LABA/LAMA fixed-dose combinations in patients with COPD: a systematic review

Figures & data

Figure 1 PRISMA flow diagram for the identification of studies included in the systematic review concerning the impact of LABA/LAMA FDCs in COPD.

Abbreviations: FDCs, fixed-dose combinations; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; PRISMA, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1 Study characteristics and investigated outcomes

Study	Trial number identifier	Study duration (weeks)	FDCs	Compar- ators	Device	Main patients’ characteristics	Investigated outcomes extracted from the studies
							FEV1 (trough, peak)	Dyspnea (TDI)	Quality of life (SGRQ)	Exacer- bations	Exercise tolerance (endurance time)	Inspira- tory capacity	Rescue medi- cation	Jadad score
D’Urzo et al^Citation11	NCT1572792	52	FOR/ACL 12/400 µg	FOR 12 µg, ACL 400 µg	DPI: Genuair™/Pressair^®	Postbronchodilator FEV1 (% predicted): 53.5; ≥1 AECOPD in the previous year (%): 21.2	Yes	Yes	Yes	Yes	No	No	Yes	5
Donohue et al^Citation12	NCT1437540	52	FOR/ACL 12/400 µg	FOR 12 µg	DPI: Genuair™/Pressair^®	Postbronchodilator FEV1 (% predicted): 51.2; ≥1 AECOPD in the previous year (%): 24.5	Yes	No	No	Yes	No	No	Yes	4
Vogelmeier et al^Citation13	NCT1908140	24	FOR/ACL 12/400 µg	SAL/FLU 50/500 µg	DPI: Genuair™/Pressair^®, Accuhaler^®	Postbronchodilator FEV1 (% predicted): 53.3; ≥1 AECOPD in the previous year (%): 32.1; AECOPD in the previous year (n): 0.43	Yes	Yes	Yes	No	No	No	No	5
Singh et al^Citation14	NCT1462942	24	FOR/ACL 12/400 µg	FOR 12 µg, ACL 400 µg	DPI: Genuair™/Pressair^®	Postbronchodilator FEV1 (% predicted): 54.3; AECOPD history: NA	Yes	Yes	Yes	No	No	No	Yes	4
D’Urzo et al^Citation15	NCT1437397	24	FOR/ACL 12/400 µg	FOR 12 µg, ACL 400 µg	DPI: Genuair™/Pressair^®	Postbronchodilator FEV1 (% predicted): 53.5; AECOPD history: NA	Yes	Yes	Yes	No	No	No	Yes	3
Martinez et al^Citation16	NCT1854645, NCT1854658	24	FOR/GLY 9.6/18 µg	GLY 18 µg, FOR 9.6, TIO 18 µg	MDI: Co-Suspension Delivery Technology, non–Co-Suspension Delivery Technology; DPI: HandiHaler^®	Postbronchodilator FEV1 (% predicted): 51.5; AECOPD history: NA	Yes	No	Yes	No	No	No	Yes	4
Hanania et al^Citation17	NCT1970878	52	FOR/GLY 9.6/18 µg	GLY 18 µg, FOR 9.6, TIO 18 µg	MDI: Co-Suspension Delivery Technology, non–Co-Suspension Delivery Technology; DPI: HandiHaler^®	FEV1 at baseline (% predicted): 43.0; 1 AECOPD in the previous year (%): 16.1; ≥2 AECOPD in the previous year (%): 6.7	Yes	Yes	Yes	Yes	No	No	Yes	4
Vogelmeier et al^Citation18	NCT1985334	12	IND/GLY 110/50 µg	ICS/LABA, LABAs, LAMAs	NA	Postbronchodilator FEV1 (% predicted): 63.6; 1 AECOPD in the previous year (%): 22.9; ≥2 AECOPD in the previous year (%): 0.6	Yes	Yes	No	No	No	No	Yes	3
Ferguson et al^Citation19	NCT1682863	52	IND/GLY 27.5/15.6 µg	IND 75 µg	DPI: Neohaler^®	Postbronchodilator FEV1 (% predicted): 54.4; 1 AECOPD in the previous year (%): 25.2; ≥2 AECOPD in the previous year (%): 7.6	Yes	No	No	Yes	No	No	Yes	4
Wedzicha et al^Citation20	NCT1782326	52	IND/GLY 110/50 µg	SAL/FLU 50/500 µg	DPI; NA, Accuhaler^®	Postbronchodilator FEV1 (% predicted): 44.1; 1 AECOPD in the previous year (%): 100; ≥2 AECOPD in the previous year (%): 19.3	Yes	No	Yes	Yes	No	No	Yes	5
Zhong et al^Citation21	NCT1709903	26	IND/GLY 110/50 µg	SAL/FLU 50/500 µg	DPI; Breezhaler^®, Accuhaler^®	Postbronchodilator FEV1 (% predicted): 51.8; 1 AECOPD in the previous year (%): 20.7; ≥2 AECOPD in the previous year (%): 0.2	Yes	Yes	Yes	No	No	No	Yes	5
