Cost versus utility of aclidinium bromide 400 µg plus formoterol fumarate dihydrate 12 µg compared to aclidinium bromide 400 µg alone in the management of moderate-to-severe COPD

Figures & data

Figure 1 Five-health-state model structure.

Note: Patients can enter the model in the mild, moderate, severe, and very severe health states. Orange arrows represent the possibility for a patient to move to a less severe health state as a result of initiation of treatment. Black arrows represent the natural progression of the disease resulting in patients moving to a more severe health state. In each health state there is also the possibility to die.

Table 1 Summary of baseline features and stages of GOLD criteria

Baseline features		ACLIFORM^Citation7,Citation8	AUGMENT^Citation7,Citation8	Pooled analysis^Citation7,Citation8
Patients, n		1,726	1,668	3,394
Age, years
	Mean (SD)	63.2 (8)	63.9 (8.9)	65.3 (8.4)
	Range	40–85	40–93	40–93
Sex
	Male patients, n (%)	1,166 (67.6)	887 (57.2)	2,053 (60.5)
Current smokers, n (%)		816 (47.3)	860 (51.6)	1,676 (49.4)
Pack-years, n (SD)		40.3 (20.6)	52.7 (26.3)	46.4 (26.4)
Patients by COPD severity, n (%)
	Stage I – mild	1 (0.1)	4 (0.2)	5 (0.1)
	Stage II – moderate	1,037 (60.1)	950 (57)	1,987 (58.6)
	Stage III – severe	685 (39.7)	697 (41.8)	1,382 (40.8)
	Stage VI – very severe	2 (0.1)	12 (0.7)	14 (0.4)

Height (cm)		Mean value	Reference
	Males	175	^Citation20
	Females	162

Limits, midpoint of GOLD criteria,^Citation9 and baseline FEV1 of each health state
	Postbronchodilator FEV1 % of predicted normal value			Baseline FEV1 by sex (L)
COPD health states	Minimum	Maximum	Midpoint	Females	Males
Moderate	≥50%	<80%	65%	1.61	2.3
Severe	≥30%	<50%	40%	0.99	1.42
Very severe	≥0%	<30%	15%	0.37	0.53

Health state defined switch limits in terms of predicted normal postbronchodilator FEV1 and according to GOLD criteria
Postbronchodilator FEV1 (L)	% Predicted normal value	Predicted normal value (L)
COPD health states	Maximum	Females	Males
Mild → moderate	<80%	1.971	2.842
Moderate → severe	<50%	1.232	1.776
Severe → very severe	<30%	0.739	1.066

Note: Reproduced from European Medicines Agency. Duaklir Genuair Assessement report. 2014. © European Medicines Agency, 2014;⁷ Reproduced from Bateman ED, Chapman KR, Singh D, et al. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). Respir Res. 2015;16:92.⁸

Abbreviations: SD, standard deviation; GOLD, Global Initiative of Chronic Obstructive Lung Disease; FEV₁, forced expiratory volume in 1 second.

Table 2 Lung-function improvement, exacerbation, and pneumonia and mortality data

Mean difference in peak FEV1 by treatment at 24 weeks (mL)		24 weeks		4 weeks		PSA
		Mean	95% CI	Mean	95% CIa	Distribution (α, β)
LAMA + LABA	Aclidinium–formoterol 400/12 µg	293.2	265–321	53.1	48–58.2	N (293, 14)
LAMA alone	Aclidinium 400 µg	175	147–203	31.7	26.6–36.8	N (175, 14)

Exacerbation by health state^Citation10		OWSAb		PSAc
	Mean	Lower	Higher	Distribution (α, β)
Mild
Monthly risk of having an exacerbation	19%	16.2%	21.9%	β (138, 589)
Percentage of exacerbations treated in hospital	68.4%			NA
Moderate
Monthly risk of having an exacerbation	19%	16.2%	21.9%	β (138, 589)
Percentage of exacerbations treated in hospital	68.4%			NA
Severe
Monthly risk of having an exacerbation	24%	20.4%	27.6%	β (130, 410)
Percentage of exacerbations treated in hospital	62.5%			NA
Very severe
Monthly risk of having an exacerbation	30%	25.5%	34.5%	β (119, 278)
Percentage of exacerbations treated in hospital	66.7%			NA

Risk of pneumonia by treatment^Citation7,Citation8	Mean		OWSAd	PSAe
	Year	Month	Lower	Higher	Distribution (α, β)
LAMA	0.0069	0.0006
LABA	0.0098	0.0008
LABA + LAMA	0.0125	0.0010
Weighted average	0.0097	0.0008	0.0007	0.0009	β (21, 2158)

Mortality by health state	Mild	Moderate	Severe	Very severe
Monthly risk of dying per health state^Citation31	0.005080	0.005957	0.006645	0.008115

Notes:

a Confidence intervals were used to define upper and lower bounds of OWSA and to estimate uncertainty around the mean of PSA;

b 15% variability was considered to estimate the upper and lower bounds;

c α- and β-parameters were estimated based on the mean value and the extremes of confidence intervals;

d 30% variability was considered to estimate the upper and lower bounds;

e total number of events of pneumonia per month and total number of observed patients in subgroup analysis were considered as figures for the α- and β-parameters, respectively. Reproduced from European Medicines Agency. Duaklir Genuair Assessement report. 2014. © European Medicines Agency, 2014.⁷ Reproduced from Bateman ED, Chapman KR, Singh D, et al. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). Respir Res. 2015;16:92.⁸ Republished with permission of Dove Medical Press Limited, from Karabis A, Mocarski M, Eijgelshoven I, Bergman G. Economic evaluation of aclidinium bromide in the management of moderate to severe COPD: an analysis over 5 years. Clinicoecon Outcomes Res. 2014;6 © 2016; permission conveyed through Copyright Clearance Center, Inc.¹⁰

Abbreviations: CI, confidence interval; SD, standard deviation; FEV₁, forced expiratory volume in 1 second; OWSA, one-way sensitivity analysis; PSA, probabilistic sensitivity analysis; LAMA, long-acting muscarinic antagonist; LABA, long-acting β₂-agonist; NA, not applicable; β, Beta distribution; N, Normal distribution.

