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Prof. Mateja Kaja Jezovnik
Prof. Pavel Poredos,
Having the polymerase chain reaction, the three CYPs and two VKORCs tested, predicts the part of the patient’s response to warfarin, owing to these relevant genes. With 5% or more of serious adverse events in patients using warfarin, this information may be useful to the physician, seeking the perfect dosage. However, pharmacogenetic testing comes at a cost.
Anticoagulation treatment is challenging. The most commonly prescribed oral anticoagulant drug is warfarin. It is used for primary and secondary prevention of venous and arterial thromboembolic disorders, atrial fibrillation, mechanical prosthetic valves and a few other indications. Its use is complicated by a narrow therapeutic window and high variability in dose requirements, resulting in serious adverse events in 5% or more of patients (1). Although drug interactions, liver disease, general state of health and differences in diet commonly contribute to this wide patient-to-patient variation, genetic factors may also account for some of the variability in response to warfarin (2).
In recent years, great efforts have been made towards “individualised” management of the disease based on the individual selection of therapeutic options, including individualising the optimal drug dosage. Among factors creating sensitivity to drugs, are genetic polymorphisms, which determine personal differences in efficacy and tolerance to drug therapies. Knowing the factors that influence individual responses to warfarin would help in tailoring the dose needed to maintain appropriate anticoagulation with fewer cases of serious complications. Recent evidence has suggested that nucleotide polymorphism in the genes-encoding enzymes - involved in the metabolism of warfarin -determine the effective and safe dose of warfarin to prescribe. Thus, a patient's response to warfarin is also influenced by genome and therefore pharmacogenetics could be used to estimate warfarin dosage and to minimise the risk of overdose during warfarin induction.
The major determinants of warfarin metabolism and related dose requirements are vitamin K epoxide reductase complex (VKORC1) and cytochrome P450 family 2, subfamily C, polypeptide 9 (CYP 2C9). Warfarin is an equal mixture of the enantiomers S-warfarin and R-warfarin, with S-warfarin being 3-5 times more potent than R-warfarin. The metabolism of S-warfarin acts through cytochrome P450 2C9 enzyme, while metabolism of the less potent R-warfarin acts through CYP 2C19, CYP 1A2 and CYP 3A4. Patients who metabolise warfarin normally are homozygous for the usual (wild type) cytochrome allele CYP 2C9*1. Two other clinically relevant nucleotide polymorphisms have been identified in CYP 2C9 (*2 and *3), responsible for reduced enzymatic activity and therefore reduced warfarin metabolism. The *2/*2 homozygous genotype leads to 12% reduction in CYP 2C9 activity and the *3/*3 homozygous genotype has less than 5% of wild type CYP 2C9 activity. Approximately 1% of the population are homozygous for CYP 2C9*2 and 22% are heterozygous carriers of this allele. The corresponding figures for CYP 2C9*3 are 0.4 % and 15%. Another 1.4% of people are compound heterozygotes (CYP 2C9*2*3). The second determinant of variability in sensitivity to warfarin appears to be related to different genetic polymorphisms in the C1 sub-unit of the vitamin K 2,3 epoxide reductase complex. Warfarin exerts its anticoagulant effect by inhibiting VKORC1. Polymorphisms of these receptors are associated with a need for lower doses of warfarin (3). The VKORC1 genotype alone may explain nearly 30% of the variability in response to warfarin (4). Nevertheless, knowing both a patient’s CYP 2C9 and VKORC1 status, predicts less than half of the variation in the response to warfarin (5). Further attempts have been made to recognise other single nucleotide genes, but their additive effect on the predictive value in response to warfarin seems less important.
