Introduction

Long-acting beta-2-receptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) have demonstrated improvement in pulmonary function and quality of life as well as reduction in chronic obstructive pulmonary disease (COPD) exacerbations and hospitalizations. However, neither of these drugs have shown a significant effect on disease progression and mortality. At present, there is no clarity on the optimal first-line therapy for symptomatic COPD. It is not clearly known the benefits of initial LABA/LAMA combination therapy are superior to monotherapy with either LABA or LAMA.

Aim

This study assesses whether the efficacy and safety of LABA/LAMA combination therapy is superior to LABA or LAMA monotherapy in COPD patients who complain of dyspnea and/or exercise intolerance

Methods

Study Design

• Systematic review and meta-analysis of randomized controlled trials (RCTs)

Treatment Strategy

• RCTs enrolling patients with COPD who complain of dyspnea and/or exercise intolerance, that compare LABA/LAMA combination therapy to LABA or LAMA monotherapy were included
• Extensive search of MEDLINE, EMBASE, and the Cochrane Library databases was conducted
• A systematic approach was used to screen, abstract, and critically appraise the emerging study evidence
• The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach evaluated the quality of the evidence

Endpoints

• Dyspnea
• Hospital admissions
• Rate of acute exacerbations
• Health-related quality of life
• Treatment-related adverse events (TEAEs)
• Incidence of pneumonia
• All-cause mortality
• Forced expiratory volume in 1 sec (FEV1)

Results

• A total of 24 studies with 45,441 COPD patients were included
• Pairwise random-effects meta-analysis revealed that LABA/LAMA dual therapy was associated with reductions in hospital admissions (11% reduction, p<0.01) and acute exacerbations of COPD (20% reduction, p<0.002) as compared to monotherapy
• The LABA/LAMA dual therapy demonstrated increased dyspnea score indicating reduced dyspnea in 11 studies (0.10 standardized mean difference (SMD), p<0.001), however did not attain meaningful clinically important difference (MCID)
• Improvement in health-related quality of life was seen in 11 studies, favoring dual therapy vs monotherapy (-0.13 standardized mean difference (SMD), p<0.001). However, the value did not meet a clinical meaningful difference threshold
• There was no significant difference in the risk of TEAEs (risk ratio=0.99, p=0.34) between combination therapy and either LAMA or LABA monotherapy
• The risk of pneumonia and all-cause mortality was similar in the dual therapy vs monotherapy groups with risk ratios of 1.07 and 0.92; p=0.36 and p=0.44, respectively
• Increased FEV1 with dual therapy was seen in 14 studies as compared to monotherapy; p<0.00001

Conclusion

• The long-acting beta-2-receptor agonist (LABA) and long-acting muscarinic antagonist (LAMA) combination therapy was associated with reduced risk of exacerbations and hospitalizations in chronic obstructive pulmonary disease (COPD) patients who complain of dyspnea and/or exercise intolerance as compared to LABA or LAMA monotherapy
• Reduced dyspnea and improved quality of life also favored dual therapy over monotherapy in patients with symptomatic COPD.

Ann Am Thorac Soc. 2020 Jun 12. Doi: 10.1513/AnnalsATS.201912-915OC.