Genotype-guided Warfarin Dosing Research Articles

Cost-Effectiveness Analysis of Pharmacogenomics-Guided Versus Standard Dosing of Warfarin in Patients with Mechanical Prosthetic Heart Valve.

Warfarin is the only approved anticoagulant for antithrombotic treatment in patients with mechanical prosthetic heart valves (MPHV). However, dosing warfarin is challenging due to its narrow therapeutic window and highly variable clinical outcomes. Both low and high doses of warfarin can lead to thrombotic and bleeding events, respectively, with these complications being more severe in individuals with sensitive genetic polymorphisms. Incorporating genetic testing could enhance the accuracy of warfarin dosing and minimize its adverse events. This study aims to evaluate the utilities and cost-effectiveness of pharmacogenomics-guided versus standard dosing of warfarin in patients with MPHV in Iran. In this economic evaluation study, a cost-effectiveness analysis was conducted to compare pharmacogenomics-guided versus standard warfarin dosing. Data related to quality of life (QoL) were collected through a cross-sectional study involving 105 randomly selected MPHV patients using the EuroQol-5D (EQ-5D) Questionnaire. Costs were calculated with input from clinical experts and a review of relevant guidelines. Additional clinical data were extracted from published literature. The pharmacoeconomic threshold set for medical interventions within Iran's healthcare system was $1,500. A decision tree model was designed from the perspective of Iran's healthcare system with a one-year study horizon. Sensitivity analyses were also performed to assess the uncertainty of input parameters. The utility scores derived from the questionnaire for standard and pharmacogenomics-guided warfarin treatments were 0.68 and 0.76, respectively. Genotype-guided dosing of warfarin was more costly compared to the standard dosing ($246 vs $69), and the calculated incremental cost-effectiveness ratio (ICER) was $2474 per quality-adjusted life year (QALY) gained. One-way sensitivity analyses showed that our model is sensitive to the percentage of time in the therapeutic range (PTTR), the cost of genetic tests, and the utility of both pharmacogenomics-guided and standard dosing arms. However, the probabilistic sensitivity analysis demonstrates the robustness of our model. Warfarin dosing with pharmacogenomics testing is currently not cost-effective. However, if the cost of genotyping tests decreases to $118, the ICER would become cost-effective.

Developing Chinese race-specific warfarin dose prediction algorithms.

Numerous genotype-guided warfarin dosing algorithms have been developed to individualize warfarin doses, but they can only explain 47-52% of the variability. This study aimed to develop new warfarin algorithms suitable to predict the stable warfarin dose for the Chinese population and to compare their prediction performance with those of the most commonly used algorithms. Multiple linear regression analysis with the warfarin optimal dose (WOD), logarithm (log) WOD, 1/WOD, and [Formula: see text], respectively, as the dependent variables were performed to deduce a new warfarin algorithm (NEW-Warfarin). WOD was the stable dose that maintained the international normalized ratio (INR) within the target range (2.0-3.0). Three major genotype-guided warfarin dosing algorithms were selected and compared against NEW-Warfarin predictive performance using the mean absolute error (MAE). Furthermore, patients were divided into five groups according to warfarin indications [atrial fibrillation (AF), pulmonary embolism (PE), cardiac-related disease (CRD), deep vein thrombosis (DVT), and other diseases (OD)]. Multiple linear regression analyses were also performed for each group. The regression equation with [Formula: see text] as the dependent variable had the highest coefficient of determination (R2 = 0.489). The NEW-Warfarin had the best predictive accuracy compared to the three algorithms selected. Group analysis, according to indications, showed that the R2 of the five groups were PE (0.902) > DVT (0.608) > CRD (0.569) > OD (0.436) > AF (0.424). Dosing algorithms based on warfarin indications are more suitable for predicting warfarin doses. Our research provides a novel strategy to develop indication-specific warfarin dosing algorithms to improve the efficacy and safety of warfarin prescribing.

Pharmacogenetics of warfarin dosing in Chinese adults with nonvalvular atrial fibrillation.

