Tommy Ekström

Comparison of formoterol and terbutaline for as-needed treatment of asthma: a randomised trial.

BACKGROUND Asthma guidelines recommend that long-acting inhaled beta-agonists should be used as maintenance therapy for patients with asthma inadequately controlled on an inhaled corticosteroid. We studied the safety and efficacy of the long-acting beta-agonist formoterol compared with terbutaline, each taken as needed, in patients with moderate to severe asthma. METHODS Patients were taking an inhaled corticosteroid (mean dose 870 microg daily) and had a forced expiratory volume in 1 s (FEV1) of at least 50% predicted (mean 74%). Those requiring an inhaled beta-agonist three to eight times a day during the study run-in period (362 of 621 who started) were randomly assigned formoterol 4.5 microg or terbutaline 0.5 mg as needed by Turbuhaler in daily doses up to 54 microg and 6 mg, respectively, for 12 weeks in a double-blind, parallel-group study. Analyses were by intention to treat. FINDINGS The 362 randomised patients (157 men, 205 women) had a mean age of 47 years. Patients taking formoterol had a longer time to their first severe asthma exacerbation (relative-risk ratio 0.55 [95% CI 0.34-0.89]), took fewer inhalations of study drug, and had larger increases in FEV1 (5%) and morning and evening peak expiratory flow (mean difference in increase 11 L/min and 8 L/min) than those taking terbutaline. No safety issues were identified. INTERPRETATION When taken as needed, formoterol 4.5 microg provided better asthma control than terbutaline 0.5 mg in patients requiring moderate doses of relief medication despite inhaled corticosteroid treatment. Safety studies should be extended to a wider population of patients with asthma.

Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma: an efficacy and cost-effectiveness study.

ABSTRACT Objective: To evaluate efficacy and costeffectiveness of budesonide/formoterol (Symbicort*) maintenance (one dose once or twice daily) plus additional doses as needed (Symbicort Maintenance And Reliever Therapy, SMART) compared with a higher fixed dose of budesonide/ formoterol with formoterol as needed in patients with persistent asthma. * Symbicort is a registered trade name of the AstraZeneca group of companies Study design and methods: 6‐month, open, randomised study of 465 patients either not well controlled on an inhaled corticosteroid (ICS), or well controlled on a combination of ICS and a long-acting β2‐agonist (LABA). Treatments: budesonide/formoterol 160/4.5 µg, one inhalation, once or twice daily maintenance plus additional doses as-needed (1 × SMART or 2 × SMART), or budesonide/formoterol 160/4.5 µg two inhalations twice daily plus formoterol 4.5 µg as needed (2 × 2 FIX + F). Children 6–11 years old used an 80/4.5 µg dose strength. Primary variables of efficacy were the changes in the Asthma Control Questionnaire (ACQ5) and morning peak expiratory flow (PEF). Results: Mean age of patients 40 years (range 6–82 years); 53% female. No differences between the groups were found in ACQ5 scores or asthma exacerbation rates. Morning PEF was higher in the 2 × 2 FIX + F group vs. the 1 × SMART and 2 × SMART groups (differences 13 L/min and 9 L/min, respectively; p < 0.002). The 1 × SMART group showed a significant decrease in asthma controlled days compared with the two other groups. No difference was seen between the 2 × SMART group and the 2 × 2 FIX + F group. Treatment costs were significantly lower in the SMART groups compared with the 2 × 2 FIX + F group. Conclusion: Compared with the 2 × 2 FIX + F treatment the use of budesonide/formoterol was 30–40% lower in the SMART groups while maintaining equal ACQ5 scores. Daily asthma control improved equally with 2 × SMART compared to 2 × 2 FIX + F with a reduction in asthma medication cost. The one dose once daily maintenance treatment (1 × SMART) resulted in a low level of treatment failure (exacerbations) but led to more days with symptoms. Therefore, a daily dose of two inhalations seems to be the lowest appropriate dose in patients with moderate persistent asthma.

Poor adherence with inhaled corticosteroids for asthma: can using a single inhaler containing budesonide and formoterol help?

