Efficacy And Safety Of Triple Versus Dual Therapy In Stable COPD:a Systematic Review And Meta-analysis

Background and ObjectiveFor patients with COPD who have already been treated with dual therapy（ICS/LABA or LABA/LAMA）but still experience further exacerbations,the GOLD guideline recommends upgrading to triple therapy,which consists of long-acting muscarinic antagonist（LAMA）,long-actingβ₂-agonist（LABA）and inhaled glucocorticoid（ICS）.However,the treatment of triple therapy for stable COPD patients is controversial.Therefore,comprehensive evidence collection is required for systematic review and meta-analysis to compare the efficacy and safety of triple and dual therapy in COPD patients.MethodsPub Med,Embase,Web of Science,Cochrane Library,CENTRAL,Clinical Trials,CBM,CNKI,Wan Fang and VIP databases were searched from inception to March,2020.Based on the inclusion and exclusion criteria,we only collected randomized controlled trials（RCTs）evaluating the efficacy and safety of triple and dual therapy in stable COPD patients.The literature screening,quality evaluation and data extraction were independently conducted by two reviewers,then we used Stata 14.2 software（for pairwise meta-analysis）and Win Bugs 1.4.3 software（for network meta-analysis）to perform the meta-analysis.ResultsFifteen studies with a total of 23384 patients（triple therapy:10653 patients,ICS/LABA:7351 patients,LABA/LAMA:5380 patients）were included in this meta-analysis.The results indicated that triple therapy reduced the rate of moderate-to-severe exacerbations compared to ICS/LABA（RR=0.83,95%CI,0.79-0.87,P<0.001）and LABA/LAMA（RR=0.78,95%CI,0.66-0.92,P=0.003）in COPD patients.What’s more,triple therapy significantly reduced the rate of moderate-to-severe exacerbations compared to LABA/LAMA in patients with blood eosinophil counts≥150/μl（RR=0.64,95%CI,0.48-0.86,P=0.003）,the benefit was greater when blood eosinophil counts≥300/μl（RR=0.62,95%CI,0.47-0.81,P=0.001）.In addition,triple therapy was more effective than dual therapy in improving trough FEV₁ and reducing SGRQ scores.There were no significant differences in serious adverse events（SAEs）,cardiovascular SAEs and mortality rates between the two groups.However,triple therapy was found for the risk of pneumonia compared to LABA/LAMA（RR=1.31,95%CI,1.06-1.62,P=0.013）.Subgroup analysis showed that the incidence of pneumonia was significantly higher in fluticasone group（RR=1.36,95%CI,1.01-1.83,P=0.043）.A total of 1326 Asian patients with COPD（triple therapy:554 patients,ICS/LABA:410 patients,LABA/LAMA:362patients）were included in this meta-analysis.It demonstrated that triple therapy significantly reduced the rate of moderate-to-severe exacerbations compared to LABA/LAMA（RR=0.52,95%CI,0.38-0.72,P<0.001）.Also,triple therapy significantly increased the trough FEV₁ compared to ICS/LABA（WMD=113.98ml,95%CI,58.89-169.07,P<0.001）.Similarly,no significant difference was found in adverse events between triple therapy and dual therapy.However,pneumonia was higher with triple therapy than with LABA/LAMA（RR=2.82,95%CI,1.08-7.40,P=0.035）.Conclusion1.Triple therapy reduced the rate of moderate-to-severe exacerbations,improved lung function and quality of life when compared to dual therapy in COPD patients.For patients who have already used LABA/LAMA,those with higher blood eosinophil counts could benefit more from ICS compared to those with lower blood eosinophil counts.2.There were no significant differences in adverse events except pneumonia between triple and dual therapy,which was associated with fluticasone.3.Among Asian COPD patients,triple therapy resulted in reducing the rate of moderate-to-severe exacerbations and improving lung function compared to dual therapy,and the adverse events were comparable between them.