Rivaroxaban for non-valvular atrial fibrillation and venous thromboembolism in the Netherlands: a real-world data based cost-effectiveness analysis

Figures & data

Figure 1. Progression-of-disease tree for patients with VTE. The health states for both branches of rivaroxaban and VKA therapy are identical. Abbreviations. DVT, deep vein thromboembolism; ICH, intracranial haemorrhage; NMCRB, non-major clinically relevant bleeding; PE, pulmonary embolism; PTS, post-thrombotic syndrome; VTE, venous thromboembolism.

Figure 2. Progression-of-disease tree for patients with non-valvular atrial fibrillation. The health states for both branches of rivaroxaban and VKA therapy are identical. Abbreviation. AF, atrial fibrillation.

Table 1. Event costs used in cost-effectiveness analysis.

Event	Costs (fixed)	Range	Source
IS	€37,966	Fixed	Baeten et al.^37
ICH acute	€33,378	€19,078–€51,610	Stevanovic et al.^38
ICH annually	€14,942^a	Fixed	Stevanovic et al.^38
MB	€5,072	€2,033–€13,847	van Leent et al.^39
NMCRB	€102	€76–€127	van Leent et al.^39
MI	€5,117	€5,030–€5,203	Stevanovic et al.^40
MI annually	€200	€186–€210	Stevanovic et al.^40
Severe PTS	€25,550	€14,604–€39,507	Stevanovic et al.^38
PE	€5,071	€2,533–€10,141	van Leent et al.^39
DVT	€1,592	€796–€3,184	van Leent et al.^39

Abbreviations. DVT, deep vein thromboembolism; ICH, intracranial haemorrhage; IS, ischemic stroke; MB, major bleeding; MI, myocardial infarction; NMCRB, non-major clinically relevant bleeding; PE, pulmonary embolism; PTS, post-thrombotic syndrome.

^a Average of mild, moderate, and severe ICH.

Table 2. Resource utilization and costs of NVAF and VTE.

Parameter	Mean	Range	Source
Number of INR measurements per year
Median	20.80	15.70–27.00	FNT^4
Stable patients	20.27		FNT^4
Unstable patients	25.97		FNT^4
INR measuring costs
First quartile extra costs SM	€377.11	Fixed	NZa^30
Monitoring SM (per quartile)	€182.84	Fixed	NZa^30
INR control (at home)	€28.79	Fixed	NZa^30
INR control (near-patient, per quartile)	€190.90	Fixed	NZa^30
Travelling costs (per km)	€0.50	Fixed
Duration of treatment (days)
NOAC for VTE patients	184	Fixed	Ageno et al.^21
VKA for VTE patients	179	Fixed	Ageno et al.^21
LMWH for VTE patients	5	Fixed	Ageno et al.^21
Drug costs
VKA	€0.08	Fixed	ZiN^29
LMWH	€10.50	Fixed	ZiN^41
Rivaroxaban	€2.16	Fixed	ZiN^29
Length of hospitalization (days)
PE; use of LMWH/VKA	7.5	Fixed	van Bellen et al.^42
PE; use of Rivaroxaban	6.6	Fixed	van Bellen et al.^42
DVT; use of LMWH/VKA	7.9	Fixed	van Bellen et al.^42
DVT; use of Rivaroxaban	6.2	Fixed	van Bellen et al.^42
AF; use of Warfarin	3.02	Fixed	Laliberte et al.^43
AF; use of Rivaroxaban	2.11	Fixed	Laliberte et al.^43
Hospitalization costs
Hospitalization costs (per day)	€447.07	Fixed	Hakkaart-van Roijen et al.^31
Outpatient clinic costs (per visit)	€80.47	Fixed	Hakkaart-van Roijen et al.^31
General practitioner (per visit)	€33.30	Fixed	Hakkaart-van Roijen et al.^31
Emergency room visit (per event)	261.38	Fixed	Hakkaart-van Roijen et al.^31
Group labile INR	16%		FNT^4
Prevalence DVT within rVTE	56%		FNT^28
Prevalence PE within rVTE	44%		FNT^28
LMWH re-treatment (days)	3		FNT^4

Abbreviations. AF, atrial fibrillation; DVT, deep vein thrombosis; INR, international normalized ratio; LMWH, low-molecular-weight heparin; NOAC, non-vitamin K antagonist oral anti-coagulant; NVAF, non-valvular atrial fibrillation; PE, pulmonary embolism; SM, self-measurement; VKA, vitamin K antagonist; (r)VTE, (recurrent) venous thromboembolism.

