Fixed-dose combination fluticasone/formoterol for asthma treatment in a real-world setting: meta-analysis of exacerbation rates and asthma control

Figures & data

Figure 1. PRISMA diagram showing the study selection process.

Table 1. Summary of data used for the meta-analysis.

Study ID	Number of patients	Observation time [months]	Severe exacerbation (N)			Asthma control (N)
			Before study	During study	Available (N)	Before study	During study	Available (N)
AFFIRM (Backer 2018) [19]	N = 2539	12	909	248	2539	723	1496^a	2220
TRANSFFFORM2 (Park 2019) [18]	N = 85; (FP/FORM n = 38)	12	24	13	85	49	64^b	85
FFAIRNESS (Schmidt 2017) [21]	N = 1410	12	575	83	1410	421	850^a	1363
EFFECTIVENESS (Wan 2017) [20]	N = 2472; (FP/FORM n = 618)	12	188	160	618	354	383^b	618
FFLUX (Usmani 2017) [22]	N = 225; (FP/FORM N = 151)	3	38	7	151	68	71^c	126

Definition of asthma control: ^aACT total score≥20; ^bRDAC; ^cGINA.

FP/FORM: fluticasone propionate and formoterol fumarate; n: number of patients.

Table 2. Risk-of-bias (ROBINS-I assessment tool) and total quality scores for individual studies.

Study ID	Bias domains							Overall risk of bias	Total score (% of max)	Total reduced score* (% of max)
	i	ii	iii	iv	v	vi	vii
FFAIRNESS	M	L	M	L	M	M	L	Moderate	56%	66%
AFFIRM	M	L	M	L	M	M	L	Moderate	66%	78%
TRANSFFFORM2	S	M	L	L	M	M	L	Serious	61%	72%
EFFECTIVENESS	L	L	L	L	M	L	L	Low	65%	76%
FFLUX	M	L	L	L	M	L	L	Moderate	75%	88%

Bias domains are as follows: I. Bias due to confounding; II. Bias in selection of participants into the study; III. Bias in classification of interventions; IV. Bias due to deviations from intended interventions; V. Bias due to missing data; VI. Bias in measurement of outcomes; VII. Bias in selection of the reported results. L: low; M: moderate; S: serious.

*Excluding questions 13 and 14.

Table 3. Results of the meta-analysis of severe exacerbation rates.

Study	Sample size	Proportion (%)	95% CI	Weight (%)
				Fixed	Random
Backer 2018	2539	9.8	8.6–10.9	52.8	21.4
Park 2019	85	15.3	8.4–24.7	1.8	17.5
Schmidt 2017	1410	5.9	4.7–7.3	29.4	21.2
Wan 2017	618	25.9	22.5–29.5	12.9	20.9
Usmani 2017	151	4.6	1.9–9.3	3.2	19.0
Total (fixed effects)	4803	10.1	9.3–10.9	100.0	100.0
Total (random effects)	4803	11.5	5.8–18.7	100.0	100.0

Figure 2. Forest plot of exacerbation rates including estimated combined effect (random effect model).

Figure 3. Forest plot of relative risk of severe asthma exacerbation including estimated combined effect (random effect model).

Table 4. Results of the meta-analysis of relative risk of severe asthma exacerbation.

Study	Sample size	Relative-Risk	95% CI	Weight (%)
				Fixed	Random
Backer 2018	2539	0.27	0.24–0.31	51.4	21.5
Park 2019	85	0.54	0.3–0.99	2.4	18.7
Schmidt 2017	1410	0.14	0.12–0.18	18.1	21.2
Wan 2017	618	0.85	0.71–1.02	26.8	21.4
Usmani 2017	151	0.18	0.09–0.40	1.4	17.2
Total (fixed effects)	4803	0.33	0.30–0.37	100.0	100.0
Total (random effects)	4803	0.32	0.16–0.66	100.0	100.0

Figure 4. Forest plot of asthma control rates including estimated combined effect (random effect model).

Table 5. Results of the meta-analysis of asthma control.

Study	Sample size	Proportion (%)	95% CI	Weight (%)
				Fixed	Random
Backer 2018	2220	67.4	65.4–69.3	52.1	25.5
Park 2019	85	58.8	48.4–69.3	1.8	12.1
Schmidt 2017	1363	62.4	59.8–64.9	29.9	24.8
Wan 2017	618	60.0	58.1–65.8	13.5	22.9
Usmani 2017	126	45.2	36.5–53.9	2.6	14.6
Total (fixed effects)	4412	64.4	63.0–65.8	100.0	100.0
Total (random effects)	4412	60.6	55.7–65.6	100.0	100.0

Figure 5. Forest-plot of odds-ratio of asthma control rate including estimated combined effect (random effect model).

