A comparative study of efficacy and safety of arformoterol and salbutamol nebulization as rescue therapy in acute non-severe asthma.

Arformoterol, a long-acting beta-2 agonist, has a rapid onset and long duration of action. Its role as rescue medication in acute asthma attack is undetermined. To compare the efficacy and tolerability of arformoterol with salbutamol nebulization, a study was conducted among 50 patients with acute non-severe asthma. Patients were randomly assigned to group 1 (n = 25) and group 2 (n = 25) who received three doses of salbutamol and arformoterol nebulization, respectively, at 20-min intervals. The peak expiratory flow rate (PEFR) was measured at the baseline and 5 min after each dose. The demographics and baseline characteristics were comparable between the two groups. The mean PEFR significantly increased in both these groups when compared with the baseline. The increases in the PEFR in two groups were similar after the third dose. The adverse effects in both these groups were minor. Arformoterol was as effective and safe as salbutamol in acute non-severe asthma.

RCT Entities:   Population Interventions Outcomes

Introduction

Long-acting beta-2 agonists such as salmeterol and formoterol are important controller medications in the maintenance therapy of chronic stable asthma, used as an add-on drug to inhaled corticosteroid.[1] However, their usefulness in the management of acute attacks of asthma has recently been recognized,[2] and they are approved for use as reliever medication in Europe.

Short-acting β2 agonists are the preferred drugs as the initial bronchodilator for acute asthma because of their rapid onset of action.[3] However, due to short duration of action they require frequent administration.

Formoterol is a unique bronchodilator having rapid onset and long duration of action with a favorable safety profile. So it can be an ideal alternative to short-acting β2 agonists in the management of acute asthma exacerbation by providing rapid bronchodilatation and reducing the need for frequent administration. Onset of action of formoterol is similar to salbutamol (1–3 min),[4] and 80–90% of brochodilatation occurs by 5–10 min of inhalation.[5] Duration of action is up to 12 h.[6] However, duration of systemic effects with formoterol is found to be as short as salbutamol.[7] The safety and tolerability of formoterol are also well documented.[8]

Arformoterol ([R, R] Formoterol) is a single isomer form of formoterol, which is available in India recently. This study compares the efficacy and safety of arformoterol and salbutamol delivered by nebulization in the management of acute non-severe asthma.

Materials and Methods

A total of 50 patients attending the Emergency Room or Chest OPD of a tertiary care hospital with acute non-severe asthma over a 6-month period from January 2010 to June 2010 were selected for this study. The inclusion criteria were as follows: (a) age > 18 years; (b) British Thoracic Society definition of acute non-severe asthma[9]; and (c) ability to perform forced expiratory maneuver. The following patients were excluded from the study: (a) patients presenting with acute severe/acute life-threatening/near-fatal asthma; (b) patients with a previous diagnosis of chronic obstructive pulmonary disease (COPD); (c) history of hypersensitivity to β2 agonists; and (d) pregnant or lactating women. The study was approved by the institutional ethics committee, and informed consent was obtained from each patient.

The age, sex, duration of asthma symptoms, and present controller medications were recorded. The pulse rate, respiratory rate, and SpO2 (measured with Fingertip Pulse Oximeter, model 6500, Nidek Medical, Kolkata, India) were also recorded at the time of initial assessment. Baseline peak expiratory flow rate (PEFR) was measured with a peak flow meter (Peak Flow Master, Cipla Ltd., Mumbai, India).

Patients were then assigned by random number allocation to either of the two groups, that is, salbutamol or arformoterol group according to the medication given to them.

In the salbutamol group, 5-mg salbutamol respules were administered through oxygen driven (6 L/min) nebulizer (Pulmo mist II nebuliser, Nidek Medical, Kolkata, India) at 20-min intervals for 1 h amounting to a total of 15 mg. In the arformoterol group, total 45 μg of the drug was administered as 15 μg respules every 20 min through the same nebulizer. The drugs were administered in a double-blind manner. To eliminate the effects of other drugs on the treatment outcome, systemic corticosteroid was added only after administration of third dose of the drug.

