Time and travel costs incurred by women attending antenatal tests: A costing study.

OBJECTIVE: to estimate the costs to women, their friends and family for different antenatal tests in the Down's syndrome (DS) screening pathway. DESIGN: questionnaire-based costing study. SETTING: eight maternity clinics across the UK. PARTICIPANTS: pregnant women (n=574) attending an appointment for DS screening, NIPT or invasive testing between December 2013 and September 2014. MEASUREMENTS: using data collected from the questionnaires we calculated the total costs to women by multiplying the time spent at the hospital and travelling to and from it by the opportunity costs of the women and accompanying person and adding travel and childcare costs. Assumptions about the value of opportunity costs were tested in one-way sensitivity analyses. The main outcome measure was the mean cost to the women and friends/family for each test (DS screening, NIPT, and invasive testing). FINDINGS: mean costs to women and their family/friend were £33.96 per visit, of which £22.47 were time costs, £9.15 were travel costs and £2.34 were childcare costs. Costs were lowest for NIPT (£22), £32 for DS screening (£44 if combined with NIPT), and highest for invasive testing (£60). Sensitivity analysis revealed that variations around the value of leisure time opportunity costs had the largest influence on the results. KEY CONCLUSIONS: there are considerable costs to women, their friends and family when attending different tests in the DS screening pathway. IMPLICATIONS FOR PRACTICE: when assessing the cost-effectiveness of changes to this pathway, costs to women should be considered.

Cost-effectiveness analysis of offering free leisure centre memberships to physically inactive members of the public receiving state benefits: a case study.

BACKGROUND: We evaluated the cost-effectiveness of the Give-it-a-Go programme, which offers free leisure centre memberships to physically inactive members of the public in a single London Borough receiving state benefits. METHODS: A decision analytic Markov model was developed to analyse lifetime costs and quality-adjusted life-years (QALYs) of 1025 people recruited to the intervention versus no intervention. In the intervention group, people were offered 4 months of free membership at a leisure centre. Physical activity levels were assessed at 0 and 4 months using the International Physical Activity Questionnaire (IPAQ). Higher levels of physical activity were assumed to decrease the risk of coronary heart disease, stroke and diabetes mellitus type II, as well as improve mental health. Costs were assessed from a National Health Service (NHS) perspective. Uncertainty was assessed using one-way and probabilistic sensitivity analyses. RESULTS: One-hundred fifty nine participants (15.5 %) completed the programme by attending the leisure centre for 4 months. Compared with no intervention, Give it a Go increased costs by £67.25 and QALYs by 0.0033 (equivalent to 1.21 days in full health) per recruited person. The incremental costs per QALY gained were £20,347. The results were highly sensitive to the magnitude of mental health gain due to physical activity and the duration of the effect of the programme (1 year in the base case analysis). When the mental health gain was omitted from the analysis, the incremental cost per QALY gained increased to almost £1.5 million. In the probabilistic sensitivity analysis, the incremental costs per QALY gained were below £20,000 in 39 % of the 5000 simulations. CONCLUSIONS: Give it a Go did not significantly increase life-expectancy, but had a positive influence on quality of life due to the mental health gain of physical activity. If the increase in physical activity caused by Give it a Go lasts for more than 1 year, the programme would be cost-effective given a willingness to pay for a QALY of £20,000.

Uptake, outcomes, and costs of implementing non-invasive prenatal testing for Down's syndrome into NHS maternity care: prospective cohort study in eight diverse maternity units.

