Background

This double-blind, 12-month study was designed to examine the effect of adding a long-acting inhaled beta-agonist (formoterol) to a lower and a higher dose of an inhaled steroid (budesonide) in patients with asthma. 

Methods

Patients were enrolled at 71 centers in 9 countries, and were eligible if they were between 18 and 70 years of age, with asthma for at least 6 months and treated with inhaled steroids for at least 3 months. FEV₁ was required to be at least 50% of predicted, with at least a 15% increase after bronchodilator treatment.

Principal exclusions: patients on high dose inhaled steroids, or who had been on more than two courses of oral steroids (or had been hospitalized for asthma) during the previous 6 months. 
 

Intervention

All patients underwent a 4-week run-in phase: 800 mcg of inhaled budesonide twice daily, plus 250 mcg of inhaled terbutaline as needed.

Patients who were compliant with the dose of inhaled budesonide (75% to 125% of the prescribed dose, as assessed by a hidden dose counter) and whose asthma was stable during the last 10 days of the run-in phase were then randomized to one of four treatment groups.

Randomization to 12 months of therapy with one of:

• 100 mcg of inhaled budesonide plus inhaled placebo, twice daily
• 100 mcg of inhaled budesonide plus 12 mcg of inhaled formoterol, twice daily
• 400 mcg of inhaled budesonide plus inhaled placebo, twice daily
• 400 mcg of inhaled budesonide plus 12 mcg of inhaled formoterol, twice daily

Analysis

Follow-up

Patients kept daily diaries which included twice daily, best-of-three, peak flow measurements, asthma symptom scores, awakening due to asthma, use of terbutaline and use of oral steroids.

There were a total of 9 clinic visits and 9 telephone follow-ups scheduled during the study.

Endpoints

The primary endpoints were the rates of severe and mild exacerbations of asthma per patient per year.

Severe exacerbations were those that required treatment with oral steroids (as judged by the investigators, and which was fixed at 10 days of treatment) or that produced a decrease in peak flow of greater than 30% from baseline for at least two consecutive days. Patients with 3 severe exacerbations within 3 months or 5 severe exacerbations total were withdrawn from the study.

Days with mild exacerbations were defined as at least two consecutive days with either a decrease in peak flow of 20% from baseline, an increase in use of terbutaline of at least three per day over baseline or night awakening due to asthma.

Results

Between April 1994 and April 1995, 1114 patients entered the run-in phase and 852 were randomized (210-215 to each of the 4 groups).

158 patients did not complete the study (44 - incorrectly randomized and ineligible; 42 - personal reasons, lost to follow up or relocated; 30 - worsening of asthma; 29 - adverse events; 13 - non compliance)

Baseline characteristics were well-matched. There were approximately equal numbers of men and women; average age was 42 years. FEV₁ at the start of the run-in period was about 75% of predicted. At the end of the run-in period, the average symptom score during the day was 0.5 (on a 0 to 3 scale) and the PEF was about 400 l/min.
 

Asthma exacerbations (primary endpoints)

Both the addition of formoterol to budesonide and increasing the dose of budesonide independently decreased the rate of mild and severe asthma exacerbations (i.e. there was no significant interaction between formoterol and budesonide).

Severe exacerbations

Adding formoterol to budesonide (both low and high dose) reduced the rate of severe exacerbations by 26%. Overall (my calculations from the data presented) 67% of patients without formoterol were free of severe exacerbations, vs. 76% of patients who received formoterol.

Increasing the dose of budesonide (both with and without formoterol) reduced the rate of severe exacerbations by 49%. Overall (again, my calculations) 66% of patients on low dose budesonide were free of severe exacerbations, vs. 76% of patients on high dose budesonide.

As noted, these effects were additive so that the high dose of budesonide plus formoterol reduced the rate of severe exacerbations by 63%. Among patients on both of these therapies, 80.8% were free of severe exacerbations.

Mild exacerbations

The addition of formoterol to budesonide decreased the rate of mild exacerbations by 40%; increasing the dose of budesonide decreased the rate by 37%. 
 

Other indices of asthma symptoms

Other parameters of asthma symptomatology that were recorded included mean percent of the year symptom-free, symptom score during the day and during the night, number of inhalations of rescue medication during the day and at night, and mean number of awakenings at night.

For all of these parameters except awakenings at night, the addition of formoterol to budesonide significantly improved symptomatology. On the other hand, increasing the budesonide dose from low to higher dose only improved symptomatology for rescue medications at night and awakenings at night.
 

Lung function

Parameters of lung function at the end of the study (FEV₁ and peak flow) were improved by both the addition of formoterol and an increase in budesonide dose. For peak flow, the initial improvement with the addition of formoterol subsequently decreased, but remained statistically significant. 
 

Adverse events

Adverse events, withdrawals due to adverse events and hospitalizations were similar in the four groups. 

Author's discussion

Although long-acting beta-agonists have been shown to improve symptomatology, it is less clear how they would decrease the rate of severe exacerbations, given their general lack of anti-inflammatory effect. The authors speculate on a number of possible mechanisms, including inhibition of smooth-muscle contraction allowing better access to steroid deposition, and a possible anti-inflammatory effect of formoterol itself.

Concern about the development of beta-agonist tolerance and long-term worsening of asthma control with long-acting beta-agonist inhalers does not seem to have been borne out by this study. An initial loss of improvement in peak flow with formoterol does imply some degree of tolerance, but this was not clinically significant.

They note that their conclusions concerning the addition of formoterol only apply in patients who are also receiving inhaled steroids. Also, patients with frequent severe exacerbations appear to be better served with higher doses of inhaled steroids than with the addition of a beta-agonist.