ORIGINALES
Cost-effectiveness analysis of apixaban compared to low-molecular-weight heparins and vitamin k antagonists for treatment and secondary prevention of venous thromboembolism
Coste-efectividad de apixaban versus heparinas y antagonistas de la vitamina k para el tratamiento y la prevención secundaria del tromboembolismo venoso
Cost-effectiveness analysis of apixaban compared to low-molecular-weight heparins and vitamin k antagonists for treatment and secondary prevention of venous thromboembolism
Farmacia Hospitalaria, vol. 40, no. 3, pp. 187-208, 2016
Sociedad Española de Farmacia Hospitalaria
This work is licensed under Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International.
Received: 25 January 2016
Accepted: 12 March 2016
Abstract:
Objective: Cost-effectiveness analysis of a 6-month treatment of apixaban (10 mg/12h, first 7 days; 5 mg/12h afterwards) for the treatment of the first event of venous thromboembolism (VTE) and prevention of recurrences, versus low-molecular-wei- ght heparins/vitamin K antagonists treatment (LMWH/VKA). Material and methods: A lifetime Markov model with 13 heal- th states was used for describing the course of the disease. Efficacy and safety data were obtained from AMPLIFY and AMPLIFY-EXT clinical trials; health outcomes were measured as life years gained (LYG) and quality-adjusted life years (QALY). The chosen perspective of this analysis has been the Spanish National Health System (NHS). Drugs, management of VTE and complications costs were obtained from several Spanish data sources (€, 2014). A 3% discount rate was applied to heal- th outcomes and costs. Univariate and probabilistic sensitivity analyses (SA) were performed in order to assess the robustness of the results.
Results: Apixaban was the most effective therapy with 7.182 LYG and 5.865 QALY, versus 7.160 LYG and 5.838 QALYs pawith LMWH/VKA. Furthermore, apixaban had a lower total cost (€13,374.70 vs €13,738.30). Probabilistic SA confirmed dominance of apixaban (led to better health outcomes with less associated costs) in 89% of the simulations.
Conclusions: Apixaban 5 mg/12h versus LMWH/VKA was an efficient therapeutic strategy for the treatment and prevention of recurrences of VTE from the NHS perspective.
Keywords: Anticoagulants, Apixaban, Cost-effectiveness, Deep veinthrombosis, Pulmonary embolism, Venous thromboembolism.
Resumen:
Objetivo: Analizar la relación coste-efectividad de 6 meses de tratamiento con apixaban (10 mg/12 h, 7 primeros días; 5 mg/12 h después) para el primer evento de tromboembolis- mo venoso (TEV) y prevención de recurrencias, frente a hepari- nas de bajo peso molecular/antagonistas de vitamina K (HBPM/ AVK).
Material y métodos: Se ha empleado un modelo de Markov con 13 estados de salud que describen la evolución de la enfermedad a lo largo de la vida de los pacientes. Los datos de eficacia y segu- ridad se han obtenido de los ensayos clínicos AMPLIFY y AMPLI- FY-EXT, calculándose los años de vida ganados (AVG) y los años de vida ajustados por calidad (AVAC) de las opciones terapéuticas evaluadas. En este análisis se adoptó la perspectiva del Sistema Nacional de Salud (SNS). El coste de la medicación, de las com- plicaciones y del manejo del TEV se obtuvo de distintas fuentes españolas (€, 2014). Se aplicó una tasa de descuento anual del 3% a costes y beneficios en salud. Se realizaron análisis de sensi- bilidad univariante y probabilístico (ASP) para evaluar la robustez de los resultados.
Resultados: Apixaban generó mejores resultados en salud con 7,182 AVG y 5,865 AVAC, frente a 7,160 AVG y 5,838 AVAC para HBPM/AVK, y con menor coste total (13.374,70 € versus 13.738,30 €). El ASP confirmó la dominancia de apixaban (produce mejores resultados con menores costes asociados) en el 89% de las simulaciones.
Conclusiones: Apixaban 5 mg/12 h versus HBPM/AVK fue una estrategia eficiente para el SNS en el tratamiento y prevención de recurrencias de TEV.
Palabras clave: Apixaban, Anticoagulante, Coste-efectividad, Embolia pulmonar, Tromboembolismo venoso, Trombosis venosa profunda.
