Budesonide/formoterol maintenance and reliever therapy: a new treatment approach for adult patients with asthma

ABSTRACT

Background: An inhaled corticosteroid (ICS) or an ICS/long-acting β₂-agonist (LABA) combination plus short-acting β₂-agonist (SABA) as needed for symptom relief is recommended for persistent asthma. Additionally, budesonide/formoterol maintenance and reliever therapy (Symbicort SMART, AstraZeneca, Sweden) has been approved for adults in the European Union. This option is well tolerated and offers greater reductions in asthma exacerbations together with similar improvements in daily symptom control, at a lower overall steroid load, compared with fixed-dose ICS/LABA plus SABA.

Scope: Two large clinical trials investigated the use of budesonide/formoterol as maintenance and reliever compared with medium or high doses of an ICS/LABA combination as controller plus SABA as reliever in adults (aged ≥ 12 years). COMPASS was a 6-month, double blind, randomized trial while COSMOS was a 1?year, dose titration study which reflected routine clinical practice. The current review focuses on the findings in both studies, among adult patients only (aged ≥ 18 years).

Findings: Among adults, the studies confirmed a 21–39% reduction in severe exacerbations in patients treated with budesonide/formoterol maintenance and reliever therapy compared with titrated salmeterol/fluticasone plus SABA (COSMOS) or fixed higher budesonide/formoterol or salmeterol/fluticasone plus SABA (COMPASS), respectively. Similar levels of daily asthma control were achieved with budesonide/formoterol maintenance and reliever therapy at a significantly lower overall steroid load compared with salmeterol/fluticasone or budesonide/formoterol plus SABA. Budesonide/formoterol maintenance and reliever therapy was as well tolerated as combination therapies.

Conclusions: In adult patients, budesonide/formoterol maintenance and reliever therapy is a safe and simplified approach to asthma management, using a single inhaler, which reduces severe exacerbations and maintains similar daily asthma control at a lower drug load compared with the traditional strategy of ICS/LABA plus SABA.     

Advances in asthma and COPD treatment: combination therapy with inhaled corticosteroids and long-acting beta 2-agonists

Asthma treatment guidelines advocate the use of long-acting beta2-agonists (LABA) in addition to inhaled corticosteroids (ICS) in patients whose asthma is uncontrolled by ICS alone, thereby addressing two processes fundamental to asthma: bronchoconstriction and inflammation. Superior control--including a reduction in severe exacerbations--of asthma and COPD by ICS/LABA combination therapy has been demonstrated. Results from clinical studies suggest additive and potentially synergistic effects when the two agents are used in combination. No new safety-related issues have been identified with ICS/LABA compared with the monocomponents. The exact mechanisms for the enhanced efficacy of ICS/LABA combinations are under investigation but likely include drug interactions at the receptor level and interwoven signalling pathways, which may result in improved function of 2- adrenoceptors and steroid receptors. Data from preclinical studies provide evidence of additive, compensatory, complementary and synergistic effects of ICS and LABA in the control of inflammation and airway and lung remodelling. These effects may contribute to the improved efficacy seen when treating asthma and COPD with ICS/LABA combinations in clinical studies. Two ICS/LABA combination products are available: budesonide/formoterol (Symbicort) and salmeterol/fluticasone propionate (SeretideTM). An ICS/LABA combination in a single inhaler represent safe, effective and convenient treatment options for the management of patients with asthma and COPD. Clinical results also suggest that adjustable dosing with budesonide/formoterol provides better asthma control than fixed dosing. Further elucidation of the underlying mechanisms responsible for this superior disease control is needed.     

Improving asthma control in patients suboptimally controlled on inhaled steroids and long-acting beta2-agonists: addition of montelukast in an open-label pilot study

