Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD)

Nobuyuki Horita; Atsushi Goto; Yuji Shibata; Erika Ota; Kentaro Nakashima; Kenjiro Nagai; Takeshi Kaneko

doi:10.1002/14651858.CD012066.pub2

安定期の慢性閉塞性肺疾患(COPD)に対する長時間作用型抗コリン薬(LAMA)+長時間作用型β刺激薬(LABA)対LABA+吸入ステロイド(ICS)

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Referencias

References to studies included in this review

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Beeh KM, Derom E, Echave‐Sustaeta J, Grönke L, Hamilton A, Zhai D, et al. The lung function profile of once‐daily tiotropium and olodaterol via Respimat is superior to that of twice‐daily salmeterol and fluticasone propionate via Accuhaler (ENERGITO study). International Journal of Chronic Obstructive Pulmonary Disease 2016;11:193‐205. [PUBMED: 26893551]

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Donohue JF, Worsley S, Zhu CQ, Hardaker L, Church A. Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate‐to‐severe COPD and infrequent exacerbations. Respiratory Medicine 2015;109(7):870‐81. [PUBMED: 26006754]

Donohue J, Worsley S, Zhu CQ, Hardaker L, Church A. Efficacy and safety of umeclidinium/vilanterol (UMEC/VI) once daily (OD) vs fluticasone/salmeterol combination (FSC) twice daily (BD) in patients with moderate‐to‐severe COPD and infrequent COPD exacerbations. Chest 2014;146(4):73A.

Donohue JF, Worsley S, Zhu CQ, Hardaker L, Church A. Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate‐to‐severe COPD and infrequent exacerbations. Respiratory Medicine 2015;109(7):870‐81. [PUBMED: 26006754]

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Vogelmeier C, Bateman E, Pallante J, Bryant H, Alagappan VD, Andrea P, et al. Once‐daily QVA149 provides superior bronchodilation and improves lung function versus twice‐daily fluticasone/salmeterol in COPD patients: the ILLUMINATE study. British Thoracic Society Winter Meeting 2012;67:A149, P194.

Vogelmeier C, Bateman ED, Pallante J, Bryant H, Alagappan V, D'Andrea, et al. QVA149 once daily is safe and well tolerated in patients with COPD: the ILLUMINATE study. American Journal of Respiratory and Critical Care Medicine 2013;187:A1477.

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Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, et al. Indacaterol‐glycopyrronium versus salmeterol‐fluticasone for COPD. New England Journal of Medicine 2016;374(23):2222‐34. [PUBMED: 27181606]

Zhong N, Wang C, Zhou X, Zhang N, Humphries M, Wang L, et al. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. International Journal of Chronic Obstructive Pulmonary Disease 2015;10:1015‐26.

References to studies excluded from this review

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Price D, Keininger D, Costa‐Scharplatz M, Mezzi K, Dimova M, Asukai Y, et al. Cost‐effectiveness of the LABA/LAMA dual bronchodilator indacaterol/glycopyrronium in a Swedish healthcare setting. Respiratory Medicine 2014;108(12):1786‐93.

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References to ongoing studies

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NCT02497001. A randomized, double‐blind, parallel‐group, 24‐week, chronic‐dosing, multi‐center study to assess the efficacy and safety of PT010, PT003, and PT009 compared with Symbicort® Turbuhaler® (Kronos). clinicaltrials.gov/show/NCT02497001 Date first received: 8 July 2015.

NCT02516592. Assessment of switching from salmeterol/fluticasone to indacaterol/glycopyrronium in a symptomatic COPD patient cohort (FLASH). Date first received: 4 August 2015.

Additional references

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References to other published versions of this review

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estudios excluidos
estudios en curso
otras referencias

Horita N, Goto A, Ota E, Nakashima K, Nagai K, Kaneko T. Long‐acting muscarinic antagonist plus long‐acting beta agonist versus long‐acting beta agonist plus inhaled corticosteroid for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2016, Issue 2. [DOI: 10.1002/14651858.CD012066]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios en curso

Beeh 2016

Methods	Design: randomised, double‐blind, cross‐over, double‐dummy, placebo‐controlled 4‐period 4‐arm trial. Countries: 8 countries (mainly EU countries). Site: 29 centres. Study duration: 6 weeks × 4 time periods. Study start: October 2013. Run‐in period: unclear.
Participants	Key inclusion criteria: %pred FEV₁ 30% to 80%, without recent exacerbation. Numbers of randomised and consequent‐treatment completed cases: 229 and 202. Age: 63.6 (SD 7.6) years. Male/female: 148/81. %pred FEV₁: unclear
Interventions	LAMA/LABA: tiotropium/olodaterol (2.5/5 μg) or tiotropium/olodaterol (5/5 μg). LABA/ICS: salmeterol/fluticasone (50/250 μg) twice daily or salmeterol/fluticasone (50/500 μg) twice daily.
Outcomes	Primary outcome: change from baseline FEV₁ AUC (0‐12 h) after 6 weeks of treatment. Tiotropium/olodaterol (2.5/5 μg): 0.295 (SE 0.014). Tiotropium/olodaterol (5/5 μg): 0.317 (SE 0.014). Salmeterol/fluticasone (50/250 μg): 0.192 (SE 0.015). Salmeterol/fluticasone (50/500 μg): 0.188 (SE 0.014).
Notes	Registration: NCT01969721. COI: sponsored by Boehringer Ingelheim.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Performance bias was not suspected.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	202/229 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 6.9% with T+O 2.5/5 > T+O 5/5 > F+S 250/50 > F+S 500/50, 17.4% with T+O 5/5 > F+S 500/50 > T+O 2.5/5 > F+S 250/50, 10.0% with F+S 250/50 > T+O 2.5/5 > F+S 500/50 > T+O 5/5, and 11.5% with F+S 500/50 > F+S 250/50 > T+O 5/5 > T+O 2.5/5 Note: This was four‐arm crossover study. Each arm used four consecutive treatments. For example, patients in the first arm were treated by T+O2.5/5, then treated by T+O5/5, then treated by F+S 250/50, then F+S 500/50.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	COI: sponsored by Boehringer Ingelheim.

