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Abstract

Background:

Some systematic reviews (SRs) on triple therapy (consisting of long-acting β₂-agonist, long-acting muscarinic antagonist, and inhaled corticosteroid, LABA/LAMA/ICS) for chronic obstructive pulmonary disease (COPD) have reported conflicting results. As the number of syntheses increases, the task of identifying and interpreting evidence becomes increasingly complex and demanding.

Objectives:

To provide a comprehensive overview of the efficacy and safety of triple therapy for COPD.

Design:

Overview of SRs.

Methods:

Two independent reviewers conducted comprehensive searches in PubMed, Embase, Web of Science, and the Cochrane Library to identify relevant SRs that compared triple therapy with any non-triple therapy for COPD, from the inception of these databases until 1 June 2023. The AMSTAR 2 and GRADE tools were utilized to assess the quality of the included studies and the evidence for each outcome.

Results:

Eighteen SRs encompassing 30 original studies and involving 47,340 participants were analyzed. The overall AMSTAR 2 rating revealed that 3 SRs were of low quality, 13 SRs were of critically low quality, and 2 SRs were of high quality. No high-certainty evidence revealed a significant advantage of triple therapy in improving lung function or reducing acute exacerbations. However, all evidence, including one high certainty, supported the benefits of improving quality of life. Regarding all-cause mortality, no significant difference was found when compared to LAMA or ICS/LABA; however, high-certainty evidence confirmed its effectiveness when compared with LABA/LAMA. Notably, high-certainty evidence indicated that triple therapy was associated with a significant increase in the risk of pneumonia compared to LABA/LAMA.

Conclusion:

Triple therapy demonstrated notable benefits in improving lung function, reducing exacerbations, improving quality of life, and reducing all-cause mortality. However, it is important to note that it may also significantly increase the risk of pneumonia.

Trial registration:

This overview protocol was prospectively registered with PROSPERO (No. CRD42023431548).

Keywords

chronic obstructive pulmonary disease overview systematic review triple therapy

Introduction

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition that is one of the top three causes of death worldwide.^1–3 Many people suffer from this disease for years and die prematurely from it or its complications. There were 3.23 million COPD-related deaths in 2019 and more than 5.4 million people worldwide will die each year from COPD and related diseases by 2060.⁴ Pharmacologic therapies are essential for COPD that can reduce COPD symptoms,⁵ the frequency and severity of exacerbations,^6,7 improve health status⁸ and exercise tolerance,⁹ and beneficial effects on lung function^10,11 and mortality.¹² Inhaled therapies are the most used type of drugs for the treatment of COPD, such as long-acting muscarinic antagonist (LAMA), long-acting β₂-agonist (LABA), inhaled corticosteroid (ICS), and combination drugs, have served as fundamental therapies for patients with stable COPD for over a decade.¹³

Triple therapy combines three types of inhaled drugs to help improve lung function, manage symptoms, and prevent exacerbations. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend triple therapy as initial treatment for ‘group E’ (consider when blood EOS ⩾ 300/µl), or as maintenance treatment for patients with frequent exacerbations, noting recent promising evidence indicating possible mortality benefits or reductions in mortality risks.¹ However, although combined ICS with LABA/LAMA can bring benefits, this increases the risk (and associated cost) of adverse events such as oral thrush, hoarseness, and pneumonia, and a large proportion of patients receive triple therapy without a clear indication.¹⁴ Furthermore, given the large individual variation among COPD patients, its safety and potential adverse effects need to be studied in more detail. In addition, as more and more systematic reviews (SRs) of triple therapy were conducted, identifying and interpreting evidence from the growing number of sometimes redundant, misleading, or conflicting syntheses becomes an onerous task, and is compounded by their variable methodological conduct (i.e. rigor with which they are undertaken) and reporting quality (i.e. complete, and transparent reporting).¹⁵ Consequently, it is important to have a single comprehensive and user-friendly document that provides the best available evidence upon which to base clinical decisions.

An overview of reviews as a newer form of evidence has evolved to address a growing need to filter information overload, improve access to targeted information, and inform healthcare decision-making.¹⁶ Therefore, given the large number of potentially relevant reviews and the likely heterogeneity in eligibility criteria and study outcomes, we have chosen to utilize an overview design in assessing the efficacy and safety of triple therapy for COPD.