BACKGROUND: Airway inflammation and symptoms often persist in asthma patients despite treatment with inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA). It is hypothesized that the leukotriene receptor antagonist montelukast, treating a pathway of inflammation distinct from that of ICS, might confer additional benefit. OBJECTIVE: To evaluate the efficacy of montelukast in improving asthma control in patients symptomatic on a fixed-association (FA) medium dose of ICS and LABA. METHODS: A 2-month, open-label, real-life observational study was undertaken by 131 Belgian pulmonologists. Patients (> or = 15 years old) suffering from persistent asthma (pre-bronchodilator FEV1 > or = 60% of predicted value) and insufficiently controlled on a FA therapy of fluticasone/salmeterol or budesonide/formoterol were given montelukast 10 mg daily as add-on therapy. Asthma control was assessed by the standardized Juniper asthma control questionnaire (ACQ) at baseline and after a 2-month treatment with montelukast. Global evaluation of therapy was made both by the patients and physicians. RESULTS: A total of 313 patients were eligible for analysis. Forty-nine per cent received inhaled fluticasone/salmeterol and the rest budesonide/formoterol. Mean ACQ score decreased significantly on montelukast (13.9 +/- 5.1 at baseline versus 7.4 +/- 4.7 on montelukast, p < 0.001), with a significant improvement in all individual symptom scores (p < 0.001) and in pre-bronchodilator FEV1 score (from 2.2 +/- 1.5 to 1.6 +/- 1.4; p < 0.001). Parallel to these results, 78.6% of the patients reported a global improvement of their asthma. The same proportion of improvement was observed in the global evaluation made by the physicians (kappa = 0.66). CONCLUSION: This pilot study suggests that addition of montelukast in patients symptomatic on a FA of ICS and LABA may result in significant improvements in asthma control. A randomised, placebo-controlled clinical trial seems warranted.     

Combination therapy in asthma--fixed or variable dosing in different patients?

The introduction of combination products, for the coadministration of an inhaled corticosteroid (ICS) with a long-acting beta2-agonist in a single inhaler, has greatly simplified asthma therapy. The two combination inhalers currently available, Symbicort (budesonide/formoterol in a single inhaler) and Seretide (salmeterol/fluticasone), comply with Step 3 of international guidelines that recommend the addition of a long-acting beta2-agonist to ICS in patients who are inadequately controlled on ICS alone. Importantly, combination inhalers ensure that patients cannot neglect their ICS maintenance therapy in favour of the long-acting beta2-agonist--which may improve adherence and overall asthma control. In vitro experiments suggest that ICS and long-acting beta2-agonists may interact beneficially when they are administered via one inhaler. The efficacy and tolerability of budesonide/formoterol and salmeterol/fluticasone have been demonstrated. There are currently two approaches for treating asthma using combination therapy--fixed and adjustable dosing. Fixed dosing with budesonide/formoterol or salmeterol/fluticasone provides effective asthma control in line with guideline goals. However, given the inherent variability of asthma, there is increasing evidence that adjusting the dose of ICS according to fluctuations in symptoms is beneficial. Findings from a series of studies comparing fixed and adjustable symptom-guided dosing regimens demonstrate that adjustable dosing may improve asthma control at an overall lower steroid dose. Ultimately, if adjustable dosing proves to be an effective treatment option, it may be possible to use budesonide/formoterol for both maintenance therapy and symptom relief, thereby overcoming the need for a separate reliever inhaler. This is because formoterol has a more rapid onset and greater dose-related effects than salmeterol in salmeterol/fluticasone. Given that all patients are different, with different disease severities and treatment preferences, both fixed and adjustable dosing strategies are likely to be important in the long-term management of asthma. It is possible that different treatment options will be used for different patients, depending on their disease severity, personality and ability to adhere to therapy.     

吸入糖皮质激素和长效β2-受体激动剂复方制剂治疗哮喘的研究进展

联合使用吸入糖皮质激素和长效β2-受体激动剂对控制哮喘的气道炎症和改善气道平滑肌功能具有协同和互补作用。吸入糖皮质激素和长效β2-受体激动剂复方制剂是目前哮喘维持治疗的重要药物,主要包括丙酸氟替卡松/沙美特罗、布地奈德/福莫特罗、二丙酸倍氯松/福莫特罗和糠酸莫米松/福莫特罗等。本文就此类复方制剂在哮喘治疗中的临床地位和研究进展作一概述。     

Efficacy of Rhizophora mangle aqueous bark extract (RMABE) in the treatment of aphthous ulcers: a pilot study

