Stable Warfarin Dose Research Articles

Pharmacogenetic-guided Warfarin Dosing Algorithm in African-Americans.

We aim to develop warfarin dosing algorithm for African-Americans. We explored demographic, clinical, and genetic data from a previously collected cohort of 163 African-American patients with a stable warfarin dose. We explored 2 approaches to develop the algorithm: multiple linear regression and artificial neural network (ANN). The clinical significance of the 2 dosing algorithms was evaluated by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual dose. Linear regression model and ANN model predicted the ideal dose in 52% and 48% of the patients, respectively. The mean absolute error using linear regression model was estimated to be 10.8 mg compared with 10.9 mg using ANN. Linear regression and ANN models identified several predictors of warfarin dose including age, weight, CYP2C9 genotype *1/*1, VKORC1 genotype, rs12777823 genotype, rs2108622 genotype, congestive heart failure, and amiodarone use. In conclusion, we developed a warfarin dosing algorithm for African-Americans. The proposed dosing algorithm has the potential to recommend warfarin doses that are close to the appropriate doses. The use of more sophisticated ANN approach did not result in improved predictive performance of the dosing algorithm except for patients of a dose of ≥49 mg/wk.

Influence of UDP-Glucuronosyltransferase Polymorphisms on Stable Warfarin Doses in Patients with Mechanical Cardiac Valves.

This study aimed to evaluate the effect of uridine diphosphate (UDP)-glucuronosyltransferase (UGT) polymorphisms on warfarin dosing requirements in patients with mechanical cardiac valves. A total of 191 patients with stable warfarin doses from the EAST Group of Warfarin were included in this study. The influence of genetic polymorphisms on stable warfarin doses was investigated by genotyping 6 single nucleotide polymorphisms (SNPs): vitamin K epoxide reductase complex 1 (VKORC1) rs9934438, cytochrome P450 (CYP) 2C9 rs1057910, CYP4F2 rs2108622, and UGT1A1 (rs887829, rs4148323, and rs4124874). An additional subgroup analysis was carried out using patients with wild-type homozygote carriers of CYP2C9. One UGT1A1 SNP of rs887829 (C>T) exhibited significant association with stable warfarin doses in the study population and subgroup. Patients with the T allele in UGT1A1 rs887829 (CT or TT) required higher doses than those with the CC genotype in the study population (6.3 ± 2.4 mg vs. 5.2 ± 1.6 mg, P = 0.003). Similarly, in the subpopulation of AA carriers in the CYP2C9 gene, patients with the T allele required significantly higher doses of warfarin than those with other genotypes of rs887829 (6.5 ± 2.4 vs. 5.3 ± 1.5 mg, P = 0.002). Approximately 45.1% of overall interindividual variability in warfarin dose requirement was explained by the multivariate regression model. VKORC1, CYP2C9, UGT1A1 rs887829, age, and CYP4F2 accounted for 28.2%, 6.6%, 5.5%, 3.0%, and 1.8% of the variability, respectively. Our results suggest that UGT1A1 could be a determinant of stable warfarin doses.

Influence of genetic polymorphisms and non-genetic factors on the maintenance dose of warfarin

OBJECTIVE To assess the influence of genetic polymorphisms and non-genetic factors on warfarin maintenance dose variations in order to provide guidance for personalized use of warfarin. METHODS Two hundred patients from outpatient and inpatient with stable international normalized ratio(INR) were recruited. Clinical data and blood samples were collected. Genotypes of 4 genes involved in warfarin metabolic pathways were determined with Sanger sequencing. Based on statistical analysis of warfarin maintenance dosage, a mathematical model was established. RESULTS Among non-genetic factors, the age and height have significant influence in warfarin dosage. The dosage is negatively correlated with age but positively correlated with height. The difference in dosage for between the 20-year-old group and 60-year-old group has reached 1.81 mg/day, and that for between the 140 cm in height and 180 cm in height groups has reached 1.06 mg/day. VKORC1 -1639G/A, CYP2C9 430C/T, CYP2C9 1075A/C and CYP4F2 V433M polymorphisms have significant influence on stable warfarin dosage. The dosage for patients with wild type and mutant genotypes has varied from 0.35 mg/day to 0.84 mg/day. CONCLUSION Non-genetic factors and genetic polymorphisms play important roles in personalized variations of warfarin maintenance dose. The establishment of mathematical models considering multiple factors is helpful in evaluating the safety and effectiveness of warfarin dosage.