Methods

This study was carried out in accordance with the preferred reporting items for overviews of reviews (PRIOR) statement.¹⁵ Its protocol has been prospectively registered on PROSPERO (CRD42023431548; https://www.crd.york.ac.uk/prospero/). The PRIOR statement defines an overview of SRs as a review that uses explicit and systematic methods to search for and identify multiple SRs on a similar topic to extract and analyze results across important outcomes. Thus, the unit of searching, inclusion, and data analysis is the SR itself.

Eligibility criteria

We included SRs with meta-analysis, published in peer-reviewed journals, that investigated the efficacy and safety of triple therapy in COPD. COPD is diagnosed according to the GOLD standard, with no restrictions on age, sex, or course of disease. We placed no restriction on the form of triple therapy (MITT-multiple inhalers or SITT-single inhaler), dose, or regimen of the review. The control group received non-triple therapy intervention (any dual therapy or monotherapy). Outcomes included lung function, exacerbations, health-related quality of life (SGRQ), adverse effects, and mortality. The language of the publication was limited to English.

Exclusion criteria

We defined SRs as peer-reviewed studies with a clearly reported research question, systematic searched of at least two databases, and conducted a systematic data synthesis that replicated the eligibility criteria used in other SRs. Such studies were excluded: ineligible comparator and outcomes, ineligible review type (network meta-analysis, literature review, overview, etc.), conference abstract, article comment, and protocols. We also excluded reviews with only one author and those that searched only one database because such reviews do not have elementary characteristics of systematic methodology. In line with the recommendations from Cochrane, we did not conduct trial level searches or a new SR within the overview.¹⁷

Information sources and search strategy

We searched PubMed, Embase, Web of Science, and the Cochrane Library of Systematic Reviews from inception until 1 June 2023. Furthermore, we hand-searched the reference lists of included studies. We did not consider the gray literature which includes working papers, policy reports, and similar material. A comprehensive search of the above electronic databases was conducted by two authors (JS and JW) on 1 June 2023. Searches were restricted to published English-language papers. Supplemental File 1 provides details of the search strategy.

Selection process

Calibration exercises were completed with the review team prior to screening to ensure reliability of the processes. Two reviewers independently screened eligible studies by title and abstract. We subsequently included eligible studies by reading the full text of the remaining studies. Any possible disagreement during the screening process was discussed and reached a consensus by two reviewers or referred to a third reviewer for decision.

Data collection process

Two reviewers independently extracted data from each SR. Data were extracted on general information (e.g. year, author, region), characteristics of the review (e.g. prospective registration, bias risk assessment tool), information on intervention comparisons (e.g. any dual therapy or monotherapy), and outcomes for the current overview. It is worth noting that only pooled analysis outcomes were extracted; descriptive results of individual studies were not extracted as they may not have been the focus of our attention. Moreover, we screened and extracted data from the original studies, and where multiple papers reported the same study, data were extracted from the paper with the most complete data relating to the primary outcome.

The overlap of included studies was appraised using the corrected covered area (CCA). The formula for CCA is CCA = N−r/rc−r, whereby N is the total number of original studies including double counting of overlapping studies, r is the number of original studies not including double counting of overlapping studies, and c is the total number of reviews. Pre-determined overlap thresholds were used for interpretation of overlap (0–5% represents a slight overlap, 6–10% a moderate overlap, 11–15% a high overlap, ⩾15% is considered as a very high overlap).¹⁸ For each comparator drug, a citation matrix and pairwise CCA tables were created in addition to the comparator drug level CCA calculations to address overlap. Overlap was presented visually as per recommendations from Pérez-Bracchiglione et al.¹⁹ at the 2019 Cochrane Colloquium.

Methodological quality assessment

Two reviewers independently appraised the methodological quality of included SRs with the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR 2) Checklist.²⁰ This tool has 16 items, 7 of which are considered critical. According to the published guidance, we classified the quality of the included SRs as high, moderate, low, or critically low. Disagreements were managed through the involvement of a third researcher as an arbiter.

