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* From the Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK.
Correspondence to: Brian J. Lipworth, MD, Professor of Allergy and Respiratory Medicine, the Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK; e-mail: b.j.lipworth{at}dundee.ac.uk
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: Fifteen patients with atopic persistent asthma were evaluated (mean age, 32.4 years; FEV1, 75.2% predicted) in a randomized, double-blind, double-dummy, placebo-controlled crossover study with a 1-week placebo washout period, comparing the following once-daily nighttime treatments: (1) formoterol (FM), 12 µg, for 2 weeks and FM, 24 µg, for 2 weeks; or (2) budesonide (BUD), 400 µg, for 2 weeks and BUD, 800 µg, for 2 weeks; or (3) FM, 12 µg, plus BUD, 400 µg, for 2 weeks and FM, 24 µg, plus BUD, 800 µg, for 2 weeks. Adenosine monophosphate (AMP) bronchial challenge, exhaled nitric oxide (NO), and serum eosinophilic cationic protein (ECP) were evaluated at 12 h postdosing after administration of each placebo and after 2 and 4 weeks of each treatment.
Results: The results of AMP challenge (provocative concentration causing a 20% fall in FEV1) at 4 weeks showed significant (p < 0.05) improvements after patients had received all active treatments compared to placebo (20 mg/mL), with FM plus BUD, 261 mg/mL, being superior (p < 0.05) to FM alone, 82 mg/mL, but not to BUD, 201 mg/mL. NO and ECP showed significant (p < 0.05) reductions compared to placebo with FM plus BUD or BUD alone but not with FM alone. Combination therapy was associated with optimal patient preference (rank order, FM plus BUD > FM > BUD; p < 0.0005), highest domiciliary peak expiratory flow, and lowest rescue inhaler usage. All three treatments produced equivalent improvements in spirometry.
Conclusions: Patients preferred once-daily combination therapy, but this had no greater effect on inflammatory markers than therapy with BUD alone. FM alone had no anti-inflammatory activity but exhibited bronchoprotection. This emphasizes the importance of first optimizing anti-inflammatory control with inhaled corticosteroids before considering adding a regular long-acting ß2-agonist.
Key Words: adenosine monophosphate • bronchial hyperresponsiveness • budesonide • exhaled nitric oxide • formoterol • inflammation
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BUD and FM are currently licensed for regular once-daily evening administration in patients with mild-to-moderate persistent asthma. Therefore, we decided to evaluate the effects of once-daily low and high doses of FM and BUD given alone or in combination on lung function and surrogate inflammatory markers, the latter assessed by adenosine monophosphate (AMP) challenge, exhaled nitric oxide (NO) levels, and eosinophilic cationic protein (ECP).7 8 9 At the same time, we wished to evaluate whether the patient’s preference for monotherapy or combination therapy was mirrored by the effects of those therapies on inflammatory markers or lung function. We selected patients with stable mild-to- moderate asthma who were already receiving regular inhaled corticosteroids in line with the accepted recommendations on the additive use of long-acting ß2-agonists.4 5
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Protocol
The study had a placebo-controlled, double-blind, double-dummy,
crossover design. The subjects attended the laboratory for the initial
screening visit in the morning between 9 AM and 11
AM, and all the subsequent visits were performed within the
same 2-h window. An AMP bronchial challenge test was performed. The
patients who had a PC20 of < 200 mg/mL entered
the run-in phase. From the start of the run-in until the end of the
trial, all therapy with theophylline, long-acting
ß2-agonists, and inhaled corticosteroids was
stopped. Inhaled ipratropium bromide (Atrovent Forte; Boehringer
Ingelheim; Bracknell, UK), 2 puffs and 40 µg/puff, was used by
subjects as required for symptomatic relief purposes as a first-line
rescue therapy, with inhaled salbutamol used as second-line rescue
therapy. During subsequent visits, the subjects did not use either
ipratropium bromide or salbutamol for at least 12 h as
well.
