Figures
Abstract
Background
Dabigatran was proven to have similar effect on the prevention of recurrence of venous thromboembolism (VTE) and a lower risk of bleeding compared to vitamin K antagonists (VKA). The aim of this study is to assess the cost-effectiveness (CE) of dabigatran for the treatment and secondary prevention in patients with VTE compared to VKAs in the Dutch setting.
Methods
Previously published Markov model was modified and updated to assess the CE of dabigatran and VKAs for the treatment and secondary prevention in patients with VTE from a societal perspective in the base-case analysis. The model was populated with efficacy and safety data from major dabigatran trials (i.e. RE-COVER, RECOVER II, RE-MEDY and RE-SONATE), Dutch specific costs, and utilities derived from dabigatran trials or other published literature. Univariate, probabilistic sensitivity and a number of scenario analyses evaluating various decision-analytic settings (e.g. the perspective of analysis, use of anticoagulants only for treatment or only for secondary prevention, or comparison to no treatment) were tested on the incremental cost-effectiveness ratio (ICER).
Results
In the base-case scenario, patients on dabigatran gained an additional 0.034 quality adjusted life year (QALY) while saving €1,598. Results of univariate sensitivity analysis were quite robust. The probability that dabigatran is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 98.1%. From the perspective of healthcare provider, extended anticoagulation with dabigatran compared to VKAs was estimated at €2,158 per QALY gained. The ICER for anticoagulation versus no treatment in patients with equipoise risk of recurrent VTE was estimated at €33,379 per QALY gained. Other scenarios showed dabigatran was cost-saving.
Citation: Stevanović J, de Jong LA, Kappelhoff BS, Dvortsin EP, Voorhaar M, Postma MJ (2016) Dabigatran for the Treatment and Secondary Prevention of Venous Thromboembolism; A Cost-Effectiveness Analysis for the Netherlands. PLoS ONE 11(10): e0163550. https://doi.org/10.1371/journal.pone.0163550
Editor: Hua Zhou, Macau University of Science and Technology, MACAO
Received: October 7, 2015; Accepted: September 11, 2016; Published: October 24, 2016
Copyright: © 2016 Stevanović et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This study was funded by Boehringer Ingelheim NL. The funder provided support in the form of salaries for authors BSK and MV, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
Competing interests: We have the following interests. This study was funded by Boehringer Ingelheim, the employer of Kappelhoff B. S. and Voorhaar M. Boehringer Ingelheim manufactures Pradaxa® (Dabigatran). Prof. Maarten J. Postma has received grants and honoraria from Pfizer, Boehringer Ingelheim and Bayer and various pharmaceutical companies not producing or marketing NOACs. There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.
Introduction
Venous thromboembolism (VTE) can manifest as deep vein thrombosis (DVT) and/or pulmonary embolism (PE) [1]. The health burden associated with VTE is mostly determined with the risk of a fatal PE and risk of considerable long-term morbidity associated with the development of post thrombotic syndrome (PTS) or chronic thromboembolic pulmonary hypertension (CTEPH). Moreover, recurrent DVT (rDVT) occurs in approximately 7% of patients per year and reaches to about one quarter to one third of patients within 8 years [2,3]. The health related quality of life (HRQoL) in VTE patients is also affected. For example, a Dutch study found distinctly lower HRQoL scores measured with SF-36 questionnaires in patients with PE compared to the general population on the subscales: social functioning, emotional, general health, physical and vitality [4].
In the Netherlands, the DVT incidence was estimated at approximately 16,000 to 20,000 cases per year [5]. Though, the overall incidence of PE in the Netherlands is unknown, a survey among Dutch pulmonologists/internists indicated an incidence of suspected PE at 2.6 per 1,000 patients per year [2], while in general practice, 0.2 PEs per 1,000 patients were reported [6].
Both national and international guidelines recommend anticoagulation therapy as an effective measure to prevent thrombus propagation and recurrence in VTE patients [1,2]. For the initial treatment phase of VTE, low-molecular-weight heparins (LMWHs) for at least 5 days combined with subsequent administration of vitamin K antagonists (VKAs; e.g. warfarin, acenocoumarol or phenprocoumon), or rivaroxaban are recommended. For the maintenance phase, the use of VKAs or rivaroxaban is recommended for at least three months [1,7]. The need to continue anticoagulation should be re-assessed in patients based on individual patients’ risk-benefit balance every three months as there is no strong nor clear differentiation between treatment and prevention phases [1,7].
VKAs present a highly effective anticoagulation treatment with low acquisition costs and conventional bleeding management. However, their use is limited by a narrow therapeutic range as defined by the international normalised ratio (INR) between 2.0 and 3.0 and several interactions with other drugs and food. To achieve the anticoagulant effect inside the required INR range, regular monitoring and dose-adjustment is required for treatment with VKAs. In the Dutch healthcare system, INR-monitoring is handled by thrombotic services or patient self-management. Though it is considered highly effective in the Netherlands, INR-monitoring of course directly affects expenditures from both healthcare provider and societal perspectives. In particular, next to the costs of material, labour, nurse visits, training and material for self-management, there are various out-of-the pocket expenses (for example travel costs of patients) and productivity loss costs associated with monitoring visits impacting the broader societal economic burden.
Recently, in the RE-COVER and RE-COVER II trials, dabigatran, a novel oral anticoagulant (NOAC) was shown to have similar effect on VTE recurrence and a lower risk of for clinically relevant non-major bleeding (CRNMB) and for any bleeding compared to VKA [8,9]. When administered for the extended treatment in patients with VTE who had completed at least three months of initial therapy, dabigatran was non-inferior in preventing rVTE events and showed a better safety profile than VKA (the RE-MEDY trial) in high risk patients (increased risk for rVTE), but a significantly better efficacy in preventing rVTE and higher risk of bleedings than placebo (the RE-SONATE trial) [10].
