Cost-effectiveness of roflumilast as an add-on to triple inhaled therapy vs triple inhaled therapy in patients with severe and very severe COPD associated with chronic bronchitis in the UK

Figures & data

Table 1 Baseline characteristics in the pooled REACT/RE²SPOND population (ITT population receiving ICS/LABA + LAMA)

Characteristic	Roflumilast	Placebo
Baseline characteristics in the pooled REACT/RE^2SPOND populationa
Population number	1,225	1,215
Proportion of patients aged ≤65 years, %	51.8	53.5
Proportion of patients aged ≥65 years, %	48.2	46.7
Proportion of men, %	70.6	68.6
Body mass index, %
<18.5 kg/m^2	5.3	5.9
18.5–<25 kg/m^2	38.9	36.3
25–<30 kg/m^2	30.9	34.1
≥30 kg/m^2	24.9	23.7
Proportion of current smokers, %	37.3	41.2
Proportion of patients with severe COPD, %	61.3	64.8
Proportion of patients with very severe COPD, %	37.2	33.9
Proportion of patients with ≥1 prior hospitalization, %	36.2	33.3
Baseline characteristics of patients in the pooled REACT/RE^2SPOND population with at least one COPD-related hospitalizationb
Population number	444	405
Proportion of patients aged ≤65 years, %	52.9	56.5
Proportion of patients aged ≥65 years, %	47.1	43.5
Proportion of men, %	72.7	67.2
Body mass index, %
<18.5 kg/m^2	5.9	5.9
18.5–<25 kg/m^2	40.8	36.3
25–<30 kg/m^2	30.2	33.3
≥30 kg/m^2	23.2	24.4
Proportion of current smokers, %	44.8	48.1
Proportion of patients with severe COPD, %	56.1	60.2
Proportion of patients with very severe COPD, %	42.3	38.8
Proportion of patients with ≥1 prior hospitalization, %	100	100

Notes:

a ITT population receiving ICS/LABA + LAMA.

b Patients with severe COPD, who had experienced two or more exacerbations and at least one COPD-related hospitalization within the previous year, despite treatment with triple inhaled therapy.

Abbreviations: ICS, inhaled corticosteroid; ITT, intention to treat; LABA, long acting ß₂-agonist; LAMA, long-acting muscarinic receptor agonist.

Table 2 Key model inputs for the base case

Parameter	Value
Mean FEV1 for patients at the start of the model, %	40
Rate of moderate exacerbations in patients receiving triple inhaled therapy (95% CI)	0.84 (0.77–0.92)
Rate of severe exacerbations in patients receiving triple inhaled therapy (95% CI)	0.37 (0.32–0.43)
Rate of moderate exacerbations in patients receiving triple inhaled therapy + ROF (95% CI)	0.77 (0.70–0.85)
Rate of severe exacerbations in patients receiving triple inhaled therapy + ROF (95% CI)	0.32 (0.27–0.37)
Rate of moderate exacerbations in patients with ≥1 prior hospitalization receiving triple inhaled therapy (95% CI)	0.77 (0.65–0.91)
Rate of severe exacerbations in patients with ≥1 prior hospitalization receiving triple inhaled therapy (95% CI)	0.73 (0.60–0.89)
Rate of moderate exacerbations in patients with ≥1 prior hospitalization receiving triple inhaled therapy + ROF (95% CI)	0.66 (0.56–0.79)
Rate of severe exacerbations in patients with ≥1 prior hospitalization receiving triple inhaled therapy + ROF (95% CI)	0.48 (0.39–0.60)
FEV1 decline per year for patients with COPD, mL (± SEM)	52 (±0.08)
Standardized mortality ratio for background mortality (excluding hospital deaths) for patients in the severe COPD state (SEM; 95% CI)^Citation10	2.5 (0.62; 1.4–3.9)
	Standardized mortality ratio for background mortality (excluding hospital deaths) for patients in the very severe COPD state (SEM; 95% CI)^Citation10	3.85 (0.76; 2.5–5.5)
Hospital case fatality rates in patients aged 72 years, % (SEM)^Citation25	15.3 (0.09)
Utility for severe COPD (SEM; 95% CI)a, ^Citation22	0.75 (0.01; 0.73–0.77)
Utility for very severe COPD (SEM; 95% CI)a, ^Citation22	0.65 (0.03; 0.60–0.70)
Disutility for moderate exacerbation (SEM; 95% CI)^Citation23	−0.017 (0.002; −0.021, −0.012)
Disutility for severe exacerbation (SEM; 95% CI)^Citation23	−0.048 (0.009; −0.065, −0.031)
Monthly cost of ROF, £b	38.24
Monthly cost of ICS/LABA, £b	39.51
Monthly cost of LAMA, £b	33.97
Monthly maintenance costs for severe COPD, £b	32.57
Monthly maintenance costs for very severe COPD, £b	106.90
Average cost of moderate exacerbation, £b	103.85
Average cost of severe exacerbation, £b	1,724.43

Notes:

a Utilities were derived using UK general population preference weights.

b Drug costs were taken from the British National Formulary.¹⁶

Abbreviations: FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting ß₂-agonist; LAMA, long-acting muscarinic receptor agonist; ROF, roflumilast; SEM, standard error of the mean.

