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Triple therapy in the management of chronic obstructive pulmonary disease: systematic review and meta-analysis

BMJ 2018; 363 doi: (Published 06 November 2018) Cite this as: BMJ 2018;363:k4388
  1. Yayuan Zheng, experimentalist1,
  2. Jianhong Zhu, pharmacist2,
  3. Yuyu Liu, professor3,
  4. Weiguang Lai, postgraduate student4,
  5. Chunyu Lin, postgraduate student4,
  6. Kaifen Qiu, professor2,
  7. Junyan Wu, professor2,
  8. Weimin Yao, professor4
  1. 1Laboratory of Physiological Sciences and Department of Pharmacy of the Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China
  2. 2Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
  3. 3Department of Pharmacology, Guangdong Medical University, Zhanjiang, China
  4. 4Department of Respiratory Medicine, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, No 57, South of Renmin Avenue, Zhanjiang 524001, China
  1. Correspondence to: W Yao yaoweimin2014{at}
  • Accepted 5 October 2018


Objective To compare the rate of moderate to severe exacerbations between triple therapy and dual therapy or monotherapy in patients with chronic obstructive pulmonary disease (COPD).

Design Systematic review and meta-analysis of randomised controlled trials.

Data sources PubMed, Embase, Cochrane databases, and clinical trial registries searched from inception to April 2018.

Eligibility criteria Randomised controlled trials comparing triple therapy with dual therapy or monotherapy in patients with COPD were eligible. Efficacy and safety outcomes of interest were also available.

Data extraction and synthesis Data were collected independently. Meta-analyses were conducted to calculate rate ratios, hazard ratios, risk ratios, and mean differences with 95% confidence intervals. Quality of evidence was summarised in accordance with GRADE methodology (grading of recommendations assessment, development, and evaluation).

Results 21 trials (19 publications) were included. Triple therapy consisted of a long acting muscarinic antagonist (LAMA), long acting β agonist (LABA), and inhaled corticosteroid (ICS). Triple therapy was associated with a significantly reduced rate of moderate or severe exacerbations compared with LAMA monotherapy (rate ratio 0.71, 95% confidence interval 0.60 to 0.85), LAMA and LABA (0.78, 0.70 to 0.88), and ICS and LABA (0.77, 0.66 to 0.91). Trough forced expiratory volume in 1 second (FEV1) and quality of life were favourable with triple therapy. The overall safety profile of triple therapy is reassuring, but pneumonia was significantly higher with triple therapy than with dual therapy of LAMA and LABA (relative risk 1.53, 95% confidence interval 1.25 to 1.87).

Conclusions Use of triple therapy resulted in a lower rate of moderate or severe exacerbations of COPD, better lung function, and better health related quality of life than dual therapy or monotherapy in patients with advanced COPD.

Study registration Prospero CRD42018077033.


  • Contributors: YZ and JZ contributed equally to this work; YZ, JZ, and YL contributed to the conception and design of the study; WL and CL contributed to the literature search and data extraction; YZ, JZ, and KQ contributed to data analysis and interpretation; YZ and JZ conducted the quality assessment; JW and WY contributed to critical revision of the manuscript. All authors contributed to writing the manuscript, and all authors approved the manuscript. JW and WY guarantees the integrity of the work. The lead authors had full access to all the data in the study and the final responsibility for the decision to submit for publication. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: No funding.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

  • The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

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