Importantly, both health and economic consequences associated with the use of dabigatran compared to VKAs need to be considered when choosing the optimal treatment strategy. A formal pharmacoeconomic comparison of the two anticoagulant treatments should be conducted to account for all the relevant health consequences such as likelihood of rVTE, bleedings, PTS, CTEPH, death and other adverse events, as well as all relevant cost parameters including the costs of drugs, administration, INR-monitoring, event-related costs and various indirect costs.
The aim of this study is to assess the cost-effectiveness (CE) of dabigatran for the treatment and secondary prevention in high risk patients of DVT and PE compared to VKAs for the Dutch situation.
Methods
Decision model
A previously published Markov model was modified and updated to assess the CE of dabigatran and VKAs for the treatment and secondary prevention of DVT and PE in the Dutch setting [11]. The health states included in the model were: index VTE, rVTE, major or clinically relevant bleeding (MCRB), CTEPH, PTS, other adverse events (i.e. myocardial infarction (MI), unstable angina (UA) and dyspepsia), off-treatment and death from other causes (Fig 1).
VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; r, recurrent; LMWH, low molecular weight heparin; CRNMB = clinically relevant non-major bleed event; ICH = intracranial haemorrhage; MB = major bleed; MI = myocardial infarction; CTEPH = chronic thromboembolic pulmonary hypertension; PTS = post thrombotic syndrome; UA, unstable angina; IHD, ischemic heart disease.
In the base-case, the use of dabigatran was compared to VKAs for up to 6 months of treatment followed by up to 18 months of secondary prevention in high risk patients. The flow of patients with an index VTE event through the Markov model is detailed elsewhere [11]. The proportion of high risk in patients with VKA or dabigatran were balanced via randomization in the study and kept the same in the model. Shortly, at the start of the simulation, a hypothetical cohort of 10,000 adult patients (mean age 54.7 years [8,9]) for whom at least 6 months of anticoagulant therapy was considered appropriate entered the model following an index VTE (i.e. index DVT or index PE) event and received initial treatment with LMWHs followed by either dabigatran or VKAs. The duration of treatment with LMWHs was assumed to be 5 days in the dabigatran treatment arm following the summaries of product characteristics (SCPs) for dabigatran, and 9 days in the VKAs arm in line with the RE-COVER trials. Patients in the index VTE state were exposed to the risk of rVTE, MCRB, CTEPH, PTS, other adverse events, treatment discontinuation and death from other causes. After the initial 6 months of treatment, patients who remained in the index health state were simulated to receive up to 18 months of anticoagulants for secondary prevention, reflecting patient profiles from the RE-MEDY trial [10].
rVTE could occur in any model cycle, however, the model was restricted to a maximum of two rVTEs [12]. Furthermore, a distinction was made between different forms of rVTE: fatal VTE, non-fatal PE, proximal DVT and distal DVT. After a first rVTE, patients from both treatment arms were assumed to stop the initial treatment and initiate or reinitiate a 6 months standard treatment course of LMWHs, followed by VKAs.
For patients experiencing a MCRB, a distinction was made between an intracranial haemorrhage (ICH), other major bleed (MB), and a CRNMB. We did not differentiate between high and low risk MCRB, as the clinical trial populations were balanced via randomization in terms of baseline bleeding risks. Regarding the VTE risk, we refer to the inclusion criteria for RECOVER, where planned treatment duration should be at least 6 months; that allows to assume that the same patient population can continue to be treated for a longer period [8,9]. Subsequently, the calibration of incidences was not applied, as low risk groups were tested in a separate scenario. If ICH occurred, in the model it could lead to permanent disability, death, or recovery. MBs were modelled to lead to death or recovery. Furthermore, it was assumed that patients can experience up to two major bleeds (ICH or MB) during the entire time they may spend on anticoagulation; one event could be experienced during treatment phase with study medication and one event during LMWHs/VKAs re-treatment [12]. CRNMB could occur at every model cycle while on anticoagulation [12]. After a MB or ICH, all patients were assumed to discontinue treatment altogether having no further risk of bleeding, but continuing to be exposed to a risk of rVTE. Other adverse events of anticoagulant therapy captured by the model are UA, MI and dyspepsia. Patients with a non-fatal MI or UA could suffer from chronic ischemic heart disease (IHD), or recover. Mortality after IHD was assumed to be part of the population mortality in the model. In the model, all patients who experienced a first or recurrent PE (rPE) were at risk to develop CTEPH, while those with an index or rDVT were at risk of PTS.
During treatment or secondary prevention phases, all patients could discontinue treatment prior to reaching the maximum planned duration of treatment due to reasons other than rVTE or ICH/MB. If discontinuation occurs, patients move to the off-treatment state where they continue to experience a risk of rVTE, but no further risk of bleeds. Finally, patients in any of the health states were at risk to die from other causes. Patient movement between health states was modeled using 1-month cycles until death.
The final outcome of the decision model is the incremental cost-effectiveness ratio (ICER) of dabigatran compared to VKAs. Quality-adjusted life-years (QALYs) and life-years (LYs) gained were estimated as a measure of effectiveness. All relevant costs reflect a societal perspective in the base-case analysis and are inflated, if necessary, to price year 2013 using the Dutch consumer price index [13]. Future costs and health effects were discounted by 4% and 1.5% annually after the first year, according to the Dutch guidelines for pharmacoeconomic research [14].