Certainty assessment

Two review authors independently evaluated the certainty of evidence for outcomes according to the grading of recommendations assessment, development, and evaluation (GRADE) criteria,²¹ and the disagreement was resolved through discussion. If SRs used GRADE, we checked the ratings and reported our assessment when the ratings differed from the originals. If GRADE was not used in the SRs, we graded the certainty of evidence ourselves using prespecified criteria (Supplemental File 2). We based our evaluations on the information provided in the review, but when needed, we confirmed the data by checking the original trial reports. Briefly, the certainty of the body of evidence was initially set to high and downgraded by one level for each of the following domains: limitation of trial design, inconsistency of results, imprecision, and publication bias. We did not upgrade the certainty of evidence for any reason, such as large effect size.

Results

Systematic review selection

Overall, 680 records were identified, of which 291 were duplicates and therefore excluded. After screening titles and abstracts, we excluded 343 irrelevant studies for reasons including wrong population (not COPD), wrong type of study (not SR), and wrong intervention (not triple therapy). Then we retrieved and scrutinized 49 studies remaining, of which we excluded 31 for reasons including ineligible review type (network meta-analysis, literature review, overview, etc.), conference abstract, article comment, protocols, and ineligible comparator or outcomes (Supplemental File 3). Finally, we judged 18 SRs^22–39 as eligible for inclusion in this overview (Figure 1).

Figure 1.

Flow of studies through review.

Characteristics of included SRs

The 18 SRs, published between 2012 and 2023, included 30 original studies and 47,340 participants. The studies were from China (n = 8), Italy (n = 3), United States (n = 2), Japan (n = 2), Korea (n = 1), Colombia (n = 1) and Uruguay (n = 1). Seventeen SRs (94.4%) were randomized controlled trials (RCTs), and one (5.6%) was a combination of RCTs and a real-world study. Table 1 describes the details of included SRs.

Table 1.

Characteristics of included systematic reviews.

Study	Country	Reporting items	Risk of bias tool	Type of original studies (N of studies and participants)	Participants (Number)	Mean age (year)	Mean FEV₁%Pred (Percent)	Form of triple therapy	Duration (week)	Outcome indicators
Rodrigo et al. (2012)	Uruguay	PRISMA	Cochrane risk of bias tool	RCT (6)	18,262	61–73	38–61	MITT	2–52	①⑧⑨⑩⑫⑬⑭⑰㉑㉓㉔
Kwak et al. (2015)	South Korea	PRISMA	Cochrane risk of bias tool	RCT (7)	20,829	61–71	38–62	MITT	4–52	①⑥⑫⑭⑮⑯⑰㉑
Rojas-Reyes et al., (2016)	Colombia	NA	Cochrane risk of bias tool	RCT (6)	25,225	61–73	38–61	MITT	12–52	⑤⑥⑫⑭⑮⑰㉑
Zheng et al. (2018)	China	PRISMA	Cochrane risk of bias tool	RCT (20)	19,277	61–73	36–62	Any form	4–52	①②③④⑦⑫⑭⑮⑰⑲㉑
Cazzola et al. (2018)	Italy	PRISMA-P	NA	RCT (14)	22,393	61–71	34–62	Any form	2–52	③⑥⑫⑰㉑
Calzetta et al. (2019)	Italy	PRISMA-P	Jadad score	RCT (13)	2,311	63–68	37–59	Any form	2–52	③⑦⑫⑬⑳㉑
Lai et al. (2019)	China	NA	Cochrane risk of bias tool	RCT (5)	16,157	64–65	36–50	SITT	24–52	③⑥⑦⑫⑰
Zayed et al. (2019)	USA	PRISMA-P	Cochrane risk of bias tool	RCT (12)	24,030	63–68	36–57	Any form	12–52	③⑥⑫⑮⑰⑲㉑㉓
Zhou et al., (2019)	China	NA	Cochrane risk of bias tool	RCT (15)	24,666	63–68	34–57	Any form	12–52	③⑥⑰
Mammen et al. (2020)	USA	NA	Cochrane risk of bias tool	RCT (10)	17,482	61–68	36–57	Any form	2–52	③⑪⑭⑰㉒
Koarai et al. (2021)	Japan	PRISMA	Cochrane risk of bias tool	RCT (6)	1601	63–68	36–50	Any form	24–52	①⑥⑫⑬⑭⑮⑰㉑
Long et al. (2021)	China	PRISMA	Cochrane risk of bias tool	RCT (6)	59,052	64–65	36–50	SITT	24–52	②③⑥⑫⑭⑮⑰⑲㉑
Watanabe et al. (2021)	Japan	NA	NA	RCT (6) + real-\|world (1)	2026	64–72	34–57	Any form	12–52	⑰
Ding et al. (2022)	China	NA	Cochrane risk of bias tool	RCT (10)	33,879	61–71	34–62	Any form	12–52	①⑥
Lai et al. (2022)	China	PRISMA	Cochrane risk of bias tool	RCT (6)	28,649	63–65	36–46	SITT	24–52	③⑥⑫⑭⑮⑰⑱⑲㉑
Rogliani et al. (2022)	Italy	PRISMA-P	Cochrane risk of bias tool & Jadad score	RCT (4)	20,073	64–65	37–50	SITT	24–52	③⑦⑫⑬⑭⑰⑳㉑
Chen et al. (2023)	China	PRISMA	Cochrane risk of bias tool	RCT (8)	24,141	63–70	34–52	Any form	12–52	⑭
Yang et al., (2023)	China	PRISMA	Cochrane risk of bias tool	RCT (11)	27,321	63–68	36–57	Any form	12–52	⑲