Effects of NAD(P)H quinone oxidoreductase 1 polymorphisms on stable warfarin doses in Korean patients with mechanical cardiac valves.

NAD(P)H dehydrogenase, encoded by NAD(P)H quinone oxidoreductase 1 (NQO1), is an enzyme that catalyzes the reduction of quinones, including vitamin K. Given its potential role in vitamin K metabolism, this study aimed to investigate the effects of NQO1 polymorphisms on stable warfarin doses. We tested a possible effect of gene polymorphisms on variability in warfarin response using 206 Korean patients with mechanical cardiac valves. Single nucleotide polymorphisms (SNPs) of NQO1 with a minor allele frequency of at least 15% were included. Also, genotypes of vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 (CYP) 2C9, CYP4F2, gamma-glutamyl carboxylase (GGCX), and GATA4 were determined. NQO1 rs1800566 (C>T) and rs10517 (C>T) were significantly associated with stable warfarin doses. Variant homozygote carriers required lower stable warfarin doses than those with wild-type C allele in rs1800566 (4.85 ± 1.61 vs. 5.61 ± 1.94 mg; p = 0.033), whereas patients with wild homozygote required lower doses than those with T allele in rs10517 (5.11 ± 1.73 vs. 5.75 ± 1.98 mg; p = 0.017). Similar results were obtained from stratified analysis using VKORC1 variant homozygote carriers in both SNPs. Multivariate analysis showed that rs10517 (C>T) increased contribution of gene variations to the overall warfarin dose variability from 42.5 to 43.8%. Our results demonstrate that NQO1 gene polymorphisms influence stable warfarin doses in Korean patients.

Effects of single nucleotide polymorphisms in c-Myc on stable warfarin doses in patients with cardiac valve replacements.

This study aimed to investigate an association between c-Myc SNPs and stable warfarin doses. The influences of genetic polymorphisms on dose requirements were investigated by genotyping ten SNPs in 201 patients with stable warfarin doses; VKORC1 (rs9923231), CYP2C9 (rs1057910), CYP4F2 (rs2108622), GATA4 (rs10090884), c-Myc (rs4645962, rs4645943, rs4645948 and rs4645974) and 8q24 (rs1447295 and rs16901979). Around 44.3% of the overall interindividual variability in warfarin dose requirements was explained by the multivariate regression model; VKORC1 genotype accounted for 26.4%, CYP2C9 genotype for 4.9%, age for 3.4%, c-Myc genotypes for 5.2% (rs4645974 for 2.4% and rs4645943 for 2.8%), CYP4F2 genotype for 2.9% and diuretic use for 1.5%. Our results revealed that c-Myc could be a determinant of stable warfarin doses.

Genome-wide association study of warfarin maintenance dose in a Brazilian sample.

Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians. Patients receiving low (≤ 20 mg/week; n = 180) or high stable warfarin doses (≥ 42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom(®) Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project. Genome-wide signals (p ≤ 5 × 10(-8)) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 × 10(-33)) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 × 10(-13)) regions. The rs9332238 polymorphism is in virtually perfect LD with CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). No other genome-wide significant regions were identified in the study. We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose. Original submitted 14 January 2015; Revision submitted 26 May 2015.

Effects of Pregnane X Receptor Genetic Polymorphisms on Stable Warfarin Doses

Pregnane X receptor (PXR) is a transcriptional regulator of many drug-metabolizing enzymes including cytochrome P450 (CYP) 2C9. The objective of this study was to assess the possible association between PXR single-nucleotide polymorphisms (SNPs) and stable warfarin doses. A total of 201 patients with stable warfarin doses from the EwhA-Severance Treatment (EAST) Group of Warfarin were included in this study. The influence of genetic polymorphisms on stable warfarin doses was investigated by genotyping 11 SNPs, that is, vitamin K epoxide reductase complex 1 (VKORC1) rs9934438, CYP2C9 rs1057910, CYP4F2 rs2108622, constitutive androstane receptor (CAR) rs2501873, hepatocyte nuclear factor 4α (HNF4α) rs3212198, and PXR (rs3814055, rs1403526, rs3732357, rs3732360, rs2276707 and rs2472682). Subgroup analysis was conducted on CYP2C9 wild-type homozygote allele (AA) carriers. One PXR SNP of rs2472682 (A>C) exhibited significant association with stable warfarin doses in study population and the subgroup; variant homozygote carriers required significantly lower daily doses of warfarin than those carrying wild allele by about 0.8 mg. Approximate 43.7% of overall interindividual variability in warfarin dose requirement was explained by multivariate regression model. VKORC1, CYP2C9, age, CYP4F2, PXR rs2472682, and CAR/HNF4α rs2501873/rs3212198 accounted for 29.6%, 5.9%, 3.7%, 2.3%, 1.3%, and 0.9% of the variability, respectively. PXR SNP of rs2472682 remained a significant factor in CYP2C9 wild-type homozygote carriers based on univariate and multivariate analyses. The combination of CAR/HNF4α/PXR SNPs of rs2501873/rs3212198/rs2472682 showed about 1 mg dose difference between grouped genotypes in study population and subgroup. Our results revealed that PXR could be a determinant of stable warfarin doses.

