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Formoterol Turbuhaler as reliever medication in patients with acute asthma

¹ Depts of Respiratory Medicine, Royal Melbourne Hospital and Melbourne University, Melbourne, ² Dept of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, ³ Dept of Emergency Medicine, Lyell McEwin Health Services, Elizabeth Vale, ⁴ Asthma and Allergy Research Institute, and Centre for Asthma, Allergy and Respiratory Research, Universtiy of Western Australia, Nedlands, and ⁵ AstraZeneca, Sydney, Australia, ⁶ AstraZeneca R&D, Lund, Sweden.

CORRESPONDENCE: A. R. Rubinfeld, Dept of Respiratory Medicine, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia. Fax: 61 393428493. E-mail: abe.rubinfeld{at}mh.org.au

Keywords: Acute asthma, formoterol, reliever medication, salbutamol, Turbuhaler®

Received: March 9, 2005
Accepted January 2, 2006

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The aim of this study was to compare the efficacy and safety of formoterol versus salbutamol as reliever medication in patients presenting at an emergency dept with acute asthma.

A randomised, double-blind, double-dummy, parallel group study was performed in four Australian emergency treatment centres. The study included a total of 78 adult patients (mean baseline forced expiratory volume in one second (FEV₁) 1.83 L; 59% predicted) with acute asthma. Based on the expected dose equivalence of formoterol Turbuhaler® 4.5 µg (delivered dose) and salbutamol pressurised metered-dose inhaler 200 µg (metered dose), patients received a total of formoterol Turbuhaler® 36 µg (delivered) or salbutamol pressurised metered-dose inhaler with spacer 1,600 µg (metered), divided into two equal doses at 0 and 30 min. FEV₁, peak expiratory flow and systemic ß₂-agonist effects were monitored for 4 h. The primary variable was FEV₁ % pred at 45 min.

At 45 min, mean increases in FEV₁ expressed in % pred were 6.6% and 9.3%, respectively, with a small adjusted mean difference in favour of salbutamol (3.0%, 95% confidence interval –2.0–8.0). Transient increases in systemic ß₂-agonist effects occurred predominantly with salbutamol, although no significant treatment differences were observed. Eight patients discontinued due to adverse events.

In this study of patients presenting at emergency depts with acute asthma, formoterol Turbuhaler® 36 µg was well tolerated and, as rescue therapy, had an efficacy that was not different from that of salbutamol pressurised metered-dose inhaler with spacer 1,600 µg in the number of patients studied.

In hospital emergency depts, the firstline treatment for patients presenting with acute exacerbations of asthma is the administration of a rapid-acting ß₂-agonist, either continuously or at regular intervals during the first hour 1, 2. Although rapid-acting ß₂-agonists are often administered via nebulisation, equivalent and more rapid bronchodilation, with fewer side-effects, can be achieved with a pressurised metered-dose inhaler (pMDI) and spacer 2–4. In the event of a severe exacerbation or no immediate response to ß₂-agonist therapy, oxygen, systemic glucocorticosteroids, and further inhaled or intravenous ß₂-agonist therapy may be needed.

Traditionally, rapid- and short-acting ß₂-agonists (e.g. salbutamol, terbutaline) have been used for symptom relief. Formoterol is a selective ß₂-agonist with a similar onset of effect to salbutamol 5 but with a longer duration of action (12 h in patients with stable asthma) 6. Politiek et al. 7 found that formoterol via Turbuhaler® was as effective as salbutamol via pMDI, relieving methacholine-induced bronchospasm within 3 min, a model for severe acute bronchospasm. Importantly, in contrast to its topical bronchodilator activity, the systemic effects of inhaled and oral formoterol are short-lived and similar to short-acting ß₂-agonists 8, 9. Moreover, a comparative dose–response study in patients with asthma suggested that the therapeutic index (i.e. the dose ratio between lung function improvements and systemic activities; for example, effects on serum potassium and QT interval corrected for heart rate (QTc)) was 2.5 times more favourable for formoterol Turbuhaler® than salbutamol pMDI, although the difference in this study was not statistically significant 10.

