Cost-effectiveness analysis of combination antifungal therapy with voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis in Spain

Figures & data

Figure 1 Decision tree model.

Note: 1- Represents the complementary probability.
Abbreviations: AE, adverse event; ANI, anidulafungin; pAEV, probability of AEs occurring with VOR monotherapy; pAEVA, probability of AEs occurring with VOR+ANI combination therapy; pMV, probability of mortality with VOR monotherapy; pMVA, probability of mortality with VOR+ANI combination therapy; pSAEV, probability of serious AEs occurring with VOR monotherapy; pSAEVA, probability of serious AEs occurring with VOR+ANI combination therapy; VOR, voriconazole.

Table 1 Economic model assumptions

Item	Average	Intervala	SD	Distribution	Alpha	Beta	References
Mortality rates, %
VOR+ANI	15.74	10.07–23.77	3.50	Beta	16.93	90.62	Marr et al^Citation9
VOR	27.27	19.82–36.26	4.19		30.51	81.35
Treatment-related AEs, %
VOR+ANI	69.74	63.49–75.33	3.02	Beta	160.49	69.65	Marr et al^Citation9
VOR	62.39	55.92–68.45	3.20		142.62	85.98
Serious treatment-related AEs, %
VOR+ANI	19.50	14.09–26.34	3.13	Beta	31.12	128.48	Marr et al^Citation9
VOR	14.18	9.37–20.90	2.94		19.85	120.06
Antifungal treatment costb €
VOR+ANI	10,899.89	10,817.01–11,126.86	79.04	Gamma	19,015.61	0.57	Ministerio de Sanidad Servicios Sociales e
VOR	6,054.74	5,971.86–6,281.71	79.04		5,867.56	1.03	Igualdad;^Citation16 Consejo General de Colegios Oficiales de Farmacéuticos^Citation13
Mild to moderate AE unit costc €
Both	457.04	365.64–548.45	46.64	Gamma	96.04	4.76	Ojeda et al;^Citation17 Martin-Iglesias;^Citation18 Llibre-Codina et al;^Citation19 Presidente de la Gerencia Regional de Salud;^Citation20 Servicio Madrileño de Salud;^Citation5 Marr et al^Citation9
Serious AE unit costc €
Both	1,859.57	1,487.66–2,231.49	189.75	Gamma	96.04	19.36	Ojeda et al;^Citation17 Ministerio de Sanidad Servicios Sociales e Igualdad;^Citation21 Holstenson et al;^Citation22 Isla et al;^Citation23 Servicio Madrileño de Salud;^Citation5 Marr et al^Citation9
Hospital stay costd €
VOR+ANI	6,815.59	5,126.41–8,728.69	918.95	Gamma	55.01	123.90	Peiró et al;^Citation38 Asensio et al;^Citation24 Marr et al^Citation9
VOR	6,274.84	4,645.32–8,127.05	888.20		49.91	125.72
Life expectancye years
Both	3.00	2.70–3.30	0.15	Gamma	384.16	0.01	Jansen et al;^Citation25 Jansen et al;^Citation26 Ament et al;^Citation27 Krueger and Nelson^Citation28

Notes:

a Interval is given as 95% CI unless otherwise indicated;

b body weight in Spanish adults (70.0 kg; 95% CI: 67.76–76.13 kg) obtained from Spanish official figures¹⁶;

c calculated on the basis of AE with significant cost (NCT00531479);

d calculated from clinical trial data,⁹ 32% of total hospital costs were subtracted as the cost of drugs to avoid double-counting;³⁸

e life expectancy of recipients of a hematopoietic stem cell transplant who survive after invasive aspergillosis treatment is ~3 years.^25–28 Interval: ±10%.

Abbreviations: AE, adverse event; ANI, anidulafungin; CI, confidence interval; SD, standard deviation; VOR, voriconazole.