Combined effects of hepatocyte nuclear factor 4α and constitutive androstane receptor on stable warfarin doses.

A possible association between the combination of genetic variations in hepatocyte nuclear factor 4α (HNF4α) and constitutive androstane receptor (CAR) and the stable doses of warfarin was examined in patients from the Ewha-Severance Treatment (EAST) Group of Warfarin. Around 42.5% of the overall interindividual variability in warfarin dose requirements was explained by the multivariate regression model; the vitamin K epoxide reductase complex 1 (VKORC1) genotype accounted for 29.6%, the cytochrome P450 (CYP) 2C9 genotype for 4.3%, age for 3.6%, the CYP4F2 genotype for 3.3%, and CAR/HNF4α (rs2501873/rs3212198) for 1.7%. Our results showed that the combination of CAR and HNF4α genotypes could be determinants of stable warfarin doses.

Moderate Effect of GGCX Polymorphisms on Patients Warfarin Dosage Requirement- A Meta-Analysis

Objective: Association studies on the effects of GGCX gene polymorphisms on warfarin stable dose have shown conflicting results. The aim of this study is to quantitatively summarize whether GGCX gene polymorphisms have potential roles in warfarin dose requirement. Methods: Publications were searched in PubMed, Medline and ISI Web of Knowledge and chosen by exact inclusion and exclusion criteria. A meta-analysis was conducted by using Revman 5.0 software to determine the association between common polymorphisms of the three genes and warfarin dose requirement. Results: Data were extracted from 13 publications with 4167 patients enrolled. Two common polymorphisms (rs699664, rs12714145) of GGCX were included for further meta-analyses. Comparing to rs699664AA geontype carriers, rs699664GG genotype carriers requered higer 3% [95% CI: 2% - 4%, P-valus < 0.0001] warfarin dose. The warfarin dosage requirement showed no significant difference between rs699664GG and rs699664GA genotype carriers, P=0.51. Compared to rs12714145AA carriers, the GG and GA genotype carriers needed 5% (95% CI, 1% - 9%; P = 0.01) and 4% (95% CI, 1% - 8%; P = 0.02) lower warfarin dosage, respectively. The warfarin dosage requirement showed no significant difference between GG and GA genotype carriers, P=0.12. Conclusion: Our study showed that GGCX polymorphisms were significantly associated with warfarin dose requirement. These polymorphisms should be considered in future warfarin personalized treatment.

The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population.

Objective:The aim was to investigate the frequency of genetic polymorphisms of cytochrome P4502C9 (CYP2C9) and vitamin K epoxide reductase complex subunit1 (VKORC1) and determine the effect of these polymorphisms on warfarin dose requirements in pediatric patients.Methods:Fifty-eight pediatric patients with cardiac disease, thrombophilia, or other conditions, taking a stable warfarin dose, aged 0.2–18 years, and with international normalized ratio (INR) between 2 and 3 and 149 healthy children as a control group were included in this prospective, observational study. Patients receiving drugs that interact with warfarin, having chronic liver or renal disease, obesity, or thyroid dysfunctions were excluded. Polymerase chain reaction (real time and restriction fragment length polymorphism) was used to analyze the CYP2C9*2, CYP2C9*3, and VKORC1 polymorphisms. The ideal warfarin dose was calculated according to the patient’s age, height, and the presence of CYP2C9*2, CYP2C9*3, and VKORC1 genetic polymorphisms. The mean daily administered doses and ideal doses were compared. Analysis of variance, Student’s t-test, logistic regression analysis, and Pearson’s correlation analysis were used for statistical analyses.Results:The frequency of the CYP2C9 and VKORC1 genetic polymorphisms was determined as CYP2C9*1/*1 (54.6%), *1/*2 (16.4%), *1/*3 (24.2%), *2/*3 (2.9%), *3/*3 (1.9%), wild-type VKORC1 (26.6%), heterozygote alleles (52.7%), and mutant alleles (20.8%). Patients with allelic variants were found to require lower warfarin doses, and a 64.5% correlation was found between the calculated ideal doses and the administered warfarin doses.Conclusion:Considering CYP2C9 and VKORC1 genetic polymorphisms prior to commencing warfarin treatment will make it easier to reach target INRs and reduce the rate of complications.

