Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma

N Engl J Med. 2016 Sep 1;375(9):840-9. doi: 10.1056/NEJMoa1606356.

Abstract

Background: Long-acting beta-agonists (LABAs) have been shown to increase the risk of asthma-related death among adults and the risk of asthma-related hospitalization among children. It is unknown whether the concomitant use of inhaled glucocorticoids with LABAs mitigates those risks. This trial prospectively evaluated the safety of the LABA salmeterol, added to fluticasone propionate, in a fixed-dose combination in children.

Methods: We randomly assigned, in a 1:1 ratio, children 4 to 11 years of age who required daily asthma medications and had a history of asthma exacerbations in the previous year to receive fluticasone propionate plus salmeterol or fluticasone alone for 26 weeks. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization), as assessed in a time-to-event analysis. The statistical design specified that noninferiority would be shown if the upper boundary of the 95% confidence interval of the hazard ratio for the primary safety end point was less than 2.675. The main efficacy end point was the first severe asthma exacerbation that led to treatment with systemic glucocorticoids, as assessed in a time-to-event analysis.

Results: Among the 6208 patients, 27 patients in the fluticasone-salmeterol group and 21 in the fluticasone-alone group had a serious asthma-related event (all were hospitalizations); the hazard ratio with fluticasone-salmeterol versus fluticasone alone was 1.28 (95% confidence interval [CI], 0.73 to 2.27), which showed the noninferiority of fluticasone-salmeterol (P=0.006). A total of 265 patients (8.5%) in the fluticasone-salmeterol group and 309 (10.0%) in the fluticasone-alone group had a severe asthma exacerbation (hazard ratio, 0.86; 95% CI, 0.73 to 1.01).

Conclusions: In this trial involving children with asthma, salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone. (Funded by GlaxoSmithKline; VESTRI ClinicalTrials.gov number, NCT01462344 .).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adrenergic beta-1 Receptor Agonists / administration & dosage
  • Adrenergic beta-1 Receptor Agonists / adverse effects
  • Adrenergic beta-2 Receptor Agonists / administration & dosage
  • Adrenergic beta-2 Receptor Agonists / adverse effects
  • Asthma / drug therapy*
  • Bronchodilator Agents / administration & dosage*
  • Bronchodilator Agents / adverse effects
  • Child
  • Child, Preschool
  • Delayed-Action Preparations
  • Double-Blind Method
  • Female
  • Fluticasone / administration & dosage*
  • Fluticasone / adverse effects
  • Fluticasone-Salmeterol Drug Combination / administration & dosage*
  • Fluticasone-Salmeterol Drug Combination / adverse effects
  • Humans
  • Male
  • Metered Dose Inhalers
  • Proportional Hazards Models

Substances

  • Adrenergic beta-1 Receptor Agonists
  • Adrenergic beta-2 Receptor Agonists
  • Bronchodilator Agents
  • Delayed-Action Preparations
  • Fluticasone-Salmeterol Drug Combination
  • Fluticasone

Associated data

  • ClinicalTrials.gov/NCT01462344