ICS, inhaled corticosteroid; MITT, multiple inhaler triple therapy; NR, not report; PRISMA, preferred reporting items for systematic reviews and meta-analyses; PRISMA-P, preferred reporting items for systematic reviews and meta-analyses protocols; RCT, randomized controlled trial; SITT, single inhaler triple therapy; ① Rate of exacerbation; ② Time to first exacerbation; ③ Moderate to severe exacerbation; ④ Rate of severe exacerbations; ⑤ Hospital admission(all causes); ⑥ FEV1; ⑦ FEV1 trough (L); ⑧ Mean final pre-bronchodilator FEV1 (mL); ⑨ Mean change in prebronchodilator FEV1 (trough) from baseline (mL); ⑩ Mean change in postbronchodilator FEV1 (peak) from baseline (mL); ⑪ Dyspnea; ⑫ SGRQ score; ⑬ Transitional dyspnea index(TDI); ⑭ All-cause mortality; ⑮ Adverse events; ⑯ Oral candidiasis; ⑰ Pneumonia events; ⑱ Respiratory tract infection; ⑲ Cardiovascular events; ⑳ Cardiovascular serious adverse events; ㉑ Serious adverse events; ㉒ Treatment-emergent adverse events; ㉓ Withdrawals due to adverse events; ㉔ Prematurely discontinued patients.

A total of 30 original studies were captured, ranging from 4 to 20 studies per SR. Twenty-seven original studies were included in two or more of the SRs identified. The CCA calculation revealed a 26.67% overlap of original studies among the SRs. Eight SRs involving 13 original studies compared to monotherapy (LAMA) in COPD, the overlap was very high with a CCA of 45.05%; 13 SRs involving 11 original studies reported triple therapy versus dual long-acting bronchodilator therapy (LABA/LAMA) revealing a very high overlap of 38.64%; 9 SRs involved 16 original studies reported triple therapy versus ICS/LABA with a CCA of 30.63% (Supplement File 4). Characteristics of original studies See Supplemental File 5.

Systematic review quality appraisal

AMSTAR 2 ratings for the included SRs are summarized in Table 2. Of the 18 included SRs, only 2 rated high, no SRs were rated moderate, and the majority rated low (3 SRs) or critically low (13 SRs) because of at least one critical weakness. Details of critical domain evaluation of included SRs were provided in Supplemental File 6.

Table 2.

AMSTAR 2 quality evaluation of included systematic reviews.

