Economic evaluations of chronic obstructive pulmonary disease pharmacotherapy: how well are the real-world issues of medication adherence, comorbidities and adverse drug-reactions addressed?

Figures & data

Table 1. Study selection criteria

Selection question	Specification
Is the article an economic evaluation?	Designs to be considered: CMA, CEA, CBA, CUA or BIA
Is the disease COPD?	Not to be considered if main study focus is: asthma, tuberculosis, bronchitis or other pulmonary diseases
Is the intervention pharmacological maintenance treatment for COPD?	Pharmacological treatment-groups to be considered: LABA, LAMA, LABA/LAMA, LABA/ICS, LABA/LAMA/ICS, PDE4

COPD Chronic Obstructive Pulmonary Disease; CMA Cost-Minimization Analysis; CEA Cost-Effectiveness Analysis; CBA Cost-Benefit Analysis; CUA Cost-Utilization Analysis; BIA Budget Impact Analysis; LAMA long-acting muscarinic antagonist; LABA long-acting beta2-agonist; ICS inhaled corticosteroids; PDE₄ phosphodiesterase 4

Figure 1. PRISMA flow diagram. This diagram shows the study selection process in steps, starting from database search, then removing duplicates, selecting by abstract screening, and full-text screening. The listed criteria for eliminating the full-text articles concern the following questions: (1) Is the article an economic evaluation? (2) Is the disease COPD? (3) Is the intervention pharmacological maintenance treatment for COPD?

Figure 2. General study characteristics of recent economic evaluations of pharmacological COPD treatments. This figure shows the percentage of studies (out of the 28 reviewed articles), with particular general study characteristics. CMA Cost-Minimization Analysis; CEA Cost-Effectiveness Analysis; CBA Cost-Benefit Analysis; CUA Cost-Utilization Analysis; BIA Budget Impact Analysis; RWE real-world evidence; LAMA long-acting muscarinic antagonist; LABA long-acting beta2-agonist; ICS inhaled corticosteroids; PDE₄ phosphodiesterase 4

