Health economics of direct oral anticoagulants in the Netherlands
de Jong, Lisa
DOI:
10.33612/diss.129441687
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de Jong, L. (2020). Health economics of direct oral anticoagulants in the Netherlands. University of Groningen. https://doi.org/10.33612/diss.129441687
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L.A. de Jong J.J. Gout-Zwart M. van den Bosch M. Koops M.J. Postma
Based on: J Med Econ 2019 Apr 22(4):306-318
fibrillation in the Netherlands: a
real-world data-based
cost-effectiveness analysis
Abstract
Background: Non-vitamin K antagonist oral anticoagulants (NOACs) are included in
international guidelines as important alternatives to vitamin K antagonists (VKAs) for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). Meanwhile, in the Netherlands, NOACs are widely used next to VKAs. The objective of this study is to estimate the cost-effectiveness of treatment with NOAC rivaroxaban compared to VKA in patients with AF in the Netherlands, using real-world data.
Methods: A decision tree model was developed based on the XANTUS (NCT01606995)
international prospective observational real-world study. The one-year cost-effectiveness of rivaroxaban use, compared to VKAs, was explored in a hypothetical population consisting of 2,000 patients with AF (base case) as well as for two additional scenarios, assessing the effect of two subpopulations: patients with AF with unstable international normalized ratio (INR), defined as the time in therapeutic range < 60% (scenario A), and patients with AF who are self-measurers and self-managers of their INR (scenario B).
Results: In the base case, rivaroxaban costs €2.89 while gaining 0.018 quality-adjusted life
year (QALY) per patient compared to VKA, resulting in an incremental cost-effectiveness ratio (ICER) of €157/QALY. In scenario A (unstable INR) and scenario B (self-measurers/ self-managers) rivaroxaban even saved €67.25 and €179.14 per patient, respectively. In the base case analysis, the probabilistic sensitivity analysis showed a probability of 47.0% for rivaroxaban being dominant (less costly, while gaining QALYs) and 99.8% at a willingness-to-pay threshold of €20,000/QALY.
Conclusions: In the general Dutch population with AF and the subpopulations with
unstable INR and self-measurers/self-managers, rivaroxaban treatment is likely to be cost-effective and a potentially cost-saving alternative to VKA.
Introduction
Atrial fibrillation (AF) is a disease associated with blood clot formation, which can be prevented by anticoagulation therapy. Vitamin K antagonists (VKAs) are mainly used as standard anticoagulation therapy in the Netherlands. Non-vitamin K antagonist oral anticoagulants (NOACs) have been included in international guidelines as an important alternative to VKAs [1]. The European Society for Cardiology guidelines recommend NOACs in preference to VKAs when oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC [1]. According to the medical report of the Federation of Dutch Thrombosis Service (FNT), a total of 296,343 patients with AF were anticoagulated with either acenocoumarol or phenprocoumon (VKAs) in the year 2015 [2]. The Dutch reimbursement authorities presume the safety and effectiveness of acenocoumarol, and phenprocoumon is comparable to warfarin, which is the most used VKA worldwide [3]. Recent years, however, have shown a steady increase in patients who are treated with a NOAC instead of VKAs [2].
AF is a disease characterized by an irregular heart rate. The arrhythmia is caused by a “circle stimulus” which leads to uncoordinated atrial activity. This causes stagnation of the blood flow in the atria, leading to blood clot formation [4]. As a result, patients who are diagnosed with AF have an increased risk of thromboembolic events. AF doubles the risk of heart-related death and is associated with a five-fold increased risk of stroke [5]. Furthermore, these clots are also known to block other arteries, causing systemic embolisms or myocardial infarctions [6].
The major drawback of the VKAs is that they have a very narrow therapeutic window which can be impacted by many drug and food interactions. For this reason VKAs require frequent monitoring of the international normalized ratio (INR) of the patients [2,7]. In the Netherlands, the INR monitoring is managed and controlled by a specialised thrombosis service.
NOACs have become available as a possible alternative to VKAs for prevention of stroke and systemic embolism in atrial fibrillation patients in the Netherlands since 2012 [8,9]. Due to the predictable pharmacokinetics and -dynamics of these drugs, routine INR monitoring is no longer required [10]. NOACs have a prominent place in international guidelines for several years now [1]. In September 2016, the Dutch association for general practitioners (NHG, Nederlands Huisartsen Genootschap) issued a statement stating that anticoagulant treatment with NOACs is equally adequate as VKAs concerning the indications AF and VTE [11]. The FNT has reported a decrease in the number of patients who started a VKA for the first time in 2015. As a reason for this decrease, the FNT states that this is mainly due to the steady increase in NOAC prescriptions [2].
