Incorporating adherence in cost-effectiveness analyses of asthma: a systematic review

Figures & data

Figure 1. A PRISMA flow diagram describing the study selection process. This figure demonstrates the approach of studies, included in this systematic review. Overall, 1,587 articles were identified through the initial search, of which 163 were assessed for their eligibility. In conclusion, a total of 23 CEA of asthma were identified, and four of the studies incorporated adherence in the analyses.

Figure 2. Diagrams demonstrating characteristics of the included studies: (a) Studies conducted to carry out the cost-effectiveness of interventions in a single or multiple countries. (b) Types of decision-analytic models, used in the analyses.

Table 1. Characteristics of the included studies.

Reference	Year	Country being studied	Participant	Intervention	Comparator	Outcome measure	Type of decision-analytic model	Perspective	Time horizon	Is the intervention cost-effective?
Altawalbeh et al.^28	2016	US	Older adults, ≥ 66 years, with asthma	Inhaled corticosteroids plus long acting beta-agonists	Inhaled corticosteroids plus leukotriene receptor antagonists	(1) Costs (2) QALY (3) ICER	Markov model	Healthcare perspective	20 years	No
Bruggenjurgen et al.^43	2010	Germany	Adults with moderate-to-severe asthma	Combination inhaler: (1) Beclomethasone dipropionate plus formoterol fumarate	Separated inhalers: (1) Beclomethasone dipropionate plus formoterol fumarate	(1) Costs (2) ICER	NR	Healthcare perspective	6 months	Yes
Campbell et al.^29	2010	US	Patients with moderate-to-severe asthma	Omalizumab plus standard therapy	Standard therapy	(1) Costs (2) QALY (3) ICER	Markov model	Healthcare perspective	Lifetime	No
Dewilde et al.^44	2006	Sweden	Patients with severe asthma	Omalizumab plus standard therapy	Standard therapy	(1) Costs (2) QALY (3) ICER	Markov model	Societal perspective	Lifetime	No
Doan et al.^38	2011	Canada	Children with asthma	Bronchodilators (metered-dose inhaler)	Bronchodilators (wet nebulization)	(1) Costs (2) ICER	Decision tree model	Hospital perspective (including emergency department and hospital admission costs)	Two days post- emergency department admissions	Yes
Doull et al.^35	2007	UK	Adults and adolescents, and children with asthma	Combination inhaler: Salmeterol xinafoate plus fluticasone propionate	(1) Fluticasone propionate (same dose) (2) Fluticasone propionate (increased dose) (3) Salmeterol xinafoate plus fluticasone propionate (separated inhalers) (4) Budesonide plus formoterol (combination inhaler)	(1) Costs (2) QALY (3) ICER	NR	Societal perspective	1 year	Yes
Faria et al.^36	2014	UK	Adults and adolescents, and children with severe asthma	Omalizumab plus standard therapy	Standard therapy	(1) Costs (2) QALY (3) ICER	Markov model	Healthcare perspective	Lifetime	No
Fuhlbrigge et al.^30	2006	US	Women, 35 years, with asthma	Inhaled corticosteroids	No inhaled corticosteroids	(1) Costs (2) QALY (3) ICER	Markov model	Societal perspective	10 year	Yes
Gerzeli et al.^40	2012	Italy	Adults with moderate-to-severe asthma	Combination inhaler: (1) Beclomethasone plus formoterol	Combination inhaler: (1) Fluticasone propionate plus salmeterol	(1) Costs (2) QALY (3) ICER (4) Time spent in successful control state	Markov model	Healthcare perspective	Lifetime	Yes
Ismaila et al.^39	2014	Canada	Patients with asthma	Combination inhaler: (1) Salmeterol xinafoate plus fluticasone propionate	(1) Fluticasone propionate (same doses: low, medium, high) (2) Fluticasone propionate (increased doses: from low to medium, medium to high)	(1) Costs (2) QALY (3) ICER	NR	Healthcare perspective	1 year	Yes (only when compared to low, medium doses, and the increased doses)
Marchetti et al.^41	2004	Italy	Adults with moderate to severe asthma	1) Beclomethasone (2) Beclomethasone- extrafine (3) Fluticasone propionate (4) Budesonide	(1) Beclomethasone (2) Beclomethasone-extrafine	(1) Costs (2) QALY (3) ICER	Decision tree and Markov models	Healthcare and societal perspectives	2 months	Yes (beclomethasone-extrafine was the most cost-effective therapy)
Norman et al.^37	2013	UK	Adults and adolescents, and children with severe asthma	Omalizumab plus standard therapy	Standard therapy	(1) Costs (2) QALY (3) ICER (4) Number of exacerbations	Markov model	Healthcare perspective	Lifetime	No
Paggiaro et al.^45	2013	UK, Netherlands, and Spain	Patients with asthma	Combination inhaler: (1) Fluticasone propionate plus salmeterol (medium and high doses)	Combination inhaler: (1) Beclomethasone plus formoterol	(1) Costs (2) QALY (3) ICER	Markov model	Healthcare perspective	6 months	No
Rodriguez-Martinez et al.^26	2013	Colombia	Children with asthma	(1) Budesonide (2) Fluticasone propionate (3) Ciclesonide	Beclomethasone dipropionate	(1) Costs (2) QALY (3) ICER	Markov model	Healthcare perspective	1 year	Yes (beclomethasone dipropionate and fluticasone propionate)
Rodriguez-Martinez et al.^34	2015	Colombia	Children with asthma	Inhaled corticosteroids (daily therapy)	Inhaled corticosteroids (intermittent)	(1) Costs (2) QALY (3) ICER	Markov model	Healthcare perspective	1 year	Yes
Rodriguez-Martinez et al.^25	2016	Colombia	Children with asthma	Budesonide (800 µg) once daily	Budesonide (400 µg) twice daily	(1) Costs (2) QALY (3) ICER	Markov model	Healthcare perspective	1 year	Yes
Shih et al.^27	2007	US	Adults and adolescents with mild-to-moderate asthma	Combination inhaler: (1) Fluticasone propionate plus salmeterol	(1) Fluticasone propionate (2) Non-fluticasone propionate inhaled corticosteroids (3) Leukotriene modifiers	(1) Costs (2) ICER	Decision tree model	Healthcare perspective	1 year	Yes
Simonella et al.^42	2006	Australia	Adults with asthma	(1) Current treatment (89% of the patients were in contact with the healthcare system, and 60% of them used inhaled corticosteroids, half of whom used it regularly) (2) Optimal treatment (all patients were in contact with the health system, except those with very mild disease, were deemed to use inhaled corticosteroids regularly and those with moderate or severe disease were deemed to use combined inhaled corticosteroids plus long acting beta-agonists)	No treatment	(1) Costs (2) YLD (3) ICER	NR	Healthcare perspective	1 year	Yes
Stanciole et al.^46	2012	Two WHO sub-regions: (1) AfrE (2) SearD	Patients with asthma	(1) Inhaled corticosteroids (low dose) (2) Inhaled corticosteroids (medium dose) (3) Inhaled corticosteroids plus long acting beta-agonists (low dose) (4) Inhaled corticosteroids plus leukotriene receptor agonists	Placebo	(1) Costs (2) DALY (3) ICER	NR	NR	Lifetime	Yes (low dose inhaled corticosteroids in AfrE and SearD, and only low dose inhaled corticosteroids plus long acting beta-agonists in AfrE)
Whittington et al.^31	2017	US	Adults with severe asthma	Mepolizumab plus standard therapy	Standard therapy	(1) Costs (2) QALY (3) ICER	Markov model	Healthcare perspective	Lifetime	No
Wu et al.^32	2007	US	Adults with severe asthma	Omalizumab plus standard therapy	Standard therapy	(1) Costs (2) QALY (3) ICER	Markov model	Societal perspective	10 years	No
Zafari et al.^24	2014	US	Adults with asthma	Full-adherence scenario: Inhaled corticosteroids or inhale corticosteroids plus long-acting beta-agonist	Status quo scenario (current status of adherence): Inhaled corticosteroids or inhale corticosteroids plus long-acting beta-agonist	(1) Costs (2) QALY (3) ICER (4) Number of exacerbations	Markov model	Societal perspective	10 years	Yes
Zafari et al.^33	2016	US	Patients with moderate-to-severe asthma	Omalizumab	Standard therapy	(1) Costs (2) QALY (3) ICER (4) Number of exacerbations	Markov model	Healthcare perspective	5 years	No

