Cost-effectiveness of edoxaban versus rivaroxaban for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) in the US

Figures & data

Figure 1 Health states in the economic model.

Abbreviations: CRNM, clinically relevant nonmajor; CV, cardiovascular; ECH, extracranial hemorrhage; ICH, intracranial hemorrhage; GI, gastrointestinal; NVAF, nonvalvular atrial fibrillation.

Table 1 Patient characteristics, clinical event rates, and stroke-severity distribution

Patient characteristicsa
Starting age (years)	72
CHADS2 distribution
0	0
1	0
2	46.81%
3	30.58%
4	15.57%
5	5.81%
6	1.23%
Clinical event rates
	Warfarin (rate per 100 person-years by CHADS2 score)a					Hazard ratio in reference to warfarin
	CHADS2 =2	CHADS2 =3	CHADS2 =4	CHADS2 =5	CHADS2 =6	Edoxabanb	Rivaroxabanb	Second-line aspirin therapyc
Ischemic stroke	0.49	0.94	1.87	2.02	2.45	0.99	1.05	1.62
Hemorrhagic stroke	0.41	0.59	0.57	0.47	0	0.59	0.68	0.84
TIA	0.42	0.31	0.71	0.59	1.25	1.07	1.05	1.56
Other ICH	0.18	0.39	0.79	0.35	1.83	0.47	0.62	0.51
MI	0.45	0.74	0.93	1.19	3.10	0.91	0.87	1.42
SE	0.04	0.11	0.13	0.24	0	0.61	1.08	1.77
Major GI bleed	0.92	1.37	1.91	1.18	2.47	1.24	1.44	1.14
Major non-GI ECH	1.30	1.28	1.42	1.66	4.95	0.62	1.03	1.14
CRNM ECH	9.42	10.28	11.27	11.71	16.63	0.84	1.05	1.04
Stroke-severity distributiona
	Ischemic stroke	Hemorrhagic stroke
Mild	58.6%	32.8%
Moderate	20.4%	16.4%
Severe	7.3%	6.7%
Fatal	13.7%	44%

Notes:

a Daiichi Sankyo, data on file, 2013; γ-distribution for all values used in the probabilistic sensitivity analysis (limit values available from the authors upon request).

b Fernandez et al;²² lognormal distribution for all values used in the probabilistic sensitivity analysis (limit values available from the authors upon request).

c Adapted with permission from Sorensen SV, Kansal AR, Connolly S, et al. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspective. Thromb Haemost. 2011;105(5):908–919;⁴¹ data from Hart et al;⁴² lognormal distribution for all values used in the probabilistic sensitivity analysis (limit values available from the authors upon request).

Abbreviations: CRNM, clinically relevant nonmajor; ECH, extracranial hemorrhage; GI, gastrointestinal; ICH, intracranial hemorrhage; MI, myocardial infarction; SE, systemic embolism; TIA, transient ischemic attack.

Table 2 Mortality estimates for model inputs

Fatality rates for clinical events (other than ischemic stroke and hemorrhagic stroke)a
	Fatality rate	Sources
Other ICH	13%	Lip et al,^Citation31 Dorian et al^Citation32
MI	13.1%	Lip et al,^Citation31 Dorian et al^Citation32
SE	9.4%	Lip et al,^Citation31 Dorian et al^Citation32
Major GI bleed	2%	Lip et al,^Citation31 Dorian et al^Citation32
Major non-GI ECH	2%	Lip et al,^Citation31 Dorian et al^Citation32
Mortality risk multipliers for chronic health statesb
	Multiplier	Sources
NVAF	1.34	Lip et al,^Citation31 Dorian et al^Citation32
Ischemic stroke
Mild	3.18	Lip et al,^Citation31 Dorian et al^Citation32
Moderate	5.84	Lip et al,^Citation31 Dorian et al^Citation32
Severe	15.75	Lip et al,^Citation31 Dorian et al^Citation32
Hemorrhagic stroke
Mild	3.18	Lip et al,^Citation31 Dorian et al^Citation32
Moderate	5.84	Lip et al,^Citation31 Dorian et al^Citation32
Severe	15.75	Lip et al,^Citation31 Dorian et al^Citation32
MI	3.36	Lip et al,^Citation31 Dorian et al^Citation32
SE	1.34	Assumed to be same as NVAF

Notes:

a Triangular distribution for all values used in the probabilistic sensitivity analysis (limit values available from the authors upon request);

b lognormal distribution for all values used in the probabilistic sensitivity analysis (limit values available from the authors upon request).

