title: Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone.
abstract: BACKGROUND
  The safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate.
  
  
  METHODS
  In this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone-salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation.
  
  
  RESULTS
  Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone-salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001).
  
  
  CONCLUSIONS
  Patients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone-salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group. (AUSTRI ClinicalTrials.gov number, NCT01475721.).
authors.affiliation: From Respiratory Clinical Development (D.A.S., I.H.R., A.M.Y., C.M.P., K.S.B., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K., A.H.E.), GlaxoSmithKline, Durham, NC.
authors.forename: David A
authors.initials: DA
authors.lastname: Stempel
authors.affiliation: From Respiratory Clinical Development (D.A.S., I.H.R., A.M.Y., C.M.P., K.S.B., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K., A.H.E.), GlaxoSmithKline, Durham, NC.
authors.forename: Ibrahim H
authors.initials: IH
authors.lastname: Raphiou
authors.affiliation: From Respiratory Clinical Development (D.A.S., I.H.R., A.M.Y., C.M.P., K.S.B., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K., A.H.E.), GlaxoSmithKline, Durham, NC.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kral
authors.affiliation: From Respiratory Clinical Development (D.A.S., I.H.R., A.M.Y., C.M.P., K.S.B., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K., A.H.E.), GlaxoSmithKline, Durham, NC.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Yeakey
authors.affiliation: From Respiratory Clinical Development (D.A.S., I.H.R., A.M.Y., C.M.P., K.S.B., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K., A.H.E.), GlaxoSmithKline, Durham, NC.
authors.forename: Amanda H
authors.initials: AH
authors.lastname: Emmett
authors.affiliation: From Respiratory Clinical Development (D.A.S., I.H.R., A.M.Y., C.M.P., K.S.B., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K., A.H.E.), GlaxoSmithKline, Durham, NC.
authors.forename: Charlene M
authors.initials: CM
authors.lastname: Prazma
authors.affiliation: From Respiratory Clinical Development (D.A.S., I.H.R., A.M.Y., C.M.P., K.S.B., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K., A.H.E.), GlaxoSmithKline, Durham, NC.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Buaron
authors.affiliation: From Respiratory Clinical Development (D.A.S., I.H.R., A.M.Y., C.M.P., K.S.B., S.J.P.) and Research and Development, Clinical Platforms and Sciences, Clinical Statistics (K.M.K., A.H.E.), GlaxoSmithKline, Durham, NC.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Pascoe
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000368:Aged; D001249:Asthma / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D002648:Child; D004311:Double-Blind Method; D005260:Female; D000068298:Fluticasone / Q000627:therapeutic use*; D000068297:Fluticasone-Salmeterol Drug Combination / Q000627:therapeutic use*; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012720:Severity of Illness Index
chemical_list: D001993:Bronchodilator Agents; D000068297:Fluticasone-Salmeterol Drug Combination; D000068298:Fluticasone