Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out-of-range International Normalized Ratio (INR) values and adverse events are common.
In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy.
The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, perioperative blood loss, liver disease, INR values, and dose history to predict the therapeutic dose. The R2 was 82% in a derivation cohort (N = 86), and 70% when used prospectively (N = 146). The R2 of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (N = 178), and 48% in a prospective validation cohort (N = 146). In one month of prospective follow-up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7%–11.7%) in the pharmacogenetic cohort. The risk of laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.29–0.97).
Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non-randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene-guided warfarin dosing we created a non-profit website, www.WarfarinDosing.org.
Warfarin; Pharmacogenetics; Dosing Algorithm; Anticoagulants; Orthopedic Surgery
CYP2C9 and VKORC1 genotypes predict therapeutic warfarin dose at initiation of therapy; however, the predictive ability of genetic information after a week or longer is unknown. Experts have hypothesized that genotype becomes irrelevant once International Normalized Ratio (INR) values are available because INR response reflects warfarin sensitivity.
We genotyped the participants in the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, who had idiopathic venous thromboemboli and began low-intensity warfarin (therapeutic INR 1.5-2.0) using a standard dosing protocol. To develop pharmacogenetic models, we quantified the effect of genotypes, clinical factors, previous doses, and INR on therapeutic warfarin dose in the 223 PREVENT participants who were randomized to warfarin and achieved stable therapeutic INRs.
A pharmacogenetic model using data from day 0 (before therapy initiation) explained 54% of the variability in therapeutic dose (R2). The R2 increased to 68% at day 7, 75% at day 14, and 77% at day 21, because of increasing contributions from prior doses and INR response. Although CYP2C9 and VKORC1 genotypes were significant independent predictors of therapeutic dose at each weekly interval, the magnitude of their predictive ability diminished over time: partial R2 of genotype was 43% at day 0, 12% at day 7, 4% at day 14, and 1% at day 21.
Over the first weeks of warfarin therapy, INR and prior dose become increasingly predictive of therapeutic dose, and genotype becomes less relevant. However, at day 7, genotype remains clinically relevant, accounting for 12% of therapeutic dose variability.
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.
To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms using INR values on day 4 or 5 of therapy, clinical factors, and genotype.
After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R2 of 48% (median absolute error [MAE]: 7.0 mg/week); the pharmacogenetic algorithm had an R2 of 63% (MAE: 5.5 mg/week) in the derivation set (N=969). In independent validation, the R2 was 26%-43% with the clinical algorithm, and 42%-58% adding genotype (P = 0.002).
After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response, alone.
pharmacogenetics; warfarin; dose-refinement
Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE).
Methods and design
This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a stable INR within the therapeutic range; 3) Number of INR determinations within the therapeutic range in the first six weeks of treatment.
To date, there are no clinical trials comparing pharmacogenetic acenocoumarol dosing algorithm versus routine clinical practice in VTE. Implementation of this pharmacogenetic algorithm in the clinical practice routine could reduce side effects and improve patient safety.
Eudra CT. Identifier: 2009-016643-18.
Pharmacogenetic; Acenocoumarol; Hematology
Variable warfarin response during treatment initiation poses a significant challenge to providing optimal anticoagulation therapy. We investigated the determinants of initial warfarin response in a cohort of 167 patients. During the first nine days of treatment with pharmacogenetics-guided dosing, S-warfarin plasma levels and international normalized ratio were obtained to serve as inputs to a pharmacokinetic-pharmacodynamic (PK-PD) model. Individual PK (S-warfarin clearance) and PD (Imax) parameter values were estimated. Regression analysis demonstrated that CYP2C9 genotype, kidney function, and gender were independent determinants of S-warfarin clearance. The values for Imax were dependent on VKORC1 and CYP4F2 genotypes, vitamin K status (as measured by plasma concentrations of proteins induced by vitamin K absence, PIVKA-II) and weight. Importantly, indication for warfarin was a major independent determinant of Imax during initiation, where PD sensitivity was greater in atrial fibrillation than venous thromboembolism. To demonstrate the utility of the global PK-PD model, we compared the predicted initial anticoagulation responses with previously established warfarin dosing algorithms. These insights and modeling approaches have application to personalized warfarin therapy.