Table 2. Pharmacological COPD treatments compared within the studies

Pharmacological group of the studied medicine	Studied medicine	Comparator	Study identification
LAMA	Umeclidinium bromide	Tiotropium glycopyrronium	Shah et al. 2018 [24]
	Tiotropium	Glycopyrronium	Eklund et al. 2016 [33]
	Tiotropium on top of SoC	SoC	Iannazzo et al. 2016 [41]
LABA/LAMA	Umeclidinium bromide/vilanterol	Tiotropium/olodaterol	Driessen et al. 2018 ES [22]
	Tiotropium/olodaterol	Indacaterol/glycopyrronium, umeclidinium/vilanterol, aclidinium bromide/formoterol fumarate, tiotropium + salmeterol	Tebboth et al. 2016 [28]
	Aclidinium/formoterol	Tiotropium/olodaterol FDC	Capel et al. 2018 [37]
	Glycopyrronium bromide/indacaterol	Free combination of tiotropium bromide and indacaterol	Zyryanov et al. 2018 [44]
	Umeclidinium bromide/vilanterol	Tiotropium, tiotropium + LABA administered twice daily, or no long-acting bronchodilator treatment (where no such long – acting COPD maintenance treatment was administered)	Wilson et al. 2017 [27]
	Tiotropium/olodaterol	Tiotropium	Hoogendoorn et al. 2019 [19]
	Tiotropium/olodaterol	Tiotropium	van Boven et al. 2016 [29]
	Aclidinium bromide + formoterol fumarate dihydrate	Aclidinium bromide	Ramos et al. 2016 [30]
	Tiotropium/olodaterol	Tiotropium	Selya-Hammer et al. 2016 [32]
	Umeclidinium/vilanterol	Tiotropium	Miravittles et al. 2016 [34]
	Indacaterol/glycopyrronium	Tiotropium or salmeterol/fluticasone	Chan et al. 2018 [25]
	Indacaterol/glycopyrronium	Umeclidinium/vilanterol, tiotropium bromide/olodaterol, glycopyrrolate/formoterol fumarate	Rajagopalan et al. 2018 [20]
	Vilanterol/umeclidiniumbromide, indacaterol/glycopyrroniumbromide, formoterol/aclidiniumbromide, olodaterol/tiotropiumbromide	Salmeterol/fluticason, formoterol/budesonide, formoterol/beclometason, vilanterol/fluticasonfuroaat or those with addition of tiotropium bromide, aclidinium bromide, glycopyrronium bromide, umeclidinium bromide	Fens et al. 2019 [15]
	Indacaterol/glycopyrronium	Salmeterol/fluticasone	Skoupa et al. 2018 [23]
	Indacaterol/glycopyrronium	Salmeterol/fluticasone	Bjermer et al. 2017 [26]
	Indacaterol/glycopyrronium	Salmeterol/fluticasone	Maleki-Yazdi et al. 2016 [31]
	Indacaterol/glycopyrronium	Salmeterol/fluticasone combination	Tee et al. 2018 [36]
	Indacaterol/glycopyrronium vilanterol/umeclidinium formoterol/aclidinium olodaterol/tiotropium	Salmeterol/fluticasone, formoterol/budesonide, vilanterol/fluticasone formoterol/beclomethasone	Aiello et al. 2018 [40]
LABA/LAMA/ICS	Single-inhaler fluticasone furoate/umeclidinium/vilanterol	Fluticasone furoate/vilanterol or umeclidinium/vilanterol	Ismaila et al. 2019 [18]
	Fluticasone furoate/umeclidinium/vilanterol	Budesonide/formoterol	Schroeder et al. 2019 [35]
	Umeclidinium as add-on to fluticasone furoate/vilanterol, fluticasone propionate/salmeterol	Fluticasone furoate/vilanterol; fluticasone propionate/salmeterol	Driessen et al. 2018 UK [21]
LABA/ICS	Budesonide & formoterol	Delivered as Spiromax® or Turbuhaler®	Lewis et al. 2017 [42]
	Budesonide/formoterol FDC	Delivered as Symbicort® Turbuhaler® or Rilast® Turbuhaler.	Darba et al 2017 [38]
	Fluticasone furoate/vilanterol	SoC including: LABA and LAMA bronchodilators alone or in combination, ICS alone or in combination with a single long-acting bronchodilator, and ICS in combination with LAMA and LABA.	Vallejo-Aparicio et al. 2018 [39]
PDE4	Roflumilast maintenance treatment added on to triple inhaled therapy (LABA/ICS + LAMA)	Triple inhaled therapy alone (ICS/LABA + LAMA)	Kiff et al.2018 [43]

LAMA long-acting muscarinic antagonist; LABA long-acting beta2-agonist; ICS inhaled corticosteroids; PDE₄ phosphodiesterase 4; SoC standard of care; FDC fixed-dose combination

Figure 3. Inclusion of real-world outcomes in recent economic evaluations of COPD treatment (N = 28). ADR-Adverse Drug Reaction; This figure shows the percentage of studies (out of the 28 reviewed articles), reflecting the characteristics of the main review outcomes, first displaying the percentage of studies accounting for the real-world parameter (adherence, comorbidity and occurrence of ADR), secondly, the way of inclusion, and lastly the inclusion per adherence proportion, comorbidity type or ADR

Figure 4. Total QHES score per article

Figure 5. Percentage of study adherence to the reporting format for BIAs. *these articles combined BIA and economic evaluations when estimating the cost – effectiveness

Shah D, Driessen M, Risebrough N, et al. Cost-effectiveness of umeclidinium compared with tiotropium and glycopyrronium as monotherapy for chronic obstructive pulmonary disease: a UK perspective. Cost Eff Resour Alloc. 2018;16:16.

 PubMed Web of Science ®Google Scholar

Eklund O, Afzal F, Borgström F, et al. Cost-effectiveness of tiotropium versus glycopyrronium in moderate to very severe chronic obstructive pulmonary disease in Canada, Spain, Sweden, and the UK. Clinicoecon Outcomes Res. 2016;8:243–252.