Table 3 Unit costs, resource use, and utility data

Drug costs (£)	Price/pack	Doses, n	DDD	Cost/DDD	Cost/month	Reference
Aclidinium 400 µg	28.6	60	2	0.95	29.02	^Citation32
Aclidinium/formoterol 400/12 µg	32.5	30	1	1.08	32.97	NA

Unit cost of resources (£/updated to 2014)
Cost category	Unit cost	Cost code or assumption	References
Outpatient GP visit	45		^Citation33, ^Citation35
Outpatient visit, respiratory physician	137	WF01A	^Citation34, ^Citation35
Spirometry	87.28	DZ45Z
Influenza vaccination	4.15	Injection, suspension of propiolactone-inactivated influenza virus (surface antigen, grown in fertilized hens’ eggs), net price 0.5 mL prefilled syringe £4.15	^Citation32
Oxygen therapy	14.26	Cost per day of €12.64 has been inflated from 2001 to 2014 values and converted to UK£	^Citation26, ^Citation35

Monthly cost of managing COPD by health state (£)			Mean	OWSAa		PSAb
				Lower	Higher	Distribution (α, β)
Mild (assumed as the outpatient of a GP visit assumed to be the cost of 1 outpatient GP visit described for the moderate health state)
Total cost			7.53	5.27	9.79	γ (1, 7.53)
Moderate
Cost category	Unit cost	Resource use^Citation26	Cost
Outpatient GP visit	45	0.17	7.53
Spirometry	87.28	0.17	14.61
Influenza vaccination	4.15	0.06	0.26
Total cost			22.41	15.68	29.13	γ (1, 22.41)
Severe
Cost category	Unit cost	Resource use^Citation26	Cost
Outpatient respiratory physician visit	137	0.17	22.94
Spirometry	87.28	0.17	14.61
Influenza vaccination	4.15	0.06	0.26
Oxygen therapy	14.72	1.22	17.35
Total cost			55.16	34	61	γ (1, 55.16)
Very severe
Cost category	Unit cost	Resource use^Citation26	Cost
Outpatient respiratory physician visit	137	0.33	45.67
Spirometry	87.28	0.33	29.09
Influenza vaccination	4.15	0.06	0.26
Oxygen therapy	14.72	6.08	86.73
Total cost			164.75	122	176	γ (1, 164.75)

Cost of events (£)	Mean	OWSAa		PSAb	References
		Lower	Higher	Distribution (α, β)
Exacerbation treated in hospital care	1,423	1,097	1,740	γ (1, 1,423)	^Citation11, ^Citation35
Exacerbation treated in community care	68	42	92	γ (1, 68)
Treating pneumonia	2,267	1,587	2,948	γ (1, 2,267)	^Citation34^–^Citation36

Utilities of health states and utility reduction related to events		OWSA		PSAd	Reference
Utility of health states	Mean	Lowerc	Higherc	Distribution (α, β)
Mild	0.787	0.771	0.802	β (2,109, 571)	^Citation37
Moderate	0.787	0.771	0.802
Severe	0.75	0.731	0.768	β (394, 131)
Very severe	0.647	0.598	0.695	β (241, 131)
Utility reduction
Multiplicative factor		Lowere	Highere
Exacerbation in community care	0.85	0.68	1	Normal (0.85, 0.077)	^Citation38
Exacerbation in hospital care	0.5	0.4	0.6	Normal (0.5, 0.051)	^Citation39
Pneumonia	0.5	0.4	0.6		Assumption

Notes:

a 30% variation of the mean applied;

b α- and β-parameters estimated assuming uncertainty equal to mean⁴⁰;

c 95% CIs used to define upper and lower bounds of OWSA;

d α- and β-parameters determined based on mean value and extremes of CIs;

e 20% variation of the mean applied.

Abbreviations: CI, confidence interval; SD, standard deviation; FEV₁, forced expiratory volume in 1 second; OWSA, one-way sensitivity analysis; PSA, probabilistic sensitivity analysis; LAMA, long-acting muscarinic antagonist; LABA, long-acting β₂-agonist; DDD, defined daily dose; γ, Gamma distribution; β, Beta distribution; N, Normal distribution; NA, not applicable; DZ45Z, Lung Volume Studies - Procedures in Outpatients - Lung Volume Studies ; WF01A, Consultant Led Outpatient Attendances -respiratory medicine - Non-Admitted Face to Face Attendance, Follow-up.

Figure 2 Tornado diagram of top ten drivers in comparison of aclidinium–formoterol 400/12 µg and aclidinium 400 µg (based on NMB).

Abbreviations: NMB, net monetary benefit; FEV₁, forced expiratory volume in 1 second; LAMA, long-acting muscarinic antagonist; LABA, long-acting β₂-agonist; FDC 400/12 µg, aclidinium–formoterol 400/12 µg.

Figure 3 Cost-effectiveness scatterplot of aclidinium–formoterol 400/12 µg versus aclidinium 400 µg.

Abbreviations: PSA, probabilistic sensitivity analysis; BC, base case; QALYGs, quality-adjusted life-years gained.

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