Abbreviations. AfrE, Countries in sub-Saharan Africa with very high adult and high child; mortality DALY, disability-adjusted life years; ICER, incremental cost-effectiveness ratios; QALY, quality-adjusted life years; SearD, Countries in South East Asia with high adult and high child mortality; YLD, years-lived with disability.

Table 2. Adherence data.

Reference (year)	Adherence data
	Definitions	Levels	Data sources
Shih et al. (2007)^27	Refill patterns among patients with mild-to-moderate persistent asthma	(1) Salmeterol/fluticasone propionate: 34% (2) Fluticasone propionate: 19% (3) Non-fluticasone propionate inhale corticosteroids: 19% (4) Leukotriene modifiers: 38%	Observational studies/patients claim data^47–51
Rodriguez-Martinez et al. (2013)^26	The reported frequency of administration by counting the remaining doses in an inhaler, and applied the assumptions regarding the decrease adherence over time	(1) Budesonide and ciclesonide (once-daily): 88% (3 months), 62% (9 months) and 61% (12 months) (2) Beclomethasone dipropionate and fluticasone propionate (twice-daily): 77% (3 months), 54% (9 months) and 53% (12 months)	Randomized controlled trial^52 and randomized single-blind trial^53
Zafari et al. (2014)^24	Proportion of days covered by patients	(1) Patients who were not using any controller medication: 0% (2) Patients who received low-dose controller therapy: 25% (3) Patients who received medium or high dose of controller therapy: 75%	Randomized controlled trial^55
Rodriguez-Martinez et al. (2016)^25	The reported frequency of administration using a device that recorded the date and time of an inhaler actuation, and applied the assumptions regarding the decrease adherence over time	(1)Budesonide (once-daily): 47.6% (2 months), 39.6% (4 months), 35.9% (6 months), 28.5% (8 months), 29.7% (10 months) and 28.5% (12 months) (2)Budesonide (twice-daily): 58.3% (2 months), 48.5% (4 months), 43.9% (6 months), 34.9% (8 months), 36.4% (10 months) and 34.9% (12 months)	Observational study^54 and randomized single-blind trial^53