 PubMed Web of Science ®Google Scholar

Iannazzo S, Distante C, Corsico AG. Costs of Tiotropium Bromide Delivered via the Respimat® Inhaler in COPD Patients in Italy. Glob Reg Health Technol Assess. 2016;3:GRHTA.5000220. .

 Web of Science ®Google Scholar

Driessen MT, Whalen J, Seewoodharry Buguth B, et al. Cost-effectiveness analysis of umeclidinium bromide/vilanterol 62. 5/25mcg versus tiotropium/olodaterol 5/5 mcg in symptomatic patients with chronic obstructive pulmonary disease: a Spanish national healthcare system perspective. Respir Res. 2018;19. DOI:10.1186/s12931-018-0916-7.

 Web of Science ®Google Scholar

Tebboth A, Ternouth A, Gonzalez-Rojas N. UK-specific cost-effectiveness of tiotropium + olodaterol fixed-dose combination versus other LAMA + LABA combinations in patients with COPD. Clinicoecon Outcomes Res. 2016;8:667–674.

 PubMedGoogle Scholar

Capel M, Mareque M, Álvarez CJ, et al. Cost-effectiveness of fixed-dose combinations therapies for chronic obstructive pulmonary disease treatment. Clin Drug Investig. 2018;38:611–620.

 PubMed Web of Science ®Google Scholar

Зырянов СК, Дьяков ИН. Фармакоэкономическая оценка двойной бронходилатационной терапии у пациентов с хронической обструктивной болезнью легких. Пульмонология. 2018:61–68. Available from https://journal.pulmonology.ru/pulm/article/view/962

 Google Scholar

Wilson MR, Patel JG, Coleman A, et al. Cost-effectiveness analysis of umeclidinium/vilanterol for the management of patients with moderate to very severe COPD using an economic model. Int J Chron Obstruct Pulmon Dis. 2017;12:997–1008.

 PubMed Web of Science ®Google Scholar

Hoogendoorn M, Corro Ramos I, Baldwin M, et al. Long-term cost-effectiveness of the fixed-dose combination of tiotropium plus olodaterol based on the DYNAGITO trial results. Int J Chron Obstruct Pulmon Dis. 2019;14:447–456.

 PubMed Web of Science ®Google Scholar

van Boven JF, Kocks JW, Postma MJ. Cost-effectiveness and budget impact of the fixed-dose dual bronchodilator combination tiotropium–olodaterol for patients with COPD in the Netherlands. Int J Chron Obstruct Pulmon Dis. 2016;11:2191–2201.

 PubMed Web of Science ®Google Scholar

Ramos M, Haughney J, Henry N, et al. 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. Clinicoecon Outcomes Res. 2016;8:445–456.

 PubMed Web of Science ®Google Scholar

Selya-Hammer C, Gonzalez-Rojas Guix N, Baldwin M, et al. Development of an enhanced health-economic model and cost-effectiveness analysis of tiotropium + olodaterol Respimat® fixed-dose combination for chronic obstructive pulmonary disease patients in Italy. Ther Adv Respir Dis. 2016;10:391–401.

 PubMed Web of Science ®Google Scholar

Miravitlles M, Gáldiz JB, Huerta A, et al. Cost-effectiveness of combination therapy umeclidinium/vilanterol versus tiotropium in symptomatic COPD Spanish patients. Int J Chron Obstruct Pulmon Dis. 2016;11:123–132.

 PubMed Web of Science ®Google Scholar

Chan M-C, Tan EC-H, Yang M-C. Cost-effectiveness analysis of a fixed-dose combination of indacaterol and glycopyrronium as maintenance treatment for COPD. Int J Chron Obstruct Pulmon Dis. 2018;1079–1088. DOI:10.2147/COPD.S159103

 PubMed Web of Science ®Google Scholar

Rajagopalan K, Bloudek L, Marvel J, et al. Cost-effectiveness of twice-daily indacaterol/glycopyrrolate inhalation powder for the treatment of moderate to severe COPD in the US. Int J Chron Obstruct Pulmon Dis. 2018;13:3867–3877.