A review of a priori regression models for warfarin maintenance dose prediction.

A number of a priori warfarin dosing algorithms, derived using linear regression methods, have been proposed. Although these dosing algorithms may have been validated using patients derived from the same centre, rarely have they been validated using a patient cohort recruited from another centre. In order to undertake external validation, two cohorts were utilised. One cohort formed by patients from a prospective trial and the second formed by patients in the control arm of the EU-PACT trial. Of these, 641 patients were identified as having attained stable dosing and formed the dataset used for validation. Predicted maintenance doses from six criterion fulfilling regression models were then compared to individual patient stable warfarin dose. Predictive ability was assessed with reference to several statistics including the R-square and mean absolute error. The six regression models explained different amounts of variability in the stable maintenance warfarin dose requirements of the patients in the two validation cohorts; adjusted R-squared values ranged from 24.2% to 68.6%. An overview of the summary statistics demonstrated that no one dosing algorithm could be considered optimal. The larger validation cohort from the prospective trial produced more consistent statistics across the six dosing algorithms. The study found that all the regression models performed worse in the validation cohort when compared to the derivation cohort. Further, there was little difference between regression models that contained pharmacogenetic coefficients and algorithms containing just non-pharmacogenetic coefficients. The inconsistency of results between the validation cohorts suggests that unaccounted population specific factors cause variability in dosing algorithm performance. Better methods for dosing that take into account inter- and intra-individual variability, at the initiation and maintenance phases of warfarin treatment, are needed.

Genetic variant in folate homeostasis is associated with lower warfarin dose in African Americans

AbstractThe anticoagulant warfarin has >30 million prescriptions per year in the United States. Doses can vary 20-fold between patients, and incorrect dosing can result in serious adverse events. Variation in warfarin pharmacokinetic and pharmacodynamic genes, such as CYP2C9 and VKORC1, do not fully explain the dose variability in African Americans. To identify additional genetic contributors to warfarin dose, we exome sequenced 103 African Americans on stable doses of warfarin at extremes (≤35 and ≥49 mg/week). We found an association between lower warfarin dose and a population-specific regulatory variant, rs7856096 (P = 1.82 × 10−8, minor allele frequency = 20.4%), in the folate homeostasis gene folylpolyglutamate synthase (FPGS). We replicated this association in an independent cohort of 372 African American subjects whose stable warfarin doses represented the full dosing spectrum (P = .046). In a combined cohort, adding rs7856096 to the International Warfarin Pharmacogenetic Consortium pharmacogenetic dosing algorithm resulted in a 5.8 mg/week (P = 3.93 × 10−5) decrease in warfarin dose for each allele carried. The variant overlaps functional elements and was associated (P = .01) with FPGS gene expression in lymphoblastoid cell lines derived from combined HapMap African populations (N = 326). Our results provide the first evidence linking genetic variation in folate homeostasis to warfarin response.

P1-27-6 - Investigation of Drug Interaction Between Warfarin and Gemcitabine -Increase in Anticoagulant Effect of Warfarin-

The anticoagulant drug warfarin is used to prevent conditions such as venous thrombosis. Since warfarin has many interactions with other drugs and large inter-individual variability in pharmacodynamics, its dosage must be adjusted according to the prothrombin time/international normalized ratio (PT-INR) in individual patients. Gemcitabine is commonly used to treat malignancies. Potential interactions between gemcitabine and warfarin have been documented in case reports, but remain to be clarified. We investigated drug interactions in patients who were receiving warfarin as well as gemcitabine at the Japanese Red Cross Nagoya Daiichi Hospital from February 1, 2009 to October 31, 2013. The subjects were 4 patients who were receiving stable doses of warfarin before initiation of gemcitabine therapy. Gemcitabine-induced changes in the anticoagulant effect of warfarin were investigated retrospectively. The PT-INR significantly increased (from 1.69±0.37 to 3.02 ± 0.87, P = 0.03) after the initiation of gemcitabine. However, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine (SCre), serum albumin (Alb) levels did not change significantly after treatment with gemcitabine. There were no changes in diet or severe episodes of nausea or vomiting in any patient. These results suggest that the anticoagulant effect of warfarin increased after gemcitabine therapy. Therefore, the PT-INR should be closely monitored for several days after the start of gemcitabine therapy, and patients who are receiving warfarin should be informed in advance about the potential risks of concurrent treatment with gemcitabine.

Impact of GATA4 variants on stable warfarin doses in patients with prosthetic heart valves.

Interindividual variability in stable warfarin doses is largely attributed to VKORC1 and CYP2C9 variants. On the basis of a recent finding of the role of GATA4 in control of CYP2C9 expression, we tested a possible effect of GATA4 genotypes on variability in warfarin response using 201 Korean patients with prosthetic cardiac valves. Two single-nucleotide polymorphisms (SNPs), rs2645400 (G>T) and rs4841588 (G>T), were significantly associated with stable warfarin doses in patients carrying CYP2C9 wild-type homozygotes; homozygote carriers of these two SNPs required higher doses than those with other genotypes (5.94±1.73 versus 5.34±1.88 mg, P=0.026; 5.94±1.66 versus 5.37±1.92, P=0.036, respectively). Multivariate analysis showed that two GATA4 combinations, rs867858 (G>T)/rs10090884 (A>C) and rs2645400 (G>T)/rs4841588 (G>T), increased contribution to the overall warfarin dose variability from 36.4 to 40.9%. This study revealed that GATA4 can be predictive of stable warfarin dose and extended warfarin pharmacogenetics further to the regulation of CYP2C9 expression.

Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects.

Warfarin is used in paediatric populations, but dosing algorithms incorporating pharmacogenetic data have not been developed for children. Previous studies have produced estimates of the effect of polymorphisms in CYP2C9 and VKORC1 on stable warfarin dosing, but data on time in therapeutic range, initial dosing and adverse effects are limited. Participants (n=97) were recruited, and routine clinical data and salivary DNA samples were collected from all participants, and analysed for CYP2C9*2, *3 and VKORC1-1639 polymorphisms.VKORC1 -1639 was associated with a greater proportion of the first six months’ treatment time spent within the target INR range, accounting for an additional 9.5% of the variance in the proportion of time. CYP2C9*2 was associated with a greater likelihood of INR values exceeding the target range during the initiation of treatment (OR [per additional copy] 4.18, 95% CI 1.42, 12.34). CYP2C9*2 and VKORC1-1639 were associated with a lower dose requirement, and accounted for almost 12% of the variance in stable dose. VKORC1-1639 was associated with an increased likelihood of mild bleeding complications (OR [heterozygotes vs homozygotes] 4.53, 95% CI 1.59, 12.93). These data show novel associations between VKORC1-1639 and CYP2C9*2 and INR values in children taking warfarin, as well as replicating previous findings with regard to stable dose requirements. The development of pharmacogenomic dosing algorithms for children using warfarin has the potential to improve clinical care in this population.

Impact of six genetic polymorphisms on Warfarin maintenance dose variation in Chinese Han population

To evaluate the effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms on Warfarin maintenance dose variation in Chinese Han Population. Four hundred eighty-eight patients with prosthetic heart valves, atrial fibrillation or pulmonary thromboembolism and achieved stable Warfarin dose were enrolled. TaqMan probe or direct sequencing were used to genotype Y9VKORC1, CYP2C9, GGCX, EPHX1 and CYP4F2 gene polymorphisms. Demographic characteristics, stable therapeutic dose of Warfarin and concomitant medications were collected for all patients. The effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms, demographic characteristics and concomitant medications on Warfarin daily maintenance dose were analyzed with statistical method. VKORC1 and CYP2C9 gene polymorphisms could explain more than 50% Warfarin maintenance dose variation in recruited patients, while CYP4F2 gene polymorphisms could only explain 1%. GGCX, PROC and EPHX1 gene polymorphisms had no impact no Warfarin maintenance dose. VKORC1 and CYP2C9 gene polymorphisms have a greater impact on Warfarin maintenance dose compared with demographic characteristics and concomitant medications. VKORC1 and CYP2C9 gene polymorphisms have a significant impact on Warfarin maintenance dose in Chinese Han population.

Verification of pharmacogenetics-based warfarin dosing algorithms in Han-Chinese patients undertaking mechanic heart valve replacement.

ObjectiveTo study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement.MethodsWe searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms.ResultsA total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88–4.38 mg/day) than the low-dose range (<1.88 mg/day). Among the 8 algorithms compared, the algorithms of Wei, Huang, and Miao showed a lower MAE and higher percentage within 20% in both the initial and the stable warfarin dose prediction and in the low-dose and the ideal-dose ranges.ConclusionsAll of the selected pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han-Chinese patients undertaking mechanic heart valve replacement.

CVS to phase out tobacco sales, launch smoking cessation program

Calling the decision "simply the right thing to do for the good of our customers and our company," CVS Caremark will stop selling all tobacco products at its more than 7,600 CVS/pharmacy locations by October 1. The February 5 announcement came a week after the U.S. Surgeon General issued renewed warnings about tobacco use on the 50th anniversary of the Surgeon General's landmark report linking smoking and poor health.

Dosage Individualization of Warfarin Using Artificial Neural Networks

Our objective was to explore artificial neural networks (ANNs) as a possible tool for dosage individualization of warfarin. Demographic, clinical, and genetic data were gathered from a previously collected cohort of patients with a stable warfarin dosage who were able to achieve an observed international normalized ratio of 2-3. Data from a cohort of 3,415 patients were used to develop an ANN dosing algorithm. Data from another cohort of 856 were used to validate the algorithm. The clinical significance of the ANN dosing algorithm was evaluated by calculating the percentage of patients whose predicted dosage of warfarin was within 20% of the actual stable therapeutic dose. The clinical significance was also compared with a previously published dosing algorithm. A feed-forward neural network with three layers was able to successfully predict the ideal warfarin dosage in 48% of the patients. The neural network model explained 48% and 43% of the dosage variability observed among patients in the derivation and validation cohorts, respectively. ANN analysis identified several predictors of warfarin dosage including race; age; height; weight; cytochrome P450 (CYP)2C9 genotype; VKORC1 genotype; sulfonamide, azole antifungals, or macrolide administration; carbamazepine, phenytoin, or rifampicin administration; and amiodarone administration. An ANN was applied to develop a warfarin dosing algorithm. The proposed dosing algorithm has the potential to recommend warfarin dosages that are close to the appropriate dosages.

Influence of regular physical activity on warfarin dose and risk of hemorrhagic complications.

To determine the influence of regular physical activity on stable warfarin dose and risk of major hemorrhage in patients on chronic anticoagulation therapy. Regular physical activity (maintained over > 80% of visits) was ascertained by self-report at initiation of warfarin therapy (target international normalized ratio [INR] = 2-3) in 1272 patients, with changes documented at monthly anticoagulation clinic visits in a population-based prospective cohort. Multi-variable linear regression and survival analysis, respectively, were used to assess influence on warfarin and risk of hemorrhage. Outpatient anticoagulation clinic 1272 anticoagulated patients There were 683 (53.7%) patients who were regularly physically active (≥ 30 min ≥ 3 times/week). Physically active patients required warfarin doses that were 6.9% higher (p=0.006) than in physically inactive patients after controlling for sociodemographic factors, vitamin K intake, clinical factors, and genetic variations.The overall incidence of major hemorrhagic events was 7.6/100 person-years (p-yrs, 95% confidence interval [CI] 6.4-8.9) in our population. The incidence was lower for physically active patients (5.6/100 p-yrs, 95% CI 4.2-7.2) than in inactive patients (10.3/100 p-yrs, 95% CI 8.2-12.9, p=0.0004). Active patients had a 38% lower risk of hemorrhage (hazard ratio 0.62, 95% CI 0.42-0.98, p=0.03) compared with inactive patients. Regular physical activity is associated with higher warfarin dose requirements and lower risk of hemorrhage. The influence of physical activity on drug response needs to be further explored, and the mechanisms through which it exerts these effects need to be elucidated