Table 3. Utilities and disutilities used in the cost-effectiveness analysis.

Parameter	Mean	Range (95% CI)	Source
Venous thromboembolism
Baseline utility VTE	0.9000	0.8566–0.9363	van Leent et al.^39
(r)DVT (1 month)	0.8000	0.6056–0.9388	van Leent et al.^39
Non-fatal PE (1 month)	0.6000	0.3408–0.8316	van Leent et al.^39
Major bleeding (14 days)	0.7000	0.5006–0.8658	van Leent et al.^39
NMCRB (2 days)	0.7000	0.6848–0.7148	van Leent et al.^39
Minor bleeding (5 days)	0.9000	0.8200–0.9583	van Leent et al.^39
Disutility severe PTS (lifetime)	0.0700	0.0131–0.1685	Lenert and Soetikno^44
Atrial fibrillation
Baseline utility AF	0.6980	0.5542–0.8242	Stevanovic et al.^40
Stroke mild	0.6704	0.5337–0.7937	Stevanovic et al.^40
Stroke moderate	0.6165	0.4929–0.7328	Stevanovic et al.^40
Stroke severe	0.4416	0.3562–0.5287	Stevanovic et al.^40
Stroke average	0.5762	Fixed	Stevanovic et al.^40
Myocardial infarct	0.5328	0.4281–0.6360	Stevanovic et al.^40
Disutility other ICH (6 weeks)	0.1385	0.1125–0.1666	Stevanovic et al.^40
Disutility of NMCRB (2 days)	0.0600	0.0487–0.0722	Stevanovic et al.^40
Medication
Rivaroxaban	0.9730		Ahmad and Lip^45
Vitamin K antagonists	0.9480		Robinson et al.^46

Abbreviations. AF, atrial fibrillation; (r)DVT, (recurrent) deep vein thrombosis; ICH, intracranial haemorrhage; NMCRB, non-major clinically relevant bleeding; PE, pulmonary embolism; PTS, post-thrombotic syndrome; VTE, venous thromboembolism.

Table 4. Different populations taken into consideration for the cost-effectiveness analysis of rivaroxaban vs VKA.

Scenario	Included patient population
Base-case	VTE/NVAF
A	VTE
B	NVAF
C	NVAF without stable INR group (TTR < 60%)
D	NVAF only self-measures and self-managers

Abbreviations. INR, international normalized ratio; NVAF, non-valvular atrial fibrillation; TTR, time in therapeutic range; VTE, venous thromboembolism.

Table 5. Deterministic costs, effects (2,000 simulations), and incremental cost effectiveness ratios per patient of the five selected populations.

	Costs		Effects (QALY)		Incremental
	SoC	Rivaroxaban	SoC	Rivaroxaban	Costs	Effects (QALY)	ICER
Base-case	€1.887.277	€1.815.353	672,911	696,956	–€71.923	24,045	Dominant
Scenario A	€3.100.632	€2.704.499	817,92	866,277	–€396.133	48,357	Dominant
Scenario B	€1.607.272	€1.610.166	639,447	657,882	€2.894	18,435	€157/QALY
Scenario C	€1.677.419	€1.610.166	639,447	657,882	–€67.253	18,435	Dominant
Scenario D	€1.789.302	€1.610.166	639,447	657,882	–€179.136	18,435	Dominant

Abbreviations. QALY, quality adjusted life-year; SoC, Standard of Care.

Figure 3. Probabilistic sensitivity analysis of the base-case scenario. Abbreviation. QALY, quality-adjusted life-years.

Figure 4. Cost-effectiveness acceptability curve of the base-case scenario (VTE + NVAF patients) and scenarios A, B, C, and D. Abbreviations. CE, cost-effectiveness; NVAF, non-valvular atrial fibrillation; QALY, quality-adjusted life-years; VTE, venous thromboembolism.

Table 6. Results of the one-way sensitivity analysis for the base-case scenario.