OBJECTIVE:  To investigate the benefits and costs of implementing non-invasive prenatal testing (NIPT) for Down's syndrome into the NHS maternity care pathway. DESIGN:  Prospective cohort study. SETTING:  Eight maternity units across the United Kingdom between 1 November 2013 and 28 February 2015. PARTICIPANTS:  All pregnant women with a current Down's syndrome risk on screening of at least 1/1000. MAIN OUTCOME MEASURES:  Outcomes were uptake of NIPT, number of cases of Down's syndrome detected, invasive tests performed, and miscarriages avoided. Pregnancy outcomes and costs associated with implementation of NIPT, compared with current screening, were determined using study data on NIPT uptake and invasive testing in combination with national datasets. RESULTS:  NIPT was prospectively offered to 3175 pregnant women. In 934 women with a Down's syndrome risk greater than 1/150, 695 (74.4%) chose NIPT, 166 (17.8%) chose invasive testing, and 73 (7.8%) declined further testing. Of 2241 women with risks between 1/151 and 1/1000, 1799 (80.3%) chose NIPT. Of 71 pregnancies with a confirmed diagnosis of Down's syndrome, 13/42 (31%) with the diagnosis after NIPT and 2/29 (7%) after direct invasive testing continued, resulting in 12 live births. In an annual screening population of 698 500, offering NIPT as a contingent test to women with a Down's syndrome screening risk of at least 1/150 would increase detection by 195 (95% uncertainty interval -34 to 480) cases with 3368 (2279 to 4027) fewer invasive tests and 17 (7 to 30) fewer procedure related miscarriages, for a non-significant difference in total costs (£-46 000, £-1 802 000 to £2 661 000). The marginal cost of NIPT testing strategies versus current screening is very sensitive to NIPT costs; at a screening threshold of 1/150, NIPT would be cheaper than current screening if it cost less than £256. Lowering the risk threshold increases the number of Down's syndrome cases detected and overall costs, while maintaining the reduction in invasive tests and procedure related miscarriages. CONCLUSIONS:  Implementation of NIPT as a contingent test within a public sector Down's syndrome screening programme can improve quality of care, choices for women, and overall performance within the current budget. As some women use NIPT for information only, the Down's syndrome live birth rate may not change significantly. Future research should consider NIPT uptake and informed decision making outside of a research setting.

Non-invasive prenatal diagnosis (NIPD) for single gene disorders: cost analysis of NIPD and invasive testing pathways.

OBJECTIVE: Evaluate the costs of offering non-invasive prenatal diagnosis (NIPD) for single gene disorders compared to traditional invasive testing to inform NIPD implementation into clinical practice. METHOD: Total costs of diagnosis using NIPD or invasive testing pathways were compared for a representative set of single gene disorders. RESULTS: For autosomal dominant conditions, where NIPD molecular techniques are straightforward, NIPD cost £314 less than invasive testing. NIPD for autosomal recessive and X-linked conditions requires more complicated technical approaches and total costs were more than invasive testing, e.g. NIPD for spinal muscular atrophy was £1090 more than invasive testing. Impact of test uptake on costs was assessed using sickle cell disorder as an example. Anticipated high uptake of NIPD resulted in an incremental cost of NIPD over invasive testing of £48 635 per 100 pregnancies at risk of sickle cell disorder. CONCLUSION: Total costs of NIPD are dependent upon the complexity of the testing technique required. Anticipated increased demand for testing may have economic implications for prenatal diagnostic services. Ethical issues requiring further consideration are highlighted including directing resources to NIPD when used for information only and restricting access to safe tests if it is not cost-effective to develop NIPD for rare conditions. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Cost-effectiveness of a physical exercise programme for residents of care homes: a pilot study.

BACKGROUND: Oomph! Wellness organises interactive exercise and activity classes (Oomph! classes) for older people in care homes. We investigated the cost-effectiveness of Oomph! classes. METHODS: Health-related quality of life was measured using the EQ-5D-5 L questionnaire at three time points; 3 months and 1 week prior to the start of the classes and after 3 months of Oomph! classes. Costs included the costs of organising the classes, training instructors and health service use (General Practitioner (GP) and hospital outpatient visits). To determine the cost-effectiveness of Oomph! classes, total costs and quality-adjusted life-years (QALYs) during the 3 months after initiation of the classes were compared to the total costs and QALYs of the 3 months prior to the classes and extrapolated to a 1-year time horizon. Uncertainty was taken into account using one-way and probabilistic sensitivity analysis. RESULTS: Sixteen residents completed all three EQ-5D-5 L questionnaires. There was a decrease in mean health related quality of life per participant in the 3 months before Oomph! classes (0.56 to 0.52, p = 0.26) and an increase in the 3 months after the start of Oomph! classes (0.52 to 0.60, p = 0.06), but the changes were not statistically significant. There were more GP visits after the start of Oomph! classes and fewer hospital outpatient visits, leading to a slight decrease in NHS costs (mean £132 vs £141 per participant), but the differences were not statistically significant (p = 0.79). In the base case scenario, total costs for Oomph! classes were £113 higher per participant than without Oomph! classes (£677 vs £564) and total QALYs were 0.074 higher (0.594 vs 0.520). The incremental costs per QALY gained were therefore £1531. The 95 % confidence intervals around the cost/QALY gained varied from dominant to dominated, meaning there was large uncertainty around the cost-effectiveness results. Given a willingness to pay threshold of £20,000 per QALY gained, Oomph! classes had a 62 %-86 % probability of being cost-effective depending on the scenario used. CONCLUSIONS: Preliminary evidence suggests that Oomph! classes may be cost-effective, but further evidence is needed about its impact on health-related quality of life and health service use.