The guide for the use of genotype-guided warfarin dosing in patients for the treatment of non-valvular atrial fibrillation (AF) is still lacking. We aimed to evaluate whether genotype-guided warfarin dosing is superior to conventional clinical dosing for the outcomes of interest in Chinese patients. Our study consisted of 508 newly recruited and 471 existing Chinese AF patients. Among the total 979 patients, 585 patients received their dose of warfarin determined by a genetic and clinical factor (gene group), while the remaining 394 patients whose dosing was determined empirically in control group. We incorporated CYP2C9 and VKORC1 genotypes into the gene group. The international normalized ratio (INR) measurement and standard protocols were used for further dose adjustment in both groups. The primary outcomes were the percentage of time in the therapeutic range (%TTR) and INR during 12-month follow-up. Secondary safety outcome included bleeding and thrombotic events. Compared with the control group, the average TTR of the gene group was higher [68.4 ± 20.6% vs 48.5 ± 21.6%, P < 0.001]. The average INR monitoring times to reach the therapeutic time in the gene group was lower (P < 0.001). The risk ratios (RR) for cumulative incidence of total bleeding events, minor bleeding events, gastrointestinal bleeding, and intracerebral bleeding events were not significantly different between the two groups (P > 0.05). Comparing to the analysis using existing 471 patients, the analysis using total 979 patients showed that the gene group experienced a lower (RR 0.4 (95% CI 0.2 to 0.8), P = 0.008) incidence of cumulative ischemic stroke. Genotype-guided warfarin administration increases the average TTR, reaches higher TTR levels in the early anticoagulant phase, and significantly reduces the risk of ischemic stroke events.

Pharmacogenetics of warfarin and healthcare costs - Real-world data analysis.

Variants in CYP2C9 and VKORC1 genes have been associated with individuals' sensitivity to warfarin. The aim of this study was to investigate the differences of healthcare costs of genetically normal and genetically sensitive warfarin responder groups. This was a retrospective study linking genotype data from three Finnish biobanks (THL Biobank, Auria Biobank, Helsinki Biobank) with healthcare encounter data of the Finnish Institute of Health and Welfare (THL), drug dispensation data from the Social Insurance Institution of Finland (Kela) and laboratory data from Finnish hospital districts and municipalities. We compared the normal and sensitive warfarin responder groups in terms of healthcare costs related to bleeding and thromboembolic events, INR tests and medication purchases. We found a trend towards increased bleeding-related hospital costs in the sensitive warfarin responder group (881 patients) when compared with the normal responders (1627 patients) with a per patient difference of 150.9€/year (95% CI: -55.1, 414.6€/year, p=0.087). INR test costs were higher in the sensitive responder group with a difference of 7.2€/year (95% CI: -1.5, 16.4€/year, p=0.047). Medication costs were significantly lower in the sensitive responder group with a difference of -14.4€/year (95% CI: -15.8, -12.9€/year, p < 0.001). The difference in the costs of bleeding-related hospitalization between genetically sensitive and normal warfarin responders may justify genotype-guided warfarin dosing. Further studies with larger sample sizes would be needed to verify the result.

Oral anticoagulants: a systematic overview of reviews on efficacy and safety, genotyping, self-monitoring, and stakeholder experiences

BackgroundThis systematic overview was commissioned by England’s Department of Health and Social Care (DHSC) to assess the evidence on direct (previously ‘novel’) oral anticoagulants (OACs), compared with usual care, in adults, to prevent stroke related to atrial fibrillation (AF), and to prevent and treat venous thromboembolism (VTE). Specifically, to assess efficacy and safety, genotyping, self-monitoring, and patient and clinician experiences of OACs.MethodsWe searched MEDLINE, Embase, ASSIA, and CINAHL, in October, 2017, updated in November 2021. We included systematic reviews, published from 2014, in English, assessing OACs, in adults. We rated review quality using AMSTAR2 or the JBI checklist. Two reviewers extracted and synthesised the main findings from the included reviews.ResultsWe included 49 systematic reviews; one evaluated efficacy, safety, and cost-effectiveness, 17 assessed genotyping, 23 self-monitoring or adherence, and 15 experiences (seven assessed two topics). Generally, the direct OACs, particularly apixaban (5 mg twice daily), were more effective and safer than warfarin in preventing AF-related stroke. For VTE, there was little evidence of differences in efficacy between direct OACs and low-molecular-weight heparin (prevention), warfarin (treatment), and warfarin or aspirin (secondary prevention). The evidence suggested that some direct OACs may reduce the risk of bleeding, compared with warfarin. One review of genotype-guided warfarin dosing assessed AF patients; no significant differences in stroke prevention were reported. Education about OACs, in patients with AF, could improve adherence. Pharmacist management of coagulation may be better than primary care management. Patients were more adherent to direct OACs than warfarin. Drug efficacy was highly valued by patients and most clinicians, followed by safety. No other factors consistently affected patients’ choice of anticoagulant and adherence to treatment. Patients were more satisfied with direct OACs than warfarin.ConclusionsFor stroke prevention in AF, direct OACs seem to be more effective and safer than usual care, and apixaban (5 mg twice daily) had the best profile. For VTE, there was no strong evidence that direct OACs were better than usual care. Education and pharmacist management could improve coagulation control. Both clinicians and patients rated efficacy and safety as the most important factors in managing AF and VTE.Systematic review registrationPROSPERO CRD42017084263—one deviation; efficacy and safety were from one review.