ItemStudy	①	②	③	④	⑤	⑥	⑦	⑧	⑨	⑩	⑪	⑫	⑬	⑭	⑮	⑯	Quality
Rodrigo et al. (2012)	Y	P	Y	P	Y	Y	N	Y	Y	N	Y	Y	Y	Y	N	Y	Critically low
Kwak et al. (2015)	Y	Y	Y	P	Y	Y	N	P	Y	N	N	N	N	Y	N	Y	Critically low
Rojas-Reyes et al. (2016)	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	High
Cazzola et al. (2018)	Y	Y	Y	P	Y	Y	N	P	Y	N	Y	Y	Y	Y	N	Y	Critically low
Zheng et al. (2018)	Y	Y	Y	P	N	Y	Y	P	Y	Y	Y	Y	Y	Y	Y	Y	High
Calzetta et al. (2019)	Y	Y	Y	P	Y	Y	N	P	Y	N	Y	Y	Y	Y	Y	Y	Low
Lai et al. (2019)	Y	P	Y	N	Y	Y	N	P	Y	N	Y	Y	Y	Y	Y	Y	Critically low
Zayed et al. (2019)	Y	N	Y	N	Y	Y	N	P	Y	N	Y	N	Y	Y	Y	Y	Critically low
Zhou et al. (2019)	Y	P	Y	P	Y	Y	N	P	Y	Y	N	N	Y	Y	N	N	Critically low
Mammen et al. (2020)	Y	P	Y	P	Y	Y	N	P	Y	N	Y	N	N	N	N	N	Critically low
Koarai et al. (2021)	Y	P	Y	P	Y	Y	N	P	Y	N	N	N	N	N	N	Y	Critically low
Long et al. (2021)	Y	Y	Y	N	Y	Y	N	P	Y	N	Y	N	N	N	N	Y	Critically low
Watanabe et al. (2021)	Y	N	Y	N	N	N	N	P	N	N	N	N	N	Y	N	Y	Critically low
Ding et al. (2022)	Y	N	Y	N	Y	Y	N	P	Y	N	N	N	N	Y	Y	Y	Critically low
Lai et al. (2022)	Y	Y	Y	P	N	N	N	Y	Y	N	Y	Y	Y	Y	Y	Y	Low
Rogliani et al. (2022)	Y	Y	Y	P	Y	Y	N	P	Y	N	Y	N	Y	N	N	Y	Critically low
Chen et al. (2023)	Y	Y	Y	P	Y	Y	N	P	Y	N	Y	Y	Y	Y	Y	N	Low
Yang et al. (2023)	Y	Y	Y	N	Y	Y	N	P	Y	N	Y	Y	Y	Y	Y	Y	Critically low

AMSTAR 2, A Measurement Tool to Assess Systematic Reviews; Y, Yes; P, Partial Yes; N, No; ① Did the research questions and inclusion criteria for the review include the components of PICO? ② Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol? ③ Did the review authors explain their selection of the study designs for inclusion in the review? ④ Did the review authors use a comprehensive literature search strategy? ⑤ Did the review authors perform study selection in duplicate? ⑥ Did the review authors perform data extraction in duplicate? ⑦ Did the review authors provide a list of excluded studies and justify the exclusions? ⑧ Did the review authors describe the included studies in adequate detail? ⑨ Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? ⑩ Did the review authors report on the sources of funding for the studies included in the review? ⑪ If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results? ⑫ If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis? ⑬ Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review? ⑭ Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? ⑮ If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review? ⑯ Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review? High, No or one non-critical weakness, the systematic review provides an accurate and comprehensive summary of the results of the available studies that address the question of interest; Moderate, More than one non-critical weakness, the systematic review has more than one weakness but no critical flaws. It may provide an accurate summary of the results of the available studies that were included in the review; Low, One critical flaw with or without non-critical weaknesses, the review has a critical flaw and may not provide an accurate and comprehensive summary of the available studies that address the question of interest; Critically low, More than one critical flaw with or without non-critical weaknesses, the review has more than one critical flaw and should not be relied on to provide an accurate and comprehensive summary of the available studies.