Transition probabilities
In the base-case, to estimate the transition probabilities between the health states in the model during the treatment and prevention phases, data were used from a published meta-analysis of the RE-COVER and RE-COVER II trials [8,9] and the RE-MEDY trial [10], respectively. This was in line with the previously published Markov model [11].
In particular, the baseline probabilities of rVTE and MCRB were calculated from the observed incidence in the VKA arm of the aforementioned trials. For the treatment phase, the incidences of rVTE and MCRB were log transformed with respect to time, to better reflect the occurrence pattern of these events in the trials. For the secondary prevention phase, the incidences were not varied with time. To calculate the probabilities of events while on dabigatran, the estimated treatment effect (hazard ratio (HR)) for each trial endpoint was applied to the risk in the VKA arm (Table 1).
CI, confidence interval; r VTE, recurrent venous thromboembolism; MCRB, major or clinically relevant bleeding; VKA, vitamin K antagonists; HR, hazard ratio; D, Dirichlet distribution applying to 2 or 3 linked probabilities with the parameter corresponding to the specific marginal Beta distribution in italics; DVT, deep vein thrombosis; PE, pulmonary embolism; CRNMB = clinically relevant non-major bleed event; ICH = intracranial haemorrhage; MB = major bleed; MI = myocardial infarction; UA, unstable angina; CTEPH = chronic thromboembolic pulmonary hypertension; PTS = post thrombotic syndrome.
Furthermore, the probabilities of having a fatal VTE, non-fatal PE, proximal DVT, or distal DVT, were based on the incidences of these events in the aforementioned trials, and they were modelled to be conditional on having a VTE event. Similarly, the probabilities of having an ICH, other MB, fatal MB (including ICH) or CRNMB were conditional on having a MCRB. The proportion of ICH leading to permanent disability was assumed to be 65.3% [15].
Beyond the duration of the anticoagulant treatment, the lifetime probability of rVTE was calculated from the assumed 10-year cumulative incidence of 39.9% [16], assuming a constant hazard. The risk of bleeding after treatment discontinuation was assumed at zero for simplification, as the risk of bleeding will be equal in both arms and will not impact incremental QALYs. Probabilities of MI, UA and dyspepsia were estimated from the dabigatran trials [8–10]. For the treatment followed by secondary prevention, probabilities of MI, fatal MI and UA were calculated as the sum of probabilities in the treatment and secondary prevention trials. Events were assumed to occur at a constant rate during the trial follow-up. For simplicity, events were assigned to occur at the midpoint (i.e., three months). Additionally, we assumed 14% of MIs and UAs would lead to IHD [17].
The rate for CTEPH for index PE was estimated at 3.8% for two years [18]. For patients experiencing non-fatal rPE events, the risk of CTEPH was applied monthly up to 2 years [18].
Published evidence suggests that mild PTS has little detrimental effect on HRQoL [6], therefore, the model included only severe PTS. For all patients in index DVT, the 5-year rate of PTS was estimated to be 8.1% at model start [19]. A monthly probability of PTS subsequent to non-fatal rDVT events was applied up to 5 years [19]. Finally, the probability of death due to other causes was obtained from Statistics Netherlands.
Utilities
Table 2 summarises the utilities used in the model. Patients were assigned baseline age- and gender-specific utilities derived from the general Dutch population [20]. These estimates formed the baseline from which the utility decrements associated with VTE, bleeding and other adverse events were subtracted.
CRNMB = clinically relevant non-major bleed event; DVT = deep vein thrombosis; ICH = intracranial haemorrhage; LMWH = low molecular-weight heparin; MB = major bleed; MI = myocardial infarction; PE = pulmonary embolism; CTEPH = chronic thromboembolic pulmonary hypertension; PTS = post thrombotic syndrome.
Utility decrements associated with index and rVTE, MB and CRNMB were based on a meta-analysis of EQ-5D data collected in the RE-COVER and RE-COVER II trials and applied in the model similarly to the previously published study [11].
Utility decrements following the occurrence of other adverse events (i.e. MI, UA, dyspepsia, disabled from ICH, CTEPH, and severe PTS) were derived from the published studies and applied additively for a specific time interval in the model [6,21–25].
Costs
In the base-case analysis, all costs were collected from a societal perspective, therefore, both direct (inside and outside healthcare) and indirect costs were included (Table 3). Direct costs inside healthcare included the costs related to: drugs, visits to general practitioner (GP), administration, INR-monitoring and event-related resource use. Costs of dabigatran (price per defined daily dose at 2x 150mg), VKAs and LMWHs were taken from the official Dutch price list (Z-index) [26]. Importantly, the price of dabigatran extracted from Z-index is established for other registered indications of dabigatran in the Netherlands (i.e. prevention of VTE in patients who have undergone elective total hip replacement surgery or total knee replacement surgery, and prevention of stroke and systemic embolism in non-valvular atrial fibrillation). Acenocoumarol and phenprocoumon are the only VKAs registered in the Netherlands, therefore, the cost of VKAs was estimated as a weighted average of the costs of those drugs based on their usage in the Netherlands (80%:20%, respectively) [27]. The cost of LMWHs was assumed as a weighted average cost of enoxaparin, dalteparin, tinzaparin and nadroparin [26]. All treatment alternatives were assumed to have a cost of one initial GP visit in the first month and one follow up visit in the 4th month of a treatment.
