Budesonide/Formoterol Maintenance and Reliever Therapy: a New Treatment Approach for Adult Patients With Asthma

By Buhl, R Vogelmeier, C

Key words: Asthma – Budesonide/formoterol – Budesonide/ formoterol maintenance and reliever therapy – Exacerbations – Salmeterol/fluticasone ABSTRACT

Background: fisi inhaled corticosteroid (ICS) or an ICS/ long- acting beta2-agonist (LABA) combination plus short-acting ss^sub 2^- 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.

Introduction

Treatment guidelines for the management of persistent asthma in adults recommend an inhaled corticosteroid (ICS) or, for patients not controlled on ICS alone, an ICS/long-acting beta^sub 2^-agonist (LABA) combination administered with a short-acting beta^sub 2^- agonist (SABA) as needed for symptom relief. To date, only two ICS/ LABA combination inhalers have been widely used, budesonide/ formoterol and salmeterol/fluticasone, both offering improvements in control in patients with persistent asthma compared with ICS therapy alone2-4. Combination therapies are routinely used as part of regimens where the maintenance dose of ICS/LABA is titrated up to achieve stable asthma control, and, when adequate control is maintained, titrated down with the aim of minimizing the overall drug load whilst maintaining stable control15.

Budesonide/formoterol maintenance and reliever therapy is a novel approach to asthma management, which simplifies treatment for both patients and clinicians by delivering effective asthma control using a single inhaler. Treatment with budesonide/ formoterol as maintenance and reliever provides rapid relief of symptoms, alleviating the need for a separate SABA inhaler, with every dose being accompanied by additional anti-inflammatory therapy6. Previously, attempts to increase ICS during periods of deteriorating control have used complex action plans based on symptoms or measures of increased inflammation7,8. Budesonide/formoterol as maintenance and reliever enables patients to respond at the first sign of symptoms by taking additional as-needed inhalations of budesonide/ formoterol, achieving rapid and sustained relief together with improved asthma control6.

Several large-scale clinical trials conducted in asthma patients aged >/= 4 years have highlighted the benefits of budesonide/ formoterol as maintenance and reliever for asthma management over similar or higher doses of maintenance budesonide/formoterol6,9,10 or salmeterol/ fluticasone10,11, both with as-needed SABA. This clinical trial programme led to the approval of budesonide/ formoterol maintenance and reliever therapy in October 2006 in the European Union (EU) for use in adults (aged >/= 18 years) for the regular treatment of asthma, where the use of an ICS/LABA combination is appropriate. Additionally, this treatment approach has been endorsed by the recently updated Global Initiative for Asthma (GINA) 2006 guidelines as an effective treatment strategy for preventing asthma exacerbations and improving control1.

With the recent availability of budesonide/formoterol maintenance and reliever therapy for adult use in the EU and its introduction into the GINA guidelines, the present article provides a timely opportunity to review the evidence for this novel asthma management strategy. Specifically, the efficacy and tolerability of budesonide/ formoterol maintenance and reliever therapy in adults, using data from the only two clinical trials10,11 where this approach was compared with medium or high maintenance doses of ICS/LABA plus as- needed SABA. Data from adolescents are excluded from these new analyses as budesonide/formoterol maintenance and reliever therapy is not currently approved in the EU for use in this population. However, this therapy option is approved for younger age groups in a number of other countries (including Switzerland, Canada and Australia). The COMPASS trial evaluated this novel treatment approach compared with the traditional asthma management strategy, using two separate higher fixed maintenance doses of ICS/LABA combination therapy (budesonide/formoterol or salmeterol/ fluticasone) plus as-needed SABA in a 6-month double-blind, double- dummy study10. The COSMOS study aimed to reflect routine clinical practice by comparing budesonide/formoterol as maintenance and reliever with a salmeterol/fluticasone combination plus SABA, in a 1 -year study where all clinicians were permitted to titrate maintenance therapy up and down to achieve optimal asthma control at an appropriate dose11.

Fixed dose approaches – is there room for improvement?

