title: Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Yaa-Hui
authors.initials: YH
authors.lastname: Dong
authors.forename: Hsien-Ho
authors.initials: HH
authors.lastname: Lin
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Shau
authors.forename: Yun-Chun
authors.initials: YC
authors.lastname: Wu
authors.forename: Chia-Hsuin
authors.initials: CH
authors.lastname: Chang
authors.forename: Mei-Shu
authors.initials: MS
authors.lastname: Lai
mesh_terms: D005260:Female; D006801:Humans; D008297:Male; D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000009:adverse effects; D000420:Albuterol / Q000008:administration & dosage / Q000009:adverse effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D011379:Prognosis; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D012129:Respiratory Function Tests; D018570:Risk Assessment; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000009:adverse effects; D012720:Severity of Illness Index; D015996:Survival Rate; D000069447:Tiotropium Bromide; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D000420:Albuterol; D001993:Bronchodilator Agents; D004338:Drug Combinations; D012602:Scopolamine Derivatives; D000069447:Tiotropium Bromide