Table 3. Quality assessment of the study methodology.

Reference (year)	Checklist items
	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	20
Altawalbeh et al. (2016)^28	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
Bruggenjurgen et al. (2010)^43	Y	Y	N	Y	N	Y	Y	Y	Y	Y	Y	Y	NA	Y	Y	Y	Y	N	Y	N
Campbell et al. (2010)^29	Y	Y	N	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	N
Dewilde et al. (2006)^44	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	N
Doan et al. (2011)^38	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	NA	Y	Y	Y	Y	Y	Y	N
Doull et al. (2007)^35	N	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	N
Faria et al. (2014)^36	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
Fuhlbrigge et al. (2006)^30	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y
Gerzeli et al. (2012)^40	N	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
Ismaila et al. (2014)^39	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	N
Marchetti et al. (2004)^41	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	N	N
Norman et al. (2013)^37	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y
Paggiaro et al. (2013)^45	N	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y
Rodriguez-Martinez et al. (2013)^26	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y
Rodriguez-Martinez et al. (2015)^34	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y
Rodriguez-Martinez et al. (2016)^25	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
Shih et al. (2007)^27	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	NA	Y	Y	Y	Y	Y	N	Y
Simonella et al. (2006)^42	N	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	NA	Y	Y	Y	Y	N	Y	Y
Stanciole et al. (2012)^46	N	Y	N	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y
Whittington et al. (2017)^31	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y
Wu et al. (2007)^32	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
Zafari et al. (2014)^24	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y
Zafari et al. (2016)^33	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y

Abbreviations. N, no; NA, not applicable; Y, yes.

Table 4. Quality assessment of the reported studies.

First author (year)	Checklist items
	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	20	21	22	23	24
Altawalbeh et al. (2016)^28	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y
Bruggenjurgen et al. (2010)^43	Y	N	Y	Y	Y	Y	Y	Y	N	Y	N	Y	Y	Y	N	N	Y	N	Y	Y	N	Y	Y	N
Campbell et al. (2010)^29	N	Y	Y	Y	Y	Y	Y	N	N	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	N	Y	Y	N
Dewilde et al. (2006)^44	N	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	N	Y	Y	N
Doan et al. (2011)^38	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	N	Y	Y	N
Doull et al. (2007)^35	N	N	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	N	Y	N	Y	Y	Y	N
Faria et al. (2014)^36	N	N	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y
Fuhlbrigge et al. (2006)^30	N	N	Y	Y	Y	Y	Y	N	N	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y
Gerzeli et al. (2012)^40	Y	Y	Y	N	Y	Y	Y	N	N	Y	N	Y	Y	Y	Y	Y	Y	N	Y	Y	N	Y	Y	Y
Ismaila et al. (2014)^39	N	Y	Y	Y	Y	Y	Y	N	N	Y	Y	Y	Y	Y	N	Y	Y	N	Y	Y	N	Y	Y	N
Marchetti et al. (2004)^41	N	N	Y	Y	Y	Y	Y	N	N	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	N	N
Norman et al. (2013)^37	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N
Paggiaro et al. (2013)^45	N	N	Y	N	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	N	N	Y	Y	Y
Rodriguez-Martinez et al. (2013)^26	N	N	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	N	Y	Y	Y	Y
Rodriguez-Martinez et al. (2015)^34	Y	N	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y
Rodriguez-Martinez et al. (2016)^25	Y	N	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	N	Y	Y	Y	Y
Shih et al. (2007)^27	N	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y
Simonella et al. (2006)^42	N	N	Y	N	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	N	N	Y	N	Y	Y	N	Y	Y	Y
Stanciole et al. (2012)^46	N	N	Y	N	Y	N	Y	N	N	Y	N	Y	Y	Y	N	Y	Y	N	Y	Y	Y	Y	Y	Y
Whittington et al. (2017)^31	N	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y
Wu et al. (2007)^32	N	N	Y	Y	Y	Y	Y	N	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
Zafari et al. (2014)^24	N	N	Y	Y	Y	Y	Y	N	N	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y
Zafari et al. (2016)^33	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	N	Y	Y	Y

Abbreviations. N, no; Y, yes.

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