One of these NOACs, rivaroxaban, has proven to be at least as effective and safe as VKAs in the ROCKET-AF (NCT00403767) clinical trial [12]. Recently, also an international prospective observational study with real-world data has been published on the effectiveness and safety of rivaroxaban. This single-arm study, XANTUS (NCT01606995), included 6,784 patients and showed low rates of stroke and major bleeding in routine clinical practice [13].
The objective of this analysis is to estimate the cost-effectiveness of treatment with rivaroxaban compared to VKA in patients with AF, using real-world data from the XANTUS study.
Methods
A model was developed with a time horizon of one year, populated with patients from the real-world study XANTUS (NCT01606995) [13]. The cost-effectiveness was explored in three subgroups: general Dutch population with AF, patients with AF with unstable INR and patients with AF using INR self-measuring or self-management devices (Table 1). For example, the subgroup of patients with unstable INR is chosen separately, as these patients can be assumed to have a higher INR measurement frequency, which is associated with higher costs [2]. Unstable patients were assumed to have a time in therapeutic range (TTR) of < 60% which was consistent with 16% of the total hypothetical population, based on 3,978 patients in the Euro Heart Survey on AF with complete follow-up [14]. The hypothetical cohort was based on a previously published study (XANTUS) and, therefore, a formal ethics review committee approval and consent of patients was not needed. The primary result of the cost-effectiveness analysis is the incremental cost effectiveness ratio (ICER), presented in costs per quality-adjusted life year (QALY). Sensitivity analyses were conducted to show the robustness of the model.
Table 1. Different populations taken into consideration for the cost-effectiveness analysis of rivaroxaban versus VKA.
Scenario Included patient population
Base-case AF
A AF with unstable INR group (TTR < 60%)
B AF only self-measures/self-managers of INR
Abbreviations: AF, atrial fibrillation; INR, international normalized ratio; TTR, time in therapeutic range.
The model
Transition probabilities were based on a comparison of the XANTUS and ROCKET-AF studies [12,13]. In the ROCKET-AF study, the control group is treated with warfarin, which is a VKA that is not available in the Netherlands. Because therapy with warfarin, acenocoumarol, and phenprocoumon all depend on dose adjustments based on patient INR values, their safety and efficacy are considered the same and, therefore, the ROCKET-AF study data can be considered reflective of the Dutch situation including the comparator therapy [3]. Treatment with rivaroxaban and VKA were continued during the one-year time horizon of the model, which is line with the duration of the XANTUS trial [13].
The patient populations of the rivaroxaban arm of both studies were matched in order to account for the differences in characteristics [15]. The rivaroxaban arm of the
XANTUS trial comprised 60.5% of patients aged 75 years or greater and 25.5% between the age of 65 and 75. Of this same population, 50.6% had a CHADS2 (Congestive Heart Failure, Hypertension, Age (≥75 years), Diabetes Mellitus, prior Stroke/transient ischaemic attack) score of 2, 27.6% had a score of 3, and 21.8% had a score of 4 or higher [15]. With this correction, represented as the Matching Adjusted Indirect Comparison (MAIC ratios), the rivaroxaban transition probabilities of the ROCKET-AF reflect the XANTUS results. Application of the MAIC ratio was only possible for primary endpoints listed by the study of Camm et al. [15]. Therefore, we only included health states based on the primary endpoint presented in this comparative study, namely: ‘no event’, ‘myocardial infarction’, ‘ischaemic stroke’, ‘major bleeding’, ‘vascular death’ and ‘death by any cause’ (Figure 1). The transition probabilities are shown in Table 2.
Figure 1. Model structure.
Table 2. Transition probabilities used in the model.
Transition probability Value (range) Source
Transition probability
VKA RR rivaroxaban versus VKA
No event 0.9151 (fixed) 1.0109 (0.6048 – 1.0208) [15]
Ischaemic stroke 0.0196 (0.0165 – 0.0230) 0.7661 (0.5962 – 0.9843) [15]
Myocardial infarction 0.0112 (0.0089 – 0.0138) 0.6663 (0.4710 – 0.9424) [15]
Major bleeding 0.0340 (0.0299 – 0.0383) 0.9106 (0.7610 – 1.0896) [15]
Vascular death 0.0171 (0.0142 – 0.0202) 1.0647 (0.8325 – 1.3617) [15]
Death any cause 0.0030 (0.0019 – 0.0044) 1.0893 (0.6048 – 1.9620) [15]
Abbreviations: RR, relative risk; VKA, vitamin K antagonist.