SUMMARY

The introduction of combination products, for the co-administration of an inhaled corticosteroid (ICS) with a long-acting β2-agonist in a single inhaler, has greatly simplified asthma therapy. The two combination inhalers currently available, Symbicort* (budesonide/formoterol in a single inhaler) and Seretidet (salmeterol/fluticasone), comply with Step 3 of international guidelines that recommend the addition of a long-acting β2-agonist to ICS in patients who are inadequately controlled on ICS alone. Importantly, combination inhalers ensure that patients cannot neglect their ICS maintenance therapy in favour of the long-acting β2-agonist -which may improve adherence and overall asthma control. In vitro experiments suggest that ICS and long-acting β2-agonists may interact beneficially when they are administered via one inhaler. The efficacy and tolerability of budesonide/formoterol and salmeterol/fluticasone have been demonstrated. There are currently two approaches for treating asthma using combination therapy - fixed and adjustable dosing. Fixed dosing with budesonide/ formoterol or salmeterol/fluticasone provides effective asthma control in line with guideline goals. However, given the inherent variability of asthma, there is increasing evidence that adjusting the dose of ICS according to fluctuations in symptoms is beneficial. Findings from a series of studies comparing fixed and adjustable symptom-guided dosing regimens demonstrate that adjustable dosing may improve asthma control at an overall lower steroid dose. Ultimately, if adjustable dosing proves to be an effective treatment option, it may be possible to use budesonide/formoterol for both maintenance therapy and symptom relief, thereby overcoming the need for a separate reliever inhaler. This is because formoterol has a more rapid onset and greater dose-related effects than salmeterol in salmeterol/fluticasone. Given that all patients are different, with different disease severities and treatment preferences, both fixed and adjustable dosing strategies are likely to be important in the long-term management of asthma. It is possible that different treatment options will be used for different patients, depending on their disease severity, personality and ability to adhere to therapy.     

Cost-effectiveness analysis of budesonide/formoterol maintenance and reliever therapy versus fixed combination treatments for asthma in Finland

ABSTRACT

Background: Budesonide/formoterol maintenance and reliever therapy has shown its effectiveness as a treatment for moderate-to-severe asthma.

Objective: To explore the cost-effectiveness of budesonide/formoterol maintenance and reliever therapy as compared to fixed combination therapies (budesonide/formoterol and salmeterol/fluticasone) with terbutaline as needed in the treatment of asthma in Finland.

Methods: Patients without asthma exacerbations during a 6-month period were used as the effectiveness variable in the within-trial economic analysis. Finnish unit costs were applied to pooled resource use data, and multinomial cost-effectiveness plane and acceptability curves were formed based on bootstrapping.

Results: Use of budesonide/formoterol maintenance and reliever therapy significantly reduced the rate of severe asthma exacerbations as compared with a fixed dose of budesonide/formoterol or salmeterol/fluticasone and terbutaline as needed. Total costs over 6 months were €496 per patient for those who used the budesonide/formoterol maintenance and reliever therapy treatment model, which was €78–101 lower than the cost of fixed combinations of salmeterol/fluticasone or budesonide/formoterol with terbutaline as needed. The results indicate that the budesonide/formoterol maintenance and reliever therapy achieves a high probability (> 93%) of cost effectiveness irrespective of willingness to pay level.

Conclusions: Budesonide/formoterol maintenance and reliever therapy may be considered in the treatment of moderate-to-severe asthma instead of conventional treatment with combination products in view of its good clinical efficacy and a high probability of cost-effectiveness in the Finnish setting. However, a cost-effectiveness analysis with a longer time horizon, more Finnish-specific data, and ICS + short/long-acting inhaled β₂-agonist as an additional comparator is still warranted.     

Comparing the efficacy and safety of salmeterol/fluticasone pMDI versus its mono-components,other LABA/ICS pMDIs and salmeterol/fluticasone Diskus in patients with asthma

Introduction: Pressurized metered dose inhalers (pMDIs) are evolving to be a very effective drug delivery option in patients with airway diseases. They offer comparable lung deposition and reduced oropharyngeal deposition similar with the dry powder inhalers. As recommended by the Global Initiative for Asthma guidelines, the ideal maintenance treatment for asthma is a combination of long acting β₂-agonists (LABAs) and inhaled corticosteroids (ICSs). One of the available LABA/ICS combinations is the salmeterol/fluticasone propionate combination (SFC) and a plethora of evidence supports its clinical efficacy and safety.

