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Meta-Analysis
. 2017 Mar 17:12:907-922.
doi: 10.2147/COPD.S130482. eCollection 2017.

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

Gustavo J Rodrigo  1 , David Price  2 , Antonio Anzueto  3 , Dave Singh  4 , Pablo Altman  5 , Giovanni Bader  6 , Francesco Patalano  6 , Robert Fogel  5 , Konstantinos Kostikas  6
Affiliations
Meta-Analysis

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

Gustavo J Rodrigo et al. Int J Chron Obstruct Pulmon Dis. .

Abstract

Background: Randomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as β2-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments. The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to-very-severe COPD.

Methods: This systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing ≥12 weeks' LABA/LAMA treatment with LAMA and/or LABA/ICS (approved doses only). Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.

Results: Eighteen studies (23 trials) were eligible (N=20,185). LABA/LAMA significantly improved trough forced expiratory volume in 1 second (FEV1) from baseline to week 12 versus both LAMA and LABA/ICS (0.07 L and 0.08 L, P<0.0001), with patients more likely to achieve clinically important improvements in FEV1 of >100 mL (risk ratio [RR]: 1.33, 95% confidence interval [CI]: [1.20, 1.46] and RR: 1.44, 95% CI: [1.33, 1.56], respectively, the number needed to treat being eight and six, respectively). LABA/LAMA improved transitional dyspnea index and St George's Respiratory Questionnaire scores at week 12 versus LAMA (both P<0.0001), but not versus LABA/ICS, and reduced rescue medication use versus both (P<0.0001 and P=0.001, respectively). LABA/LAMA significantly reduced moderate/severe exacerbation rate compared with LABA/ICS (RR 0.82, 95% CI: [0.75, 0.91]). Adverse event (AE) incidence was no different for LABA/LAMA versus LAMA treatment, but it was lower versus LABA/ICS (RR 0.94, 95% CI: [0.89, 0.99]), including a lower pneumonia risk (RR 0.59, 95% CI: [0.43, 0.81]). LABA/LAMA presented a lower risk for withdrawals due to lack of efficacy versus LAMA (RR: 0.66, 95% CI: [0.51, 0.87]) and due to AEs versus LABA/ICS (RR: 0.83, 95% CI: [0.69, 0.99]).

Conclusion: The greater efficacy and comparable safety profiles observed with LABA/LAMA combinations versus LAMA or LABA/ICS support their potential role as first-line treatment options in COPD. These findings are of direct relevance to clinical practice because we included all currently available LABA/LAMAs and comparators, only at doses approved for clinical use.

Keywords: COPD; LABA/ICS; LABA/LAMA combinations; LAMA; meta-analysis.

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Conflict of interest statement

Disclosure GJR has participated as a lecturer, speaker and advisor in scientific meetings and courses under the sponsorship of Air Products and Chemicals Inc, Almirall, AstraZeneca, Boehringer Ingelheim, Laboratorios Dr Esteve, GlaxoSmithKline, Merck Sharp & Dome and Novartis. DP has board membership with Aerocrine, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, and Teva Pharmaceuticals; consultancy agreements with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Pfizer, Teva Pharmaceuticals, and Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from Aerocrine, AKL Ltd, AstraZeneca, Boehringer Ingelheim, British Lung Foundation, Chiesi, Meda, Mundipharma, Napp, Novartis, Pfizer, Respiratory Effectiveness Group, Takeda, Teva Pharmaceuticals, Theravance, UK National Health Service, Zentiva; payment for lectures/speaking engagements from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Meda, Merck, Mundipharma, Novartis, Pfizer, Skyepharma, Takeda, and Teva Pharmaceuticals; payment for manuscript preparation from Mundipharma and Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma and Novartis; payment for travel/accommodation/meeting expenses from Aerocrine, AstraZeneca, Boehringer Ingelheim, Mundipharma, Napp, Novartis, and Teva Pharmaceuticals; funding for patient enrolment or completion of research from Chiesi, Novartis, Teva Pharmaceuticals, and Zentiva; stock/stock options from AKL Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd, UK and 74% of Observational and Pragmatic Research Institute Pte Ltd, Singapore; and is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme, HTA, and Medical Research Council. AA has acted as a Consultant and has served on advisory boards for Novartis Pharma AG, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Sunnovion. DS has received sponsorship to attend international meetings, honoraria for lecturing or attending advisory boards and research grants from various pharmaceutical companies, including Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Merck, Napp, Novartis, Pfizer, Respivert, Skyepharma, Takeda, Teva, Therevance and Verona. PA, GB, FP, RF and KK are employees and shareholders of Novartis Pharma AG. KK had previously received honoraria for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, Elpen, and Novartis, and participated on advisory boards arranged by AstraZeneca, Chiesi, Elpen, and Novartis. The authors report no other conflicts of interest in this work.

Figures

Figure 1
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.
Figure 2
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
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.
Figure 4
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.
Figure 5
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 5
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
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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