Background The polymorphisms of VKORC1 and CYP2C9 play increasingly important roles in the inter-individual variability in warfarin dose. This study aimed to evaluate the feasibility of clinical application of pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality with rheumatic heart disease after valve replacement in a randomized and controlled trial. Methods One hundred and one consecutive patients of Han nationality with rheumatic heart disease undergoing valve surgery were enrolled and randomly assigned to an experimental group (n=50, based on CYP2C9 and VKORC1 genotypes, pharmacogenetic-based “predicted warfarin dose” for 3 days and then was adjusted to INR until stable warfarin maintenance dose) or a control group (n=51, 2.5mg/d for 3 days and then was adjusted to INR until stable warfarin maintenance dose). All included patients were followed for 50 days after initiation of warfarin therapy. The primary end-point was the time to reach a stable warfarin maintenance dose. Results During the follow-up, 84.0% patients in the experimental group and 58.8% patients in the control group received warfarin maintenance dose. Compared with control group, patients in the experimental group had shorter mean time elapse from initiation of warfarin therapy until warfarin maintenance dose (27.5±1.8 d versus 34.7±1.8 d, p<0.001). Cox regression revealed that group (HR for experimental versus control group: 1.568, 95%CI 1.103-3.284) and age were two significant variables related to the time elapse from initiation of warfarin therapy until warfarin maintenance dose. The predicted warfarin maintenance dose was prominently correlated with the actual warfarin maintenance dose (r=0.684, p<0.001). Conclusion: Based on CYP2C9 and VKORC1 genotypes, the pharmacogenetic-based warfarin-dosing algorithm may shorten the time elapse from initiation of warfarin therapy until warfarin maintenance dose. It is feasible for the clinical application of the pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality with rheumatic heart disease after valve replacement.
Pharmacogenetics; Individualized warfarin therapy; Rheumatic valve surgery; Trial.
The risk of venous thromboembolism (VTE) is higher after total hip or knee replacement surgery than after almost any other surgical procedure; warfarin sodium is commonly prescribed to reduce this peri-operative risk. Warfarin has a narrow therapeutic window with high inter-individual dose variability and can cause hemorrhage. The Genetics-InFormatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis (DVT) is a 2×2 factorial-design, randomized controlled trial designed to compare the safety and effectiveness of warfarin-dosing strategies. GIFT will answer two questions: (1) Does pharmacogenetic (PGx) dosing reduce the rate of adverse events in orthopedic patients; and (2) Is a lower target International Normalized Ratio (INR) non-inferior to a higher target INR in orthopedic participants? The composite primary endpoint of the trial is symptomatic and asymptomatic VTE (identified on screening ultrasonography), major hemorrhage, INR ≥ 4, and death.
pharmacogenetics; warfarin; randomized controlled trial; dosing algorithm
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.
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 (R2 = 51%).
Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients.
algorithm; CYP2C9; genotyping; personalized medicine; pharmacogenetics; VKORC1; warfarin
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 m2), 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.
There has been significant interest in the pharmacogenetics of warfarin therapy with the recent package insert update highlighting its potential role in improving the safety and effectiveness of warfarin. Herein we review the evidence of the influence of the two key genes of interest, CYP2C9 and VKORC1, on warfarin response, and discuss the implications of current knowledge for clinical practice.
The influence of CYP2C9 and VKORC1 genotype on warfarin dose requirements has been consistently demonstrated in diverse racial/ ethnic patient groups in observational studies and randomized clinical trails. Dosing algorithms have been developed that incorporate clinical, demographic, and genetic information to help select a starting warfarin dose. Furthermore, CYP2C9 variant genotypes have been associated with a significantly increased risk of serious bleeding events.
However evidence to date from prospective, controlled studies has not demonstrated an added benefit of incorporating genotype-guided therapy in improving anticoagulation control, preventing or reducing the risk of hemorrhagic or thromboembolic complications. Research efforts designed to evaluate the effectiveness of genotype-guided therapy in improving outcomes are underway. However the routine use of CYP2C9 and VKORC1 genotyping in the general patient population initiating warfarin therapy is not supported by evidence currently available.