Areas covered: This article focuses on the SFC hydrofluroalkane pMDI and compares the efficacy and tolerability with salmeterol and fluticasone given individually, and with other fixed-dose combinations namely formoterol/fluticasone, formoterol/beclometasone and formoterol/mometasone furoate, all delivered via pMDI. Also discussed is the efficacy and tolerability of the SFC delivered via a pMDI, as compared to the SFC via Diskus.

Expert opinion: pMDIs play an important role in inhalation therapy given the low price, low maintenance and convenience of use. LABA/ICS combinations are the preferred choice of medication for asthma treatment and will remain the mainstay for the decades to come. In our opinion, pMDI should be the choice of device to administer LABA/ICS maintenance therapy, as it is already being used by the patients for reliever therapy, which may eventually improve patient adherence and compliance.     

RETRACTED ARTICLE: Inhaled corticosteroids and long-acting beta-agonists in adult asthma: a winning combination in all?

In the recent years, considerable insight has been gained in to the optimal management of adult asthma. Most adult patients with asthma have mild intermittent and persistent disease, and it is acknowledged that many patients do not reach full control of all symptoms and signs of asthma. Those with mild persistent asthma are usually not well controlled without inhaled corticosteroids (ICS). Studies have provided firm evidence that these patients can be well controlled when receiving ICS, especially when disease is of recent onset. This treatment should be given on a daily basis at a low dose and when providing a good response should be maintained to prevent severe exacerbations and disease deterioration. Intermittent ICS treatment at the time of an exacerbation has also been suggested as a strategy for mild persistent asthma, but it is less effective than low-dose regular treatment for most outcomes. Adding a long-acting beta-agonist (LABA) to ICS appears to be unnecessary in most of these patients for optimising control of their asthma. Patients with moderate persistent asthma can be regarded as those who are not ideally controlled on low-dose ICS alone. The combination of an ICS and LABA is preferred in these patients, irrespective of the brand of medicine, and this combination is better than doubling or even quadrupling the dose of ICS to achieve better asthma control and reduce exacerbation risks. An ICS/LABA combination in a single inhaler represents a safe, effective and convenient treatment option for the management of patients with asthma unstable on inhaled steroids alone. Ideally, once asthma is under full control, the dose of inhaled steroids should be reduced, which is possible in many patients. The duration of treatment before initiating this dose reduction has, however, not been fully established. One of the combinations available to treat asthma (budesonide and formoterol) has also been assessed as both maintenance and rescue therapy with a further reduction in the risk for a severe exacerbation. Clinical effectiveness in the real world now has to be established, since this approach likely improves compliance with regular maintenance therapy.     

Safe use of long-acting β-agonists: what have we learnt?

INTRODUCTION: Long-acting β-agonists (LABAs) added to inhaled corticosteroids (ICS) reduce symptoms, improve lung function and enhance overall asthma control. However, several studies have indicated an increased risk of asthma mortality and asthma-related serious adverse events and the FDA recently mandated restrictions to the use of LABAs in asthma. AREAS COVERED: This review highlights the clinical studies on which safety analyses pertaining to salmeterol and formoterol have been based and then focuses on recent meta-analyses of safety outcomes with and without consideration of concomitant ICS. EXPERT OPINION: The phenomenon of masking of inflammation by LABA if ICS dose is insufficient underscores the potential for confounding in determining real safety risks. Under-treatment with ICS and differential dosing of ICS in many trials are major factors driving the LABA safety concern. The FDA meta-analysis, when stratified for mandatory ICS use, found no significant increase in the composite outcome of asthma mortality, intubations and hospitalizations. Add-on therapy with LABA is effective and safe if the dose of ICS is adequate to treat airway inflammation. LABA and ICS given in a single device will negate the possibility of LABA monotherapy which is contraindicated. The FDA has recommended that LABAs be withdrawn when control is achieved with combination therapy but recent evidence suggests this may result in loss of symptom control.     

