HotSpots
Using pharmacogenetics in real time to guide therapy: the warfarin example References 1. Wadelius M, Chen LY, Lindh JD et al. The largest prospective warfarintreated cohort supports genetic forecasting. Blood 2009: 113 (4): 784–792. 2. Jorgensen AL, FitzGerald RJ, Oyee J, Pirmohamed M, Williamson PR. Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis. PLoS One 2012: 7 (8): e44064. 3. Yang J, Chen Y, Li X et al. Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol 2013: 168 (4): 4234–4243.
A randomized trial of genotype-guided dosing of warfarin Pirmohamed et al. (2013) N Engl J Med; 369(24):2294–303 Warfarin is a commonly prescribed anticoagulant for the treatment and prevention of thrombosis and thromboembolism, and for the prevention of stroke
in patients with atrial fibrillation. As a vitamin K antagonist, it inhibits vitamin K epoxide reductase, otherwise known as VKOR, thereby disrupting the vitamin K cycle important for blood coagulation (Fig. 2). Since its approval in 1954, warfarin has remained the most widely prescribed oral anticoagulant till date. Despite its effectiveness, warfarin therapy has a narrow therapeutic index, with wide inter-patient variation in the daily doses. As a consequence, patients sometimes suffer from insufficient anticoagulation or excessive bleeding events which are the most common cause of hospitalizations. Warfarin-associated morbidity and mortality remain unacceptably high, and consideration of patient-specific factors in the initiation and maintenance of therapy is critical and remains a challenge. The substantial inter-individual variability in warfarin dosing even when considering known clinical risk factors suggests an underlying genetic component. Wadelius et al., have already showed that genetic variants of cytochrome P450 2C9 (CYP2C9*2 and *3 ), which encodes an enzyme involved in the metabolism of S -warfarin and vitamin K epoxide reductase (VKORC1 -1639G>A) which encodes an enzyme involved in the vitamin K cycle, significantly influenced warfarin dosing and predicted unstable anticoagulation. As yet, no definitive evidence-based data existed to support the use of genetic testing for these polymorphisms in patients with an indication for warfarin therapy. This study however now provided robust evidence for the clinical implementation of geneticguided warfarin therapy to improve patient care and clinical outcomes (1). This led to the development of a pharmacogenetic-based algorithm for warfarin dosing and the updating and revision of the warfarin label by the Food and Drug Administration. A key question of public health interest is whether these pharmacogenetic guidelines informed by VKORC1 and CYP2C9 genotypes in patients are superior to standard clinical practice guidelines for warfarin therapy. Several observational and small clinical trials have attempt to answer this question, with many of the studies providing supporting evidence in favor of genetic-guided warfarin dosing schemes. Pirmohamed and his collaborators as part of the European Pharmacogenetics of Anticoagulant
533
HotSpots across different religions, cultures, ethnicities and nations. Finally, the re-imbursements for hospitals and clinical laboratories offering these tests to patients still need to be addressed by most health insurance schemes. F. Aminkeng Vitamin K
Liver
CYP2C9
S - Warfarin
VKORC1
Vitamin KH2
Vitamin K oxide
Fig. 2. An overview of warfarin interactive pathways and the main genes involved in warfarin pharmacokinetics and pharmacodynamics. This figure illustrates the main genes involved in the biotransformation of warfarin and vitamin K. CYP2C9 is associated with warfarin biotransformation while VKORC1 is involve in vitamin K biotransformation.
Therapy (EU-PACT) consortium performed a large randomized control trial, with patients from the United Kingdom and Sweden, who were to receive warfarin therapy for either atrial fibrillation or venous thromboembolism. A total of 455 patients were randomized into a genotype-guided dosing group (n = 227 patients) and a standard/control dosing group (n = 228 patients). The genotype-guided dosing group was genotyped for CYP2C9*2 , CYP2C9*3 , and VKORC1 (−1639G → A). They showed that genotype-guided warfarin dosing was superior to standard dosing at the initiation of warfarin therapy. The warfarin pharmacogenetic-based dosing algorithm informed by CYP2C9*2 , CYP2C9*3 , and VKORC1 (−1639G → A) genotypes significantly increased the time in the therapeutic range and reduced the incidence of excessive anticoagulation, the time required to reach the international normalized ratio, the time required to reach a stable warfarin dose, and the number of adjustments in the dose of warfarin. This is consistent with previous observation and randomized control trials (2, 3). This randomized control trial for warfarin therapy shows the significant potential of using pharmacogenetics in real time to improve patient care. However, warfarin pharmacogenetic testing is not routinely performed despite extensive scientific evidence establishing CYP2C9 and VKORC1 variations as being important to warfarin-dose requirements. The major issues that have to be dealt with include the education of clinicians on how to incorporate pharmacogenetic information into clinical practice and the development of objective clinical practice guidelines that include pharmacogenetic information. Additional issues include the ethical, legal and privacy issues related to the access of electronic health records containing genetic information and in the perception and acceptance of genetic testing
534
The Canadian Pharmacogenomic Network for Drug Safety (CPNDS), Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z4H4, Canada [email protected]
Using pharmacogenetics in real time to guide therapy: the warfarin example References 1. Wadelius M, Chen LY, Lindh JD et al. The largest prospective warfarintreated cohort supports genetic forecasting. Blood 2009: 113 (4): 784–792. 2. Jorgensen AL, FitzGerald RJ, Oyee J, Pirmohamed M, Williamson PR. Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis. PLoS One 2012: 7 (8): e44064. 3. Yang J, Chen Y, Li X et al. Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol 2013: 168 (4): 4234–4243.