Donohue 2015a

Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial. Countries: 7 countries (US and European countries). Site: 63 centres. Study duration: 12 weeks. Study start: March 2013. Run‐in period: 7 to 14 days.
Participants	Key inclusion criteria: %pred FEV₁ 30% to 70%, mMRC ≥ 2, no recent exacerbation. Numbers of randomised and completed cases: 707 and 634. Age: 62.8 (SD 9.0) years. Male/female: 497/213. %pred FEV₁: 49.4% (SD 10.9).
Interventions	LAMA/LABA: umeclidinium/vilanterol (62.5/25 μg). LABA/ICS: salmeterol/fluticasone (50/250 μg) twice daily.
Outcomes	Primary endpoint: change from baseline in 24‐h weighted‐mean serial FEV₁ on day 84. Umeclidinium/vilanterol (62.5/25 μg): 0.165 (SE 0.0130). Salmeterol/fluticasone (50/250 μg) twice daily: 0.091 (SE 0.0131).
Notes	Registration: NCT01817764, GSK‐DB2114930. COI: sponsored by GlaxoSmithKline.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central randomisation schedule was generated using a validated computer system (RanAll, GSK).
Allocation concealment (selection bias)	Low risk	Centred randomisation prevented the foreknowledge of intervention assignments by neither researchers nor participants.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Performance bias was not suspected.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	634/707 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 9.6% in umeclidinium/vilanterol arm and 10.8% in salmeterol/fluticasone arms.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	COI: sponsored by GlaxoSmithKline.

Donohue 2015b

Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial. Countries: 7 countries (US and European countries and Russia). Site: 71 centres. Study duration: 12 weeks. Study start: June 2013. Run‐in period: 7 to 14 days.
Participants	Key inclusion criteria: %pred FEV₁ 30% to 70%, mMRC ≥ 2, no recent exacerbation. Numbers of randomised and completed cases: 700 and 638. Age: 63.6 (SD 8.9) years. Male/female: 528/169. %pred FEV₁: 49.5% (SD 10.9).
Interventions	LAMA/LABA: umeclidinium/vilanterol (62.5/25 μg). LABA/ICS: salmeterol/fluticasone (50/250 μg) twice daily.
Outcomes	Primary endpoint: Change from baseline in 24‐h weighted‐mean serial FEV₁ on treatment day 84. Umeclidinium/vilanterol (62.5/25 μg): 0.213 (SE 0.0137). Salmeterol/fluticasone (50/250 μg) twice daily: 0.112 (SE 0.0139).
Notes	Registration: NCT01879410, GSK‐DB2114951. COI: sponsored by GlaxoSmithKline.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central randomisation schedule was generated using a validated computer system (RanAll, GSK).
Allocation concealment (selection bias)	Low risk	Centralised randomisation prevented the foreknowledge of intervention assignments by neither researchers nor participants.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Performance bias was not suspected.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	638/700 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 6.9% in umeclidinium/vilanterol arm and 10.9% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	COI: sponsored by GlaxoSmithKline.

Hoshino 2015

Methods	Design: randomised, parallel‐group, open‐label trial. Countries: 1 country (Japan). Site: 1 centre. Study duration: 16 weeks. Study start: unclear. Run‐in period: 21 days.
Participants	Key inclusion criteria: %pred FEV₁ 30% to 80%, without recent exacerbation. Numbers of randomised and completed cases: 46 and 43. Age: LAMA/LABA, 72 years (SD 7); LABA/ICS, 69 years (SD 6). Male/female: 36/7. %pred FEV₁: LAMA/LABA, 61.9% (SD 16.3%); LABA/ICS, 60.8% (SD 16.4%).
Interventions	LAMA/LABA: tiotropium/indacaterol (18/150 μg). LABA/ICS: salmeterol/fluticasone (50/250 μg) twice daily.
Outcomes	Primary outcomes: Effects on airway dimensions. Tiotropium plus indacaterol significantly increased CT‐indices including Ai corrected for body surface area (Ai/BSA), and decreased WA/BSA, WA/Ao and T/√BSA compared with Advair(p < 0.05, respectively).
Notes	Registration: none. COI: none.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Performance bias was suspected due to open‐label study design.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Detection bias was suspected due to open‐label study design.
Incomplete outcome data (attrition bias) All outcomes	Low risk	43/46 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 8.3% in tiotropium/indacaterol arm and 4.5% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	High risk	Reporting bias could not be denied because this trial was not registered.
Other bias	Low risk	Authors found no risk of other bias.

