Is it safe to add long-acting β-2 agonists to inhaled corticosteroids in patients with persistent asthma?

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Possibly. Long-acting β-2 agonists (LABAs) used in combination with inhaled corticosteroids (ICS) don’t appear to increase all-cause mortality or serious adverse events in patients with persistent asthma compared with ICS alone. Studies showing an increase in catastrophic events had serious methodologic issues. A large surveillance study is ongoing (strength of recommendation: A, meta-analysis of randomized controlled trials [RCTs]).

No significant difference in combination therapy vs ICS alone

In 2013, a Cochrane review analyzed the risk of mortality and nonfatal serious adverse events in patients treated with the LABA salmeterol in combination with ICS, compared with patients receiving the same dose of ICS alone.1 The review included 35 RCTs of moderate quality with 13,447 adolescents and adults and 5 RCTs with 1862 children. Patients had all stages of asthma; mean study duration was 34 weeks in adult trials and 15 weeks in trials of children.

Seven deaths from all causes occurred in both the salmeterol-plus-ICS group and the ICS-alone group (35 trials, N=13,447; Peto odds ratio [OR]=0.90; 95% confidence interval [CI], 0.31-2.6). No deaths in children and no asthma-related deaths occurred in any study participants (40 trials, N=15,309).

Adults treated with ICS alone showed no significant difference from adults receiving combination therapy in the frequency of serious adverse events (defined as life threatening, requiring hospitalization or prolongation of existing hospitalization, or resulting in persistent or significant disability or incapacity). Adults on ICS had 21 events per 1000 compared with 24 per 1000 in adults on combination treatment (35 trials, N=13,447; Peto OR=1.2; 95% CI, 0.91-1.4).

Asthma-related serious adverse events were reported in 29 of 6986 adults in the combination group and 23 of 6461 in the ICS-alone group, a nonsignificant difference (35 trials, N=13,447; Peto OR=1.1; 95% CI, 0.65-1.9).

Only one serious asthma-related adverse event occurred in each group of children (ICS- and combination-treated); (5 trials, N=1862; Peto OR=0.99; 95% CI, 0.6-16). Because the number of events was so small and the results were so imprecise, a relative increase in all-cause mortality or nonfatal adverse events can’t be completely ruled out.

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