Global asthma guidelines state that, compared with administering ICS and LABA separately, fixed ICS/LABA combination treatments offer greater convenience and simplicity for patients’. Additionally, fixed combinations have been reported to increase adherence to long- term anti-inflammatory therapy12″15. In a UK prescription-based cohort analysis, Angus and colleagues evaluated the effectiveness of introducing combination therapy compared with ICS alone using 6- month prescription records for SABA inhalers and oral steroid courses (OSC) as surrogate measures of asthma control pre- and post- index16. A step-up to an ICS/LABA combination resulted in a reduction in SABA prescriptions and a reduction in the proportion of patients prescribed an OSC among those receiving single inhaler combination therapy, with greater benefits compared with ICS and LABA provided using separate inhalers. However, according to prescription records 62% of patients using a single inhaler of salmeterol/fluticasone still required SABA on a daily basis and 14% required an OSC during the 6-month assessment16. Furthermore, the International Asthma Patient Insight Research (INSPIRE) study was the first multinational study to investigate patients with a clinician-confirmed diagnosis of asthma and who were receiving regular maintenance therapy with an ICS, with two-thirds of the study population using ICS plus LABA therapy17. This questionnaire- based survey confirmed that 74% of patients used SABA therapy every day in the week preceding the interview and approximately half had needed an unscheduled asthma-related visit to their physician in the previous 17 year17.

The lower than recommended levels of asthma control reported by prescription records and questionnaire suggest that suboptimal asthma control is prevalent despite the availability of effective therapies. These findings highlight the need for alternative treatment approaches which may deliver more effective asthma management. Budesonide/formoterol maintenance and reliever therapy offers a more patient-focused management approach using a single inhaler, without the need for a separate SABA. With budesonide/ formoterol as reliever therapy, every dose of asneeded medication is accompanied by an extra dose of ICS, resulting in an increase in anti-inflammatory therapy during periods of increased disease activity6. In addition, during periods of stable symptom control, when no reliever medication is used, asthma is managed using a low maintenance dose of budesonide/ formoterol. Previously, studies investigating the effect of budesonide/formoterol used as maintenance and reliever reported a reduction in the risk of experiencing severe exacerbations by 39-54% compared with a twoto four-fold higher maintenance dose of budesonide6,9,18. By comparison, two recent systematic reviews have suggested traditional fixed-dose ICS/LABA therapy results in an exacerbation risk reduction of 12-14% when compared with a two- to four-fold higher maintenance dose of ICS alone19,20. Compared with the same maintenance dose of budesonide/formoterol plus SABA, budesonide/ formoterol used as maintenance and reliever has also resulted in a 45% reduction of the risk of severe exacerbations and improved daily symptom control, which highlights the efficacy of using budesonide/ formoterol as a reliever compared with SABA alone6,21. Furthermore, budesonide/formoterol maintenance and reliever therapy is associated with a favourable safety profile1,6,8,9,21, similar to budesonide/ formoterol plus SABA. However, the actual benefits of this management approach, in adult patients, can mainly be determined by comparison with a traditional approach using medium or high maintenance doses of ICS/LABA therapy with a separate SABA as needed. The two studies that have undertaken such a comparison are reviewed here: COMPASS (study code: SD-039-0735)10 and COSMOS (SD- 039-0691)11. Outcomes in adult patients included in COMPASS and COSMOS

The data reviewed represent the efficacy and safety for the adult population (aged >/= 18 years) in COMPASS and COSMOS, which were 80% and 96% of the population, respectively. The primary objective of the 6-month, double-blind, randomized, controlled trial, COMPASS, was to investigate whether budesonide/ formoterol maintenance and reliever therapy was more effective at prolonging the time to a first severe exacerbation compared with fixed-dose salmeterol/ fluticasone plus SABA for relief. The secondary objectives of the COMPASS study were to examine the efficacy of budesonide/formoterol maintenance and reliever therapy on daily asthma control and in reducing exacerbations and controlling symptoms compared with fixed- dose budesonide/formoterol plus SABA for relief. Finally, an analysis not related to budesonide/formoterol maintenance and reliever therapy was conducted to compare the efficacy of both fixed- dose ICS/LABA regimens10.

The COSMOS study more closely mirrored routine clinical practice by allowing clinicians to titrate the maintenance dose of the ICS/ LABA, salmeterol/ fluticasone, over a 1-year follow-up period. The primary objective of this study evaluated whether budesonide/ formoterol maintenance and reliever therapy prolonged the time to first severe exacerbation compared with titration of the maintenance salmeterol/ fluticasone dose plus SABA as needed”. Secondary objectives were to compare clinic forced expiratory volume in 1 s (FEV^sub1^), as-needed medication use in the 2 weeks before clinic visits, asthma control assessed by a questionnaire at clinic visits and safety between the two treatment groups.

