Formoterol and budesonide reduced exacerbations and improved lung function in patients with stable asthma
ACP J Club. 1998 May-June;128:67. doi:10.7326/ACPJC-1998-128-3-067
Pauwels RA, Löfdahl CG, Postma DS, et al., for the Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med. 1997 Nov 13;337:1405-11.
To determine whether formoterol added to low-dose or high-dose budesonide reduces exacerbations in adults with stable asthma.
1-year randomized controlled trial (factorial design).
71 centers in 9 countries.
852 patients (mean age 42 y, 51% women) who had asthma for ≥ 6 months. Inclusion criteria were use of inhaled glucocorticoids for ≥ 3 months and FEV1 ≥ 50% of predicted value with an increase of ≥ 15% in FEV1 after inhalation of terbutaline, 1 mg. Exclusion criteria were use of high doses of inhaled steroids, multiple courses of oral steroids, or recent hospitalization. 81% of patients finished the study.
After a 4-week run-in period that included budesonide, 1600 µg/d, and terbutaline, 250 µg/d as needed, patients who had stable asthma were allocated to budesonide, 200 µg/d, and placebo (n = 213); budesonide, 200 µg/d, and formoterol, 24 µg/d (n = 210); budesonide, 800 µg/d, and placebo (n = 214); or budesonide, 800 µg/d, and formoterol, 24 µg/d (n = 215). A dry-powder inhaler was used.
Main outcome measures
Rate of severe and mild exacerbations per patient/y, episode-free days, symptoms, use of rescue medication, lung function, and adverse events.
The study showed reductions in mild and severe exacerbations that were independent and additive for both formoterol and for an increased dose of budesonide (Table). The independent effect of high-dose budesonide alone was greater than that of formoterol alone. Similar patterns were shown for day symptom scores and number of awakenings per night (Table). Withdrawals because of side effects were < 5%; drug tolerance was not seen.
Formoterol provided an independent and additive benefit to higher doses of budesonide without development of tolerance for patients with stable asthma.
Source of funding: Astra Draco.
For article reprint: Dr. R.A. Pauwels, Department of Respiratory Diseases, University Hospital, De Pintelaan 185, B9000 Ghent, Belgium. FAX 32-9-240-4990.
Table. Budesonide (BUD) and formoterol (FOM) for stable asthma
|Outcomes at 1 yr*||Low-dose BUD||Low-dose BUD and FOM||High-dose BUD||High-dose BUD and FOM|
|Severe exacerbations per patient/y||0.91||0.67||0.46||0.34|
|Mild exacerbations per patient/y||35.4||21.3||22.3||13.4|
|Awakenings per night||0.14||0.11||0.10||0.05|
|Day symptom score||0.57||0.46||0.53||0.33|
* P ≤ 0.03 for formoterol vs placebo; P ≤ 0.01 for high- vs low-dose budesonide.
Patients with chronic asthma whose symptoms persist despite low-dose inhaled corticosteroid therapy have many options for maintenance: increasing the dose of inhaled corticosteroids; adding long-acting inhaled β2 agonists, such as formoterol; and adding theophylline. Evans and Pauwels and their colleagues evaluate these options using controlled trials.
Theophylline has anti-inflammatory and immunomodulatory activity (1) and provides a compliance advantage over inhaled medications (2). However, we need further information on the additive benefit of theophylline at concentrations that are lower than conventional therapeutic levels (3). The study by Evans and colleagues provides data for this question—their median level of theophylline was 8.7 µg/mL. The durability of the benefit of long-acting β2 agonists has also been questioned because of tolerance, and the 12-month study by Pauwels and colleagues addresses this issue. Because the exclusion criteria included recent courses of oral corticosteroids, the results of both studies are most relevant to patients with moderate rather than severe asthma.
The studies showed improvements of similar magnitude in many clinically important subjective and objective outcomes for both additive approaches. In general, theophylline was at least as effective as higher-dose budesonide and was associated with statistically, but not clinically, significant improvements in FEV1 and FVC that were not evident with higher-dose budesonide.
It is important to note that the benefits in the patients who received theophylline were obtained at median serum levels that were below conventional levels; theophylline also did not cause adverse reactions in most patients. Controlled studies of academic performance and behavior that include toxicity assessments have been reported and are reassuring, particularly because the study by Evans and colleagues shows that the additive benefits were obtained at low levels (3). Adverse effects may also be further reduced by a gradual stepwise introduction of theophylline.
The comments by Evans and colleagues on the relative cost of the various therapeutic options are welcome and suggest a cost advantage for theophylline. However, therapy with theophylline requires that both the clinician and the patient have adequate knowledge of the potential for toxicity and drug interactions; risk factors include lack of continuity of care and older age (4).
The strength of the conclusions from the study by Evans and colleagues is limited, however, by the flat dose-response profile of budesonide. Higher-dose budesonide cannot be assumed to provide much greater benefit in all patients, and the 2-week run-in period may have been insufficient to attain full beneficial effect on lung function. Given the absence of an appropriate control group, subsequent improvements in either therapeutic group are difficult to interpret.
The study by Pauwels and colleagues achieved a follow-up of > 80% of patients over 12 months and showed reductions in moderate and severe exacerbations that were independent and additive for formoterol and for an increased dose of budesonide. Patients did not build up a tolerance to the long-acting inhaled β2 agonist at 12 months.
Formoterol was superior to higher-dose budesonide for increasing the number of episode-free days. Improvements in most other outcomes were at least similar for formoterol as for higher-dose budesonide, and adverse effects were infrequent.
In summary, theophylline was well tolerated in most patients, outcomes with theophylline were at least similar to higher-dose budesonide, compliance with theophylline may be superior to that with inhaled therapies, and theophylline is less expensive than budesonide. In selected patients, therefore, an argument can be made for the careful addition of theophylline to low-dose inhaled corticosteroids when symptoms persist. If adverse effects occur, prompt consideration must be given to switching to a higher dose of inhaled corticosteroids or adding long-acting inhaled β2 agonists. Such additive approaches may reduce adverse effects because each drug may be used within a safer dose range rather than in the higher doses required for monotherapy.
Neither study was designed to comprehensively evaluate potential long-term or rare adverse effects. These issues warrant further evaluation.
Brian J. Smith, MBBS
Queen Elizabeth HospitalWoodville, South Australia, Australia