Cost-Utility Study of Warfarin Genotyping in the VACHS Affiliated Anticoagulation Clinic of Puerto Rico.

OBJECTIVE: To evaluate the cost-utility of the pharmacogenetic-guided dosing of warfarin (PGx), when compared to the current dosing strategy. METHODS: A Markov model was developed to assess the impact of the genotypingguided warfarin dosing in a hypothetical cohort of patients. The model was based on the percentage of time patients spent within the therapeutic international normalized ratio (INR) range (PTTR). PTTR estimates and genotype distribution were derived from a cohort of patients (n = 206) treated in the Veteran Affairs Caribbean Healthcare System (VACHS) and from results of other research study. Costs, utilities and event probability data were obtained from the literature. Probabilistic and one-way sensitivity analyses were performed to explore the range of plausible results. Willingness to pay was established at $50,000 per Quality Adjusted Life Year (QALY) gained. RESULTS: According to our model, the PGx strategy showed a QALY increase of 0.0021, with an increase in total cost of $272. This corresponds to an incremental cost-utility ratio (ICUR) of $127,501, ranging from $95,690 to $148,611. One-way sensitivity analysis revealed that the ICURs were more sensitive to the cost of genotyping and the effect of genotyping on the PTTR. CONCLUSION: Our model suggests that the warfarin PGx was not superior to the standard of care dosing strategy in terms of cost-utility.

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study.

Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the CYP2C9 locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics.

A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics.

AIM: This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. PATIENTS & METHODS: A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals. RESULTS: The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p<0.001). The admixture-driven pharmacogenetic algorithm predicted 58% of warfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias). CONCLUSIONS: Results supported our rationale to incorporate individual's genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics. TRIAL REGISTRATION: ClinicalTrials.gov NCT01318057.

Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients.

AIM: This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. PATIENTS & METHODS: A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. RESULTS: The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better 'ideal dose' estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R(2) = 51%). CONCLUSION: Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients.

Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes.

BACKGROUND: The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients. OBJECTIVE: To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm. METHODS: A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested. RESULTS: Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-range INR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in an extreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients. CONCLUSIONS: This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA-guided warfarin dosing algorithm.

Intervention to decrease glyburide use in elderly patients with renal insufficiency.

OBJECTIVES: The objectives of this study were to describe changes in glyburide prescribing in cohorts that were and were not targeted by a risk reduction project, assess factors associated with glyburide discontinuation, and evaluate changes in glycated hemoglobin (ie, HbA(1c)) levels and rates of serious hypoglycemia. METHODS: This historical cohort study included a targeted cohort of 4368 outpatient veterans aged ≥65 years with active prescriptions for glyburide between April 1, 2007 and June 30, 2007 and serum creatinine (SCr) ≥2 mg/dL and a nontargeted cohort of 1886 outpatients meeting these same criteria between July 1, 2007 and September 3, 2007. The intervention in the risk reduction project took place on September 4, 2007 and entailed giving regional pharmacy leaders information about the increased risk of hypoglycemia with glyburide and the list of targeted patients for follow up with providers. For each patient, the study period was the time between the date they first met the eligibility criteria and March 31, 2008. All data were obtained from Veterans Affairs (VA) administrative databases. The primary outcome was the discontinuation of glyburide. Secondary outcomes were the change in HbA(1c) after stopping glyburide and the rate of serious hypoglycemia after intervention. RESULTS: Incidence rate ratios (IRRs) for glyburide discontinuation in targeted versus nontargeted cohorts were statistically significantly elevated in September (IRR 2.1; 95% CI 1.7-2.5), October (IRR 1.3; 95% CI 1.1-1.6), and November 2007 (IRR 1.4; 95% CI 1.1-1.7). The intervention, black race, SCr, Charlson comorbidity score, new glyburide use, and VA region were independently associated with discontinuation. Among patients in the targeted cohort who discontinued glyburide, mean (SD) HbA(1c) at baseline and after discontinuation were 7.17% (1.35%), and 7.22% (1.34%), respectively (P = 0.36). The hypoglycemia rates/1000 person-days were 0.093 before the intervention and 0.070 afterwards (P = 0.10). CONCLUSION: A one-time intervention in a risk reduction project decreased glyburide use over a 3-month period in elderly outpatients with renal insufficiency without compromising glucose control.