Warfarin; Pharmacogenetics; Cytochrome P4502C9; Vitamin K epoxide reductase
Emergency department (ED) patients with venous thromboembolism (VTE) are eventually treated with a standard dose of warfarin despite the fact that a number of patients are known to be sensitive to warfarin and may experience supra-therapeutic INRs and adverse bleeding events. Pharmacogenetics is an emerging field of medical practice that seeks to improve drug safety and efficacy in an individual patient by tailoring treatment to the patient’s known genetic makeup.
To identify patients with risk for warfarin sensitivity among an ED population with VTE and to assess if the warfarin sensitivity mutations were of significant enough prevalence to be of clinical significance in customizing treatment of VTE. We sought in a pilot study to identify if testing for common CYP2C9 and VKORC1 single nucleotide polymorphisms (SNPs) in patients who were likely to begin warfarin treatment was feasible in an ED setting.
A prospective study that identified and enrolled patients presenting to our ED with high clinical suspicion of VTE. Those with high clinical suspicion of VTE were defined as those who had a Doppler ultrasound or computed tomography pulmonary angiography (CTPA) ordered by the primary emergency physician. Blood was taken and processed to ascertain the following SNPs: CYP2C9*2, CYP2C9*3, and VKORC1 3673.
Of the 194 patients enrolled, 132 (68.0%) had at least one known warfarin sensitivity mutation and 114 (58.8%) had the most clinically significant VKORC1 3673 mutation.
A majority of our patients had at least one mutation associated with the atypical metabolism of warfarin. Over half of our population had the most clinically significant VKORC1 3673 mutation. They would likely benefit from individualized warfarin dosing if ever needing anticoagulation. Our initial pilot study shows that allele frequencies of target warfarin sensitivity SNPs in our patient population are frequent enough to make initiation of personalized warfarin dosing feasible.
The aim of this study was to compare the accuracy of genetic tables and formal pharmacogenetic algorithms for warfarin dosing.
Pharmacogenetic algorithms based on regression equations can predict warfarin dose, but they require detailed mathematical calculations. A simpler alternative, recently added to the warfarin label by the U.S. Food and Drug Administration, is to use genotype-stratified tables to estimate warfarin dose. This table may potentially increase the use of pharmacogenetic warfarin dosing in clinical practice; however, its accuracy has not been quantified.
A retrospective cohort study of 1,378 patients from 3 anticoagulation centers was conducted. Inclusion criteria were stable therapeutic warfarin dose and complete genetic and clinical data. Five dose prediction methods were compared: 2 methods using only clinical information (empiric 5 mg/day dosing and a formal clinical algorithm), 2 genetic tables (the new warfarin label table and a table based on mean dose stratified by genotype), and 1 formal pharmacogenetic algorithm, using both clinical and genetic information. For each method, the proportion of patients whose predicted doses were within 20% of their actual therapeutic doses was determined. Dosing methods were compared using McNemar’s chi-square test.
Warfarin dose prediction was significantly more accurate (all p < 0.001) with the pharmacogenetic algorithm (52%) than with all other methods: empiric dosing (37%; odds ratio [OR]: 2.2), clinical algorithm (39%; OR: 2.2), warfarin label (43%; OR: 1.8), and genotype mean dose table (44%; OR: 1.9).
Although genetic tables predicted warfarin dose better than empiric dosing, formal pharmacogenetic algorithms were the most accurate.
coumarins; dose prediction; dosing algorithms; FDA label; genetic tables; pharmacogenetics; warfarin
Pharmacogenetic (PGx) testing can inform drug dosing and selection by aiding in estimating a patient’s genetic risk of adverse response and/or failure to respond. Some PGx tests may generate ancillary clinical information unrelated to the drug treatment question for which testing is done – an informational “side effect.” We aimed to assess public interest and concerns about PGx tests and ancillary information.
We conducted a random-digit-dial phone survey of a sample of the U.S. public.
We achieved an overall response rate of 42% (n=1,139). When the potential for ancillary information was presented, 85% (±2.82%) of respondents expressed interest in PGx testing, compared to 82% (±3.02%) prior to discussion of ancillary information. Most respondents (89%±2.27%) indicated that physicians should inform patients that a PGx test may reveal ancillary risk information before testing is ordered. Respondents’ interest in actually learning of the ancillary risk finding significantly differed based on disease severity, availability of an intervention, and test validity, even after adjusting for age, gender, education and race.
