| Oral anticoagulant drugs are essential in the treatment and prevention of thromboembolic events in certain prothrombotic conditions. Atrial fibrillation is the most prevalent arrhythmia, and is the main indication for chronic oral anticoagulation due to its thrombotic complications. Vitamin K antagonists (VKA) were until recently the only therapeutic options of this class in Portugal, namely in the form of warfarin and acenocoumarol. Despite proven efficacy, VKAs have a large pharmacodynamic variability owing to multiple potential interactions with food and other drugs. The development of the non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, and rivaroxaban) increased the therapeutic armamentarium for anticoagulation. NOACs act directly by blocking thrombin or factor Xa, and exhibit an antithrombotic effect at least as effective as VKAs. Since the myriad of interactions found with VKAs are absent in NOACs, the anticoagulant effect is predictable, and does not require serial evaluations of hemostasis, making NOACs more convenient for patients and clinicians. Thus, it is reasonable to expect that NOACs may be prescribed often than VKAs. However, the approval of NOACs was based on phase III randomized controlled trials (RCTs), which are seldom planned to evaluate the safety of interventions. Additionally, NOACs are costlier than VKAs, raising the question of whether these new anticoagulants promote health gains at a sustainable cost to the Portuguese society. Therefore, it is important to better characterize the oral anticoagulants with a focus on NOACs in the population-level clinical pharmacology, namely pharmacoepidemiology, safety aspects of the oral anticoagulants (comparative safety and pharmacovigilance) and pharmacoeconomics. OBJECTIVES The aim of this dissertation was to improve the knowledge related to the oral anticoagulants in the four main fields population-level clinical pharmacology: pharmacoepidemiology, comparative effectiveness/safety, pharmacovigilance, and pharmacoeconomics. Specific objectives: 1) Pharmacoepidemiology: To assess the state of oral anticoagulation in Portugal, in terms of proportion of non-anticoagulated patients, the quality of anticoagulation, and evolution of the prescription pattern since the licensing of NOACs. 2) Comparative effectiveness/safety research: To evaluate the safety of NOACs, based on clinical trials' data, in terms of bleeding and non-bleeding adverse events, as well as the overall tolerability and acceptability of the drugs. 3) Pharmacovigilance: To identify adverse events related to oral anticoagulants most frequently reported to Pharmacovigilance Units in Portugal. 4) Pharmacoeconomics: To assess the cost and burden of AF in Portugal, and the relative cost-effectiveness of oral anticoagulants in Portugal. |