Study design and patient characteristics

The study designs of both clinical trials, described briefly here, are discussed in more detail elsewhere10,11. In COMPASS and COSMOS, patients with moderate to severe asthma with a diagnosis for >/= 6 months and >/= 1 exacerbation in the last year were eligible for these studies if using ICS >/= 500 [mu]g/day and if they fulfilled the criteria summarized in Table 1. Recruitment criteria were generally common to both studies; however, to be eligible for inclusion in COSMOS it was not necessary to have an actual or historically documented reversibility to beta^sub 2^-agonist therapy. Baseline characteristics for all adult patients are presented in Table 2. The mean FEV^sub 1^ was between 71% and 73% predicted in the two studies. Mean ICS use at study entry was in the range of 759-774 [mu]g/day in COMPASS and 887-891 [mu]g/day in COSMOS, and the average number of as-needed inhalations was similar across all groups at baseline.

In the COMPASS study, following a 2-week runin on ICS alone, eligible patients were randomized to one of three treatment regimens for the full 6 months: (1) budesonide/formoterol (Symbicort Turbuhaler AstraZeneca, Sweden) 160/4.5 pg one inhalation twice daily (b.i.d.) for maintenance plus additional inhalations as needed (Symbicort SMART; AstraZeneca, Sweden); (2) fixed-dose salmeterol/ fluticasone (Seretide/Advair Evohaler [pressurized metered-dose inhaler (pMDI)]; GlaxoSmithKline, UK) 25/125 [mu]g two inhalations b.i.d. plus terbutaline (Bricanyl; AstraZeneca, Sweden) as reliever medication or (3) budesonide/formoterol 320/9 [mu]g one inhalation b.i.d. plus terbutaline.

Table 1. COMPASS10 and COSMOS11 main study entry criteria

Table 2. Demography of adult patients (>/= 18 years) in COMPASS10 and COSMOS11

In the COSMOS 1-year study, after a 2-week run-in period using ICS (and LABA, if appropriate) patients were randomized open-label to either: (1) budesonide/ formoterol (Symbicort Turbuhaler) 160/ 4.5 [mu]g two inhalations b.i.d. for maintenance plus 1 60/4.5 [mu]g as needed (Symbicort SMART) or (2) salmeterol/ fluticasone (Seretide Diskus; GlaxoSmithKline, UK) 50/250 [mu]g b.i.d. plus salbutamol (Ventolin; GlaxoSmithKline, UK) as reliever medication.

At the first post-randomization visit (Week 4) patients in both groups could have their maintenance therapy titrated up or down in the salmeterol/fluticasone arm (permitted range: 100/200-100/1000 [mu]g/day) or titrated downwards in the budesonide/formoterol group (permitted range: 640/18-320/9 [mu]g/day) to achieve or maintain stable asthma control at an appropriate dose according to clinicians’ judgement. The titration of maintenance doses up or down was permitted on multiple occasions at scheduled or unscheduled visits over the remaining 11 months, provided the upper dose limit was not exceeded (640/18 [mu]g/day for budesonide/formoterol or 100/ 1000 [mu]g/day for salmeterol/ fluticasone).

Assessments in COMPASS and COSMOS

The primary objective of both studies was to compare the efficacy of budesonide/formoterol maintenance and reliever therapy with salmeterol/fluticasone plus as-needed SABA on severe exacerbations, defined as deterioration in asthma resulting in hospitalization/ emergency room (ER) treatment, oral steroids for >/= 3 days (in COSMOS an unscheduled visit leading to treatment change was also defined as an exacerbation)10,11. In the current analysis, in addition to examining exacerbations as defined in the two protocols, the number of days when oral corticosteroids were used for exacerbation treatment was also investigated. In the COMPASS study patients completed a daily diary to record daytime and night-time asthma symptoms, nighttime awakenings, use of as-needed reliever medication, intake of maintenance therapy and peak expiratory flow (PEF). Clinic assessments of asthma control were undertaken in both studies, using spirometry and the previously validated Asthma Control Questionnaire (ACQ) 5-item version22,23. As the COSMOS study was intended to reflect normal clinical practice, patients did not need to withdraw from LABA therapy in the run-in or demonstrate reversibility and daily asthma diaries were only recorded during this period. At clinic visits post-randomization, maintenance and as- needed medication use were self-reported, by recall, for the 2 weeks preceding each clinic visit. In both studies, tolerability was assessed by the recording of adverse events, spontaneously and in response to a standard question at clinic visits. Causality was judged based on a set of instructions which were provided to each investigator.

