternative of VKAs. For the VKAs dosing algorithms were studied and it was shown that also dosing algorithms with clinical information but without genotype information already might improve the time patients are within the therapeutic INR range. Furthermore, it appears that age is an important determinant for the performance of a dosing algorithm. Especially in patients younger than 75 years a dosing algorithm for phenprocoumon appears to be beneficial. The studies on DOACs showed that the combination of a DOAC and a platelet inhibitor or SSRI increases the risk on major bleeding while the combination with an inhibitor of CYP3A4 and/or P-glycoprotein does not increase this bleeding risk. Finally, our study on dose adjustments of DOACs when combined with an interacting drug taught us that further education of health care practitioners on the safe use of DOACs is needed.