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 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.