The combination of a LABA and an ICS has beneficial effects in patients with asthma.
13,14 Intuitively, the increased efficacy of the combination of a LABA and an ICS over the individual drugs makes sense given the pathophysiology of asthma (inflammation and bronchoconstriction). Evidence exists to suggest that administration of a LABA and an ICS from the same inhaler is more effective than taking the medications separately.
14 Synergy between the two classes of medications was noted when comparing FEV
1 measurements of patients receiving 4 weeks of budesonide plus formoterol versus 4 weeks of budesonide alone, and in comparing 4 weeks of fluticasone plus salmeterol versus 4 weeks of fluticasone alone.
13 The mean FEV
1 was improved in patients receiving the combination therapy versus the ICS monotherapy. Although ICSs are considered to be safe, they are not without adverse effects. Therefore, the National Heart, Lung, and Blood Institute in the National Asthma Education and Prevention Program
1 endorses the goal of using the lowest effective dose of an inhaled steroid to control asthma. To that end, LABAs function as steroid-sparing agents and may be used in combination with an ICS to lower the ICS dose needed for optimal asthma control.
The effectiveness of salmeterol's steroid-sparing effect is noted in a randomized, double-blind, parallel-group study of 458 patients who required moderate doses of an ICS to maintain asthma control. Adding a LABA (salmeterol xinafoate 50 μg twice a day) to the ICS allowed the dose of the ICS to be tapered by 60%.
15 Participants whose asthma was controlled with a regimen of 220 μg twice a day (or equivalent) of fluticasone propionate MDI were given either fluticasone propionate/salmeterol xinafoate (100 μg/50 μg) dry powder twice a day or fluticasone propionate (250 μg) dry powder alone twice a day for 24 weeks. Efficacy of the therapy was assessed by FEV
1 along with morning and evening PEF measurements, percentage of symptom-free days, daily asthma symptom score, albuterol use per 24-hour period, percentage of rescue-medication–free days, and nighttime awakenings. Overall, the patients taking 100 μg of fluticasone propionate plus 50 μg of salmeterol xinafoate either had improved or equivalent measures of lung function and quality of life compared with those taking 250 μg of fluticasone propionate alone.
15 These data indicate that the dose of an ICS can be safely reduced after the addition of a LABA to the therapeutic regimen.
Reduction of the steroid dose in patients with asthma raises the concern of accompanying subclinical airway inflammation. However, a 50% decrease in the ICS dose and the addition of a LABA result in no worsening of airway inflammation.
16 Bronchoalveolar lavage in subjects receiving combination therapy (200 μg of fluticasone propionate with 50 μg twice a day salmeterol) compared with subjects taking an ICS alone (500 μg of fluticasone propionate twice a day) showed no increase in submucosal eosinophils or mast cells. This study also corroborated findings of improved or stable lung function noted elsewhere.
13–15 Therefore, LABAs function synergistically with ICSs by improving asthma control while reducing the amount of ICS necessary to achieve control.
There appears to be a point of diminishing returns beyond which further reduction of the ICS dose results in worsening of asthma control. This point was shown in a study of airway inflammation in patients with asthma who were using both an ICS and a LABA. Their sputum eosinophil levels, symptom scores, and FEV
1 values were compared with those of patients with asthma who were using the same ICS dose with placebo.
17 The subjects on the combination ICS and LABA therapy were symptom free with stable symptom scores and FEV
1 values following a stepwise reduction in the ICS dose. However, these patients were found to have significantly higher sputum eosinophil levels prior to exacerbation compared with the patients taking placebo with the same dose of ICS. In this study, the LABA appeared to mask airway inflammation, whereas patients taking the low-dose ICS plus placebo reported asthma symptom scores that correlated with increasing sputum eosinophil levels. Presumably, the patients taking the low-dose ICS plus the LABA were not aware of their worsening asthma while those taking an ICS plus placebo had symptoms coexistent with increasing airway inflammation that would allow them to escalate therapy or seek medical attention.