At the start of the initial 1-week placebo run-in period, the patients were given placebo BUD via an inhaler (Turbohaler; AstraZeneca; Kings Langley, UK) along with placebo FM via a Turbohaler on a regular basis once daily at 8 PM. The patients were taught the correct technique for using the inhaler, making sure that they were able to generate an inspiratory flow of at least 60 L/min using a Turbohaler training device (AstraZeneca; Lund, Sweden).
The subjects made the next visit to the laboratory after the 7-day placebo run-in period, having taken the last dose of the placebo at 8 PM the previous evening. The patients collected their urine overnight for a 10-h cortisol collection test from 10 PM until 8 AM prior to making the visit. At this first study visit, the patients had 5 mL of blood taken for the measurement of ECP followed by measurement of exhaled NO. After that, the subjects underwent baseline spirometry testing followed by an AMP challenge. The subjects then were given their randomized treatments with one of the following: (1) inhaled FM (eformoterol fumarate, 12 µg/puff; Oxis Turbohaler; AstraZeneca), 1 puff once daily, with a placebo, 1 puff; (2) inhaled BUD (400 µg/puff; Pulmicort Turbohaler, AstraZeneca), 1 puff once daily, with a placebo, 1 puff; or (3) inhaled FM, 1 puff of 12 µg once daily, with inhaled BUD, 1 puff of 400 µg once daily. One puff of both inhalers was taken at 8 PM each night for the first 2 weeks. The subjects also were instructed to record the best of three values for their morning and evening peak flows, the latter measured using a peak expiratory flowmeter (Mini-Wright; Clement Clarke Ltd; Harlow, UK) prior to taking the evening medication and recorded on a diary card. The subjects also recorded the total number of puffs of ipratropium bromide or salbutamol rescue therapy taken each day.
The subjects made the next visit to the laboratory after 2 weeks of each randomized treatment, 12 h after taking the 14th dose of their randomized treatment, and bringing along their overnight urinary cortisol collection and diary cards. The same process was repeated for the measurement of NO, for spirometry, and for AMP challenge except that a sample for ECP was not collected at this occasion. The patients then were instructed to start taking 2 puffs from the same randomized inhalers each evening for a further 2 weeks and to record their peak flows and rescue inhaler use on a new diary card. The subjects then returned to the laboratory after another 2 weeks, 12 h after taking their 28th dose (the 14th dose of the 2 puffs/d period). At this third visit, a sample for the measurement of ECP levels was collected, and measurement of exhaled NO, spirometry, and AMP challenge were performed.
The subjects then entered a 7-day washout period in which they again used the two placebo inhalers once daily, at night. The same process was repeated with the next randomized treatment once daily, for 2 weeks (1 puff) and 4 weeks (2 puffs). This process was again followed by another 7-day placebo washout period and a subsequent randomized 4-week treatment block. Patient preference was evaluated at the second and third sequences after 2 and 4 weeks of treatment.
Measurements
Spirometry:
Spirometry was performed according to American
Thoracic Society11
criteria using a compact spirometer
(Vitalograph Ltd; Buckinghamshire, UK) with a pneumotachograph head and
pressure transducer, and an on-line computer-assisted determination of
FEV1 and FEF25–75.
AMP Bronchial Challenge: An AMP bronchial challenge test was performed as previously described.12 The test was continued until the FEV1 had dropped by > 20% from the baseline level or until the maximum concentration of 800 mg/mL had been administered. The PC20 was calculated using a computer-assisted curve-fitting package (Biolab Assistant, version 1.1; University of Dundee; Dundee, UK). If the FEV1 did not show a 20% fall after the maximum concentration had been given, or if the curve fitting revealed an extrapolated value > 1,600 mg/mL, a censored PC20 value of 1,600 mg/mL (double of the maximum concentration) was assigned for that test for the purpose of statistical analysis.13
ECP: The samples for measuring ECP levels were collected in silica gel-containing tubes (Vacutainer Hemogard SST; Becton Dickinson Vacutainer Systems Europe; France). After collection, the samples were kept at room temperature for 90 min before being spun at 3,000 rotations/min for 10 min. The supernatant was collected in a separate aliquot bottle and was frozen until analysis at the end of the study. The ECP was measured using a radioimmunoassay kit (Pharmacia & Upjohn Diagnostics AB; Uppsala, Sweden). The interassay coefficient of variation was 6.3%.
