LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis

Figures & data

Table 1 Characteristics of included studies

Comparisons of interesta	Study with reference no	Study type, duration, weeks	No of randomized patients analyzed		Outcomes measured
			LABA/LAMA	Comparator
LABA/LAMAs versus LAMAs
Ind/Gly 110/50 μg od versus Tio 18 μg od and Gly 50 μg od	NCT1285492^Citation24	Multicenter, 52	119	39	bAE, FEV1, FVC, HS, RMU
	NCT1202188^Citation25	Multicenter, 26	474	473/480 (Gly/Tio)	bFEV1, Dys, HS, RMU, With, EX, AE
	NCT1120691^Citation26	Multicenter, 64	741	741/742 (Gly/Tio)	EX, bHS, RMU, With, AE
	NCT1610037^Citation27	Multicenter, 52	407	405 (Tio)	bSAE, SAF, FEV1, HS, FVC, RMU
Ind/Gly 27.5/15.6 μg bid versus Gly 15.6 μg bid	NCT1727141	Multicenter, 12	260	261	bFEV1 AUC0–12h, Dys, HS, RMU
	NCT1712516^Citation28		250	251
Umec/Vi 62.5/25 μg versus Tio 18 μg od and Umec 62.5 μg od	NCT1316900	Multicenter, 24	212	208 (Tio)	bFEV1, Dys, HS, EX, SAF
	NCT1316913^Citation29		217	215 (Tio)
	NCT1313650^Citation30	Multicenter, 24	413	418 (Umec)	bFEV1, FVC, Dys, HS, EX, RMU, SAF
	NCT1777334^Citation31	Multicenter, 24	454	451 (Tio)	bFEV1, Dys, HS, EX, SAF
Acli/For 400/12 μg bid versus Acli 400 μg bid	NCT1437397^Citation15	Multicenter, 24	338	340	bFEV1, Dys, HS, EX, RMU, SAF
	NCT1462942^Citation32	Multicenter, 24	385	385	bFEV1, Dys, HS, EX, RMU, SAF
Tio/Olo 5/5 μg od versus Tio 5 μg od	NCT1431274	Multicenter, 52	522	527	bFEV1, bFEV1 AUC0–3h, bHS, Dys, FVC
	NCT1431287^Citation7		507	506
	NCT1964352	Multicenter, 12	204	204	bHS, bFEV1, AUC0–3h, bFEV1, Dys, FVC, SAF
	NCT2006732^Citation33		202	203
LABA/LAMAs versus LABA/ICS
Ind/Gly 110/50 μg od versus Sal/FP 50/500 μg bid	NCT1315249^Citation34	Multicenter, 26	258	264	bFEV1, AUC0–12h, FEV1, FVC, Dys, HS, RMU, SAF
	NCT1709903^Citation35	Multicenter, 26	372	369	bFEV1, FEV1 AUC0–4h, peak FEV1, FVC, HS, Dys
	NCT1782326^Citation36	Multicenter, 52	1,678	1,680	bEX, FEV1, HS, RMU, SAF, FVC, AE
Umec/Vi 62.5/25 μg od versus Sal/FP 50/250 or 500 μg bid	NCT1817764	Multicenter, 12	353	353	bFEV1, Dys, HS, EX, SAF
	NCT1879410^Citation37		349	348	bSAF, FEV1, EX
	NCT1822899^Citation38	Multicenter, 12	334	340	bFEV1, Dys, HS, RMU, SAF
Acli/For 400/12 μg bid versus Sal/FP 50/500 μg bid	NCT1908140^Citation39	Multicenter, 24	467	466	bFEV1, Dys, HS, EX, SAF

Notes:

a Only patients randomized to approved doses were included in the meta-analysis; some trials included additional comparisons.

b Primary end point.

Abbreviations: Acli, aclidinium; AE, adverse events (including serious AEs/deaths); AUC, area under the curve; bid, twice daily; Dys, dyspnea; EX, exacerbation; FEV₁, forced expiratory volume in 1 second; For, formoterol; FVC, forced vital capacity; Gly, glycopyrronium; HS, health status; Ind, indacaterol; NA, data not available; SAF, safety; od, once daily; Olo, olodaterol; Pl, placebo; QVA149, fixed-dose combination of indacaterol and glycopyrronium; RMU, rescue medication use; Sal/FP, salmeterol/fluticasone propionate; Tio, tiotropium; Umec, umeclidinium; Vi, vilanterol; With, withdrawal; CI, confidence interval; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; od, once daily; bid, twice daily.

Figure 1 Study selection process: PRISMA flow diagram identifying studies included in the meta-analysis.

Abbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 2 Effect of LABA/LAMA versus LAMA or LABA/ICS on trough and peak FEV₁

Outcome measure	Studies included	No of patients		Estimate	Effect (95% CI)	I^2, % (P-value)
		LABA/LAMA	Comparator
Trough FEV1 (L) from baseline to
LABA/LAMA versus LAMA
Week 12	^Citation7, ^Citation15, ^Citation24–Citation33	5,565	6,615	Mean difference	0.07 (0.05, 0.09)	91 (<0.0001)
Week 24–26	^Citation15, ^Citation24–Citation33	4,584	5,552		0.07 (0.05, 0.08)	56 (<0.0001)
Week 52	^Citation24, ^Citation26, ^Citation27, ^Citation33	2,015	2,488		0.07 (0.05, 0.10)	63 (<0.0001)
Total assessed for MCIDa	^Citation25, ^Citation29–Citation31	1,765	2,240	Relative risk	1.33 (1.20, 1.46)	55 (<0.0001)
Total with MCID		1,018	978	NNTB	8 (6, 9)
LABA/LAMA versus LABA/ICS
Week 12	^Citation34–Citation36, ^Citation39	3,142	3,123	Mean difference	0.08 (0.07, 0.09)	0 (<0.0001)
Week 24–26	^Citation34–Citation38	2,563	2,537		0.06 (0.00, 0.12)	90 (0.04)
Total assessed for MCID	^Citation35, ^Citation37, ^Citation38	1,371	1,383	Relative risk	1.44 (1.33, 1.56)	0 (<0.0001)
Total with MCID				NNTB	6 (5, 7)
Peak FEV1 (L) from baseline to
LABA/LAMA versus LAMA
Week 12	^Citation28, ^Citation32	893	868	Mean difference	0.10 (0.08, 0.12)	0 (<0.0001)
Week 24–26	^Citation25, ^Citation29–Citation32	2,150	2,625		0.11 (0.09, 0.12)	0 (<0.0001)
LABA/LAMA versus LABA/ICS
Week 12	^Citation34, ^Citation35, ^Citation37, ^Citation38	1,552	1,544	Mean difference	0.12 (0.10, 0.14)	0 (<0.0001)
Week 24–26	^Citation34, ^Citation35, ^Citation39	953	932		0.12 (0.09, 0.15)	62 (<0.0001)

Note:

a MCID ≥100 mL above baseline.

Abbreviations: CI, confidence interval; MCID, minimum clinically important difference; NNTB, number needed to treat for benefit; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; FEV₁, forced expiratory volume in 1 second; TDI, transitional dyspnea index.

Figure 2 Pooled mean difference for trough FEV₁ (change from baseline, L) at week 12, with 95% CIs, for eligible studies comparing approved doses of LABA/LAMA combinations with approved LAMAs.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; SD, standard deviation; IV, intravenous; od, once daily; bid, twice daily.

Figure 3 Pooled mean difference for trough FEV₁ (change from baseline, L) at (A) week 12 and (B) weeks 24–26, with 95% CIs, for eligible studies comparing approved LABA/LAMA combinations with approved LABA/ICS combinations.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; SE, standard error; od, once daily; bid, twice daily; FP, fluticasone propionate.

Table 3 Effect of LABA/LAMA versus LAMA or LABA/ICS on secondary COPD outcomes

Outcome measure	Studies included	No of patients		Estimate	Effect (95% CI)	I^2, % (P-value)
		LABA/LAMA	Comparator
TDI focal score from baseline to
LABA/LAMA versus LAMA
Week 12	^Citation25, ^Citation28–Citation30, ^Citation33	2,059	2,471	Mean difference	0.50 (0.32, 0.68)	0 (<0.0001)
Week 24	^Citation7, ^Citation25, ^Citation29, ^Citation30, ^Citation32	2,653	3,064		0.29 (0.12, 0.46)	0 (0.0006)
Total assessed for MCIDa	^Citation7, ^Citation15, ^Citation25, ^Citation28–Citation31, ^Citation33	2,444	2,865	Relative risk	1.12 (1.06, 1.18)	18 (0.0002)
Total with MCID		1,500	1,604	NNTB	19 (12, 36)
LABA/LAMA versus LABA/ICS
Week 12	^Citation34, ^Citation35, ^Citation37, ^Citation38	1,581	1,567	Mean difference	0.20 (−0.03, 0.42)	3 (0.09)
Week 26	^Citation34, ^Citation35	579	575		0.33 (−0.28, 0.95)	0 (0.29)
Health status (SGRQ) from baseline to
LABA/LAMA versus LAMA
Week 12	^Citation7, ^Citation25, ^Citation26, ^Citation28–Citation31, ^Citation33	4,101	5,189	Mean difference	−1.84 (−2.31, –1.37)	0 (<0.0001)
Week 24	^Citation7, ^Citation25, ^Citation26, ^Citation29, ^Citation31, ^Citation32	3,679	4,750		−1.34 (−1.94, −0.75)	0 (<0.0001)
Week 52	^Citation7, ^Citation26	1,987	2,539		−1.21 (−2.64, 0.21)	58 (0.09)
Total assessed for MCIDb	^Citation7, ^Citation15, ^Citation25, ^Citation26, ^Citation28–Citation31, ^Citation33	4,450	5,385	Relative risk	1.14 (1.09, 1.20)	39 (<0.0001)
Total with MCID		2,493	2,668	NNTB	16 (12, 22)
LABA/LAMA versus LABA/ICS
Week 12	^Citation34–Citation38	3,122	3,099	Mean difference	−0.43 (−1.28, 0.42)	48 (0.32)
Week 26	^Citation34–Citation36	2,160	2,143		−1.131 (−1.78, −0.48)	0 (0.0006)
Rescue medication use at EOT versus baseline
LABA/LAMA versus LAMA
Treatment period range (12–64 weeks)	^Citation25, ^Citation26, ^Citation28–Citation31	2,769	3,744	Mean difference	−0.58 (−0.70, −0.45)	0 (<0.0001)
LABA/LAMA versus LABA/ICS
Treatment period range (12–26 weeks)	^Citation34–Citation38	3,275	3,289	Mean difference	−0.18 (−0.28, −0.07)	0 (0.001)

