Cost-effectiveness of rivaroxaban in the prevention of venous thromboembolism: A Canadian analysis using the Ontario Ministry of Health Perspective

Figures & data

Table 1.  Cost and resource use (95% CI where necessary)^a.

	Resource use	Cost	Source
Prophylaxis-related drug costs
Rivaroxaban	10 mg per day	C$8.86 per day	Ontario Drug Benefit Formulary22
Enoxaparin	40 mg per day	C$8.20 per day	Ontario Drug Benefit Formulary22
Dalteparin	5000 units per day	C$10.28 per day	Ontario Drug Benefit Formulary22
Prophylaxis-related administration and monitoring
Rivaroxaban	None required	C$0	Assumption
Enoxaparin and dalteparin	Homecare visits in outpatient period (19% patients)	C$61.23 per visit	Harrison et al.23; OACCAC24 ^b
Prophylaxis-related major bleeding
Bleeding	Non-fatal	C$10,442.95 ($9,819.17–11,066.73)	OCCI Acute Inpatient Databases for 2005/06 and 2006/0725 ^b
	Fatal	C$38,512.35 ($31,815.36–45,209.34)	OCCI Acute Inpatient Databases for 2005/06 and 2006/0725 ^b
VTE diagnosis
PE diagnosis	1 ventilation lung scan (50% patients) 1 spiral CT scan (50% patients)	C$729.08 per test ($457.14–1,000.14) C$480.58 per test ($388.94–572.32)	Skedgel et al.20; OCCI Acute Inpatient Databases for 2005/06 and 2006/0725 ^b; Ontario Schedule of Benefits26
DVT diagnosis	1 Doppler ultrasound	C$281.74 per test ($225.58–332.66)	OCCI Acute Inpatient Databases for 2005/06 and 2006/0725 ^b; Ontario Schedule of Benefits26
VTE treatment
Inpatient treatment	Extra cost of DVT during index hospitalization (7.44 additional days)	C$3149.71per stay	OCCI Acute Inpatient Databases for 2005/06 and 2006/0725 ^b
	Extra cost of PE during index hospitalization (7.13 additional days)	C$7639.81 per stay	OCCI Acute Inpatient Databases for 2005/06 and 2006/0725 ^b
	Hospitalization due to DVT (7 days)	C$9110.40 per stay	OCCI Acute Inpatient Databases for 2005/06 and 2006/0725 ^b
	Hospitalization due to PE (7.25 days)	C$7690.69 per stay	OCCI Acute Inpatient Databases for 2005/06 and 2006/0725 ^b
	First haematologist visit	C$157.00	Ontario Schedule of Benefits26
	Follow-up haematologist visit	C$105.25per hospital day	Ontario Schedule of Benefits26
	Outpatient visit	C$157.00	Skedgel et al.20; Ontario Schedule of Benefits26
	Warfarin^c	C$0.33 per day^d	Skedgel et al.20; Ontario Drug Benefit Formulary22
	INR tests every 5 days (16.5 tests)	C$12.07 per test	Skedgel et al.20; Medical Services Commission Payment Schedule27
	1 INR test per month (3 months)	C$11.74 per test	Skedgel et al.20 ^b
Outpatient management	1 GP visit	C$77.20 per visit	Skedgel et al.20; Ontario Schedule of Benefits26
	1 specialist consultation	C$157.00 per visit	Skedgel et al.20; Ontario Schedule of Benefits26
	2 specialist follow-ups	C$105.25 per visit	Skedgel et al.20; Ontario Schedule of Benefits26
	2 complete blood counts	C$10.96 per test	Skedgel et al.20; Medical Services Commission Payment Schedule27
	5 days’ LMWH	C$14.37 per day^e	Skedgel et al.20; Ontario Drug Benefit Formulary28
	5 home care visits (19% of patients)	C$61.23 per visit	Skedgel et al.20; OACCAC24 ^b
	90 days’ warfarin	C$0.33 per day	Skedgel et al.20; Ontario Drug Benefit Formulary22
	3 months’ INR monitoring	C$11.74 per month	Skedgel et al.20 ^b
	17 INR tests	C$12.07 per test	Skedgel et al.20; Medical Services Commission Payment Schedule27
Long-term complications
Recurrent VTE	Same as treating DVT post-discharge		Assumption
PTS	Diagnosis	C$1115.54 ($780.88–1450.20)	Caprini et al.29 ^f
	Treatment	C$832.13 ($582.49–1081.77)	Caprini et al.29 ^f

^aAll costs use a gamma distribution in the probabilistic sensitivity analysis, except for non-fatal bleeding (normal distribution).

