Anticoagulation endpoints with clinical implementation of warfarin pharmacogenetic dosing in a real‐world setting: A proposal for a new pharmacogenetic dosing approach
Prompt achievement of therapeutic anticoagulation is a major goal when initiating warfarin, especially in patients with acute thromboembolism, because the rates of thrombotic progression and reoccurrence are highest in the first few months after diagnosis.9 At the same time, the risk for major bleeding events is 10‐fold higher during the first month following warfarin initiation than for the remainder of therapy,14 likely influenced by inappropriate initial warfarin dosing. Traditionally, warfarin is started at a fixed dose of 5 mg/day, with dose adjustment based on the international normalized ratio (INR) response.3 However, time to achieve therapeutic anticoagulation is often prolonged with this approach, placing patients at increased risk for thrombotic events and/or bleeding complications.15
Genetic variation significantly influences warfarin dose requirements, time to achieve therapeutic anticoagulation, rate of INR increase, and risk for supratherapeutic anticoagulation and major bleeding.17 The two most relevant pharmacogenes are those encoding for vitamin K epoxide reductase complex 1 (VKORC1), warfarin's pharmacological target, and cytochrome P450 (CYP)2C9, the primary metabolic enzyme for S‐warfarin.19 The reduced‐function VKORC1 ‐1639A and CYP2C9*2, *3, *5, *6, and *11 alleles are associated with increased warfarin sensitivity, lower warfarin dose requirements, and an increased risk for supratherapeutic anticoagulation and major bleeding during warfarin initiation.7 The VKORC1 AA genotype is associated with decreased time to achieve therapeutic anticoagulation.17
In an effort to improve warfarin dosing, decrease the time to reach therapeutic anticoagulation, and reduce the risk for supratherapeutic anticoagulation, we clinically implemented genotype‐guided warfarin dosing utilizing recommended pharmacogenetic algorithms23 for hospitalized patients newly starting warfarin at the University of Illinois Hospital and Health Sciences System (UI Health) in 2012.27 The purpose of this study was to compare anticoagulation‐related endpoints by genotype group among patients receiving genotype‐guided dosing with the use of recommended pharmacogenetic dosing algorithms in a real‐world setting. We also sought to derive a novel dosing nomogram to more optimally dose warfarin.