A randomized trial of genotype-guided dosing of warfarin Pirmohamed et al. (2013) N Engl J Med; 369(24):2294–303 Warfarin is a commonly prescribed anticoagulant for the treatment and prevention of thrombosis and thromboembolism, and for the prevention of stroke
in patients with atrial fibrillation. As a vitamin K antagonist, it inhibits vitamin K epoxide reductase, otherwise known as VKOR, thereby disrupting the vitamin K cycle important for blood coagulation (Fig. 2). Since its approval in 1954, warfarin has remained the most widely prescribed oral anticoagulant till date. Despite its effectiveness, warfarin therapy has a narrow therapeutic index, with wide inter-patient variation in the daily doses. As a consequence, patients sometimes suffer from insufficient anticoagulation or excessive bleeding events which are the most common cause of hospitalizations. Warfarin-associated morbidity and mortality remain unacceptably high, and consideration of patient-specific factors in the initiation and maintenance of therapy is critical and remains a challenge. The substantial inter-individual variability in warfarin dosing even when considering known clinical risk factors suggests an underlying genetic component. Wadelius et al., have already showed that genetic variants of cytochrome P450 2C9 (CYP2C9*2 and *3 ), which encodes an enzyme involved in the metabolism of S -warfarin and vitamin K epoxide reductase (VKORC1 -1639G>A) which encodes an enzyme involved in the vitamin K cycle, significantly influenced warfarin dosing and predicted unstable anticoagulation. As yet, no definitive evidence-based data existed to support the use of genetic testing for these polymorphisms in patients with an indication for warfarin therapy. This study however now provided robust evidence for the clinical implementation of geneticguided warfarin therapy to improve patient care and clinical outcomes (1). This led to the development of a pharmacogenetic-based algorithm for warfarin dosing and the updating and revision of the warfarin label by the Food and Drug Administration. A key question of public health interest is whether these pharmacogenetic guidelines informed by VKORC1 and CYP2C9 genotypes in patients are superior to standard clinical practice guidelines for warfarin therapy. Several observational and small clinical trials have attempt to answer this question, with many of the studies providing supporting evidence in favor of genetic-guided warfarin dosing schemes. Pirmohamed and his collaborators as part of the European Pharmacogenetics of Anticoagulant
533
HotSpots across different religions, cultures, ethnicities and nations. Finally, the re-imbursements for hospitals and clinical laboratories offering these tests to patients still need to be addressed by most health insurance schemes. F. Aminkeng Vitamin K
Liver
CYP2C9
S - Warfarin
VKORC1
Vitamin KH2
Vitamin K oxide
Fig. 2. An overview of warfarin interactive pathways and the main genes involved in warfarin pharmacokinetics and pharmacodynamics. This figure illustrates the main genes involved in the biotransformation of warfarin and vitamin K. CYP2C9 is associated with warfarin biotransformation while VKORC1 is involve in vitamin K biotransformation.
Therapy (EU-PACT) consortium performed a large randomized control trial, with patients from the United Kingdom and Sweden, who were to receive warfarin therapy for either atrial fibrillation or venous thromboembolism. A total of 455 patients were randomized into a genotype-guided dosing group (n = 227 patients) and a standard/control dosing group (n = 228 patients). The genotype-guided dosing group was genotyped for CYP2C9*2 , CYP2C9*3 , and VKORC1 (−1639G → A). They showed that genotype-guided warfarin dosing was superior to standard dosing at the initiation of warfarin therapy. The warfarin pharmacogenetic-based dosing algorithm informed by CYP2C9*2 , CYP2C9*3 , and VKORC1 (−1639G → A) genotypes significantly increased the time in the therapeutic range and reduced the incidence of excessive anticoagulation, the time required to reach the international normalized ratio, the time required to reach a stable warfarin dose, and the number of adjustments in the dose of warfarin. This is consistent with previous observation and randomized control trials (2, 3). This randomized control trial for warfarin therapy shows the significant potential of using pharmacogenetics in real time to improve patient care. However, warfarin pharmacogenetic testing is not routinely performed despite extensive scientific evidence establishing CYP2C9 and VKORC1 variations as being important to warfarin-dose requirements. The major issues that have to be dealt with include the education of clinicians on how to incorporate pharmacogenetic information into clinical practice and the development of objective clinical practice guidelines that include pharmacogenetic information. Additional issues include the ethical, legal and privacy issues related to the access of electronic health records containing genetic information and in the perception and acceptance of genetic testing
534
The Canadian Pharmacogenomic Network for Drug Safety (CPNDS), Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z4H4, Canada [email protected]