Under the limited information conditions presented in the survey, the potential of ancillary information does not negatively impact public interest in PGx testing. Interest in learning ancillary information is well-aligned with the public’s desire to be informed about potential benefits and risks prior to testing, promoting patient autonomy.
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.
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.
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.
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.
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.
CYP2C9; genotyping; pharmacogenomics; VKORC1; warfarin
Warfarin therapy has been used clinically for over 60 years, yet continues to be problematic because of its narrow therapeutic index and large inter-individual variability in patient response. As a result, warfarin is a leading cause of serious medication-related adverse events, and its efficacy is also suboptimal.
To review factors that are responsible for variable response to warfarin, including clinical, environmental, and genetic factors, and to explore some possible approaches to improving warfarin therapy.
Recent efforts have focused on developing dosing algorithms that included genetic information to try to improve warfarin dosing. These dosing algorithms hold promise, but have not been fully validated or tested in rigorous clinical trials. Perhaps equally importantly, adherence to warfarin is a major problem that should be addressed with innovative and cost-effective interventions.
Additional research is needed to further test whether interventions can be used to improve warfarin dosing and outcomes.
adherence; pharmacogenetics; prediction; warfarin
Warfarin dosing remains challenging because of its narrow therapeutic window and large variability in dose response. We sought to analyze new factors involved in its dosing and to evaluate eight dosing algorithms, including two developed by the International Warfarin Pharmacogenetics Consortium (IWPC).
we enrolled 108 patients on chronic warfarin therapy and obtained complete clinical and pharmacy records; we genotyped single nucleotide polymorphisms relevant to the VKORC1, CYP2C9, and CYP4F2 genes using integrated fluidic circuits made by Fluidigm.
When applying the IWPC pharmacogenetic algorithm to our cohort of patients, the percentage of patients within 1 mg/d of the therapeutic warfarin dose increases from 54% to 63% using clinical factors only, or from 38% using a fixed-dose approach. CYP4F2 adds 4% to the fraction of the variability in dose (R2) explained by the IWPC pharmacogenetic algorithm (P < 0.05). Importantly, we show that pooling rare variants substantially increases the R2 for CYP2C9 (rare variants: P =0.0065, R2 = 6%; common variants: P= 0.0034, R2 = 7%; rare and common variants: P =0.00018; R2 = 12%), indicating that relatively rare variants not genotyped in genome-wide association studies may be important. In addition, the IWPC pharmacogenetic algorithm and the Gage (2008) algorithm perform best (IWPC: R2 = 50%; Gage: R2 = 49%), and all pharmacogenetic algorithms outperform the IWPC clinical equation (R2 = 22%). VKORC1 and CYP2C9 genotypes did not affect long-term variability in dose. Finally, the Fluidigm platform, a novel warfarin genotyping method, showed 99.65% concordance between different operators and instruments.
CYP4F2 and pooled rare variants of CYP2C9 significantly improve the ability to estimate warfarin dose.
algorithms; CYP2C9; CYP4F2; dosing; IWPC; kinetics; pharmacogenetics; rare variants; VKORC1; warfarin
There are potential risks associated with the use of warfarin in children, particularly as the dosing requirements may decrease as patients get older.
Our facility is a 715‐bed freestanding pediatric tertiary care center with a large cardiac surgery center. A significant number of patients receive warfarin for treatment or prophylaxis of thromboembolic events while in hospital.
Key measures for improvement
Initial dose of warfarin and time taken to achieve goal therapeutic international normalized ratio (INR).
Strategies for change
The intervention included: (1) revision of hospital drug formulary so that warfarin dosing was in accordance with the most recent guidelines; (2) warfarin administration restricted to one time of the day (12.00 noon); (3) target therapeutic INR level documented with each warfarin order; and (4) pharmacy computer system mandated that the pharmacist confirmed the target INR, documented the most current INR, and compared the dose with the formulary guidelines. If the warfarin dose was not in accordance with the formulary guidelines, the pharmacist contacted the physician and made dosing recommendations according to the guidelines.
Effects of change
The number of patients with supratherapeutic INR values during the hospital admission was decreased by more than 50% and goal INR values were documented more frequently in the medical record. There was also an increase in subtherapeutic INR values. The intervention had no effect on the time taken to achieve the goal therapeutic INR.
