Health economics of direct oral anticoagulants in the Netherlands
de Jong, Lisa
DOI:
10.33612/diss.129441687
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Publication date: 2020
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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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Lisa A. de Jong Judith J. Gout-Zwart Marina van den Bosch Mike Koops Maarten J. Postma
Based on: J Med Econ 2019 Apr 22(4):306-318
venous thromboembolism in the
Netherlands: a real-world data-based
cost-effectiveness analysis
Abstract
Background: Non-vitamin K antagonist oral anticoagulants (NOACs) have been included
in international guidelines as important alternatives to vitamin K antagonists (VKAs) for the treatment and prevention of venous thromboembolism (VTE). Meanwhile, in the Netherlands, NOACs are widely used next to VKAs. The objective of this study is to estimate the one-year cost-effectiveness of treatment with NOAC rivaroxaban compared to five days of low molecular weight heparin (LMWH) followed by six months of VKA treatment in Dutch patients experiencing VTE, using real-world data.
Methods: A decision tree model was developed based on the and XALIA (NCT01619007)
international prospective observational real-world study. The one-year cost-effectiveness of rivaroxaban use, compared to LMWH/VKA, was explored in a hypothetical population consisting of 2,000 patients with VTE. The primary outcome of the cost-effectiveness analysis was the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were conducted to test the robustness of the model.
Results: Rivaroxaban saved €398 and gained 0.035 quality-adjusted life year (QALY) per
patient per year compared to LMWH/VKA, resulting in a dominant ICER. The probabilistic sensitivity analysis showed a probability of 98.8% for rivaroxaban being dominant and 99.7% at a willingness-to-pay threshold of €20,000/QALY.
Conclusions: In Dutch patients experiencing VTE, rivaroxaban treatment is likely to be
Introduction
Venous thromboembolism (VTE) is a disease associated with blood clot formation, and is treated and prevented with 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 American College for Chest Physicians guidelines even suggested the use of NOACs over VKAs for the initial treatment and secondary prevention of VTE in patients without cancer [2]. According to the medical report of the Federation of Dutch Thrombosis Service (FNT), a total of 66,667 patients with VTE were anticoagulated with either acenocoumarol or phenprocoumon (VKAs) in the year 2015 [3]. Dutch reimbursement authorities presume the safety and efficacy of acenocoumarol, and phenprocoumon is comparable to warfarin, which is the most used VKA worldwide [4]. However, recent years, have shown a steady increase in patients who are treated with a NOAC instead of VKAs [3].
VTE is the formation of a blood clot in the veins and can be sub-divided into deep vein thrombosis (DVT) or pulmonary embolism (PE). Long-term effects of VTE can be post thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH) [5]. VKAs, in combination with low-molecular-weight heparins (LMWH), have been the standard anticoagulation treatment of VTE patients for decades and have proven to be very effective in preventing thromboembolic events [6]. However, 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 these reasons, VKAs require frequent monitoring of the international normalized ratio (INR) [3,7]. In the Netherlands, the INR measurement is managed by anticoagulation clinics.
In the Netherlands, one of the NOACs, rivaroxaban, is reimbursed as a possible alternative to LMWH/VKAs for the treatment and prevention of VTE since 2012 [8]. Due to the predictable pharmacokinetics and -dynamics of the NOACs, routine coagulation monitoring is no longer required [9]. 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 [10]. 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 mentions the steady increase in NOAC prescriptions [3].
Rivaroxaban has proven to be at least as effective and safe as LMWH/VKA in the EINSTEIN (NCT00440193 and NCT00439777) randomised clinical trials [11,12]. Recently, also international prospective observational studies with real-world data have been published on the effectiveness and safety of rivaroxaban. The XALIA (NCT01619007) study included 5,136 patients and examined the efficacy and safety in VTE patients using rivaroxaban, compared to standard of care in the real-world setting [13]. The results of this study confirmed that rivaroxaban is a safe and effective alternative to LMWH/VKA in a broad range of patients. The rates of major bleeding and recurrent VTE were low in the
patients treated with rivaroxaban and were consistent with the findings of the EINSTEIN trials.
