Cost-effectiveness analysis of rivaroxaban for treatment and secondary prevention of venous thromboembolism in the Netherlands

Figures & data

Table 1. Baseline characteristics of modeled populations, based on ITT in EINSTEIN phase III clinical study program (combined across treatment arms).

Patient characteristics	Index DVT^24	Index PE with or without DVT^23
n	3,449	4,832
with 3-month duration	411 (12%)	249 (5%)
with 6-month duration	2,166 (63%)	2,774 (57%)
with 12-month duration	872 (25%)	1,809 (37%)
Mean age (years)	55.8	57.7
Proportion male	57.4%	52.9%
Idiopathic	62.0%	64.5%

Figure 1. Model structure depicting both the index-PE and index-DVT module. Dashed health states/arrows indicate additional states/pathways in index-PE module with respect to index-DVT module. All patients who have had a PE are at risk of CTEPH, with the exception of those in the acute IC and post-IC bleed states (as these states are considered worse than CTEPH). On Tx, On treatment; Off Tx, Off treatment; rVTE, Recurrent VTE event; DVT, Deep-vein thrombosis (ipsilateral and contralateral); PE, Pulmonary embolism; PTS, Post-thrombotic syndrome; CTEPH, Chronic thromboembolic pulmonary hypertension; IC, Intracranial; EC, Extracranial; CRNM, Clinically relevant non-major. *Health states with increased mortality risk. ‡ Health state in the index-PE module for patients who have experienced a DVT and are, therefore, at risk of PTS. † PTS costs and utilities are applied to proportion of patients in the Off Tx post-DVT state.

Table 2. Baseline risks (LMWH/VKA) and hazard ratios (rivaroxaban) based on the pooled EINSTEIN trial data (DVT/PE). Figures regarding major bleed are based on the first major bleed event (Prins et al.²⁵ considered first bleed event).

Duration group	Period	Baseline risk recurrent VTE (95% CI)	Baseline risk major bleed (95% CI)	Baseline risk CRNM bleed (95% CI)
3 months	0–3 months	1.54% (0.20–2.88%)	2.79% (0.99–4.58%)	6.19% (3.56–8.82%)
6 months	0–3 months	1.94% (1.40–2.49%)	1.10% (0.69–1.51%)	5.85% (4.92–6.78%)
	3–6 months	0.22% (0.03–0.41%)	0.63% (0.29–0.96%)	1.83% (1.25–2.40%)
12 months	0–3 months	2.17% (1.39–2.95%)	1.20% (0.62–1.79%)	5.78% (4.53–7.03%)
	3–6 months	0.48% (0.10–0.86%)	0.26% (0.00–0.55%)	2.76% (1.82–3.71%)
	6–12 months	0.16% (0.00–0.39%) quart. prob.: 0.08%	0.38% (0.01–0.75%) quart. prob.: 0.19%	3.23% (2.16–4.30%) quart. prob.: 1.63%
Rivaroxaban hazard ratio	0–12 months	0.89 (0.66–1.19)	0.54 (0.37–0.79)	1.02 (0.89–1.18)

Table 3. Health state utility weights, as applied in the cost-effectiveness analysis.

Health state	Utility	Source
Population norm	0.899	Lamers et al.^47 (2006)
Disutility VKA treatment	0.948 (multiplier while on treatment)	Robinson et al.^50 (2001)
Deep-vein thrombosis	0.884^a (multiplier for duration of 1 month)	Locadia et al.^10 (2004)
Pulmonary embolism	0.663^b (multiplier for duration of 1 month)	Locadia et al.^10 (2004)
Bleed
Extracranial:
major	0.684^c (multiplier for duration of 1 month)	Locadia et al.^10 (2004)
minor	0.0049 (utility decrement for cycle duration)	Sullivan et al.^51 (2011)
Intracranial:
intracranial	0.451	Baeten et al.^52 (2010)
post-intracranial	0.666	Baeten et al.^52 (2010)
Chronic thromboembolic pulmonary hypertension
acute CTEPH	0.560	Meads et al.^53 (2008)
long-term CTEPH	0.560	Meads et al.^53 (2008)
Post-thrombotic syndrome
mild/moderate PTS	0.98 (multiplier for cycle duration)	Lenert et al.^56 (1997)
severe PTS	0.863^d (multiplier for cycle duration)	Locadia et al.^10 (2004)

^a DVT utility/norm = 0.84/0.95 = 0.884;

^b PE utility/norm = 0.63/0.95 = 0.663;

^c gastrointestinal bleed utility/norm = 0.65/0.95 = 0.684;

^d severe PTS utility/norm = 0.82/0.95 = 0.863¹⁰.

Table 4. Quarterly treatment-related costs (2015).

