title: Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review.
abstract: BACKGROUND
  Safety of long-acting beta agonists (LABA) has been questioned and recent evidence suggested a detrimental effect on asthma control as well as an increased risk of death.
  
  
  OBJECTIVE
  To evaluate the safety of regular use of LABA compared with placebo or LABA added to inhaled corticosteroids (ICS) compared with ICS in persistent asthma.
  
  
  METHODS
  Randomized studies from MEDLINE, EMBASE, and Cochrane Controlled Trials Register were identified. Additionally, AstraZeneca, GlaxoSmithKline, Novartis and FDA clinical trials databases were searched. Primary outcomes were asthma exacerbations (AE) requiring systemic corticosteroids or hospitalization, life-threatening exacerbations and asthma-related deaths.
  
  
  RESULTS
  We identified 92 randomized clinical trials with 74,092 subjects. LABA (as monotherapy) reduced exacerbations requiring corticosteroids (Relative Risk [RR]=0.80; 95% CI, 0.73-0.88), without detrimental effects on hospitalizations or life-threatening episodes. Contrarily, LABA showed a significant increase in asthma-related deaths (Relative Risk=3.83; 95% CI, 1.21-12.14). Subgroup analysis suggests that children, patients receiving salmeterol, and a duration of treatment>12 weeks are associated with a higher risk of serious adverse effects; also there was a protective effect of concomitant use of ICS. On the other hand, combination of LABA/ICS reduced exacerbations (RR=0.73; 95% CI, 0.67-0.79), and hospitalizations (RR=0.58, 95% CI, 0.45-0.74). Combined therapy was also equivalent to ICS in terms of life-threatening episodes and asthma-related deaths. Again, children and use of salmeterol were associated with an increased risk of some severe outcomes as compared with adults and formoterol users, respectively.
  
  
  CONCLUSIONS
  This review reinforced the international recommendations in terms of the use of LABA remains the preferred add-on therapy to ICS for patients whose disease cannot adequately controlled with ICS, and that LABA cannot be prescribed as a monotherapy. Nevertheless, in spite of the protective effect of the ICS, children and salmeterol use still show an increased risk of non-fatal serious adverse events.
authors.affiliation: Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Av. 8 de Octubre 3020, Montevideo 11600, Uruguay. gurodrig@adinet.com.uy
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Rodrigo
authors.forename: Vicente Plaza
authors.initials: VP
authors.lastname: Moral
authors.forename: Luis García
authors.initials: LG
authors.lastname: Marcos
authors.forename: José A
authors.initials: JA
authors.lastname: Castro-Rodriguez
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000009:adverse effects* / Q000627:therapeutic use; D000328:Adult; D000420:Albuterol / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy; D001993:Bronchodilator Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D000068299:Salmeterol Xinafoate
chemical_list: D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D005938:Glucocorticoids; D000068299:Salmeterol Xinafoate; D000420:Albuterol