Effect of triple therapy on mortality and cardiovascular risk in patients with moderate to severe COPD: a meta-analysis of randomized controlled trials
Abstract Background Chronic obstructive pulmonary disease (COPD), the third leading cause of global mortality, remains a significant challenge in long-term management. While dual bronchodilators (LAMA/LABA) and inhaled corticosteroid combination therapies (ICS/LABA) alleviate symptoms, patients cont...
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2025-07-01
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| author | Yubing Li Jun Li Hongxia Yang Yong Zhang |
| author_facet | Yubing Li Jun Li Hongxia Yang Yong Zhang |
| author_sort | Yubing Li |
| collection | DOAJ |
| description | Abstract Background Chronic obstructive pulmonary disease (COPD), the third leading cause of global mortality, remains a significant challenge in long-term management. While dual bronchodilators (LAMA/LABA) and inhaled corticosteroid combination therapies (ICS/LABA) alleviate symptoms, patients continue to face elevated risks of all-cause mortality and cardiovascular events. Recent studies suggest that triple therapy (ICS/LAMA/LABA) may improve outcomes by reducing acute exacerbations and systemic inflammation. However, its long-term effects on mortality and cardiovascular safety remain controversial, highlighting the critical need for systematic evidence to inform clinical decision-making. Methods A systematic search of PubMed, Embase, and the Cochrane Library (up to July 2024) identified 13 randomized controlled trials (RCTs) comparing triple therapy with dual therapies (LAMA/LABA or ICS/LABA) in patients with moderate-to-severe COPD. Outcomes included all-cause mortality, exacerbation rates, and cardiovascular adverse events of special interest (CVAESI). Risk ratios (RR) with 95% confidence intervals (CI) were calculated using fixed- or random-effects models based on heterogeneity (assessed via I² statistics). Subgroup analyses explored heterogeneity across drug combinations, supplemented by sensitivity analyses and publication bias assessments. Results Compared to LAMA/LABA dual therapy, triple therapy significantly reduced all-cause mortality (RR = 0.76, 95% CI = 0.60–0.97, p = 0.03), moderate-to-severe exacerbation risk (RR = 0.93, 95% CI = 0.90–0.97, p = 0.0003), and overall CVAESI incidence (RR = 0.75, 95% CI = 0.61–0.93, p = 0.008), with a 38% reduction in severe CVAESI (hospitalized or fatal events: RR = 0.62, 95% CI = 0.45–0.86, p = 0.004). Subgroup analyses demonstrated that the BGF regimen achieved superior reductions in CVAESI (RR = 0.72, 95% CI = 0.58–0.89, p = 0.003) and severe CVAESI (RR = 0.61, 95% CI = 0.47–0.79, p = 0.0002) compared to other triple therapies. Although BGF showed only a nonsignificant trend toward mortality reduction (RR = 0.77, 95% CI = 0.58–1.03, p = 0.08), it exhibited greater efficacy in reducing exacerbations (RR = 0.72 vs. non-BGF regimens) and cardiovascular risks. Non-BGF triple therapies yielded inconclusive results due to limited sample sizes and substantial heterogeneity (I²=62–83%, subgroup difference p < 0.05). Sensitivity analyses confirmed the stability of pooled estimates (< 5% variation upon study exclusion), with no significant publication bias detected via funnel plots or Begg’s test (p > 0.05). Conclusion This study confirms that ICS/LAMA/LABA triple therapy significantly reduces mortality, exacerbations, and cardiovascular risks in moderate-to-severe COPD compared to LAMA/LABA dual therapy. The BGF regimen, with optimized drug delivery and synergistic anti-inflammatory/bronchodilatory effects, shows superior clinical benefits, especially in high-risk patients. However, triple therapy did not improve survival or cardiovascular outcomes versus ICS/LABA. Differences in ICS pharmacokinetics highlight the need for personalized strategies based on eosinophil levels and adherence. BGF may be considered a preferred option for patients at high risk of exacerbations or with cardiovascular comorbidities. Future studies should compare triple therapies head-to-head and standardize cardiovascular endpoints to clarify long-term outcomes. |
| format | Article |
| id | doaj-art-8a6986b684b6445d8ad253f6fe64473d |
| institution | DOAJ |
| issn | 1471-2466 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | BMC Pulmonary Medicine |
| spelling | doaj-art-8a6986b684b6445d8ad253f6fe64473d2025-08-20T03:04:21ZengBMCBMC Pulmonary Medicine1471-24662025-07-0125111410.1186/s12890-025-03823-6Effect of triple therapy on mortality and cardiovascular risk in patients with moderate to severe COPD: a meta-analysis of randomized controlled trialsYubing Li0Jun Li1Hongxia Yang2Yong Zhang3Department of Respiratory and Critical Care Medicine, Jianli People’s Hospital, Affiliated Jianli Hospital of China Three Gorges UniversityDepartment of Respiratory and Critical Care Medicine, Jianli People’s Hospital, Affiliated Jianli Hospital of China Three Gorges UniversityDepartment of Respiratory and Critical Care Medicine, Jianli People’s Hospital, Affiliated Jianli Hospital of China Three Gorges UniversityDepartment of Nephrology, Jianli People’s Hospital, Affiliated Jianli Hospital of China Three Gorges UniversityAbstract