Long-acting Muscarinic Antagonist Versus Inhaled Corticosteroid when Added to Long-acting β-agonist for COPD: A Meta-analysis

Figures & data

Figure 1. Study selection.

Table 1. Study characteristics of included trials.

Study, year (Reference)	Location	Patients, n	Follow-up (weeks)	Treatment comparisons (mcg)	Mean age (SD)	Male %	Current smoker %	Baseline FEV^1 % (SD)^†	Baseline FEV^1 (SD) (L)^†	Inclusion criteria	Exclusion criteria
Vogelmeier et al. (14)	Europe Canada South Africa	933	24	ACL/FM 400/12 bid FP/SAL 500/50 bid	63.4 (7.8)	65.1	NR	NR	1.39 (0.55)	Age > 40 years GOLD criteria FEV^1 < 80% CAT score > 10	Asthma LTOT > 15 hours/day History of COPD exacerbation within 6 weeks (3 months if hospitalized) prior to enrollment Significant cardiovascular disease
Zhong et al. (15)	South America China	741	26	IND/Glyco 110/50 qd FP/SAL 500/50 bid	65.0 (7.9)	90.7	25.9	51.8 (12.8)	1.34 (0.40)	Age > 40 years GOLD criteria FEV^1 30–80% mMRC grade > 2 History of 1 or less exacerbation in the previous year	Asthma Concomitant lung disease QTC > 450 ms on ECG
Vogelmeier et al. (16)	Europe Korea	522	26	IND/Glyco 110/50 qd FP/SAL 500/50 bid	63.3 (7.9)	70.9	47.9	60.2 (10.6)	1.70 (0.45)	Age > 40 years GOLD criteria FEV^1 40–80%	Asthma concomitant lung disease LTOT History of COPD exacerbation within a year prior to enrollment Certain cardiovascular disease
Donohue et al. (17)	United States Europe South America	706	12	UMEC/VI 62.5/25 bid FP/SAL 250/50 bid	62.8 (9.0)	70.4	43.1	49.4 (10.9)	1.45 (0.44)	Age > 40 years ATS/ERS criteria FEV^1 30–70% mMRC grade > 2	Asthma concomitant lung disease LTOT > 12 hours/day History of COPD exacerbation within a year prior to enrollment Significant cardiovascular disease
Donohue et al. (17)	United States Europe Chile Mexico Russia South Africa	697	12	UMEC/VI 62.5/25 bid FP/SAL 250/50 bid	63.6 (8.6)	75.8	52.1	49.5 (10.8)	1.49 (0.46)	Same as above	Same as above
Singh et al. (18)	Europe Russia	716	12	UMEC/VI 62.5/25 bid FP/SAL 250/50 bid	61.6 (8.0)	71.9	58.8	49.4 (10.5)	1.57 (0.46)	Same as above	Same as above

^† post-bronchodilator or peak.

ACL/FM, aclidinium/formoterol; ATS/ERS, American Thoracic Society/European Respiratory Society; bid, twice a day; CAT, COPD assessment test; FEV¹, forced expiratory volume in 1 second; ECG, electrocardiogram; GOLD, global initiative for chronic obstructive Lung disease; FP/SAL, fluticasone propionate/salmeterol; IND/Glyco, indacaterol/glycopyrronium; LTOT, long-term oxygen therapy; mMRC, modified Medical Research Council; NR, not reported; SD, standard deviation; UMEC/VI, umeclidinium/vilanterol; qd, once a day; QTC, corrected QT interval.

Table 2. GRADE evidence profile and summary of findings: LABA/LAMA versus LABA/ICS combinations for patients with COPD.

Quality assessment					No. of patients			Effect
No. of studies	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	LABA/LAMA	LABA/ICS	Relative (95% CI)	Absolute (95% CI)	Quality
Mortality
6	Not serious	Not serious	Not serious	Very serious ^a,b	Undetected	6/2159 (0.3%)	5/2160 (0.2%)	RR 1.06 (0.35–3.21)	0 fewer per 1,000 (from 2 to 5)	⊕⊕◯◯LOW
Moderate-to-severe exacerbations
6	Not serious	Not serious	Not serious	Serious^b,c	Undetected	165/2159 (7.6%)	191/2160 (8.8%)	RR 0.87 (0.68–1.11)	11 fewer per 1,000 (from 10 to 28)	⊕⊕⊕◯MODERATE
Severe exacerbations
6	Not serious	Serious^d	Not serious	Very serious^a,b	Undetected	28/2159 (1.3%)	34/2160 (1.6%)	RR 0.80 (0.37–1.75)	3 fewer per 1,000 (from 10 to 12)	⊕⊕◯◯LOW
Pneumonia
6	Not serious	Not serious	Not serious	Serious^b,e	Undetected	7/2159 (0.3%)	19/2160 (0.9%)	RR 0.41 (0.18–0.94)	5 fewer per 1,000 (from 1 to 7)	⊕⊕⊕◯MODERATE
							14.3%^§		84 fewer per 1,000 (from 9 to 117)
Change from baseline in FEV^1(L)
6	Not serious	Not serious	Not serious	Not serious	Undetected	2,050	2,027	—	MD 90 ml higher (70–110)	⊕⊕⊕⊕HIGH
Change from baseline in SGRQ
5	Not serious	Not serious	Not serious	Not serious	Undetected	1,561	1,566	—	MD 0.12 lower (1.12 to 0.92)	⊕⊕⊕⊕HIGH
Transition Dyspnea Index
6	Not serious	Not serious	Not serious	Not serious	Undetected	2,049	2,042	—	MD 0.15 higher (0.05 to 0.35)	⊕⊕⊕⊕HIGH

^a Small number of events and a very wide confidence interval.

^b Optimal information size was not met.

^c Confidence interval failed to exclude important benefit or harm.

^d I²> 30%.

^{e §}Small total number of events.

Estimated from observational data (21).

FEV¹, forced expiratory volume in 1 second; GRADE, grading of recommendations assessment development and evaluation; LABA/ICS, long-acting beta-agonist/inhaled corticosteroid; LABA/LAMA, long-acting beta-agonist/long-acting muscarinic antagonist; MD, mean difference; RR, relative risk; SGRQ, St. George's Respiratory Questionnaire.

Figure 2. Summary effects of LABA/LAMA combination versus LABA/ICS on changes in FEV¹ (L). FEV¹, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist.

Figure 3. Summary effects of LABA/LAMA combination versus LABA/ICS on COPD exacerbations (A: moderate-to-severe; B: severe). ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist.

Figure 4. Summary effects of LABA/LAMA combination versus LABA/ICS on health status (A: change from baseline in SGRQ; B: TDI; C: change from baseline in CAT). CAT, COPD assessment test; ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist; SGRQ, St. George's Respiratory Questionnaire; TDI, transitional dyspnea index.

Figure 5. Summary effects of LABA/LAMA combination versus LABA/ICS on (A) mortality and (B) cardiac SAEs. ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist; SAE, serious adverse event.

Figure 6. Summary effects of LABA/LAMA combination versus LABA/ICS on (A) total SAEs and (B) dropouts due to adverse event. ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist; SAE, serious adverse event.

Figure 7. Summary effects of LABA/LAMA combination versus LABA/ICS on pneumonia. ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist.

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