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 ß2 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.

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 ß(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.

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 ß(2)-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 (ACQ(5)) 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 ACQ(5) 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. ACQ(5) 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.

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.

Budesonide/formoterol as effective as prednisolone plus formoterol in acute exacerbations of COPD. A double-blind, randomised, non-inferiority, parallel-group, multicentre study.

BACKGROUND: Oral corticosteroids and inhaled bronchodilators with or without antibiotics represent standard treatment of COPD exacerbations of moderate severity. Frequent courses of oral steroids may be a safety issue. We wanted to evaluate in an out-patient setting whether a 2-week course of inhaled budesonide/formoterol would be equally effective for treatment of acute COPD exacerbations as standard therapy in patients judged by the investigator not to require hospitalisation. METHODS: This was a double-blind, randomised, non-inferiority, parallel-group, multicentre study comparing two treatment strategies; two weeks' treatment with inhaled budesonide/formoterol (320/9 microg, qid) was compared with prednisolone (30 mg once daily) plus inhaled formoterol (9 microg bid) in patients with acute exacerbations of COPD attending a primary health care centre. Inclusion criteria were progressive dyspnoea for less than one week, FEV1 30-60% of predicted normal after acute treatment with a single dose of oral corticosteroid plus nebulised salbutamol/ipratropium bromide and no requirement for subsequent immediate hospitalisation, i.e the clinical status after the acute treatment allowed for sending the patient home.A total of 109 patients (mean age 67 years, 33 pack-years, mean FEV1 45% of predicted) were randomized to two weeks' double-blind treatment with budesonide/formoterol or prednisolone plus formoterol and subsequent open-label budesonide/formoterol (320/9 microg bid) for another 12 weeks. Change in FEV1 was the primary efficacy variable. Non-inferiority was predefined. RESULTS: Non-inferiority of budesonide/formoterol was proven because the lower limit of FEV1-change (97.5% CI) was above 90% of the efficacy of the alternative treatment. Symptoms, quality of life, treatment failures, need for reliever medication (and exacerbations during follow-up) did not differ between the groups. No safety concerns were identified. CONCLUSION: High dose budesonide/formoterol was as effective as prednisolone plus formoterol for the ambulatory treatment of acute exacerbations in non-hospitalized COPD patients. An early increase in budesonide/formoterol dose may therefore be tried before oral corticosteroids are used. CLINICAL TRIAL REGISTRATION: NCT00259779.

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.

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.

OBJECTIVE: To evaluate efficacy and cost-effectiveness 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. 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 beta(2)-agonist (LABA). TREATMENTS: budesonide/formoterol 160/4.5 microg, one inhalation, once or twice daily maintenance plus additional doses as-needed (1 x SMART or 2 x SMART), or budesonide/formoterol 160/4.5 microg two inhalations twice daily plus formoterol 4.5 microg as needed (2 x 2 FIX + F). Children 6-11 years old used an 80/4.5 microg dose strength. Primary variables of efficacy were the changes in the Asthma Control Questionnaire (ACQ(5)) 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 ACQ(5) scores or asthma exacerbation rates. Morning PEF was higher in the 2 x 2 FIX + F group vs. the 1 x SMART and 2 x SMART groups (differences 13 L/min and 9 L/min, respectively; p < 0.002). The 1 x SMART group showed a significant decrease in asthma controlled days compared with the two other groups. No difference was seen between the 2 x SMART group and the 2 x 2 FIX + F group. Treatment costs were significantly lower in the SMART groups compared with the 2 x 2 FIX + F group. CONCLUSION: Compared with the 2 x 2 FIX + F treatment the use of budesonide/formoterol was 30-40% lower in the SMART groups while maintaining equal ACQ(5) scores. Daily asthma control improved equally with 2 x SMART compared to 2 x 2 FIX + F with a reduction in asthma medication cost. The one dose once daily maintenance treatment (1 x 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.

Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma.

