![]() #ENGAGE AF TIMI 48 TRIAL#The Hokusai VTE trial was a randomised, multinational, double-blind, non-inferiority study to evaluate the safety and efficacy of edoxaban versus warfarin (dosed to an international normalised ratio (INR) of 2.0 to 3.0) in patients with VTE initially treated with heparin. Similar to the ENGAGE AF-TIMI 48 study, DNA samples were collected in the Hokusai-venous thromboembolism (Hokusai VTE) trial, allowing for a comparison of clinical outcomes by genotype. However, it is not known whether similar genetically based elevated bleeding risks associated with warfarin also exist for patients with VTE when transitioning from heparin to oral anticoagulants. These results confirmed that for stroke prevention in patients with AF, compared with warfarin, edoxaban was associated with a greater reduction in bleeding risk in sensitive and highly sensitive responders than in normal responders in the first 90 days. 13 This effect was observed during the first 90 days of warfarin therapy, but was not present afterwards, suggesting that the effect of genetics on warfarin-induced bleeding risk is strongest during the initiation of therapy when the warfarin dose is still being optimised. In a recent subanalysis of the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) study, a large double-blind, double-dummy, randomised study comparing edoxaban to warfarin for the prevention of stroke and systemic embolic events in patients with atrial fibrillation (AF), patients randomised to receive warfarin and classified as sensitive or highly sensitive warfarin responders, based on CYP2C9 and VKORC1 genotypes, experienced more warfarin-associated bleeding and spent more time overanticoagulated relative to normal responders. 11 12 Together, the polymorphisms in these two genes account for up to 50% of the variability in warfarin dose in patients of European descent. 11 Conversely, the prevalence of the VKORC1 allele that is associated with greatest increase in warfarin sensitivity is the highest in individuals of Asian descent. 6 8–10 The CYP2C9 alleles that are the most associated with increased warfarin sensitivity are more common in individuals of European descent compared with African or Asian descent. 3 6–9 Genetic factors influencing the response to VKAs include polymorphisms in the vitamin K epoxide reductase ( VKORC1) and cytochrome P450 2C9 ( CYP2C9) genes. The individual response to VKAs, such as warfarin, is influenced by demographics, clinical characteristics and genetic factors. As a class, compared with VKAs, these agents are at least as efficacious, are associated with a lower risk of major bleeding, have more predictable pharmacodynamics and require less frequent laboratory monitoring in individuals with VTE. 4 To overcome some of the limitations of VKAs, direct oral anticoagulants such as edoxaban, a potent factor Xa inhibitor, were developed. 3 Possibly due to this variability and the narrow therapeutic window of VKAs, their use is often associated with serious bleeding complications. 2 However, there is a high degree of interindividual variability in the dose–response relationship to VKAs, which necessitates frequent inconvenient laboratory monitoring of coagulation status. 1 Vitamin K antagonists (VKAs) with initial heparinisation have long been considered a mainstay for the management of VTE. Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant health problem with an estimated annual incidence of approximately 1– people among the general population. ![]()
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