Figure 1 Calculation of average time to very severe COPD state, used to calculate transition probabilities.

Abbreviations: FEV 1, forced expiratory volume in 1 second; L, litres.

Table 3 Exacerbation rates in the pooled REACT and RE²SPOND population (base case) and in the scenario analyses

Exacerbation severity	Exacerbation rate (95% CI)		Rate ratio (triple inhaled therapy + ROF vs triple inhaled therapy alone) (95% CI)	P-value
	Triple inhaled therapy + ROF	Triple inhaled therapy alone
Base case analysis
Moderate or severe	1.21 (1.11–1.33)a	1.37 (1.26–1.49)b	0.89 (0.78–1.00)	0.056
Moderate	0.77 (0.70–0.85)a	0.84 (0.77–0.92)b	0.92 (0.81–1.05)	0.220
Severe	0.32 (0.27–0.37)a	0.37 (0.32–0.43)b	0.86 (0.70–1.05)	0.137
Scenario analysis in patient population with prior hospitalization
Moderate or severe	1.28 (1.10–1.49)c	1.72 (1.49–1.99)d	0.74 (0.60–0.92)	0.005
Moderate	0.66 (0.56–0.79)c	0.77 (0.65–0.91)d	0.86 (0.68–1.09)	0.214
Severe	0.48 (0.39–0.60)c	0.73 (0.60–0.89)d	0.66 (0.49–0.88)	0.004

Notes:

a n=1,225;

b n=1,215;

c n=444;

d n=405.

Abbreviation: ROF, roflumilast.

Table 4 Costs and QALYs in the pooled REACT and RE²SPOND population (base case) and in the scenario analyses

Scenario (where applicable)	Treatment group	Total costs, £	Total QALYs	Incremental costs, £	Incremental QALYs	ICER, £ per QALY gained
Base case (deterministic)
	Triple inhaled therapy + ROF	19,524	5.23
	Triple inhaled therapy	16,016	5.09	3,508	0.14	24,976
Sensitivity analysis of the base case (probabilistic)
	Triple inhaled therapy + ROF	19,599	5.25
	Triple inhaled therapy	16,071	5.11	3,528	0.14	24,682
Scenario analyses varying post-hospitalization mortality (deterministic)
Scenario 1 Roberts et al (2002)^Citation26	Triple inhaled therapy + ROF Triple inhaled therapy	19,883 16,358	5.31 5.17
				3,525	0.13	26,526
Scenario 2 Soler-Cataluña et al (2005)^Citation27	Triple inhaled therapy + ROF Triple inhaled therapy	17,606 14,509	4.82 4.72
				3,097	0.10	31,202
Scenario 3 Hartl et al (2016)^Citation28	Triple inhaled therapy + ROF Triple inhaled therapy	20,578 17,027	5.46 5.34
				3,552	0.12	30,349
Scenario 4 Wildman et al (2009)^Citation29	Triple inhaled therapy + ROF Triple inhaled therapy	15,760 12,545	4.38 4.18
				3,214	0.20	16,293
Scenario analysis in patient population with prior hospitalization (deterministic)
	Triple inhaled therapy + ROF	20,173	5.16
	Triple inhaled therapy	16,773	4.68	3,401	0.48	7,087

Abbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; ROF, roflumilast.

Figure 2 Probabilistic sensitivity analyses for the base case scenario.

Note: (A) Cost-effectiveness acceptability curve and (B) incremental cost-effectiveness scatter plot.
Abbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; ROF, roflumilast.

Figure 3 Tornado diagram for base case one-way sensitivity analysis.

Abbreviations: ICS, inhaled corticosteroids; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist; SMR, standardized mortality rate; ROF, roflumilast.