Cost considerations of therapeutic options for children with asthma

Asthma is a prevalent health condition in children, with economic implications for the individual and their family, as well as for societies with nationalized healthcare. Pharmaceutical cost is the main driver of healthcare expenditure in asthma. Existent explicit guidelines are meant to guide asthma management across all age groups, but they are failing. Pharmacologic management of asthma consists of a stepwise treatment approach to achieve symptom control. Various studies suggest a significant number of medical practitioners are prescribing inhaled corticosteroids (ICS) and ICS/long-acting beta agonist (LABA) combination inhalers inappropriately, including prescribing high doses of ICS without specialist consultation. ICS/LABA combination inhalers should only be used in persistent asthmatics, which account for approximately 5% of all children with asthma. Despite this, there is an increase in prescribing rates of ICS/LABA combination inhalers in the context of a decrease in the prevalence of asthma. Furthermore, there is inappropriate prescribing of ICS/LABA combination inhalers in children under 5 years of age, and initiation of relatively more expensive ICS/LABA combination inhalers in patients who have not previously been prescribed ICS. There is evidence to suggest that cost is a significant barrier to asthma management, especially for the more expensive ICS/LABA combination inhalers. Hence, prescribing cost-effective asthma medications appropriately is one of the most important strategies in reducing the morbidity and mortality associated with asthma. It is incumbent on every medical practitioner to not prescribe expensive medications if not indicated, both for the sake of the patient and for society.     

Budesonide/formoterol: a review of its use as maintenance and reliever inhalation therapy in asthma

The use of combination budesonide/formoterol dry powder inhaler (Symbicort Turbuhaler) for both daily maintenance therapy and as-needed relief of breakthrough symptoms using a single inhaler is a new approach to asthma management that is indicated in patients with persistent asthma not adequately controlled by conventional regimens using reliever therapy with a short-acting beta(2)-adrenoceptor agonist alone. The administration of additional corticosteroid with each reliever inhalation in response to symptoms is expected to provide improved control of airway inflammation.Budesonide/formoterol maintenance and reliever therapy reduced the risk of severe asthma exacerbations compared with conventional regimens using a short-acting beta(2)-adrenoceptor agonist alone as reliever therapy in the majority of trials, while providing similar or better daily asthma control than higher fixed maintenance doses of budesonide or inhaled corticosteroid/long-acting beta(2)-adrenoceptor agonist combination therapy in patients with generally moderate to severe, uncontrolled, persistent asthma. The strategy offers the convenience of a single inhaler and simplifies treatment by providing immediate additional anti-inflammatory medication in response to asthma symptoms and immediate step-down when symptoms abate. The improved efficacy, with respect to exacerbation prevention, observed with budesonide/formoterol maintenance and reliever therapy in all double-blind comparative trials was achieved with a lower mean daily dose of inhaled corticosteroid or with fewer daily inhalations of reliever medication. Budesonide/formoterol maintenance and reliever therapy was well tolerated with an incidence of adverse events similar to that with conventional regimens. Therefore, it offers a new approach to therapy in patients with uncontrolled, persistent asthma; providing improved efficacy with a lower overall drug load.     

Improving asthma control in patients suboptimally controlled on inhaled steroids and long-acting β2‐agonists: addition of montelukast in an open-label pilot study

ABSTRACT

Background: Airway inflammation and symptoms often persist in asthma patients despite treatment with inhaled corticosteroids (ICS) and long-acting β₂-agonists (LABA). It is hypothesized that the leukotriene receptor antagonist montelukast, treating a pathway of inflammation distinct from that of ICS, might confer additional benefit.

Objective: To evaluate the efficacy of montelukast in improving asthma control in patients symptomatic on a fixed-association (FA) medium dose of ICS and LABA.

Methods: A 2-month, open-label, real-life observational study was undertaken by 131 Belgian pulmonologists. Patients (≥ 15 years old) suffering from persistent asthma (pre-bronchodilator FEV₁ ≥ 60% of predicted value) and insufficiently controlled on a FA therapy of fluticasone/salmeterol or budesonide/formoterol were given montelukast 10?mg daily as add-on therapy. Asthma control was assessed by the standardized Juniper asthma control questionnaire (ACQ) at baseline and after a 2-month treatment with montelukast. Global evaluation of therapy was made both by the patients and physicians.

Results: A total of 313 patients were eligible for analysis. Forty-nine per cent received inhaled fluticasone/salmeterol and the rest budesonide/formoterol. Mean ACQ score decreased significantly on montelukast (13.9 ± 5.1 at baseline versus 7.4 ± 4.7 on montelukast, p < 0.001), with a significant improvement in all individual symptom scores (?p < 0.001) and in pre-bronchodilator FEV₁ score (from 2.2 ± 1.5 to 1.6 ± 1.4; p < 0.001). Parallel to these results, 78.6% of the patients reported a global improvement of their asthma. The same proportion of improvement was observed in the global evaluation made by the physicians (κ = 0.66).