	Lower bound ICER	Upper bound ICER
Disease rates VKA—All disease rates VKA	Dominant	Dominant
Risk ratio rivaroxaban vs VKA—All disease rates VKA	€1,194*	€3,706
Baseline utilities	–€2,695	–€2,649
Utility for diseases	–€2,928	Dominant
Utility for the use of rivaroxaban	Dominated	Dominant
Utility for the use of VKA	–€1,238	€5,590*
Costs of rivaroxaban	Dominant	€19
INR measurement	–€2,991	Dominant
New patients self-measurers/self-managers (%)	–€2,979	Dominant
Disease costs	–€1,010	Dominant

Values indicated with a * are located in the southwest quadrant of the cost-effectiveness plane, meaning rivaroxaban treatment has lower costs and lower health effects than VKA treatment.

Abbreviations. ICER, incremental cost-effectiveness analysis; INR, international normalized ratio; VKA, vitamin K antagonist.

Table A1. XALIA treatment-emergent clinical outcome results with propensity score adjustment.

Type of event	Rivaroxaban (n = 2,505)	SoC (n = 2,010)	Source
Major bleeding	19 (0.8%)	43 (2.1%)	Ageno et al.^21
Recurrent venous thromboembolism	36 (1.4%)	47 (2.3%)	Ageno et al.^21
All-cause mortality	11 (0.4%)	69 (3.4%)	Ageno et al.^21
Major adverse cardiovascular events	9 (0.4%)	12 (0.6%)	Ageno et al.^21
Other thromboembolic events	4 (0.2%)	(0.3%)	Ageno et al.^21

Abbreviation. SoC, Standard of Care.

Table A2. Transition probabilities used in the VTE model.

Transition probability	Value (95% CI/range)		Distribution	Source
	Rivaroxaban	Vitamin K-antagonists
Recurrent VTE and VTE related deaths
rVTE	0.0140 (0.0098–0.0190)	0.0230 (0.0169–0.0300)	Beta	Ageno et al.^21
non-fatal PE	0.0060 (0.0034–0.0094)	0.0071 (0.0039–0.0112)	Beta	Ageno et al.^21
fatal PE	0.0010 (0.0002–0.0026)	0.0009 (0.0001–0.0026)	Beta	Ageno et al.^21
DVT	0.0050 (0.0026–0.0081)	0.0124 (0.0080–0.0177)	Beta	Ageno et al.^21
DVT & PE	0.0010 (0.0002–0.0026)	0.0018 (0.0004–0.0040)	Beta	Ageno et al.^21
Bleeding events
MB	0.0080 (0.0049–0.0118)	0.0210 (0.0152–0.0277)	Beta	Ageno et al.^21
Non-fatal MB	0.0080 (0.0049–0.0118)	0.0201 (0.0144–0.0267)	Beta	Ageno et al.^21
Fatal MB	0.0000	0.0009	Fixed	Ageno et al.^21
NMCRB	0.1140 (0.1021–0.1264)	0.1010 (0.0886–0.1141)	Beta	Ageno et al.^21
ICH	0.0020 (0.0007–0.0040)	0.0020 (0.0006–0.0043)	Beta	Ageno et al.^21
Secondary outcomes
No event	0.8580	0.8190	Fixed	Ageno et al.^21
PTS given no event	0.0056	0.0056	Fixed	Kahn and Ginsberg^24
Death any cause	0.0040 (0.0019–0.0068)	0.0340 (0.0265–0.0423)	Beta	Ageno et al.^21

Abbreviations. DVT, deep venous thromboembolism; ICH, intracranial haemorrhage; MB, major bleeding; NMCRB, non-major clinically relevant bleeding; PE, pulmonary embolism; rVTE, recurrent venous thromboembolism; VTE, venous thromboembolism.

TABLE A3. Transition probabilities used in the NVAF model.

Transition probability	Value (95% CI/range)		Distribution	Source
	Warfarin	Rivaroxaban
No event	0.9151	0.9251	Fixed	Camm^25
IS	0.0196 (0.0165–0.0230)	0.0150 (0.0123–0.0180)	Beta	Camm^25
MI	0.0112 (0.0089–0.0138)	0.0075 (0.0056–0.0096)	Beta	Camm^25
MB	0.0340 (0.0299–0.0383)	0.0310 (0.0271–0.0351)	Beta	Camm^25
Vascular death	0.0171 (0.0142–0.0202)	0.0182 (0.0152–0.0215)	Beta	Camm^25
Death any cause	0.0030 (0.0019–0.0044)	0.0033 (0.0021–0.0047)	Beta	Camm^25

Abbreviations. IS, ischemic stroke; MI, myocardial infarction; MB, major bleeding.