Instituting changes in a number of aspects of anticoagulation management and incorporating an intensive educational effort across a breadth of healthcare providers can improve anticoagulation management with warfarin in challenging patient populations such as children. Similar methods could possibly improve anticoagulation with other agents such as unfractionated heparin or low molecular weight heparin.
warfarin; children; quality improvement; anticoagulation
Pharmacogenetic dosing algorithms help predict warfarin maintenance doses, but their predictive performance differs in different populations, possibly due to unsuspected population-specific genetic variants. The objectives of this study were to quantify the effect of the VKORC1 D36Y variant (a marker of warfarin resistance previously described in 4% of Ashkenazi Jews) on warfarin maintenance doses and to examine how this variant affects the performance of the International Warfarin Pharmacogenetic Consortium (IWPC) dose prediction model. In 210 Israeli patients on chronic warfarin therapy recruited at a tertiary care center, we applied the IWPC model and then added D36Y genotype as covariate to the model (IWPC+D36Y) and compared predicted with actual doses. Median weekly warfarin dose was 35 mg (interquartile range [IQR], 24.5 to 52.5 mg). Among 16 heterozygous D36Y carriers (minor allele frequency = 3.8%), warfarin weekly dose was increased by a median of 43.7 mg (IQR, 40.5 to 47.2 mg) compared to non-carriers after adjustment for all IWPC parameters, a greater than 2-fold dose increase. The IWPC model performed suboptimally (coefficient of determination R2=27.0%; mean absolute error (MAE), 14.4 ± 16.2 mg/week). Accounting for D36Y genotype using the IWPC+D36Y model resulted in a significantly better model performance (R2=47.2%, MAE=12.6±12.4 mg/week). In conclusion, even at low frequencies, variants with a strong impact on warfarin dose may greatly decrease the performance of a commonly used dose prediction model. Unexpected discrepancies of the performance of universal prediction models in subpopulations should prompt searching for unsuspected confounders, including rare genetic variants.
Warfarin; pharmacogenetics; VKORC1; dose prediction; ethnicity
Although warfarin is widely recommended to prevent atrial fibrillation-related thromboembolism, many eligible patients do not take warfarin. The objective of this study was to describe factors associated with warfarin discontinuation in people newly starting warfarin for atrial fibrillation.
Methods and Results
We identified 4,188 subjects newly starting warfarin in the ATRIA Study and tracked longitudinal warfarin use using pharmacy and laboratory databases. Data on patient characteristics, international normalized ratio (INR) tests, and incident hospitalizations for hemorrhage were obtained from clinical and laboratory databases. Multivariable Cox regression analysis was used to identify independent predictors of prolonged warfarin discontinuation, defined as ≥ 180 consecutive days off warfarin.
Within one year after warfarin initiation, 26.3% of subjects discontinued therapy despite few hospitalizations for hemorrhage (2.3% of patients). The risk of discontinuation was higher in patients aged < 65 years (adjusted hazard ratio and 95%CI [HR] 1.33 [1.03-1.72] compared to age ≥ 85 years), patients with poorer anticoagulation control (HR 1.46 [1.42-1.49] for every 10% decrease in time in therapeutic INR range) and lower stroke risk (HR 2.54 [1.86-3.47] for CHADS2 stroke risk index of 0 compared to 4-6).
More than one in four individuals newly starting warfarin for atrial fibrillation discontinued therapy in the first year despite a low overall hemorrhage rate. Individuals deriving potentially less benefit from warfarin, including those with younger age, fewer stroke risk factors, and poorer INR control, were less likely to remain on warfarin. Maximizing the benefits of anticoagulation for atrial fibrillation depends upon determining which patients are most appropriately initiated and maintained on therapy.
anticoagulation; atrial fibrillation; discontinuation; stroke prevention; warfarin
Warfarin dosage regimens using CYP2C9 and VKORC1 polymorphisms have been extensively studied in adults and is included in US Food and Drug Administration-approved warfarin labeling. However, no dosage algorithm is available for pediatric patients.
To derive a genetics-based pediatric dosge regimen for warfarin, including starting dose and titration scheme.