Introduction
Venous Thromboembolism (VTE), which includes both Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), represents the third cause of cardiovascular death at a global level1. With approximately 60% of DVT and 40% of PE2,3, the total prevalence of VTE in Spain has been calculated in 0.11%4, with a progressive increase in cases, reaching a diagnosis rate of 154/100,000 inhabitants, including non-hospital diagnosis5.
Patients with VTE have a high risk of recurrences, which is higher during the first two years6, as well as of longterm complications such as Post-Thrombotic Syndrome (PTS) and Chronic Pulmonary Hypertension (CTEPH)7. VTE generates an important use of resources due to these complications and the recurrences which require hospitalization. The studies available have calculated the total cost associated with VTE in Spain in over 75.5 million euros, with an annual 8-9% increase, out of which 79.3% is assigned to hospital healthcare8.
The treatment for VTE is anticoagulation; other treatments such as thrombolysis or inferior vena cava filters are reserved for special situations7. Current treatment guidelines recommend parenteral anticoagulation during the acute phase, with low-molecular-weight heparins (LMWH) during the first 5,6,7,8,9,10 days, followed by oral anticoagulation during a minimum period of 3 months with Vitamin K antagonists (VKA), such as dabigatran or edoxaban, or otherwise initiating oral treatment with apixaban or rivaroxaban, not requiring any previous parenteral treatment9.
Apixaban is an oral, direct, highly selective Xa factor inhibitor; unlike VKA, it does not need continuous monitoring of the INR value to stay within the therapeutic range and, therefore, it does not require any dose adjustment10.
The efficacy of apixaban for VTE treatment and prevention of recurrences has been supported by the out- comes of a Phase-III clinical trial11, which demonstrated non-inferiority vs. LMWH/VKA.
Additionally to its efficacy assessment, it is interesting to develop other type of studies, with complementary information demonstrating that new therapies are cost-effective vs. other options available.
The objective of the present study was to conduct a cost-effectiveness analysis of apixaban versus LMWH/ VKA for treatment of the first VTE event, and prevention of the recurrences.
Methods
The costs and health outcomes of the therapeutic options were estimated through an analytic model, in a cohort of Spanish patients who required anticoagulant treatment for a first VTE event and its recurrences.
Model Structure
The cost-effectiveness analysis was conducted through a Markov Model which simulates the evolution of pa tients with an acute VTE episode. This technique, widely used for the economic evaluation of medications12,13, represents the natural history of the disease, through the definition of selective health states which show the potential events and situations that a patient can experience. The structure has been based on models accepted by the National Institute for Health and Care Excellence for this condition14,15,16, and was validated by a board of national experts (2 Internal Medicine Specialists and one Hospital Pharmacist). Figure 1 shows the diagram of the model with 13 health states, representative of the clinical events derived of the evolution of the condition or its treatment, and the potential transitions between them. Patients are initially placed in the “first PE or DVT event” health states, and transitions are conducted in 3-month cycles.
Treatment options
The assessed therapies included the combined treatment with LMWH/VKA, represented by enoxaparin and acenocoumarol, vs. apixaban. The dosing schedules considered were enoxaparin 1 mg/kg twice a day and VKA 6 mg/day on the 6 first days, and VKA 3 mg/day until treatment completion. Treatment with apixaban included 10 mg twice a day on the 7 first days, and 5 mg twice a day until completing 6 months, which was the total duration of treatment planned for both arms. The dosing regimens and duration of treatments were those used in the clinical trials of reference. For recurrent events, the treatment initially administered was repeated, except in the case of initial treatment discontinuation before completing the 6 months, where patients were always treated with LMWH/VKA.
Figure 1.
Markov Model.
Perspective, discount rate, and time horizon
This analysis was conducted from the perspective of the Spanish National Healthcare System (NHS), applying a 3% annual discount rate to costs and health outcomes17. The time horizon of the analysis was lifetime.
Health outcomes
The model considers the risk of developing the following clinical events: recurrent VTE and VTE-related death, major bleeding, clinically relevant non-major bleeding (CRNM), PTS and CTEPH (Table 1). In each cycle, each patient could only present one event.