Asthma exacerbations

Budesonide/formoterol maintenance and reliever-treated adult patients in COMPASS and COSMOS experienced a significant reduction in the rate of severe exacerbations compared with salmeterol/ fluticasone plus SABA-treated patients – in COMPASS by 39% (relative rate [RR] 0.61; 95% CI 0.49-0.77; ? < 0.001) compared with a fixed dose of salmeterol/fluticasone and in COSMOS by 21% (RR 0.79; 95% CI 0.67-0.93; p = 0.0051) compared with a titrated dose of salmeterol/ fluticasone (Table 3). In COMPASS, the rate of asthma exacerbations was reduced by 29% ^RR 0.71; 95% CI 0.56-0.89; p = 0.0039) compared with fixed-dose budesonide/formoterol. In the COSMOS study, the risk of a first severe exacerbation was reduced by 24% (risk ratio 0.76; 95% CI 0.62-0.94; p = 0.011) with budesonide/formoterol maintenance and reliever therapy for all exacerbations compared with salmeterol/ fluticasone plus SABA. When data excluding unscheduled visits not resulting in oral glucocorticosteroid therapy were analysed separately to test the robustness of this outcome measure, treatment with budesonide/formoterol maintenance and reliever therapy reduced the risk by a similar 21% compared with salmeterol/fluticasone plus SABA (risk ratio 0.79; 95% CI 0.63-1.00; p = 0.049).

Asthma control measures

Daily asthma control

No significant difference in daily measures of asthma control from patient diaries was seen between any of the treatment groups in the COMPASS study (Figure 1). No similar diary data were available for the COSMOS study. However, the use of / = 4 inhalations per week of as-needed medication during the 6-month period were 48%, 51% and 49% in the budesonide/formoterol maintenance and reliever treatment group, fixed-dose salmeterol/ fluticasone group and fixed-dose budesonide/formoterol treatment group, respectively (Figure 2a). In the open-label dose-titration study (COSMOS), 76% of patients in the budesonide/formoterol maintenance and reliever therapy group used

Table 3. Severe exacerbation burden in adult patients (>. 18 years) in the COMPASS10 and COSMOS11 clinical trials

Asthma control assessed at clinic visits

Results demonstrated similar improvements in ACQ-5 in adult patients across all three treatment groups in COMPASS (Figure 3a). A change of 0.5 units from run-in (>/= 0.5 unit decrease) in overall score indicates a clinically relevant improvement23. The frequency of patients with a clinically relevant decrease was 60% of budesonide/formoterol maintenance and reliever-treated patients and 59% of those in both fixed-dose treatment groups. Results from the COSMOS study (Figure 3b) show a clinically relevant change from baseline in ACQ-5 in 54% of the budesonide/formoterol maintenance and reliever therapy group and 52% of the salmeterol/ fluticasone treatment group. No statistical difference was seen on any measure of ACQ-5 between the groups in either study. There was no significant difference in the improvement in FEV1 among adults in any of the combination treatment groups in either COMPASS or COSMOS studies (Table 4). Drug load and safety

Overall treatment load

The average range of beclomethasone dipropionate (BDP)- equivalent ICS doses (calculations based on GINA estimations of equipotence of ICS in metered doses: fluticasone 500 [mu]g= budesonide 800 [mu]g = beclomethasone 1000 [mu]g^sup -1^) for adult patients in both studies are presented in Figure 4(a and b). In COMPASS, the average ICS dose was 231 [mu]g/day (p < 0.001) lower in the budesonide/formoterol maintenance and reliever therapy group versus the salmeterol/fluticasone and budesonide/formoterol fixed- dose groups. Patients in COSMOS had a 149 [mu]g/day (p < 0.001) lower overall mean ICS dose (Figure 4b). These differences were also accompanied by significant reductions in the need for oral corticosteroids in both studies. In COMPASS, budesonide/formoterol maintenance and reliever patients had a significantly lower number of oral corticosteroid days for exacerbation treatment compared with the salmeterol/fluticasone (1.41 fewer days/patient-year; p = 0.0004) and budesonide/ formoterol (1.15 fewer days/patient-year; p = 0.0046) treatment groups. Similarly, in COSMOS, oral corticosteroids for exacerbations were required on significantly fewer days among the budesonide/ formoterol maintenance and reliever therapy group compared with salmeterol/fluticasone treatment (1.05 fewer days/patient-year; p = 0.026).

