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

Nobuhiko Fukuda; Nobuyuki Horita; Ayami Kaneko; Atsushi Goto; Takeshi Kaneko; Erika Ota; Kayleigh M Kew

doi:10.1002/14651858.CD012066.pub3

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Figure 1

PRISMA study flow diagram

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Figure 2

Risk of bias summary: included studies had generally low risk of bias for random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting.

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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: Exacerbations

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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 events

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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: Quality of life as measured by the St George's Respiratory Questionnaire (SGRQ) total score change from baseline

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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 FEV₁ mean change (litres)

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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 improvement ≥ 4 points

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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: Exacerbations (fixed‐effect sensitivity)

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Analysis 1.9

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 9: Serious adverse events (fixed‐effect sensitivity)

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Analysis 1.10

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 10: SGRQ mean change (fixed‐effect sensitivity)

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Analysis 1.11

Comparison 1: Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS), Outcome 11: Trough FEV₁ mean change (fixed‐effect sensitivity)

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Summary of findings 1. 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 plus LABA versus LABA plus ICS for stable COPD
Population: people with 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 (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	LABA+ICS	LAMA+LABA	Relative effects (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
Exacerbations (number of people experiencing ≥ 1 exacerbations) Follow‐up: 6 to 52 weeks	291 per 1000	272 per 1000 (243 to 303)	OR 0.91 (0.78 to 1.06)	20,960 (13 RCTs)	⊕⊕⊕⊝ Moderate^a‐e	Low OR means favourable outcome
Serious adverse events (number of people experiencing ≥ 1 SAEs) Follow‐up: 6 to 52 weeks	148 per 1000	150 per 1000 (136 to 166)	OR 1.02 (0.91 to 1.15)	23,183 (18 RCTs)	⊕⊕⊕⊕ High^b,c,d,e	Low OR means favourable outcome. Herth 2020 was discarded as no events were reported in either arm.
Quality of life as measured by SGRQ total score change from baseline (MD) Follow‐up: 12 to 52 weeks Scale 0 to 100	‐	‐	MD ‐0.57 (1.36 lower to 0.21 higher)	14,437 (9 RCTs)	⊕⊕⊕⊝ Moderate^a‐e	Low MD means favourable outcome
Trough FEV₁ change from baseline Follow‐up: 6 to 52 weeks	‐	‐	MD 0.07 L (0.05 to 0.08)	14,681 (12 RCTs)	⊕⊕⊕⊝ Moderate^a,b,d,e	High MD means favourable outcome
Pneumonia Follow‐up: 12 to 52 weeks	45 per 1000	28 per 1000 (24 to 33)	OR 0.61 (0.52 to 0.72)	21,829 (14 RCTs)	⊕⊕⊕⊕ High^b,d,e	Low OR means favourable outcome
All‐cause death Follow‐up: 6 to 52 weeks	10 per 1000	14 per 1000 (11 to 18)	OR 1.35 (1.05 to 1.75)	21,510 (15 RCTs)	⊕⊕⊕⊝ Moderate^b,d,e,f	Low OR means favourable outcome
SGRQ total score change from baseline (≥ 4 points, MCID) Follow‐up: 26 to 52 weeks	373 per 1000	387 per 1000 (349 to 427)	OR 1.06 (0.90 to 1.25)	13,614 (4 RCTs)	⊕⊕⊕⊝ Moderate^a‐e	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 certainty: we are very confident that the true effect lies close to that of the estimate of effect. Moderate certainty: 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 certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aThere was a considerable heterogeneity, I² > 50%. ^bStudies varied in their inclusion criteria around recent history of exacerbation, baseline percentage predicted FEV₁ and exclusion of asthma. No indirectness downgrades, but impacts interpretation and applicability of results (see Discussion). ^cConfidence interval includes benefit of either treatment but lies within predefined threshold for clinical importance (0.7 to 1.5 for OR outcomes; 4‐point MCID for SGRQ) ‐ no downgrade for imprecision ^dNo downgrades for publication bias. Funnel plots examined for primary outcomes (exacerbations, serious adverse events, SGRQ, FEV₁) do not show obvious asymmetry (see Figure 3; Figure 3; Figure 4; Figure 6). Nearly all studies included in pneumonia and all‐cause death analyses. Only 4 studies included in SGRQ 4+ change analysis but not specified in most studies. ^eNo downgrades for risk of bias. Across outcomes, all or almost all studies were at high risk of 'other' bias due to conflicts of interest, and studies contributing between 18.5% and 35.9% of the analysis weight were rated high risk of bias in at least one other domain. We did not prespecify a threshold or specific domains for downgrading, but considered it insufficient to downgrade if studies contributing more than half the analysis weight were at low or unclear risk of bias in all but the 'other' domain. ^fThere was imprecision due to a low number of events.