BACKGROUND Poor adherence with inhaled corticosteroids is an important problem in asthma management. Previous approaches to improving adherence have had limited success. AIM To determine whether treatment with a single inhaler containing a long-acting beta(2)-agonist and a corticosteroid for maintenance treatment and symptom relief can overcome the problem of poor adherence with inhaled corticosteroids. DESIGN OF STUDY Randomised, parallel group, open-label trial. SETTING Forty-four general practices in Nottinghamshire. METHOD Participants who used less than 70% of their prescribed dose of inhaled corticosteroid and had poorly controlled asthma were randomised to budesonide 200 microg one puff twice daily plus their own short-acting beta(2)-agonist as required (control group), or budesonide/formoterol 200/6 microg one puff once daily and as required (active group) for 6 months. The primary outcome was inhaled corticosteroid dose. RESULTS Seventy-one participants (35 control, 36 active group) were randomised. Adherence with budesonide in the control group was approximately 60% of the prescribed dose. Participants in the active group used approximately 80% more budesonide than participants in the control group (448 versus 252 microg/day, mean difference 196 mug, 95% confidence interval 113 to 279; P<0.001) and were less likely to withdraw from the study (3 versus 13; P<0.01). No safety issues were identified. CONCLUSION Using a single inhaler for both maintenance treatment and symptom relief approximately doubled the dose of inhaled corticosteroid taken, suggesting this could be a useful strategy to overcome the problems related to poor adherence with inhaled corticosteroids.

A real-life cost-effectiveness evaluation of budesonide/formoterol maintenance and reliever therapy in asthma

OBJECTIVE To evaluate direct asthma-related costs in Swedish primary care in a real-life setting. DESIGN 12-month open-label study. SETTING Swedish primary care in a real-life setting. PARTICIPANTS 1776 patients with persistent asthma. INTERVENTIONS Patients with persistent asthma were randomised to one of three treatments: a free adjustable combination of budesonide (100-400 microg/inhalation) and formoterol (4.5 or 9 microg/inhalation) via separate inhalers plus terbutaline as needed; budesonide/formoterol (160/4.5 microg or 80/4.5 microg, two inhalations twice daily) plus terbutaline as needed; budesonide/formoterol (160/4.5 microg or 80/4.5 microg, one inhalation twice daily or two inhalations once daily), for maintenance plus additional inhalations as needed. Doses depended on previous inhaled corticosteroid dose. Patients attended the clinic at 0, 1.5, and 12 months. Telephone interviews were conducted at 4, 6, 8, and 10 months. MAIN OUTCOME MEASURES The primary endpoint was direct asthma-related healthcare costs. RESULTS Statistically significant reductions in annual direct costs per patient were observed with budesonide/formoterol maintenance and reliever therapy compared with the free adjustable combination of budesonide and formoterol (-13%, P<0.001) and fixed-dose budesonide/formoterol plus terbutaline (-20%, P<0.001). Time to first severe exacerbation did not differ significantly across treatment groups, with a mean reduction of 28% versus the free adjustable combination of budesonide and formoterol (P=0.076). Patients receiving budesonide/formoterol maintenance and reliever therapy used a significantly lower daily dose of budesonide compared with the conventional (P<0.001). CONCLUSIONS This study reports direct cost savings with budesonide/formoterol maintenance and reliever therapy compared with conventional treatment regimens with at least equivalent efficacy.

Effect of formoterol with or without budesonide in repeated low-dose allergen challenge

The use of combination therapy in mild asthma is debated. The current authors evaluated the effects of formoterol alone and a formoterol/budesonide combination inhaler on asthma deterioration induced by repeated low-dose allergen exposure. In total, 15 subjects with intermittent allergic asthma inhaled low doses of allergen on seven consecutive weekdays in a three-period, crossover, double-blind, double-dummy comparison between formoterol 4.5 μg TurbuhalerTM, budesonide 160 μg/formoterol 4.5 μg TurbuhalerTM and placebo, each taken as two puffs 30 min after allergen dosing. The outcome variables were: provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD20), exhaled nitric oxide fraction (FeNO), sputum eosinophils and prostaglandin D2, and diary card recordings of symptoms (on a scale of 0–10), short-acting β2-agonist use and evening forced expiratory volume in one second (FEV1). With placebo treatment, allergen exposure caused significant increases in airway hyperresponsiveness (geometric mean (coefficient of variation) PD20: 397 (98) μg before versus 168 (82) μg after), FeNO (mean±sd 46±31 ppb before versus 73±46 ppb after) and asthma symptom score (mean±sd 0.39±0.55 before versus 0.68±0.67 after). Budesonide/formoterol abolished these changes and significantly improved baseline FEV1. Formoterol alone, while providing symptom relief, was no better than placebo in protecting against the allergen-induced increase in airway inflammation. Signs of deteriorating asthma, provoked by low-dose allergen, are prevented by short-term use of budesonide/formoterol but not by temporary use of formoterol alone.