Conclusion: This pilot study suggests that addition of montelukast in patients symptomatic on a FA of ICS and LABA may result in significant improvements in asthma control. A randomised, placebo-controlled clinical trial seems warranted.     

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.

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.     

Adjustable maintenance dosing with budesonide/formoterol compared with fixed-dose salmeterol/fluticasone in moderate to severe asthma

BACKGROUND: Current asthma guidelines recommend that patients are educated to adjust their medication according to their asthma severity using physician-guided self-management plans. However, many patients take a fixed dose of their controller medication and adjust their reliever medication according to asthma symptoms. OBJECTIVES: This study examined whether asthma control improved if patients adjusted the maintenance dose of budesonide/formoterol (Symbicort Turbuhaler* 160/4.5 microg) according to asthma severity compared with traditional fixed dosing (FD) regimens. METHODS: Symptomatic patients with asthma (n = 658, mean symptom score 1.5, mean inhaled corticosteroids 735 microg/day, mean forced expiratory volume in 1 second [FEV(1)] 84% predicted) were randomised after 2 weeks' run-in to either: budesonide/formoterol adjustable maintenance dosing (AMD), budesonide/formoterol FD or salmeterol/fluticasone (Seretide Diskus dagger 50/250 microg) FD. In a 4-week double-blind period, both budesonide/formoterol AMD and FD groups received two inhalations twice daily (bid) and salmeterol/fluticasone FD patients received one inhalation bid. In the following 6-month open extension, both FD groups continued with the same treatment. Patients in the AMD group with well-controlled asthma stepped down to one inhalation bid; others continued with two inhalations bid. All AMD patients could increase to four inhalations bid for 7-14 days if symptoms worsened. All patients used terbutaline or salbutamol for symptom relief throughout. The primary variable was the odds of achieving a well-controlled asthma week (WCAW). RESULTS: The odds ratio for achieving a WCAW did not differ between the FD regimens; however, during the open period, budesonide/formoterol AMD increased the odds of achieving a WCAW vs. budesonide/formoterol FD (odds ratio 1.335; 95% CI: 1.001, 1.783; p = 0.049) despite a 15% reduction in average study drug use. Budesonide/formoterol AMD patients had a lower exacerbation rate over the study: 40% lower vs. salmeterol/fluticasone FD (p = 0.018); 32% lower vs. budesonide/formoterol FD (NS). During the double-blind period, there were no clinically relevant differences between the budesonide/formoterol FD and salmeterol/fluticasone FD groups. Budesonide/formoterol AMD patients used less reliever medication in the open extension: 0.58 vs. 0.92 occasions/day for budesonide/formoterol FD (p = 0.001) and 0.80 occasions/day for salmeterol/fluticasone FD (p = 0.011). CONCLUSIONS: Adjustable maintenance dosing with budesonide/formoterol provides more effective asthma control by reducing exacerbations and reliever medication usage compared with fixed-dose salmeterol/fluticasone.     

The effect of budesonide and formoterol in one pressurized metered-dose inhaler on patient-reported outcomes in adults with mild-to-moderate persistent asthma

ABSTRACT

Objective: To determine the effects of budesonide and formoterol administered via one pressurized metered-dose inhaler (budesonide/formoterol pMDI) on patient-reported outcomes (PROs) and to determine the contributions of budesonide and formoterol to those effects in adults with asthma.

Research design and methods: A 12-week, random­ized, double-blind, double-dummy, placebo-controlled, multicenter study was conducted in 480 patients aged ≥?12 years with mild-to-moderate persistent asthma. After a 2-week run-in period during which current asthma therapy was discontinued, patients were randomized to receive two inhalations twice daily of budesonide/formo­terol pMDI 80/4.5?μg (160/9?μg), budesonide pMDI 80?μg (160?μg), formoterol via dry powder inhaler (DPI) 4.5?μg (9?μg), or placebo.

