Oral anticoagulant therapy has been limited to one group of drugs, the vitamin K antagonists (VKA), for decades. Among them, the most widely used was and still is warfarin. Treatment with VKA is very effective, but has some limitations. A narrow therapeutic window together with variable pharmacokinetics, which is affected by both genetic factors as well as external factors, require frequent monitoring of coagulation and dose adjustments. The development of anticoagulant therapy was focused on the optimization of treatment with existing medicines on the one hand and on discovery of new medicines on the other. In recent years, new oral anticoagulants (NOACs) were introduced. They do not require frequent monitoring of the effect or dose adjustments and therefore simplify treatment management. Some technologies that should improve management with VKA, such as genotype-based dosing, were also developed. However, every new technology should demonstrate positive effects on health relative to the current practice and economic viability before implementation. Therefore, novelties in the process of deciding about their financing are subject to additional examination. In this context, health economic evaluation helps us to determine the most optimal use of available resources. Such an evaluation is especially worthwhile in the field of anticoagulant therapy, where nearly every innovation influences the organization of anticoagulation care. In this doctoral thesis we evaluated new technologies in the field of anticoagulant therapy.
Specifically, we assessed clinical outcomes, the quality of life impact and economic influences of the potential introduction of new oral anticoagulants and genotype dosing of warfarin. We further explored the impact of the quality of anticoagulation control as it determines the outcomes of warfarin treatment, which is the main treatment strategy in practice to which outcomes of new technologies are compared. Additionally, we examined the accumulation of evidence about the clinical benefits of genotype dosing of warfarin and their impact on the financial risk of decisions about its implementation in clinical practice. Moreover, we studied the importance of the organization of anticoagulant therapy to the integration of new technologies and also the impact of new technologies on the organization of anticoagulation care. The cost-effectiveness of new technologies was assessed with a computer model developed specifically for this purpose. The model simulates the anticoagulant therapy in patients with atrial fibrillation and records the long-term or life-long outcomes of different treatment strategies. We were also able to simulate treatment with warfarin at different levels of anticoagulation control. Cost-effectiveness was estimated by comparing expected life years, quality adjusted life years and costs among new technologies and standard of care. Effectiveness was based on clinical trials, while the costs considered were limited to the direct medical costs covered by national insurance. The base case analysis at an average level of anticoagulation control resulted in 7.2 quality adjusted life years (QALYs) for warfarin. Treatment with NOAC promises better clinical outcomes and a quality adjusted survival improvement of approximately 0.2 QALY. The total NOAC treatment costs were also higher, but the estimated incremental cost-effectiveness ratio (ICER) was below the limit of 25,000 EUR/QALY, which is considered as threshold ICER for medicines in Slovenia. This result confirms our hypothesis that treatments with NOACs are cost-effective alternatives to standard treatment with warfarin. The results were sensitive to anticoagulation control, which reflects the quality of management. The simulated outcomes of well-managed warfarin therapy were even higher than the simulated outcomes of alternative strategies. This finding confirms the hypothesis that the quality of work in anticoagulation clinics, which is reflected in anticoagulation control, significantly affects the cost-effectiveness of NOACs. The results are also sensitive to clinical efficacy data, while monitoring costs have a minor impact. The model was further adapted to estimate the cost-effectiveness and financial risk of potential inclusion of genotype-guided dosing of warfarin into the healthcare system. Financial risk was determined at several time points, at which the available evidence about clinical efficacy was considered. The difference in financial risk was used as a value of clinical trials that were conducted between defined time points or in other words, as the monetary value of additional information about clinical efficacy that they represent to the potential payer. In a systematic review of published articles, we identified 9 randomized clinical trials that examined the benefits of genotype-guided dosing of warfarin. The cumulative meta-analysis of their findings revealed a relatively good estimation of anticipated benefits based on early trials. The estimated mean difference in the time in therapeutic range between test and control groups was 5.57 percentage points (95% CI: - 8.98 to 20.12) at the end of 2007 and 4.28 percentage points (95% CI: -0.49 to 9.05) at the end of 2013. In the interim period, several clinical trials were published with different conclusions, but the cumulative effect remained stable. However, the uncertainty surrounding estimated effect constantly decreased during this period. These findings also Zdravstveno ekonomsko vrednotenje antikoagulacijskega zdravljenja 7 reflected the estimated financial risk, on which additional research has had a minor effect. As a result, we were unable to completely confirm the hypothesis about the declining monetary value of information over time. In the initial period, the financial value of additional information declined, but afterward it did not change significantly, despite the volume of evidence that the clinical benefit increased. This is mainly due to the relatively accurate estimation of the effect size of genotyping in early clinical trials, as results of further trials agreed with this estimation. As mentioned before, the point estimate did not vary greatly, but the CI narrowed across all the years, suggesting more precise estimates with each new study. However, the observed decline in the price of genotyping, which is probably more acceptable to payers given the potential clinical benefits, has had a major impact on potential financial risk. As shown in this case, early clinical trials are important to provide rough estimate of the effect size so we can predict the financial risk of the potential introduction of new health technology. Within this thesis we also studied the importance of the organization of anticoagulant
therapy on the integration of new technologies as well as the impact of new technologies on the organization of anticoagulation care. For this purpose, we used a combination of qualitative and quantitative methods. Face-to-face interviews with key stakeholders—opinion leaders, roviders of anticoagulation services, responsible persons for managing anticoagulation clinics and representatives of public payers—provided us insight into the organization and evolvement of anticoagulation care. Delivered information was further explored by analysis of nationwide data on drug prescriptions and realization of health care services in Slovenia. It was revealed that systemic aspects of the organization of
anticoagulation care were taken into account in the reimbursement decision for NOACs. This was a key reason that drove the decision to introduce NOACs widely in Slovenian clinical practice, as the network was not big enough to be able to satisfy patient’s needs. As a consequence, it was expected that the burden of anticoagulation clinics would be reduced. However, this was not observed despite high penetration of NOACs in clinical practice. The main reason is probably the enormous expansion of the population treated; this population increased from 37,000 to 54,000 in the last 5 years. Additionally, patients treated with NOACs are still managed through specialized anticoagulation clinics. Key stakeholders are convinced that such organization of anticoagulation care provide high quality and effective treatment, including treatment with NOACs. On the other hand, as expressed by the payer, such an organization does not represent an additional financial burden, since the needs of the population remain similar. A revised organization for management of patients with NOACs would only result in a change of providers, but the financial burden for the national healthcare payer would be comparable, as the system of financing is similar. These findings partly confirm our hypothesis that the organization of specialized anticoagulation clinics significantly influences the budget impact of new strategies of anticoagulant therapy. The introduction of NOACs has had a huge impact on the total expenditure for anticoagulation care, which doubled in the first three years after introducing NOACs. At the same time, the specialized anticoagulation clinics and their core organization were not affected. However, other factors related to organization are also important, such as the significant increase in the number of patients in need of anticoagulant therapy.
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