The objective of this analysis is to estimate the cost-effectiveness of treatment with rivaroxaban compared to LMWH/VKA in Dutch patients experiencing VTE, using real-world data from the XALIA study.
Methods
A model was developed with a time horizon of one year, populated with patients from XALIA (NCT01619007) study comparing rivaroxaban with LMWH/VKA [13]. The hypothetical cohort was based on the patient characteristics of the XALIA study. 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 used to test the effect of the model input parameters on the ICER.
The model
The model structure is shown in Figure 1. A population of 2,000 patients experiencing a VTE event entered the model in the ‘index VTE’ health state, and could subsequently move to ‘no event’, ‘recurrent VTE’, clinically relevant non-major bleeding (‘CRNMB’), ‘major bleeding’, ‘intracranial haemorrhage’, and ‘death by any cause’. ‘Recurrent VTE’ was subdivided into ‘DVT’, ‘PE’, and ‘VTE related death’. Patients who did not experience a recurrent VTE, bleeding event, or death by any cause were assumed to be in the ‘no event’ health state. In the ‘no event’ health state it was assumed that 56% of the patients experienced a DVT in the past [14]. These patients were at risk of PTS. For PTS, a conservative estimation was made only accounting for severe PTS at 1% risk for ‘no event’ patients who already experienced a DVT [15]. Patients who experienced a PE are at risk of developing CTEPH, which was conservatively not taken into account as event rates for PE as well as CTEPH are low [15], especially within the study time horizon.
Figure 1. Progression-of-disease tree for patients with venous thromboembolism.
Abbreviations: CRNMB, clinically relevant non-major bleeding; DVT, deep vein thrombosis; PE, pulmonary embolism; PTS, post-thrombotic syndrome; VTE, venous thromboembolism.
Patient data from the XALIA study were used to calculate the relative risks of rivaroxaban versus LMWH/VKA. Death by any cause was based on the all-cause mortality rate from the XALIA study [13]. The population in the XALIA study treated with rivaroxaban was on average 59 years of age and 55% male. The population initially treated with an unfractionated heparin, LMWH, or fondaparinux followed by VKA was on average 66 years of age and 52% male. Due to this difference, a correction was made using the propensity-scored primary outcomes of the XALIA study, but since this was only done for a part of the health states included in the model we were unable to use these outcomes [13]. All transition probabilities, for both rivaroxaban and LMWH/VKA, included in the model are based on the treatment period of 184 days, which is the duration of the XALIA study. The transition probabilities are summarized in Table 1.
Table 1. Transition probabilities used in the model.
Value (range) Source
Transition probability
LMWH/VKA RR rivaroxaban versus LMWH/VKA
Recurrent VTE and VTE related deaths
Non-fatal PE 0.0071 (0.0039 – 0.0112) 0.8478 (0.4116 – 1.7464) [13]
VTE related death 0.0009 (0.0001 – 0.0026) 1.1304 (0.1656 – 7.7189) [13]
DVT 0.0124 (0.0080 – 0.0177) 0.4037 (0.2053 – 0.7941) [13]
DVT & PE 0.0018 (0.0004 – 0.0040) 0.5652 (0.1123 – 2.8437) [13]
Bleeding events
Non-fatal major bleeding 0.0201 (0.0144 – 0.0267) 0.3983 (0.2339 – 0.6782) [13]
Fatal major bleeding 0.0009 (0.0096 – 0.2627) 0.4372 (0.0383 – 4.9933) [13]
CRNMB 0.1010 (0.0886 – 0.1141) 1.1287 (0.9568 – 1.3315) [13]
Intracranial haemorrhage 0.0020 (0.0006 – 0.0043) 1.0000 (0.2796 – 3.5763) [13]
Other events
No event 0.8190 (0.8093 – 0.8674) 1.0282 (1.0012 – 1.0560) [13]
PTS 0.0056 1.0000 [15]
Death by any cause 0.0340 (0.0265 – 0.0423) 0.5100 (0.3502 – 0.7426) [13]
Abbreviations: DVT, deep venous thromboembolism; CRNMB, clinically relevant non-major bleeding; LMWH, low molecular weight heparin; PE, pulmonary embolism; PTS, post-thrombotic syndrome; VKA, vitamin K antagonist; VTE, venous thromboembolism.