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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
Ferguson 2018	Glycopyrronium/formoterol fumarate (18/9.6 μg)	Formoterol/budesonide/ fumarate (160/4.8 μg) twice daily	CAT ≥ 10, %pred FEV₁ 25% to 80%, not required to have exacerbation	24	65	943
Frith 2018	Glycopyrronium/indacaterol (50/110 μg)	Salmeterol/fluticasone (50/500 μg) twice daily	CAT ≥ 10, %pred FEV1 30% to 80%, Ex(+)	12	65	502
Herth 2020	Tiotropium/olodaterol (5/5 μg)	Salmeterol/fluticasone (50/500 μg)	%pred FEV₁ < 70%, Ex(‐)	6	62	76
Hoshino 2015	Tiotropium/indacaterol (18/150 μg)	Salmeterol/fluticasone (50/250 μg) twice daily	%pred FEV₁ 30% to 80%, Ex(‐)	16	71	46
Lipson 2018	Umeclidinium/vilanterol (62.5/25 μg)	Vilanterol/fluticasone furoate (25/100 μg)	CAT ≥ 10, %pred FEV₁ < 80%, Ex(+)	52	65	6204
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
Mostafa 2021	Tiotropium (18 μg) once daily/formoterol (9 μg) twice daily	Formoterol/budesonide (160/4.5 μg) twice daily	%pred FEV₁ 30% to 80%, Ex(‐)	12	64	40
NCT03240575	Tiotropium (5μg)/olodaterol (5μg) once daily	Salmeterol/fluticasone (50μg/250μg) twice daily	%pred FEV₁ 30% to 80%, Ex(‐)	12	64	302
Rabe 2008	Tiotropium/formoterol (18/24 μg) twice daily	Salmeterol/fluticasone (50/500 μg) twice daily	%pred FEV₁ ≤ 65%, Ex(‐)	6	62	605
Rabe 2020	Glycopyrronium/formoterol (9/4.8 µg) twice daily.	Formoterol/budesonide (4.8/160 µg) twice daily.	%pred FEV₁ 25‐65%, CAT ≥ 10, Ex(+)	52	65	4294
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	%pred FEV₁ 30% to 80%, 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
Vogelmeier 2017	Glycopyrronium/Indacaterol (50/110 μg)	any	%pred FEV₁ 50% ‐80%, mMRC ≥ 1, Ex(+)	12	65	1083
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	%pred FEV₁ 30% to 80%, 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. ORBIT matrix of outcome reporting across included studies