VKA, vitamin K antagonists; LMWH, low molecular weight heparins; INR, international normalised ratio; MCRB, major or clinically relevant bleeding; DVT, deep vein thrombosis; PE, pulmonary embolism; CRNMB = clinically relevant non-major bleed event; ICH = intracranial haemorrhage; MB = major bleed; MI = myocardial infarction; UA, unstable angina; CTEPH = chronic thromboembolic pulmonary hypertension; PTS = post thrombotic syndrome GP, general practitioner.
The cost of administration of LMWHs was estimated to reflect the costs of administration in hospital and at home. For patients receiving LMWHs in hospital, the costs of administration were adjusted for the percentage of patients and time they spent being hospitalized for DVT and for PE [28]. The costs of administration at home accounted for the costs of self-injection and costs for patients requiring a nurse visit for injection (Table 3)[28,29].
The costs of INR-monitoring reflected the costs of monitoring handled by thrombotic services and costs for patient self-management (Table 3). In the Netherlands, self-management is applied by 14.9% of patients on treatment with VKAs. Therefore, the costs of initial training for self-management and monthly follow up costs associated with the rental of equipment were applied for this patient population (Table 3). Resource use associated with INR-monitoring at thrombotic services (i.e. number of visits) was based on the annual medical reports from the Dutch thrombotic services [30][31]. In particular, in the first month of a treatment, the cost of INR-monitoring by thrombotic services reflected an average of 5.5 visits to thrombotic services. In follow up months (2nd until 6th month), the cost of 1.4 visits per month was assumed [30][31]. For the application of VKAs longer than 6 months (i.e. secondary prevention phase), the costs of INR-monitoring by thrombotic services reflected an average of 1.4 visits per month beyond the initial 6-month period [30,31]. Moreover, direct costs outside healthcare (i.e. travel costs) were attributed to the nurse visits for injection of LMWHs. Acute care costs associated with clinical events (e.g. DVT, PE, ICH, other MB, CRNMB, PTS, CTEPH, MI, UA, and dyspepsia) were adopted from previous costing studies conducted in the Netherlands. Patients surviving acute ICH, MI, PTS and CTEPH were assigned with long-term maintenance costs.
Indirect costs outside healthcare included: productivity loss costs, caregiver time costs for patients experiencing ICH and travel costs for the visits of patients to thrombotic services. A 2-hour productivity loss costs were assumed for all INR-monitoring visits to thrombotic services and all GP-related visits. Additionally, productivity loss costs associated with hospitalizations due to DVT (0.63 days), PE (7 days) and MI (5.6 days) were included. The number of productivity loss hours for each of the aforementioned hospitalizations was estimated in order to account for regular working hours (8 hours per day) was corrected for the weekends and the labour-time elasticity of production according to the friction costing method [14,32].
Sensitivity analyses
Univariate sensitivity analyses were performed to identify the key determinants of CE by varying parameters individually over the ranges derived from their 95% confidence intervals. Where confidence intervals and standard deviations of parameters were unavailable, the standard error was assumed to be 25% of the mean. The exceptions were made when varying discount rates which were varied between 0 and 5%, and the number of days on treatment with LMWHs which were varied between 5 and 9 days. The results were defined in terms of incremental cost per QALY and are presented diagrammatically in the form of a tornado diagram.
Additionally, a probabilistic sensitivity analysis (PSA) was performed to assess the robustness of the findings by performing 5000 simulations to generate ICERs in which event risks and HRs, costs and utilities were simultaneously varied randomly within their ranges. HRs of the even rates were sampled from a normal distribution on the log scale and other probabilities were sampled from a beta distribution. The related distribution of the type of recurrent event were sampled from a Dirichlet distribution. Costs were sampled from a gamma distribution. For utilities, a gamma distribution was used, except for utilities assigned to DVT and PE, for which a normal distribution was used. Results from the PSA were plotted on a CE plane.
Scenario analyses
To investigate the impact of applying dabigatran under different decision making settings seven scenario analyses were conducted. First scenario compared the use of dabigatran and VKAs for treatment and secondary prevention in high risk patients from the healthcare provider perspective. Second scenario compared the use of dabigatran to VKAs for up to 6 months of treatment only. Third scenario assessed the use of anticoagulants for up to 18 months of secondary prevention only (not considering the preceding treatment duration). In the fourth scenario, the use of dabigatran for up to 6 months of secondary prevention (not considering the preceding treatment duration) was compared to placebo. Here, study population simulated the profile of the patients in the RE-SONATE trial, i.e. low risk patients (i.e. patients for whom the need for secondary prevention is at equipoise [10]). Data from the RE-SONATE trial were the main sources used to estimate the transition probabilities between the health states in the model in this scenario. In the fifth scenario disutilities associated with VKA use were applied to the model. Furthermore, as an alternative source the costs of ICH as applied by Ten Cate-Hoek et al. was applied to the model (scenario 6), lacking however the detailing of separate cost figures for mild, moderate and severe ICH [32]. In the last scenario the transition probabilities of ICH were reduced to half of its base-case values.
All assumptions used in the model are summarized in Table 4.
Results
In the base-case, in a hypothetical cohort of 10,000 patients with a VTE event followed over their lifetime starting at age 54.7 years, dabigatran averted 720 MCRBs compared with VKAs but resulted in an additional 86 rVTEs, and 65 MIs (Table 5). A comparable number of PTS, CTEPH and UA was observed in both dabigatran and VKAs treatment arms. Dabigatran was associated with a projected discounted quality-adjusted life expectancy of 19.187 QALYs compared with 19.154 QALYs for patients receiving VKAs.