Several studies have established a role for regular formoterol treatment in combination with inhaled glucocorticosteroids in preventing severe asthma exacerbations 11, 12. These effects have been confirmed when formoterol has been used as-needed compared with as-needed terbutaline or salbutamol 13, 14.

Formoterol is the only long-acting ß₂-agonist that has been approved for use as both maintenance and reliever therapy for chronic symptomatic asthma. As a result, some patients may be using formoterol as their only ß₂-agonist bronchodilator. In the event of acute asthma worsening, such patients must be able to rely on their inhaler and may use several doses within a short period of time. It is therefore important to understand the efficacy and tolerability of higher-than-normal doses in an emergency situation.

Although as-needed formoterol is well tolerated and effective in preventing severe exacerbations, few studies have addressed its efficacy compared with more traditional reliever therapy during severe, acute asthma exacerbations. Salbutamol via pMDI and spacer, at a dose of 1,000 µg at regular intervals within the first hour is recommended for the initial treatment of acute asthma 2. The present study compares the efficacy and safety of two administrations of formoterol Turbuhaler® (Oxis®; AstraZeneca, Lund, Sweden; 4x4.5 µg inhalations (18 µg)) given 30 min apart with salbutamol via pMDI (Norton Healthcare, Harlow, UK) with spacer (Volumatic^TM; GlaxoSmithKline, Uxbridge, UK; four separate inhalations of two actuations of 100 µg (800 µg)) for up to 4 h in patients with acute asthma presenting at a hospital emergency dept. The doses selected in the study were based on an expected dose equivalence of formoterol Turbuhaler® 4.5 µg and salbutamol pMDI 200 µg established in previous studies in patients with stable asthma 9, 10.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Study design and patients
This was a randomised, double-blind, double-dummy, parallel group study conducted at four centres in Australia. Patients (aged 18–70 yrs) presenting at the emergency dept with acute asthma 15 were included in the study if their forced expiratory volume in one second (FEV₁) was >30% of predicted and, if aged 50 yrs, they had a pulse rate 100 beats·min^–1 on presentation. Patients were excluded from the study if: they had a significant cardiovascular or respiratory disease (other than asthma); they required transfer to the intensive care unit, or nebulised or intravenous ß₂-agonists at the initial assessment; or their arterial oxygen saturation (S_a,O2) was <93% on room air. Females who were pregnant, lactating or of childbearing potential, meaning they were not using adequate contraception, were excluded.

The study was conducted according to the principles of the Declaration of Helsinki. An agreed protocol was followed, which was approved at each institution by independent ethics committees. Patients gave initial verbal informed consent before participation in the study and detailed written informed consent was obtained as soon as improvement in asthma symptoms permitted. Eligible subjects were assigned to receive either formoterol or salbutamol therapy, according to a computer-generated randomisation code. Treatment was initiated within 30 min of arriving in the emergency dept. Each treatment was given twice, at time 0 and 30 min, and consisted of either formoterol Turbuhaler®, administered as 4x4.5 µg inhalations (18 µg), or salbutamol pMDI via spacer, as four separate inhalations of two actuations of 100 µg (800 µg). To achieve double-dummy conditions, patients also used either four inhalations of placebo Turbuhaler® or four inhalations of two actuations of pMDI as appropriate; inhalations were started with Turbuhaler® or pMDI in pre-arranged order according to randomisation number. Oral prednisolone (50 mg) was administered as a single dose 60 min after the first dose of study drug. If the investigator considered that an oral formulation would not be tolerated, a single dose of intravenous hydrocortisone (100–200 mg) was administered instead. Oxygen was administered throughout the study.

Assessments
FEV₁ and peak expiratory flow (PEF) were measured by spirometry at baseline (0), 15, 45, 75, 90, 120, 180 and 240 min after first administration of the study drug. Spirometry was performed three times at each assessment and the highest FEV₁ value was recorded. All centres used the same type of spirometer (MicroLab^TM Rochester, UK), which met the American Thoracic Society standard for accuracy (±3% of reading or ±0.05 L). The primary efficacy variable was the change from baseline in FEV₁ % pred, 45 min after the first dose of study drug and 15 min before the administration of prednisolone. Secondary efficacy variables included the increase from baseline in FEV₁ (%), from baseline to 15 min, and the average and maximum change in FEV₁ between 45 and 240 min after administration of study drug. PEF was also assessed at each time point. Estimations of FEV₁ % pred and PEF values were made for each patient, taking into account age, height and sex 16, 17.