^bPrices inflated to 2011 prices.

^c90 days’ warfarin treatment minus duration of hospitalization.

^dThe following adjustments were made to the prophylaxis cost post-discharge: 8% mark-up; C$7 dispensing fee; C$2 co-payment.

^eThe typical dose of Lovenox® (enoxaparin) for VTE treatment is 60–80 mg/day (Lovenox® is a registered trademark of Sanofi-Aventis). Therefore, 60 mg/day Lovenox® (enoxaparin) was assumed and costs adjusted as follows: 8% mark-up; C$7 dispensing fee; C$2 co-payment.

^fConverted to C$30 and inflated to 2011 prices.

DVT, deep vein thrombosis; GP, general practitioner; INR, international normalized ratio; LMWH, low molecular weight heparin; OCCI, Ontario Case Costing Initiative; PE, pulmonary embolism; PTS, post-thrombotic syndrome; VTE, venous thromboembolism.

Figure 1.  Decision tree.

Figure 2.  Markov model.

Table 2.  Event probabilities used in the model (95% CI)^a.

	THR: 35 days' rivaroxaban vs 35 days’ enoxaparin		THR: 35 days' rivaroxaban vs 14 days’ enoxaparin		TKR: 14 days' rivaroxaban vs 14 days’ enoxaparin
	Rivaroxaban	Enoxaparin	Rivaroxaban	Enoxaparin	Rivaroxaban		Enoxaparin
Prophylaxis period^b
VTE	0.0113 (0.0056–0.0169)	0.0372 (0.0220–0.0629)	0.0197 (0.0098–0.0295)	0.0932 (0.0562–0.1514)	0.0959 (0.0479–0.1438)		0.1881 (0.1478–0.2458)
Symptomatic VTE	0.0027 (0.0014–0.0041)	0.0050 (0.0019–0.0139)	0.0025 (0.0012–0.0037)	0.0124 (0.0036–0.0424)	0.0067 (0.0033–00.10)		0.0197 (0.0089–0.0444)
Non-fatal PE	0.0025 (0.0013–0.0038)	0.0006 (0.0000–0.0034)	0.0012 (0.0006–0.0017)	0.0046 (0.0000–0.0096)	0.0000 (0.0000–0.0000)		0.0000 (0.0046–0.0100)
Major bleeding	0.0027 (0.0014–0.0041)	0.0009 (0.0002–0.0045)	0.0008 (0.0004–0.0012)	0.0008 (0.0004–0.0012)	0.0057 (0.0029–0.0086)		0.0048 (0.0016–0.0143)
post-prophylaxis period
Probability of asymptomatic VTE becoming symptomatic	0.2045 (0.1721–0.2394)^c					0.0472 (0.0253–0.0662)^c
Probability of asymptomatic VTE becoming PE	0.0443^d*					0.0157^d*
Long-term complications
PTS: year 1	0.1800^e*					0.1800^e*
PTS: year 2	0.0792^f*					0.0792^f*
PTS: year 3–5 (annual)	0.0230^f*					0.0230^e*
Recurrent VTE: year 1–5 (annual)	0.0315^g*					0.0315^g*

^aAll event probabilities use a beta distribution in the probabilistic sensitivity analysis.

^bData from RECORD1--3 clinical trials.

^cCalculated from Quinlan et al.37

^dCalculated from White et al.38

^eReported in Prandoni et al.9

^fCalculated from Prandoni et al.9

^gCalculated from Kearon et al.39

*Values have been calculated using estimates from the literature, many of which do not report 95% CI. For the probabilistic sensitivity analysis (PSA), assumptions were made regarding the variance to inform the beta distributions. For more information regarding distributional assumptions for the PSA, please contact the corresponding author.

CI, confidence interval; PE, pulmonary embolism; PTS, post-thrombotic syndrome; THR, total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism.

NB: When comparing the above data with similar tables from Diamantopoulos et al.18, please note that, although the same model structure has been used, observed event rates are presented rather than statistically significant differences alone.

Table 3.  Utility values.