Cost item	Rivaroxaban			Reference	LMWH/VKA			Reference
	Unit cost	Units	Costs		Unit cost	Units	Costs
Anticoagulant	€2.16	111 90	€239.76€194.40	Pharmacist purchasing price, December 2015	€0.08	90	€7.12	Pharmacist purchasing price, December 2015, phenprocoumon, acenocoumarol^57
LMWH	—	—	—	—	€9.44	8	€75.54	Pharmacist purchasing price, December 2015, enoxaparin, nadroparin, dalteparin^57
Home care compression therapy^a	€576.33	1	€576.33	Dutch AMUSE study^58	€576.33	1	€576.33	Dutch AMUSE study^58
INR monitoring (medical costs)^b	—	—	—	—	€15.37	12.2 3.0	€187.45€45.35	Reference tariff^59, Dutch participants in EINSTEIN clinical study program (n = 450)
GP visit	€30.59	3 1	€91.77€30.59	Dutch costing manual^61	€30.59	3 1	€91.77€30.59	Dutch costing manual^61
Patient travel costs associated with INR monitoring visits^c	—	—	—	Dutch costing manual^61	€10.36	12.23.0	€126.32€30.56	Dutch costing manual^61

In case of two rows per cost item: 1st row represents 1st cycle; 2nd row represents subsequent cycles.

^a Only applies to DVT outpatients.

^b For inpatients, INR monitoring during LMWH therapy (4.2 out of 12.2) is included in the overall event cost and not counted separately.

^c Applicable to 57.5% of patients⁶⁴.

Table 5. Quarterly event-associated costs (2015).

Event	Cost	Reference
Deep-vein thrombosis—inpatient	€3,534.38	DRG code 141418
Deep-vein thrombosis—outpatient	€385.36	Ultrasound lower extremities; DRG code 77433 (D-dimer); Emergency admission^61
Pulmonary embolism—inpatient	€4,488.29	DRG code 141419
Bleed
Extracranial:
major	€10,167.21	Gastrointestinal^62
minor	€260.68	Emergency admission^61
Intracranial:
acute^a	€24,815	Stroke^52
post-intracranial	€1,819	Post-stroke^52
Chronic thromboembolic pulmonary hypertension
acute CTEPH	€212.47	DRG code 140709 (diagnosis)
ongoing care CTEPH^b	€254.52	DRG code 140458 (rehabilitation)
CTEPH surgery	€7,207.86	DRG code 140307 (treatment)
Post-thrombotic syndrome
mild/moderate PTS—1st year	€170.28	Mild-to-moderate PTS^63
mild/moderate PTS—subsequent years	€69.21	Mild-to-moderate PTS^63
severe PTS—1st year	€774.66	Severe^63
severe PTS—subsequent years	€340.35	Severe^63

^a Additional costs accrued during the first four quarters, compared to subsequent quarters, were accumulated in quarter 1; while correcting for mortality.

^b Also applicable to first quarter.

Table 6. Event and treatment-related number of days absent from work.

Event	Days absent from work	Source
VTE event
deep-vein thrombosis—inpatient	3.0 (4.2 × 5/7)	ICD10 I80 hospitalization 2013^67
deep-vein thrombosis—outpatient	1	Assumption
Pulmonary embolism—inpatient	5.7 (8 × 5/7)	Assumed equal to acute LMWH treatment period
Monitoring
outpatient hospital visit	0.25 (2 h)	Hospital visit^68
GP/physician visit	0.13 (1 h)	Hospital visit^68 × 0.5
AC clinic visit (INR)	0.13 (1 h)	Hospital visit^68 × 0.5
home visit (INR)	0.06 (0.5 h)	Assumption
Bleed
Extracranial:
major	2.7 (3.8 × 5/7)	ICD10 K92 hospitalization 2013^67
minor	1	Assumption
Intracranial	61	Stroke absence 1993 (221–249 days)^66
Chronic thromboembolic pulmonary hypertension
acute CTEPH	4.3 (6.0 × 5/7)	ICD10 I27 hospitalization 2013^67
ongoing impact CTEPH	1/quarter	Assumption
Post-thrombotic syndrome
mild/moderate PTS—1st year	0	Assumption
mild/moderate PTS—subsequent years	0	Assumption
severe PTS—1st year	3.8 (5.3 × 5/7)	ICD10 I87 hospitalization 2013^67
severe PTS—subsequent years	1/quarter	Assumption
Death	61	Definition

Table 7. Lifetime time-horizon results (base case: costs discounted at 4% and effects at 1.5%).

