Triple Therapy versus Dual or Monotherapy with Long-acting Bronchodilators for COPD: A Systematic Review and Meta-Analysis.

OBJECTIVES We conducted a systematic review and meta-analyses to estimate the safety and efficacy of using triple therapy (ICS/LABA/LAMA) compared to LABA/LAMA dual therapy or monotherapy with a single long-acting bronchodilator in patients with stable chronic obstructive pulmonary disease (COPD) who complain of dyspnea and/or exercise intolerance. METHODS A search of MEDLINE, EMBASE, and the Cochrane library databases was conducted for randomized controlled trials (RCTs) pertaining to the clinical question. A systematic approach was used to screen, abstract, and critically appraise the studies. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method was applied to rate the certainty/quality of the evidence. RESULTS Eleven studies were eligible for inclusion (n= 14,145 patients). Pairwise random-effects meta-analysis revealed an increase in the risk of pneumonia (relative risk = 1.47, 95% CI 1.20 to 1.80, p<0.001) and decreased risk of acute exacerbations of COPD (AECOPD) (relative risk = 0.75, 95% CI 0.68 to 0.82, p<0.001) with triple therapy compared to treatment with dual and monotherapy long-acting bronchodilator therapy. No significant difference in dyspnea scores (standardized mean difference = 0.09, 95% CI -0.02 to 0.19, p=0.09) or risk of hospitalization (rate ratio = 0.78, 95% CI: 0.58 - 1.06, p=0.11) was noted. When subgroup analysis was performed, based on inhaler class, no significant difference was noted between the groups in any of the critical outcomes studied. For patients with a history of one or more AECOPD in the past year, triple therapy resulted in 230 fewer AECOPD and 16 more pneumonias per 1,000 patients. CONCLUSIONS In patients with COPD who complain of dyspnea and/or exercise intolerance, triple therapy is not superior to maintenance long-acting bronchodilator therapy, except for patients with a history of one or more exacerbations in the past year, in whom the benefits of reduction in AECOPD outweigh the increased risk of pneumonia.