Efficacy and safety of genotype-guided warfarin dosing versus non-genotype-guided warfarin dosing strategies: A systematic review and meta-analysis of 27 randomized controlled trials

ObjectiveTo evaluate the efficacy and safety of genotype-guided dosing (GD) strategies compared to non−genotype−guided dosing (non-GD) strategies for warfarin. MethodsDatabases were searched up to July 2021. Meta-analysis was conducted with the Review Manager software (version 5.4) and R (version 4.0.5). Risk ratio (RR), mean difference (MD), and 95% confidence intervals (CIs) were used. Subgroup analyses were conducted based on ethnicity and dosing regimen in non-GD group. Meta-regression was performed to evaluate the relation of covariates. This study is registered with PROSPERO (CRD42021245654). Results27 randomized controlled trials with a total of 9906 patients were included. The GD group resulted in a significantly improved time in therapeutic range compared with non-GD group in follow-up duration within 30 days (MD: 5.95, 95%CI: 2.41–9.22, P = 0.001) and beyond 30 days (MD: 4.93, 1.40–8.47, P = 0.006), time to the first therapeutic international normalized ratio (MD: −1.80, −2.69 - −0.92, P < 0.0001), and time to reach stable dose (MD: −5.08, −7.09 - −3.07, P < 0.00001), incidence of major bleeding events (RR: 0.50, 0.33–0.75, P = 0.0008), total bleeding events (RR: 0.83, 0.73–0.95, P = 0.006), and thromboembolism (RR: 0.69, 0.49–0.96, P = 0.03). No differences were found in stable dose achievement, minor bleeding events, over anticoagulation, and all-cause mortality. Four improved efficacy outcomes were observed in GD group compared with fixed dosing group. Only time to the therapeutic INR was shortened in GD group compared with clinical adjusted dosing group. The result showed no difference of safety outcomes between GD group and fixed dosing group whereas a decreased incidence of major bleeding events was observed when comparing to clinical adjusted dosing group. ConclusionGD strategy was superior to fixed dosing strategy in term of efficacy outcomes and comparable to fixed dosing strategy in safety outcomes. Clinical adjusted regimen could partly substitute the genotype-guided dosing strategy for efficacy in insufficient conditions, but the risk of major bleeding events should be monitored.

Influence of CYP2C9 Polymorphisms on Plasma Concentration of Warfarin and 7-Hydroxy Warfarin in South Indian Patients.