Potential economic consequences of a cardioprotective agent for patients with myocardial infarction: modelling study.

OBJECTIVE: To investigate the cost-effectiveness of a hypothetical cardioprotective agent used to reduce infarct size in patients undergoing percutaneous coronary intervention (PCI) after anterior ST-elevation myocardial infarction. DESIGN: A cost-utility analysis using a Markov model. SETTING: The National Health Service in the UK. PATIENTS: Patients undergoing PCI after anterior ST-elevation myocardial infarction. INTERVENTIONS: A cardioprotective agent given at the time of reperfusion compared to no cardioprotection. We assumed the cardioprotective agent (given at the time of reperfusion) would reduce the risk and severity of heart failure (HF) after PCI and the risk of mortality after PCI (with a relative risk ranging from 0.6 to 1). The costs of the cardioprotective agent were assumed to be in the range £1000-4000. MAIN OUTCOME MEASURES: The incremental costs per quality-adjusted life-year (QALY) gained, using 95% CIs from 1000 simulations. RESULTS: Incremental costs ranged from £933 to £3820 and incremental QALYs from 0.04 to 0.38. The incremental cost-effectiveness ratio (ICER) ranged from £3311 to £63 480 per QALY gained. The results were highly dependent on the costs of a cardioprotective agent, patient age, and the relative risk of HF after PCI. The ICER was below the willingness-to-pay threshold of £20 000 per QALY gained in 71% of the simulations. CONCLUSIONS: A cardioprotective agent that can reduce the risk of HF and mortality after PCI has a high chance of being cost-effective. This chance depends on the price of the agent, the age of the patient and the relative risk of HF after PCI.

Comparison of dosing algorithms for acenocoumarol and phenprocoumon using clinical factors with the standard care in the Netherlands.

BACKGROUND: It has not been investigated how much the use of clinical factors in a dosing algorithm improves the percentage of time in therapeutic range (TTR). The present study aimed to compare the effect of dosing algorithms for acenocoumarol and phenprocoumon including clinical patient characteristics with standard care in the Netherlands. SETTING: The pre-EU-PACT study, an observational study in the Netherlands, was used to obtain standard care data. Data from the Dutch patients in the EU-PACT trial (comparing the use of a clinical algorithm with and without genetic information) was used for the clinical dosing algorithm. METHODS: For both acenocoumarol and phenprocoumon, the percentage of time in, below and above therapeutic International Normalized Ratio (INR) range during 12weeks after treatment initiation were assessed in both studies. RESULTS: During the weeks 2-12, the clinical dosing algorithm of acenocoumarol (80 patients) led to a higher TTR (74.3% versus 68.0% in range 2.0-3.5, 95% Confidence interval [CI] difference: 0.5% to 11.8%), and a reduced percentage of time below INR 2 and above INR 3.5, compared with standard care (272 patients). For phenprocoumon, compared with standard care (484 patients), 80 patients treated by the dosing algorithm did not obtained a significantly higher TTR in range 2.0-3.5 or a lower percentage of time above 3.5, however, they spent more time with INR below 2. CONCLUSION: The use of a clinical dosing algorithm for acenocoumarol seemed to improve the quality of anticoagulation therapy during the treatment of initial 2-12 weeks. For phenprocoumon, there was no statistically difference in anticoagulation control.

Quality of life in patients with venous thromboembolism and atrial fibrillation treated with coumarin anticoagulants.

