Clinical and Economic Consequences of Pharmacogenetic-guided Dosing of Warfarin

Talitha I Verhoef; Tom Schalekamp; William K Redekop; Anthonius de Boer; Anke-Hilse Maitland-van der Zee

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2010;10(4):375-378. 

In This Article

Abstract and Introduction

Abstract

Patients using warfarin for oral anticoagulant therapy need to be frequently monitored because of warfarin's narrow therapeutic range and the large variation in dose requirements among patients. Patients receiving the wrong dose have an increased risk of bleeding or thromboembolic events. The required dose is influenced by environmental factors, such as gender, age, diet and concomitant medication, as well as genetic factors. Pharmacogenetic testing prior to warfarin initiation might improve dosing accuracy and, therefore, safety and efficacy of warfarin treatment. Meckley et al. studied the clinical consequences and costs of genotyping before warfarin treatment. The results of their study suggest that pharmacogenetic-guided dosing of patients initiating warfarin could improve health (quality-adjusted life-years) but at a high cost per quality-adjusted life-year gained. Owing to the inevitable assumptions that have to be made in all cost–effectiveness models, great uncertainty remains regarding the cost–effectiveness of pharmacogenetic-guided warfarin dosing.

Introduction

Warfarin is a drug widely used for oral anticoagulation in patients with atrial fibrillation, venous thromboembolism or a prosthetic heart valve to reduce the risk of thromboembolic events.[1] The optimal warfarin dose is assessed by measuring the international normalized ratio (INR), which should be kept within a narrow range, since the risk of thromboembolic events decreases with an increasing INR, while the risk of bleeding events increases. A large inter- and intra-patient variability in warfarin dose requirement makes frequent INR monitoring necessary. The required dosage is influenced by several factors, such as gender, age, diet, concomitant medication and genetic factors.

Polymorphisms in both the CYP2C9 gene, encoding for the main metabolizing enzyme, cytochrome P450 2C9 (CYP2C9), and the VKORC1 gene, encoding the target enzyme vitamin K epoxide reductase multiprotein complex 1, explain approximately a third of the variation in warfarin dose requirement. Information regarding the genotype of a patient can therefore be used to predict the warfarin maintenance dose. Although the ability of genotype-guided dosing to improve the safety and efficacy of warfarin treatment has been investigated in a few small randomized controlled trials, there is still no clear evidence about the effectiveness of this dosing strategy.[2]

The economic impact of genotyping patients prior to warfarin use is also not clear. Results from cost–effectiveness analyses of warfarin pharmacogenetics (using genetic information to determine the required dose) do not all point in the same direction.[3–5] In one of these studies genotyping appeared to be the dominant strategy, meaning that genotyping was more effective and less costly than not genotyping.[4] By contrast, other studies found that the gain in effectiveness was coupled with higher costs.[3,5] In most studies the effect of genotyping was based directly on its observed or assumed impact on the risk of bleeding and thromboembolic events, although the studies performed to date have not been large enough to detect reductions of adverse events. Using the association between the level of INR with the risk of bleeding and thromboembolic events, Meckley et al. developed a policy model to evaluate the clinical and economic consequences of pharmacogenetic-guided warfarin dosing, based on the effect of genotyping on INR levels.[1]

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