Abbreviations: ECH, extracranial hemorrhage; GI, gastrointestinal; ICH, intracranial hemorrhage; MI, myocardial infarction; NVAF, nonvalvular atrial fibrillation; SE, systemic embolism.

Table 3 Health state utilities and disutilities

	Utility/disutility valuea	Sources
NVAF	0.836	Magnuson et al^Citation45
Ischemic stroke (acute and chronic)
Mild	−0.209	Canestaro et al,^Citation73 Sullivan et al^Citation74
Moderate	−0.2926	Canestaro et al,^Citation73 Sullivan et al^Citation74
Severe	−0.51	Canestaro et al,^Citation73 Sullivan et al^Citation74
Hemorrhagic stroke (acute and chronic)
Mild	−0.209	Canestaro et al,^Citation73 Sullivan et al^Citation74
Moderate	−0.2926	Canestaro et al,^Citation73 Sullivan et al^Citation74
Severe	−0.51	Canestaro et al,^Citation73 Sullivan et al^Citation74
TIA	−0.013	Freeman et al,^Citation39 Coyle et al^Citation64
Other ICH	−0.1511	Lip et al,^Citation31 Dorian et al,^Citation32 Sullivan et al^Citation75
MI (acute and chronic)	−0.1087	Canestaro et al^Citation73
SE (acute and chronic)	−0.1087	Assumed equal to MI
Major GI bleed	−0.1511	Lip et al,^Citation31 Dorian et al,^Citation32 Sullivan et al^Citation75
Major non-GI ECH	−0.1511	Lip et al,^Citation31 Dorian et al,^Citation32 Sullivan et al^Citation75
CRNM ECH	−0.0582	Lip et al,^Citation31 Dorian et al,^Citation32 Sullivan et al^Citation75
NOAC or aspirin use	−0.002	Lip et al,^Citation31 Dorian et al^Citation32

Notes:

a Triangular distribution for all values used in the probabilistic sensitivity analysis, except for chronic MI and CRNM ECH, where normal distribution was used (limit values available from the authors upon request).

Abbreviations: CRNM, clinically relevant nonmajor; ECH, extracranial hemorrhage; GI, gastrointestinal; ICH, intracranial hemorrhage; MI, myocardial infarction; NOAC, novel oral anticoagulant; NVAF, nonvalvular atrial fibrillation; SE, systemic embolism; TIA, transient ischemic attack.

Table 4 Cost inputs

Drug costs (2015 US$)
	Monthly cost		Sources
Edoxaban 60 mg, 30 mg	$277.20		First Databank^Citation46
Rivaroxaban 20 mg, 15 mg	$314.70		First Databank^Citation46
Aspirin	$2.00		Assumption
Clinical event costs (2014 US$)
	Acute cost (per episode)a	Monthly maintenance costb	Sources
Ischemic stroke
Mild	$18,836	$943	Canestaro et al,^Citation73 Eckman et al,^Citation76 Vilain et al^Citation77
Moderate	$21,943	$2,575	Canestaro et al,^Citation73 Eckman et al,^Citation76 You^Citation78
Severe	$28,192	$5,593	Canestaro et al,^Citation73 Eckman et al,^Citation76 You^Citation78
Fatal	$28,192	–	Canestaro et al,^Citation73 Eckman et al^Citation76
Hemorrhagic stroke
Mild	$20,631	$943	Canestaro et al,^Citation73 Eckman et al,^Citation76 Vilain et al^Citation77
Moderate	$29,178	$2,575	Canestaro et al,^Citation73 Eckman et al,^Citation76 You^Citation78
Severe	$37,725	$5,912	Canestaro et al,^Citation73 Eckman et al,^Citation76 You^Citation78
Fatal	$37,725		Canestaro et al,^Citation73 Eckman et al^Citation76
TIA	$3,788	–	Computed as per 2011 CMS Medicare and Medicaid reimbursement rate for MS-DRG 69, inflated to 2014 US$, and multiplied by 1.2 to account for physician fees
Other ICH	$21,964	–	Canestaro et al,^Citation73 Eckman et al^Citation76
MI	$19,151	$313	Freeman et al,^Citation39 Canestaro et al,^Citation73 Harrington et al^Citation57
SE	$21,184	–	Canestaro et al,^Citation73 Eckman et al^Citation76
Major GI bleed	$7,979	–	Agency for Healthcare Research and Quality^Citation47 (computed from all-age mean cost for DRG 378)
Major non-GI ECH	$12,064	–	Canestaro et al,^Citation73 Eckman et al^Citation76
CRNM ECH	$1,016	–	Magnuson et al^Citation45

Notes:

a Lognormal distribution for all values used in the probabilistic sensitivity analysis, except for major non-GI ECH, where triangular distribution was used (limit values available from the authors upon request);

b triangular distribution for all values used in the probabilistic sensitivity analysis (limit values available from the authors upon request).