Efficacy

Outcomes varied considerably between SRs, and similar outcomes were measured using different methods at different points in time. Forest plots, based on different control group interventions, served as qualitative descriptions of each outcome. These plots visualized key information from the analysis of various SRs, including the number of original studies, sample sizes, effect sizes with 95% confidence intervals (CIs), heterogeneity, p values, and the GRADE certainty level. This visualization allowed us to quickly determine the effectiveness of triple therapy, whether the results were controversial, and the quality of the evidence. Supplemental File 7 details all outcomes and their evidence certainty levels using the GRADE system. Supplemental File 8 provides forest maps for the synthesis of different outcomes.

Lung function

Fifteen SRs, encompassing a total of 28 original studies, provided insights into the efficacy in improving lung function. Although these studies suggested an improvement in lung function when compared to monotherapy, LABA/LAMA, and ICS/LABA, the existing evidence lacks the robustness required for high-certainty conclusions.

Exacerbation

Fifteen SRs, comprising 22 original studies, investigated the evidence regarding exacerbations. Except for two studies that were not statistically significant, the remaining studies, although lacking high certainty evidence, suggested that triple therapy effectively reduces acute exacerbations compared to LAMA monotherapy, LABA/LAMA, and ICS/LABA.

Quality of life (SGRQ)

Twelve SRs, encompassing 21 original studies presented evidence on quality of life. Among these reviews, 5 SRs (covering 8 original studies) explored LAMA, 8 SRs (covering 7 original studies) examined LABA/LAMA, and 7 SRs (covering 12 original studies) investigated ICS/LABA as control interventions, respectively. Overall, the studies, including one high-certainty evidence study comparing triple therapy with LABA/LAMA, consistently favored the effectiveness of triple therapy in improving quality of life.

All-cause mortality

Ten SRs, encompassing 23 original studies, investigated the efficacy of all-cause mortality. No significant difference was observed in reducing all-cause mortality when compared to LAMA monotherapy. In contrast, when compared with LABA/LAMA, two out of seven studies indicated no significant difference, while the remaining five studies, including one high certainty, demonstrated a significant reduction in the risk of all-cause mortality. Comparatively, there was no significant difference in all-cause mortality reduction when compared with ICS/LABA.

Adverse events

Sixteen SRs included 30 original studies that reported evidence regarding adverse events (AEs). Among these, 7 SRs reported on overall AEs, and 11 SRs reported on overall severe adverse events (SAEs). AEs included some symptoms such as dry mouth, cough, headache, and back pain, as well as complications such as pneumonia, hypertension, cardiac failure, myocardial infarction, etc. SAEs are defined as any events leading to hospitalizations, cancer, life-threatening events, or death, such as respiratory failure, pneumonia, cardiovascular events requiring hospitalization or even admission to the intensive care unit, and even death, as reported in the original studies.

Compared with LAMA monotherapy, triple therapy was not associated with an increased risk of AEs, pneumonia events, cardiovascular events, oral candidiasis, treatment-emergent AEs, or withdrawals due to AEs. However, among the five studies that reported on SAEs, two studies concluded triple therapy was associated with a decreased risk, whereas the remaining three studies showed no significant difference.

Compared with LABA/LAMA, triple therapy was not associated with increased risk of AEs, SAEs, respiratory tract infection, cardiovascular events, cardiovascular SAEs, treatment-emergent AEs, or withdrawals due to AEs. Nevertheless, except for 1 study that yielded nonsignificant results, the remaining 10 studies, including 1 high certainty, consistently demonstrated a significant risk of pneumonia associated with triple therapy.

Compared with ICS/LABA, triple therapy did not increase the risk of AEs, SAEs, respiratory tract infections, and withdrawals due to AEs. However, among the seven SRs that reported on pneumonia events, one study indicated a significant increase in the risk of pneumonia, whereas the remaining six studies found no significant difference. Regarding cardiovascular SAEs, two studies demonstrated a significantly increased risk, whereas the remaining five studies were inconclusive.

