The efficacy and safety of three types of combination therapies in patients with moderate to very severe COPD: a systematic review and meta-analysis

Inhaled drugs, including long-acting muscarinic antagonists (LAMAs), long-acting β₂-agonists (LABAs) and inhaled corticosteroids (ICSs), are the main therapeutic options for patients with chronic obstructive pulmonary disease (COPD). We conducted a systematic review and meta-analysis to compare the efficacy and safety of LAMA+LABA+ICS, LAMA+LABA and LABA+ICS therapies. The Pubmed, Embase and Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing the efficacy (moderate-to-severe exacerbations, lung function and quality of life) and safety (adverse events (AEs), severe adverse events (SAEs), withdrawals due to AEs, deaths and pneumonia) of LAMA+LABA+ICS, LAMA+LABA and LABA+ICS in COPD patients. Two investigators independently searched eligible studies and extracted relevant information. The data were analyzed using the Review Manager software, and the quality of included studies was assessed using the Cochrane risk of bias tool. A total of 27 studies were included, and majority of the studies showed low risk of bias. Moderate­to­severe exacerbations were lower after LAMA+LABA+ICS therapy compared with the LABA+ICS (RR = 0.66; 95% CI: 0.59–0.74) and LAMA+LABA therapies (RR = 0.88; 95% CI: 0.82–0.94). Lung function was significantly improved after LAMA+LABA+ICS compared with LAMA+ICS treatment. FEV1, peak FEV1 and trough FEV1 were significantly increased by 100 mL, 150 mL and 120 mL, respectively, in LAMA+LABA+ICS therapy compared with LAMA+ICS. In addition, LAMA+LABA therapy resulted in increased FEV1, peak FEV1 and trough FEV1 by 80 mL, 90 mL and 70 mL, respectively, compared with LAMA+ICS. SGRQ-total score was used to assess quality of life of COPD patients, which indicated that LAMA+LABA+ICS therapy was associated with slightly greater decrease compared with LABA+ICS (MD = –1.33; 95% CI: –2.35 to –0.30). No significant differences were found across all three treatment combinations in term of AEs, SAEs, withdrawals due to AEs and deaths. However, the risk of pneumonia was higher in the triple therapy group than that in the LABA+ICS (RR = 1.16; 95% CI: 1.01–1.33) or LAMA+LABA (RR = 1.31; 95% CI: 1.06–1.62) groups, and significantly lower in the LAMA+LABA group compared with LABA+ICS (RR = 0.64; 95% CI: 0.54–0.76). LAMA+LABA+ICS therapy offered greater efficacy and comparable safety compared with the LAMA+LABAor LABA+ICS therapies. However, triple therapy could increase the risk of pneumonia compared with LAMA+LABA or LABA+ICS therapies. People who have higher risk of pneumonia should carefully consider the use of triple therapy. LAMA+LABA therapy offered greater efficacy and lower risk of pneumonia to LABA+ICS therapy. Collectively, LAMA+LABA therapy might be a better choice than LABA+ICS.