Costs
Rivaroxaban treatment consisted of a 21-day course of 15 mg twice a day, followed by 20 mg once daily [6]. Costs of the LMWH were based on the costs of a daily injection of enoxaparin for five days, since this was the most used LMWH in the XALIA study [13]. 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 [14]. All drug costs were based on the Dutch price list [16].
The costs of the INR measurement were based on INR measurements at the thrombotic service. Travel costs to the thrombotic service were taken into account. For patients experiencing a PE as well as a DVT, the costs of PE alone were used as a conservative estimate. 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 2. A complete overview of the utilization and costs associated with the treatment of rivaroxaban and LMWH/VKA is shown in Table 3.
Table 2. Event costs used in cost-effectiveness analysis.
Event Costs Range Source
PE €5,071 €2,533 – €10,141 [17]
DVT €1,592 €796 – €3,184 [17]
VTE related death €261 €209 – €314 [18]
PTS €25,550 €14,604 – €39,507 [19]
Major bleeding €5,072 €2,033 – €13,847 [17]
Intracranial haemorrhage acute €33,378 €19,078 – €51,610 [19]
Intracranial haemorrhage annually €200 €186 – €210 [19]
CRNMB €102 €76 – €127 [17]
Death by any cause - Fixed
Abbreviations: CRNMB, clinically relevant non-major bleeding; DVT, deep vein thrombosis; ICH, intracranial haemorrhage; PE, pulmonary embolism; PTS, post-thrombotic syndrome; VTE, venous thromboembolism.
Table 3. Resource utilization and costs.
Parameter Mean Range Source
INR measurement costs
Number of INR measurements per year 20.80 Fixed [3]
Cost of one INR measurement €15.37 €12.30 – €18.44 [20]
Traveling costs (per km) €0.50 €0.40 – €0.60 [18]
Travel distance (km) 7 Fixed [18]
Duration of treatment (days)
Rivaroxaban 184 Fixed [13] LMWH 5 Fixed [13] LMWH re-treatment 3 Fixed [3] VKA 179 Fixed [13] Drug costs Rivaroxaban €2.29 Fixed [16] LMWH €11.12 Fixed [21] VKA €0.09 Fixed [16]
Length of hospitalisation (days)
PE – rivaroxaban 6.6 Fixed [22]
PE – LMWH/VKA 7.5 Fixed [22]
DVT – rivaroxaban 6.2 Fixed [22]
DVT – LMWH/VKA 7.9 Fixed [22]
Hospitalisation costs
Hospitalisation costs (per day) €447.07 €223.54 – €647.90 [18]
Outpatient clinic costs (per visit) €80.47 €64.59 – €96.88 [18]
Table 3. Resource utilization and costs. (continued)
Parameter Mean Range Source
General practitioner (per visit) €33.30 €26.64 – €39.96 [18]
Emergency room visit (per event) €261.38 €209.10 – €313.66 [18]
Homecare (per hour) €58.53 €46.83 - €70.24 [18]
Duration homecare administration LMWH
(hours) 0.25 Fixed Assumption
Abbreviations: DVT, deep vein thrombosis; INR, international normalized ratio; LMWH, low molecular weight heparin; PE, pulmonary embolism; VKA, vitamin K antagonist.
Utilities
A specific baseline utility was used for patients in the ‘no event’ health state. The impact of all possible events on the patients’ utilities was taken into account (Table 4). Upon the occurrence of certain events a (dis)utility for a specific time frame was used to calculate QALYs.
Table 4. Utilities used in the cost-effectiveness analysis.