VKA, vitamin K antagonists; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; r, recurrent; LMWH, low molecular weight heparin; CRNMB = clinically relevant non-major bleed event; ICH = intracranial haemorrhage; MB = major bleed; MI = myocardial infarction; CTEPH = chronic thromboembolic pulmonary hypertension; PTS = post thrombotic syndrome; UA, unstable angina; INR, international normalised ratio.
Costs allocation across different categories indicated that costs associated with handling rVTE, bleeding and other adverse events were the major contributors to the total expenditures. In VKAs treatment arm, these costs were higher compared to dabigatran arm (€12,409 vs €11,074). Expenditures for event-related costs were followed by monitoring, GP visit, productivity losses and administration costs which were higher with VKAs compared to dabigatran (€3,512 vs. €1,140), and the total drug costs that were higher with dabigatran than VKAs (€1,550 vs. €298). Finally, accounting for all the aforementioned cost categories resulted in the total lifetime costs varied from €12,133 per person for VKAs to €10,209 per person for dabigatran at a discount rate of 4%. In total, savings of €1,924 and an additional 0.0339 discounted QALYs per patient where observed when applying dabigatran compared to VKAs (Table 6).
VKA, vitamin K antagonists; ICER, incremental cost-effectiveness ratio; QALY, quality adjusted life year; LY, life year.
Sensitivity analyses
The results of univariate sensitivity analyses for the top 15 parameters by the order of influence they have to the ICERs are presented in the form of a tornado diagram (Fig 2). Specifically, the ICER was mostly influenced by variations in the probability of VTE-related death, probability of MCRBs-related and probability of ICH. The results of 5,000 iterations in PSA are presented through an incremental CE plane in Fig 3. The probability that dabigatran is cost-effective at a willingness-to-pay (WTP) threshold of €20,000/QALY was 98.1%, and 87.2% when ICERs with negative quality of life were counted as not cost-effective. 87.2% of the simulations are located in the second quadrant of the CE plane, in which costs are negative and QALYs are positive. At a WTP threshold of €50,000/QALY dabigatran is cost-effective in 87.4% of the simulations (ICERs with negative QALYs included as not cost-effective).
Tornado diagram of ICERs from sensitivity analyses for dabigatran vs. vitamin-K antagonists, illustrating the impact of varying each of input parameters on the ICER while holding all the other model parameters fixed. Light grey bars show the influence of using the upper limit and dark grey bars that of the lower limit of the input parameters investigated. The solid vertical line represents the base case incremental costs per QALY for dabigatran compared to VKA. Horizontal bars indicate the range of incremental costs per QALY obtained by setting each variable to the values shown while holding all other values constant. ICER, incremental cost-effectiveness ratio; QALY, quality adjusted life year; VKA, vitamin K antagonists; VTE, venous thromboembolism; r, recurrent; ICH = intracranial haemorrhage; MBE = major bleeding event; HR, hazard ratio.
Scenario analyses
The results of the scenario analyses are presented in Table 6. In the scenario comparing dabigatran to VKAs for the treatment, and in the one comparing them for the secondary prevention in high-risk patients, dabigatran remained cost-saving. The scenario including the disutility associated with VKA treatment, as well as the last two scenarios concerning the costs and transition probabilities of ICH, also remained cost-saving. Comparing dabigatran to VKAs for treatment and secondary prevention from the healthcare provider perspective dabigatran was cost-effective with an ICER of €2,158 per QALY gained. Finally, in the scenario examining the prevention of recurrent VTE in patients with equipoise risk of recurrent VTE after completion of acute treatment, anticoagulation treatment with dabigatran compared to no treatment (placebo risks from the clinical trial being used), yielded an ICER of €33,379 per QALY gained.
Discussion
Our base-case result from the decision analysis demonstrated dabigatran may be a cost–saving alternative to VKAs for the treatment and secondary prevention of VTE from the societal perspective. Patients on dabigatran gained an additional 0.0336 discounted QALYs over lifetime and savings of €1,598. The key drivers of the CE of dabigatran relative to VKA are based on its ability to reduce MCRBs as found in the RECOVER trials. Particularly, the use of dabigatran resulted in 720 less all MCRB events (i.e. 19 ICHs, 109 other MBs, 582 CRNMBs and 10 deaths from bleeding) in a cohort of 10,000 patients.
Results were sensitive to the probability of VTE-related death, MCRBs-related death and ICH, yet, they all indicated dabigatran to be cost-saving compared to VKAs. Moreover, the PSA showed that the likelihood of dabigatran being cost-effective at WTP threshold of €20,000 per QALY was 98.1%. This also included the cost-effective ICERs in the south eastern part of the CE plane, in which QALYs and costs are negative. Since a reduction of quality of life is not desirable, these ICERs might not be considered cost-effective. Therefore, the probability of being cost-effective at a WTP thresholds of €20,000/QALY and €50,000/QALY while not lowering the quality of life was 87.2% and 87.4%, respectively. For economic analyses determining the cost-effectiveness of preventive drugs, for example for vaccines, a WTP threshold of 50,000/QALY can be used [39]. In this economic evaluation dabigatran showed to be already highly cost-effective at a WTP threshold of €20,000/QALY, leading to only a marginal increase of being cost-effective with a higher threshold.