Abbreviations: CRNM, clinically relevant nonmajor; DRG, diagnosis-related group; ECH, extracranial hemorrhage; GI, gastrointestinal; ICH, intracranial hemorrhage; MI, myocardial infarction; MS, Medicare severity; SE, systemic embolism; TIA, transient ischemic attack; CMS, Centers for Medicare & Medicaid Services.

Table 5 Analysis results

Variable	Edoxaban	Rivaroxaban
Number of events (per cohort of 100 patients)
Ischemic stroke	17.3	17.6
Recurrent ischemic stroke	2.1	2.1
Hemorrhagic stroke	4.0	4.4
Recurrent hemorrhagic stroke	0.4	0.4
TIA	6.8	6.7
Other ICH	2.4	2.9
MI	8.5	8.3
SE	1.6	1.9
Major GI bleed	20.0	24.6
Major non-GI ECH	10.6	18.9
CRNM ECH	130.1	153.4
Event-related death	6.8	7.3
Non-event-related death	93.2	92.7
Health outcomes (per cohort of 100 patients)a
LYs	899.2	892.8
QALYs	729.9	723.8
Costs (per cohort of 100 patients), US$a
Acute events	1,055,006	1,219,727
Chronic health states	1,456,128	1,499,310
Drug treatment	2,024,687	2,228,136
Total	4,535,821	4,947,173
Base-case cost-effectiveness analysis (per cohort of 100 patients)a
ΔCost (edoxaban vs rivaroxaban)	−$411,352
ΔQALYs (edoxaban vs rivaroxaban)	6.1
ICER	Edoxaban dominantb

Notes:

a Discounted at 3% per annum;

b edoxaban confers greater effectiveness at lower cost, as indicated by the positive ΔQALY and negative Δcost values versus rivaroxaban.

Abbreviations: CRNM, clinically relevant nonmajor; ECH, extracranial hemorrhage; GI, gastrointestinal; ICER, incremental cost-effectiveness ratio; ICH, intracranial hemorrhage; MI, myocardial infarction; QALYs, quality-adjusted life years; SE, systemic embolism; TIA, transient ischemic attack; LYs, life years.

Table 6 Results of one-way sensitivity analyses

Analysis variables	∆Cost and ∆QALYs versus rivaroxaban
	Low value	High value
Base-case analysis (edoxaban vs rivaroxaban)	Edoxaban dominanta
	ΔCost = −US$4,114
	ΔQALYs = +0.061
Acquisition cost of edoxaban ±13.5%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$6,845	ΔCost = −$1,382
	ΔQALYs = +0.061	ΔQALYs = +0.061
Mean starting age of cohort (60 years/80 years)	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,945	ΔCost = −$3,481
	ΔQALYs = +0.067	ΔQALYs = +0.049
Cost of ischemic stroke ±10%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,085	ΔCost = −$4,142
	ΔQALYs = +0.061	ΔQALYs = +0.061
Cost of hemorrhagic stroke ±10%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,072	ΔCost = −$4,155
	ΔQALYs = +0.061	ΔQALYs = +0.061
Cost of SE ±10%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,108	ΔCost = −$4,119
	ΔQALYs = +0.061	ΔQALYs = +0.061
Cost of major GI bleed±10%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,083	ΔCost = −$4,144
	ΔQALYs = +0.061	ΔQALYs = +0.061
Cost of non-GI ECH ±10%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,032	ΔCost = −$4,195
	ΔQALYs = +0.061	ΔQALYs = +0.061
Cost of CRNM ECH ±10%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,094	ΔCost = −$4,133
	ΔQALYs = +0.061	ΔQALYs = +0.061
Utility decrement of ischemic stroke ±25%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,114	ΔCost = −$4,114
	ΔQALYs = +0.061	ΔQALYs = +0.061
Utility decrement of hemorrhagic stroke ±25%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,114	ΔCost = −$4,114
	ΔQALYs = +0.059	ΔQALYs = +0.062
Utility decrement of SE ±25%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,114	ΔCost = −$4,114
	ΔQALYs = +0.061	ΔQALYs = +0.061
Utility decrement of major GI bleed ±25%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,114	ΔCost = −$4,114
	ΔQALYs = +0.060	ΔQALYs = +0.061
Utility decrement of non-GI ECH ±25%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,114	ΔCost = −$4,114
	ΔQALYs = +0.060	ΔQALYs = +0.061
Utility decrement of CRNM ECH ±25%	Edoxaban dominant	Edoxaban dominant
	ΔCost = −$4,114	ΔCost = −$4,114
	ΔQALYs = +0.060	ΔQALYs = +0.061

Note:

a Edoxaban confers greater effectiveness at lower cost, as indicated by the positive ΔQALY and negative Δcost values versus rivaroxaban.