Parameter Mean Range Source
Baseline utility 0.9000 0.8566 – 0.9363 [17]
DVT (one month) 0.8000 0.5337 – 0.7937 [17]
Non-fatal PE (one month) 0.6000 0.4929 – 0.7328 [17]
Non-fatal major bleeding (14 days) 0.7000 0.3562 – 0.5287 [17]
CRNMB (two days) 0.7000 Fixed [17]
Disutility ICH (six weeks) 0.1385 0.1125 – 0.1667 [23]
Disutility PTS (continuous) 0.0700 0.5006 – 0.8659 [17]
Medication
Rivaroxaban 0.9730 Fixed [24]
VKA 0.9480 Fixed [25]
Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism
Sensitivity analyses
In order to determine 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
curve (CEAC). 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 rivaroxaban and LMWH/VKA are shown in Table 5. The total costs for one-year treatment with rivaroxaban and LMWH/VKA were €2,729 and €3,101, respectively. The treatment costs and the event costs per patient were both lower for rivaroxaban than for LMWH/VKA: €2,710 versus €2,416 and €391 versus €313, respectively. The patient’s quality-of-life is on average higher for patients treated with rivaroxaban versus LMWH/VKA: 0.852 QALY versus 0.818 QALY. Compared to LMWH/ VKA, rivaroxaban saves €373 per year per patient, while increasing the patient’s health with 0.035 QALY, resulting in a dominant ICER.
Table 5. Deterministic costs, effects and incremental cost effectiveness ratios per patient
Costs Effects (QALYs) Incremental
Rivaroxaban LMWH/VKA Rivaroxaban LMWH/VKA Costs (€) (QALY)Effects (€/QALY)ICER
€2,729 €3,101 0.852 0.818 €-398 0.035 Dominant
Abbreviations: ICER, incremental cost-effectiveness ratio; LMWH, low molecular weight heparin; QALY, quality-adjusted life year; VKA, vitamin K antagonist.
Sensitivity analyses
A PSA is executed with 2,000 iterations. The cost-effectiveness plane and corresponding CEAC are shown in Figure 2 and 3. In the Netherlands, a WTP threshold of €20,000/ QALY is used for preventive treatments. The probability of being cost-effective at a WTP threshold of €20,000/QALY is 99.7%. Compared to a WTP threshold of €0/QALY, rivaroxaban use has a probability of 98.2% of being dominant compared to LMWH/VKA treatment.
Results of the one-way sensitivity analysis in the base case scenario are shown in Table 6, representing the ten parameters with the biggest influence on the ICER. The relative risk of rivaroxaban versus LMWH/VKA for CRNMB, the costs of hospitalisation and relative risk of rivaroxaban versus LMWH/VKA for intracranial haemorrhage were the parameters with the biggest influence on the ICER, however all ICERs remained cost-saving (dominant).
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, and scenarios A and B. Abbreviations. CE, cost-effective; QALY, quality-adjusted life year.
Table 6. Results of the one-way sensitivity analysis for the base-case scenario. Lower bound ICER (€/QALY) Upper bound ICER (€/QALY)
RR rivaroxaban versus LMWH/VKA – CRNMB Dominant Dominant
Costs – hospitalisation (per day) Dominant Dominant
RR rivaroxaban versus LMWH/VKA – intracranial
haemorrhage Dominant Dominant
Transition probability LMWH/VKA – CRNMB Dominant Dominant
Costs – major bleeding Dominant Dominant
Transition probability LMWH/VKA – Death by any cause Dominant Dominant
RR rivaroxaban versus LMWH/VKA – Non-fatal PE Dominant Dominant
RR rivaroxaban versus LMWH/VKA – Non-fatal major
bleeding Dominant Dominant
Transition probability rivaroxaban – Death by any cause Dominant Dominant
RR rivaroxaban versus LMWH/VKA – DVT Dominant Dominant
Abbreviations: CRNMB, clinically relevant non-major bleeding; DVT, deep vein thrombosis; ICER, incremental cost-effectiveness ratio; LMWH, low molecular weight heparin; PE, pulmonary embolism; QALY, quality-adjusted life year; RR, relative risk; VKA, vitamin K antagonist.
Discussion
Rivaroxaban treatment was associated with a gain of additional 0.035 QALY and savings of €373 per patient over a period of one year compared to LMWH/VKA treatment. Even though the drug costs of rivaroxaban are higher than those of VKAs, the total treatment costs are lower, due to the additional costs for INR monitoring and the relatively higher bleeding risks associated with VKA treatment. The results of the cost-effectiveness analysis appeared to be robust. At a WTP threshold of €20,000/QALY, rivaroxaban has a probability of being cost-effective 99.7% compared to LMWH/VKA. Rivaroxaban has a probability of 98.2% of being cost-saving compared to LMWH/VKA.