A model-based approach was developed based on a previously validated warfarin dosage model in adults, with subsequent comparison to pediatric data from pediatric warfarin dose, genotyping, and international normalized ratio (INR) results. The adult model was based on a previously established model from the CROWN (CReating an Optimal Warfarin dosing Nomogram) trial. Pediatric warfarin data were obtained from a study conducted at the Children’s Hospital of Los Angeles with 26 subjects. Variant alleles of CYP2C9 (rs1799853 or *2, and rs1057910 or *3) and the VKORC1 single nucleotide polymorphism (SNP) rs9923231 (−1639 G>A) were assessed, where the rs numbers are reference SNP identification tags assigned by the National Center for Biotechnology Information.
A pediatric warfarin model was derived using the previously validated model and clinical pharmacology considerations. The model was validated, and clinical trial simulation and stochastic modeling were used to optimize pediatric dosage and titration. The final dosage regimen was optimized based on simulations targeting a high (≥60%) proportion of INRs within the therapeutic range by week 2 of warfarin therapy while minimizing INRs >3.5 or <2.
The proposed pediatric warfarin dosage scheme based on individual CYP2C9 (alleles *1,*2,*3) and VKORC1 rs9923231 (-1639 G>A) genotypes may offer improved dosage compared to current treatment strategies, especially in patients with variant CYP2C9 and VKORC1 alleles. This pilot study provides the foundation for a larger prospective evaluation of genetics-based warfarin dosage in pediatric patients.
CYP2C9; pediatrics; pharmacogenetics; VKORC1; warfarin
Warfarin dosing algorithms do not account for genetic mutations that can affect anticoagulation response. We retrospectively assessed to what extent the VKORC1 variant genotype would alter the likelihood of being a hyperresponder or hyporesponder to warfarin in patients undergoing total joint arthroplasty. We used the international normalized ratio (INR) on the third postoperative day of 3.0 or greater to define warfarin hyperresponders and 1.07 or less to define hyporesponders. A control group of normal responders was identified. From a cohort of 1125 patients receiving warfarin thromboprophylaxis, we identified 30 free of predisposing factors that could affect warfarin response: 10 hyperresponders, eight hyporesponders, and 12 normal responders. Homozygous carriers of the VKORC1 mutant AA genotype were more likely (compared with carriers of GA or GG genotypes) to be hyperresponders (odds ratio, 7.5; 95% confidence interval, 1.04–54.1). Homozygous carriers of the GG (normal) genotype were more likely (compared with carriers of AA or GA genotypes) to be hyporesponders (odds ratio, 9; 95% confidence interval, 1.14–71). Preoperative screening for the VKORC-1 genotype could identify patients with a greater potential for being a hyperresponder or hyporesponder to warfarin. This may allow an adjusted pharmacogenetic-based warfarin dose to optimize anticoagulation, reducing postoperative risks of bleeding and thrombosis or embolism.
Level of Evidence: Level III, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.
Although multiple reports have documented the influence of CYP2C9 and VKORC1 variantson warfarin dose, risk of over-anticoagulation and hemorrhage, their influence on anticoagulation maintenance and individual proportion of time spent in target INR range (PPTR) is limited. Moreover the potential benefit of genotype-guided dosing implemented after initiation of therapy in a racially diverse population has not been explored. Herein we present the influence of CYP2C9 and VKORC1 C1173T on warfarin response during the first 30 days of therapy.
Warfarin dose was empirically determined in 250 African Americans 271 European Americans. The influence of CYP2C9 and VKORC1 on rate of INR increase, anticoagulation maintenance, risk of over-anticoagulation, and change in dose over 30days was evaluated after adjustment for socio-demographic, lifestyle and clinical factors.
Possession of variant VKORC1 (± variant CYP2C9) genotype was associated with a more rapid attainment of target INR and higher frequency of dose adjustments. Patients possessing variant genotypes spent less time in target range. However adjustment for rate of INR increase rendered the association non-significant. European Americans (but not African Americans) possessing variant VKORC1 (± variant CYP2C9) genotype had a higher risk of over-anticoagulation. Neither CYP2C9 nor VKORC1 influenced the risk of minor hemorrhage. CYP2C9 and VKORC1 explained 6.3% of the variance in dose change over the first 30 days of therapy demonstrating that the usefulness of genotype-guided dosing may extend beyond first day of therapy.
The benefit of genotype-based dose prediction may extend beyond first few days of therapy. Whether genotype-guided dosing will decrease the risk of over-anticoagulation, improve anticoagulation control and most importantly improve outcomes for chronic warfarin users remains to be proven.
