Cost-effectiveness analysis of pharmacogenetic-guided warfarin dosing in Thailand.

INTRODUCTION: Pharmacogenetic (PGx) test is a useful tool for guiding physician on an initiation of an optimal warfarin dose. To implement of such strategy, the evidence on the economic value is needed. This study aimed to determine the cost-effectiveness of PGx-guided warfarin dosing compared with usual care (UC). METHODS: A decision analytic model was used to compare projected lifetime costs and quality-adjusted life years (QALYs) accrued to warfarin users through PGx or UC for a hypothetical cohort of 1,000 patients. The model was populated with relevant information from systematic review, and electronic hospital-database. Incremental cost-effectiveness ratios (ICERs) were calculated based on healthcare system and societal perspectives. All costs were presented at year 2013. A series of sensitivity analyses were performed to determine the robustness of the findings. RESULTS: From healthcare system perspective, PGx increases QALY by 0.002 and cost by 2,959 THB (99 USD) compared with UC. Thus, the ICER is 1,477,042 THB (49,234 USD) per QALY gained. From societal perspective, PGx results in 0.002 QALY gained, and increases costs by 2,953 THB (98 USD) compared with UC (ICER 1,473,852 THB [49,128 USD] per QALY gained). Results are sensitive to the risk ratio (RR) of major bleeding in VKORC1 variant, the efficacy of PGx-guided dosing, and the cost of PGx test. CONCLUSION: Our finding suggests that PGx-guided warfarin dosing is unlikely to be a cost-effective intervention in Thailand. This evidence assists policy makers and clinicians in efficiently allocating scarce resources.

Using pharmacogenetics knowledge to increase accuracy of alerts for adverse drug events.

Adverse drug event (ADE) has significant implications on patient safety and is recognized as a major cause of fatalities and hospital expenses. Although some medical systems today can help reduce the number of ADE occurrences, these primarily take into account clinical factors-even though recent studies show the significance of genetic profiles in ADE detection. Incorporating pharmacogenetics knowledge and data from genetic test results into these systems can improve the accuracy of preliminary alerts about potential ADEs. However, pharmacogenetics knowledge is unstructured, making it inappropriate for use in a system that involves automatic processing. We propose a methodology that can help incorporate the pharmacogenetics knowledge. Specifically, we show how pharmacogenetics knowledge can be expressed in a medical system and used together with the patient genetic data to provide alerts about ADEs at the point of care.

Patient-specific decision-making for warfarin therapy in nonvalvular atrial fibrillation: how will screening with genetics and imaging help?

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) accounts for a majority of long-term morbidity and mortality associated with bleeding while on warfarin. Both ICH and warfarin-related ICH appear to have a genetic component. Furthermore, advanced neuroimaging using MRI can now identify individuals at increased risk of ICH. We explore whether screening strategies that include genetic profiling and neuroimaging might improve the safety of chronic anticoagulation for atrial fibrillation by identifying individuals from whom warfarin should be withheld. METHODS: We used a Markov state transition decision model. Effectiveness was measured in quality-adjusted life-years. Data sources included the English language literature using MEDLINE searches and bibliographies from selected articles along with empirical data from our institutions. The base case was a 69-year-old man with newly diagnosed nonvalvular atrial fibrillation. RESULTS: For patients at average risk for thromboembolic events and known to possess a hypothetical genetic profile increasing risk for warfarin ICH, anticoagulation remains the preferred strategy until the relative hazard of ICH exceeds 23.8. Genetic profiling would be favored for patients at low risk of thromboembolism (1.5% per year) if the hypothetical gene variant(s) conferred a relative risk of ICH >4.1. Screening strategies in which patients underwent genotyping and MRI before anticoagulation did not improve aggregate patient outcomes unless the predictive power of MRI exceeded current best guess estimates and patients were at low to moderate risk of thromboembolism. CONCLUSIONS: Currently identified genetic markers of bleeding risk do not confer a risk of ICH sufficiently high to warrant routine genetic testing for patients at average risk of thromboembolism. Even if patients undergo screening with MRI as well as genotyping, currently available data on the role of MRI on risk of ICH and warfarin ICH do not support use of these tests for withholding anticoagulation in patients with atrial fibrillation.

Cost-effectiveness of screening and extended anticoagulation for carriers of both factor V Leiden and prothrombin G20210A.

Carriers of a double thrombophilic mutation (factor V Leiden and prothrombin G20210A) are at high risk of a recurrent venous thromboembolism (VTE), and may benefit from a longer course of secondary prophylaxis. We examined the costs and health benefits of screening for both the mutations, provided that double heterozygotes undergo 2 years of anticoagulation as compared to the standard 6 months. We thus pooled the available evidence and calculated that the OR for recurrence in double heterozygotes was 5.9 (95% CI 2.65-13.20). A Markov model tracked patients' health lifelong, and calculated that prolonged prophylaxis saved 26 quality-adjusted days of life and $410 per double heterozygote treated. Screening all the patients with venous thromboembolism thus provided one additional day of life at the cost of 13624 $/QALY (95% CI 12 965-22 889). Screening was not cost-effective in those cohorts with a low prevalence of the mutations, a high bleeding risk or in those where prophylaxis prevented <65% of recurrences. Screening for factor V Leiden and prothrombin G20210A, with prolonged prophylaxis of double carriers, is cost-effective in most patients with VTE.

Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment.

The inherited thrombophilias--deficiencies of protein C, protein S, and antithrombin III--and the prothrombotic polymorphisms factor V G1691A and factor II G20210A predispose patients toward venous thromboembolism (VTE). The aim of this study was to determine the prevalence of single and combined prothrombotic factors in patients with idiopathic VTE and to estimate the associated risks. The study group consisted of 162 patients referred for work-up of thrombophilia after documented VTE. The controls were 336 consecutively admitted patients. In all subjects factor V G1691A, factor II G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T were analyzed by specific polymerase chain reactions and restriction enzymes. Activities of antithrombin III and protein C, free protein S antigen, and lupus anticoagulant were determined in a subset of 109 patients who were not receiving oral anticoagulants. The prevalences of heterozygotes and homozygotes for factor V G1691A and factor II G20210A among patients and controls were 40.1% versus 3.9% and 18.5% versus 5.4%, respectively (P=0.0001). The prevalence of homozygotes for MTHFR C677T in patients was 22.8% and in controls, 14.3% (P=0.025). Heterozygous and homozygous factor V G1691A, factor II G20210A, and homozygous MTHFR C677T were found to be independent risk factors for VTE, with odds ratios of 16.3, 3.6, and 2.1, respectively. Two or more polymorphisms were detected in 27 of 162 patients (16.7%) and in 3 of 336 controls (0.9%). Logistic regression analysis disclosed odds ratios of 58.6 (confidence interval [CI], 22.1 to 155.2) for joint occurrence of factor V and factor II polymorphisms, of 35.0 (CI, 14.5 to 84.7) for factor V and MTHFR polymorphisms, and of 7.7 (CI, 3.0 to 19.6) for factor II and MTHFR polymorphisms. Among 109 patients in whom a complete thrombophilic work-up was performed, 74% had at least 1 underlying defect. These data indicate that in most patients referred for evaluation of thrombophilia due to idiopathic VTE, 1 or more underlying genetic predispositions were discernible. The presence of >1 of the prothrombotic polymorphisms was associated with a substantial risk of VTE.

Epidemiology of factor V Leiden: clinical implications.

Inherited resistance to activated protein C (APC) has been recently recognized as a novel cause underlying venous thrombophilia. In most cases APC resistance is due to a single point mutation in the factor V gene leading to a replacement of Arg506 with Gln (factor V Leiden). Factor V Leiden allele is present in about 5% of the Caucasian individuals (Europeans, Jews, Israeli Arabs, and Indians) and is virtually absent in Africans, Asians, and races with Asian ancestry such as Amerindians, Eskimos, and Polynesians; this suggests a single origin of the mutation, which has been proven by haplotype analysis. A low prevalence of the mutation (1%) was noticed in African-Americans for recent racial admixture. Factor V Leiden presents not a major role as risk factor for arterial thrombosis, while it is present in 18% of Caucasian patients with venous thrombosis. This high incidence prevalence mirrors the incidence in the corresponding general populations and can be even higher in some areas according to the ethnic background. Conversely, factor V Leiden is usually not found in non-Caucasian thrombotic patients; this could give reason of the lower incidence of venous thrombotic disease in Africa and Asia in comparison with Europe. Therefore, screening for factor V Leiden is suggested for all Caucasian individuals with previous venous thrombosis; inclusion criteria for the screening should not be stringent because clinical manifestations associated with the mutant genotype can be also mild or secondary to circumstantial risk factors or manifesting at advanced age. Factor V Leiden can act also as concurrent risk factor in individuals with deficiency of natural inhibitors or mild hyperhomocysteinemia. So far, screening for the mutation in individuals with no history of thrombosis is recommended only for relatives of proband patients identified as carriers; the available data do not justify indiscriminate screening before risk situations such as oral contraceptives intake, pregnancy, or high-risk surgery.

[Public health economic evaluation of screening for APC resistance (Leiden mutation) in new oral contraceptive users]. / Gesundheitsökonomische Evaluation des Screenings auf APC-Resistenz (Mutation Leiden) bei Neuanwenderinnen von Ovulationshemmern

BACKGROUND: Thromboembolic events in users of oral contraceptives rank among the most important complications with potential economic consequences. It is well known that a large part of thromboembolic complications correlates with hereditary thrombophilias. The relative high prevalence of the newly described resistance of activated protein C and an easy test for it rise up the question if general screening of new users of oral contraceptives is sensible of health economic view. METHOD: We conducted a cost-effectiveness analysis using decision analytic techniques, analysing the costs and outcomes in a hypothetical cohort of 10,000 women. RESULT AND CONCLUSION: From a third party payer perspective we estimate that screening for APC resistance by new users of oral contraceptives is more cost-effective than many other primary preventive methods. The cost per life-year gained of testing for APC resistance were in the order of DM 1544,--including direct medical cost only. From perspective of sickness insurance fund as cost unit we estimate that screening for APC resistance by new users of oral contraceptives is more cost-effective than many other primary preventive methods.