	Reported utility	Adjusted for THR	Adjusted for TKR	Source
No venous thromboembolic event	1	0.805	0.807	Assumed utility of 1 for perfect health, adjusted for utility after THR and TKR44
Prophylaxis-related bleeding	0.66	0.531 (0.66 × 0.805)	0.532 (0.66 × 0.807)	Lenert and Soetikno45, adjusted for utility after THR and TKR44
Asymptomatic DVT		0.805	0.807	Assumed to be the same as no VTE
Symptomatic DVT	0.84	0.676 (0.84 × 0.805)	0.678 (0.84 × 0.807)	Haentjens et al.23 adjusted for utility after THR and TKR44
PE	0.76	0.612 (0.76 × 0.805)	0.613 (0.76 × 0.807)	Haentjens et al.23 adjusted for utility after THR and TKR44
PTS	0.93	0.93	0.93	Lenert and Soetikno45
Recurrent VTE		0.96 (0.84 × 3/12) + (1 × 9/12)	0.96 (0.84 × 3/12) + (1 × 9/12)	Assumed the same as symptomatic DVT, applied for 3 months of the 1-year cycle
Long-term utility—no venous thromboembolic event		1	1	Assumed utility of 1 for perfect health
Death		0	0	Assumption

DVT, deep vein thrombosis; PE, pulmonary embolism; PTS, post-thrombotic syndrome; THR, total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism.

Table 4.  Costs and cost-effectiveness of rivaroxaban vs enoxaparin following THR.

	Rivaroxaban 35 days vs enoxaparin 35 days			Rivaroxaban 35 days vs enoxaparin 14 days
	Rivaroxaban	Enoxaparin	Incremental	Rivaroxaban	Enoxaparin	Incremental
Total cost, C$ (Medication + direct costs)	$437.80	$734.75	− $296.95	$418.60	$383.25	$35.35
Medication costs (C$)	$334.63	$310.05	$24.57	$334.62	$120.21	$214.41
Direct medical costs (C$)	$103.18	$424.70	−$321.52	$83.98	$263.04	−$179.06
QALY	4.1858	4.1825	0.0033	4.1857	4.1805	0.0052
Symptomatic VTE	0.0052	0.0132	−0.0081	0.0069	0.0332	−0.0263
Incremental cost per QALY (C$)			Rivaroxaban dominates			$6741.96
Incremental cost per VTE event averted (C$)			Rivaroxaban dominates			$1342.21

THR, total hip replacement; QALY, quality-adjusted life year; VTE, venous thromboembolism.

Table 5.  Costs and cost-effectiveness of thromboprophylactic intervention following TKR.

	Rivaroxaban 14 days	Enoxaparin 14 days	Incremental
Total cost, C$ (Medication + direct costs)	$279.68	$430.12	−$150.44
Medication costs (C$)	$134.71	$125.04	$9.67
Direct medical costs (C$)	$144.97	$205.08	−$160.11
QALY	4.1870	4.1851	0.0019
Symptomatic VTE	0.0125	0.0319	−0.0194
Cost per QALY			Rivaroxaban dominates
Incremental cost per VTE event averted			Rivaroxaban dominates

TKR, total knee replacement; QALY, quality-adjusted life year; VTE, venous thromboembolism.

Figure 3.  (a) Cost-utility plane for economic evaluation comparing 35 days’ rivaroxaban 10 mg od vs 35 days’ enoxaparin 40 mg od following total hip replacement. (b) Cost-utility plane for economic evaluation comparing 35 days' rivaroxaban 10 mg od vs 14 days' enoxaparin 40 mg od following total hip replacemnt over a 5-year time horizon.

Table 6.  One-way sensitivity analysis results: THR.

Sensitivity analysis	Rivaroxaban 35 days vs enoxaparin 35 days			Rivaroxaban 35 days vs enoxaparin 14 days
	Incremental cost (C$)	Incremental QALYs gained	Result	Incremental cost (C$)	Incremental QALYs gained	Result
90-day time horizon	−$286.75	0.0008	Rivaroxaban dominates	$63.74	0.0038	$16,802
0% discount rate for costs and outcomes	−$297.88	0.0037	Rivaroxaban dominates	$32.73	0.0057	$,5754
Duration of hospitalization (+2 days)	−$273.79	0.0033	Rivaroxaban dominates	$58.51	0.0052	$11,159
Duration of hospitalization (−2 days)	−$320.11	0.0033	Rivaroxaban dominates	$12.19	0.0052	$2325
8% using home care for enoxaparin injections	−$112.12	0.0033	Rivaroxaban dominates	$78.73	0.0052	$15,015
39% using home care for enoxaparin injections	−$632.99	0.0033	Rivaroxaban dominates	−$43.52	0.0052	Rivaroxaban dominates
Rivaroxaban vs dalteparin	−$374.17	0.0033	Rivaroxaban dominates	$5.22	0.0052	$996

QALY, quality-adjusted life year; THR, total hip replacement.