The results of the scenario analyses comparing dabigatran to VKAs for the treatment and secondary prevention in high-risk patients of VTE, were quite robust, all indicating dabigatran may be cost-saving alternative to VKAs. Changing the duration of anticoagulation to life long has only a marginal impact on the ICER (results not explicitly shown). Although ICH risks showed to be sensitive in the sensitivity analysis, the two scenarios concerning the costs and the transition probabilities of ICH showed to be still cost-saving, However, in the scenario examining the CE of anticoagulants for the treatment and secondary prevention from the healthcare provider perspective, dabigatran was shown to be a cost-effective alternative to VKAs with an ICER of €2,158 per QALY gained. Interestingly, although the variability in productivity loss costs showed an impact on the estimated ICER in the univariate sensitivity analyses, excluding these costs together with other indirect costs still led to highly cost-effective findings in the aforementioned scenario. Finally, in the scenario examining the prevention of recurrent VTE in patients who are at equipoise for anticoagulation treatment, treatment with dabigatran compared to placebo was estimated with an ICER of €33,379 per QALY and may be considered cost-effective at the proposed cost-effectiveness threshold of €50,000 per QALY gained in the Netherlands [39]. This finding reflects the higher total costs associated with greater number of MCRBs and drug costs in dabigatran treatment arm compared to placebo arm. We do note that anticoagulation treatment in this population is not established, current treatment guidelines leave the decision about treatment to the choice of physicians [2], despite projected potential lowering of rVTEs. Further confirmations of results might definitely be needed for this patient population before widespread use in clinical practice can be expected.
To our knowledge, this is the first study that examined the use of dabigatran compared to VKAs for the treatment and prevention of VTE in the Dutch setting. In terms of the economic consequences of using dabigatran compared to VKAs, our findings are similar to the ones by Braidy et al [40]. In this study a cost-minimisation analysis investigated the use of NOACs and VKAs for the prevention of VTE and stroke in patients with atrial fibrillation from the third-party payer perspective in an Australian setting [40]. Dabigatran was found to be dominant over VKA (cost savings at approximately $AUS40 per patient) in terms of cost of drug administration and therapeutic monitoring. Notably, a direct comparability between the two studies is hampered due to differences in the underlying patients’ characteristics, safety and effectiveness data used, country-specific cost estimates and study perspective.
Our study is confronted with several potential limitations. One limitation might be that the duration of initial treatment with LMWHs was assumed to be different in dabigatran and VKAs treatment arms in the base-case analysis (i.e. 5 and 9 days respectively). Notably, the duration of treatment with LMWHs was assumed to have no impact on the effectiveness of the follow up use of dabigatran and VKAs. We varied the duration of LMWHs treatment between 5 and 9 days for both treatment alternatives in univariate sensitivity analyses. The results remained robust to variability in the duration of LMWHs use. Furthermore, this study simulated the occurrences of all MCRBs further subdivided into ICHs, other MBs, CRNMBs and deaths from bleeding, however, the meta-analysis of the RE-COVER trials indicated that there was only a marginally significant reduction of MBs observed in the double-dummy period in dabigatran arm compared to VKA. Therefore, simulating the occurrences of MBs might overestimate the benefits in the dabigatran arm compared to VKA. Yet, acute coronary syndromes (i.e. MIs and UAs) were also modelled in this study although their incidence was only numerically higher with dabigatran compared to VKAs. A further potential limitation in our study concerns the assumption that patients in both treatment arms who experience a first recurrent VTE event would switch to a 6-months standard treatment course of LMWH followed by VKAs. This may not always be the case and patients might alternatively be switched to other NOACs. However, there are currently no available efficacy and safety data that could characterize such a switch.
A maximum of two rVTEs over the lifetime of the patients and two MBs during the anticoagulation treatment were modelled. This assumption may be considered conservative given that a better safety profile of dabigatran treatment would be associated with a lower number of MBs and consequent lower costs compared to treatment with VKAs. Another limitation concerns treatment discontinuation that was assumed for patients who experience a MB or ICH. In a real-life setting such a decision would likely be based on individual patient characteristics. Finally, given the lack of specific treatment recommendations for patients experiencing CRNMBs, the discontinuation of treatment due to CRNMB was not modelled. Notably, in daily practice, patients may discontinue with the treatment after a certain number of consequent CRNMBs. However, as dabigatran can now be reversed by idarucizumab (Praxbind), we postulate that the manageability is not the major contributor of severity and outcome of the bleed, but rather the underlying disease and other disorders [41]. Notably, given all limitations listed, further investigations could be guided by a formal value-of-information (VOI) analysis. The current version of the model does not yet foresee in this option and we felt that the current analysis would hardly benefit from incorporating it. Firstly and most notably, strongly differing from UK’s NICE, the Netherlands lack a formal willingness-to-pay threshold for a QALY [42], crucially hampering any straightforward interpretation of and inferencing from the VOI. Secondly, part of the need for further data generation is already addressed via initiation of the RECOVER registry (phase IV clinical trial), designed to evaluate dabigatran for DVT and PE in real life [8,9]. Finally, regarding uncertainty and within the framework of a general model validation for NICE, we previously already analyzed inserting alternative distributions in the PSA, showing that this had only limited impact on the results of the model [43]. In conclusion, from a societal perspective, this modelling study suggests that the use of dabigatran for treatment and secondary prevention of VTE is likely to be a cost-saving alternative to VKAs in the Netherlands. Importantly, even when the comparison between dabigatran and VKAs was assessed from the healthcare provider perspective, dabigatran remained highly cost-effective with an ICER of €2,158 per QALY gained as compared to a minimal WTP threshold €20,000 per QALY. Ergo, in addition to some established advantages of dabigatran (e.g. better safety profile than VKAs; excludes the need for INR-monitoring), our study estimated the long-term economic benefits associated with its use. Yet, it must be acknowledged that such benefits in a “real life” setting are still to be proven. Finally, given that dabigatran is the second NOAC registered in Europe for the treatment and secondary prevention of VTE and further are to be expected, further investigations are needed to estimate comparative effectiveness and CE among the individual NOACs and as a class effect.