Figure 1. Change in daily asthma control from run-in in adult patients (>/= 18 years) in the COMPASS10 study. NS: not significant; SAL/FLU: salmeterol/fluticasone; BUD/FORM: budesonide/formoterol; SABA: short-acting beta^sub 2^-agonist. COMPASS doses: SAL/FLU 50/ 250 [mu]g b.i.d.; BUD/FORM 320/9 [mu]g b.i.d.; BUD/FORM maintenance (160/4.5 [mu]g b.i.d.) plus as-needed

Figure 2. The proportion of patients using /= 18 years) in COMPASS10 and COSMOS11 NS: not significant; SAL/FLU: salmeterol/fluticasone; BUD/ FORM: budesonide/formoterol; SABA: short-acting beta^sub 2^- agonist. COMPASS doses: SAL/FLU 50/250 [mu]g b.i.d.; BUD/FORM 320/9 [mu]g b.i.d.; BUD/FORM maintenance (160/4.5 [mu]g b.i.d.) plus as needed; COSMOS doses: SAL/FLU 100/50-500/50 [mu]g b.i.d.; BUD/FORM maintenance plus as needed 640/18-320/9 [mu]/day

Safety

Budesonide/formoterol maintenance and reliever therapy was well tolerated in adult patients in both studies and there were no notable between-group differences in the number or severity of adverse events or the number of discontinuations due to adverse events (Table 5). Two deaths were reported during the COMPASS study, one in the salmeterol/fluticasone group (cardiac failure) and one in the budesonide/ formoterol maintenance and reliever treatment group (respiratory failure), and one death occurred in COSMOS (cerebral haemorrhage), in the salmeterol/ fluticasone treatment group. None of these events were considered by the investigators to be causally related to the study medication (Table 5).

Table 4. Clinic FEV^sub 1^ in adult patients (>/= 18 years) in the COMPASS10 and COSMOS11 clinical trials

Figure 3. Measures of asthma control assessed by questionnaire in adult patients (>/= 18 years) in the COMPASS10 and COSMOS11 studies. SAL/FLU: salmeterol/fluticasone; BUD/FORM: budesonide/formoterol; SABA: short-acting beta^sub 2^-agonist; ACQ: asthma control questionnaire

Discussion

Data for patients aged S 18 years from the only two published clinical trials that have examined budesonide/ formoterol maintenance and reliever therapy compared with medium or higher dose fixed-dose ICS/LABA therapy, one highly controlled (COMPASS) and the other reflecting normal clinical practice (COSMOS), show that budesonide/formoterol maintenance and reliever therapy offers a more effective, with regard to exacerbations, and simpler treatment approach than fixed-dose ICS/LABA plus SABA. This novel treatment strategy consistently reduced the rate of severe asthma exacerbations by at least 21% in both trials, compared with traditional combination therapies across their dose range. Treatment with budesonide/ formoterol maintenance and reliever therapy achieved this benefit with a significant reduction in overall steroid load (inhaled and oral) while maintaining the same level of daily symptom control across treatment groups. These findings in adult patients are consistent with results from the overall study populations, which included adolescents (aged >/= 12 years)10,11. The results also demonstrate that budesonide/formoterol maintenance and reliever therapy is as well tolerated in adults as traditional combination therapies across their dose range.

Figure 4. Average daily dose of inhaled corticosteroid (ICS) in beclomethasone dipropionate (BDP) equivalents (maintenance and as- needed) in adult patients (>/= 18 years) in the COMPASS10 and COSMOS11 studies. SAL/FLU: salmeterol/fluticasone; BUD/FORM: budesonide/formoterol; SABA: short-acting beta^sub 2^-agonist. * Average daily ICS dose administered as budesonide or fluticasone (unadjusted for BDP equivalents)

Table 5. Safety in adult patients (>/= 18 years) in the COMPASS10 and COSMOS11 clinical trials

In adults, budesonide/formoterol maintenance and reliever therapy reduced the rate of a severe exacerbation by 39% and 21% compared with salmeterol/fluticasone plus SABA, in COMPASS and COSMOS, respectively, and by 29% compared with fixed-dose budesonide/ formoterol in COMPASS. Observations from Rabe and colleagues indicate that the improved efficacy observed with as-needed budesonide/formoterol in patients with moderate to severe persistent asthma receiving budesonide/ formoterol combination maintenance therapy results from both the as-needed formoterol and as-needed budesonide components2′. The exact mechanism for the beneficial effect of budesonide/formoterol maintenance and reliever therapy over traditional treatment options has yet to be fully elucidated. However, it is now known that budesonide influences the chronic and acute inflammation associated with asthma by affecting eosinophils25 and by enhancing the protective effects of formoterol26 on the responsiveness of mast cells in the airways. Formoterol, a full beta^sub 2^-agonist, influences processes not affected by steroids – stabilization of mast cell membranes, relaxation of smooth muscle cells, inhibition of capillary plasma leak and sensory nerve activation – and has also been reported to have beneficial effects on neutrophilic inflammation27. Furthermore, formoterol is thought to be more efficacious than salmeterol, a partial beta^sub 2^- agonist, during periods of increased inflammation or challenge2829. The complementary actions of budesonide and formoterol most likely contribute to the beneficial effects of budesonide/formoterol when used for maintenance and reliever therapy26.