Comparison of two twice-daily doses of budesonide/formoterol maintenance and reliever therapy

The aim of this study was to compare two budesonide/formoterol maintenance doses within the budesonide/formoterol maintenance and reliever therapy concept and to identify possible patient characteristics at baseline which would predict a better response to a higher than standard maintenance dose. A total of 8,424 patients with symptomatic asthma when using an inhaled corticosteroid (ICS) with or without a long-acting &bgr;2-agonist were randomised to budesonide/formoterol 160/4.5 μg, one (1×2) or two (2×2) inhalations b.i.d. Patients used the same inhaler as needed for symptom relief. The primary outcome variable was time to first severe asthma exacerbation. In the total study population, the time to first severe asthma exacerbation was prolonged by 18% with 2×2 versus 1×2 (hazard ratio 0.82; p = 0.03). Lung function (peak expiratory flow) was the only statistically significant predictor of a better response to 2×2. The mean daily ICS doses were 737 and 463 μg in the 2×2 and 1×2 groups, respectively. In a real-life setting, budesonide/formoterol maintenance and reliever therapy at the 2×2 maintenance dose did prolong time to first severe exacerbation but at a higher medication load. Patients with low lung function benefited most from the higher maintenance dose.

COPD health care in Sweden – A study in primary and secondary care

OBJECTIVES To map out-patients with Chronic Obstructive Pulmonary Disease (COPD) with special reference to patients suffering from acute exacerbations, and to describe COPD health care structure and process in Swedish clinical practice in a real life setting. DESIGN Retrospective, non-interventional, epidemiological survey. SETTING 141 hospital based out patient clinics (OPC, n=30) and primary health care clinics (PC, n=111) were included in the structure evaluation. SUBJECTS 1004 COPD diagnosed patients from 100 of the centres (OPC, n=26) participated in the process evaluation. METHODS All Swedish OPC (n=40) and a random sample of 180 PC were asked to answer a questionnaire regarding COPD care. In addition, data from 10 randomly selected patients with a documented COPD disease were analysed from the centres. RESULTS Spirometers were available at all OPCs and at 99% of the PCs. Spirometry had been performed in 52% of PC-patients and in 89% of OPC-patients during the last 2 years prior to the study. More severe patients, as judged by investigator and lung function data, were treated at OPCs than at PCs. Physiotherapists, occupational therapists and dieticians were available at >80% of centres. Exacerbation rate was higher at PCs without a specialized nurse, 2.2/year versus 0.9/year at centres with a specialized nurse. CONCLUSIONS Special attention to COPD, marked by a specialised nurse in primary care improves the quality, as assessed by a lower number of exacerbations. The structure of COPD care in Sweden for diagnosed individuals seems satisfactory, but could be improved mainly through higher availability and educational activities.

Do asthmatic smokers benefit as much as non-smokers on budesonide/formoterol maintenance and reliever therapy? Results of an open label study.

BACKGROUND Studies with inhaled corticosteroids (ICS) in smoking asthmatics have mostly shown poorer treatment responses than in non-smoking asthmatics. METHODS EuroSMART, an open, randomised, 6-month study, compared budesonide/formoterol (Symbicort (®) Turbuhaler(®))(h) maintenance and reliever therapy (Symbicort SMART(®)) at two maintenance doses of budesonide/formoterol (160/4.5 μg), 1 × 2 and 2 × 2, in patients with asthma who were symptomatic despite treatment with ICS ± long-acting β(2)-agonists. The 8424 randomised patients included 886 smokers (11%; aged <40 years or with a smoking history <10 pack-years if older), who were compared with a propensity-matched group of non-smokers. At baseline, smokers had lower post-bronchodilator peak expiratory flow, lower peak flow reversibility and used more reliever medication per day. Severe asthma exacerbations were counted and changes in five-item Asthma Control Questionnaire (ACQ-5) scores from baseline calculated. RESULTS There were 48 and 47 exacerbations in smokers and non-smokers, respectively. Mean time to first severe exacerbation was not statistically different between the two groups. The mean change in ACQ-5 score was significantly greater in non-smokers. Considering the two treatment options there was a statistically significant prolonged time to first severe exacerbation with 2 × 2 versus 1 × 2 in the smokers, but not in the non-smokers. In smokers, the reductions in ACQ-5 scores, asthma symptoms, use of as-needed medication and awakenings were also all significant in favour of 2 × 2 with similar or greater changes than in smokers treated with 1 × 2. CONCLUSION Asthmatic patients with a limited smoking history benefit from treatment with budesonide/formoterol maintenance and reliever therapy with dosing 2 × 2 being superior to 1 × 2.