	Rivaroxaban	LMWH/VKA	Incremental
Effects
Life years	19.73	19.72	0.017
life years (4% discounted)	14.94	14.92	0.013
QALYs	17.53	17.48	0.047
QALYs (4% discounted)	13.27	13.23	0.042
QALYs (scenario without VKA disutility)	17.53	17.51	0.022
Costs
Total	€8,509	€8,813	–€304
Direct	€7,256	€7,390	–€133
drug	€495	€92	€403
INR monitoring visits^b	€429	€709	–€280
VTE-related^a	€4,468	€4,465	€3.73
bleed-related	€230	€489	–€259
PTS/CTEPH	€1,634	€1,636	–€1.57
Indirect costs	€1,253	€1,424	–€171

^a Visit (medical costs; contributing 72% to incremental INR monitoring costs [–€202]) and patient travel costs to visits (non-medical; contributing 28% to incremental INR monitoring costs [–€78]).

^b Including index event costs.

Figure 2. Tornado diagram for total discounted (1.5%) incremental QALYs per patient (top 15 parameters).

Figure 3. Tornado diagram for total discounted (4%) incremental costs per patient (top 15 parameters).

Figure 4. Scatter plot of probabilistic sensitivity analysis; incremental costs per patient vs incremental QALYs per patient.

Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510

 PubMed Web of Science ®Google Scholar

Büller HR, Prins MH, Lensin AWA, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97

 PubMed Web of Science ®Google Scholar

Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013;11:21

 PubMedGoogle Scholar

Lamers LM, McDonnell J, Stalmeier PFM, et al. The Dutch tariff: results and arguments for an effective design for national EQ-5D valuation studies. Health Econ 2006;1132:1121-32

 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;6:92-8

 PubMedGoogle Scholar

Locadia M, Bossuyt PMM, Stalmeier PFM, et al. Treatment of venous thromboembolism with vitamin K antagonists: patients’ health state valuations and treatment preferences. Thromb Haemost 2004;92:1336-41

 PubMed Web of Science ®Google Scholar

Sullivan PW, Slejko JF, Sculpher MJ, et al. Catalogue of EQ-5D scores for the United Kingdom. Med Decis Making. 2011;31:800-4

 PubMed Web of Science ®Google Scholar

Baeten SA, van Exel NJA, 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

 PubMedGoogle Scholar

Meads DM, McKenna SP, Doughty N, et al. The responsiveness and validity of the CAMPHOR Utility Index. Eur Respir J Off J Eur Soc Clin Respir Physiol 2008;32:1513-9

 PubMed Web of Science ®Google Scholar

Lenert LA, Soetikno RM. Automated computer interviews to elicit utilities: Potential applications in the treatment of deep venous thrombosis. J Am Med Informatics Assoc 1997;4:49-56

 PubMed Web of Science ®Google Scholar

Netherlands Health Care Institute. Drug Information System [Internet]. http://www.gipdatabank.nl, Zorginstituut Nederland, Diemen, the Netherlands. Accessed January 1, 2016.

 Google Scholar

Ten Cate-Hoek AJ, Toll DB, Büller HR, et al. Cost-effectiveness of ruling out deep venous thrombosis in primary care versus care as usual. J Thromb Haemost. 2009;7:2042-9

 PubMed Web of Science ®Google Scholar

Nederlandse Zorgautoriteit (NZA). Beleidsregel TB/CU-2066-01, Prestatie- en tariefbeschikking DOT. NZA; 2016. Utrecht, the Netherlands

 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. 2015. Zorginstituut Nederland, Diemen, the Netherlands

 Google Scholar

Caprini JA, Botteman MF, Stephens JM, et al. Economic burden of long-term complications of deep vein thrombosis after total hip replacement surgery in the United States. Value Health. International Society for Pharmacoeconomics and Outcomes Research (ISPOR); 2003;6:59-74

 PubMed Web of Science ®Google Scholar

Federatie van Nederlandse Trombosediensten. Samenvatting medische jaarverslagen 2013. Voorschoten, the Netherlands

 Google Scholar

Vonkeman HE, Klok RM, Postma MJ, et al. Direct medical costs of serious gastrointestinal ulcers among users of NSAIDs. Drugs Aging. 2007;24:681-90

 PubMed Web of Science ®Google Scholar

National Board of Health and Welfare. Swedish Health and Welfare Statistical Databases [Internet]. 2009. Stockholm, Sweden. http://www.socialstyrelsen.se/Statistik/statistikdatabas. Accessed January 1, 2013

 Google Scholar

Ericson L, Bergfeldt L, Björholt I. Atrial fibrillation: the cost of illness in Sweden. Eur J Health Econ. 2011;12:479-87

 PubMed Web of Science ®Google Scholar

College van Toezicht Sociale Verzekeringen. Bestanden ziekteverzuim uit de diagnostatistiek ziekengeldenverzekering 1993. Zoetermeer: College van Toezicht Sociale Verzekeringen; 2006

 Google Scholar