Mahler et al^Citation22	NCT1727141, NCT1712516	12	IND/GLY 27.5/15.6 µg	IND 27.5 µg, GLY 15.6 µg	DPI: Neohaler^®	Postbronchodilator FEV1 (% predicted): 54.6; 1 AECOPD in the previous year (%): 24.2; ≥2 AECOPD in the previous year (%): 6.9	Yes	Yes	Yes	No	No	No	Yes	5
Beeh et al^Citation23	NCT1294787	3	IND/GLY 110/50 µg	TIO 18 µg	DPI: Breezhaler^®, HandiHaler^®	Postbronchodilator FEV1 (% predicted): 55.9; 1 AECOPD in the previous year (%): 14.3; ≥2 AECOPD in the previous year (%): 2.4	No	No	No	No	Yes	Yes	No	5
Bateman et al^Citation24	NCT1202188	26	IND/GLY 110/50 µg	GLY 50 µg, IND 150, TIO 18 µg	DPI: Breezhaler^®, HandiHaler^®	Postbronchodilator FEV1 (% predicted): 55.2; 1 AECOPD in the previous year (%): 19.3; ≥2 AECOPD in the previous year (%): 5.6	Yes	Yes	Yes	No	No	No	Yes	4
Wedzicha et al^Citation25	NCT1120691	64	IND/GLY 110/50 µg	GLY 50 µg, TIO 18 µg	DPI: Breezhaler^®, HandiHaler^®	Postbronchodilator FEV1 (% predicted): 37.2; 1 AECOPD in the previous year (%): 76.0; ≥2 AECOPD in the previous year (%): 22.3	Yes	No	Yes	Yes	No	No	Yes	5
Vogelmeier et al^Citation26	NCT1315249	26	IND/GLY 110/50 µg	SAL/FLU 50/500 µg	DPI; Breezhaler^®, Accuhaler^®	Postbronchodilator FEV1 (% predicted): 50.9; ≥1 AECOPD in the previous year (%): 0.2	Yes	Yes	Yes	No	No	No	Yes	5
Ferguson et al^Citation27	NCT1431274, NCT1431287	52	OLO/TIO 5/5 µg	OLO 5 µg, TIO 5 µg	SMI: Respimat^®	Postbronchodilator FEV1 (% predicted): 52.6; AECOPD history: NA	No	Yes	No	No	No	No	No	3
O’Donnell et al^Citation28	NCT1533922, NCT1533935	6	OLO/TIO 5/5 µg	OLO 5 µg, TIO 5 µg	SMI: Respimat^®	Postbronchodilator FEV1 (% predicted): 52.0; AECOPD history: NA	No	No	No	No	Yes	Yes	No	3
Buhl et al^Citation29	NCT1431274, NCT1431287	52	OLO/TIO 5/5 µg	OLO 5 µg, TIO 5 µg	SMI: Respimat^®	Postbronchodilator FEV1 (% predicted): 50.0; AECOPD history: NA	Yes	No	Yes	No	No	No	Yes	3
Singh et al^Citation30	NCT1964352, NCT2006732	12	OLO/TIO 5/5 µg	TIO 5 µg	SMI: Respimat^®	Postbronchodilator FEV1 (% predicted): 55.1; AECOPD history: NA	Yes	Yes	Yes	No	No	No	No	3
Kerwin et al^Citation31	NCT1899742	12	VIL/UME 25/62.5 µg	TIO 18 µg	DPI: Ellipta^®, HandiHaler^®	Postbronchodilator FEV1 (% predicted): 59.6; ≥1 AECOPD in the previous year (%): 34.0	Yes	Yes	Yes	No	No	No	Yes	5
Singh et al^Citation32	NCT1822899	12	VIL/UME 25/62.5 µg	SAL/FLU 50/500 µg	DPI: Ellipta^®, Diskus^®	Postbronchodilator FEV1 (% predicted): 50.6; ≥1 AECOPD in the previous year (%): 0.0	Yes	Yes	Yes	No	No	No	Yes	5
Donohue et al^Citation33	NCT1817764, NCT1879410	12	VIL/UME 25/62.5 µg	SAL/FLU 25/250 µg	DPI: Ellipta^®, Diskus^®	Postbronchodilator FEV1 (% predicted): 49.5; ≥1 AECOPD in the previous year (%): 0.0	Yes	Yes	Yes	No	No	No	Yes	5
Decramer et al^Citation34	NCT1316900, NCT1316913	24	VIL/UME 25/62.5 µg	VIL 25 µg, TIO 18 µg	DPI: Ellipta^®, HandiHaler^®	Postbronchodilator FEV1 (% predicted): 47.4; ≥1 AECOPD in the previous year (%): 38.1	Yes	Yes	Yes	No	No	No	Yes	5
Maleki-Yazdi et al^Citation35	NCT1777334	24	VIL/UME 25/62.5 µg	TIO 18 µg	DPI: Ellipta^®, HandiHaler^®	Postbronchodilator FEV1 (% predicted): 46.4; AECOPD history: NA	Yes	No	Yes	No	No	No	Yes	5
Maltais et al^Citation36	NCT1323660, NCT1328444	12	VIL/UME 25/62.5 µg	VIL 25 µg, UME 62.5 µg	DPI: Ellipta^®	Postbronchodilator FEV1 (% predicted): 51.3; AECOPD history: NA	Yes	No	No	No	Yes	Yes	Yes	4
Donohue et al^Citation37	NCT1313650	24	VIL/UME 25/62.5 µg	VIL 25 µg, UME 62.5 µg	DPI: NA	Postbronchodilator FEV1 (% predicted): 47.4; AECOPD history: NA	Yes	Yes	Yes	No	No	No	Yes	4