Supporting Information
S1 Fig. VTE Tx Model v2.0_update v13_js_121014_EDLJ.xlsm.
The Microsoft Excel model of Dabigatran for the treatment and secondary prevention of venous thromboembolism; a cost-effectiveness analysis for the Netherlands.
https://doi.org/10.1371/journal.pone.0163550.s001
(XLSM)
Author Contributions
- Conceptualization: MJP JS.
- Data curation: JS LAdJ MJP.
- Formal analysis: JS LAdJ.
- Funding acquisition: MJP BSK MV.
- Investigation: JS LAdJ EPD.
- Methodology: MJP JS.
- Project administration: MJP LAdJ EPD.
- Resources: JS EPD LAdJ BSK.
- Software: JS LAdJ.
- Supervision: MJP BSK MV EPD.
- Validation: JS LAdJ EPD.
- Visualization: JS LAdJ.
- Writing – original draft: JS EPD.
- Writing – review & editing: EPD LAdJ MJP.
References
- 1. Guyatt GH, Akl EA, Crowther M, Schünemann HJ, Gutterman DD, Lewis SZ, Introduction to the ninth edition: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines. CHEST Journal (2012);141(2_suppl):48S–52S.
- 2.
CBO. Richtlijn Diagnostiek, Preventie en Behandeling van Veneuze Trombo-embolie en Secundaire Preventie Arteriële Trombose. Hoofdstuk 1: Diagnostiek bij diep veneuze trombose; Hoofdstuk 2: Diagnostiek van longembolie; Hoofdstuk 4: Medicamenteuze behandeling van veneuze trombo-embolie. 2008; Available at: https://www.nvkc.nl/kwaliteitsborging/documents/Richtlijnveneuzetrombodefinitief—130109.pdfAccessed201406/08.
- 3. Cushman M, Tsai AW, White RH, Heckbert SR, Rosamond WD, Enright P, et al.Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med (2004);117(1):19–25. pmid:15210384
- 4. van Es J, den Exter PL, Kaptein AA, Andela CD, Erkens PMG, Klok FA, et al.Quality of life after pulmonary embolism as assessed with SF-36 and PEmb-QoL. Thromb Res (2013);132(5):500–505. pmid:24090607
- 5.
Rijksinstituut voor Volksgezondheid en Milieu. RIVM rapport 260242001/2010. Risico's door gebrekkige afstemming in de trombosezorg. Bilthoven: RIVM, 2010. Available at: http://www.rivm.nl/dsresource?objectid=rivmp:11843&type=org&disposition=inline&ns_nc=1Accessed201501/20.
- 6. Lenert LA,Soetikno RM. Automated computer interviews to elicit utilities: potential applications in the treatment of deep venous thrombosis. J Am Med Inform Assoc (1997);4(1):49–56. pmid:8988474
- 7. Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. The Lancet (2012);379(9828):1835–1846.
- 8. Schulman S, Kearon C, Kakkar AK, Mimetti P, Schellog S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med (2009);361(24):2342–2352. pmid:19966341
- 9. Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, et al.Treatment of Acute Venous Thromboembolism with Dabigatran or Warfarin and Pooled Analysis. Circulation (2014):CIRCULATIONAHA. 113.004450.
- 10. Schulman S, Kearon C, Kakkar AK, schellong S, Eriksson H, Baanstra D, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med (2013);368(8):709–718. pmid:23425163
- 11. Jugrin AV, Ustyugova A, Urbich M, Lamotte M, Sunderland T.The Cost-utility of Dabigatran Etexilate Compared with Warfarin in Treatment and Extended Anticoagulation of Acute Venous Thromboembolism in the UK. Thromb Haemost (2015) 114/4 (Oct) pp. 657–867.
- 12.
The Dabigatran submission to the Dutch National Care Institute. Available at: https://www.zorginstituutnederland.nl/binaries/content/documents/zinl-www/documenten/publicaties/geneesmiddelbeoordelingen/2015/1506-dabigatran-pradaxa/dabigatran+(Pradaxa).pdf Accessed2013July.
- 13.
Statistics Netherlands, Den Haag/Heerlen. Consumer prices. Available at: http://statline.cbs.nl/StatWeb/publication/?DM=SLEN&PA=71099ENG&D1=0&D2=64,77,90,103,116,129,142,155,168,181,194,207,220,l&LA=EN&VW=TAccessed2013July.
- 14.
Hakkaart-van Roijen L, Tan S, Bouwmans C. Manual for Dutch cost research: Handleiding voor kostenonderzoek. Methoden en standaard kostprijzen voor economische evaluaties in de gezondheidszorg. Updated version (2010).
- 15. Rosand J, Eckman MH, Knudsen KA, Singer DA, Greenberg SM.The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med (2004);164(8):880–884. pmid:15111374
- 16. Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica (2007);92(2):199–205. pmid:17296569
- 17. Brouwer MA, van den Bergh PJ, Aengevaeren WR, Veen G, Luijten HE, Hertzberger DP, et al. Aspirin plus coumarin versus aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of the Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis (APRICOT)-2 Trial. Circulation (2002);106(6):659–665. pmid:12163424
- 18. Pengo V, Lensing AW, Prins MH, Machiori A, Davidson BL, Tiozzo F, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med (2004);350(22):2257–2264. pmid:15163775
- 19. Prandoni P, Villalta S, Bagatella P, Rossi L, Marchiori A, Piccioli A, et al. The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. Haematologica (1997);82(4):423–428. pmid:9299855
- 20.
