Effectiveness and safety of new oral anticoagulants in patients with nonvalvular atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common heart rhythm disorder affecting over 33 million people worldwide. It is a leading cause of stroke, making up one-fourth of all strokes encountered in clinical practice. For many decades, warfarin and other vitamin K antagonist oral anticoagulants have been the only effective treatment for stroke prevention in AF. However, their use is limited by the narrow therapeutic range, multiple drug/food interactions, and concerns for bleeding risk. These limitations posed several challenges to clinical management, contributing to the underuse of oral anticoagulants. The utilisation of oral anticoagulants has not been systematically compared between ethnicities; however, it is generally believed that oral anticoagulants are mostly underused among Asians, as they tend to prescribe conservatively due to concerns for bleeding risk.

The large unmet need for better anticoagulation options has prompted the development of new oral anticoagulants (NOACs). Dabigatran was the first NOAC approved for clinical use, which has a comparable efficacy of stroke prevention and fewer drug/food interactions as compared to warfarin. However, evidence on bleeding risk has been inconclusive: some studies suggested a higher risk of bleeding with dabigatran, while some studies reported lower or no increased risk. In addition, a recent animal study suggested that dabigatran use may be associated with a lower risk of osteoporotic fractures when compared to warfarin. However, no similar study was conducted in humans.

To address the above knowledge gaps, this thesis had three main objectives: (1) to examine the local utilisation pattern of oral anticoagulants in patients with AF; (2) to compare the bleeding risk between dabigatran and warfarin; and (3) to compare the risk of osteoporotic fractures between dabigatran and warfarin.

The studies described in this thesis utilised the population-wide database managed by the Hong Kong Hospital Authority, whose service is accessible to over 7 million people in Hong Kong. The results revealed that: (1) among patients with AF and a high risk of stroke, only 23% received oral anticoagulants, and 61% received antiplatelet drugs alone perceivably as a strategy to reduce bleeding risk. Notably, further analyses showed that the use of antiplatelet drugs did not result in fewer bleeding events, but was associated with a higher risk of stroke and mortality when compared to warfarin; (2) Dabigatran use was associated with a comparable incidence of bleeding but a higher risk of 30-day recurrent bleeding, suggesting closer monitoring of patients after hospital discharge may be beneficial to improve the safety of dabigatran use; (3) Dabigatran use was associated with a lower risk of osteoporotic fractures when compared to warfarin, which raised an opportunity to reduce fracture risk in patients requiring anticoagulation therapy.

This was the largest pharmacoepidemiological study that examined the use of oral anticoagulants among Southern Chinese. The study findings suggest the need to optimise oral anticoagulation therapy in patients with AF. It also provided novel data to facilitate a better understanding of the place of NOACs in the current management of AF.