Magnussen 2012

Methods	Design: randomised, double‐blind, cross‐over, double‐dummy, placebo‐controlled trial. Countries: 7 countries. Site: 40 centres. Study duration: 8 weeks twice daily. Study start: September 2007. Run‐in period: 15 days.
Participants	Key inclusion criteria: %pred FEV₁ ≤ 65%, without recent exacerbation. Numbers of randomised and completed cases: 344 and 300. Age: 61.0 years (SD 7.6). Male/female: 247/97. %pred FEV₁: 47% (SD 12%).
Interventions	LAMA/LABA: tiotropium/salmeterol (18/50 μg) twice daily. LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily.
Outcomes	Co‐primary endpoints 1: post‐dose thoracic gas volume (functional residual capacity) (after 8 weeks). Mean difference ‐0.087 (SE 0.044). Co‐primary endpoints 2: endurance time (after 8 weeks). Mean difference 3.0 (95% CI ‐9.5 to 27.5).
Notes	Registration: NCT00530842. COI: sponsored by Boehringer Ingelheim and Pfizer.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Centralised randomisations of 4 blocks stratified according to sites.
Allocation concealment (selection bias)	Low risk	Centralised randomisations of 4 blocks stratified according to sites.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Performance bias was not suspected.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	300/344 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 13.4% in tiotropium/salmeterol > salmeterol/fluticasone arm and 12.2% in salmeterol/fluticasone > tiotropium/salmeterol arms.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described. Authors found no risk of reporting bias.
Other bias	High risk	COI: sponsored by Boehringer Ingelheim and Pfizer.

Rabe 2008

Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial. Countries: 8 countries, mainly EU. Site: multi‐centre. Study duration: 6 weeks. Study start: November 2003. Run‐in period: 2 to 4 weeks.
Participants	Key inclusion criteria: %pred FEV₁ ≤ 65% without recent exacerbation. Numbers of randomised and completed cases: 605 and unclear. Age: 62 years (SD 9). Male/female: 414/191. %pred FEV₁: 55% (SD 13%).
Interventions	LAMA/LABA: tiotropium/formoterol (18 μg/24 μg) twice daily. LABA/ICS: salmeterol/fluticasone propionate (50 μg/500 μg) twice daily.
Outcomes	Co‐primary endpoints 1: FEV₁ AUC (0 to 12 h) after 6 weeks of treatment. Mean difference 78 mL (95% CI 34 to 122) higher in tiotropium/formoterol arm. Co‐primary endpoints 2: peak FEV₁ measured after 6 weeks of treatment. Mean difference 103 mL (95% CI 55 to 150) higher in tiotropium/formoterol arm.
Notes	Registration: NCT00239421. COI: sponsored by Boehringer and Pfizer.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Peak FEV₁ measured after 6 weeks of treatment.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Performance bias was not suspected.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	592/605 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 2.3% in tiotropium/formoterol arms and 2.0% in salmeterol/fluticasone propionate arms.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described. Authors found no risk of reporting bias.
Other bias	High risk	COI: sponsored by Boehringer and Pfizer.

Singh 2015

Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial. Countries: 8 countries (mainly EU). Site: 79 centres. Study duration: 12 weeks. Study start: April 2013. Run‐in period: 7 to 14 days.
Participants	Key inclusion criteria: %pred FEV₁ 30% to 70%, mMRC ≥ 2, without recent exacerbation. Numbers of randomised and completed cases: 717 and 674. Age: 61.6 years (SD 8.0). Male/female: 515/201. %pred FEV₁: 50.6% (SD 10.7%).
Interventions	LAMA/LABA: umeclidinium/vilanterol (62.5/25 μg). LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily.
Outcomes	Primary outcome: change from baseline in 0 to 24 h weighted mean serial FEV₁ at day 84. Mean difference 0.080 L (95% CI 0.046 to 0.113) (P < 0.001).
Notes	Registration: NCT01822899, GSK‐DB2116134. COI: sponsored by GlaxoSmithKline.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Validated computer system (RandAll) was used to generate central randomisation.
Allocation concealment (selection bias)	Low risk	Validated computer system (RandAll) was used to generate central randomisation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Performance bias was not suspected.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	674/717 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 6.7% in umeclidinium/vilanterol arm and 5.0% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described. Authors found no risk of reporting bias.
Other bias	High risk	COI: sponsored by GlaxoSmithKline.

Vogelmeier 2013

Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial. Countries: 10 countries (mainly EU). Site: 92 centres. Study duration: 26 weeks. Study start: March 2011. Run‐in period: 14 days.
Participants	Key inclusion criteria: stage II/III, without recent exacerbation. Numbers of randomised and completed cases: 523 and 432. Age: LAMA/LABA, 63.2 years (SD 8.2); LABA/ICS, 63.4 years (SD 7.7). Male/female: LAMA/LABA, 181/77; LABA/ICS, 189/75. %pred FEV₁: LAMA/LABA, 60.5% (SD 10.5%); LABA/ICS, 60.0% (SD 10.7%).
Interventions	LAMA/LABA: indacaterol/glycopyrronium (110/50 μg). LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily.
Outcomes	Primary outcome: FEV₁ AUC (0 to 12 h). LAMA/LABA: 1.69 (SE 0.027). LABA/ICS: 1.56 (SE 0.026).
Notes	Registration: NCT01315249. COI: sponsored by Novartis. Study name: ILLUMINATE.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Investigators used an automated, interactive response technology to assign randomisation numbers to participants.
Allocation concealment (selection bias)	Low risk	Investigators used an automated, interactive response technology to assign randomisation numbers to participants.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Performance bias was not suspected.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	432/523 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 17.0% in indacaterol/glycopyrronium arm and 17.0% in salmeterol/fluticasone arms.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	COI: sponsored by Novartis.