Discussion

Summarize the main findings

This comprehensive overview of SRs summarized the evidence on the efficacy and safety of triple therapy compared to LAMA monotherapy, LABA/LAMA, and ICS/LABA. Results indicate that triple therapy usage was associated with significant improvements in lung function when compared to LAMA monotherapy (low to moderate certainty), LABA/LAMA (low to moderate certainty), and ICS/LABA (very low to low certainty). Evidence of low to moderate certainty showed a notable advantage in reducing exacerbations. Moreover, one high- and low-to-moderate certainty evidence supported substantial benefits in improving quality of life, as measured by the SGRQ. Regarding all-cause mortality, no significant difference was observed in comparisons with LAMA monotherapy (low certainty) or ICS/LABA (low to moderate certainty). However, among the seven SRs comparing triple therapy with LABA/LAMA, the findings were contentious. Although two evidence revealed no significant difference (low certainty), the remaining five concluded a significantly reduced risk (low to high certainty). Although the majority of evidence indicated no significant increase in the risk of AEs, it is noteworthy that evidence of low to high certainty evidence suggested a significant increase in the risk of pneumonia with triple therapy compared to LABA/LAMA. Moreover, only one out of seven moderate certainty evidence suggested a potential increase in the risk of pneumonia when comparing triple therapy with ICS/LABA, whereas two out of seven moderate certainty evidence revealed a significantly increased risk of cardiovascular events.

Provide a general interpretation of the results in the context of other evidence

This study provided comprehensive evidence for triple therapy derived from 18 SRs. Overall, triple therapy showed some advantages in improving lung function and quality of life, reducing exacerbations and all-cause mortality, but there are also concerns about increased risk of pneumonia. Observational studies also confirmed the benefits of triple therapy in improving lung function, symptom control, and reduction in exacerbations.^40,41 However, it is worth noting that the reduction in mortality risk with triple therapy may be driven by a reduction in exacerbations, which was conferred by the ICS component,⁴² but the application of ICS may increase the risk of pneumonia. Moreover, while our assessment of SRs does not clearly show consistent associations, it is important to note that 1 SR did conclude an increased risk of cardiovascular risk with triple therapy when compared with ICS/LABA.³⁹ The current study recommends triple therapy for patients who had frequent exacerbations (⩾2) and higher (⩾300 cells/µL) eosinophil counts.^6,43 Nevertheless, given that most of the SRs did not consider the different forms and dosages of triple therapy and the individual components, this may result in a certain bias that reduces the reliability of conclusions, and the low quality of most SRs may confound the evidence from high quality, multicenter, large-sample RCTs for triple therapy which are the gold standard.

Although some SRs have demonstrated SITT and MITT exhibit equivalent efficacy and safety,^22,29 other studies suggested that SITT may offer potential advantages in practicality and therapy adherence compared with MITT.^44–46 Besides, a study of two replicate Phase IV trials concluded that SITT may offer more consistent and sustained lung function benefits throughout the dosing interval compared with MITT for patients who wish to simplify their treatment regimen from MITT to SITT.⁴⁷ Regarding the various ICS/LABA/LAMA combinations, there appear to be no significant differences in clinical outcomes, including acute exacerbation and all-cause mortality in patients with moderate to very severe COPD.^48,49 But a network meta-analysis revealed favorable efficacy with single-inhaler triple therapy comprising fluticasone furoate/umeclidinium/vilanterol versus any triple (ICS/LABA/LAMA) combinations and dual therapies.⁵⁰ Unfortunately, because triple therapy has various combinations of multiple components, it is difficult to analyze comparisons of the effects of different dosages. However, research shows that medium-dose ICS-containing plays an important role in reducing the risk of mortality, whereas high-dose ICS-containing has more advantages in reducing the risk of total exacerbation.^51,52

To further reveal the individualized population for which triple therapy is indicated, we counted the subject characteristics of the 30 original studies. The results showed the mean age of the study subjects was 61–73 years old, the mean values of FEV₁%Pred ranged from 34 to 62, and the longest study period was 52 weeks. Notably, 80% of the original studies required subjects to have a smoking history of no less than 10 pack-years, which may lead to bias in the evidence for younger patients, mild status (GOLD 1) (relevant trial is already underway⁵³), or never smokers. Despite some studies suggesting the benefit of triple therapy may not be related to age or lung function,^54,55 the evidence appears to be insufficient. Furthermore, a SR confirmed the absolute benefit appeared to be greater for ex-smokers;⁵⁶ however, we have not yet found whether there is a difference in benefit for never-smoking patients.