Warfarin is primarily metabolized by cytochrome P450 2C9 (CYP2C9) enzyme, which is encoded by the CYP2C9 gene. CYP2C9*2 and CYP2C9*3 variants significantly influence warfarin metabolism and subsequently the required dose of warfarin. The current retrospective study was aimed to determine the influence of CYP2C9 variants on warfarin metabolic ratio (MR, warfarin/7-hydroxy warfarin) and warfarin maintenance therapy in 210 patients (mean age 44.6±11.6 (SD) years; male to female ratio 81:129). High-performance liquid chromatography (HPLC) with UV detector was used to measure plasma concentrations of warfarin and 7-hydroxy warfarin. Plasma samples were collected 12 h after the previous dose of warfarin was administered. CYP2C9 variants (rs1799853 and rs1057910) were identified using real-time polymerase chain reaction allele-discrimination method. The mean daily maintenance dose of warfarin was 4.6±1.8 (SD) mg. The mean plasma warfarin and 7-hydroxy warfarin concentrations were 3.7±1.6 (SD) μg/mL and 1.1±0.54 (SD) μg/mL, respectively. Patients carrying other CYP2C9 variants required 39% lower warfarin maintenance dose 3.3±1.2(SD)mg than CYP2C9*1*1 carrier 4.9±1.8(SD)mg, (p<0.0001). MRs differed significantly between CYP2C9 variant carriers (8.1±5.1) and normal genotype carriers (4.8±3.9) (p<0.0001). Probit analysis identified an MR value of 7.6 as the anti-mode (sensitivity of 84% and specificity of 55%) to differentiate poor and intermediate metabolizers (carriers of any CYP2C9*2 or CYP2C9*3 variants) from normal metabolizers (CYP2C9*1*1 genotype). The present study results provide, insights on the effect of CYP2C9 genetic polymorphisms on inter-individual variability in warfarin metabolism and emphasizes utility of phenotyping in a setting of genotype-guided dosing of warfarin in South Indian population.

Influence of PSRC1, CELSR2, and SORT1 Gene Polymorphisms on the Variability of Warfarin Dosage and Susceptibility to Cardiovascular Disease.

BackgroundCardiovascular disease is one of the most common causes of morbidity and mortality worldwide. Several cardiovascular diseases require therapy with warfarin, an anticoagulant with large interindividual variability resulting in dosing difficulties. The selected genes and their polymorphisms have been implicated in several Genome-Wide Association Study (GWAS) to be associated with cardiovascular disease.ObjectiveThe goal of this study is to discover if there are any associations between rs646776 of PSRC1, rs660240 and rs12740374 of CELSR2, and rs602633 of SORT1 to coronary heart disease (CHD) and warfarin dose variability in patients diagnosed with cardiovascular disease undergoing warfarin therapy.MethodsThe study was directed at the Queen Alia Hospital Anticoagulation Clinic in Amman, Jordan. DNA was extracted and genotyped using the Mass ARRAY™ system, statistical analysis was done using SPSS.ResultsThe study found several associations between the selected SNPs with warfarin, but none with cardiovascular disease. All 4 studied SNPs were found to be correlated to warfarin sensitivity during the stabilization phase except rs602633 and with warfarin dose variability at the initiation phase. CELSR2 SNPs also showed association with dose variability during the stabilization phase. Also, rs646776 and rs12740374 were linked to warfarin sensitivity over the initiation phase. Only rs602633 was associated with INR treatment outcomes.ConclusionThe findings presented in this study found new pharmacogenomic associations for warfarin, that warrant further research in the field of genotype-guided warfarin dosing.

Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial.

Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients. We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Eligible patients were ≥18 years of age, with atrial fibrillation or deep vein thrombosis without previous treatment of warfarin or a bleeding disorder. Nine follow-up visits were performed during the 12-week study period. The primary outcome measure was the percentage of time in the therapeutic range of the international normalized ratio during the first 12 weeks after starting warfarin therapy. A total of 660 participants were enrolled and randomly assigned to a genotype-guided dosing group or a control group under standard dosing. The genotype-guided dosing group had a significantly higher percentage of time in the therapeutic range than the control group (58.8% versus 53.2% [95% CI of group difference, 1.1-10.2]; P=0.01). The genotype-guided dosing group also achieved the target international normalized ratio sooner than the control group. In subgroup analyses, warfarin normal sensitivity group had an even higher percentage of time in the therapeutic range during the first 12 weeks compared with the control group (60.8% versus 48.9% [95% CI, 1.1-24.4]). The incidence of adverse events was low in both groups. The outcomes of genotype-guided warfarin dosing were superior to those of clinical standard dosing. These findings raise the prospect of precision warfarin treatment in China. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02211326.