Table A4. Results of the one-way sensitivity analysis for scenario A.

	Lower bound ICER	Upper bound ICER
Disease rates VKA – Major bleed	Dominant	Dominant
Disease rates VKA – NMCR bleeding	Dominant	Dominant
Disease rates VKA – Intracranial bleeding	Dominant	Dominant
Disease rates VKA – All disease rates VKA	Dominant	Dominant
Risk ratio Rivaroxaban vs VKA – Major bleed	Dominant	Dominant
Risk ratio Rivaroxaban vs VKA – NMCR bleeding	Dominant	Dominant
Risk ratio Rivaroxaban vs VKA – Intracranial bleeding	Dominant	Dominant
Risk ratio Rivaroxaban vs VKA – All disease rates VKA	Dominant	Dominant
Baseline utility norm population	Dominant	Dominant
Utility for diseases	Dominant	Dominant
Utility for the use of Rivaroxaban	€23,812/QALY*	Dominant
Utility for the use of VKA	Dominant	Dominant
Costs of Rivaroxaban	Dominant	Dominant
INR measurement	Dominant	Dominant
New patients self-measurers/self-managers (%)	Dominant	Dominant
Disease costs	Dominant	Dominant

Values indicated with a * are located in the southwest quadrant of the cost-effectiveness plane, meaning Rivaroxaban has lower costs and lower health effects than VKAs.

Abbreviations. ICER, incremental cost-effectiveness ratio; INR, international normalized ratio; NMCR, non-major clinically relevant; QALY, quality adjusted life-year; VKA, vitamin K antagonist.

Table A5. Results of the one-way sensitivity analysis for scenario B.

	Lower bound ICER	Upper bound ICER
Disease rates VKA – Major bleed	€255	€51
Disease rates VKA – Stroke	€1,627	Dominant
Disease rates VKA – MI	€466	Dominant
Disease rates VKA – All disease rates VKA	€1,954	Dominant
Risk ratio Rivaroxaban vs VKA – Major bleed	Dominant	€1,496
Risk ratio Rivaroxaban vs VKA – Stroke	Dominant	€8,219
Risk ratio Rivaroxaban vs VKA – MI	Dominant	€1,336
Risk ratio Rivaroxaban vs VKA – All disease rates VKA	€696*	€7,008
Baseline utility AF	€198	€133
Utility for diseases	€152	€162
Utility for the use of Rivaroxaban	Dominated	€78.88
Utility for the use of VKA	€57	Dominated
Costs of Rivaroxaban	Dominant	€4,434
New patients self-measurers/self-managers (%)	€177	€137
Disease costs	€1,820	Dominant

Values indicated with a * are located in the southwest quadrant of the cost-effectiveness plane, meaning Rivaroxaban has lower costs and lower health effects than VKAs.

Abbreviations. AF, atrial fibrillation; ICER, incremental cost-effectiveness ratio; VKA, vitamin K antagonist.

Figure A1. Probabilistic sensitivity analysis of population A, venous thromboembolism. Abbreviations. CE, cost-effectiveness; QALY, quality adjusted life-year.

Figure A2. Probabilistic sensitivity analysis of scenario B, non-valvular atrial fibrillation. Abbreviations. CE, cost-effectiveness; QALY, quality adjusted life-year.

Figure A3. Probabilistic sensitivity analysis of population C, NVAF without stable INR group (TTR < 60%). Abbreviations. CE, cost-effectiveness; QALY, quality adjusted life-year.

Figure A4. Probabilistic sensitivity analysis of population D, NVAF only self-measures and self-managers. Abbreviations. CE, cost-effectiveness; QALY, quality adjusted life-year.

Baeten S, van Exel N, Dirks M, et al. Lifetime health effects and medical costs of integrated stroke services - a non-randomized controlled cluster-trial based life table approach. Cost Eff Resour Alloc. 2010;8(21):7547–7548.