Safety variables were measured at baseline, 15, 45, 75, 120, 180 and 240 min during the 4-h observation period. Blood samples were taken for serum potassium measurements. Radial pulse, blood pressure (systolic and diastolic) and electrocardiogram (ECG) were recorded using standard local procedures. The QTc was calculated using Bazett's formula. Adverse events (AEs) reported or observed during the treatment period were also recorded. Both direct and open-ended questioning at the end of the 4-h study period was used to collect AE reports.

Patients who failed to respond to the second dose of study medication (S_a,O2 <93% or FEV₁ 30% pred, or there was a fall or no improvement in FEV₁ within 15 min of the second dose of study drug) were withdrawn and received routine emergency dept treatment.

Statistical analysis
The primary efficacy variable, change in FEV₁ % pred at 45 min, was compared between treatments using an additive ANOVA model with treatments and centre as fixed factors, using baseline FEV₁ as covariate. Similar ANOVA models were used to compare the secondary efficacy variables based on FEV₁ and PEF, and the safety variables (average and minimum serum potassium and diastolic blood pressure, maximum and average systolic blood pressure, pulse rate, QTc). Treatment difference was expressed as the mean difference and 95% confidence intervals (CI). Sinus rhythm and overall ECG were presented by descriptive statistics. All efficacy analyses followed the intention-to-treat approach. Only patients who took at least one dose of study treatment were included in the safety analysis. The number of patients withdrawn from the study within 4 h of administration of the first dose of study drug was compared between treatments using a Chi-squared test. A p-value of <0.05 was considered statistically significant.

Due to limitations in recruitment rates at the participating sites, the total number of patients had to be maximised at 80. With 40 patients in each group, an 80% power existed to detect a difference of FEV₁ 7% pred at 45 min, assuming an SD of 11% and a two-sided t-test at the 5% significance level.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Of the 78 patients enrolled in the study, 38 were randomised to formoterol and 40 to salbutamol treatment (table 1). The treatment groups were generally well matched for the level of airway obstruction at entry (the mean FEV₁ % pred was 57% in the formoterol group and 60% in the salbutamol group). However, some differences in demographics between the groups were apparent, with a higher male ratio in the formoterol group (42 versus 25% in the salbutamol group) and greater use of concomitant medications before study entry in the formoterol group versus the salbutamol group. The mean dose of inhaled corticosteroid was also higher in the formoterol group (1,313 versus 908 µg·day^–1) and more patients had previously used long-acting ß₂-agonists (42 versus 30%). At 60 min, all patients received oral prednisolone, except for three patients who received intravenous hydrocortisone. During the study, 22 patients discontinued treatment (nine in the formoterol group, 13 in the salbutamol group; p = 0.39); eight of these were due to AEs (three formoterol, five salbutamol), two (one in each group) failed to meet eligibility criteria, and 12 (five formoterol, seven salbutamol) were due to other reasons.

View larger version (10K): [in this window] [in a new window]   Fig. 1— Effect of formoterol via Turbuhaler® (2x18 µg; •) and salbutamol (2x800 µg; ) via pressurised metered-dose inhaler plus spacer on forced expiratory volume in one second (FEV1), expressed as mean change in % predicted from baseline. First dose administered at baseline; administration of second dose indicated by dotted line.

Safety
Mean safety parameter measurements are shown in table 3. There were no statistically significant differences between the two treatment groups. Systolic and diastolic blood pressure decreased after the first dose of study drug in both treatment groups. Mean heart rate decreased on treatment in both groups over the 4-h period. However, an initial transient and minor increase in heart rate was observed in the salbutamol group and this was accompanied by similar changes in QTc at the 45-min time point (fig. 2). During the 4-h study period, the profiles of the changes in mean serum potassium values were similar to the changes in QTc, i.e. minor in both treatment groups, with numerically greater decreases in the salbutamol group (fig. 3).