Genotype-guided warfarin dosing may benefit patients with mechanical aortic valve replacements: randomized controlled study

This prospective, single-blind, randomized study was designed to evaluate the effect of genotype-based warfarin dosing compared with standard warfarin dosing in Korean patients with mechanical cardiac valves. Patients were assigned to either the genotype-based dosing group or the standard dosing group using stratified block randomization. The genotype-based dosing equation was adopted from a previous study which included VKORC1 rs9934438, CYP2C9 rs1057910, CYP4F2 rs2108622, and age. Primary outcomes included the percentage of time in the therapeutic range (pTTR): (i) during the first week following initiation of warfarin therapy, (ii) during hospitalization and (iii) until the first outpatient visit. A total of 91 patients were included in the analysis, 42 treated with genotype-based warfarin dosing and 49 treated with standard warfarin dosing. The genotype frequency differences of the three SNPs included in this study (ie, VKORC1, CYP2C9, CYP4F2), between the genotype-based dosing and standard dosing groups were not different. The genotype-based dosing group trended toward higher pTTR when compared with the standard dosing group, although this difference was not statistically significant. In patients with aortic valve replacement, TTRTraditional and TTRRosendaal were significantly higher in the genotype-based dosing group when compared with the standard dosing group during the first week following treatment initiation [ie, 58.5% vs. 38.1% (p = 0.009) and 64.0% vs. 44.6% (p = 0.012), respectively]. Based on the results, the genotype-guided dosing did not offer a significant clinical advantage, but a possible benefit in patients with aortic valve replacement has been suggested.

Genotype-guided warfarin therapy: Still of only questionable value two decades on.

Despite an apparently sound pharmacological basis, clinical studies of genotype-guided warfarin dosing have yielded mixed and conflicting results, leading to reluctance in its clinical implementation. The objective of this critique is to re-evaluate key warfarin pharmacogenetic studies with a view to explaining why this may be so. Major widely-cited warfarin pharmacogenetic studies as well as recent meta-analyses were identified and a critical analysis of these was undertaken to identify factors that may account for poor clinical implementation of pre-treatment genotyping. Critical examination of major warfarin pharmacogenetic studies identified a number of methodological concerns such as marked variations in study designs with different variously-defined measures of outcome. Genotype testing involved only a limited number of CYP2C9/VKORC1 alleles. Claims of benefits of genotyping are based almost exclusively on INR-related parameters which are known to be highly time-labile and of limited value in predicting clinical risk or benefit. This is evidenced by lack of any significant effect of genotyping on rates of bleeding or thromboembolic events. Neither have the effects of potential phenoconversion or medication non-adherence in study populations been adequately investigated. Although the effect of ethnicity/race is now better characterised, studies lack the power to determine whether any benefits claimed are indication-sensitive. Since 60% of inter-individual variability in warfarin dose/response is due to other factors (many of which are non-genetic), expectations of eliminating this variability simply by CYP2C9/VKORC1 genotyping are over-optimistic and efforts cost-ineffective. Real-world studies have not always corroborated trials-based claims of clinical benefit. It is time to consider redirecting scarce resources away from the study of warfarin pharmacogenetics to pharmacogenetic research of potentially greater clinical relevance.

Comparative efficacy and safety of warfarin care bundles and novel oral anticoagulants in patients with atrial fibrillation: a systematic review and network meta-analysis

Warfarin care bundles (e.g. genotype-guided warfarin dosing, patient’s self-testing [PST] or patient’s self-management [PSM] and left atrial appendage closure) are based on the concept of combining several interventions to improve anticoagulation care. NOACs are also introduced for stroke prevention in atrial fibrillation (SPAF). However, these interventions have not been compared in head-to-head trials yet. We did a network meta-analysis based on a systematic review of randomized controlled trials comparing anticoagulant interventions for SPAF. Studies comparing these interventions in adults, whether administered alone or as care bundles were included in the analyses. The primary efficacy outcome was stroke and the primary safety outcome was major bleeding. Thirty-seven studies, involving 100,142 patients were assessed. Compared to usual care, PSM significantly reduced the risk of stroke (risk ratio [RR] 0.24, 95% CI 0.08–0.68). For major bleeding, edoxaban 60 mg (0.80, 0.71–0.90), edoxaban 30 mg (0.48, 0.42–0.56), and dabigatran 110 mg (0.81, 0.71–0.94) significantly reduced the risk of major bleeding compared with usual warfarin care. Cluster rank plot incorporating stroke and major bleeding outcomes indicates that some warfarin care bundles perform as well as NOACs. Both interventions are therefore viable options to be considered for SPAF. Additional studies including head-to-head trials and cost-effectiveness evaluation are still warranted.