 Google Scholar

Stevanovic J, de Jong LA, Kappelhoff BS, et al. Dabigatran for the treatment and secondary prevention of venous thromboembolism; a cost-effectiveness analysis for the Netherlands. PLoS One. 2016;11(10):e0163550.

 PubMed Web of Science ®Google Scholar

van Leent MW, Stevanovic J, Jansman FG, et al. 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;10(8):e0135054.

 PubMed Web of Science ®Google Scholar

Stevanovic J, Pompen M, Le HH, 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.

 PubMed Web of Science ®Google Scholar

Federation Dutch Thombotic Services (FNT). Samenvatting medische jaarverslagen. FNT; 2015 [cited 2016 Nov]. Leiden, the Netherlands. Available from: https://s3.eu-central-1.amazonaws.com/storage.topsite.nl/fnt.nl/uploads/docs/jaarverslagen/Medisch_Jaarverslag_2015.pdf.

 Google Scholar

Nederlandse Zorgautoriteit (NZa). Table of Dutch healthcare product tariffs (2016). [cited 2017 Jan]. Utrecht, the Netherlands. Available from: https://www.nza.nl/regelgeving/tarieven-en-prestaties/20150710_Tarieventabel_DBC_zorgproducten_en_overige_producten_per_1_januari_2016.

 Google Scholar

Ageno W, Mantovani LG, Haas S, 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;3(1):e12–21.

 PubMed Web of Science ®Google Scholar

Zorginstituut Nederland (ZiN). Dutch Drug reimbursement [cited 2016 Nov]. The Hague, the Netherlands. Available from: https://www.medicijnkosten.nl/.

 Google Scholar

College voor Zorgverzekeringen (Zorginstituut Nederland, ZiN). Recommendation to the minister: assessment rivaroxaban. CvZ; 2012 [cited 2017 Jan]. The Hague, Netherlands. Available from: https://www.zorginstituutnederland.nl/binaries/zinl/documenten/rapport/2012/10/26/rivaroxaban-xarelto-bij-preventies-bij-diep-veneuze-trombose-dvt/Rivaroxaban+%28Xarelto%29+bij+preventies+bij+Diep+veneuze+trombose+%28DVT%29.pdf.

 Google Scholar

van Bellen B, Bamber L, Correa de Carvalho F, et al. 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):829–837.

 PubMed Web of Science ®Google Scholar

Laliberte F, Cloutier M, Crivera C, et al. Effects of rivaroxaban versus warfarin on hospitalization days and other health care resource utilization in patients with nonvalvular atrial fibrillation: an observational study from a cohort of matched users. Clin Ther. 2015;37(3):554–562.

 PubMed Web of Science ®Google Scholar

Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, et al. Kostenhandleiding. Methodologie van kostenonderzoek en referentieprijzen voor economische evaluaties in de gezondheidszorg. In opdracht van Zorginstituut Nederland. Geactualiseerde versie 2015.

 Google Scholar

Federation Dutch Thombotic Services (FNT). Samenvatting medische jaarverslagen. FNT; 2014 [cited 2016 Nov]. Leiden, the Netherlands. Available from: https://s3.eu-central-1.amazonaws.com/storage.topsite.nl/fnt.nl/uploads/docs/jaarverslagen/FNT_Samenvatting_Medisch_JV_2014.pdf.

 Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Ahmad Y, Lip GY. Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: NICE guidance. Heart. 2012;98(19):1404–1406.

 PubMed Web of Science ®Google Scholar

Robinson A, Thomson R, Parkin D, et al. How patients with atrial fibrillation value different health outcomes: a standard gamble study. J Health Serv Res Policy. 2001;6(2):92–98.

 PubMedGoogle Scholar

Kahn SR, Ginsberg JS. The post-thrombotic syndrome: current knowledge, controversies, and directions for future research. Blood Rev. 2002;16(3):155–165.

 PubMed Web of Science ®Google Scholar

Camm A. Real-world versus randomized trial outcomes in similar populations of rivaroxaban treated patients with non-valvular atrial fibrillation in ROCKET-AF and XANTUS: Abstract 084 presented at the American College of Cardiology (ACC) 66th annual scientific session and expo, Washington DC, USA, 17–19 March 2017.

 Google Scholar