Exhaled NO: Patients had a measurement of exhaled NO using an integrated, clinical, real-time NO gas analyzer (model LR2000; Logan Research; Rochester, UK) with an accuracy of two parts per billion NO and a response time of 2 s using the procedure described by Kharitonov et al.14 Patients exhaled at a constant rate into the analyzer via Teflon tubing, from total lung capacity to residual volume, for approximately 30 s. Temperature, flow pressure, and mouth pressure were standardized throughout the study.15 Three measurements of NO were made, and the results were analyzed as the average of the three values.
Urinary Free Cortisol: The urinary cortisol was extracted from urine using dichlormethane prior to analysis. Urinary cortisol level was measured using a commercial radioimmunoassay kit (Incstar Ltd., Wokingham, Berkshire UK) that has no cross-reactivity for BUD. For urine-free cortisol excretion, the within-assay coefficient of variation was 7.9%, and 12.1% for between the assays.
Statistical Analysis
The study was powered at 80% to detect a one doubling-dose
(twofold) difference in AMP PC20 (the primary end
point). The data for PC20, exhaled NO levels, and
ECP levels were all log-transformed to normalize their distribution
prior to analysis. The parameters were analyzed as geometric mean
values and as fold differences (with 95% confidence intervals
[CIs]). The first visits for all three randomized treatments
(ie, after the placebo run-in period or the placebo washout
period) were compared according to their order in sequence. In
addition, the first visits for all three treatments were compared
irrespective of sequence (ie, prior to receiving FM alone,
BUD alone, and FM plus BUD, respectively). A pooled placebo then was
calculated and used for comparison with active treatments.
The statistical analysis was performed for within-treatment effects
(ie, comparing each active treatment at 2 and 4 weeks to
pooled placebo) and between-treatment effects (ie, comparing
the three active treatments at 2 weeks and 4 weeks). The statistical
analysis was performed by multifactorial analysis of variance using
subject, treatment, visit, and sequence as factors. This was followed
by Bonferroni multiple-range testing (set at 95% CI) to obviate
multiple pairwise comparisons, in order not to confound the overall 
error (p < 0.05; two-tailed test). Hence, all parameters are
described as being significant (p < 0.05) or not according to the
Bonferroni test. The patient preference was analyzed using the Friedman
rank test. All data analysis was performed using a statistical software
package (Statgraphics; STSC Software Publishing Group; Rockville, MD).
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Domiciliary Diary Cards
The domiciliary peak flow recordings showed significant
improvements after subjects received BUD plus FM compared to results of
receiving FM or BUD alone (Fig 1
). The following results were obtained for morning peak flow
measurements (reported as the mean over 4 weeks): FM plus BUD, 473
L/min; vs FM alone, 460 L/min (95% CI for difference, 2 to 22); vs BUD
alone, 453 L/min (95% CI for difference, 9 to 29). Similarly, the
following results were obtained for evening peak flow measurement: FM
plus BUD, 486 L/min; vs FM alone, 472 L/min (95% CI for difference, 5
to 22); vs BUD alone, 476 L/min (95% CI for difference, 1 to 19). The
level of salbutamol use for rescue was much less than that for
ipratropium bromide. The inhaler use for ipratropium bromide rescue
therapy was significantly lower after therapy with FM plus BUD compared
to FM alone, but not compared to therapy with BUD alone, while
salbutamol usage was significantly lower after therapy with FM plus BUD
compared to BUD alone, but not compared to therapy with FM
alone.
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Prechallenge Spirometry
The prechallenge spirometry results showed significant
improvements in FEV1 and
FEF25–75 with all active treatments compared to
the pooled placebo, but there were no significant differences between
treatments (Fig 2
).