In the present review, equally effective daily asthma control (assessed by daily diaries in COMPASS and at clinic visits in both studies) was observed in the budesonide/formoterol maintenance and reliever treatment group compared with either of the fixed-dose regimens in COMPASS and salmeterol/fluticasone in COSMOS. In COMPASS, approximately half of the patient population in each group used

Recently the safety of LABA treatment in patients with asthma has been questioned. Although results from a case-control study reported no adverse effects on mortality with medium- to long-term use of LABAs33, a recent meta-analysis by Salpeter and colleagues, designed to investigate the safety of LABA use, reported an increase in severe and life-threatening asthma exacerbations, as well as asthma- related deaths, associated with LABAs when use of ICS was not mandatory43. However, the Canadian Asthma Guideline Group have called for an independent re-analysis of this data44, stating that the paper fails to acknowledge the essential need for all LABAs to be used in combination with an ICS and selectively draws its conclusions from studies where the use of ICS was inconsistent44. By contrast, a separate meta-analysis of 1 8 double-blind efficacy studies performed with formoterol as add-on therapy to ICS versus ICS alone including 12229 participants (17 of these trials were omitted from the Salpeter meta-analysis), showed that adding formoterol to ICS significantly reduced hospital admissions and asthma-related serious adverse events by at least 41% compared with ICS alone45. Irrespective of this, budesonide/formoterol maintenance and reliever therapy is the only current asthma treatment strategy definitely preventing over-reliance on and overuse of SABA or LABA alone. Budesonide/formoterol maintenance and reliever therapy has been shown to be well tolerated6,9’21, and in at least three separate studies9,10,21 has been shown to significantly reduce the risk of hospitalizations/ER visits due to asthma compared with alternative groups using higher maintenance doses of ICS or ICS/ LABA. Thus, in addition to improving overall efficacy, it appears this novel regimen may also contribute to the safety of combination therapy.

Conclusion

In adult patients, budesonide/formoterol maintenance and reliever therapy 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 combinations plus SABA. In conclusion, for adult patients with persistent asthma, budesonide/ formoterol maintenance and reliever therapy represents a novel treatment approach that is simpler and, with regard to exacerbations, more effective than fixed- dose ICS/LABA combinations with a separate SABA inhaler for relief.

Acknowledgements

Declaration of interest: RB has received reimbursement for attending scientific conferences, and/or fees for speaking and/or consulting from Aerocrine, Altana, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer and Zambon. The Pulmonary Department at Mainz University Hospital received financial compensation for services performed during participation in single- and multicentre clinical phase I-IV trials organized by various pharmaceutical companies.

CV gave presentations at industry symposia sponsored by Altana, AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, GlaxoSmithKline and Merck Darmstadt. CV also received fees for consulting from Altana, AstraZeneca, Bayer, Boehringer Ingelheim, and GlaxoSmithKline.

The authors would like to acknowledge Piotr Kuna and thank all of the investigators who recruited and treated patients in the COMPASS and COSMOS clinical trials. We also thank Stefan Peterson (AstraZeneca, Lund, Sweden), who performed the data analyses, and Dr Louise Brady (MediTech Media, London, UK), who provided medical writing support on behalf of AstraZeneca.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-4001_5, Accepted for publication: 07 June 2007

Published Online: 29 June 2007

doi:10.1185/030079907X210769

R Buhl(a) and C Vogelmeier(b)

a Pulmonary Department, Mainz University Hospital, Mainz, Germany

b Universitatsklinik Giessen und Marburg, Standort Marburg, Marburg, Germany

Address for correspondence: Roland Buhl, Mainz University Hospital, Langenbeckstrasse 1, D-55131 Mainz, Germany. Tel.: +49 613 117 7270; Fax: +49 613 117 5545; e-mail: r.buhl@3-med.klinik.uni- mainz.de

Copyright Librapharm Aug 2007

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