Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin

Abstract

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% ...

Warfarin pharmacogenetics: development of a dosing algorithm for Omani patients

“…Limdi et al, 1 in a recent study demonstrated that VKORC1 3673G4A polymorphism was predictive of warfarin dose across three racial groups, namely Asians, Blacks and Whites, but its contribution varies between 11 and 32% amongst Caucasians, 30% in Asians and 4-10% in African Americans, reflecting its relative frequency in each population. 9,10,15,16 28 (20) 17 (24) n.s.…”

“…9,15 Contribution of the CYP2C9 variant alleles to warfarin dose variability differed widely across geographical groups collectively classified as Whites (2.5-18.3 mg per day). 10,11,15,16 Lee et al, 17 in a study from Singapore, showed that the CYP2C9 genotype accounted for 29, 7 and 0% of warfarin dose variance among Indians, Chinese and Malay patients, respectively. Cavallari et al 9 reported that the influence of CYP2C9 variant alleles on warfarin dose was around 15% in a predominantly African American population and inclusion of the CYP2C9*5, *6, *8 and *11 alleles further improved the predictive ability beyond that seen with CYP2C9*2 and *3.…”

Accuracy assessment of pharmacogenetic algorithms for warfarin dose prediction in Chinese patients

“…Algorithms were selected based on the following criteria: the algorithms that included nongenetic or genetic variables not available in our study, and included only a minority of clinical variables, and were based on relatively small clinical populations were excluded; algorithms that were derived from Asian with the consideration of race of each algorithm made up of at least 15% Asians in original populations, and algorithms validated best in Asians were included. This process identified eight algorithms [12][13][14][15][16][17][18][19]. The characteristics and equations of selected algorithms are listed in Supporting Information Tables II and III. Collection of subjects and clinical data.…”

“…In the interest of determining an accurate predictive pharmacogenetic algorithm to promote rational treatment, especially for Chinese outliers, we attempted to assess the predictive ability of published warfarin pharmacogenetic dosing algorithms in Mainland Han Chinese [12][13][14][15][16][17][18][19].…”

Engaging Hmong adults in genomic and pharmacogenomic research: Toward reducing health disparities in genomic knowledge using a community-based participatory research approach

“…For the pharmacogenomic results associated with altered response to warfarin (based on analysis of CYP2C9*2, CYP2C9*3, and VKORC1), we informed participants that the Hmong displayed a prevalence of individuals who may have a lower dosage requirement for the drug warfarin compared to nonHmong. Specifically, approximately 30% of participants would need less than usual dose, and 2% would need more than usual dose (Gage et al 2008;Klein et al 2009), compared to a combined Han-Chinese and Japanese cohort (International HapMap Project 2010; Tham et al 2006). For both genomic and pharmacogenomic results, we cautioned participants about the limited scope of translational significance of these observations, and provided general advice concerning reducing individual's risk to develop T2DM and discussing possible need for genetic testing should anyone be prescribed warfarin in the future.…”