Strengths and limitations of this review

We performed a comprehensive literature search, conducted every step of the review in duplicate, investigated industry ties for all trials included in the 18 SRs that contributed with an effect estimate for COPD, and registered our overview prospectively. However, there were some limitations to the current study, several of which were inherent to the overview’s methodology. Only studies published in English were included, which may have introduced selection bias. The definitions of some clinical outcomes were inconsistent across studies, which may lead to biased estimates. For 177 comparisons, evidence on the effectiveness and safety of triple therapy for COPD was mostly of moderate quality, meaning further research is likely to have an important impact on our confidence in the estimate of effect and may change it. Assessing publication bias is challenging due to the limited number of trials in most comparisons. For example, only 8 of the 177 comparisons had 10 or more trials, which is the minimum number of studies recommended when assessing publication bias using funnel plots. Only 2/18 SRs were considered to have high methodological quality assessed by AMSTAR 2 tool, the low methodological quality of most SRs may have an impact on treatment effect estimates. Furthermore, we used the CCA and citation matrices to assess the impact of overlap on our overview findings, an approach that allows for a more comprehensive data mapping exercise that captures all relevant original studies but also results in the potential for redundant reviews to be included. Some SRs had discrepancies in the data they extracted from, or the quality they assessed of the same studies. Data extracted from the SRs were not cross-checked for accuracy or missing information, except in cases of discrepancies. In addition, this overview relied on the results and interpretation of the authors of the SRs and may not capture the heterogeneity in methods and assumptions across the SRs included. Therefore, in addition to the current evidence being of poor quality, the findings of this overview had limitations from the shortcomings associated with the overview methodology and therefore need to be interpreted with caution.

Implications for practice

This overview provided the most up-to-date evidence on the comparative effectiveness and safety of triple therapy and non-triple therapy interventions for COPD from currently published SRs. Generally, we found moderate to low certainty evidence for most outcomes. It is important to note when compared with LABA/LAMA, two reviews with high certainty evidence, respectively, showed the benefit in improving quality of life and reducing all-cause mortality, whereas 1 SR with high certainty evidence showed triple therapy significantly increased the risk of pneumonia events. That’s a hint that patients should always be closely reviewed and followed up after escalation to triple therapy and that health professionals should consider de-escalating ICS to the LABA/LAMA regimen if a pneumonia event occurs, which is also consistent with the guideline recommendations. These results reinforce the need for adherence to guideline-recommended treatment for patients with COPD to improve outcomes and reduce the economic burden of COPD.

Implications for research

To the extent that the influence of the pharmaceutical industry on outcomes of clinical trials has been recognized as a source of bias in trials, future reviews should carry out sensitivity analyses based on industry funding when possible, and there may be a need for an increased number of trials independent of pharmaceutical industry involvement to mitigate bias and enhance the reliability of research findings. Long-term data on the efficacy and safety of triple inhalation therapies, especially in subjects with less advanced or young COPD, are needed in the future to document better its uniform efficacy in all stages of COPD or its selective efficacy in certain stages. The risks and benefits of receiving triple therapy may vary among different patient populations, such as milder, younger, smokers, ex-smokers, non-smokers, patients with high or low body mass index values, and those with concomitant chronic conditions (e.g. asthma, cardiovascular disease, musculoskeletal impairment, diabetes mellitus), which may be an area where more research is needed. Moreover, researchers should be encouraged to measure outcomes such as exercise capacity, cost of treatment, long-term benefits, fatigue, and psychological well-being, which may also be important to patients, health professionals, and regulatory authorities.

Conclusion

This overview provides evidence on the comparative effectiveness and safety of triple therapy versus non-triple therapy interventions for COPD, drawn from 18 currently published SRs. Triple therapy significantly improves lung function, reduces exacerbations, enhances quality of life, and decreases all-cause mortality, but it also carries an increased risk of pneumonia. Additionally, the current evidence is mostly based on moderately to severely elderly patients with a history of smoking. The potential differences in efficacy due to factors such as younger age, milder disease, absence of smoking history, and de-escalation criteria deserve further study. This would help to provide a more individualized treatment plan to maximize benefits for patients.

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Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Shujuan Zhang

Hailong Zhang

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