Abbreviations: ACL, aclidinium bromide; AECOPD, acute exacerbation of COPD; DPI, dry powder inhaler; FDC, fixed-dose combination; FEV₁, forced expiratory volume in 1 second; FLU, fluticasone fumarate; FOR, formoterol fumarate; GLY, glycopyrronium or glycopyrrolate; ICS, inhaled corticosteroid; IND, indacaterol; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; MDI, metered dose inhaler; NA, not available; OLO, olodaterol; SAL, salmeterol; SGRQ, St George’s Respiratory Questionnaire; SMI, soft mist inhaler; TDI, transition dyspnea index; TIO, tiotropium; UME, umeclidinium; VIL, vilanterol.

Table 2 Synthesis of the main pharmacological characteristics of LABAs, LAMAs, and ICS investigated in the clinical trials included in this systematic review

Drugs	Main pharmacological targets				Functional selectivity β2/β1 ratio	References
	β2 -AR
	pKi	IA (% isoprenaline)	Onset of action (t½, minutes)	Duration of action (hours)
LABAs
Formoterol	8.06	95.0	5.9	0.93	130	^Citation55–Citation61
Indacaterol	7.64	86.0	10.9	9.75	12.5	^Citation55–Citation58, ^Citation60, ^Citation61
Olodaterol	9.14	88	NA	NA	65	^Citation55, ^Citation59, ^Citation61
Salmeterol	9.35	39.50	13.65	≈12	1,595	^Citation55–Citation59
Vilanterol	9.42	70.00	3.45	NA	2,400	^Citation55, ^Citation56, ^Citation61
	M3 mAChR				M3/M2 ratio
	pKi	K (h^−1 off)	Onset of action (t½, minutes)	Duration of action (hours)
LAMAs
Aclidinium	9.85	0.071	8.20	10.7	5.9	^Citation61–Citation66
Glycopyrronium	9.28	0.11	8.72	6.1	16.5	^Citation61–Citation65, ^Citation67
Tiotropium	9.72	0.091	10.2	27	8.7	^Citation61–Citation65, ^Citation67
Umeclidinium	9.80	0.53	9.0	1.37	8.7	^Citation61, ^Citation63, ^Citation65, ^Citation68
	Relative lipophilicity	Receptor binding affinity (relative to binding affinity with dexamethasone =1)	Onset of action (t½, minutes)	Receptor complex half- life (hours)	Topical skin blanching potency (relative to dexamethasone =1)
ICS
Fluticasone	4.50	18.00	864	10.50	599.40	^Citation69, ^Citation70

Abbreviations: AR, adrenergic receptor; IA, intrinsic activity; ICS, inhaled corticosteroid; K_off, dissociation rate; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; mAChR, muscarinic acetylcholine receptor; NA, not available; pKi, the negative logarithm to base 10 of the equilibrium dissociation constant; t½, residence half-life.