PEFR was also measured 5 min after each dose. At each time, best of the three PEFR measurements was recorded. The patients were followed up for the next 6 h following the third dose. They were asked to report any adverse effect noted by them.

Differences in mean PEFR between the two groups were analyzed by unpaired t-test. One-sample test was used to compare PEFR before and after each dose of the drug to determine whether there was significant improvement in either group.

Results

Among 50 patients satisfying the inclusion criteria, 25 patients received salbutamol and 25 patients received arformoterol therapy. Table 1 shows the demographic profile and baseline PEFR of these patients.

Table 1

Baseline characteristics of the patients (n = 50) receiving salbutamol and arformoterol therapy

From the table, it is evident that the demographic profile and baseline PEFR in the two groups were comparable.

In both the groups, PEFR showed significant increase over the baseline values and the increase was evident after each dose of the drug. The increases in PEFR after the first and the second dose were significantly more with arformoterol than with salbutamol, but the increase in PEFR after the third dose was similar in these two groups. The comparison of improvement following the therapy with salbutamol and arformoterol is shown in Table 2.

Table 2

Improvement in PEFR after each dose of bronchodilator when compared with the baseline

Both drugs were well tolerated; no major adverse effect was noted in either group. The adverse effects and their frequency are shown in Table 3.

Table 3

Adverse effect profile of salbutamol and arformoterol in acute non-severe asthma

Discussion

As arformoterol is the only long-acting β2 agonist available in India as a nebulizing solution, we have used this drug considering the fact that the clinical pharmacology will be similar with formoterol.

Our study has shown that both salbutamol and arformoterol are equally effective as a reliever medication as nebulizing solution in acute non-severe asthma. Improvement in PEFR was demonstrated in both the groups and following each dose of the drugs. The absolute increase in the PEFR after the first and the second dose were more with arformoterol than with salbutamol, but the increase in the PEFR after the third dose was similar with these two drugs.

Relatively, hydrophilic drugs such as salbutamol have a rapid onset of action due to their ability to reach the β2 receptor from the aqueous phase.[10] Formoterol is a moderately lipophilic drug, about 300 times more than salbutamol.[11] The aqueous portion rapidly activates the β2 receptor, whereas the lipophilic portion is taken up into the cell membrane from which it diffuses slowly to stimulate β2 receptor over a prolonged period. This accounts for rapid on set along with long duration of action of formoterol.[12] Our study has also proved that arformoterol has a rapid onset of action.

Several studies have shown the efficacy of formoterol in acute non-severe asthma, acute severe asthma, exercise induced bronchospasm, childhood asthma, and COPD.[13-17] Most of the studies have used formoterol with terbuhaler,[814] aerolizer,[13] or metered dose inhaler.[1718] However, studies using formoterol nebulization are lacking. Although few studies have shown clinically significant improvement in lung function (FEV1) with formoterol when compared with salbutamol,[14] most studies have shown a comparable efficacy.[1315] Safety of formoterol is also well documented even at high doses in patients with asthma and COPD.[818] Although it is a long-acting drug, systemic effects with formoterol are as short as salbutamol.[7] In few studies, the impact of high-dose formoterol on heart rate, blood pressure, serum potassium, electrocardiogram changes, and arterial blood gas were assessed which showed identical changes comparable with salbutamol.[1418] We did not study these parameters but evaluated only the side effects reported by the patients. The side effects were very few, non-severe, and comparable between these two drugs. Dryness of mouth was the most reported side effect of formoterol inhalation in one study,[13] but we found oral irritation and headache as common side effects.

Our study has few limitations. The sample size is relatively small which limits our ability to detect small but potentially significant differences. This study is restricted to patients of acute non-severe asthma only; efficacy and tolerability of arformoterol in other acute settings such as acute severe asthma and acute exacerbation of COPD are yet to be explored. The side effect profile studied by us was only on the basis of the self-reported symptoms of the patients, and objective assessment and laboratory abnormalities were not assessed. We also did not follow the patients after discharge; so long-term efficacy and safety were not studied. Further studies are thus needed to clarify the efficacy, actual dose, dose frequency, cost-effectiveness, and long-term safety of arformoterol in acute exacerbations of asthma and COPD with different levels of severity.