INTRODUCTION: Little is known about the overall quality of life (QOL) in patients newly diagnosed with venous thromboembolism (VTE) and atrial fibrillation (AF). We studied QOL in patients with VTE and AF immediately after the start of anticoagulant therapy, and after three months of treatment. Furthermore we identified whether QOL was affected by age, gender and nationality. MATERIALS AND METHODS: The European pharmacogenetics of anticoagulant therapy (EU-PACT) study was a multicentre, randomized controlled trial of patients aged >18years diagnosed with VTE or AF. QOL was assessed using EuroQol 5 dimensions (EQ-5D) questionnaires. RESULTS: The EQ-5D questionnaires were completed by 187 patients with VTE and 660 patients with AF. The QOL in patients diagnosed with VTE or AF was significantly impaired, however, during a 3months treatment period, patients experienced an improvement (p<0.05). The QOL in patients diagnosed with VTE improved with increasing age, with similar effects seen in men and women. Men and women diagnosed with AF differed in QOL (respectively 0.84 and 0.74, p<0.05), and QOL decreased with age. Comparison between countries showed significant differences in the EQ-Index score at follow-up of patients with VTE, and in both EQ-Index score and EQ-VAS of patients with AF. CONCLUSIONS: The QOL in patients with VTE and AF is strongly reduced directly after the start of anticoagulant treatment, but improves within 3months. Moreover, QOL is influenced by demographic and disease-specific variables. These findings provide useful information for future cost-effectiveness studies.

Non-invasive prenatal diagnosis for cystic fibrosis: detection of paternal mutations, exploration of patient preferences and cost analysis.

OBJECTIVES: We aim to develop non-invasive prenatal diagnosis (NIPD) for cystic fibrosis (CF) and determine costs and implications for implementation. METHODS: A next-generation sequencing assay was developed to detect ten common CF mutations for exclusion of the paternal mutation in maternal plasma. Using uptake data from a study exploring views on NIPD for CF, total test-related costs were estimated for the current care pathway and compared with those incorporating NIPD. RESULTS: The assay reliably predicted mutation status in all control and maternal plasma samples. Of carrier or affected adults with CF (n = 142) surveyed, only 43.5% reported willingness to have invasive testing for CF with 94.4% saying they would have NIPD. Using these potential uptake data, the incremental costs of NIPD over invasive testing per 100 pregnancies at risk of CF are £9025 for paternal mutation exclusion, and £26,510 for direct diagnosis. CONCLUSIONS: We have developed NIPD for risk stratification in around a third of CF families. There are economic implications due to potential increased test demand to inform postnatal management rather than to inform decisions around termination of an affected pregnancy.

Economic evaluation of a pharmacogenetic dosing algorithm for coumarin anticoagulants in The Netherlands.

AIM: To investigate the cost-effectiveness of a pharmacogenetic dosing algorithm versus a clinical dosing algorithm for coumarin anticoagulants in The Netherlands. MATERIALS & METHODS: A decision-analytic Markov model was used to analyze the cost-effectiveness of pharmacogenetic dosing of phenprocoumon and acenocoumarol versus clinical dosing. RESULTS: Pharmacogenetic dosing increased costs by €33 and quality-adjusted life-years (QALYs) by 0.001. The incremental cost-effectiveness ratios were €28,349 and €24,427 per QALY gained for phenprocoumon and acenocoumarol, respectively. At a willingness-to-pay threshold of €20,000 per QALY, the pharmacogenetic dosing algorithm was not likely to be cost effective compared with the clinical dosing algorithm. CONCLUSION: Pharmacogenetic dosing improves health only slightly when compared with clinical dosing. However, availability of low-cost genotyping would make it a cost-effective option.

Genotype-guided coumarin dosing: where are we now and where do we need to go next?

INTRODUCTION: A large proportion of the coumarin dose variability is explained by environmental factors and by common genetic variants in the VKORC1 and CYP2C9 genes. Genotype-guided coumarin dosing has been proposed for a more accurate prediction of the coumarin dose in order to reduce the incidence of coumarin-related complications. AREAS COVERED: This review discusses the current state of coumarin pharmacogenetics, the evidence from recent randomized controlled trials and economic evaluations regarding the possible clinical implementation of genotype-guided coumarin dosing. EXPERT OPINION: When the VKORC1 and CYP2C9 genotypes are available before the start of coumarin therapy in individuals of European ancestry, a genetic-guided algorithm should be used for dose determination. Ethnicity-specific pharmacogenetic algorithms should be tested in other populations. At this moment the evidence is not sufficient to support genotyping before coumarin therapy initiation. Based on results from recent randomized controlled trials, a clinical dosing algorithm could be considered in the initial phase of coumarin treatment. Current economic studies indicate that genotype-guided dosing could be cost-effective, but the clinical implementation of genetic-guided coumarin therapy will depend on the cost of pharmacogenetic tests and the availability of novel oral anticoagulants.

Cost-effectiveness and pricing of antibacterial drugs.