Notes:

a MCID of TDI: ≥1 unit.

b MCID of SGRQL ≥4 units.

Abbreviations: CI, confidence interval; EOT, end of treatment; MCID, minimum clinically important difference; NNTB, number needed to treat for benefit; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnea index; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist.

Figure 4 Pooled relative risk of annualized rates of (A) moderate and/or severe exacerbations or (B) severe exacerbations, with 95% CIs, for eligible studies comparing approved LABA/LAMA combinations with approved LABA/ICS combinations.

Note: Insufficient data prevented a similar analysis to be conducted versus approved LAMAs.
Abbreviations: CI, confidence interval; ICS, inhaled corticosteroid; FEV₁, forced expiratory volume in 1 second; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist.

Table 4 Effect of LABA/LAMA versus LAMA or LABA/ICS on safety outcomes

Outcome measure	Studies included	No of patients		Relative risk
		LABA/LAMA	Comparator	Effect (95% CI)	I^2, % (P-value)
Any AE
LABA/LAMA versus LAMA	^Citation7, ^Citation15, ^Citation24–Citation33	5,687	6,840	1.00 (0.98, 1.02)	0 (0.95)
LABA/LAMA versus LABA/ICS	^Citation34–Citation39	3,835	3,838	0.94 (0.89, 0.99) NNTH: 32 (18, 100)	23 (0.02)
Serious AEs
LABA/LAMA versus LAMA	^Citation7, ^Citation15, ^Citation24–Citation33	5,687	6,840	1.01 (0.88, 1.15)	21 (0.94)
LABA/LAMA versus LABA/ICS	^Citation34–Citation39	3,616	3,656	0.90 (0.74, 1.10)	18 (0.32)
Pneumonia
LABA/LAMA versus LAMA	^Citation7, ^Citation24–Citation27, ^Citation29–Citation32, ^Citation36	4,439	5,584	1.04 (0.78, 1.38)	0 (0.79)
LABA/LAMA versus LABA/ICS	^Citation34–Citation39	3,835	3,838	0.59 (0.43, 0.81) NNTH: 84 (54, 184)	0 (0.001)
Cardiac/cardiovascular disorders
LABA/LAMA versus LAMA	^Citation24–Citation31	3,533	4,679	1.09 (0.77, 1.55)	32 (0.62)
LABA/LAMA versus LABA/ICS	^Citation34–Citation39	3,835	3,838	1.17 (0.78, 1.76)	0 (0.45)
Deaths
LABA/LAMA versus LAMA	^Citation7, ^Citation15, ^Citation24–Citation32	5,282	6,434	−0.00 (−0.00, 0.00)	0 (0.46)
LABA/LAMA versus LABA/ICS	^Citation34–Citation39	3,835	3,838	0.00 (−0.00, 0.00)	0 (0.65)
Withdrawals due to AEs
LABA/LAMA versus LAMA	^Citation7, ^Citation15, ^Citation24–Citation26, ^Citation28–Citation33	5,300	6,448	0.97 (0.80, 1.18)	19 (0.78)
LABA/LAMA versus LABA/ICS	^Citation34–Citation39	3,836	3,841	0.83 (0.69, 0.99) NNTH: 88 (45, 1,228)	0 (0.04)
Withdrawals due to lack of efficacy
LABA/LAMA versus LAMA	^Citation15, ^Citation25, ^Citation26, ^Citation28–Citation33	3,947	5,173	0.66 (0.51, 0.87) NNTH: 90 (56, 218)	0 (0.003)
LABA/LAMA versus LABA/ICS	^Citation34–Citation38	1,691	1,695	1.10 (0.60, 2.03)	0 (0.75)

Abbreviations: AE, adverse event; CI, confidence interval; NNTH, number needed to treat for harm; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist.

Figure 5 Pooled relative risk of AE incidence at end of treatment, with 95% CIs, for eligible studies comparing approved doses of LABA/LAMAs with approved doses of (A) LAMAs and (B) LABA/ICS combinations.

Abbreviations: AE, adverse event; CI, confidence interval; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; M–H, Mantel–Haenszel test.

Figure 6 Pooled relative risk of pneumonia incidence, with 95% CIs, for eligible studies comparing approved doses of LABA/LAMAs with approved doses of LABA/ICS combinations.

Abbreviations: CI, confidence interval; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; M–H, Mantel–Haenszel test.

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