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Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials
  1. Yaa-Hui Dong1,
  2. Hsien-Ho Lin1,
  3. Wen-Yi Shau2,
  4. Yun-Chun Wu1,
  5. Chia-Hsuin Chang1,3,
  6. Mei-Shu Lai1
  1. 1Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
  2. 2Division of Health Technology Assessment, Center for Drug Evaluation, Taipei, Taiwan
  3. 3Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
  1. Correspondence to Dr Mei-Shu Lai, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, 17, Xuzhou Road, Taipei City 10055, Taiwan; mslai{at}ntu.edu.tw Dr Chia-Hsuin Chang, Department of Internal Medicine, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, 10002, Taiwan; chiahsuin123{at}yahoo.com.tw

Abstract

Background The active-treatment comparative safety information for all inhaled medications in patients with chronic obstructive pulmonary disease (COPD) is limited. We aimed to compare the risk of overall and cardiovascular death for inhaled medications in patients with COPD.

Methods Through systematic database searching, we identified randomised controlled trials of tiotropium Soft Mist Inhaler, tiotropium HandiHaler, long-acting β2 agonists (LABAs), inhaled corticosteroids (ICS), and LABA-ICS combination with at least a 6-month treatment duration. Direct comparison and mixed treatment comparison (MTC) meta-analyses were conducted to estimate the pooled ORs of death for each comparison.

Results 42 trials with 52 516 subjects were included. The MTC meta-analysis with the fixed effect model indicated tiotropium Soft Mist Inhaler was associated with an universally increased risk of overall death compared with placebo (OR 1.51; 95% CI 1.06 to 2.19), tiotropium HandiHaler (OR 1.65; 95% CI 1.13 to 2.43), LABA (OR 1.63; 95% CI 1.10 to 2.44) and LABA-ICS (OR 1.90; 95% CI 1.28 to 2.86). The risk was more evident for cardiovascular death, in patients with severe COPD, and at a higher daily dose. LABA-ICS was associated with the lowest risk of death among all treatments. No excess risk was noted for tiotropium HandiHaler or LABA. The results were similar for MTC and direct comparison meta-analyses, with less precision in the random effects model.

Conclusion Our study provided a comparative safety spectrum for each category of inhaled medications. Tiotropium Soft Mist Inhaler had a higher risk of mortality and should be used with caution.

  • Chronic obstructive pulmonary disease
  • tiotropium
  • long-acting β2 agonists
  • inhaled corticosteroids
  • mortality
  • clinical epidemiology
  • COPD pharmacology
  • respiratory infection
  • tuberculosis
  • innate immunity
  • long-term oxygen therapy
  • lung cancer
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Footnotes

  • Funding This study was in part supported by the Taiwan Department of Health grant DOH098-TD-D-113-098016, which did not play any role in the study design, literature search, study selection, collection and analysis of data, interpretation of results, or drafting of the manuscript.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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