LONDON AND UXBRIDGE, UK--Physicians have long debated whether it is safe to manage symptomatic asthma by adding a ß-agonist to the maintenance regimen. Two new British studies indicate that this strategy does not increase the asthma exacerbation rate, thus suggesting that regular use of a ß-agonist, in conjunction with an inhaled corticosteroid, does not allow the underlying inflammation to worsen.

However, the benefit of adding a ß-agonist to the maintenance regimen remains somewhat unclear. One of these studies failed to detect any significant benefit from the regular use of the short-acting ß-agonist albuterol.[1] The second study, a meta-analysis of nine previous investigations, showed that regular use of the long-acting agent salmeterol improves lung function and reduces asthma symptoms and exacerbations.[2]

These discordant results may reflect the difference between long- and short-acting drugs; however, further research must be done to elucidate this point.

PROS AND CONS

Support for the addition of a long-acting ß-agonist comes from the Meta-analysis of Increased Dose of Inhaled Steroid or Addition of Salmeterol in Symptomatic Asthma (MIASMA).[2] In an interview with RESPIRATORY REVIEWS, Stephen Shrewsbury, MD, lead author of this study, explained, "There are still those who worry that adding salmeterol might mask underlying inflammation and, therefore, trigger exacerbations. But it is beginning to look like adding the long-acting bronchodilator to a fairly low dose of the inhaled steroid actually provides better asthma control without an increase in exacerbations."

In contrast, no convincing evidence in favor of adding a short-acting ß-agonist was found in the second British study, The Regular Use of Salbutamol Trial (TRUST).[2] "In our study, there was only a small improvement in asthma patients regularly using salbutamol [albuterol]," one of the authors, Tak H. Lee, MD, said in an interview with RESPIRATORY REVIEWS.

LONG-TERM ALBUTEROL USE

The TRUST study was performed because previous research associated chronic regular ß-agonist use with increased asthma exacerbations, greater airway responsiveness to methacholine challenge, and other deleterious effects. Because albuterol is the most commonly used bronchodilator for asthma in the UK, it was critical to address the drug's safety, said Dr. Lee. It was also important to know whether such use could improve asthma control.

The randomized, double-blind, placebo-controlled study included 983 adult asthma patients who had been using albuterol at least twice a week for six months. Ninety percent of these patients also used inhaled corticosteroids. The daily corticosteroid dose was 2 mg or less in all cases.

The patients were recruited between August 1995 and September 1997 from 115 general practices in the United Kingdom. "We purposely avoided hospitalized patients, since most asthma treatment in the UK is done by community physicians," commented Dr. Lee, head of the Department of Respiratory Medicine and Allergy at Guy's Hospital in London.

Baseline data on the patients' asthma severity and control were gathered during a three-week "run-in" period. All patients had to display greater than 15% spontaneous variability in peak expiratory flow (PEF) values on at least four days of a two-week span and/or a PEF increase of 15% or more within 15 minutes of albuterol or terbutaline inhalation.

After the run-in period, patients were stratified by their use of inhaled corticosteroids (no use, up to 800 µg/d, or 801 to 2,000 µg/d). In each group, patients were randomly assigned to receive either 400 µg of inhaled dry-powder albuterol or placebo four times a day for 12 months. All patients were allowed to use their usual inhaled bronchodilator when necessary for symptom control. In addition, the patients receiving an inhaled corticosteroid were asked not to alter the dosage of that drug during the study, unless an asthma exacerbation occurred.

When the two treatment arms were compared, no differences in the frequency or duration of exacerbations were detected. The patients given albuterol did have a small increase in mean evening PEF, but mean morning PEF was similar to baseline in both groups. Albuterol administration also resulted in a small increase in the proportion of symptom-free days, but not of symptom-free nights. Both groups experienced a decreased need for rescue medications during the course of the study, but the size of this decrease was greater in the patients given albuterol.

WEIGHING THE BENEFITS

These findings do not constitute evidence of a beneficial effect of regular albuterol use on asthma control, asserted Malcolm R. Sears, MD, in an editorial accompanying the TRUST study.[3] Dr. Sears, a Professor of Medicine at McMaster University in Hamilton, Ontario, concluded, "Short-acting inhaled ß-agonists should be used only as needed for symptom relief and not for maintenance therapy."

The main message from TRUST, said Dr. Lee, is that if a patient with unstable asthma is regularly using albuterol, this is a sign that the asthma is not optimally controlled and additional medication, such as an anti-inflammatory drug, should be prescribed. However, it should not be assumed that poorly controlled asthma is being caused by the regular use of albuterol.

SALMETEROL VERSUS MORE STEROIDS

For their meta-analysis, Dr. Shrewsbury and colleagues searched the MEDLINE, EMBASE, and GlaxoWellcome databases for randomized, controlled studies that directly compared the addition of salmeterol with at least a doubling of inhaled corticosteroid dosages in patients with asthma. To be included, a study had to have at least a 12-week duration; subjects had to be no younger than age 12 years and have symptomatic asthma despite regular use of an inhaled corticosteroid. Nine such studies--with a combined enrollment of 3,685 patients--were found.

Because the severity of asthma exacerbations was not always reported, the authors tried to collect the original patient data for each study and did so for all but two studies. "All included studies were sponsored by GlaxoWellcome," they acknowledged. However, they stressed, these studies "were conducted according to good clinical practice, and all had received ethical approval."

The meta-analysis found that, at three and six months, mean morning PEF was higher (by 22.4 and 27.7 L/min, respectively) in the patients given salmeterol than in those receiving the increased inhaled corticosteroid dosages. Forced expiratory volume in one second was also higher (by 0.1 and 0.8 L, respectively) in the salmeterol group. In addition, patients given salmeterol were significantly less likely to have day and nighttime asthma symptoms and slightly less likely to have mild, moderate, or severe exacerbations; also, they needed rescue therapy less often.

"Clinicians can now feel confident that when they've got asthma patients who are symptomatic, they can add the long-acting bronchodilator and rest assured that inflammation will not rampage uncontrolled." concluded Dr. Shrewsbury, the Senior Program Head of Respiratory Clinical Development at GlaxoWellcome in Research Triangle Park, NC. Instead, adding salmeterol provides a safe alternative to increasing the inhaled corticosteroid dosage, he believes.

--Timothy Begany

References
1. Dennis SM, Sharp SJ, Vickers MR, et al. Regular inhaled salbutamol and asthma control: the TRUST randomized trial. Lancet. 2000;355:1675-1679.
2. Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). BMJ. 2000;320:1368-1373.
3. Sears MR. Short-acting inhaled ß-agonists: to be taken regularly or as needed? Lancet. 2000;355:1658-1659.