 PubMed Web of Science ®Google Scholar

Fens T, van der Pol S, Kocks JWH, et al. Economic impact of reducing inappropriate inhaled corticosteroids use in patients with chronic obstructive pulmonary disease: ISPOR’s guidance on budget impact in practice. Value Health. 2019;22:1092–1101.

 PubMed Web of Science ®Google Scholar

Skoupa J, Kasak V, Klimes J, et al. Indacaterol/glycopyrronium versus salmeterol/fluticasone in patients with COPD—a cost-effectiveness analysis in the Czech Republic. Value Health Reg Issues. 2018;16:112–118.

 PubMedGoogle Scholar

Bjermer L, van Boven JFM, Costa-Scharplatz M, et al. Indacaterol/glycopyrronium is cost-effective compared to salmeterol/fluticasone in COPD: FLAME-based modelling in a Swedish population. Respir Res. 2017;18:206.

 PubMed Web of Science ®Google Scholar

Reza Maleki-Yazdi M, Molimard M, Keininger DL, et al. Cost effectiveness of the long-acting β2-adrenergic agonist (LABA)/long-acting muscarinic antagonist dual bronchodilator indacaterol/glycopyrronium versus the LABA/inhaled corticosteroid combination salmeterol/fluticasone in patients with chronic obstructive pulmonary disease: analyses conducted for Canada, France, Italy, and Portugal. Appl Health Econ Health Policy. 2016;14:579–594.

 PubMed Web of Science ®Google Scholar

Tee A, Chow WL, Burke C, et al. Cost-effectiveness of indacaterol/glycopyrronium in comparison with salmeterol/fluticasone combination for patients with moderate-to-severe chronic obstructive pulmonary disease: a LANTERN population analysis from Singapore. Singapore Med J. 2018;59:383–389.

 PubMed Web of Science ®Google Scholar

Aiello A, Ritrovato D, Pitotti C. Budget impact model of indacaterol/glycopyrronium in the treatment of chronic obstructive pulmonary disease in Italy based on the FLAME study. Glob Reg Health Technol Assess. 2018:2284240318804808.

 Web of Science ®Google Scholar

Ismaila AS, Risebrough N, Schroeder M, et al. Cost-effectiveness of once-daily single-inhaler triple therapy in COPD: the IMPACT trial. Int J Chron Obstruct Pulmon Dis. 2019;14:2681–2695.

 PubMed Web of Science ®Google Scholar

Schroeder M, Shah D, Risebrough N, et al. Cost-effectiveness analysis of a single-inhaler triple therapy for patients with advanced chronic obstructive pulmonary disease (COPD) using the FULFIL trial: A UK perspective. Respirat Med. 2019;1:100008.

 Google Scholar

Driessen M, Shah D, Risebrough N, et al. Cost-effectiveness of umeclidinium as add-on to ICS/LABA therapy in COPD: A UK perspective. Respir Med. 2018;145:130–137.

 PubMed Web of Science ®Google Scholar

Lewis A, Torvinen S, Dekhuijzen PNR, et al. Budesonide + formoterol delivered via Spiromax® for the management of asthma and COPD: the potential impact on unscheduled healthcare costs of improving inhalation technique compared with Turbuhaler®. Respir Med. 2017;129:179–188.

 PubMed Web of Science ®Google Scholar

Darbà J, Ramírez G, García-Rivero JL, et al. Estimating the economic consequences of an increased medication adherence due to a potential improvement in the inhaler technique with Spiromax® compared with Turbuhaler® in patients with moderate-to-severe chronic obstructive pulmonary disease in Spain. Clinicoecon Outcomes Res. 2017;9:127–137.

 PubMed Web of Science ®Google Scholar

Vallejo-Aparicio LA, Peces-Barba G, Gil A, et al. Cost–consequence analysis of fluticasone furoate/vilanterol 92/22 mcg for the management of COPD in the Spanish NHS. Clinicoecon Outcomes Res. 2018;Volume 10:501–510.

 Web of Science ®Google Scholar

Kiff C, Ruiz S, Varol N, et al. 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. Int J Chron Obstruct Pulmon Dis. 2018;13:2707–2720.

 PubMed Web of Science ®Google Scholar