	Objective or semi‐objective outcomes (investigator‐assessed)					Subjective outcomes (patient‐reported)
	Exacerbations	SAEs	Trough FEV₁	Pneumonia	All‐cause death	SGRQ (mean)	SGRQ ≥ 4 unit benefit
Indacaterol/glycopyrronium studies
Frith 2018	X	X	X	X	X
Vogelmeier 2013	X	X	X	X	X	X	X
Vogelmeier 2017	X	X	X	X	X
Wedzicha 2016	X	X	X	X	X	X	X
Zhong 2015	X	X		X	X
Umeclidinium/vilanterol studies
Donohue 2015a	X	X	X	X	X	X
Donohue 2015b	X	X	X	X	X	X
Lipson 2018	X	X	X	X	X	X	X
Singh 2015	X	X	X	X	X	X
Other LAMA/LABA inhaler studies
Beeh 2016		X	X	X	X
Ferguson 2018		X	X	X	X	X
Herth 2020			X
Hoshino 2015						X
Magnussen 2012	X	X
Mostafa 2021		X			X
NCT03240575		X	X	X	X
Rabe 2008	X	X
Rabe 2020	X	X		X	X	X	X
Vogelmeier 2016	X	X		X
Outcomes shown are those included in the summary of findings table. Outcomes are classed as objective or subjective for the purposes of risk of bias assessment to consider differences in performance and detection bias. FEV₁: forced expiratory volume in one second; ORBIT: outcome reporting bias in trials; SAEs: serious adverse events; SGRQ: St George’s Respiratory Questionnaire

Table 2. ORBIT matrix of outcome reporting across included studies

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Table 3. 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 3. 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
1.1 Exacerbations Show forest plot	13	20960	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.78, 1.06]

1.1.1 Indacaterol/glycopyrronium	5	6200	Odds Ratio (M‐H, Random, 95% CI)	0.72 [0.63, 0.83]
1.1.2 Umeclidinium/vilanterol	4	8323	Odds Ratio (M‐H, Random, 95% CI)	1.20 [1.03, 1.40]
1.1.3 Other LAMA/LABA inhalers	4	6437	Odds Ratio (M‐H, Random, 95% CI)	0.97 [0.87, 1.08]
1.2 Serious adverse events Show forest plot	18	23158	Odds Ratio (M‐H, Random, 95% CI)	1.02 [0.91, 1.15]

1.2.1 Indacaterol/glycopyrronium	5	6204	Odds Ratio (M‐H, Random, 95% CI)	0.88 [0.76, 1.03]
1.2.2 Umeclidinium/vilanterol	4	8323	Odds Ratio (M‐H, Random, 95% CI)	1.07 [0.73, 1.55]
1.2.3 Other LAMA/LABA inhalers	9	8631	Odds Ratio (M‐H, Random, 95% CI)	1.04 [0.92, 1.19]
1.3 Quality of life as measured by the St George's Respiratory Questionnaire (SGRQ) total score change from baseline Show forest plot	9	14437	Mean Difference (IV, Random, 95% CI)	‐0.57 [‐1.36, 0.21]

1.3.1 Indacaterol/glycopyrronium	2	3693	Mean Difference (IV, Random, 95% CI)	‐1.29 [‐2.08, ‐0.50]
1.3.2 Umeclidinium/vilanterol	4	6615	Mean Difference (IV, Random, 95% CI)	‐0.00 [‐0.02, 0.02]
1.3.3 Other LAMA/LABA inhalers	3	4129	Mean Difference (IV, Random, 95% CI)	‐1.14 [‐4.06, 1.78]
1.4 Trough FEV₁ mean change (litres) Show forest plot	12	14681	Mean Difference (IV, Random, 95% CI)	0.07 [0.05, 0.08]

1.4.1 Indacaterol/glycopyrronium	4	5843	Mean Difference (IV, Random, 95% CI)	0.07 [0.05, 0.09]
1.4.2 Umeclidinium/vilanterol	4	6669	Mean Difference (IV, Random, 95% CI)	0.08 [0.04, 0.11]
1.4.3 Other LAMA/LABA inhalers	4	2169	Mean Difference (IV, Random, 95% CI)	0.07 [0.02, 0.11]
1.5 Pneumonia Show forest plot	14	21829	Odds Ratio (M‐H, Random, 95% CI)	0.61 [0.52, 0.72]