Vogelmeier 2016

Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial. Countries: 14 countries (mainly EU). Site: 126 centres. Study duration: 24 weeks. Study start: September 2013. Run‐in period: unclear.
Participants	Key inclusion criteria: %pred FEV₁ < 80%, CAT ≥ 10, without recent exacerbation. Numbers of randomised and completed cases: 933 and 788. Age: 63.4 years (SD 7.8). Male/female: 607/326.
Interventions	LAMA/LABA: aclidinium/formoterol (400/12 μg) twice daily. LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily.
Outcomes	Primary outcome: peak FEV₁ at week 24. LAMA/LABA: 1.655 (SE 0.011). LABA/ICS: 1.562 (SE 0.011).
Notes	Registration: NCT01908140, EudraCT 2013‐000116‐14. COI: sponsored by AstraZeneca.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Performance bias was not suspected.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	788/933 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 14.1% in aclidinium/formoterol arm and 17.0% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described. Authors found no risk of reporting bias.
Other bias	High risk	COI: sponsored by AstraZeneca.

Wedzicha 2016

Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial. Countries: 43 countries. Site: 496 centres. Study duration: 52 weeks. Study start: July 2013. Run‐in period: 4 weeks.
Participants	Key inclusion criteria: %pred FEV₁ 25% to 60%, mMRC ≥ 2, with recent exacerbation. Numbers of randomised and completed cases: 3362 and 2760. Age: 64.6 years (SD 7.8). Male/female: 2557/805. %pred FEV₁: 44.1% (SD 9.5%).
Interventions	LAMA/LABA: indacaterol/glycopyrronium (110/50 μg). LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily.
Outcomes	Primary outcome: rate of COPD exacerbations per year. LAMA/LABA: 3.59 (95% CI 3.28 to 3.94). LABA/ICS: 4.03 (95% CI 3.68 to 4.41).
Notes	Registration: NCT01782326. COI: sponsored by Novartis. Study name: FLAME.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised via Interactive Response Technology to 1 of the treatment arms.
Allocation concealment (selection bias)	Low risk	Participants were randomised via Interactive Response Technology to 1 of the treatment arms.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Performance bias was not suspected.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	2760/3362 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 16.6% in indacaterol/glycopyrronium arm and 19.0% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	COI: sponsored by Novartis.

Zhong 2015

Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial. Countries: 4 countries (recruited mainly in China). Site: 56 centres. Study duration: 26 weeks. Study start: November 2012. Run‐in period: 14 days.
Participants	Key inclusion criteria: stage II/III mMRC ≥ 2, without recent exacerbation. Numbers of randomised and completed cases: 744 and 676. Age: LAMA/LABA 64.8 years (SD 7.8); LABA/ICS 65.3 years (SD 7.9). Male/female: 672/69. %pred FEV₁: LAMA/LABA 51.6% (SD 12.8%), LABA/ICS 52.0% (SD 12.9%).
Interventions	LAMA/LABA: indacaterol/glycopyrronium (110/50 μg). LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily.
Outcomes	Primary outcome: trough FEV₁ following 26 weeks of treatment to demonstrate the non‐inferiority of indacaterol/glycopyrronium to salmeterol/fluticasone. LAMA/LABA: 1.248 L (SE 0.0173). LABA/ICS: 1.176 L (SE 0.0172).
Notes	Registration: NCT01709903. COI: sponsored by Novartis. Study name: LANTERN.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised via Interactive Response Technology to 1 of the treatment arms.
Allocation concealment (selection bias)	Low risk	Participants were randomised via Interactive Response Technology to 1 of the treatment arms.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Performance bias was not suspected.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	676/744 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 7.8% in indacaterol/glycopyrronium arm and 10.4% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	COI: sponsored by Novartis.

%pred FEV₁: % predicted forced expiratory volume in one second; AUC: area under curve; CAT: chronic obstructive pulmonary disease assessment test; CI: confidence interval; COI: conflicts of interest; COPD: chronic obstructive pulmonary disease; FEV₁: forced expiratory volume in one second; h: hour; ICS: inhaled corticosteroid; LABA: long‐acting beta‐agonist; LAMA: long‐acting muscarinic antagonist; mMRC: modified Medical Research Council dyspnoea scale; SD: standard deviation; SE: standard error.

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos
estudios en curso

Study	Reason for exclusion
Bruhn 2003	Not comparing LAMA+LABA vs LABA+ICS. (Comparing LABA+ICS (salmeterol/fluticasone propionate) vs LABA (salmeterol) vs ICS (fluticasone propionate).)
Calverley 2007	Not comparing LAMA+LABA vs LABA+ICS. (Comparing LABA+ICS (salmeterol/fluticasone propionate) vs LAMA (tiotropium).)
Knobil 2004a	Not comparing LAMA+LABA vs LABA+ICS. (Comparing LABA+ICS (salmeterol/fluticasone propionate) vs ipratropium/albuterol. Ipratropium is not LAMA.)
Knobil 2004b	Not comparing LAMA+LABA vs LABA+ICS. (Comparing LABA+ICS (salmeterol/fluticasone propionate) vs ipratropium/albuterol. Ipratropium is not LAMA.)
NCT00120978	Not comparing LAMA+LABA vs LABA+ICS. (Comparing LABA+ICS (salmeterol/fluticasone propionate) vs ICS (fluticasone propionate).)
Price 2014	Cost‐effectiveness analysis using previously published data. (Cost‐effectiveness of the LABA/LAMA (indacaterol/glycopyrronium.)
Sciurba 2004	Not comparing LAMA+LABA vs LABA+ICS. (Comparing LABA+ICS (salmeterol/fluticasone propionate) vs ipratropium/albuterol. Ipratropium is not LAMA.)

ICS: inhaled corticosteroids; LABA: long‐acting beta‐agonist; LAMA: long‐acting muscarinic antagonist.

