This systematic review aimed to investigate the long-term effects (≥ 24 weeks) of single-inhaler triple therapy, compared with single-inhaler dual therapy for the treatment of COPD. Our results suggest that the ICS/LAMA/LABA combination was more effective in reducing all-cause mortality, risk of moderate or severe COPD exacerbations and prolonging time of first exacerbation than ICS/LABA or LABA/LAMA combinations. Furthermore, single-inhaler triple therapy had a significantly higher impact on both lung function (FEV1 trough) and health-related quality of life (HRQL: SGRQ score), compared to single-inhaler dual therapy. However, risk of pneumonia was significantly higher with ICS/LAMA/LABA than with LABA/LAMA.
Two recent meta-analyses showed that single-inhaler triple therapy was more effective in reducing acute exacerbations, and improving lung function and HRQL, compared with single-inhaler dual therapy.  However, to the best of our knowledge, this meta-analysis is the first to show a reduction in all-cause mortality in stable COPD with fixed-dose triple therapy vs ICS/LABA or LABA/LAMA combinations.
The goal of COPD management is to decrease the risk of exacerbations and mortality. Exacerbations are major determinants of patient's health status and strong predictors of mortality.  The present study concluded that, compared with single-inhaler dual therapy, single-inhaler triple therapy reduced the frequency of moderate and severe exacerbations by 22%. In IMPACT  (FF/UMEC/VI vs. UMEC/VI) and ETHOS  (BUD/GLY/FOR (320-µg– budesonide) vs. GLY/FOR) analyses, the risk of death from any cause was reduced by 29% and 46%, respectively. The all-cause mortality reduction by ICS/LAMA/LABA may be due to the reduction in total exacerbations. In ETHOS  study, compared with GLY/FOR, BUD/GLY/FOR (320-µg– budesonide) largely reduced the frequency of moderate and severe exacerbations by 24%. IMPACT  study illustrated 25% of decrease in the rate of COPD exacerbations when comparing FF/UMEC/VI and UMEC/VI and 34% of reduction in COPD hospitalizations for this comparison. Perhaps, the decline in exacerbation events can improve patients’ health and decrease the rate of hospitalization, thus decreasing associated morbidity and mortality in COPD patients. However, some included RCTs did not display that single-inhaler triple therapy improved mortality compared with LABA/LAMA, partly due to the short follow-up period. Of these, the KRONOS study was only of 24 weeks in duration, and it was limited in the reporting of such final health outcomes. It is also partly due to differences in the inclusion criteria of patients. In IMPACT  and ETHOS  studies, all-cause mortality exhibited a difference, which may be due to the high-risk nature of part of the included population experiencing cardiovascular events. In the 52 weeks TRIBUTE  study, the patients suffering from clinically significant cardiovascular disorders were excluded. Single-inhaler triple therapy may have direct or indirect effects on cardiovascular comorbidities in COPD patients, which possibly has been confirmed by the results before, suggesting that the risk of non-respiratory fatal events was significantly decreased with ICS/LAMA/LABA versus LABA/LAMA.
Our findings suggest that single-inhaler triple therapy was statistically more effective than single-inhaler dual therapy in terms of lung function and quality of life. According to Jones 2013 and Bateman 2014, the consensus on the minimal clinically important differences (MCID) for trough FEV1 is 60mL, and, for SGRQ, 4 points of the total score. Thus, the benefit of single-inhaler triple therapy on trough FEV1 (81 ml) outweighed the MCID. This was not the case however for HRQL.
Patients under single-inhaler triple therapy showed a significant increase in risk of pneumonia vs. single-inhaler dual therapy. Results differed when comparing the two sub-groups. Risk of pneumonia was higher when taking ICS/LAMA/LABA than for the LABA/LAMA group: Differences were not significant when ICS/LAMA/LABA vs. ICS/LABA group. This confirms previous findings  
The GOLD guidelines recommend that triple therapy be considered for the most severe COPD patients.  Patients using multiple devices are more likely to have an inappropriate inhalation technique.  Also, previous research has shown that COPD patients have a lower adherence to treatment persistence with multiple inhaler therapy than single-inhaler therapy.  Single-inhaler therapy is simpler, and thus may lead to better compliance and improve clinical outcomes for COPD patients  and therefore decrease healthcare resource utilization.   If these outcomes are achieved without increasing costs, this may reduce economic and healthcare resource burden.
Our research has some limitations. Firstly, some of the included RCTs were performed over only 24 weeks, thus limiting their relevance for outcomes such as all-cause mortality. Secondly, both analyzed RCTs illustrated similar criteria for eligible patients, while with some differences, thus resulting in that patients suffer from different severity and complication. Further studies are needed to determine whether any specific subgroup of COPD patients is more likely to benefit from single-inhaler triple therapy. Finally, patients obtained dual or triple therapies at baseline; it is therefore unclear whether the abrupt discontinuation of previous medication could have contributed to our results.
In conclusion, our meta-analysis suggests a beneficial effect of single-inhaler triple therapy versus single-inhaler dual therapy in terms of mortality, frequency of moderate or severe COPD exacerbations, and lung function for symptomatic COPD patients. However, ICS/LAMA/LABA is associated with an increased risk of pneumonia when compared to a dual therapy of LABA/LAMA.