Costs
The patients were treated with 15 mg or 20 mg rivaroxaban once daily [16]. The costs of VKAs were based on a weighted average of the use of acenocoumarol (5 mg) and phenprocoumon (3 mg) in 2014, estimated at 77% and 23%, respectively [17]. All drug costs were based on the Dutch price list [18].
Based on the 2015 annual medical report of the FNT, a distinction was made between measurement at the thrombosis service, at home, and self-measurement/self-management [2]. The INR should be within the range of 2.0–3.5. The costs of a vascular death were assumed to be equal to the costs of one visit to an emergency room [19]. All costs were based on the societal perspective and corrected to the year 2016. A total overview of the event-related costs is shown in Table 3.
Table 3. Event costs used in cost-effectiveness analysis.
Event Costs Range Source
Ischaemic stroke €37,966 €30,373 – €45,559 [20]
Major bleeding €5,072 €2,033 – €13,847 [21]
Myocardial infarction acute €5,117 €5,030 – €5,203 [22]
Myocardial infarction long-term (monthly) €200 €186 – €210 [22]
Vascular death €261 €209 – €314 [23]
Death by any cause - Fixed
A complete overview of the utilization and costs associated with the treatment of VKA and rivaroxaban is shown in Table 4, as well as the frequency of INR measurements per year. To calculate the mean number of INR measurements for stable or unstable patients with AF in one year, the following formula is used:
The median number of correctly dosed (stable) patients with AF is 80.2% [2].
Table 4. Resource utilization and costs.
Parameter Mean Range Source
Number of INR measurements per year
Median 20.80 Fixed [2]
Stable patients 20.27 Fixed [2]
Unstable patients 25.97 Fixed [2]
INR measuring costs
Initiation of SM (first quartile) €377.11 €301.69 – €452.53 [19]
SM (per quartile) €182.84 €146.27 – €219.41 [19]
INR control (at home) €28.79 €23.03 – €34.55 [19]
INR control (near-patient, per quartile) €190.90 €152.72 – €229.08 [19]
Traveling costs (per km) €0.50 €0.40 – €0.60 [23]
Drug costs
VKA €0.09 Fixed [18]
Rivaroxaban €2.29 Fixed [18]
Length of hospitalization (days)
VKA 3.02 Fixed [24]
Rivaroxaban 2.11 Fixed [24]
Hospitalization costs
Hospitalization costs (per day) €447.07 €223.54 – €647.90 [23]
Outpatient clinic costs (per visit) €80.47 €64.59 – €96.88 [23]
General practitioner (per visit) €33.30 €26.64 – €39.96 [23]
Emergency room visit (per event) €261.38 €209.10 – €313.66 [23]
Group unstable INR 16% Fixed [2]
Abbreviations: INR, international normalized ratio; SM, self-measurement; VKA, vitamin K antagonist.
Utilities
A baseline utility was used for the ‘no event’ health state. The impact of all possible events on the patients’ quality-of-life was taken into account (Table 5). Upon the occurrence of certain events a (dis)utility for a specific time range was used to calculate quality-adjusted life-years (QALYs). The utility of ischaemic stroke was calculated based on the average of a
mild, moderate or severe event. The utilities of the health states ‘vascular death’ and ‘death by any cause’ were assumed to be equal to zero.
Table 5. Utilities used in the cost-effectiveness analysis.
Parameter Mean Range Source
Baseline utility AF 0.6980 0.5542 – 0.8242 [22]
Ischaemic stroke mild 0.6704 0.5337 – 0.7937 [22]
Ischaemic stroke moderate 0.6165 0.4929 – 0.7328 [22]
Ischaemic stroke severe 0.4416 0.3562 – 0.5287 [22]
Ischaemic stroke average 0.5762 Fixed [22]
Myocardial infarct 0.5328 0.4281 – 0.6360 [22]
Major bleeding 0.7000 0.5006 – 0.8659 [21]
Medication
Rivaroxaban 0.9730 Fixed [25]
VKA 0.9480 Fixed [26]
Abbreviations: AF, atrial fibrillation; VKA, vitamin K antagonist.
Sensitivity analyses
In order to determine the effect of uncertainty around input parameters we performed a probabilistic sensitivity analysis (PSA). The distributions applied on the 95% confidence interval (CI), or if a 95%CI was not available a range of 20%, of the input parameters were beta for probabilities and utilities, normal for relative risks and differences, and gamma for costs. For the three different populations a PSA was performed using a Monte Carlo simulation with 2,000 iterations. Results were plotted in a cost-effectiveness plane with a willingness-to-pay (WTP) threshold of €20,000/QALY. These results were used to produce cost-effectiveness acceptability curves (CEACs). Additionally, a one-way sensitivity analysis was conducted to determine which parameters have the biggest influence on the ICER of the base case analysis.