View larger version (8K): [in this window] [in a new window]   Fig. 2— Effect of formoterol via Turbuhaler® (2x18 µg) and salbutamol (2x800 µg) via pressurised metered-dose inhaler plus spacer on mean change in QTc. First dose administered at baseline; administration of second dose indicated by dotted line.

View larger version (9K): [in this window] [in a new window]   Fig. 3— Effect of formoterol via Turbuhaler® (2x18 µg) and salbutamol (2x800 µg) via pressurised metered-dose inhaler plus spacer on mean change in serum potassium. First dose administered at baseline; administration of second dose indicated by dotted line.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
A severe asthma exacerbation can be life threatening and needs emergency intervention to provide relief from bronchospasm. Previous studies have shown that formoterol has a rapid onset of effect in asthma patients 6, which is as fast as salbutamol 5, 7. Furthermore, there is some evidence to suggest that formoterol Turbuhaler® has a more favourable therapeutic index than salbutamol delivered by pMDI 10. In the current study, in patients with acute asthma, formoterol 36 µg by Turbuhaler® produced a rapid and clinically relevant improvement in FEV₁, which was not statistically significantly different from that of salbutamol 1,600 µg by pMDI and spacer at all time points.

Acute asthma is characterised by breathlessness, wheeze and change in airway function over a short period of time. In this study, mean baseline FEV₁ was 59% pred. Despite the wide range of FEV₁ in both groups (varying from 30% to >100% pred), all patients presented with acute breathlessness, audible wheeze and clinical criteria consistent with acute asthma. The actual acute decrease in FEV₁ was unknown, a scenario often encountered in patients with acute asthma presenting to the emergency dept.

There was a male predominance and a more extensive previous use of inhaled corticosteroids and long-acting ß₂-agonists by patients in the formoterol treatment group. These baseline differences cannot be explained; they are probably chance findings in a randomised study. Patients were not stratified according to these criteria as all fulfilled the same symptomatic characteristics of acute worsening of asthma, precipitating a visit to the emergency dept. The higher level of previous treatment in the formoterol group may indicate more severe disease in this group, with less potential for acute response than the salbutamol group.

For the emergency treatment of acute asthma with a salbutamol pMDI plus spacer at home, the Global Initiative for Asthma guidelines 2 suggest up to 1,000 µg of salbutamol should be used at less than hourly intervals, with further subsequent doses depending on the level and sustainability of response over 3–4 h. The total salbutamol dose chosen for the present study, 1,600 µg, is consistent with these guidelines for initial treatment, and well within the Australian National Asthma Council guidelines 1. Previous experience in patients with asthma and healthy volunteers suggested that a dose of formoterol 36 µg via Turbuhaler® (48 µg metered dose) would be the nearest equivalent dose to salbutamol 1,600 µg 9, 10.

Another similar emergency dept study comparing formoterol 54 µg via Turbuhaler® and salbutamol 2,400 µg via pMDI plus spacer 18 reported that formoterol was at least as effective as salbutamol in patients with acute asthma. That study used the same dosing ratio for formoterol 4.5 µg versus salbutamol 200 µg, although the total doses were higher with an additional 18 µg formoterol or 800 µg salbutamol dose at 60 min.

As well as the dosing regimen, some other important differences between the two studies. Mean baseline FEV₁ % pred was lower in the Boonsawat et al. 18 study (44% pred) than in the present study (59%). They reported greater maximal improvements in FEV₁ (expressed as percentage increase from baseline: formoterol 51% versus salbutamol 36%) than in the present study (formoterol 24% versus salbutamol 26%, data not shown). There are a number of possible explanations for the differences in maximal improvements in FEV₁ between the studies: 1) higher doses of ß₂-agonists in the Boonsawat et al. 18 study may have produced the greater responses; 2) there may be a difference in responsiveness to ß₂-agonists between Thai and Australian patients; and 3) treatment before presentation to the emergency dept may have been different in the two groups. Nearly all of the present study's patients had taken (often considerable) doses of salbutamol or terbutaline and presented due to treatment failure. The authors are unaware of how the data in Boonsawat et al. 18 compare in this regard.