Development and Validation of a Novel Warfarin Dosing Algorithm for Korean Patients With VKORC1 1173C.

BackgroundDifferences in the performance of suggested warfarin dosing algorithms among different ethnicities and genotypes have been reported; this necessitates the development of an algorithm with enhanced performance for specific population groups. Previous warfarin dosing algorithms underestimated warfarin doses in VKORC1 1173C carriers. We aimed to develop and validate a new warfarin dosing algorithm for Korean patients with VKORC1 1173C.MethodsA total of 109 patients carrying VKORC1 1173CT (N=105) or 1173CC (N=4) were included in this study. Multiple regression analysis was performed to deduce a new dosing algorithm. Following literature searches for genotype-guided warfarin dosing algorithms, 21 algorithms were selected and evaluated using the correlation coefficient (ρ) of actual dose and estimated dose, mean error, and root mean square error.ResultsThe developed algorithm is as follows: maintenance dose (mg/week)=exp [3.223−0.009×(age)+0.577×(body surface area [BSA])+0.178×(sex)−0.481×(CYP2C9 genotype)+0.227×(VKORC1 genotype)]. Integrated variables explained 44% of the variance in the maintenance dose. The predicted and actual doses showed moderate correlation (ρ=0.641) with the best performance with a mean error of −1.30 mg/week. The proportion of underestimated groups was 17%, which was lower than with the other algorithms.ConclusionsThis is the first study to develop and validate a warfarin dosing algorithm based on data from VKORC1 1173C carriers; it showed superior predictive performance compared with previously published algorithms.

Chinese Patients With Heart Valve Replacement Do Not Benefit From Warfarin Pharmacogenetic Testing on Anticoagulation Outcomes.

Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry; yet, its utility in Chinese patients with heart valve replacement remains unresolved. A total of 2264 patients who underwent heart valve replacement at Wuhan Asia Heart Hospital were enrolled in this study. Patients were randomly divided into 2 groups, namely, a genotype-guided and a traditional clinically guided warfarin dosing group. In the genotype-guided group (n = 1134), genotyping for CYP2C9 and VKORC1 (-1639 G→A) was performed using TaqMan genotyping assay. Warfarin doses were predicted with the International Warfarin Pharmacogenetics Consortium algorithm. Patients in the control group (n = 1130) were clinically guided. The primary outcome was to compare the incidence of adverse events (major bleeding and thrombotic) during a 90-day follow-up period between 2 groups. Secondary objectives were to describe effects of the pharmacogenetic intervention on the first therapeutic-target-achieving time, the stable maintenance dose, and the hospitalization days. A total of 2245 patients were included in the analysis. Forty-nine events occurred during follow-up. Genotype-guided dosing strategy did not result in a reduction in major bleeding (0.26% versus 0.63%; hazard ratio, 0.44; 95% confidence interval, 0.13-1.53; P = 0.20) and thrombotic events (0.89% versus 1.61%; hazard ratio, 0.56; 95% confidence interval, 0.27-1.17; P = 0.12) compared with clinical dosing group. Compared with traditional dosing, patients in the genotype-guided group reached their therapeutic international normalized ratio in a shorter time (3.8 ± 2.0 versus 4.4 ± 2.0 days, P < 0.001). There was no difference in hospitalization days (P = 0.28). Warfarin pharmacogenetic testing according to the International Warfarin Pharmacogenetics Consortium algorithm cannot improve anticoagulation outcomes in Chinese patients with heart valve replacement.