Results
Cost-effectiveness analysis
The deterministic results of the three populations for VKA and rivaroxaban are shown in Table 6. Rivaroxaban was not only cost-effective at this threshold but even cost-saving in the populations assessed in scenario A and B. In the base case analysis rivaroxaban leads to health gains of 0.018 QALY and costs of €48.44 per patient, compared to VKA, resulting in an ICER of €2,628/QALY. Scenarios A and B showed a dominant ICER, with savings of €21.71 and €133.59 per patient with AF.
Table 6. Deterministic costs, effects and incremental cost effectiveness ratios per patient of the three selected populations.
Costs Effects (QALYs) Incremental
VKA Rivaroxaban VKA Rivaroxaban Costs Effects (QALY) ICER Base case €1,609 €1,657 0.639 0.658 €48.44 0.018 €2,628/QALY
Scenario A €1,679 €1,657 0.639 0.658 €-21.71 0.018 Dominant
Scenario B €1,791 €1,657 0.639 0.658 €-133.59 0.018 Dominant Abbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; VKA, vitamin K antagonist.
Sensitivity analyses
For all three populations, a PSA was executed with 2,000 iterations. The cost-effectiveness plane for the base case analysis is shown in Figure 2. The other cost-effectiveness planes are presented in Appendix Figures A1–A2. The probability of being cost-effective at a WTP threshold of €20,000/QALY is 99.8% in the base case and 100% in the two other scenarios. Compared to a WTP threshold of €0/QALY, rivaroxaban use in the base case analysis has a probability of 25.7% of being cost-saving compared to VKA treatment. The probabilities of being cost-saving for scenarios A and B were 57.4%, and 88.1% respectively. The corresponding CEACs are displayed in Figure 3.
Results of the one-way sensitivity analysis in the base case analysis are shown in Table 7, representing the ten parameters with the biggest influence on the ICER. The relative risk of rivaroxaban versus VKA for ischaemic stroke, the costs of INR monitoring at home and the costs of ischaemic stroke were the parameters with the biggest influence on the ICER, but the ICERs remained either cost-saving (dominant) or cost-effective compared to a WTP threshold of €20,000/QALY.
Figure 2. Probabilistic sensitivity analysis of the base-case scenario. Abbreviation: QALY, quality-adjusted life year.
Figure 3. Cost-effectiveness acceptability curve of the base case analysis, and scenarios A and B. Abbreviations: CE, cost-effective; CEAC, cost-effectiveness acceptability curve; QALY, quality-adjusted life year; VKA, vitamin K antagonist.
Table 7. Results of the one-way sensitivity analysis for the base case analysis. Lower bound ICER Costs/QALY Upper bound ICER Costs/QALY
RR rivaroxaban versus VKA – Ischaemic stroke Dominant €10,484
Costs – INR control (at home) €4,795 €236
Costs – Ischaemic stroke €4,421 €648
Transition probability VKA – Ischaemic stroke €4,048 €1,032
Costs – SM (per quartile) €3,875 €1,251
RR rivaroxaban versus VKA – Other death Dominated €1,972
RR rivaroxaban versus VKA – Major bleeding €1,511 €3,514
Costs – Major bleeding €3,302 €1,410
RR rivaroxaban versus VKA – Myocardial infarction €1,814 €3,666
Costs – Travel costs (per km) €3,347 €1,834
Abbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; RR, relative risk; SM, self-measurement/-management; VKA, vitamin K antagonist.
Discussion
In the base case analysis, rivaroxaban treatment was associated with a gain of 0.018 QALY and extra costs of €48.44 per patient over a period of one year compared to VKA treatment, resulting in an ICER of €2,628/QALY. These results suggest that, in the base case, rivaroxaban is cost-effective compared to VKA for patients with AF at a WTP threshold of €20,000/QALY. In the scenarios including patients with unstable INR and self-measurers/self-managers, the use of rivaroxaban provided cost savings and health gains compared to VKA.
To our knowledge this is the first Dutch economic evaluation of rivaroxaban vs VKA based on real-world data, whereas most cost-effectiveness studies are based on clinical trial data. The input parameters for the INR measurement were also obtained from real-world data of the Dutch thrombosis service, as documented in the FNT medical annual report [2]. Still, there are some uncertainties and limitations to be discussed.