Several dosing algorithms to predict dose requirements of warfarin which include clinical factors and demographic variables have been validated in clinical practice in recent years (6-8). Recently, information coming from genetic testing was also implemented in these models. Algorithms incorporating pharmacogenetics to estimate warfarin dosage show that it is possible to reduce the risk of complications related to overdose during warfarin induction (9). In 2007, the United States Food and Drug Administration (FDA) approved an update to warfarin prescribing information suggesting the use of genetic – based warfarin dosing (10). However, in spite of initial enthusiasm, recent data show that models incorporating genetic factors account for only approximately half of the dose variability (11). Further, genetic testing is not widely available and is expensive. Therefore, other researchers prefer standardised warfarin initiation normograms without genetic testing. In the study of Lazo-Langner and co-workers, it was shown that standardised warfarin initiation normograms are safe and that maintenance of warfarin dose can be accurately predicted using the individual response to standard warfarin initiation normograms, thus without the need for costly genetic testing (12). Martin and co-workers, in a recent overview of the pharmacogenetics of warfarin concluded that testing is not useful in routine clinical practise because it does not predict all the variability in a patient’s response to warfarin and its contribution to improved clinical outcomes is uncertain (13). Other currently available literature related to the use of pharmacogenomic testing in the initiation of warfarin therapy also does not show improved outcomes in either safety nor efficacy with warfarin therapy and therefore does not support the routine use of pharmacogenomic testing when initiating warfarin therapy (14). Clinical outcomes such as bleeding are rare in patients followed in anticoagulation clinics if warfarin therapy is closely monitored and individualised, and in these cases genetic testing does not significantly improve the safety of the drug. Therefore, at present, genotyping is not an option for the screening of the whole patient population. However, there is currently no consensus regarding which patient groups would benefit from screening.
The costs of pharmacogenetic testing include the polymerase chain reaction tests for the three CYP and two VKORC genes and the costs of clinical interpretation, estimated at a price range of 250 – 450 euro per person, with a turnaround time of three hours (15). This indicates that routine genetic testing of all patients treated with warfarin represents a high total cost and is probably less cost-effective than careful clinical monitoring using initiation normograms without genetic testing.
Table 1: Arguments for and against pharmacogenetic testing
1. Bleeding during antithrombotic therapy in patients with atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. Arch Intern Med 1996;156:409-416 2. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119:8S-21S 3. Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005;352:2285-2293 4. D'Andrea G, D'Ambrosio RL, Di Perna P, et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 2005;105:645-649 5. Caldwell MD, Berg RL, Zhang KQ, et al. Evaluation of genetic factors for warfarin dose prediction. Clin Med Res 2007;5:8-16 6. Lenzini PA, Grice GR, Milligan PE, et al. Optimal Initial Dose Adjustment of Warfarin in Orthopedic Patients. Ann Pharmacother 2007;41:1798-1804 7. Kovacs MJ, Rodger M, Anderson DR, et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med 2003;138:714-719 8. Lazo-Langner A, Monkman K, Kovacs MJ. Predicting warfarin maintenance dose in patients with venous thromboembolism based on the response to a standardized warfarin initiation nomogram. J Thromb Haemost 2009;7:1276-1283 9. Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives. Thromb Res 2007;120:1-10 10. FDA Approves Updated Warfarin (Coumadin) Prescribing Information. 11. Wadelius M, Chen LY, Lindh JD, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009;113:784-792 12. Monkman K, Lazo-Langner A, Kovacs MJ. A 10 mg warfarin initiation nomogram is safe and effective in outpatients starting oral anticoagulant therapy for venous thromboembolism. Thromb Res 2009;124:275-280 13. Martin HJ. Pharmacogenetics of warfarin - is testing clinically indicated? Australian Prescriber 2009;32:76-80 14. Hynicka LM, Cahoon WD, Jr., Bukaveckas BL. Genetic testing for warfarin therapy initiation. Ann Pharmacother 2008;42:1298-1303 15. Eckman MH, Greenberg SM, Rosand J. Should we test for CYP2C9 before initiating anticoagulant therapy in patients with atrial fibrillation? J Gen Intern Med 2009;24:543-549
Pavel Poredos, MD., Ph.D. Mateja Kaja Jezovnik, MD., Ph.D.