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Exhaled NO
For FM alone, there were no significant differences at either dose
compared to pooled placebo. Doses of both BUD alone and combination
therapy yielded significantly lower NO levels (Fig 3) compared
to placebo (Table 2)
. For therapy with BUD alone at both doses and for
combination therapy at high dose, there were significant reductions in
exhaled NO compared to NO levels after therapy with FM alone
(ie, FM, 12 µg, vs BUD, 400 µg, yielded a 1.7-fold
difference [95% CI, 1.2- to 2.4-fold]; FM, 24 µg, vs BUD, 800
µg, yielded a 2.1-fold difference [95% CI, 1.1- to 3.4-fold]; and
FM, 24 µg, vs FM, 24 µg, plus BUD, 800 µg, yielded a
1.8-fold difference [95% CI, 1.1- to 2.9-fold]). Rank order for
effects on exhaled NO levels showed significant (p = 0.004)
differences with both BUD-containing arms compared to FM alone.
ECP
There were significant reductions in ECP levels after therapy with
both BUD-containing arms of the study. There was no significant
reduction in ECP levels (measured only at visit 3) after FM treatment
compared with pooled placebo (the 95% CI for fold difference included
unity due to the wider intrasubject variance (Table 2)
.
Patient Preference
The patients preferred the combined treatment as their first
choice followed by therapy with FM alone and then BUD alone in rank
order (p < 0.0005)
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the study of Pauwels et al,1 adding therapy with twice-daily administration of FM to that with BUD produced improvements in peak expiratory flow and reductions in exacerbation rates. Our data showed that once-daily FM administration conferred additive effects on peak expiratory flow but exhibited no significant anti-inflammatory activity on its own. In a subgroup analysis of the study by Pauwels et al,1 therapy with the combination of FM and low-dose BUD showed no significant difference in the levels of induced sputum eosinophils after 1 year compared to the effects of high-dose BUD as monotherapy.16 The use of salmeterol on its own or in addition to inhaled corticosteroids has been shown to have no significant effect on inflammatory cell profiles or activation markers derived from bronchial biopsy specimens or BAL fluid.17 18 However, some data have suggested that twice-daily monotherapy with FM may reduce the number of mast cells and eosinophils in bronchial biopsy specimens taken from patients with mild atopic asthma.19
This begs the question as to the underlying mechanism for the reduction in exacerbation rates with therapy with FM plus BUD. The study of Pauwels et al1 showed that there was a proportionally greater reduction in exacerbation rates by increasing the dose of BUD as monotherapy (from 200 to 800 µg/d) compared to the additive effects of therapy with FM. This is in keeping with our own data, in that doubling the dose of BUD exhibited further protection against AMP challenge irrespective of the addition of FM. Our results, showing greater suppression of exhaled NO and bronchial hyperreactivity (as in the AMP challenge) with therapy with BUD alone compared to therapy with FM alone, are similar to the observations of Verberne et al20 and Simons,21 in which beclomethasone dipropionate was superior to salmeterol for effects on bronchial hyperreactivity (as in a methacholine challenge) and exacerbation rates.
Studies have shown that adding salmeterol to inhaled corticosteroids is as effective as doubling the corticosteroid dose in controlling exacerbation rates.2 3 However, adding salmeterol has been shown to potentially mask the underlying airway inflammation in terms of increased induced sputum eosinophils with unchanged symptoms and lung function prior to an exacerbation, during the step-down with inhaled beclomethasone.6 This emphasizes the importance of optimizing anti-inflammatory control with inhaled corticosteroids before considering the addition of regular long-acting ß2-agonist treatment.
We observed a patient preference for the combination treatment compared to treatment with the corticosteroid alone, which was associated with increased peak expiratory flow rates and lower rescue requirements. This preference may reflect patients’ perceptions of a rapid onset of bronchodilator response with FM as compared to the more gradual onset of action with the corticosteroid. Combining long-acting ß2-agonists and inhaled corticosteroids in the same inhaler formulation (eg, fluticasone plus salmeterol [Seretide; Glaxo Wellcome; Oxbridge, UK]) might conceivably result in improved compliance, at least when initiating therapy.