The risk of developing some event was divided into 2 periods: one initial acute phase of 6 months (sub-divided into 0-3 and 3-6 months), which shows the outcomes observed in the direct comparison study between the alternative options (AMPLIFY study)11 and a subsequent period until reaching the time horizon of the analysis, the entire life of the patient. The risk of suffering an event after permanent treatment discontinuation (by withdrawal or completing treatment) was obtained from literature18,19 and from the extension study arm (AMPLIFY-EXT), where placebo was used as comparator20. The frequency of CTEPH (1,25%)21 and the prevalence of PTS (8.1%)22, which was considered constant, were obtained from scientific literature.
The anticoagulant treatment received had no impact on the nature of fatal haemorrhages, considering that 13- 46% of all major bleedings were fatal; and 13.97% of those non-fatal were intracranial23. Besides, after 18 months from the embolic event, an incremental risk factor of bleeding was applied of 0.197 per decade of life, because age is an additional risk factor for bleeding24. Regarding discontinuation due to hemorrhagic events, according to data from a secondary analysis of the AMPLIFY study validated by the board of experts, a 2-day discontinuation was considered in CRNM bleeding, and permanent in case of intracranial haemorrhages. For non-intracranial major bleeding 47.27% of patients discontinued treatment during 14 days, while the rest discontinued permanently.
Measurement of health outcomes
The efficacy of alternative treatments determined the development of clinical events and, consequently, the life expectancy of patients. Efficiency was estimated considering total costs and health outcomes in terms of life years gained (LYG), which were subsequently adjusted with the relevant utility values to be expressed as quality-adjusted life years (QALY), accumulated at the end of the simulation. The incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) between the assessed therapies (apixaban vs. LMWH/VKA) was calculated with the following formulas:
Quality of life
In economic evaluations, the health related quality of life is included through the calculation of QALY, which is derived from the adjustment of survival in LYG, with a utility value which represents the subjective preference of patients for a specific health state.
The model considered different utilities according to the different health states, A baseline utility of 0.82525 was accepted for patients with VTE without a previous history of complications. The development of intracranial haemorrhage or CTEPH was associated with utilities of 0.33026 and 0.65027, respectively.
Decrements of utilities associated with clinical events and bleedings were taken into account, as well as those associated with the way of administration of the anticoagulant treatment, with a higher impact of the parenteral way in the final utility value (Table 1)26,28,29,30,31,32.
Resources and costs
In line with the analysis perspective, only direct healthcare costs were included (pharmaceutical costs, administration, INR monitoring, and management of VTE and its complications). Non-healthcare or indirect costs were not included. The cost of pharmaceutical treatments was calculated by retail price33, applying the current deductions as relevant34. The board of experts provided the identification and calculation of the necessary resources (medication, number of consultations required, diagnostic tests, etc.) for treatment monitoring and management of the disease and its complications. Unit costs (Table 2) were obtained from scientific literature and a national database of healthcare costs; in those cases where necessary, the variation of the index of consumer prices until the year of this analysis was implemented35,36,37,38. All costs included in the model were expressed in 2014 euros.
Sensitivity analysis
One-way deterministic sensitivity analyses (DSA) as well as probabilistic (PSA) were conducted, in order to assess the impact of certain parameters on the results. In the univariate sensitivity analysis, the following individual modifications were conducted: treatment duration (3 months, 12 months, and lifetime), time horizon (1, 5 and 10 years) and discount rate (0-5%). The PSA involved the simultaneous variation (2,000 Montecarlo simulations) of all parameters considered relevant according to a distribution previously assigned and adjusted to the type of variability presented. The distribution functions applied were: beta (events and utility rates), lognormal (relative costs and risks), gamma (event rates and costs), and Dirichlet (distribution of recurrent VTE according to
* Discontinuation regardless of the clinical events included in the model.** Determined by a board of experts.AR: Absolute Risk; CRNM: clinically relevant non-major; DVT: Deep Vein Thrombosis; IC: intracranial; LMWH: Low Molecular Weight Heparins;PE: Pulmonary Embolism; PTS: Post-thrombotic Syndrome; RR: Relative Risk; VKA: Vitamin K antagonists; VTE: Venous Thromboembolism.
percentage of death associated with VTE, percentage of non-fatal PE and DVT). The parameters for distributions were calculated with the standard error and confidence intervals for each parameter.
