Help patients control their asthma
For most asthma patients, long-term symptom control requires the frequent monitoring and aggressive medication management that family physicians are well positioned to provide.
A dose increase avoids both the additional risk of adverse drug reactions and the added cost associated with another medication. But the easiest solution is not necessarily the best. Consider the evidence detailed below, which includes findings from studies published after the NHLBI’s guidelines.
The research on LABAs
LABAs have been widely used as adjunctive therapy for adults with asthma. However, a 2006 study raised safety concerns.16
The Salmeterol Multicenter Asthma Research Trial (SMART) compared the safety of the LABA salmeterol with a placebo added to usual asthma care over a 28-week treatment period. Overall, the primary composite end point—the number of respiratory-related deaths or life-threatening events—was low, and not statistically significant for salmeterol (50 vs 36; relative risk [RR]=1.40; 95% confidence interval [CI], 0.91-2.14).16 However, individual outcomes—respiratory-related deaths, asthma-related deaths, and asthma-related deaths or life-threatening episodes—were significantly more likely in the salmeterol group compared with the placebo group. In subgroup analysis, African American patients were found to be at greatest risk.16
It is hard to draw general conclusions from these data because the study was terminated early and poor outcomes were limited to a particular study year. Nonetheless, many physicians remain wary of LABAs as adjunctive therapy because of these findings and the media publicity they generated.
A 2010 Cochrane review provided additional data on the safety and efficacy of the combination of a LABA and ICS compared with a higher dose of ICS.17 The review, which included 48 randomized controlled trials, found that combination therapy had a lower risk of exacerbations for which oral corticosteroids were required than a higher dose of ICS (RR=0.88; 95% CI, 0.78-0.98; P=.02). The median number needed to treat (NNT) was 73. No significant difference in the risk of overall adverse events (RR=0.99; 95% CI, 0.95-1.03) was found, but there was an increase in the risk of tremor (RR=1.84; 95% CI, 1.20-2.82) and a decrease in risk for oral thrush (RR=0.58; 95% CI, 0.40-0.86) in the combination therapy group.
While the Cochrane review did not show a combination of LABA and ICS to be less safe overall than higher doses of ICS alone, the findings were less favorable for children and patients with higher baseline lung function, in circumstances in which the combination therapy was taken for a longer duration, and when the LABA being studied was formoterol.17
Overall, it is when a LABA is delivered via separate inhaler that adverse outcomes have been reported. Findings have been positive when the LABA is combined with ICS, and this combination is recommended as maintenance therapy for moderate to severe asthma.
Two new studies, published in March 2013, reported successful use of a LABA-ICS combination not only for maintenance via scheduled dosing, but also for early phases of exacerbation via extra dosing—an approach called Single inhaler Maintenance and Reliever Therapy (SMART).18,19 In both studies, SMART resulted in less excessive use of SABAs and less need for oral steroids, fewer hospitalizations for asthma, and fewer cases of progression to a full-blown exacerbation.
The takeaway: LABAs should be reserved for use as an adjunct to ICS in adults with poor baseline pulmonary function tests or severe asthma, and delivered as a combination product with ICS, not as a separate inhaled medication. SMART is a safe and effective means of administering LABA-ICS therapy for some patients at risk for frequent severe exacerbations.
When to consider LTRAs
LTRAs can be valuable medications in asthma management and there are extensive data on their use, particularly in the treatment of children with asthma. A Cochrane review published in 2012, however, supported current guideline recommendations, finding that as monotherapy, ICS are superior to LTRAs.20
When LTRAs as an adjunctive therapy to ICS were compared with ICS monotherapy, researchers found a modest improvement in PEF (weighted mean difference [WMD] =7.7 L/min; 95% CI, 3.6-11.8) in the group receiving combination therapy and a decrease in the need for a SABA as rescue therapy (WMD=1 puff/week; 95% CI, 0.5-2.0).21 There was no significant reduction in the risk of exacerbations requiring systemic steroids (RR=0.64; 95% CI, 0.38-1.07).
LABAs and LTRAs go head to head. A 2010 Cochrane review compared the efficacy and safety of a daily LABA vs a LTRA as add-on therapy for patients whose asthma was not well controlled with ICS monotherapy.22 The LABA/ICS combination was significantly better at reducing the risk of exacerbations requiring systemic corticosteroids than monotherapy with either a LTRA or ICS, reducing the risk from 11% to 9% (RR=0.83; 95% CI, 0.71-0.97). The NNT to prevent one exacerbation over 48 weeks was 38 (95% CI, 22-244).22