We accept the limitations of our study in that we used a relatively small sample of patients who had mild-to-moderate asthma. We chose patients with mild-to-moderate asthma as we intended to evaluate the comparative effects of BUD and FM, and, consequently with the washout period, there was a potential 6-week period when the patients might conceivably not be taking any inhaled corticosteroids. In order to make sure that the patients did not develop short-term worsening of their disease control, it was decided to evaluate those patients who were using < 1,000 µg/d of inhaled corticosteroids. Interestingly, the mean PC20 value (29 mg/mL) at recruitment prior to the initial placebo run-in was similar to the value after the run-in (22 mg/mL), suggesting that patients may not have been complying with their usual inhaled corticosteroid therapy at the time of recruitment. This is supported by the subsequent improvement in mean PC20 values to 109 mg/mL after 2 weeks of therapy with BUD, 400 µg/d, compared to the average corticosteroid dose of 473 µg/d at recruitment.
We used the BUD Turbohaler once daily, as it is licensed for use in the United Kingdom, up to 800 µg/d in patients with mild-to-moderate asthma. In the present study, at 12 h after the administration of BUD, 400 µg, once daily for 2 weeks, there was a 2.5-doubling dilution shift in AMP PC20. This compares to a 2.7-doubling dilution shift in AMP PC20 in a previous study at 24 h after the administration of the BUD inhaler, 400 µg, once daily for 2 weeks.22 Furthermore, we also have shown that at 12 h after the administration of the BUD inhaler, 200 µg, twice daily for 3 weeks, there was a 2.5-doubling dilution shift in AMP PC20.23 Taken together, the results of these trials suggest that the results of the present study with once-daily treatment can probably be extrapolated to what happens with twice-daily therapy.
We elected to use AMP challenge, ECP levels, and exhaled NO levels together as surrogate end points of airway inflammation, as it is possible that a given marker may not correlate with active inflammation in different patients. In previous studies, the effects of BUD were proportionately greater for AMP challenge than for methacholine challenge.23 24 This reflects the indirect nature of AMP challenge in terms of mast cell priming and release of inflammatory mediators in contrast to the direct effect of methacholine on bronchial smooth muscle. It has been postulated that AMP is a more appropriate marker of bronchial inflammation in the evaluation of corticosteroid responses.7 The effects of FM on AMP challenge are thought to be partly due to the direct inhibition of mast cell ß2-adrenoceptors and partly due to the stimulation of bronchial smooth muscle ß2-adrenoceptors.25
Exhaled NO has a positive correlation with sputum eosinophil count and responsiveness to methacholine bronchial challenge.26 We found no further suppression of exhaled NO by increasing the dose of BUD from 400 to 800 µg/d. This is in keeping with other data from the study of BUD by Jatakanon et al27 in which dose-related reductions in exhaled NO and sputum eosinophil levels showed a plateau effect at a dose of 400 µg/d from the BUD Turbohaler. We also have previously performed a dose-ranging study with the BUD Turbohaler in which a plateau in response to exhaled NO was seen at a dose of 400 µg/d of BUD, in contrast to dose-related improvements in AMP and methacholine reactivity up to 1,600 µg/d in patients with mild-to-moderate atopic asthma.23 Serum ECP level may be used as a surrogate inflammatory marker in atopic asthmatics and has been shown to correlate with ECP levels in BAL fluid, with eosinophil numbers in bronchial biopsy specimens, and with asthma exacerbations.28 29 30 Thus, we thought that by choosing serum ECP levels, exhaled NO levels, and AMP challenge reactions, we were broadly assessing the underlying inflammatory process.
In summary, we have found that optimal patient preference, improved peak flow rates, and reduced rescue medication with combined once-daily BUD and FM therapy were not associated with significantly better anti-inflammatory control than the same dose of BUD as monotherapy, while all three treatments produced equivalent improvements in spirometry. FM as monotherapy did not appear to exhibit significant anti-inflammatory effects and produced less bronchoprotection than BUD as monotherapy. Our results support optimizing the anti-inflammatory efficacy of inhaled corticosteroid therapy first before considering the addition of long-acting ß2-agonists.
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Acknowledgements |
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Footnotes |
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This study was supported by University of Dundee departmental grant and received no pharmaceutical funding.
The Asthma and Allergy Research Group has received financial support for postgraduate education and attending scientific meetings from Astra-Zeneca, which makes formoterol and budesonide.
Received November 16, 1999; revision accepted April 25, 2000.
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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