* The number of INR tests and visits was reduced by 70% from the second quarter, both in Primary Care and at hospital level.CRNM: Clinically relevant non-major; CTEPH: Chronic Thromboembolic Pulmonary Hypertension; DVT: Deep Vein Thrombosis; EC: extracranial;IC: intracranial; IC: intracranial; INR: International Normalized Ratio; LMWH: Low Molecular Weight Heparins; PE: Pulmonary Embolism; PTS: Post-thromboticSyndrome; RP-VAT: retail price + VAT; VKA: Vitamin K Antagonists; VTE: Venous Thromboembolism
Results
The results obtained for a cohort of 1,000 patients and a lifetime horizon revealed that VTE patients treated with apixaban experienced a lower number of recurrent embolic events, major bleedings and CRNM bleeding than those treated with LMWH/VKA. Table 3 shows the number of events, the LYG and QALY, and the costs associated with the anticoagulant therapy and management of clinical events.
In terms of survival, apixaban provided 7.182 LYG versus 7.160 LYG achieved with LMWH/VKA. Considering the utility values, the average QALY obtained with apixaban was 5.865, versus 5.838 in patients with LMWH/VKA. The total cost was €13,374.70/patient with apixaban and €13,738.30 with LMWH/VKA. The cost items with the highest differences between the therapeutic options were those associated with anticoagulant treatment (drug cost, administration and monitoring), major bleeding and CRNM bleeding. Treatment with apixaban led to a reduction of €363.6/patient, compared with LMWH/VKA, with 0.022 LYG and 0.027 QALY gained.
Considering the number of events occurred, LYG and QALY and the costs, it is observed that treatment with apixaban presents higher efficacy in the reduction of recurrent VTE events, bleedings and haemorrhages, with an increase in survival, as well as savings in costs of patient management.
The analysis demonstrated that treatment with apixaban was a dominant treatment option (lower cost and better health outcomes) relative to the use of LMWH/ VKA.
Apixaban appeared as dominant treatment vs. LMWH/ VKA in all DSA (Table 4), except in the scenario with a lifetime treatment duration, where the total cost of treatment with apixaban was higher than with LMWH/ VKA, and could be considered a cost-effective option, because the ICUR (€4,751 / QALY) was lower than the threshold of willingness to pay more frequently used as reference in Spain (€30,000 / additional QALY) 39. Apixaban was a dominant strategy vs. LMWH/ VKA in 89% of the PSA simulations (Figure 2).
CRNM: Clinically relevant non-major; CTEPH: Chronic Thromboembolic Pulmonary Hypertension; EC: extracranial; IC: intracranial;INR: International Normalized Ratio; LMWH: Low Molecular Weight Heparins; LYG: Life Years Gained; PE: Pulmonary Embolism;PTS: Post-Thrombotic Syndrome; QALY: Quality-adjusted life years; VKA: Vitamin K Antagonists; VTE: Venous Thromboembolism.
Discussion
VTE represents a major public health problem, which affects many millions of people in the world every year. The approximate cost of preventing or treating VTE is 1,300 million dollars in the Western countries; and in Spain, specifically, the cost of hospitalization for PE can reach 20 million euros per year6. Besides, those patients who survive can present chronic episodes that require hospitalization and additional treatments, and many individuals will suffer a reduction in their working ability
LMWH: Low Molecular Weight Heparins; LYG: Life Years Gained; QALY: Quality-adjusted Life Years; VKA: Vitamin K Antagonists.
(less working hours, frequent sick leaves, reduction in productivity, etc.), which increases the clinical and economic impact of VTE.
There is no doubt that standard therapies with VKA are effective, though they entail certain drawbacks inherent to their mechanism of action which can affect the quality of life of patients, such as the potential interactions with drugs and food, and the need for continuous INR monitoring to conduct dose adjustments in order to guarantee good patient control. The existence of poorly-controlled patients is associated with an increase in
Figure 2.
Cost-effectiveness plane of apixaban vs. LMWH/VKA
the risk of complications and in the cost that the NHS must assign for its management, and this shows that there is a real need to develop therapies which not only are more effective, but also offer benefits in terms of safety and quality of life.
The inclusion of new treatment options will frequent- ly represent an increase in pharmaceutical costs, which can be compensated or even lead to savings in the total costs by a lower use of resources for patient management. The new direct-acting oral anticoagulants, such as apixaban, will avoid, for example, the costs associated to INR monitoring required by VKA.