Szende A, Williams. A Measuring self-reported population health: An international perspective based onEQ-5D. EuroQol Group (2014).
- 21. Baeten SA, van Exel N Job A, Dirks M, Koopmanschap MA, Dippel DWJ, Niessen LW. Lifetime health effects and medical costs of integrated stroke services-a non-randomized controlled cluster-trial based life table approach. Cost Effectiveness and Resource Allocation (2010);8(1):21.
- 22. Sullivan PW, Slejko JF, Sculpher MJ, Ghushchyan V. Catalogue of EQ-5D scores for the United Kingdom. Med Decis Making (2011);31(6):800–804. pmid:21422468
- 23. Gerson LB, Ullah N, Hastie T, Triadafilopoulos G, Goldstein M. Patient-derived health state utilities for gastroesophageal reflux disease. Am J Gastroenterol (2005);100(3):524–533. pmid:15743346
- 24. McKenna SP, Ratcliffe J, Meads DM, Brazier J,. Development and validation of a preference based measure derived from the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) for use in cost utility analyses. Health Qual Life Outcomes (2008);6:65. pmid:18718016
- 25. Marchetti M, Pistorio A, Barone M, Serafini S, Barosi G. Low-molecular-weight heparin versus warfarin for secondary prophylaxis of venous thromboembolism: a cost-effectiveness analysis. Am J Med (2001);111(2):130–139. pmid:11498067
- 26.
Z-index WMG-geneesmiddelen. Accessed2014.
- 27.
De Federatie van Nederlandse Trombosediensten. De waarde van trombosediensten in Nederland. 2011; Available at: http://www.fnt.nl/media/docs/Positionpaper_FNT.pdfAccessed1309/13.
- 28. van Bellen B, Bamber L, Correa de Carvalho F, Prins M, Wang M, Lensing AW. Reduction in the length of stay with rivaroxaban as a single-drug regimen for the treatment of deep vein thrombosis and pulmonary embolism. Current Medical Research & Opinion (2014);30(5):829–837.
- 29. Postma MJ, Kappelhoff BS, van Hulst M, Brouwers JR. Economic evaluation of dabigatran etexilate for the primary prevention of venous tromboembolic events following major orthopedic surgery in the Netherlands. Journal of medical economics (2012);15(5):878–886. pmid:22563715
- 30.
Federation of Dutch thrombotic services (FNT). Annual medical report. 2013. URL: http://www.fnt.nl/media/docs/jaarverslagen/FNT_Samenvatting_Medisch_JV_2.0.pdf Accessed 2015 December
- 31.
Federation of Dutch thrombotic services (FNT). De kunst van het doseren. 2015. URL: http://www.fnt.nl/media/docs/overig/KvhD__versie_23_november_2015.pdf Accessed 2015 December
- 32. Ten Cate-Hoek AJ, Toll DB, Büller HR, Hoes AW, Moons KG, Oudega R, et al. Cost-effectiveness of ruling out deep venous thrombosis in primary care versus care as usual. Journal of thrombosis and haemostasis (2009);7(12):2042–2049. pmid:19793189
- 33.
Nederlandse Zorgautoriteit (NZa). Beleidsregel voor trombosediensten. Available at: http://www.nza.nl/137706/145406/623721/BR-CU-2083-rombosediensten.pdfAccessed201406/06.
- 34. Soekhlal RR, Burgers LT, Redekop WK, Tan SS. Treatment costs of acute myocardial infarction in the Netherlands. Netherlands Heart Journal (2013):1–6.
- 35. Greving JP, Visseren FL, de Wit GA, Algra A. Statin treatment for primary prevention of vascular disease: whom to treat? Cost-effectiveness analysis. BMJ (2011);342.
- 36. Boersma C, Radeva JI, Koopmanschap MA, Voors AA, Postma MJ. Economic evaluation of valsartan in patients with chronic heart failure: results from Val-HeFT adapted to the Netherlands. Journal of Medical Economics (2006);9(1–4):121–131.
- 37.
CFH-rapport rivaroxaban. Rapportnr 12/13. Diemen. College voor zorgverzekeringen (2012).
- 38. Van den Berg B, Brouwer W, van Exel J, Koopmanschap M, van den Bos GA, Rutten F. Economic valuation of informal care: lessons from the application of the opportunity costs and proxy good methods. Soc Sci Med (2006);62(4):835–845. pmid:16137814
- 39. Rozenbaum MH, Sanders EA, van Hoek AJ, Jansen AG, van der Ende A, van den Dobbelsteen G, et al. Cost effectiveness of pneumococcal vaccination among Dutch infants: economic analysis of the seven valent pneumococcal conjugated vaccine and forecast for the 10 valent and 13 valent vaccines. BMJ (2010);340:c2509. pmid:20519267
- 40. Braidy N, Bui K, Bajorek B. Evaluating the impact of new anticoagulants in the hospital setting. Pharmacy practice (2011);9(1):1–10. pmid:25132883
- 41. Eikelboom JW, Quinlan DJ, van Ryn J, Weitz JI. Idarucizumab: The antidote for Reversal of Dabigatran. Circulation (2015);132(25):2412–22. pmid:26700008
- 42.
College voor zorgverzekeringen, Kosteneffeciviteit in de zorg. 2013. URL: https://www.rijksoverheid.nl/documenten/rapporten/2013/09/30/kosteneffectiviteit-in-de-zorg. Assessed 2016 January.
- 43.
Dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. NICE. URL: https://www.nice.org.uk/guidance/ta327. Assessed 2016 January.