Efficacy and safety of LABA/LAMA combinations in COPD: A network meta-analysis

The most recent Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, published in 2013, introduced a new classification system for patients with chronic obstructive pulmonary disease (COPD) based primarily on symptom burden and further by forced expiratory volume in 1 second [FEV₁] and exacerbation history.

For one low-risk and both high-risk groups, a therapy recommendation refers to the use of a long-acting beta-agonist (LABA) in combination with a long acting anti-muscarinic (LAMA) - referred to more specifically in the guidelines as a long acting anticholinergic (LAAC) - as an “alternative” treatment option. The exact place in therapy of LABA/LAMA combination products currently on the market and in development is still unclear.

The study

A network meta-analysis (NMA) of 23 clinical trials (n= 27,172) in stable COPD patients without an acute or recent exacerbation has assessed the efficacy and safety of LABA/LAMA combination therapy vs. monotherapy with either agent or placebo.

Two authors separately searched appropriate sources for randomized clinical trials, published and unpublished, that evaluated the efficacy and safety of LABA/LAMA combination therapies in stable COPD patients without an acute or recent exacerbation within the past month. Randomized control trials had to be at least 12 weeks in duration and included a control intervention of a placebo, LABA, or LAMA. Concomitant use of inhaled corticosteroids (ICS) was allowed by all but two studies. 

Outcome assessment criteria chosen for the purpose of the meta-analysis included change from baseline (CFB) in trough FEV₁ in liters, Transitional Dyspnea Index (TDI), CFB in St. George’s Respiratory Scale (SGRQ), proportion of SGRQ and TDI responders, COPD exacerbations, mortality, total serious adverse events (SAEs), cardiac SAEs, and dropouts due to adverse events.

After independently screening the studies for appropriateness, the authors extracted data on moderate-to-severe exacerbations, defined as those requiring systemic corticosteroids and/or antibiotics, and severe exacerbations, defined as rapid deterioration which required hospitalization. The primary analyses were NMA using a Bayesian Markov chain Monte Carlo (MCMC) method.

Findings

The greatest improvement in trough FEV₁ was seen in patients treated with LABA/LAMA combination at three, six, and 12 months, with a mean improvement over placebo of 201 mL (95% credible interval (CrI) 172, 230) to 243 mL (95% CrI 139,351). LAMAs and LABAs ranked second and third when compared to LABA/LAMA combination with mean differences of 64 mL (95% CrI 51, 78) to 73 mL (95% CrI 43,149) and 95 mL (95% CrI 71, 117) to 104 mL (95% CrI 84, 126) respectively.

The LABA/LAMA combination therapies also ranked highest in improvement in SGRQ and TDI scores. The proportion of SGRQ and TDI responders was significantly greater in patients treated with a LABA/LAMA combination than it was in patients treated with monotherapies (OR 1.23 (95% (CrI) 1.06-1.39), OR 1.34 (95% CrI 1.19-1.50) vs. LABAs and OR 1.24 (95% CrI 1.11-1.36), OR 1.31 (95% CrI 1.18-1.46) vs. LAMAs, respectively. 

Fewer moderate-to-severe exacerbations were associated with the LABA/LAMA combination than with LABAs (HR 0.82 (95% CrI 0.73-0.93), but not as compared to LAMAs (HR 0.92 (95% CrI 0.84-1.00). 

There was no statistically significant decrease in severe exacerbations attributable to any treatment group. No difference in mortality, total SAEs, or dropouts due to SAEs were detected between a LABA/LAMA combination therapy and any comparator.

Despite a large degree of overlap, any arm including placebo could have been considered the best therapy in all safety outcomes except for LAMAs in cardiac SAEs and mortality and LABAs in cardiac SAEs.

Conclusion

Although combination therapy was the most effective treatment option with regard to improvement in lung function, quality of life scores, symptom scores, and reduction of moderate-to-severe exacerbations, this systematic review did not definitively show that the combination therapy should be preferentially used over either monotherapy in patients with stable COPD.

The analysis also did not address cost-effectiveness, which is particularly relevant in light of the high healthcare related costs associated with use of the branded combination products currently available.

Further studies comparing LABA/LAMA, LABA/ICS, and LABA/LAMA/ICS combination therapies, including a cost effectiveness analysis, would provide more clinically relevant guidance for healthcare practitioners.

This study supports the use of LABA/LAMA combination therapy in patients with stable COPD who may not be achieving desirable surrogate outcomes on monotherapy with either agent alone.

References

1. Oba Y, Sarva ST, Dias S. Efficacy and safety of long-acting Beta-agonist/long-acting muscarinic antagonist combinations in COPD: A network meta-analysis. Thorax. 2016;71(1):15-25. www.ncbi.nlm.nih.gov/pubmed/26490732

2. Mannino D, Yu T-C, Zhou H, et al. Effects of GOLD-adherent prescribing on COPD symptom burden, exacerbations, and health care utilization in real-world setting. J COPD F. 2015; 2(3):223-235. http://journal.copdfoundation.org/jcopdf/id/1065/Effects-of-GOLD-Adherent-Prescribing-on-COPD-Symptom-Burden-Exacerbations-and-Health-Care-Utilization-in-a-Real-World-Setting 

Christopher Carnaroliis adjunct assistant professor of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Conn.