Background Chronic obstructive pulmonary disease (COPD), the third leading cause of global mortality, remains a significant challenge in long-term management. While dual bronchodilators (LAMA/LABA) and inhaled corticosteroid combination therapies (ICS/LABA) alleviate symptoms, patients continue to face elevated risks of all-cause mortality and cardiovascular events. Recent studies suggest that triple therapy (ICS/LAMA/LABA) may improve outcomes by reducing acute exacerbations and systemic inflammation. However, its long-term effects on mortality and cardiovascular safety remain controversial, highlighting the critical need for systematic evidence to inform clinical decision-making. Methods A systematic search of PubMed, Embase, and the Cochrane Library (up to July 2024) identified 13 randomized controlled trials (RCTs) comparing triple therapy with dual therapies (LAMA/LABA or ICS/LABA) in patients with moderate-to-severe COPD. Outcomes included all-cause mortality, exacerbation rates, and cardiovascular adverse events of special interest (CVAESI). Risk ratios (RR) with 95% confidence intervals (CI) were calculated using fixed- or random-effects models based on heterogeneity (assessed via I² statistics). Subgroup analyses explored heterogeneity across drug combinations, supplemented by sensitivity analyses and publication bias assessments. Results Compared to LAMA/LABA dual therapy, triple therapy significantly reduced all-cause mortality (RR = 0.76, 95% CI = 0.60–0.97, p = 0.03), moderate-to-severe exacerbation risk (RR = 0.93, 95% CI = 0.90–0.97, p = 0.0003), and overall CVAESI incidence (RR = 0.75, 95% CI = 0.61–0.93, p = 0.008), with a 38% reduction in severe CVAESI (hospitalized or fatal events: RR = 0.62, 95% CI = 0.45–0.86, p = 0.004). Subgroup analyses demonstrated that the BGF regimen achieved superior reductions in CVAESI (RR = 0.72, 95% CI = 0.58–0.89, p = 0.003) and severe CVAESI (RR = 0.61, 95% CI = 0.47–0.79, p = 0.0002) compared to other triple therapies. Although BGF showed only a nonsignificant trend toward mortality reduction (RR = 0.77, 95% CI = 0.58–1.03, p = 0.08), it exhibited greater efficacy in reducing exacerbations (RR = 0.72 vs. non-BGF regimens) and cardiovascular risks. Non-BGF triple therapies yielded inconclusive results due to limited sample sizes and substantial heterogeneity (I²=62–83%, subgroup difference p < 0.05). Sensitivity analyses confirmed the stability of pooled estimates (< 5% variation upon study exclusion), with no significant publication bias detected via funnel plots or Begg’s test (p > 0.05). Conclusion This study confirms that ICS/LAMA/LABA triple therapy significantly reduces mortality, exacerbations, and cardiovascular risks in moderate-to-severe COPD compared to LAMA/LABA dual therapy. The BGF regimen, with optimized drug delivery and synergistic anti-inflammatory/bronchodilatory effects, shows superior clinical benefits, especially in high-risk patients. However, triple therapy did not improve survival or cardiovascular outcomes versus ICS/LABA. Differences in ICS pharmacokinetics highlight the need for personalized strategies based on eosinophil levels and adherence. BGF may be considered a preferred option for patients at high risk of exacerbations or with cardiovascular comorbidities. Future studies should compare triple therapies head-to-head and standardize cardiovascular endpoints to clarify long-term outcomes.https://doi.org/10.1186/s12890-025-03823-6Chronic obstructive pulmonary diseaseTriple therapyMortalityExacerbationsCardiovascular adverse eventsRandomized controlled trials |
| spellingShingle | Yubing Li Jun Li Hongxia Yang Yong Zhang Effect of triple therapy on mortality and cardiovascular risk in patients with moderate to severe COPD: a meta-analysis of randomized controlled trials BMC Pulmonary Medicine Chronic obstructive pulmonary disease Triple therapy Mortality Exacerbations Cardiovascular adverse events Randomized controlled trials |
| title | Effect of triple therapy on mortality and cardiovascular risk in patients with moderate to severe COPD: a meta-analysis of randomized controlled trials |
| title_full | Effect of triple therapy on mortality and cardiovascular risk in patients with moderate to severe COPD: a meta-analysis of randomized controlled trials |
| title_fullStr | Effect of triple therapy on mortality and cardiovascular risk in patients with moderate to severe COPD: a meta-analysis of randomized controlled trials |
| title_full_unstemmed | Effect of triple therapy on mortality and cardiovascular risk in patients with moderate to severe COPD: a meta-analysis of randomized controlled trials |
| title_short | Effect of triple therapy on mortality and cardiovascular risk in patients with moderate to severe COPD: a meta-analysis of randomized controlled trials |
| title_sort | effect of triple therapy on mortality and cardiovascular risk in patients with moderate to severe copd a meta analysis of randomized controlled trials |
| topic | Chronic obstructive pulmonary disease Triple therapy Mortality Exacerbations Cardiovascular adverse events Randomized controlled trials |
| url | https://doi.org/10.1186/s12890-025-03823-6 |
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