Growing resistance to antibacterial agents has increased the need for the development of new drugs to treat bacterial infections. Given increasing pressure on limited health budgets, it is important to study the cost-effectiveness of these drugs, as well as their safety and efficacy, to find out whether or not they provide value for money and should be reimbursed. In this article, we systematically reviewed 38 cost-effectiveness analyses of new antibacterial agents. Most studies showed the new antibacterial drugs were cost-effective compared to older generation drugs. Drug pricing is a complicated process, involving different stakeholders, and has a large influence on cost-effectiveness. Value-based pricing is a method to determine the price of a drug at which it can be cost-effective. It is currently unclear what the influence of value-based pricing will be on the prices of new antibacterial agents, but an important factor will be the definition of 'value', which as well as the impact of the drug on patient health might also include other factors such as wider social impact and the health impact of disease.

Cost effectiveness of new oral anticoagulants for stroke prevention in patients with atrial fibrillation in two different European healthcare settings.

OBJECTIVES: Our objectives were to investigate the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives for stroke prevention in patients with atrial fibrillation in a country with specialized anticoagulation clinics (the Netherlands) and in a country without these clinics (the UK). METHODS: A decision-analytic Markov model was used to analyse the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives in the Netherlands and the UK over a lifetime horizon. RESULTS: In the Netherlands, the use of rivaroxaban, apixaban, or dabigatran increased health by 0.166, 0.365, and 0.374 quality-adjusted life-years (QALYs) compared with coumarin derivatives, but also increased costs by 5,681, 4,754, and 5,465, respectively. The incremental cost-effectiveness ratios (ICERs) were 34,248, 13,024, and 14,626 per QALY gained. In the UK, health was increased by 0.302, 0.455, and 0.461 QALYs, and the incremental costs were similar for all three new oral anticoagulants (5,118-5,217). The ICERs varied from 11,172 to 16,949 per QALY gained. In the Netherlands, apixaban had the highest chance (37 %) of being cost effective at a threshold of 20,000; in the UK, this chance was 41 % for dabigatran. The quality of care, reflected in time in therapeutic range, had an important influence on the ICER. CONCLUSIONS: Apixaban, rivaroxaban, and dabigatran are cost-effective alternatives to coumarin derivatives in the UK, while in the Netherlands, only apixaban and dabigatran could be considered cost effective. The cost effectiveness of the new oral anticoagulants is largely dependent on the setting and quality of local anticoagulant care facilities.

Beliefs about medicines in Dutch acenocoumarol and phenprocoumon users.

AIMS: Adherence to the generally complex regimen of coumarin derivatives is vital in order to keep patients in the adequate International Normalized Ratio range. Patients' beliefs about medicines are associated with the level of therapy adherence. Our first aim was to assess beliefs about coumarins. Secondly, we compared the beliefs about coumarins with the beliefs about other cardiovascular drugs. METHODS: The Beliefs about Medicines Questionnaire was used to assess medication beliefs. The questionnaire was completed by new users of coumarins indicated for venous thromboembolism or atrial fibrillation. A necessity score and a concerns score were calculated for all patients. The analyses were repeated for users of antihypertensive drugs or statins (not using coumarins). RESULTS: Three hundred and twenty patients were included in the analysis of the beliefs about coumarins. The mean necessity score was 15.3, the concerns score 12.3 and the necessity-concerns differential 3.0. Patients with venous thromboembolism (n = 71) had higher necessity scores than patients with atrial fibrillation (n = 249; 16.8 vs. 14.9, P < 0.001). The mean necessity score in 493 users of other cardiovascular drugs was 16.1, the concerns score 13.5 and the necessity-concerns differential 2.6. The necessity score was higher in chronic cardiovascular drug users (n = 192) than in new users (n = 301; 17.9 vs. 14.9, P < 0.001). CONCLUSIONS: Coumarin users score higher on the necessity scale than on the concerns scale, which is also the case in users of other cardiovascular drugs. Patients with atrial fibrillation have a less positive attitude towards these drugs than patients with venous thromboembolism, and could therefore benefit more from specific attention.

Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon.

Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose-response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials.

A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon.

BACKGROUND: Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy. METHODS: We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks. RESULTS: A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events. CONCLUSIONS: Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy. (Funded by the European Commission Seventh Framework Programme and others; EU-PACT ClinicalTrials.gov numbers, NCT01119261 and NCT01119274.).

Cost-effectiveness of pharmacogenetic-guided dosing of phenprocoumon in atrial fibrillation.