Table 7.  One-way sensitivity analysis results: TKR.

	Incremental cost (C$)	Incremental QALYs gained	Result
90-day time horizon	−$129.84	0.0023	Rivaroxaban dominates
0% discount rate for costs and outcomes	−$152.35	0.0020	Rivaroxaban dominates
Duration of hospitalization (+2 days)	−$126.03	0.0019	Rivaroxaban dominates
Duration of hospitalization (−2 days)	−$174.85	0.0019	Rivaroxaban dominates
8% using home care for enoxaparin injections	−$96.56	0.0019	Rivaroxaban dominates
39% using home care for enoxaparin injections	−$248.41	0.0019	Rivaroxaban dominates
Rivaroxaban vs dalteparin	−$180.83	0.0019	Rivaroxaban dominates

QALY, quality-adjusted life year; TKR, total knee replacement.

Figure 4.  Cost-utility plane for economic evaluation comparing 14 days’ rivaroxaban 10 mg od vs 14 days’ enoxaparin 40 mg od following total knee replacement over a 5-year time horizon.

Ontario Ministry of Health and Long-Term Care. Government of Ontario, Canada. 2012. https://www.healthinfo.moh.gov.on.ca/formulary/index.jsp. Accessed February 16, 2012

 Google Scholar

Harrison L, McGinnis J, Crowther M, et al. Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med 1998;158:2001-3

 PubMedGoogle Scholar

Anonymous. Ontario Association of Community Care Access Centres (OACCAC). 2010

 Google Scholar

Ontario Case Costing Initiative (OCCI). Acute Inpatient Databases for 2005/06 and 2006/07. Toronto: Ministry of Health and Long-Term Care, 2007

 Google Scholar

Skedgel C, Goeree R, Pleasance S, et al. The cost-effectiveness of extended-duration antithrombotic prophylaxis after total hip arthroplasty. J Bone Joint Surg Am 2007;89:819-28

 PubMed Web of Science ®Google Scholar

Ontario Schedule of Benefits. Physician Services under the Health Insurance Act (September 1, 2011). Toronto: Ministry of Health and Long-Term Care, 2011

 Google Scholar

Government of British Columbia. Medical Services Commission Payment Schedule. British Columbia: Government of British Columbia. 2011. http://www.health.gov.bc.ca/msp/infoprac/physbilling/payschedule/index.html Accessed February 16, 2012

 Google Scholar

Ontario Drug Benefit Formulary 2008. Ministry of Health and Long-Term Care. Toronto: Government of Ontario, Canada, 2008. http://www.health.gov.on.ca/english/providers/program/drugs/odbf_mn.html Accessed January 17, 2008

 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 2003;6:59-74

 PubMed Web of Science ®Google Scholar

X-RatesTM. http://www.x-rates.com/. Accessed March 17, 2008

 Google Scholar

Quinlan DJ, Eikelboom JW, Dahl OE, et al. Association between asymptomatic deep vein thrombosis detected by venography and symptomatic venous thromboembolism in patients undergoing elective hip or knee surgery. J Thromb Haemost 2007;5:1438-43

 PubMed Web of Science ®Google Scholar

White RH, Romano PS, Zhou H, et al. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med 1998;158:1525-31

 PubMed Web of Science ®Google Scholar

Prandoni P, Villalta S, Bagatella P, et al. The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. Haematologica 1997;82:423-8

 PubMed Web of Science ®Google Scholar

Kearon C, Ginsberg JS, Hirsh J. The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Ann Intern Med 1998;129:1044-9

 PubMed Web of Science ®Google Scholar

Diamantopoulos A, Lees M, Wells PS, et al. Cost-effectiveness of rivaroxaban versus enoxaparin for the prevention of postsurgical venous thromboembolism in Canada. Thromb Haemost 2010;104:760-70

 PubMed Web of Science ®Google Scholar

Räsänen P, Paavolainen P, Sintonen H, et al. Effectiveness of hip or knee replacement surgery in terms of quality-adjusted life years and costs. Acta Orthop 2007;78:108-15

 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 Inform Assoc 1997;4:49-56

 PubMed Web of Science ®Google Scholar