Initiation of warfarin therapy using trial-and-error dosing is problematic. our goal was to develop and validate a pharmacogenetic algorithm. in the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism −1639/3673 g>a (−28% per allele), body surface area (Bsa) (+11% per 0.25 m 2 ), CYP2C9*3 (−33% per allele), CYP2C9*2 (−19% per allele), age (−7% per decade), target international normalized ratio (inr) (+11% per 0.5 unit increase), amiodarone use (−22%), smoker status (+10%), race (−9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53−54% of the variability in the warfarin dose in the derivation and validation (N = 292) cohorts. For comparison, a clinical equation explained only 17−22% of the dose variability (P < 0.001). in the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.Correspondence: BF Gage (E-mail: bgage@im.wustl.edu). CONFLICT OF INTEREST Dr Gage has consulted for Bristol-Myers Squibb on work unrelated to this article. Drs Rieder and Rettie report having applied for a patent (application serial no. 10/967,879) on the use of VKORC1 haplotypes and SNPs. The other authors declared no conflict of interest. NIH Public Access RESULTSIn the derivation cohort (N = 1,015), the daily therapeutic warfarin dose ranged from 1 to 18 mg/day. The mean age was 65 (range of 18−93); 83% were Caucasian, and 64% were male. The (geometric) mean daily warfarin dose was 4.8 mg ( Table 1). The most common indications for warfarin therapy were atrial fibrillation (N = 392) and prior venous thromboembolism (N = 376; 13 of whom also had atrial fibrillation). Patients in the validation cohort (N = 292) were younger, more often female, and had more often (77%) undergone joint replacement as their indication for warfarin therapy (Table 1).VKORC1 alleles were highly heterogeneous (Table 2), reflecting their original selection as common (>5% allele frequency), informative tagging SNPs (Table 2). 12 VKORC1 3673G>A was in high linkage disequilibrium with VKORC1 6853G>C (D' = 0.97). In both cohorts, all alleles were in Hardy-Weinberg equilibrium. Genotype data from all participants at Washington University and University of Florida have been submitted to the PharmGKB (accession numbers: PS207479 and PS207480 pending). Pharmacogenetic model developmentThe VKORC1 3673G>A SNP was the first variable to enter the stepwise regression model (Table 3); each VKORC1 3673A allele was associated with a 28% reduction (95% confidence interval 25−30%) in the therapeutic warfarin dose. Once VKORC1 3673G>A entered the model, none of the other VKORC1 SNPs was an independent predictor of warfarin dose. Body surface area (BSA) was the second variable to enter the model, and each 0.25 m 2 increase in BSA was associated with an 11% ...
Background-Well characterized genes affecting warfarin metabolism (CYP2C9) and sensitivity (VKORC1) explain one-third of the variability in therapeutic dose before the International Normalized Ratio (INR) is measured.
Cytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C9*2 and CYP2C9*3) reduce the clearance of warfarin, increase the risk of bleeding, and prolong the time to stable dosing. Whether prospective use of a retrospectively developed algorithm that incorporates CYP2C9 genotype and nongenetic factors can ameliorate the propensity to bleeding and delay in achieving a stable warfarin dose is unknown. We initiated warfarin therapy in 48 orthopedic patients tailored to the following variables: CYP2C9 genotype, age, weight, height, gender, race, and use of simvastatin or amiodarone. By using pharmacogenetics-based dosing, patients with a CYP2C9 variant achieved a stable, therapeutic warfarin dose without excessive delay. However compared to those without a CYP2C9 variant, patients with a variant continued to be at increased risk (hazard ratio 3.6, 95% confidence interval 1.4-9.5, p = 0.01) for an adverse outcome (principally INR > 4), despite pharmacogenetics-based dosing. There was a linear relationship (R(2) = 0.42, p < 0.001) between the pharmacogenetics-predicted warfarin doses and the warfarin maintenance doses, prospectively validating the dosing algorithm. Prospective, perioperative pharmacogenetics-based dosing of warfarin is feasible; however, further evaluation in a randomized, controlled study is recommended.
IntroductionWarfarin sodium is characterized by a narrow therapeutic range (eg, an international normalized ratio [INR]) of 2.0-3.0), a marked interindividual variation in dosing requirements, and an increased risk of adverse events when the dose is too high or low. 1,2 To minimize the high incidence of such events, [3][4][5] particularly during the first few weeks of initiating therapy, 1,6 most guidelines recommend prescribing warfarin at or near the anticipated maintenance dose and then adjusting the dose by trial and error. 1,7,8 While algorithms for predicting this maintenance dose a priori have improved, [9][10][11][12][13][14][15][16] there remains little guidance on how this starting dose should be adjusted a posteriori based on the subsequent INR values. We hypothesized that use of genetic markers could help optimize these dose refinements.Two common single nucleotide polymorphisms (SNPs) in the cytochrome P450 (CYP) 2C9 system are associated with impaired metabolism of warfarin, [3][4][5][6]11,17 while SNPs in the gene for vitamin K epoxide reductase complex 1 (VKORC1) correlate with warfarin sensitivity and resistance. 2,[18][19][20] No prior study has examined the impact of these SNPs on warfarin-dose adjustments. Given the current knowledge about these markers, we hypothesize that for a given INR, a patient who is a slow metabolizer of warfarin may need a more cautious adjustment in their dose than a similar patient who is a normal metabolizer. Failure to tailor dose refinements during warfarin induction in poor metabolizers may have contributed to the 3-fold increased risk of (laboratory or clinical) adverse events among poor metabolizers in our initial prospective study of pharmacogenetic-based warfarin therapy. 4 The purpose of this study was to develop a dose-refinement nomogram to guide clinicians in adjusting warfarin doses. This nomogram would be similar to prior algorithms, 21,22 but will have 2 advantages: (1) it will allow for, but not require, a first dose that is tailored to clinical and/or genetic factors and (2) it will incorporate genetics and clinical factors that are independent predictors of how much the dose should be refined. 1,11 If successful, the proposed warfarin nomogram would simplify and standardize warfarin initiation. Patients, materials, and methodsThe study was a retrospective analysis of 2 cohorts of orthopedic surgery patients who had participated in 2 prospective studies of pharmacogeneticbased warfarin therapy. The Human Research Protection Office at Washington University Medical Center approved these studies. PatientsFor patients in both cohorts, we offered participation if they were scheduled for primary or revision total knee or hip arthroplasty at Washington University Medical Center and if they were 18 years or older. We excluded patients who had previously taken warfarin or who had contraindications to warfarin treatment. To allow time for genotyping, we also excluded patients scheduled for surgery fewer than 7 days following referral to our anticoagulation s...
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