Characteristics of ongoing studies [ordered by study ID]

Ir a:

estudios incluidos
estudios excluidos

NCT02497001

Trial name or title	A Randomized, Double‐blind, Parallel‐Group, 24‐Week, Chronic‐Dosing, Multi‐center Study to Assess the Efficacy and Safety of PT010, PT003, and PT009 Compared with Symbicort® Turbuhaler® (Kronos).
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial. Countries: 2 countries (US and Canada). Site: 94 centres. Study duration: 24 weeks. Study start: July 2015. Run‐in period: unclear.
Participants	Key inclusion criteria: %pred FEV₁ < 80%. Estimated enrolment: 1800.
Interventions	4‐arm trial. Budesonide + glycopyrronium + formoterol fumarate inhalation aerosol (MDI, 320/14.4/9.6 μg, PT010). Glycopyrronium + formoterol fumarate inhalation aerosol (MDI, 14.4/9.6 μg, PT003). Budesonide + formoterol fumarate inhalation aerosol (MDI, 320/9.6 μg, PT009). Budesonide + formoterol fumarate inhalation powder (Turbuhaler)
Outcomes	Change from baseline in morning pre‐dose trough FEV₁ after follow‐up.
Starting date	July 2015.
Contact information	Raul Lima, 862‐777‐8094.
Notes	Completion date: March 2017. Registration: NCT02497001. COI: Sponsored by Pearl Therapeutics, Inc.

NCT02516592

Trial name or title	Assessment of Switching from Salmeterol/Fluticasone to Indacaterol/Glycopyrronium in a Symptomatic COPD Patient Cohort (FLASH).
Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial. Countries: 11 countries. Site: 55 centres. Study duration: 12 weeks. Study start: October 2015. Run‐in period: unclear.
Participants	%pred FEV₁ 30% to 80%, CAT ≥ 10, without recent exacerbation. Estimated enrolment: 492.
Interventions	Will investigate whether switching people with symptomatic COPD from a fixed‐dose combination of salmeterol/fluticasone 50/500 µg twice daily to a fixed‐dose combination of indacaterol/glycopyrronium 110/50 µg once daily. LAMA/LABA: switching from salmeterol/fluticasone (50/500 μg) twice daily to indacaterol/glycopyrronium (110/50 μg). LABA/ICS: continuing salmeterol/fluticasone (50/500 μg) twice daily.
Outcomes	Change from baseline in trough pre‐dose FEV₁ in both arms after follow‐up.
Starting date	October 2015.
Contact information	Novartis Pharmaceuticals +41613241111.
Notes	Completion date: August 2016. Registration: NCT02516592. COI: Sponsored by Novartis.

%pred FEV₁: % predicted forced expiratory volume in one second; CAT: chronic obstructive pulmonary disease assessment test; COI: conflicts of interest; COPD: chronic obstructive pulmonary disease; FEV₁: forced expiratory volume in one second; ICS: inhaled corticosteroids; LABA: long‐acting beta‐agonist; LAMA: long‐acting muscarinic antagonist; MDI: metered dose inhaler.

Data and analyses

Open in table viewer

Comparison 1. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Exacerbation Show forest plot	9	8922	Odds Ratio (M‐H, Random, 95% CI)	0.82 [0.70, 0.96]
Open in figure viewer Analysis 1.1 Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 1 Exacerbation.
1.1 Indacaterol/glycopyrronium	3	4617	Odds Ratio (M‐H, Random, 95% CI)	0.72 [0.63, 0.83]
1.2 Umeclidinium/vilanterol	3	2119	Odds Ratio (M‐H, Random, 95% CI)	1.15 [0.64, 2.06]
1.3 Other LAMA/LABA inhalers	3	2186	Odds Ratio (M‐H, Random, 95% CI)	1.02 [0.78, 1.34]
2 Serious adverse effect Show forest plot	10	9793	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.79, 1.05]
Open in figure viewer Analysis 1.2 Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 2 Serious adverse effect.
2.1 Indacaterol/glycopyrronium	3	4621	Odds Ratio (M‐H, Random, 95% CI)	0.82 [0.61, 1.10]
2.2 Umeclidinium/vilanterol	3	2119	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.43, 2.31]
2.3 Other LAMA/LABA inhalers	4	3053	Odds Ratio (M‐H, Random, 95% CI)	1.10 [0.77, 1.57]
3 St. George's Respiratory Questionnaire (SGRQ) total score change from the baseline (mean difference) Show forest plot	6	5858	Mean Difference (Random, 95% CI)	‐1.22 [‐2.52, 0.07]
Open in figure viewer Analysis 1.3 Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 3 St. George's Respiratory Questionnaire (SGRQ) total score change from the baseline (mean difference).
3.1 Indacaterol/glycopyrronium	2	3693	Mean Difference (Random, 95% CI)	‐1.29 [‐2.08, ‐0.50]
3.2 Umeclidinium/vilanterol	3	2119	Mean Difference (Random, 95% CI)	‐0.08 [‐1.34, 1.18]
3.3 Other LAMA/LABA inhalers	1	46	Mean Difference (Random, 95% CI)	‐5.0 [‐7.35, ‐2.65]
4 Trough forced expiratory volume in 1 second (FEV₁) change from the baseline Show forest plot	6	7277	Mean Difference (Random, 95% CI)	0.08 [0.06, 0.09]
Open in figure viewer Analysis 1.4 Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 4 Trough forced expiratory volume in 1 second (FEV₁) change from the baseline.
4.1 Indacaterol/glycopyrronium	2	4291	Mean Difference (Random, 95% CI)	0.08 [0.04, 0.12]
4.2 Umeclidinium/vilanterol	3	2119	Mean Difference (Random, 95% CI)	0.09 [0.07, 0.11]
4.3 Other LAMA/LABA inhalers	1	867	Mean Difference (Random, 95% CI)	0.05 [0.02, 0.08]
5 Pneumonia Show forest plot	8	8540	Odds Ratio (M‐H, Random, 95% CI)	0.57 [0.42, 0.79]
Open in figure viewer Analysis 1.5 Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 5 Pneumonia.
5.1 Indacaterol/glycopyrronium	3	4621	Odds Ratio (M‐H, Random, 95% CI)	0.50 [0.25, 1.00]
5.2 Umeclidinium/vilanterol	3	2119	Odds Ratio (M‐H, Random, 95% CI)	0.37 [0.11, 1.29]
5.3 Other LAMA/LABA inhalers	2	1800	Odds Ratio (M‐H, Random, 95% CI)	0.40 [0.09, 1.76]
6 All‐cause death Show forest plot	8	8200	Odds Ratio (M‐H, Random, 95% CI)	1.01 [0.61, 1.67]
Open in figure viewer Analysis 1.6 Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 6 All‐cause death.
6.1 Indacaterol/glycopyrronium	3	4621	Odds Ratio (M‐H, Random, 95% CI)	1.02 [0.59, 1.78]
6.2 Umeclidinium/vilanterol	3	2120	Odds Ratio (M‐H, Random, 95% CI)	0.78 [0.19, 3.18]
6.3 Other LAMA/LABA inhalers	2	1459	Odds Ratio (M‐H, Random, 95% CI)	1.59 [0.20, 12.96]
7 SGRQ total score improvement from the baseline (≥ 4 units) Show forest plot	2	3192	Odds Ratio (M‐H, Random, 95% CI)	1.25 [1.09, 1.44]
Open in figure viewer Analysis 1.7 Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 7 SGRQ total score improvement from the baseline (≥ 4 units).
7.1 Indacaterol/glycopyrronium	2	3192	Odds Ratio (M‐H, Random, 95% CI)	1.25 [1.09, 1.44]
8 Total SGRQ change from the baseline (excluding unblinded studies) Show forest plot	5	6360	Mean Difference (Random, 95% CI)	‐0.70 [‐1.58, 0.18]
Open in figure viewer Analysis 1.8 Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 8 Total SGRQ change from the baseline (excluding unblinded studies).
8.1 Indacaterol/glycopyrronium	2	4241	Mean Difference (Random, 95% CI)	‐1.29 [‐2.08, ‐0.50]
8.2 Umeclidinium/vilanterol	3	2119	Mean Difference (Random, 95% CI)	‐0.08 [‐1.34, 1.18]