Table S1 Drug costs used in the model

Drug	Pack size	Pack cost	Cost per dose
Roflumilast
Roflumilast 500 µg	30	£37.71	£1.26
Roflumilast 500 µg	90	£113.14	£1.26
Average cost
LAMA
Tiotropium bromide 18 µg	30	£33.50	£1.12
ICS/LABA
Budesonide/formoterol fumerate dihydrate (200/6) (x2)	120	£38.00	£0.63
Budesonide/formoterol fumerate dihydrate (400/12)	60	£38.00	£0.63
Fluticasone propionate/salmetrol 500	60	£40.92	£0.68
Average cost (x2)a			£1.30
Prednisoloneb
Prednisolone 5 mg	28	£1.24	£0.04
Prednisolone 25 mg	56	£75.00	£1.34
Combined cost (30 mg dose)			£1.38
Monthly drug costs
Drug	Average cost per pill/tablet	Days of treatment	Cost per month
Roflumilast	£1.26	30.42c	£38.24
LAMA	£1.12	30.42c	£33.97
ICS/LABA	£1.30	30.42c	£39.51
Prednisolone 30 mg	£1.38	7	£9.69
Prednisolone 30 mg	£1.38	14	£19.37

Notes:

a Unit costs doubled to ensure correct dosage.

b Lowest bill burden for patients via this combination.

c Number of days in each model cycle equivalent to 365/12.

Abbreviations: ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic receptor antagonist.

Table S2 Costs associated with COPD maintenance and exacerbations

Maintenance costs
Component	Resource use (severe COPD)	Resource use (very severe COPD)	Cost per use	Cost per month (severe COPD)	Cost per month (very severe COPD)	Resource use source	Cost source
GP consultations, per year (per month, SEM)	2 (0.17, 0.05)	2 (0.17, 0.05)	£44.00	£7.33	£7.33	BMJ Best Practice (2016)^Citation17	PSSRU (2015)^Citation19
Spirometry, days per year (days per month)	2 (0.17, 0.001)	4 (0.33, 0.03)	£50.05a	£8.34	£16.68	Oostenbrink et al (2005)^Citation18	Samyshkin et al (2014)^Citation11
Influenza vaccination, % of patients (per month, SEM)	75 (6.25, 0.01)	75 (6.25, 0.01)	£6.29	£0.39	£0.39	Oostenbrink et al (2005)^Citation18	BNF (July 2016)^Citation16
Oxygen therapy, days per month (SEM)	1.22 (0.23)	6.08 (1.04)	£13.56b	£16.50	£82.49	Oostenbrink et al (2005)^Citation18	Oostenbrink et al (2005)^Citation18
Total monthly cost				£32.57	£106.90
Exacerbation costs
Component	Mean value	Cost per use	Cost per exacerbation	Resource use reference	Cost reference
Moderate exacerbations
Excess GP consultations, per year (SEM)	2.03 (0.61)	£44.00 (£9.76)	£89.32	BMJ Best Practice (2016)^Citation17 Thomas et al (2014)^Citation21	PSSRU (2015)^Citation19
Prednisolone (7 days) (% of patients)	50	£9.69	£4.84	Assumptionc	BNF (July 2016)^Citation16
Prednisolone (14 days) (% of patients)	50	£19.37	£9.69	Assumptionc	BNF (July 2016)^Citation16
Total cost			£103.85
Severe exacerbations
Excess GP consultations, per year (SEM)	8.03 (2.42)	£44.00 (£9.76)	£353.32	BMJ Best Practice (2016)^Citation17 Thomas et al (2014)^Citation21	PSSRU (2015)^Citation19
Hospital admission (% of patients)	100	£1,183.06 (£102.99)	£1,183.06	By definition	NHS reference costs (DZ65)d
Ambulance transport (% of patients)	90	£223.02 (£15.22)	£209.72	Assumption	NHS reference costs (ASS02)
Total cost			£1,724.43

Notes:

a Indexed to 2015.

b Indexed to 2015 and converted at PPP exchange rate.

c Assumed that 50% of patients will receive treatment with prednisolone for 7 days and 50% for 14 days when they have had a moderate exacerbation.

d Weighted average of non-elective short stay and long stay.

Abbreviations: BMJ, British Medical Journal; BNF, British National Formulary; GP, general practitioner; NHS, National Health Service; PPP, Purchasing Power Parity; PSSRU, Personal Social Services Research Unit.

Table S3 Probability distributions used in probabilistic sensitivity analyses

Parameter	Distribution
FEV1 decline per annum	Gamma
Covariates in the exacerbation regression equations	Normal
Rates of treatment-emergent adverse events and treatment-emergent severe adverse events	Beta
Resource use, except prednisolone use, hospital admission and ambulance transport	Beta or gamma
Unit costs, except spirometry, influenza vaccination and oxygen therapy	Gamma
COPD health state utilities and COPD exacerbation disutilities	Beta
Standardized mortality ratios	Gamma
Case fatality rate for severe exacerbations	Beta

Note: For parameterization, alpha and beta were calculated from the mean and standard error for all parameters except covariates in the exacerbation regression equations, for which a covariance matrix was used.

Abbreviation: FEV₁, forced expiratory volume in 1 second.

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