Effect of inhaled formoterol and budesonide on exacerbations of asthma 

Authors Pauwels R, Löfdahl C, Postma D, Tattersfield A, O'Byrne P, Barnes P, Ullman A (for the FACET international study group). 
Source New England Journal of Medicine. 337:1405-11. November 13, 1997. 
Institutions Multi-institutional in Belgium, Sweden, the Netherlands, United Kingdom and Canada. 
Support Astra Draco, Sweden. 

 

Background

The addition of long-acting inhaled beta-agonists to inhaled corticosteroids for the treatment of moderate to severe asthma has been shown to improve symptoms, but concerns about the development of tolerance, the masking of symptoms of inflammation and long term effects have been raised.

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

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
All patients were allowed 250 mcg of inhaled terbutaline as rescue medication. 
 

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

Patients

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

The authors note that the addition of formoterol to budesonide improved symptoms and reduced the rate of mild and severe exacerbations, without any evidence of worsening of control after 12 months of treatment. Increasing the dose of budesonide also reduced the rate of mild and especially of severe exacerbations.

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.

Comment

This study examined the effect of adding a long-acting inhaled beta-agonist (formoterol) to two different doses of an inhaled steroid (budesonide). The addition of formoterol significantly decreased the rate of mild and severe exacerbations and also improved indices of symptoms. Increasing the dose of the steroid was additive, was more effective in controlling severe exacerbations and equally effective in controlling mild exacerbations. Other indices of symptomatology, which were not primary endpoints, were better controlled with formoterol than with increasing the dose of the steroid.

Given the inflammatory nature of asthma, the use of an inhaled steroid is considered a mainstay of therapy in patients with moderate to severe, persistent asthma. No claim can be made based on this study for using formoterol or any other long-acting beta-agonist without an inhaled steroid. However, asthma is a chronic disease, many patients will be treated starting at a young age, and inhaled steroids have at least a theoretical potential for causing systemic side-effects. If the addition of a long-acting beta-agonist inhaler will allow a reduction in steroid dose, this could conceivably be advantageous in patients with mild to moderate disease who require continuous treatment. 

November 28, 1997


References

References related to this article from the NLM's PubMed database. 
 


Reader Comments

Date: Wed, 3 Dec 1997
From: "Mark Leber" <besterdoc@email.msn.com>

Several questions need to be asked before we can accept the results of this study and apply them to our patient population. First, were these patients true asthma patients? Did they exhibit reversibility using beta agonists? How many smoked or had other comorbid conditions such as diabetes, hypertension, kidney disease or copd? What was the racial and ethnic character of the experimental group? The population group may not be the same as the patients you treat. How many patients displayed multiple allergies or eosinophilia?

Second, I noticed that the patients only used diaries to detail their asthma attacks. Was there a trend in using more formoterol over the course of the study? Did any of these patients end up being seen in an emergency department or hospitalized? The main goals of treatment should be to reduce the long term deterioration in pulmonary function observed in asthma patients without the steroid side effects not how to treat mild asthmatics which I believe is fairly easy to do as demonstrated in this study.

Mark Leber,M.D.
 
 

    These patients were required to have at least a 15% improvement in FEV1 with beta-agonists. How many of them were atopic asthmatics, how many smoked and how many had COPD was not specified and might make a difference in the applicability of the results. I don't see how diabetes, hypertension or kidney disease would influence the results. The ethnic make-up of the study was not reported.

    Formoterol dosage was specified a priori and was not to change during the study. There were 11 hospitalizations for asthma: 1 in the low-dose budesonide plus formoterol group, 2 in the high-dose budesonide plus formoterol group, 3 in the low-dose budesonide only group and 5 in the high dose budesonide only group.    -- mj 


May 4, 1998

Letters to the editor about this article, from the April 9, 1998 New England Journal of Medicine. 
 

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