Table 2 Drug acquisition cost calculation

Body weighta (kg)	Item	Day 1	Days 2–7	Days 2–14	Days 8–42	Total cost (€)
Voriconazole
70.0	Dose (mg/kg)b	840	560	–	600	–
	Administrationc	IV	IV	–	Oral	–
	Cost (€)d	517.95	2,071.79	–	3,465.00	6,054.74
67.8	Dose (mg/kg)b	813	542	–	600	–
	Administrationc	IV	IV	–	Oral	–
	Cost (€)d	501.37	2,005.48	–	3,465.00	5,971.86
76.1	Dose (mg/kg)b	914	609	–	600	–
	Administrationc	IV	IV	–	Oral	–
	Cost (€)d	563.34	–	2,253.36	3,465.00	6,281.71
Anidulafungin
Any	Dose (mg)b	200	–	100	–
	Administrationc	IV	IV	IV	–	–
	Cost (€)	646.02	–	4,199.13	–	4,845.15

Notes:

a Body weight in Spanish adults (70.0 kg; 95% CI: 67.76–76.13 kg) obtained from Spanish official figures^16,39;

b doses calculated from Marr et al⁹;

c obtained from Summary of Product Characteristics¹³;

d drug acquisition costs were obtained from the approved ex-factory prices in Spain with official 7.5% discount rate as of early 2016.¹³

Abbreviations: CI, confidence interval; IV, intravenous.

Table 3 Deterministic analysis results: base-case

Treatment	Costs (€)	Cost differences (€)	Life-years	LYG	Cost per LYGa (€)
VOR+ANI	17,902	5,493	2.529	0.348	15,785
VOR	12,409		2.181

Notes:

a Incremental cost-effectiveness ratio (cost per LYG with VOR+ANI versus VOR monotherapy).

Abbreviations: ANI, anidulafungin; LYG, life-year gained; VOR, voriconazole.

Figure 2 Tornado plot (deterministic sensitivity analysis).

Abbreviations: AE, adverse event; ANI, anidulafungin; EV, expected value of incremental cost-effectiveness ratio (€15,784.84 per LYG); LYG, life-year gained; VOR, voriconazole.

Figure 3 Cost-effectiveness plane (Monte Carlo simulation) at: (A) a willingness-to-pay threshold of €30,000; and (B) a willingness-to-pay threshold of €45,000.

Abbreviations: ANI, anidulafungin; LYG, life-year gained; VOR, voriconazole; WTP, willingness-to-pay threshold.

Figure 4 Cost-effectiveness acceptability curve.

Abbreviations: ANI, anidulafungin; VOR, voriconazole.

Table 4 Probabilistic analysis results

	Cost, € (95% CI)	LYG (95% CI)	Cost per LYGa (95% CI)
VOR+ANI	18,063 (16,431–20,020)	2.534 (2.224–2.843)	15,774 (15,763–16,692)
VOR	12,385 (10,720–14,206)	2.174 (1.862–2.495)

Notes:

a Incremental cost-effectiveness ratio (cost per LYG with VOR+ANI combination therapy vs VOR monotherapy).

Abbreviations: ANI, anidulafungin; CI, confidence interval; LYG, life-year gained; VOR, voriconazole.

MarrKASchlammHTHerbrechtRCombination antifungal therapy for invasive aspergillosis: a randomized trialAnn Intern Med20151622818925599346

 PubMed Web of Science ®Google Scholar

Ministerio de Sanidad Servicios Sociales e IgualdadTalla y peso medio, según grupo de edad y sexo [Updated 2001 July 13]. Available from: http://www.msssi.gob.es/estadEstudios/estadisticas/inforRecopilaciones/atlas/atlasDatos.htmAccessed July 6, 2016

 Google Scholar

Consejo General de Colegios Oficiales de Farmacéuticos. Bot Plus 2.0 [Updated 2016 January 26]. Available from: https://botplusweb.portalfarma.com/Accessed June 25, 2016

 Google Scholar

OjedaBde SandeLMCasadoAMerinoPCasadoMACost-minimisation analysis of pegylated liposomal doxorubicin hydrochloride versus topotecan in the treatment of patients with recurrent epithelial ovarian cancer in SpainBr J Cancer20038961002100712966416

