Add-on therapy options in asthma not adequately controlled by inhaled corticosteroids: a comprehensive review

Abstract

Many patients with persistent asthma can be controlled with inhaled corticosteroids (ICS). However, a considerable proportion of patients remain symptomatic, despite the use of ICS. We present systematically evidence that supports the different treatment options. A literature search was made of Medline/PubMed to identify randomised and blinded trials. To demonstrate the benefit that can be obtained by increasing the dose of ICS, dose-response studies with at least three different ICS doses were identified. To demonstrate whether more benefit can be obtained by adding long-acting beta2-agonist (LABA), leukotriene antagonist (LTRA) or theophylline than by increasing the dose of ICS, studies comparing these options were identified. Thirdly, studies comparing the different "add-on" options were identified. The addition of a LABA is more effective than increasing the dose of ICS in improving asthma control. By increasing the dose of ICS, clinical improvement is likely to be of small magnitude. Addition of a LTRA or theophylline to the treatment regimen appears to be equivalent to doubling the dose of ICS. Addition of a LABA seems to be superior to an LTRA in improving lung function. However, addition of LABA and LTRA may be equal with respect to asthma exacerbations. However, more and longer studies are needed to better clarify the role of LTRAs and theophylline as add-on therapies.

Figure 1

Mean change from baseline in morning peak expiratory flow (PEF) in patients treated with placebo or various doses of budesonide. A significant dose-response effect is seen. However, it should be noted that the difference between placebo and low-dose budesonide is greater than the difference between low-dose budesonide and high-dose budesonide and that there is no statistically significant difference between the various doses of budesonide. Reproduced from reference 33 with permission.

Figure 2

The dose-response curve of inhaled glucocorticoids.

Figure 3

Formoterol add-on study showing forced expiratory volume in one second (FEV₁) (panel A, from ref 64 with permission) and the estimated yearly rates (no. patients/year) of severe asthma exacerbations in the different treatment groups of the study (panel B). For estimated yearly rate of exacerbations, the P-values given were formoterol vs placebo P = 0.01 and lower vs higher dose of budesonide P < 0.001.

Figure 4

A. Change in supplemental salbutamol use before and after exacerbation in patients treated with fluticasone and salmeterol combination or with high-dose fluticasone (with permission from ref 90), B. Change in morning PEF (percent fall from day -14) over the 14 d before and 14 d after an exacerbation in relation to treatment as analyzed from a subgroup of a FACET study (with permission from ref 89).

Figure 5

Effect of addition of montelukast (10 mg/d) or doubling the dose of ICS on morning peak expiratory flow (AM PEF) over 12 week treatment period in patients not adequately controlled by budesonide 800 μg/d (solid line = montelukast + budesonide 800 mg/d, dashed line = budesonide 1600 μg/d) (with permission from ref 93).

Figure 6

Mean (+- SE) change in FEV₁ in 31 asthma patients treated with high-dose budesonide (1600 μg/d) and 31 patients given low-dose budesonide (800 μg/d) and theophylline (with permission from ref 106).