Cost-effectiveness of warfarin care bundles and novel oral anticoagulants for stroke prevention in patients with atrial fibrillation in Thailand

IntroductionNovel oral anticoagulants (NOACs) and warfarin care bundles (e.g. genotyping, patient self-testing or self-management) are alternatives to usual warfarin care for stroke prevention in patients with atrial fibrillation (AF). We aim to evaluate the cost-effectiveness of NOACs and warfarin care bundles in patients with AF in a middle-income country, Thailand. Materials and methodsA Markov model was used to evaluate the economic and treatment outcomes of warfarin care bundles and NOACs compared with usual warfarin care. Cost-effectiveness was assessed from a societal perspective over a lifetime horizon with 3% discount rate in a hypothetical cohort of 65-year-old atrial fibrillation patients. Input parameters were derived from published literature, meta-analysis and local data when available. The outcome measure was incremental cost per quality-adjusted life years (QALY) gained (ICER). ResultsUsing USD5104 as the threshold of willingness-to-pay per QALY, patient's self-management of warfarin was cost-effective when compared to usual warfarin care, with an ICER of USD1395/QALY from societal perspective. All NOACs were not cost-effective in Thailand, with ICER ranging from USD8678 to USD14,247/QALY. When compared to the next most effective intervention, patient's self-testing and genotype-guided warfarin dosing were dominated. In the cost-effectiveness acceptability curve, patient's self-management had the highest probability of being cost-effective in Thailand, approximately 78%. Results were robust over a range of inputs in sensitivity analyses. ConclusionsIn Thailand, NOACs were unlikely to be cost-effective at current prices. Conversely, patient's self-management is a highly cost-effective intervention and may be considered for adoption in developing regions with resource-limited healthcare systems.

PCV55 COST-EFFECTIVENESS OF WARFARIN CARE BUNDLES AND NOVEL ORAL ANTICOAGULANTS FOR STROKE PREVENTION IN PATIENTS WITH ATRIAL FIBRILLATION IN THAILAND

To evaluate the cost-effectiveness of warfarin care bundles (combination of warfarin with another intervention such as genotyping, patient’s self-testing [PST] or patient’s self-management [PSM]) and novel oral anticoagulants (NOACs) for stroke prevention in patients with atrial fibrillation (SPAF). A Markov model was used to evaluate the lifetime costs and quality-adjusted life years (QALYs) of warfarin care bundles and NOACs compared with usual warfarin care. The model was performed from the societal perspective over a lifetime horizon using a 3% discount rate. Clinical events considered in the model were ischemic stroke, intracranial haemorrhage, major extracranial haemorrhage and myocardial infarction. Input parameters were derived from a combination of published literature, meta-analysis and local data when available. A willingness-to-pay of USD5,104/QALY was used as the threshold of being cost-effective. Model’s robustness was tested using one-way sensitivity analyses and probabilistic sensitivity analysis. From societal perspective, PSM is a cost-effective intervention when compared to usual warfarin care, with an incremental cost-effectiveness ratio (ICER) of USD1,395/QALY. All NOACs were not cost-effective for SPAF in Thailand, with ICER ranging from USD8,678 to USD14,247/QALY. When compared to the next most effective intervention, NOACs, PST, and genotype-guided warfarin dosing were dominated. The cost-effectiveness acceptability curve revealed that PSM had the highest potential to be a cost-effective strategy versus other anticoagulant interventions, with a 78% probability of being cost-effective. Results were robust over a range of inputs in sensitivity analyses. In the context of limited health recourses like Thailand, NOACs were unlikely to be cost-effective, at their current prices. Conversely, our findings indicated that PSM is a highly cost-effective intervention compared with usual warfarin care and appears to be economically valuable to be considered for adoption in a resource-limited healthcare system.

Processes and barriers to implementation of point-of-care genotype-guided dosing of warfarin into UK outpatient anticoagulation clinics.

Processes and barriers to implementation of point-of-care genotype-guided dosing of warfarin into UK outpatient anticoagulation clinics.

Implementation of genotype-guided dosing of warfarin with point-of-care genetic testing in three UK clinics: a matched cohort study