 PubMed Web of Science ®Google Scholar

Martin-IglesiasSEstudio de costes y efectividad de la intervención enfermera en el estreñimiento crónico [Updated 2006 November 24]. Available from: http://www.isciii.es/ISCIII/es/contenidos/fd-el-instituto/fd-organizacion/fd-estructura-directiva/fd-subdireccion-general-servicios-aplicados-formacion-investigacion/fd-centros-unidades/fd-investen-isciii-2/docus/2006_X_encuentro_Investen_Albacete.pdfAccessed July 7, 2016

 Google Scholar

Llibre-CodinaJMCasado-GómezMASánchez-de la RosaRCost of nucleoside analogue reverse transcriptase inhibitor-related toxicity in HIV-1-infected patientsEnferm Infecc Microbiol Clin200725298107 Spanish17288907

 PubMed Web of Science ®Google Scholar

Presidente de la Gerencia Regional de Salud. Resolution of July 1, 2008 [Updated 2008 July 1]. Available from: http://www.saludcastil-layleon.es/institucion/es/recopilacion-normativa/asistencia-sanitaria/prestaciones-derechos/resolucion-1-julio-2008-presidente-gerencia-regional-salud-Accessed July 6, 2016

 Google Scholar

Servicio Madrileño de Salud. Order 731/2013 [Updated 2013 April 13]. Available from: http://www.madrid.org/wleg/servlet/Servidor?opcion=VerHtml&nmnorma=8275&cdestado=P#_ftn1Accessed July 6, 2016

 Google Scholar

Ministerio de Sanidad Servicios Sociales e IgualdadNorma estatal de los AP GRD V23 por cluster 2009 [Updated 2009 November 6]. Available from: http://www.msps.es/estadEstudios/estadisticas/docs/NormaGRD2009/NORMA_2009_AP_GRD_V23_CLUSTER.xlsAccessed July 6, 2016

 Google Scholar

HolstensonERingborgALindgrenPPredictors of costs related to cardiovascular disease among patients with atrial fibrillation in five European countriesEuropace2011131233020823043

 PubMed Web of Science ®Google Scholar

IslaDGonzález-RojasNNievesDBrosaMFinnernHWTreatment patterns, use of resources, and costs of advanced non-small-cell lung cancer patients in Spain: results from a Delphi panelClin Transl Oncol201113746047121775273

 PubMed Web of Science ®Google Scholar

PeiróSGómezGRejasJGuadarramaIBlancaABLength of stay and antifungal treatments costs in patients with systemic mycosis: description and associated factorsValue Health200256564

 Web of Science ®Google Scholar

AsensioABouzaEGrauSRubio-RodríguezDRubio-TerrésCCost of Clostridium difficile associated diarrhea in SpainRev Esp Salud Publica20138712533 Spanish23748655

 PubMed Web of Science ®Google Scholar

JansenJPMeisJFBlijlevensNMvan’t WoutJWEconomic evaluation of voriconazole in the treatment of invasive aspergillosis in the NetherlandsCurr Med Res Opin200521101535154616238893

 PubMed Web of Science ®Google Scholar

JansenJPKernWVCornelyOAEconomic evaluation of voriconazole versus conventional amphotericin B in the treatment of invasive aspergillosis in GermanyValue Health200691122316441520

 PubMed Web of Science ®Google Scholar

AmentAJHübbenMWVerweijPEEconomic evaluation of targeted treatments of invasive aspergillosis in adult haematopoietic stem cell transplant recipients in the Netherlands: a modelling approachJ Antimicrob Chemother200760238539317561501

 PubMed Web of Science ®Google Scholar

KruegerKPNelsonACEconomic considerations in the treatment of invasive aspergillosis: a review of voriconazole pharmacoeconomic studiesClinicoecon Outcomes Res2009200913543

 Google Scholar

Grau CerratoSMateu-de AntonioJSoto AlvarezJEconomic evaluation of voriconazole versus amphotericin B in the treatment of invasive aspergilosisFarm Hosp2005291510 Spanish15773796

 PubMedGoogle Scholar