To our knowledge this is one of the first Dutch economic evaluation of rivaroxaban compared to LMWH/VKA based on real-world data, whereas most cost-effectiveness studies are based on clinical trial data. Also, the input parameters for the INR measurement were obtained from real-world data of the Dutch thrombotic service, as documented in the FNT report [3]. However, there are some uncertainties and limitations that arise from the use of real-world data for cost-effectiveness analysis.
The event rates we used in our analysis to calculate the transition probabilities were not propensity score-adjusted. The XALIA study [13] did include an analysis using propensity score-adjustment, however, we were unable to use these adjusted values, since they were only available for major bleeding, recurrent VTE, all-cause mortality, major adverse cardiovascular events, and other thromboembolic events. The use of unadjusted
relative risks might have led to an over-estimation of the effect of rivaroxaban, and therefore an under-estimation of the cost-effectiveness. Furthermore, the health states in the model were based on the measured outcomes included in the XALIA study [13], which were still much less explicit than the outcomes included in the trials [11,12].
The XALIA study consisted of 184 treatment days (equal to six months). It should be mentioned that six months of VKA treatment differs from the Dutch guidelines in which three months of treatment is recommended for a provoked first episode of recurrent VTE in patients without cancer [6]. The Dutch guideline for treatment duration of NOACs is not specific. Therefore, we remained consistent with the six-month treatment in the XALIA study, although it might overestimate the ICER, mainly due to increasing incremental costs, driven by the large difference in drug costs.
In the real-world the initial therapy with LMWH in VTE treated patients might not be necessary, or needs to be prolonged, which is not taken into account. This could mean a potential under- or overestimation of the ICER. Also, treatment interruption, treatment switch, or permanent discontinuation was not taken into account. Another cost parameter that may cause uncertainty on the ICER is the costs of a patient experiencing a PE and DVT during one event. A conservative assumption was made to only account for the costs of a PE, since this was the more expensive one of the two events. Still, this may have resulted in an underestimation of the costs of this event and, therefore, an overestimation of the ICER.
The results of this analysis can be used to confirm the results previously found in trial-based cost-effectiveness analyses. In the Dutch reimbursement dossier of rivaroxaban for patients with VTE, an ICER of €5,896/QALY was reported [21]. This is less favourable than the results we found. This difference may be the result of different factors. We used the XALIA study, whereas the ICER from the reimbursement dossier was calculated based on the results of the EINSTEIN studies. Although the authors of the XALIA study concluded that their results were consistent with the EINSTEIN trials, numerical differences can lead to differences in cost-effectiveness results. Moreover, as mentioned before, the health states of our model were based on the outcomes of the XALIA study, which may have been less explicit than those based on the EINSTEIN trials, leading to differences in model structures. Another factor concerns the price of rivaroxaban, which has decreased since the assessment of the reimbursement dossier: the price of rivaroxaban was €2.54 in the dossier and €2.29 in our analysis.
Other model settings that may have contributed to different cost-effectiveness results are the treatment duration, time horizon and the perspective. In our analysis we used a treatment duration of six months for all patients, whereas the model from the reimbursement dossier distributed the patients over three treatment duration groups (three, six and twelve months) in accordance with the EINSTEIN data. The time horizon used in the reimbursement dossier was lifetime, which is in accordance with the guideline
reimbursement dossier was calculated from a healthcare payer’s perspective, and therefore excluded indirect costs. The effect of including indirect costs was assessed in one of the scenario analyses. The scenario assessing the influence of equal event rates for all treatment duration groups resulted in an ICER of €4,031/QALY when excluding indirect costs, but became dominant when including indirect costs. All and all, the comparison of trial-based and real-world data-based cost-effectiveness appears to be challenging.
Conclusions
In conclusion, treatment with rivaroxaban was cost-saving and provided health gains compared to treatment with LMWH/VKA in Dutch patients experiencing VTE. In the sensitivity analysis, rivaroxaban showed to have a high probability of being cost-saving compared to LMWH/VKA.
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 his 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 results were not influenced by Bayer Pharmaceutical’s funding.
References
1. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016 Jan 1;37(38):2893–962.
2. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016 Feb 1;149(2):315–52.