Main outcome measures: Analyses included a subpopulation of 405 patients aged ≥?18 years. PROs included the standardized Asthma Quality of Life Questionnaire (AQLQ(S)), the Medical Outcomes Study (MOS) Sleep Scale, the Patient Satisfaction with Asthma Medication (PSAM) questionnaire, and asthma control variables (recorded via electronic diaries), such as asthma symptoms, rescue medication use, and nighttime awakenings due to asthma. Patient and physician global assessments were collected at the end of the study.

Results: Patients aged ≥?18 years receiving budesonide/formoterol pMDI reported significantly greater improvements from baseline in AQLQ overall and domain scores, MOS Sleep Scale domain scores, and asthma control variables than patients receiving placebo (?p ≤ 0.033). Improvements from baseline in AQLQ(S) overall and domain scores, daily asthma symptoms scores, percentage of symptom-free days, percentage of rescue medication-free days, and percentage of asthma control days were significantly greater in patients receiving budesonide/formoterol pMDI versus formoterol DPI (?p ≤ 0.042). Patients receiving budesonide/formoterol pMDI reported significantly greater PSAM scores than did patients in all other treatment arms (?p ≤ 0.004). Study limitations may include the fact that the formoterol-alone arm used a different device and formulation than the other active arms as well as the absence of a treatment arm with budesonide and formoterol administered concomit­antly in separate inhalers. In addition, these results may not be generalized to all patients with asthma, as this analysis included only patients aged ≥?18 years.

Conclusions: Patients receiving treatment with budesonide/for­moterol pMDI experienced significantly greater improvements from baseline in asthma-related quality of life, quality of sleep, and asthma control and greater satisfaction with treatment than patients receiving placebo. The combination of budesonide and formoterol in one pMDI is beneficial in improving how a patient feels and functions as a result of treatment.     

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Inhaled corticosteroid (ICS) therapy in combination with long-acting β-adrenergic agonists represents the most important treatment for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an attenuation of the yearly rate of deterioration in lung function. The addition of long-acting β-agonist (LABA) therapy with ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800 μg daily dose of the ICS budesonide reduced severe exacerbation rates by 49% compared to a low dose of 200 μg daily, and addition of the LABA formoterol to budesonide (800 μg) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline in FEV₁ and the rate of exacerbations. A reduction in the rate of decline in FEV₁ of 16 ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination. A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this effect of ICS is less effective in patients with severe asthma and with COPD; however, addition of LABA may potentiate the anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients. Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition of gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. Local side effects of ICS include oral candidiasis, hoarseness and dysphonia, while systemic side effects, such as easy bruising and reduction in growth velocity or bone mineral densitometry, are usually restricted to doses above maximally recommended doses. Use of LABA alone in patients with asthma increases the risk of asthma-related events including deaths, but this is less observed with the combination of ICS and LABA. Therefore, use of LABA alone is not recommended for asthma therapy. Future progress in ICS development will be characterised by the introduction of ICS with greater efficacy with a limited side-effect profile, and by longer-acting ICS that can be used in combination with once-daily LABAs. Other agents that could improve the efficacy of corticosteroids or reverse corticosteroid insensitivity may be added to ICS. ICS in combination with LABAs will continue to remain the main focus of treatment of airways diseases.     

Anticonvulsant hypersensitivity syndrome: an update

Introduction: Long-acting β-agonists (LABAs) added to inhaled corticosteroids (ICS) reduce symptoms, improve lung function and enhance overall asthma control. However, several studies have indicated an increased risk of asthma mortality and asthma-related serious adverse events and the FDA recently mandated restrictions to the use of LABAs in asthma.

Areas covered: This review highlights the clinical studies on which safety analyses pertaining to salmeterol and formoterol have been based and then focuses on recent meta-analyses of safety outcomes with and without consideration of concomitant ICS.

Expert opinion: The phenomenon of masking of inflammation by LABA if ICS dose is insufficient underscores the potential for confounding in determining real safety risks. Under-treatment with ICS and differential dosing of ICS in many trials are major factors driving the LABA safety concern. The FDA meta-analysis, when stratified for mandatory ICS use, found no significant increase in the composite outcome of asthma mortality, intubations and hospitalizations. Add-on therapy with LABA is effective and safe if the dose of ICS is adequate to treat airway inflammation. LABA and ICS given in a single device will negate the possibility of LABA monotherapy which is contraindicated. The FDA has recommended that LABAs be withdrawn when control is achieved with combination therapy but recent evidence suggests this may result in loss of symptom control.