Abbreviations: CRNM, clinically relevant nonmajor; ECH, extracranial hemorrhage; GI, gastrointestinal; QALYs, quality-adjusted life years; SE, systemic embolism.

Figure 2 Results of the probabilistic sensitivity analysis.

Abbreviation: QALYs, quality-adjusted life years.

FernandezMMWangJYeXSystematic review and network meta-analysis of the relative efficacy and safety of edoxaban versus other nonvitamin K antagonist oral anticoagulants among patients with nonvalvular atrial fibrillation and CHADS2 score ≥2SAGE Open Med20153111

 Google Scholar

SorensenSVKansalARConnollySCost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspectiveThromb Haemost2011105590891921431243

 PubMed Web of Science ®Google Scholar

HartRGBenaventeOMcBrideRPearceLAAntithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysisAnn Intern Med1999131749250110507957

 PubMed Web of Science ®Google Scholar

LipGYKongnakornTPhatakHCost-effectiveness of apixaban versus other new oral anticoagulants for stroke prevention in atrial fibrillationClin Ther2014362192210.e2024508420

 PubMed Web of Science ®Google Scholar

DorianPKongnakornTPhatakHCost-effectiveness of apixaban vs. current standard of care for stroke prevention in patients with atrial fibrillationEur Heart J201435281897190624513791

 PubMed Web of Science ®Google Scholar

MagnusonEAVilainKWangKCost-effectiveness of edoxaban vs warfarin in patients with atrial fibrillation based on results of the ENGAGE AF-TIMI 48 trialAm Heart J201517061140115026678636

 PubMed Web of Science ®Google Scholar

CanestaroWJPatrickARAvornJCost-effectiveness of oral anticoagulants for treatment of atrial fibrillationCirc Cardiovasc Qual Outcomes20136672473124221832

 PubMed Web of Science ®Google Scholar

SullivanPWLawrenceWFGhushchyanVA national catalog of preference-based scores for chronic conditions in the United StatesMed Care200543773674915970790

 PubMed Web of Science ®Google Scholar

FreemanJVZhuRPOwensDKCost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillationAnn Intern Med2011154111121041570

 PubMed Web of Science ®Google Scholar

CoyleDCoyleKCameronCCost-effectiveness of new oral anticoagulants compared with warfarin in preventing stroke and other cardiovascular events in patients with atrial fibrillationValue Health201316449850623796283

 PubMed Web of Science ®Google Scholar

SullivanPWSlejkoJFSculpherMJGhushchyanVCatalogue of EQ-5D scores for the United KingdomMed Decis Making201131680080421422468

 PubMed Web of Science ®Google Scholar

First DatabankFDB MedKnowledge: drug pricing Available from: http://www.fdbhealth.com/fdb-medknowledge-drug-pricingAccessed January 22, 2016

 Google Scholar

EckmanMHRosandJGreenbergSMGageBFCost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillationAnn Intern Med20091502738319153410

 PubMed Web of Science ®Google Scholar

VilainKRMagnusonEALiHCosts and cost-effectiveness of carotid stenting versus endarterectomy for patients at standard surgical risk: results from the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)Stroke20124392408241622821614

 PubMed Web of Science ®Google Scholar

YouJHNovel oral anticoagulants versus warfarin therapy at various levels of anticoagulation control in atrial fibrillation – a cost-effectiveness analysisJ Gen Intern Med201429343844624132628

 PubMed Web of Science ®Google Scholar

HarringtonARArmstrongEPNolanPEJrMaloneDCCost-effectiveness of apixaban, dabigatran, rivaroxaban, and warfarin for stroke prevention in atrial fibrillationStroke20134461676168123549134

 PubMed Web of Science ®Google Scholar

Agency for Healthcare Research and QualityHealthcare Cost and Utilization Project (HCUP)2013 Available from: http://www.ahrq.gov/research/data/hcup/index.htmlAccessed January 2, 2016

 Google Scholar