Table 6. Results of meta-analysis of odds ratio of asthma control rate.

Study	Sample size	Odds-ratio	95% CI	Weight (%)
				Fixed	Random
Backer 2018	2220	4.28	3.77–4.85	49.3	21.8
Park 2019	85	2.24	1.16–4.31	1.8	16.7
Schmidt 2017	1363	3.71	3.16–4.35	30.8	21.7
Wan 2017	618	1.22	0.97–1.53	15.0	21.3
Usmani 2017	126	1.10	0.67–1.81	3.2	18.6
Total (fixed effects)	4412	3.21	2.94–3.51	100.0	100.0
Total (random effects)	4412	2.21	1.29–3.80	100.0	100.0

Table 7. Summary of treatment related adverse events.

First author and year	Backer 2018	Schmidt 2017	Usmani 2017
Study ID	AFFIRM*	FFAIRNESS **	FFLUX ***
Safety population	n = 2539	n = 1563	n = 151 (phase 1)
Treatment related adverse events by system organ class n (%)
Cardiac Disorders	NR	NR	3 (2.0%)
Gastrointestinal disorders	NR	NR	5 (3.3%)
Infections and infestations	NR	NR	4 (2.6%)
Respiratory, thoracic and mediastinal disorders	NR	NR	8 (5.3%)
Treatment related adverse events by preferred term n (%)
Asthma	50 (2.0%)	7 (0.4%)	NR
Bronchopneumonia	3 (0.1%)	NR	NR
Cough	28 (1.1%)	10 (0.6%)	NR
Dizziness	3 (0.1%)	7 (0.4%)	NR
Dry mouth	4 (0.2%)	6 (0.4%)	NR
Dysphonia	46 (1.8%)	44 (2.8%)	NR
Dyspepsia	3 (0.1%)	NR	NR
Dyspnoea	5 (0.2%)	NR	NR
Headache	10 (0.4%)	6 (0.4%)	NR
Lower RTI	7 (0.3%)	NR	NR
Nasopharyngitis	3 (0.1%)	NR	NR
Nausea	6 (0.2%)	NR	NR
Oral candidiasis	17 (0.7%)	8 (0.5%)	NR
Oral fungal infection	4 (0.2%)	NR	NR
Oropharyngeal candidiasis	3 (0.1%)	NR	NR
Oropharyngeal pain	13 (0.5%)	6 (0.4%)	NR
Palpitations	14 (0.6%)	NR	NR
RTI	3 (0.1%)	NR	NR
Sleep disorder	NR	6 (0.4%)	NR
Tachycardia	7 (0.3%)	5 (0.3%)	NR
Tremor	16 (0.6%)	11 (0.7%)	NR
Upper airway cough syndrome	3 (0.1%)	NR	NR
Upper RTI	4 (0.2%)	NR	NR

* TRAEs reported in more than 2 patients.

** TRAEs which occurred at a frequency of≥0.3%.

*** TRAEs were reported by system organ class only, preferred term was not reported.

NR: not reported, RTI: respiratory tract infection, TRAEs: treatment-related adverse event.

Backer V, Ellery A, Borzova S, et al. Non-interventional study of the safety and effectiveness of fluticasone propionate/formoterol fumarate in real-world asthma management. Ther Adv Respir Dis. 2018 Jan 20;12:175346661879698.

 Web of Science ®Google Scholar

Park H, Yoon D, Lee HY, et al. Real‐life effectiveness of inhaler device switch from dry powder inhalers to pressurized metred‐dose inhalers in patients with asthma treated with ICS/LABA. Respirology. 2019 Oct 30;24(10):972–979.

 PubMed Web of Science ®Google Scholar

Schmidt O, Petro W, Hoheisel G, et al. Real-life effectiveness of asthma treatment with a fixed-dose fluticasone/formoterol pressurised metered-dose inhaler – Results from a non-interventional study. Respir med. 2017 Oct;131:166–174.

 PubMed Web of Science ®Google Scholar

Yau Ming S W, Haughney J, Small I, et al. Initiating or changing to a fixed-dose combination of Fluticasone propionate/Formoterol over Fluticasone propionate/Salmeterol: a real-life effectiveness and cost impact evaluation. Respir med. 2017 Aug;129:199–206.

 PubMed Web of Science ®Google Scholar

Usmani OS, Kemppinen A, Gardener E, et al. A randomized pragmatic trial of changing to and stepping down fluticasone/formoterol in asthma. J Allergy Clin Immunol Pract. 2017;5(5):1378–1387.e5. Sep.

 PubMed Web of Science ®Google Scholar