1.5.1 Indacaterol/glycopyrronium	5	6204	Odds Ratio (M‐H, Random, 95% CI)	0.61 [0.44, 0.85]
1.5.2 Umeclidinium/vilanterol	4	8323	Odds Ratio (M‐H, Random, 95% CI)	0.63 [0.50, 0.80]
1.5.3 Other LAMA/LABA inhalers	5	7302	Odds Ratio (M‐H, Random, 95% CI)	0.58 [0.43, 0.78]
1.6 All‐cause death Show forest plot	15	21510	Odds Ratio (M‐H, Random, 95% CI)	1.35 [1.05, 1.75]

1.6.1 Indacaterol/glycopyrronium	5	6204	Odds Ratio (M‐H, Random, 95% CI)	1.02 [0.59, 1.76]
1.6.2 Umeclidinium/vilanterol	4	8324	Odds Ratio (M‐H, Random, 95% CI)	1.51 [1.00, 2.26]
1.6.3 Other LAMA/LABA inhalers	6	6982	Odds Ratio (M‐H, Random, 95% CI)	1.43 [0.94, 2.17]
1.7 SGRQ improvement ≥ 4 points Show forest plot	4	13614	Odds Ratio (M‐H, Random, 95% CI)	1.06 [0.90, 1.25]

1.7.1 Indacaterol/glycopyrronium	2	3192	Odds Ratio (M‐H, Random, 95% CI)	1.25 [1.09, 1.44]
1.7.2 Umeclidinium/vilanterol	1	6204	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.89, 1.12]
1.7.3 Other LAMA/LABA inhalers	1	4218	Odds Ratio (M‐H, Random, 95% CI)	0.89 [0.79, 1.01]
1.8 Exacerbations (fixed‐effect sensitivity) Show forest plot	13	20960	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.87, 1.01]

1.8.1 Indacaterol/glycopyrronium	5	6200	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.63, 0.83]
1.8.2 Umeclidinium/vilanterol	4	8323	Odds Ratio (M‐H, Fixed, 95% CI)	1.20 [1.03, 1.40]
1.8.3 Other LAMA/LABA inhalers	4	6437	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.87, 1.08]
1.9 Serious adverse events (fixed‐effect sensitivity) Show forest plot	18	23158	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.95, 1.12]

1.9.1 Indacaterol/glycopyrronium	5	6204	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.75, 1.03]
1.9.2 Umeclidinium/vilanterol	4	8323	Odds Ratio (M‐H, Fixed, 95% CI)	1.13 [0.99, 1.27]
1.9.3 Other LAMA/LABA inhalers	9	8631	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.92, 1.20]
1.10 SGRQ mean change (fixed‐effect sensitivity) Show forest plot	9	14437	Mean Difference (IV, Fixed, 95% CI)	‐0.00 [‐0.02, 0.02]

1.10.1 Indacaterol/glycopyrronium	2	3693	Mean Difference (IV, Fixed, 95% CI)	‐1.29 [‐2.08, ‐0.50]
1.10.2 Umeclidinium/vilanterol	4	6615	Mean Difference (IV, Fixed, 95% CI)	‐0.00 [‐0.02, 0.02]
1.10.3 Other LAMA/LABA inhalers	3	4129	Mean Difference (IV, Fixed, 95% CI)	‐0.23 [‐1.01, 0.54]
1.11 Trough FEV₁ mean change (fixed‐effect sensitivity) Show forest plot	12	14681	Mean Difference (IV, Fixed, 95% CI)	0.06 [0.05, 0.07]

1.11.1 Indacaterol/glycopyrronium	4	5843	Mean Difference (IV, Fixed, 95% CI)	0.07 [0.05, 0.08]
1.11.2 Umeclidinium/vilanterol	4	6669	Mean Difference (IV, Fixed, 95% CI)	0.06 [0.05, 0.07]
1.11.3 Other LAMA/LABA inhalers	4	2169	Mean Difference (IV, Fixed, 95% CI)	0.06 [0.04, 0.07]

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

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