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Forest plot of comparison: 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus ICS (inhaled corticosteroid), outcome: 1.1 Exacerbation.

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Figure 4

Forest plot of comparison: 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus ICS (inhaled corticosteroid), outcome: 1.2 Serious adverse events.

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Figure 5

Funnel plot of comparison: 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus ICS (inhaled corticosteroid), outcome: 1.2 Serious adverse events.

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Figure 6

Forest plot of comparison: 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), outcome: 1.3 St. George's Respiratory Questionnaire (SGRQ) total score change from the baseline (mean difference).

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Figure 7

Forest plot of comparison: 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus ICS (inhaled corticosteroid), outcome: 1.4 Trough forced expiratory volume in one second (FEV₁) change from the baseline.

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Analysis 1.1

Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 1 Exacerbation.

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Analysis 1.2

Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 2 Serious adverse effect.

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Analysis 1.3

Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 3 St. George's Respiratory Questionnaire (SGRQ) total score change from the baseline (mean difference).

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Analysis 1.4

Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 4 Trough forced expiratory volume in 1 second (FEV₁) change from the baseline.

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Analysis 1.5

Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 5 Pneumonia.

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Analysis 1.6

Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 6 All‐cause death.

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Analysis 1.7

Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 7 SGRQ total score improvement from the baseline (≥ 4 units).

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Analysis 1.8

Comparison 1 Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 8 Total SGRQ change from the baseline (excluding unblinded studies).

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Summary of findings for the main comparison. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD)

LAMA + LABA versus LABA + ICS for stable COPD
Population: stable COPD Setting: outpatient. Studies were conducted in > 50 countries including low‐, medium‐ and high‐income countries from all continents. Intervention: LAMA+LABA Comparison: LABA+ICS
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effects	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	LABA+ICS	LAMA+LABA	Relative effects	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
Exacerbations (number of people experiencing ≥ 1 exacerbations) Follow‐up: 12 to 52 weeks	377 per 1000	332 per 1000 (298 to 368)	OR 0.82 (0.70 to 0.96)	8922 (9 RCTs)	⊕⊕⊝⊝ Low ^1,2	Low OR means favourable outcome
Serious adverse effects Follow‐up: 12 to 52 weeks	96 per 1000	87 per 1000 (77 to 100)	OR 0.91 (0.79 to 1.05)	9793 (10 RCTs)	⊕⊕⊕⊝ Moderate ¹	Low OR means favourable outcome
SGRQ total score change from the baseline (MD) Follow‐up: 12 to 52 weeks	‐	‐	MD ‐1.22 (‐2.52 to 0.07)	6055 (6 RCTs)	⊕⊕⊝⊝ Low ^1,3	Low MD means favourable outcome
Trough FEV₁ change from the baseline Follow‐up: 12 to 52 weeks	‐	‐	MD 0.08 L (0.06 to 0.09)	6238 (6 RCTs)	⊕⊕⊕⊝ Moderate ¹	High MD means favourable outcome
Pneumonia Follow‐up: 12 to 52 weeks	26 per 1000	15 per 1000 (11 to 20)	OR 0.57 (0.42 to 0.79)	8540 (8 RCTs)	⊕⊕⊝⊝ Low ^1,4	Low OR means favourable outcome
All‐cause death Follow‐up: 12 to 52 weeks	7 per 1000	7 per 1000 (4 to 11)	OR 1.01 (0.61 to 1.67)	8200 (8 RCTs)	⊕⊕⊝⊝ Low ^1,4	Low OR means favourable outcome
SGRQ total score change from the baseline (≥ 4 points, MCID) Follow‐up: 24 to 52 weeks	445 per 1000	500 per 1000 (466 to 535)	OR 1.25 (1.09 to 1.44)	3192 (2 RCTs)	⊕⊕⊕⊝ Moderate ¹	High OR means favourable outcome
The absolute risk* (and its 95% CI) of LAMA+LABA group is based on the assumed risk in the LABA+ICS group and the OR of the intervention (and its 95% CI). CI: confidence interval; COPD: chronic obstructive pulmonary disease; FEV₁: forced expiratory volume in one second; ICS: inhaled corticosteroid; LABA: long‐acting beta‐agonist; LAMA: long‐acting muscarinic antagonist; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial; SGRQ: St. George's Respiratory Questionnaire.
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of effect but may be substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Every study had at least one domain of high risk of bias mostly due to conflicts of interest. ² Indirectness due to definition of exacerbation. ³ There was a considerable heterogeneity, I² = 71%. ⁴ Downgraded due to imprecision.