The results of this analysis establish a higher effecti- veness of treatment with apixaban due to a reduction in the number of events, which entails improvements in survival (an increase in LYG and QALY), and also represents cost savings of €363.60/patient, with apixaban as a dominant alternative option vs. LMWH/ VKA. Dominant treatment options are those that offer higher effectiveness and achieve a reduction in total costs.
Apixaban was dominant in the base case, and in almost all the alternative scenarios. When considering a lifetime treatment, there was an additional incremental cost per and QALY gained of €7,179 and €4,751, and apixaban appear to be a cost-effective option vs. LMWH/ VKA based on the cost-effectiveness thresholds presented in scientific literature (€30,000 to €45,000 / QALY)39,40.
Currently, there is no published economic evaluation in our country which compares apixaban versus LMWH/ VKA in this indication. This same model has been used for the evaluation of the efficiency of apixaban in other settings such as the United Kingdom41, which established a lifetime cost-effectiveness analysis of treatment for VTE and prevention of recurrences with apixaban vs. LMWH/ VKA, and calculated an ICER of £10,820 QALY gained, which was also considered a cost-effective option.
The present analysis has some potential limitations. The theoretical nature of any modelling might not be an accurate representation of daily clinical practice. The validity of the analysis models is determined by the quality of the data they are based upon. In this case, the source used to include efficacy in the model was the pivotal clinical trials with apixaban (AMPLIFY and AMPLIFY EXT)11,20. The use of blinded and randomized clinical trial data can be questionable, due to the rigorous inclusion criteria, and it is recommended to use prospective studies conducted in situation of daily clinical practice whenever available (real world data). The utilities used here were obtained from literature, because the clinical trials conducted with apixaban for this indication did not include the assessment of quality of life through questionnaires that provided utility values that could be used for this economic evaluation. Data from United Kingdom patients were used, because no specific values for the Spanish population were found. These utilities were validated by the board of experts as representative of patients in Spain, confirming that the utility values obtained through the EuroQol-5D questionnaire show no differences among the general population from different European countries42.
Another potential limitation was the exclusion from the model of the risk of recurrent VTE after intracranial haemorrhage and after a first relapse. However, the inclusion of these scenarios would translate into a higher reduction of events for patients on apixaban, due to the lower risk with this alternative option and, therefore, more favourable outcomes for this treatment strategy vs. LMWH/ VKA.
The results of this evaluation demonstrate that apixaban is a highly efficient option for the treatment of VTE, and represents a dominant alternative option (better health outcomes with a lower cost) vs. treatment with LMWH/ VKA; therefore, it should be the treatment option of choice for patients with VTE.
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Additional information
Contribution to scientific literature: What is known about this subject?. Venous Thromboembolism can be considered a relevant condition from the perspective of the healthcare system, because it has been established as the third cause of cardiovascular death at global level. There are currently several treatment options available in the market; the group of new oral anticoagulants are the ones offering the highest number of advantages compared with the rest, because they involve less anticoagulation monitoring in patients and, at the same time, they offer a more favourable safety profile.
What is the contribution of this study to scientificliterature?: This cost-effectiveness analysis is the first one conductedin our country in order to assess the costs andhealth outcomes associated with treatment with apixabanvs. low molecular weight heparins and vitamin Kantagonists, for treatment of a first event of venousthromboembolism, and prevention of recurrences. Theinformation and results of this study can be helpful fordecision making by the different stakeholders involved.
Conflicto de intereses: This study was funded by Bristol-Myers Squibb and Pfizer. Isabel Elías, Itziar Oyagüez and Fernando de Andrés are conducting their professional activity in PORIB, a consultancy company specialized in the economic eva- luation of health technologies, which has received finan- cial support by Bristol-Myers Squibb S.A.U. for preparing this project. Luis Antonio Álvarez-Sala and Fernando García-Bragado have received honoraries from PORIB, for their consultancy services associated with the deve- lopment of the present project. AN declares not having any conflict of interests. Paloma González is currently employed by Bristol-Myers Squibb S.A.U. Javier Soto is currently employed by Pfizer S.L.U. The authors hereby declare that this economic support has not interfered with the development of this project.