3. Federation of Dutch Thrombosis Service. Annual Medical Report. 2015.
4. Zorginstituut Nederland. GVS-advies rivaroxaban (Xarelto®) uitbreiding bijlage 2 voorwaarden bij behandeling van pulmonale embolie | Advies | Zorginstituut Nederland [Internet]. 2014.
5. Ozaki A BJ. Venous Thromboembolism (VTE) Treatment | Cleveland Clinic [Internet]. Cleveland Clinic. 2012. 6. Oudega R, Van Weert H, Stoffers H, Sival P, Schure R, Delemarre J. NHG-Standaard Diepe veneuze
trombose en longembolie. Huisarts Wet. 2008;51(1):24–37.
7. Dutch association for general practitioners (NHG, Nederlands Huisartsen Genootschap) - NHG standaard atrium fibrilleren. Huisarts Wet. 2013;56(8):392–401.
8. Zorginstituut Nederland. Rivaroxaban (Xarelto) bij preventies bij Diep veneuze trombose (DVT) en longembolie & preventie CVA en systemisch embolisme bij non-valvulair atriumfibrilleren| Report [Internet]. 2012.
9. The National Thrombosis Service. Informatie over NOAC’s [Internet].
10. van den Donk M, de Jong J, Geersing G-J, Wiersma T. Cumarinederivaten en DOAC’s voortaan gelijkwaardig. Huisarts Wet. 2016;59(9):406–9.
11. EINSTEIN Investigators, Bauersachs R, Berkowitz S, Brenner B, Buller H, Decousus H, et al. Oral rivaroxaban for symptomatic venous thromboembolism. - PubMed - NCBI. N Engl J Med. 2010;363(26):2499–510. 12. Büller HR, Prins MH, Lensing AWA, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the
treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287–97.
13. Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, et al. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. 14. Federation of Dutch Thrombotic Service. Annual Medical Report. 2014;
15. Kahn SR, Ginsberg JS. The post-thrombotic syndrome: Current knowledge, controversies, and directions for future research. Vol. 16, Blood Reviews. Elsevier; 2002. p. 155–65.
16. Zorginstituut Nederland. Dutch Drug reimbursement [Internet].
17. van Leent MWJ, Stevanović J, Jansman FG, Beinema MJ, Brouwers JRBJ, Postma MJ. Cost-Effectiveness of Dabigatran Compared to Vitamin-K Antagonists for the Treatment of Deep Venous Thrombosis in the Netherlands Using Real-World Data. PLoS One. 2015 Aug 4;10(8):e0135054.
18. Roijen LH, Linden N van der, Bouwmans C, Kanters T, Tan SS. Dutch manual for costing studies in health care. Diemen; 2015.
19. Stevanović J, de Jong LA, Kappelhoff BS, Dvortsin EP, Voorhaar M, Postma MJ. Dabigatran for the Treatment and Secondary Prevention of Venous Thromboembolism; A Cost-Effectiveness Analysis for the Netherlands. PLoS One. 2016;11(10):e0163550.
20. Dutch Healthcare Authority (NZa). Table of Dutch healthcare product tariffs (2016). [Internet]. 21. Zorginstituut Nederland. Rivaroxaban (Xarelto) diep veneuze trombose en longembolie; CVA preventie
bij non-valvulair atriumfibrilleren | Report [Internet]. 2012.
22. van Bellen B, Bamber L, Correa de Carvalho F, Prins M, Wang M, Lensing AWA. Reduction in the length of stay with rivaroxaban as a single-drug regimen for the treatment of deep vein thrombosis and pulmonary embolism. Curr Med Res Opin. 2014;30(5):829–37.
23. Stevanovic J, Pompen M, Le HH, Rozenbaum MH, Tieleman RG, Postma MJ, et al. Economic evaluation of apixaban for the prevention of stroke in non-valvular atrial fibrillation in the Netherlands. PLoS One. 2014;9(8):e103974.
24. Ahmad Y, Lip GYH. Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: NICE guidance. Vol. 98, Heart. 2012. p. 1404–6.
25. Robinson A, Thomson R, Parkin D, Sudlow M, Eccles M. How patients with atrial fibrillation value different health outcomes: A standard gamble study. J Heal Serv Res Policy. 2001;6(2):92–8.