AIM: To investigate the cost-effectiveness of pharmacogenetic-guided phenprocoumon dosing versus standard anticoagulation care in Dutch patients with atrial fibrillation. MATERIALS & METHODS: Using a decision-analytic Markov model, cost-effectiveness of pharmacogenetic-guided therapy versus standard care was estimated. RESULTS: Compared with standard care, the pharmacogenetic-guided dosing strategy increased quality-adjusted life-years (QALYs) only very slightly and increased costs by €15. The incremental cost-effectiveness ratio was €2658 per QALY gained. In sensitivity analyses, the cost of genotyping had the largest influence on the cost-effectiveness ratio. In a probabilistic sensitivity analysis, the incremental costs of genotype-guided dosing were less than €20,000 per QALY gained in 75.6% of the simulations. CONCLUSION: Pharmacogenetic-guided dosing of phenprocoumon has the potential to increase health slightly and may be able to achieve this in a cost-effective way. Owing to the many uncertainties it is too early to conclude whether or not patients starting phenprocoumon should be genotyped.

Evaluation of the effect of genetic variations in GATA-4 on the phenprocoumon and acenocoumarol maintenance dose.

AIM: To investigate whether the phenprocoumon and acenocoumarol maintenance doses are influenced by genetic variations in GATA-4, a transcription factor of CYP2C9. PATIENTS & METHODS: The influence of seven GATA-4 SNPs on the coumarin maintenance dose was investigated by performing an analysis of variance trend analysis, stratified for CYP2C9 genotypes. Results of the best-explaining SNP were validated in the Rotterdam Study cohort. RESULTS: The largest dose differences were found for rs3735814 in patients using acenocoumarol and having the common allele for CYP2C9. The mean dosages decreased from 2.92 mg/day for the patients having the GATA-4 common alleles to 2.65 mg/day for the patients carrying one GATA-4 variant allele and to 2.37 mg/day for patients carrying two GATA-4 variant alleles (p = 0.004). Results could not be replicated in the validation cohort. For phenprocoumon, no significant effects were observed. CONCLUSION: Genetic variation in GATA-4 does not seem relevant for clinical implementation.

Evaluation of the effect of statin use on the acenocoumarol and phenprocoumon maintenance dose.

BACKGROUND: Statins and coumarins are prescribed in combination on a regular basis. Some case reports suggested that statins might affect the dose requirements of coumarins. The aim of the study was to investigate whether acenocoumarol and phenprocoumon maintenance doses are influenced by statin use. METHODS: The Pre-EU-PACT database was used, which contains information on 471 acenocoumarol and 624 phenprocoumon users. The influence of individual statins on the acenocoumarol and phenprocoumon maintenance dose was investigated by comparing unadjusted and adjusted mean differences of the maintenance dose between statin and non-statin users. RESULTS: Lower adjusted acenocoumarol dose requirements were observed for patients using atorvastatin, simvastatin, pravastatin, and rosuvastatin. These patients had a reduction in adjusted mean acenocoumarol maintenance dose of 0.11, 0.29, 0.38, and 0.69 mg/day, respectively, compared with a mean adjusted dose of 2.60 mg/day for the patients not using a statin. There was no significant effect of statin use on unadjusted and adjusted phenprocoumon maintenance dose (p=0.23 and p=0.35, respectively). CONCLUSIONS: Mean acenocoumarol maintenance dosages were decreased when acenocoumarol is co-administered with the different statins. Statin use does not affect phenprocoumon maintenance doses significantly.

Cost-effectiveness of pharmacogenetics in anticoagulation: international differences in healthcare systems and costs.

Genotyping patients for CYP2C9 and VKORC1 polymorphisms can improve the accuracy of dosing during the initiation of anticoagulation with vitamin K antagonists (coumarin derivatives). The anticipated degree of improvement in the safety of anticoagulation with coumarins through genotyping may vary depending on the quality of patient care, which varies both with and among countries. The management and the cost of anticoagulant care can therefore influence the cost-effectiveness of genotyping within any given country. In this article, we provide an overview of the cost-effectiveness of pharmacogenetics-guided dosing of coumarin derivatives. We describe the organization of anticoagulant care in the UK, Sweden, The Netherlands, Greece, Germany and Austria, where a genotype-guided dosing algorithm is currently being investigated as part of the EU-PACT trial. We also explore the costs of anticoagulant care for the treatment of atrial fibrillation in these countries.