The therapeutic and target range for INR in the Netherlands was not similar to the international range (2.5–3.5 vs 2.0–3.0). The FNT has recently decided to adjust the therapeutic INR range to reflect the international values [27]. Given this, we assumed that it is not necessary to extrapolate the INR values from the XANTUS, and ROCKET-AF studies to the Dutch situation. The XANTUS study has Dutch data available, however it was not suitable for this analysis because of the absence of a control group [28]. We compared results from the total XANTUS population [13] to the Dutch XANTUS subpopulation [28], and found the number of major bleedings and thromboembolic events to be comparable (1.9% vs 2.1% and
1.6% vs 1.4%, respectively). The number of non-major bleedings was slightly lower in the total XANTUS population compared to the Dutch XANTUS subpopulation: 12.9% vs 15.8%.
The XANTUS study did not include a control group. To overcome this problem, data from the analysis of Camm et al. [13] were used to make a comparison between the XANTUS and ROCKET-AF studies [15]. The MAIC ratio was used to convert transition probabilities of the rivaroxaban arm from the ROCKET-AF trial to resemble the results in the real-world. This leads to an indirect comparison which is a limitation, but, because there was no control group included in the XANTUS study, it was the only way to make a reasonable assumption. Also, because the study of Camm et al. [15] only included five primary outcomes as shown in Figure 1, the comparison was limited to these outcomes and it was not possible to include, for example, the severity of an ischaemic stroke (e.g. mild, moderate, stroke) or major bleeding (e.g. intracranial vs non-intracranial haemorrhage). These factors might have contributed to either an over- or underestimation of the ICER.
On another note, it can be discussed that the one-year time horizon might not be ideal for modelling a population suffering from AF, since this is a chronic disease requiring lifelong treatment, as well as being associated with significant cardiovascular complications. Therefore, a model which includes the entire lifespan of the patients suffering from AF might give more informative results.
Our results are more favourable for rivaroxaban compared to results from other studies performed in Belgium and Germany [29,30]. This might be caused by the fact that the other studies are both only based on the clinical trial data from the ROCKET-AF study and that XANTUS study shows a more positive outcome for rivaroxaban. Another explanation could be that the drug costs of rivaroxaban have decreased substantially since these studies were published. This is a major contributor to the cost of the treatment and, for our study, we have used a cost of €2.29 (including VAT) per 15 mg or 20 mg rivaroxaban, whereas the Belgian and German studies used €2.70 and €3.26, respectively. The use of €2.29 in our study is based on data from the Dutch Healthcare Institute, which shows the price before a discount is agreed upon by the government and the manufacturer (list price) [18]. This makes it a conservative assumption; the price could in fact be lower, which may cause an overestimation of our ICER. However, price negotiations regarding the costs associated with the thrombosis service occur as well, which could mean an underestimation of the ICER. Moreover, differences between INR values, risk factors of patients, clinical outcomes, and differences in social health costs may explain differences of cost-effectiveness results between countries.
Conclusions
In conclusion, treatment with rivaroxaban was cost-effective or even cost-saving and provided health gains compared to treatment with a VKA in the general Dutch population with AF, as well as the other examined populations patients with unstable INR (scenario A), and self-measurers/self-managers (scenario B). In sensitivity analysis, the model has shown
to be robust. At a WTP threshold of €20,000/QALY, rivaroxaban appeared to be 99.8% cost-effective in the general Dutch population with AF.
Appendix
Figure A1. Probabilistic sensitivity analysis of scenario A, AF with unstable INR group (TTR < 60%). Abbreviation: QALY, quality-adjusted life year.
Figure A2. Probabilistic sensitivity analysis of scenario B, AF with only self-measures and self-managers. Abbreviation: QALY, quality-adjusted life year.
Acknowledgements
The models used in this study were provided to the journal’s peer reviewers for their reference when reviewing the manuscript.
This study was funded by Bayer Pharmaceuticals. M.J. Postma has received research grants from various pharmaceutical companies, including, but not limited to, Bayer, Pfizer, Bristol-Myers Squibb, GSK, Roche, and Novartis. M. van den Bosch is an employee at Bayer and was involved with the start of the research, but did not influence the results and discussion. J.J. Gout-Zwart, L.A. de Jong, and M. Koops have no conflict of interest with relation to the subject. One peer reviewer declares their role as a co-principal investigator of the Rocket AF trial, the pivotal trial for rivaroxaban. The remaining peer reviewers for this manuscript have no conflicts of interest to disclose. The authors declare that study
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