Summary of findings for the main comparison. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD)

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Table 1. Summary of characteristics of included studies

Study	LAMA+LABA	LABA+ICS	Key inclusion criteria	Follow‐up duration (weeks)	Mean/median age (years)	Number randomised
Beeh 2016	Tiotropium/olodaterol (2.5/5 μg) or tiotropium/olodaterol (5/5 μg)	Salmeterol/fluticasone (50/250 μg) twice daily or salmeterol/fluticasone (50/500 μg) twice daily.	%pred FEV₁ 30% to 80% Ex(‐)	6 × 4 time periods (cross‐over)	64	229
Donohue 2015a	Umeclidinium/vilanterol (62.5/25 μg)	Salmeterol/fluticasone (50/250 μg) twice daily	%pred FEV₁ 30% to 70%, mMRC ≥ 2, Ex(‐)	12	63	707
Donohue 2015b	Umeclidinium/vilanterol (62.5/25 μg)	Salmeterol/fluticasone (50/250 μg) twice daily	%pred FEV₁ 30% to 70%, mMRC ≥ 2, Ex(‐)	12	64	700
Hoshino 2015	Tiotropium/indacaterol (18/150 μg)	Salmeterol/fluticasone (50/250 μg) twice daily	%pred FEV₁ 30% to 80%, Ex(‐)	16	71	46
Magnussen 2012	Tiotropium/salmeterol (18/50 μg) twice daily	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV₁ ≤ 65%, Ex(‐)	8 x 2 time periods (cross‐over)	61	344
Rabe 2008	Tiotropium/formoterol (18/24 μg) twice daily	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV₁ ≤ 65%, Ex(‐)	6	62	605
Singh 2015	Umeclidinium/vilanterol (62.5/25 μg)	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV₁ 30% to 70%, mMRC ≥ 2, Ex(‐)	12	62	717
Vogelmeier 2013	Indacaterol/glycopyrronium bromide (110/50 μg)	Salmeterol/fluticasone (50/500 μg) twice daily	Stage II/III, Ex(‐)	26	63	523
Vogelmeier 2016	Aclidinium/formoterol (400/12 μg) twice daily	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV₁ < 80%, CAT ≥ 10, Ex(‐)	24	63	933
Wedzicha 2016	Indacaterol/glycopyrronium bromide (110/50 μg)	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV₁ 25% to 60%, mMRC ≥ 2, Ex(+)	52	65	3362
Zhong 2015	Indacaterol/glycopyrronium bromide (110/50 μg)	Salmeterol/fluticasone (50/500 μg) twice daily	Stage II/III, mMRC ≥ 2, Ex(‐)	26	65	744
%pred FEV₁: % predicted forced expiratory volume in one second; CAT: chronic obstructive pulmonary disease assessment test; Ex(‐): without recent exacerbation; Ex(+): with recent exacerbation; LABA: long‐acting beta‐agonist; LAMA: long‐acting muscarinic antagonist; mMRC: modified Medical Research Council dyspnoea scale.

Table 1. Summary of characteristics of included studies

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Table 2. Sponsor list for chronic obstructive pulmonary disease studies

Sponsor	Record count	% of 1723
GlaxoSmithKline	134	7.78
Novartis	128	7.43
AstraZeneca	122	7.08
Boehringer Ingelheim	113	6.56
Pfizer	84	4.88
Nycomed	49	2.84
GSK	45	2.61
Chiesi	41	2.38
Almirall	36	2.09
Merck	30	1.74
Web of Science Core Collection, advanced search for "TI=(COPD) AND TS=(inhal*)" without any restriction hit 1723 reports as of 13 June 2016. "Results analysis" > "Source Titles" output the table above.