As formoterol is known to be well tolerated at higher doses 19, 20 and to have a defined dose–response with no plateau in effect over the dose range investigated here 10, 21, it is possible that a subgroup of patients with partial responses to treatment might have gained from further doses of formoterol and salbutamol. Indeed, in one cumulative-dose study, comparing formoterol Turbuhaler® with terbutaline Turbuhaler® in acute asthma, 20 as-needed doses of formoterol up to a maximum of 90 µg were safely administered, with improved tolerability compared with 20 as-needed doses of terbutaline (total dose 10 mg) 20.

Safety was an important aspect of the present study, as stimulation of ß₂-adrenoceptors can result in extrapulmonary effects, especially at the high doses required to treat acute bronchoconstriction 22. Therefore, blood pressure, heart rate, ECG and S-potassium were monitored during the study. Importantly, no clinically meaningful increases in systemic/extrapulmonary effects were apparent with the dose of formoterol used, and there were no significant differences between the active treatments. Both treatments appeared to be well tolerated. Although several AEs were reported, most of them were pharmacologically predictable side-effects or were related to the disease under study. Discontinuations due to AEs occurred due to asthma aggravation in slightly fewer formoterol than salbutamol patients. There was a nonsignificant trend with salbutamol to produce greater effects on S-potassium, heart rate and QTc after completion of dosing, but any differences with salbutamol were transient in nature and not considered clinically important.

One limitation of the current study was its relatively small sample size. As a consequence, a lack of a statistically significant difference alone cannot be judged to indicate an equal effect of the two drugs. Bronchodilating effects and systemic potencies of ß₂-agonists are dose-dependent 9, 10. In this study, cumulative doses of salbutamol 800 µg tended to give numerically higher effects than cumulative doses of formoterol 18 µg regarding both bronchodilation and systemic effects. This probably indicates a difference in potency at the dose-relation chosen, i.e. a somewhat higher formoterol dose than 18 µg should have been chosen to match salbutamol 800 µg. In this study salbutamol pMDI was administered via spacer and this was not accounted for when choosing the dose-relation.

Another possible limitation of this study was the lack of follow-up, which may have allowed detection of a difference in efficacy or side-effect profile between the treatment groups. It could be speculated that if a follow-up period had been added, formoterol-treated patients may have been less inclined to repeat the dose with reliever therapy due to its longer duration of bronchodilation 6, 23 with potential for fewer side-effects. A further study is warranted to examine this potential benefit of formoterol. Nevertheless, this study confirms the findings of others 18, 20 that formoterol Turbuhaler® is similarly effective and well tolerated compared with salbutamol or terbutaline as reliever therapy in treating acute asthma.

Although the results of this study are unlikely to warrant a revision of current guidelines for treating asthma in an emergency setting 2, 24, they offer reassurance that formoterol may be used as-needed for treatment of mild-to-moderate asthma worsenings. The as-needed use of formoterol could simplify bronchodilator therapy and may be clinically important since, compared with traditional reliever therapy, as-needed formoterol has been shown to decrease the risk of experiencing a severe asthma exacerbation 13, 14. In the 3-month study by Tattersfield et al. 13, formoterol 4.5 µg as-needed, decreased the risk of a first severe exacerbation compared with terbutaline 0.5 mg as-needed, in a patient population with poorly controlled asthma, despite moderate-to-high doses of inhaled glucocorticosteroids. More recently, the large REal LIfe EFfectiveness of Oxis® Turbuhaler® as needed in asthmatic patients (RELIEF) study showed that as-needed formoterol 4.5 µg decreased the risk of a severe exacerbation compared with as-needed salbutamol 200 µg 14.

In conclusion, the results of this study support the argument that formoterol can be used as an alternative to salbutamol as reliever therapy in acute exacerbations of asthma. Patients having formoterol Turbuhaler® as their only ß₂-agonist bronchodilator can also rely upon its function and efficacy in an emergency situation. The exact comparative dose potencies between formoterol Turbuhaler® and salbutamol via pressurised metered-dose inhaler plus spacer in acute asthma needs further investigation.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The authors acknowledge the contribution of: J. Wilson and G. Anderson in planning of the study; R. Brander for managing the study; and T. Bengtsson for statistical analysis. They would also like to thank C. Harmston from Prime Medica Ltd who provided editing assistance (funded by AstraZeneca).

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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