Asthma control is improved by combining inhaled corticosteroids with long-acting beta2-agonists. However, fluctuating asthma control still occurs. We hypothesized that in patients receiving low maintenance dose budesonide/formoterol (bud/form), replacing short-acting beta2-agonist (SABA) reliever with as-needed bud/form would provide rapid symptom relief and simultaneous adjustment in antiinflammatory therapy, thereby reducing exacerbations. In this double-blind, randomized, parallel-group study, 2,760 patients with asthma aged 4-80 years (FEV1 60-100% predicted) received either terbutaline 0.4 mg as SABA with bud/form 80/4.5 microg twice a day (bud/form + SABA) or bud 320 microg twice a day (bud + SABA) or bud/form 80/4.5 microg twice a day with 80/4.5 microg as-needed (bud/form maintenance + relief). Children used a once-nocte maintenance dose. Bud/form maintenance + relief prolonged time to first severe exacerbation (p < 0.001; primary endpoint), resulting in a 45-47% lower exacerbation risk versus bud/form + SABA (hazard ratio, 0.55; 95% confidence interval, 0.44, 0.67) or bud + SABA (hazard ratio, 0.53; 95% confidence interval 0.43, 0.65). Bud/form maintenance + relief also prolonged the time to the first, second, and third exacerbation requiring medical intervention (p < 0.001), reduced severe exacerbation rate, and improved symptoms, awakenings, and lung function compared with both fixed dosing regimens.

Formoterol Turbuhaler 4.5 microg (delivered dose) has a rapid onset and 12-h duration of bronchodilation.

UNLABELLED: Clinical trials show that formoterol (Oxis) Turbuhaler 4.5 microg delivered dose (6 microg metered dose) has a rapid onset of bronchodilation similar to that of salbutamol and a 12-h duration of action. Maximum increase in FEV(1) and duration of bronchodilation are dose-dependent, the 4.5 microg dose being the lowest dose tested giving both effects. Clinical studies investigating onset of bronchodilation show a significant increase in specific airway conductance occurring within 1 min after inhalation of formoterol Turbuhaler 4.5 microg. When measured from 3-20 min after inhalation, formoterol Turbuhaler 4.5 microg showed similar increases in FEV(1) to salbutamol administered via pMDI. No difference in onset of bronchodilation was observed between the formoterol Turbuhaler 4.5 and 9 microg doses.Single-dose studies and studies of 1-12 weeks' duration show that formoterol Turbuhaler 4.5 microg produces a significant and clinically important mean bronchodilating effect for > or =12 h after inhalation. In the cited studies no significant differences in duration of bronchodilation were observed between the formoterol Turbuhaler 4.5 and 9 microg doses. CONCLUSION: clinical data show that formoterol Turbuhaler 4.5 microg is an effective dose in patients with asthma, with a rapid onset of bronchodilation and a duration of at least 12 h.

Asthma nurse practice improves outcomes and reduces costs in primary health care.

OBJECTIVE: The aim of this study was to elucidate the care of patients with asthma in primary health care from medical, patient self-management, health, quality of life, and health economic perspectives. METHODS: Asthma nurse practice (ANP), an alternative asthma self-management strategy, was compared with traditional asthma care in primary health care in southern Sweden regarding medical history, lifestyle, self-management, symptoms caused by asthma, effects on sick leave, state of health, quality of life and health care costs. The first part of the investigation comprised a retrospective study of a randomly selected sample of patient records of asthmatics (n=152). The second part, lasting 3 months, was prospective and included consecutive patients visits (n=347). RESULTS: The ANP approach showed better results in most of the evaluated outcomes such as asthma quality documentation and self-management and the number of asthma symptoms was significantly lower. From a health economic perspective the results were encouraging with respect to ANP. CONCLUSION: This alternative asthma strategy, ANP, improved asthma care in primary health care and resulted in economic advantages in the health care sector. However the result may only be generalized to other practices working with asthma nurses in the same way.