BackgroundWarfarin is a widely used oral anticoagulant. Determining the correct dose required to maintain the international normalised ratio (INR) within a therapeutic range can be challenging. In a previous trial, we showed that a dosing algorithm incorporating point-of-care genotyping information (‘POCT-GGD’ approach) led to improved anticoagulation control. To determine whether this approach could translate into clinical practice, we undertook an implementation project using a matched cohort design.MethodsAt three clinics (implementation group; n = 119), initial doses were calculated using the POCT-GGD approach; at another three matched clinics (control group; n = 93), patients were dosed according to the clinic’s routine practice. We also utilised data on 640 patients obtained from routinely collected data at comparable clinics. Primary outcome was percentage time in target INR range. Patients and staff from the implementation group also provided questionnaire feedback on POCT-GGD.ResultsMean percentage time in INR target range was 55.25% in the control group and 62.74% in the implementation group; therefore, 7.49% (95% CI 3.41–11.57%) higher in the implementation group (p = 0.0004). Overall, patients and staff viewed POCT-GGD positively, suggesting minor adjustments to allow smooth implementation into practice.ConclusionsIn the first demonstration of the implementation of genotype-guided dosing, we show that warfarin dosing determined using an algorithm incorporating genetic and clinical factors can be implemented smoothly into clinic, to ensure target INR range is reached sooner and maintained. The findings are like our previous randomised controlled trial, providing an alternative method for improving the risk-benefit of warfarin use in daily practice.

Efficacy and Safety of Genotype-Guided Warfarin Dosing in the Chinese Population: A Meta-analysis of Randomized Controlled Trials.

To evaluate the efficacy and safety of using genetic information to guide warfarin dosing in the Chinese population. This meta-analysis was conducted among the published, randomized, controlled trials (RCTs) in the Chinese population comparing genotype-guided warfarin dosing (PG group) with clinical or standard warfarin dosing (STD group). RCTs published on or before January 2018 were identified using the PubMed, Embase, Cochrane Library, CNKI, Chinese VIP database, and Chinese Wanfang database. Intotal, 2137 participants from 14 RCTs were included in the meta-analysis. Primary analysis showed that both bleeding events [odds ratio (OR) = 0.24; 95% confidence interval (CI), 0.11-0.52; P = 0.0003] and adverse events (OR = 0.60; 95% CI, 0.43-0.83; P = 0.002) were significantly lower in the genotype-guided group than in the clinical or standard group. The percentage of patients who received a warfarin-stable therapeutic dose during follow-up was increased in the genotype-guided group compared with the percentage in the clinical or standard group (OR = 2.68; 95% CI, 1.82-3.95; P < 0.00001). In the genotype-guided group, the time to a stable therapeutic dose (mean difference = -7.98; 95% CI, -9.08 to -6.87; P < 0.00001) and the time to the first target value (mean difference = -1.87; 95% CI, -3.41 to -0.32; P = 0.02) were shortened compared with those of the clinical or standard group, but there was no difference for international normalized ratio >4, between the 2 groups (OR = 0.42; 95% CI, 0.14-1.25; P = 0.12). Genotype-guided warfarin-dosing algorithms could improve the efficacy and safety of warfarin anticoagulation in the Chinese population.

Genotype-guided dosing versus conventional dosing of warfarin: A meta-analysis of 15 randomized controlled trials.

Genotype-guided warfarin dosing algorithm is designed to predict the initial and stable dose of warfarin. However, whether this strategy is superior to conventional dosing method has not been consistently proven. To determine the benefit of genotype-guided dosing vs conventional dosing of warfarin, we performed a meta-analysis. Literature was searched in PubMed, Embase and Central for published studies, and in clinicaltrials.gov for unpublished studies. Randomized controlled trials (RCTs) comparing genotype-guided dosing with conventional dosing of warfarin were included in the meta-analysis. Risk of bias of eligible RCTs was assessed with the Cochrane Collaboration's tool. Meta-analysis was conducted by STATA software. The reliability of currently available evidence was determined with TSA software. Fifteen RCTs with a total of 4852 patients were identified for the meta-analysis. Genotype-guided dosing of warfarin was associated with higher percentage time within therapeutic range (PTTR) and more patients achieving stable dose at >1month follow-up, shorter time to first therapeutic international normalized ratio (INR), shorter time to stable therapeutic dose, and decreased risk of warfarin-related major bleeding events compared with conventional dosing. However, there were no statistically significant differences in PTTR and incidence of patients achieving stable dose within 1month, INR >4, all bleeding events, thromboembolism and all-cause mortality. Genotype-guided dosing should be considered in patients initiating warfarin treatment, especially in those with a history of haemorrhage. However, further studies are still needed to determine the cost-effectiveness of routine warfarin-related genotypes testing.