This DGI pertains to the interaction between the VKORC1 gene, the CYP2C9 gene, and warfarin. Extensive literature and FDA warning labels indicate that specific variations in these genes can assist in the selection of a safe and effective starting dose. This DGI provides a dosing algorithm that considers both the above mentioned genes as well as clinical factors.
Clinical factors: 45 y/o Male, 210 lbs, 5’10”, amiodarone negative, enzyme inducer positive.
Genotype: VKORC1 a/g + CYP2C9 *2/*3
Maximum Recommended Starting Dose = 7.5 mg/day.
Calculated doses exceeding 7.5 mg/day are capped based on FDA recommendations for safe starting doses.
NOTE: The Vanderbilt Pharmacy and Therapeutics Committee recommends using the dose generated by the above algorithm when prescribing INITIAL warfarin dose. These guidelines were developed based on clinical trials showing reduced dosing error with integration of genetic information and subsequent validation in a Vanderbilt population.
The CYP2C9 gene encodes the CYP2C9 enzyme, which is a member of the cytochrome P450 enzyme family. It is involved in the metabolism of warfarin in the body. There are different CYP2C9 gene versions, or variants, and each has a different effect on how well warfarin works in the body. The variants termed *2 and *3 may result in a non-functioning or low-functioning CYP2C9 protein. The VKORC1 gene encodes an enzyme that is involved in the blood clotting process in the body. The two versions of VKORC1 known as “G” and “A” also affect how well warfarin works in the body.
Patients with one or more variants in either of these genes may need a lower dose of warfarin to achieve the desired effect of the drug. CYP2C9 and VKORC1 gene results, along with a patient’s individual clinical factors, are incorporated into Vanderbilt’s warfarin dose calculator, which provides the recommended initial dose of warfarin for a patient. (See Supporting Evidence)
Genotyping for VKORC1 and CYP2C9 was performed within a high complexity, certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement act of 1988. This validated clinical Laboratory Developed Test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be >99%.
Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record
Ramirez AH, Shi Y, Schildcrout JS, Delaney JT, Xu H, Oetjens MT, Zuvich RL, Basford MA, Bowton E, Jiang M, Speltz P, Zink R, Cowan J, Pulley JM, Ritchie MD, Masys DR, Roden DM, Crawford DC, Denny JC. Pharmacogenomics. 2012 Mar;13(4):407-18. Epub 2012 Feb 13.
Aim: Warfarin pharmacogenomic algorithms reduce dosing error, but perform poorly in non-European-Americans. Electronic health record (EHR) systems linked to biobanks may allow for pharmacogenomic analysis, but they have not yet been used for this purpose.
Patients and Methods: We used BioVU, the Vanderbilt EHR-linked DNA repository, to identify European-Americans (n = 1022) and African-Americans (n = 145) on stable warfarin therapy and evaluated the effect of 15 pharmacogenetic variants on stable warfarin dose.
Results: Associations between variants in VKORC1, CYP2C9 and CYP4F2 with weekly dose were observed in European-Americans as well as additional variants in CYP2C9 and CALU in African-Americans. Compared with traditional 5 mg/day dosing, implementing the US FDA recommendations or the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm reduced error in weekly dose in European-Americans (13.5-12.4 and 9.5 mg/week, respectively) but less so in African-Americans (15.2-15.0 and 13.8 mg/week, respectively). By further incorporating associated variants specific for European-Americans and African-Americans in an expanded algorithm, dose-prediction error reduced to 9.1 mg/week (95% CI: 8.4-9.6) in European-Americans and 12.4 mg/week (95% CI: 10.0-13.2) in African-Americans. The expanded algorithm explained 41 and 53% of dose variation in African-Americans and European-Americans, respectively, compared with 29 and 50%, respectively, for the IWPC algorithm. Implementing these predictions via dispensable pill regimens similarly reduced dosing error.
Conclusion: These results validate EHR-linked DNA biorepositories as real-world resources for pharmacogenomic validation and discovery.
Estimation of the warfarin dose with clinical and pharmacogenetic data
International Warfarin Pharmacogenetics Consortium, Klein T E, Altman R B, Eriksson N, Gage B F, Kimmel S E, Lee M-T M, Limdi N A, Page D, Roden D M, Wagner M J, Caldwell M D, Johnson J A in The New England journal of medicine (2009).
Background: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base.
Methods: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators.
Results: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week).
Conclusions: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation
Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications
Guruprasad P Aithal, Christopher P Day, Patrick JL Kesteven, Ann K Daly, The Lancet, Volume 353, Issue 9154, 27 February 1999, Pages 717-719, ISSN 0140-6736, 10.1016/S0140-6736(98)04474-2.
Background: The cytochrome P450 CYP2C9 is responsible for the metabolism of S-warfarin. Two known allelic variants CYP2C9*2 and CYP2C9*3 differ from the wild type CYP2C9*1 by a single aminoacid substitution in each case. The allelic variants are associated with impaired hydroxylation of S-warfarin in in-vitro expression systems. We have studied the effect of CYP2C9 polymorphism on the in-vivo warfarin dose requirement.
Methods: Patients with a daily warfarin dose requirement of 1.5 mg or less (low-dose group, n=36), randomly selected patients with a wide range of dose requirements from an anticoagulant clinic in north-east England (clinic control group, n=52), and 100 healthy controls from the community in the same region were studied. Genotyping for the CYP2C9*2 and CYP2C9*3 alleles was done by PCR analysis. Case notes were reviewed to assess the difficulties encountered during the induction of warfarin therapy and bleeding complications in the low-dose and clinic control groups.
Findings: The odds ratio for individuals with a low warfarin dose requirement having one or more CYP2C9 variant alleles compared with the normal population was 6.21 (95% CI 2.48-15.6). Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy (5.97 [2.26-15.82]) and have increased risk of major bleeding complications (rate ratio 3.68 [1.43-9.50]) when compared with randomly selected clinic controls.
Interpretation: We have shown that there is a strong association between CYP2C9 variant alleles and low warfarin dose requirement. CYP2C9 genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications.
Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation
Jeffrey L. Anderson, Benjamin D. Horne, Scott M. Stevens, Amanda S. Grove, Stephanie Barton, Zachery P. Nicholas, Samera F.S. Kahn, Heidi T. May, Kent M. Samuelson, Joseph B. Muhlestein, John F. Carlquist, and for the Couma-Gen Investigators. Circulation. 2007;116:2563-2570, published online before print November 7 2007, doi:10.1161/CIRCULATIONAHA.107.737312
Background: Pharmacogenetic-guided dosing of warfarin is a promising application of “personalized medicine” but has not been adequately tested in randomized trials.
Methods and Results: Consenting patients (n=206) being initiated on warfarin were randomized to pharmacogenetic-guided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses (P<0.001), resulting in smaller (P=0.002) and fewer (P=0.03) dosing changes and INRs (P=0.06). However, percent out-of-range INRs (pharmacogenetic = 30.7%, standard = 33.1%), the primary end point, did not differ significantly between arms. Despite this, when restricted to wild-type patients (who required larger doses; P=0.001) and multiple variant carriers (who required smaller doses; P<0.001) in exploratory analyses, results (pharmacogenetic = 29%, standard = 39%) achieved nominal significance (P=0.03). Multiple variant allele carriers were at increased risk of an INR of > or = 4 (P=0.03).
Conclusions: An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes.