Stable Warfarin Dose Research Articles

Methylation of CYP1A1 and VKORC1 promoter associated with stable dosage of warfarin in Chinese patients.

ObjectiveTo investigate the association between DNA methylation and the stable warfarin dose through genome-wide DNA methylation analysis and pyrosequencing assay.MethodThis study included 161 patients and genome-wide DNA methylation analysis was used to screen potential warfarin dose-associated CpGs through Illumina Infinium HumanMethylation 450 K BeadChip; then, the pyrosequencing assay was used to further validate the association between the stable warfarin dose and alterations in the methylation of the screened CpGs. GenomeStudio Software and R were used to analyze the differentially methylated CpGs.ResultsThe methylation levels of CpGs surrounding the xenobiotic response element (XRE) within the CYP1A1 promoter, differed significantly between the different dose groups (P < 0.05), and these CpGs presented a positive correlation (r> 0, P < 0.05) with an increase in the stable dose of warfarin. At the VKORC1 promoter, two CpGs methylation levels were significantly different between the differential dose groups (P < 0.05), and one CpG (Chr16: 31106793) presented a significant negative correlation (r < 0, P < 0.05) among different dose (low, medium, and high) groups.ConclusionThis is a novel report of the methylation levels of six CpGs surrounding the XRE within the CYP1A1 promoter and one differential CpG at the VKORC1 promoter associated with stable warfarin dosage; these methylation levels might be applied as molecular signatures for warfarin.

Genetic Associations With Stable Warfarin Dose Requirements in Han Chinese Patients.

Warfarin is a commonly prescribed anticoagulant for valvular heart disease that plays an important role in clinical management to prevent thrombotic events. In this study, we aim to perform a comprehensive study to investigate the genetic biomarkers of stable warfarin dose in the Han Chinese population. We performed an integrative study on 211 Han Chinese patients with valvular heart disease. A total of 40 single nucleotide polymorphisms (SNPs) in 10 important genes (CYP2C9, VKORC1, ABCB1, CYP4F2, APOE, PROC, GGCX, EPHX1, CALU, and SETD1A) which are involved in the warfarin metabolic pathway and equilibrium of coagulation and anticoagulation were selected. We applied MassARRAY technology to genotype the 40 SNPs identified in these Han Chinese patients. Our results showed that 13 SNPs on 6 genes (CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A) were associated with the individual stable warfarin dose. Two VKORC1 SNPs (rs9934438 and rs2359612) were the strongest genetic factors determining warfarin dose requirements (P = 8 × 10-6 and 9 × 10-6, respectively). Rs4889599 in SETD1A was first reported to be associated with warfarin dose at a significant level of 0.001 in our study (Padjust = 0.040 after Bonferroni correction). We discovered that genetic variants in CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A may affect the stable warfarin dose requirement in Han Chinese patients with valvular disease. The discovery of these potential genetic markers will facilitate the development of advanced personalized anticoagulation therapy in Han Chinese patients.

Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study.

Warfarin is the most commonly evaluated drug in pharmacogenetic-guided dosing studies. However, gaps remain regarding the influence of the genetic polymorphisms of CYP2C9, VKORC1, and CYP4F2 on specific pharmacodynamic parameters like the warfarin sensitivity index (WSI), prothrombin time international normalized ratio (PT-INR), and log-INR variability. A cross-sectional study was conducted in non-smoking adults receiving warfarin for at least 6months. Their demographics, diagnoses, warfarin dosing regimen, concomitant drugs, PT-INR, and bleeding episodes were obtained. CYP2C9 (rs1057910-*3 and rs1799853-*2 alleles), CYP4F2 (rs2108622), and VKORC1 (rs9923231) polymorphisms were assessed using real-time polymerase chain reaction. Three genotype groups (I-III) were defined based on the combined genetic polymorphisms of CYP2C9 and VKORC1 from the FDA's recommendations. Key outcome measures included anticoagulation control, time spent in therapeutic range, stable warfarin dose, WSI, log-INR variability, and Warfarin Composite Measure (WCM). The study recruited 236 patients; 75 (31.8%) carried a functional CYP2C9 variant allele, and, 143 (60.6%) had at least one T allele in CYP4F2 and 133 (56.4%) had at least one T allelein VKORC1. Groups' II and III CYP2C9 and VKORC1 genotypes were observed with reduced stable warfarin dose, increased WSI, higher log-INR variability, and increased bleeding risk. The presence of *2 or *3 allele in CYP2C9 was observed with reduced stable warfarin doses akin to the presence of T alleles in VKORC1; however, the doses increased with T alleles in CYP4F2. The evaluated genetic polymorphisms significantly influenced all the pharmacodynamic parameters of warfarin. Evaluating CYP2C9, VKORC1, and CYP4F2 genetic polymorphisms prior to warfarin initiation is likely to optimize therapeutic response.

International Normalized Ratio Elevation as a Marker for Clinical Change in Mechanical Circulatory Support Patients

Purpose To determine if an unexpectedly elevated international normalized ratio (INR) may be associated with symptomatic clinical change in mechanical circulatory support (MCS) patients on relatively stable doses of warfarin. We hypothesize that a significant INR rise while on consistent doses of warfarin may be a signal for current or pending declines in clinical status. Methods A retrospective review of 64 outpatient MCS recipients was performed during the period 9/2013-5/2018. Patient information regarding signs and symptoms of acute decompensation were collected. These included hospital admission for fluid overload, low-flow alarms with syncope, ventricular tachyarrhythmia with/without implantable cardiac defibrillator firing, right ventricular failure, or noted fluid overload at clinic visits necessitating diuretic increase. An INR rise to values >4.0 was compared to a concurrent incidence of changes in clinical status or need for intervention within the subsequent month after an unexplained labile INR. Results The cohort included both left ventricular assist device and total artificial heart patients. Sixty-two INR values >4.0 occurred at hospital admission or preceded a clinical event by 30 days or less. The average INR that fit these criteria was 5.0 +/- 1.3. The positive predictive value of an acute clinical change as a potential for INR elevation was 28.7% with a sensitivity of 0.54. Fifty-three instances of a herein defined decline in clinical status were not associated with elevated INR. The negative predictive value of an INR 4.0, nor in the 5,836 recorded INRs that were Conclusion An unexpected INR rise may be evidence of a worsening scenario for an MCS patient experiencing a change in clinical status.

Influence of renal insufficiency on anticoagulant effects and safety of warfarin in Chinese patients: analysis from a randomized controlled trial

This study aimed to analyze the influence of renal insufficiency on the anticoagulant effects and safety of warfarin in Chinese patients. Data on the creatinine levels of participants enrolled in a randomized controlled study were screened and divided into the non-renal insufficiency group, mild renal insufficiency group, and moderate renal insufficiency group, according to the creatinine clearance rate. The primary outcome measures were stable dose and average daily dose of warfarin. Secondary outcome measures were percentage of time in the therapeutic international normalized ratio (INR) (%TTR), and the first time to reach the therapeutic INR. Adverse events included bleeding events, thromboembolic events, and mortality. All participants with renal function test results and a baseline INR of less than 1.5 were included in the primary and secondary outcome analysis. The SPSS Statistics 21.0 software was used for statistical analysis. The randomized controlled trial was registered in Clinicaltrials.gov (NCT02211326). A total of 571 patients were included in this analysis. Multiple regression analysis showed that the renal function was correlated with stable dose, average daily dose, and the first time to reach therapeutic INR after adjusting for confounding factors. However, no correlation was noted between kidney function and %TTR. No significant differences were observed across the various safety parameters among the three groups. Renal function is an important consideration in patients using warfarin.

A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional.

Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype-based warfarin dosing. We carried out a network meta-analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies. Electronic records were searched for RCTs comparing genotype-based warfarin with traditional-dosing strategies. Key outcomes included were the time to first therapeutic international normalized ratio (INR); time to stable INR or warfarin dose; percent time in therapeutic range (TTR); and the proportion of patients with supra-therapeutic INR. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates. Twenty-six studies (7898 patients) were included. CYP2C9-based warfarin dosing was associated with a shorter time to first therapeutic INR (WMD: -2.73, 95% CI: -3.41, -2.05) and stable INR/warfarin dose (WMD: -8.1, 95% CI: -12.54, -3.66). CYP2C9 and VKORC1 were observed with a shorter time to first therapeutic INR (WMD: -1.92, 95% CI: -3.23, -0.61) and stable INR/warfarin dose (WMD: -4.6, 95% CI: -6.87, -2.34) along with a longer TTR (%) (WMD: 3.91, 95% CI: 1.18, 6.63). CYP2C9, VKORC1 and CYP4F2 were observed with a reduced proportion of patients with supra-therapeutic INR (OR: 0.68, 95% CI: 0.49, 0.93). Trial sequential analysis confirms the superior benefits of CYP2C9 with VKORC1 genotype. The present evidence is supportive of personalizing warfarin dose based only on CYP2C9 and VKORC1 genotypes compared to traditional strategies. More RCTs are needed to delineate any benefit for adding CYP4F2 to provide sufficient power for pooled analysis. No convincing evidence exists supporting the role of CYP2C9 alone.

Implications of Polymorphisms in the BCKDK and GATA-4 Gene Regions on Stable Warfarin Dose in African Americans.

VKORC1 and CYP2C9 genotypes explain less variability in warfarin dose requirements in African Americans compared with Europeans. Variants in BCKDK and GATA‐4 gene regions, purported to regulate VKORC1 and CYP2C9 expression, have been shown to play an important role in warfarin dose requirements in Europeans and Asians, respectively. We sought to determine whether rs56314408 near BCKDK or GATA‐4 rs2645400 influence warfarin dose requirements in 200 African Americans. Unlike the strong linkage disequilibrium (LD) between rs56314408 and VKORC1 rs9923231 in Europeans, they were not in LD in African Americans. No associations were found on univariate analysis. On multivariable analysis, rs56314408 was associated (P = 0.027) with dose in a regression model excluding VKORC1 rs9923231, and GATA‐4 rs2645400 was associated (P = 0.032) with dose in a model excluding CYP2C (CYP2C9*2, *3, *5, *6, *8, and *11, CYP2C rs12777823) variants. Neither variant contributed to dose in the model that included both VKORC1 rs9923231 and CYP2C variants. Our results do not support contributions of the studied variants to warfarin dose requirements in African Americans. However, they illustrate the value of studies in African descent populations, who have low LD in their genome, in teasing out genetic variation underlying drug response associations. They also emphasize the importance of confirming associations in persons of African ancestry.

LRP1 polymorphisms associated with warfarin stable dose in Chinese patients: a stepwise conditional analysis.

Aim: The aim of this study was to investigate whether variability in warfarin stable dose(WSD)could be influenced by vitamin K-related polymorphisms in patients with heart valve replacement. Patients & methods: Twenty-nine vitamin K-related SNPsin 208 patients who initially took warfarin and achieved WSD were genotyped. Results: After conducting conditional analysis for both VKORC1 -1639G>A and CYP2C9*3, LRP1 rs1800139 and LRP1 rs1800154 were significantly associated with WSD (p = 0.007 andp = 0.015, respectively). Multivariate analysis showed that LRP1 rs1800139 accounted for 5.9% WSD variability. Conclusion: Our results suggest that a novel vitamin K-related gene, LRP1, exerts a relevant influence on WSD, independent of VKORC1 -1639G>A and CYP2C9*3.

Plasma miRNA profiles associated with stable warfarin dosage in Chinese patients

BackgroundWe used bioinformatic analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR) assays to investigate the association between plasma microRNAs (miRNAs) and stable warfarin dosage in a Chinese Han population.MethodsBioinformatics analysis was used to screen out potential warfarin dose-associated miRNAs. Three plasma miRNAs were validated in 99 samples by RT-qPCR. Kruskal–Wallis test and multivariate logistic regression were used to compare differences in plasma miRNAs expression levels between three warfarin dosage groups.ResultsThere were significant between-group differences among the three dose groups for hsa-miR-133b expression (p = 0.005), but we observed an “n-shaped” dose-dependent curve rather than a linear relationship. Expression levels of hsa-miR-24-3p (p = 0.475) and hsa-miR-1276 (p = 0.558) were not significantly different in the multivariate logistic regression.ConclusionmiRNAs have received extensive attention as ideal biomarkers and possible therapeutic targets for various diseases. However, they are not yet widely used in precision medicine. Our results indicate that hsa-miR-133b may be a possible reference factor for the warfarin dosage algorithm. These findings emphasize the importance of a comprehensive evaluation of complex relationships in warfarin dose prediction models and provide new avenues for future pharmacogenomics studies.

Effects of rare CYP2C9 alleles on stable warfarin doses in Chinese Han patients with atrial fibrillation.

Aim: Gene polymorphisms are critical in warfarin dosing variation. Here, the role of rare CYP2C9 alleles on warfarin doses in Chinese Han patients was investigated. Methods: A retrospective study recruited 681 warfarin treated atrial fibrillation patients. The genetic and clinical data were collected. Dose-related variables were selected by univariate analyses and the warfarin-dosing algorithm was derived by multivariate regression analysis. Results: Three rare CYP2C9 alleles (CYP2C9*13, *16 and*60) were associated with lower stable doses. Inclusion of the rare CYP2C9 alleles in the prediction model added an extra 3.7% warfarin dose predictive power. Conclusion:CYP2C9*13, *16 and*60 was associated with lower stable warfarin doses in Chinese patients. The algorithm including rare CYP2C9 alleles tends to more accurately predict stable warfarin doses.

Evaluation of Stable Doses of Warfarin in a Patient Cohort.

Definitions for stable dose of warfarin varies in the reported studies. International warfarin pharmacogenetic consortium (IWPC) algorithm was generated from the data based on these definitions. In the present study, we primarily evaluated whether any significant differences exist between the definitions for stable warfarin dose. A prospective cross-sectional study in adults receiving warfarin for at least 3 months was carried out. Stable doses of warfarin as defined in previous studies were compared with the standard definition. Bland-Altman plots, Pearson's correlation and intra-class coefficients (ICC) were used to assess the correlation, reliability and agreements between the doses. Sixty-four patients were recruited. Twenty definitions were obtained from the previous studies. We observed that all but one showed very high or high positive correlations; and either excellent or good ICC. No significant differences between the doses initiated and predicted by IWPC algorithm. We observed similar stable doses between the definitions except for one. Hence, IWPC algorithm may not have any bias associated with inclusion of any studies with variable definitions for stable warfarin dose.

Pharmacogenetic-Guided Algorithm to Improve Daily Dose of Warfarin in Elder Han-Chinese Population.

ObjectivesTo verify the accuracy of the International Warfarin Pharmacogenetics Consortium (IWPC) algorithm, identify the effects of genetic and clinical factors on warfarin stable dose, and to establish a new warfarin stable dose prediction algorithm for the elderly Han-Chinese population under the guidance of pharmacogenetics.MethodsAccording to the inclusion criteria, 544 non-valvular atrial fibrillation patients taking warfarin for anticoagulation treatment were enrolled. Data information of three groups including the whole population, people under 65 years old and over 65 years old were substituted into the IWPC algorithm respectively to verify its accuracy. The basic data and clinical information of 360 elderly people were collected for statistical analysis and the genotypes of VKORC1-G1639A and CYP2C9 were detected by Sanger sequencing. The new algorithm of the elder pharmacogenetics warfarin dosing was obtained by stepwise multiple regression. The determination coefficient (R2), root mean squared error (RMSE), and the proportion of the predicted value within the true value range of ±20%(20%-p) were used to evaluate the accuracy of the IWPC algorithm and the new algorithm.ResultsAmong the three different age groups, the warfarin stable dose predictive accuracy of IWPC algorithm was the lowest in the elderly patients above 65-year-old. In this study, the important factors influencing the stable dose of warfarin in the elderly Han-Chinese were height, weight, body surface area, serum creatinine level, amiodarone usage, CYP2C9 (*1*2, *1*3), and VKORC1 (GG/GA) genotypes. By means of stepwise multiple regression analysis, we established a new elder warfarin dosing algorithm (R2=0.3714) containing height, creatinine, amiodarone usage, CYP2C9 (*1*2 or *1*3), and VKORC1 (GA or GG) genotypes. The prediction accuracy and clinical availability of the Elderly algorithm was significantly better than that of IWPC algorithm verified by RMSE, R2, and (20%-p) methods.ConclusionsThe IWPC model may not be suitable for the elder Han-Chinese population. Polymorphism of CYP2C9 and VKORC1 obviously affected warfarin stable dose of the elder Han-Chinese. Combination of genetic data with demographic and clinical factors could help to better improve warfarin doses in the elder Han-Chinese population.

Verification of accuracy of warfarin stable dose prediction models in Shandong population

To compare the accuracy of five warfarin-dosing algorithms and warfarin stable dose model (2.5 mg/day) for Shandong population. One hundred and twenty five patients who achieved stable warfarin dose were enrolled. Clinical and genetic data were used to evaluate the value of each algorithm by calculating the percentage of patients whose predicted warfarin dose was within 20% of the actual stable therapeutic dose and mean absolute error (MAE). The frequency of patients with CYP2C9*1/*1, CYP2C9*1/*3 and CYP2C9*1/*2 genotype was 92.00%, 7.20%, 0.80%, respectively. That of VKORC1-1639 AA, AG and GG genotype was 82.40%, 15.20%, 2.40%, respectively. CYP4F2*1/*1, *1/*3, *3/*3 genotype was 50.40%, 39.20%, 10.40%, respectively. With the same genotypes for other loci, patients who carried at least one VKORC1-16398G mutant allele had increased warfarin stable daily dose compared with VKORC1-1639AA. Compared with CYP4F2*1/*1, those carrying at least one CYP4F2*3 mutant allele had warfarin stable daily dose increased by 5.9%-13.00%. The percentage of ideal prediction calculated from IWPC model (59.20%), Huang model (57.60%) and Ohno model (52.80%) were higher than others. The MAE were 0.35 (95%CI: 0.11-0.49), 0.15 (95%CI: 0.10-0.32), 0.39 (95%CI: 0.12-0.51), respectively. The polymorphisms of CYP2C9, VKORC1 and CYP4F2 genes can influence the stable dose of warfarin in Shandong population. IWPC algorithm is suitable for guiding the use of warfarin in this population.

Association between polymorphisms in microRNA seed region and warfarin stable dose

BackgroundThe optimal dose of anticoagulant warfarin varies among patients to achieve the target international normalised ratio. Although genetic variations related to warfarin pharmacokinetics and vitamin K cycle are important factors...

Analysis of the Impact Factors on a Stable Warfarin Dose in Extreme Elderly (Age ≥ 80 Years) Chinese Patients with Non-Valvular Atrial Fibrillation

Purpose: The aim of this study was to investigate non-genetic and genetic factors contributing to stable warfarin dose change in the extreme elderly patients with non-valvular atrial fibrillation. Methods: A total of 40 elderly patients with stable warfarin doses were included in this study. Clinical basic data, such as age, sex, body mass index, basic disease like hypertension, diabetes and coronary heart disease had been recorded. Two nucleotide polymorphisms about VKORC1-1639G^A and CYP2C9 1075A^C genes were detected via sequencing by hybridization. Results: The elderly patients with CYP2C9 1075A^C (CA) genotype needed less warfarin daily doses than those with CYP2C9 1075A^C (AA) genotype (1.93 ± 0.79 mg/d VS 2.15 ± 0.64 mg/d), but there was no significant difference (p = 0.601). While the daily warfarin dose required for patients with VKORC1-1639G^A (AA) genotype was significantly lower than that for patients with VKORC1-1639G^A (GA) genotype (2.00 ± 0.67 mg/d VS 2.63 ± 0.38 mg/d, p = 0.012). VKORC1-1639G^A together with age and diabetes status accounted 41.7% for dose variability. The new algorithm was developed using multivariate linear regression analysis; the model was developed for: Dose = 7.731 – 0.056 * age + 0.527 * DM - 0.785 * VKORC1. Conclusions: VKORC1-1639G^A together with age and diabetes status might predict warfarin doses in age ≥ 80 years patients with non-valvularatrial fibrillation. In contrast, the polymorphism of CYP2C9 1075A^C was not associated with dose variability.

Impact of CYP2C9, VKORC1, ApoE and ABCB1 polymorphisms on stable warfarin dose requirements in elderly Chinese patients.

Aim: To analyze the impact of nongenetic factors and gene polymorphisms on warfarin dose requirements in elderly Shanghai Han Chinese patients. Materials & methods: Genotypes of CYP2C9 (rs1799853 and rs1057910), FPGS (rs7856096), ApoE (rs7412 and rs429358), GGCX (rs699664 and rs12714145), EPHX1 (rs4653436, rs1877724, rs1051740 and rs1131873), NQO1 (rs1800566 and rs10517), ABCB1 (rs1045642), VKORC1 (rs9923231) and CYP4F2 (rs2108622) in 214 patients with stable warfarin dose were determined and their demographic characteristics were recorded. Results: Multiple linear regression analysis revealed that VKORC1 rs9923231, CYP2C9*3 rs1057910, ApoE rs7412, age, BMI and concomitant amiodarone could explain 37.0% of the individual variations of daily stable warfarin dose. Conclusion:VKORC1 rs9923231, CYP2C9*3 rs1057910, ApoE rs7412, age, BMI and concomitant amiodarone play an important role in stable dose variation of warfarin in elderly Shanghai Han Chinese patients, whereas ABCB1 rs1045642 is not a significant genetic factor.

Comparison of the prediction performance of different warfarin dosing algorithms based on Chinese patients.

Aim: To compare the prediction performance of different warfarin dosing algorithms based on Chinese patients. Materials & methods: A total of 18 algorithms were tested in 325 patients. The predictive efficacy of selected algorithms was evaluated by calculating the percentage of patients whose predicted dose fell within±20% of their actual stable warfarin dose and the mean absolute error. Results: The percentage within±20% and the mean absolute error of the algorithms ranged from 11.9to 41.2% and -0.20 (-0.29 to-0.11) mg/d to -1.63 (-1.75 to-1.50) mg/d. The algorithms established by Miao et al. and Wei et al. had optimal predictive performance. Conclusion: Algorithms based on geographical populations might be more suitable for the prediction of stable warfarin doses in local patients.

Patient Satisfaction With Extended International Normalized Ratio Follow-up Intervals in a Veteran Population.

Background: For highly stable warfarin patients, limited data exists regarding patient satisfaction on extended international normalized ratio (INR) follow-up intervals and how this population compares with patients on a direct oral anticoagulant (DOAC). Objective: To assess the impact on patient satisfaction of extending INR follow-up intervals. Methods: Veterans on stable warfarin doses had extended INR follow-up intervals up to 12 weeks in a single-arm prospective cohort study for 2 years. This analysis included participants who completed at least 2 Duke Anticoagulation Satisfaction Scales (DASS). The primary outcome was the change in the DASS. A focus group described participant experiences. Participant satisfaction was compared to patients on a DOAC. Results: Of the 51 participants, 48 were included in the warfarin extended INR follow-up group. Compared with baseline, the mean DASS score (42.9 ± 12.08) was worse at 24 months (46.82 ± 15.2, P = 0.0266), with a small effect size (Cohen's d = 0.29). The 8 participants in the focus group were satisfied with the extended INR follow-up interval but would be uncomfortable extending follow-up past 2 to 3 months. The extended INR follow-up interval study had similar DASS scores as the 33 participants included on DOAC therapy (46.8 ± 15.1, P = 0.9970) but may be limited by differing populations using DOACs. Conclusion and Relevance: For patients currently stable on warfarin therapy, extending the INR follow-up interval up to 12 weeks or changing to a DOAC does not appear to improve patient satisfaction.

Impact of an extended International Normalized Ratio follow-up interval on healthcare use among veteran patients on stable warfarin doses.

To analyze the impact of a 12-week extended International Normalized Ratio (INR) follow-up interval on healthcare use. A prospective cohort study of the use of an extended INR follow-up interval of up to 12 weeks was conducted over 2 years in a pharmacist-managed anticoagulation clinic. A detailed protocol was used to extend the INR follow-up interval to 5-6 weeks and then 7-8 weeks and 11-12 weeks. The number of planned and unplanned anticoagulation encounters, procedures requiring warfarin interruption, telephone triage phone calls, emergency department visits, and hospitalizations were collected. A post hoc subanalysis was also completed on participants who were scheduled for 4 consecutive 12-week intervals. Compared to baseline, at 12 months there was a mean decrease in planned anticoagulation encounters of 2.24 visits (p < 0.001) among 44 participants. From 12 to 24 months compared to baseline, there was a mean decrease in planned anticoagulation encounters of 3.13 visits (p < 0.001) and an increase of 0.54 unplanned anticoagulation encounters (p = 0.04) among 39 participants. The remainder of healthcare use variables were not statistically significantly different from baseline at any time point. Of the 15 participants scheduled for 4 consecutive 12-week intervals, there was a decrease from baseline of approximately 5 visits over the course of a year (p < 0.001). An extended INR follow-up interval appears to decrease anticoagulation healthcare use without an increase in acute healthcare use. While this intervention could be cost-effective, institutions need to consider safety, efficacy, and feasibility prior to implementation.

VKORC1 and Novel CYP2C9 Variation Predict Warfarin Response in Alaska Native and American Indian People.

Alaska Native and American Indian (AN/AI) people have unique pharmacogene variation that may affect warfarin disposition and therapeutic response. We performed targeted genotyping for cytochrome P450 (CYP)2C9, vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1), CYP4F2,CYP4F11, and gamma‐glutamyl carboxylase (GGCX) variants in AN/AI people receiving warfarin. The primary outcome was stable warfarin dose, defined as one dose, and associated international normalized ratio within the target range, at least 6 months after starting therapy, with two matching doses at least 2 weeks apart. Genotype–phenotype relationships were assessed by multivariate regression analysis, adjusted for self‐reported heritage, age, gender, and concurrent statin use. VKORC1 genotype explained 34% of dose variability, with VKORC1 −1639G>A and 1173C>T associated with a 1.7 mg/day (P = 1.4e‐05) dose reduction. Additionally, CYP2C9 N218I was suggestively significant (P = 0.077), with heterozygotes requiring 1.1 mg/day less than reference individuals. Self‐reported heritage was significantly associated with dose, largely driven by differences in the diagnostic VKORC1 allele frequencies among AN/AI people.