Combination of budesonide/formoterol on demand improves asthma control by reducing exercise-induced bronchoconstriction

Background In mild asthma exercise-induced bronchoconstriction (EIB) is usually treated with inhaled short-acting β2 agonists (SABAs) on demand. Objective The hypothesis was that a combination of budesonide and formoterol on demand diminishes EIB equally to regular inhalation of budesonide and is more effective than terbutaline inhaled on demand. Methods Sixty-six patients with asthma (>12 years of age) with verified EIB were randomised to terbutaline (0.5 mg) on demand, regular budesonide (400 μg) and terbutaline (0.5 mg) on demand, or a combination of budesonide (200 μg)  + formoterol (6 μg) on demand in a 6-week, double-blind, parallel-group study (ClinicalTrials.gov identifier: NCT00989833). The patients were instructed to perform three to four working sessions per week. The main outcome was EIB 24 h after the last dosing of study medication. Results After 6 weeks of treatment with regular budesonide or budesonide+formoterol on demand the maximum post-exercise forced expiratory volume in 1 s fall, 24 h after the last medication, was 6.6% (mean; 95% CI −10.3 to −3.0) and 5.4% (−8.9 to −1.8) smaller, respectively. This effect was superior to inhalation of terbutaline on demand (+1.5%; −2.1 to +5.1). The total budesonide dose was approximately 2.5 times lower in the budesonide+formoterol group than in the regular budesonide group. The need for extra medication was similar in the three groups. Conclusions The combination of budesonide and formoterol on demand improves asthma control by reducing EIB in the same order of magnitude as regular budesonide treatment despite a substantially lower total steroid dose. Both these treatments were superior to terbutaline on demand, which did not alter the bronchial response to exercise. The results question the recommendation of prescribing SABAs as the only treatment for EIB in mild asthma.

Is the patient’s baseline inhaled steroid dose a factor for choosing the budesonide/formoterol maintenance and reliever therapy regimen?

Objective: Baseline inhaled corticosteroid (ICS) dose may be a factor for prescribers to consider when they select a budesonide/formoterol maintenance and reliever therapy regimen for symptomatic asthmatics. Methods: A 6-month randomized study compared two maintenance doses of budesonide/formoterol 160/4.5 µg, 1 × 2 and 2 × 2, plus as needed, in 8424 asthma patients with symptoms when treated with ICS ± an inhaled long-acting β2-agonist (LABA). In the total study population, 1339 (17%) were high-dose ICS (HD) users (≥1600 µg/day budesonide). This HD stratum was compared with the rest of the study population, divided into low-dose (LD; 400 µg/day) and medium-dose strata (MD; 401–1599 µg/day) with regard to severe asthma exacerbations and mean changes in five-item Asthma Control Questionnaire (ACQ5) scores from baseline. Results: In all three strata there were fewer exacerbations in the 2 × 2 treatment groups (yearly rates 0.268, 0.172 and 0.094) than in the 1 × 2 treatment groups (yearly rates 0.232, 0.138 and 0.764). In no stratum was the difference between the treatment groups statistically significant. There was no statistically significant difference in time to the first severe exacerbation between the treatments 2 × 2 and 1 × 2 in the HD group (hazard ratio 0.944, p = 0.75). The adjusted mean changes in ACQ5 scores in the HD, MD and LD strata were −0.89, −0.61 and −0.65, respectively, with 1 × 2 treatment and −0.90, −0.74 and −0.76, respectively, with 2 × 2 treatment. In the MD and LD strata, the difference between doses was significant in favour of 2 × 2 (MD p < 0.0001; LD p = 0.004), but not in the HD stratum (p = 0.870). No difference in serious adverse events was seen. Conclusion: Compared with the LD and MD strata, the HD stratum patients had more exacerbations and a shorter time to first exacerbation. However, there were no differences in response between the 1 × 2 and 2 × 2 groups in any of the strata. This indicates that patients using budesonide/formoterol maintenance and reliever therapy, irrespective of baseline ICS dose, can be switched to 1 × 2 with its lower steroid load. ACQ5 scores improved more in the HD stratum than in the MD and LD strata indicating, among other things, that HD patients were not overtreated at baseline. ClinicalTrials.gov registration: NCT00463866