Table 3 Studies in which LABA/LAMA combinations were significantly superior ↑, similar ≈, or inferior ↓ to comparators

LABA/LAMA FDC	Comparators	Trough FEV1	Peak FEV1	TDI	SGRQ	Exacerbations	Exercise tolerance	Isotime IC	Rescue medication use
Formoterol/aclidinium 400/12 µg BID via Genuair	LABA monotherapy	↑: [12, 14, 15]	↑: [14, 15]	↑: [11, 15]	≈: [11, 14, 15]	≈: [11, 12]			≈: [11, 12, 14]
	LAMA monotherapy	↑: [15] ≈: [11, 14]	↑: [14, 15]	↑: [11] ≈: [15]	≈: [11, 14, 15]	≈: [11]			↑: [14, 15] ≈: [11]
	LABA/ICS	≈: [13]	↑: [13]	≈: [13]	≈: [13]				≈: [13]
Formoterol/glycopyrrolate 8/9.6 µg (two actuations) BID via pMDI	LABA monotherapy	↑: [16, 17]	↑: [16, 17]	↑: [17]	≈: [16, 17]	≈: [17]			↑: [16j] ≈: [17]
	LAMA monotherapy	↑: [16a, 17]	↑: [16, 17]	↑: [17f]	↑: [16f and h, 17f]	≈: [17]			↑: [16k, 17]
	LABA/ICS
Indacaterol/glycopyrronium 110/50 µg OD via Breezhaler or 27.5/15.6 µg BID via Neohaler	LABA monotherapy	↑: [18b, 19, 22, 24]	↑: [22, 24]	↑: [18b, 22] ≈: [24]	↑: [22] ≈: [24]	≈: [19]			↑: [18b, 22, 24] ≈: [19]
	LAMA monotherapy	↑: [18b, 22, 24, 25]	↑: [22, 24]	↑: [18b, 22, 24g]	↑: [22, 24g, 25]	↑: [25f]	≈: [23]	↑: [23]	↑: [18b, 22, 24, 25]
	LABA/ICS	↑: [18, 20, 21, 26]	↑: [21, 26]	↑: [18, 26] ≈: [21]	↑: [20] ≈: [21, 26]	↑: [20]			↑: [18, 20, 26] ≈: [21]
Olodaterol/tiotropium 5/5 µg OD via Respimat	LABA monotherapy	↑: [29]		↑: [27, 29]	↑: [29]		↑: [28]	↑: [28]	↑: [29]
	LAMA monotherapy	↑: [29, 30c]		↑: [27, 29, 30]	↑: [29, 30i]		≈: [28]	↑: [28]	↑: [29]
	LABA/ICS
Vilanterol/umeclidinium 62.5/25 µg OD via Ellipta	LABA monotherapy	↑: [34, 36d, 37]	↑: [34, 37]	≈: [34, 37]	≈: [34, 37]				≈: [34, 37]
	LAMA monotherapy	↑: [31, 34, 35, 36d, 37]	↑: [34, 35, 37]	≈: [31, 34, 37]	↑: [35] ≈: [31, 34, 37]				↑: [31, 34l, 35, 37]
	LABA/ICS	↑: [32, 33e]	↑: [32, 33e]	≈: [32, 33]	≈: [32, 33]				≈: [32] ↑: [33m]

Notes: a, not superiority vs TIO in PINNACLE1; b, comparator means LABA or LAMA; c, nonsuperiority vs TIO in OTEMTO1; d, data not shown and not reported significance; e, comparator means SFC 50/250 µg; f, nonsuperiority vs TIO; g, nonsuperior to glycopyrronium; h, nonsuperiority in PINNACLE2; i, nonsuperiority vs TIO in OTEMTO2; j, nonsuperiority vs formoterol in PINNACLE1; k, nonsuperiority vs glycopyrrolate in PINNACLE1; l, nonsuperiority in Study 2; m, nonsuperiority in DB2114930.

Abbreviations: BID, twice daily; FDC, fixed-dose combination; FEV₁, forced expiratory volume in 1 second; IC, inspiratory capacity; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; OD, once daily; pMDI, pressurized metered dose inhaler; SFC, salmeterol/fluticasone; SGRQ, St George’s Respiratory Questionnaire; TDI, transition dyspnea index; TIO, tiotropium.

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