CYP2C9; VKORC1; Pharmacogenetics; percent time in target range; over-anticoagulation; hemorrhage; African American; European American
With the advent of low cost genotyping, personalized medicine (PGx) has entered the clinical realm. PGx assesses inter-individual variability of drug metabolizing enzymes prior to drug therapy. Consequently, toxicity based adverse events stemming from patient metabolism may be avoided. This paper considers two applications: a genetic test of the CYP 2C9 enzyme prior to administration of the anticoagulant warfarin, and a test of the thiopurine methyltransferase gene prior to initiating therapy with mercaptopurine drugs. Clinician experience has been limited and the biomedical literature suggests that is due to barriers to PGx. These include a perceived lack of efficacy from an absence of prospective clinical trials, legacy pharmaceutical industry and physician business models, inadequate regulatory oversight, payer reimbursement practices, and physician habits. Until these are addressed, it is unlikely that PGx will achieve wide usage. Unproven utility and entrenched business models are the most significant impediments to clinician adoption.
Background and Objective
Almorexant is the first representative of the new class of orexin receptor antagonists, which could become a new treatment option for insomnia. The present study investigated the potential interaction between almorexant and warfarin.
In this open-label, two-way crossover, drug–drug interaction study, healthy male subjects received, in a randomized fashion, almorexant 200 mg once daily for 10 days and a single dose of 25 mg warfarin co-administered on day 5 (treatment A) and a single dose of 25 mg warfarin on day 1 (treatment B). Serial blood samples for warfarin pharmacokinetics and pharmacodynamics were drawn during both treatments.
Of the 14 enrolled subjects, one withdrew due to an adverse event and 13 completed the study. Almorexant had no effect on the pharmacokinetics of warfarin. The geometric mean ratios (90 % confidence interval) for the area under the plasma concentration–time curve to infinity (AUC0–∞) of S- and R-warfarin were 0.99 (0.89, 1.09) and 1.05 (0.95, 1.16), respectively, and for the maximum plasma concentration (Cmax) were 0.99 (0.86, 1.14) and 1.00 (0.88, 1.13), respectively. The main pharmacodynamic variable was the AUC for the international normalized ratio (AUCINR). Almorexant had no effect on this variable as demonstrated by a geometric mean ratio of 0.99 (0.82, 1.19). Secondary pharmacodynamic variables including maximum effect (Emax), the time to the maximum INR, and factor VII plasma concentrations were also not affected by almorexant.
No dose adjustment of warfarin is necessary when concomitantly administered with almorexant.
Appropriate dosing of coumarins is difficult to establish, due to significant inter-individual variability in the dose required to obtain stable anticoagulation. Several genetic and other clinical factors have been associated with the coumarins dose, and some pharmacogenetic-guided dosing algorithms for warfarin and acenocoumarol have been developed for mixed populations. We recruited 147 patients with thromboembolic disease who were on stable doses and with an international normalized ratio (INR) between 2 and 3. We ascertained the influence of clinical and genetic variables on the stable acenocoumarol dose by multiple linear regression analysis in a derivation cohort (DC; n = 117) and developed an algorithm for dosing that included clinical factors (age, body mass index and concomitant drugs) and genetic variations of VKORC1, CYP2C9, CYP4F2 and APOE. For purposes of comparison, a model including only clinical data was created. The clinical factors explained 22% of the dose variability, which increased to 60.6% when pharmacogenetic information was included (p<0.001); CYP4F2 and APOE variants explained 4.9% of this variability. The mean absolute error of the predicted acenocoumarol dose (mg/week) obtained with the pharmacogenetic algorithm was 3.63 vs. 5.08 mg/week with the clinical algorithm (95% CI: 0.88 to 2.04). In the testing cohort (n = 30), clinical factors explained a mere 7% of the dose variability, compared to 39% explained by the pharmacogenetic algorithm. Considering a more clinically relevant parameter, the pharmacogenetic algorithm correctly predicted the real stable dose in 59.8% of the cases (DC) vs. only 37.6% predicted by the clinical algorithm (95% CI: 10 to 35). Therefore the number of patients needed to genotype to avoid one over- or under-dosing was estimated to be 5.