Table 2. Sponsor list for chronic obstructive pulmonary disease studies

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Comparison 1. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Exacerbation Show forest plot	9	8922	Odds Ratio (M‐H, Random, 95% CI)	0.82 [0.70, 0.96]

1.1 Indacaterol/glycopyrronium	3	4617	Odds Ratio (M‐H, Random, 95% CI)	0.72 [0.63, 0.83]
1.2 Umeclidinium/vilanterol	3	2119	Odds Ratio (M‐H, Random, 95% CI)	1.15 [0.64, 2.06]
1.3 Other LAMA/LABA inhalers	3	2186	Odds Ratio (M‐H, Random, 95% CI)	1.02 [0.78, 1.34]
2 Serious adverse effect Show forest plot	10	9793	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.79, 1.05]

2.1 Indacaterol/glycopyrronium	3	4621	Odds Ratio (M‐H, Random, 95% CI)	0.82 [0.61, 1.10]
2.2 Umeclidinium/vilanterol	3	2119	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.43, 2.31]
2.3 Other LAMA/LABA inhalers	4	3053	Odds Ratio (M‐H, Random, 95% CI)	1.10 [0.77, 1.57]
3 St. George's Respiratory Questionnaire (SGRQ) total score change from the baseline (mean difference) Show forest plot	6	5858	Mean Difference (Random, 95% CI)	‐1.22 [‐2.52, 0.07]

3.1 Indacaterol/glycopyrronium	2	3693	Mean Difference (Random, 95% CI)	‐1.29 [‐2.08, ‐0.50]
3.2 Umeclidinium/vilanterol	3	2119	Mean Difference (Random, 95% CI)	‐0.08 [‐1.34, 1.18]
3.3 Other LAMA/LABA inhalers	1	46	Mean Difference (Random, 95% CI)	‐5.0 [‐7.35, ‐2.65]
4 Trough forced expiratory volume in 1 second (FEV₁) change from the baseline Show forest plot	6	7277	Mean Difference (Random, 95% CI)	0.08 [0.06, 0.09]

4.1 Indacaterol/glycopyrronium	2	4291	Mean Difference (Random, 95% CI)	0.08 [0.04, 0.12]
4.2 Umeclidinium/vilanterol	3	2119	Mean Difference (Random, 95% CI)	0.09 [0.07, 0.11]
4.3 Other LAMA/LABA inhalers	1	867	Mean Difference (Random, 95% CI)	0.05 [0.02, 0.08]
5 Pneumonia Show forest plot	8	8540	Odds Ratio (M‐H, Random, 95% CI)	0.57 [0.42, 0.79]

5.1 Indacaterol/glycopyrronium	3	4621	Odds Ratio (M‐H, Random, 95% CI)	0.50 [0.25, 1.00]
5.2 Umeclidinium/vilanterol	3	2119	Odds Ratio (M‐H, Random, 95% CI)	0.37 [0.11, 1.29]
5.3 Other LAMA/LABA inhalers	2	1800	Odds Ratio (M‐H, Random, 95% CI)	0.40 [0.09, 1.76]
6 All‐cause death Show forest plot	8	8200	Odds Ratio (M‐H, Random, 95% CI)	1.01 [0.61, 1.67]

6.1 Indacaterol/glycopyrronium	3	4621	Odds Ratio (M‐H, Random, 95% CI)	1.02 [0.59, 1.78]
6.2 Umeclidinium/vilanterol	3	2120	Odds Ratio (M‐H, Random, 95% CI)	0.78 [0.19, 3.18]
6.3 Other LAMA/LABA inhalers	2	1459	Odds Ratio (M‐H, Random, 95% CI)	1.59 [0.20, 12.96]
7 SGRQ total score improvement from the baseline (≥ 4 units) Show forest plot	2	3192	Odds Ratio (M‐H, Random, 95% CI)	1.25 [1.09, 1.44]

7.1 Indacaterol/glycopyrronium	2	3192	Odds Ratio (M‐H, Random, 95% CI)	1.25 [1.09, 1.44]
8 Total SGRQ change from the baseline (excluding unblinded studies) Show forest plot	5	6360	Mean Difference (Random, 95% CI)	‐0.70 [‐1.58, 0.18]

8.1 Indacaterol/glycopyrronium	2	4241	Mean Difference (Random, 95% CI)	‐1.29 [‐2.08, ‐0.50]
8.2 Umeclidinium/vilanterol	3	2119	Mean Difference (Random, 95% CI)	‐0.08 [‐1.34, 1.18]

Comparison 1. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS)

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Referencias

References to studies included in this review

Beeh 2016 {published data only}

Donohue 2015a {published data only (unpublished sought but not used)}

Donohue 2015b {published data only (unpublished sought but not used)}

Hoshino 2015 {published data only}

Magnussen 2012 {published data only}

Rabe 2008 {published data only (unpublished sought but not used)}

Singh 2015 {published data only (unpublished sought but not used)}

Vogelmeier 2013 {published data only (unpublished sought but not used)}

Vogelmeier 2016 {published data only (unpublished sought but not used)}

Wedzicha 2016 {published data only (unpublished sought but not used)}

Zhong 2015 {published data only (unpublished sought but not used)}

References to studies excluded from this review

Bruhn 2003 {published data only}

Calverley 2007 {published data only}

Knobil 2004a {published data only}

Knobil 2004b {published data only}

NCT00120978 {published data only}

Price 2014 {published data only}

Sciurba 2004 {published data only}

References to ongoing studies

NCT02497001 {published data only}

NCT02516592 {published data only}

Additional references

Alagha 2014

Anderson 2014

Barnes 2010

Burrows 1966

Celli 2014

Cluzeau 2012

Drivenes 2014

Frampton 2014

GOLD 2016

GOLD 2017

GRADEpro [Computer program]

Guyatt 2008

Hanania 2008

Higgins 2003

Higgins 2011

Horita 2015a

Horita 2015b

Malerba 2014

Moher 2009

Nannini 2012

Nannini 2013

Oba 2016

Pascoe 2015

Pauwels 2001

RevMan 2014 [Computer program]

Schachter 2013

Suissa 2009

Tashkin 2004

White 2013

WHO 2015

References to other published versions of this review

Horita 2016

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Data and analyses

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