Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

16th Annual Congress of the European Respiratory Society (ERS)

Munich, Germany / September 2-6, 2006

Editorial Overview

J. Mark FitzGerald, MD, FRCPC, FRCPI, FACCP

Director, Centre for Clinical Epidemiology and Evaluation Vancouver Coastal Health Research Institute Head, Division of Respiratory Medicine Professor of Medicine, University of British Columbia Respiratory Physician, The Lung Centre Vancouver General Hospital Vancouver, British Columbia

Warning signs of an acute asthma exacerbation are recognized by patients an average of five days before peak symptoms, according to a large survey conducted in Europe, Australia, the United States and Canada. This survey suggests that there is an important window of opportunity to abort exacerbations before they lead to the most significant consequences, particularly hospitalization and the need for oral steroids. It was also revealed that patients prefer to take a more active role in managing their disease. These findings are encouraging in the context of new data suggesting that rapid patient-directed adjustment of maintenance treatments may not only produce better outcomes in asthma but in other progressive respiratory diseases as well, such as chronic obstructive pulmonary disease (COPD).

INSPIRE Survey

The traditional paradigm for treatment of asthma, as well as COPD, is to add as-needed short-acting beta2-agonists (SABAs) to baseline maintenance therapy as symptoms increase. Recent studies prompted by the development of inhalers that combine an inhaled corticosteroid (ICS) with a long-acting beta-agonist (LABA) have provided the basis for alternative strategies in both diseases. The potential advantage is not simply more practical management with a reduction in the need for multiple inhalers but also an improvement in outcomes. In asthma, a large international patient survey, called INSPIRE (International Asthma Patient Insight Research), supports an approach more oriented to patient-directed management because of the opportunities to achieve tighter symptom control and because most patients prefer to titrate their own medicines.

INSPIRE was conducted in 3415 patients taking a regular maintenance therapy that included an ICS. In data presented by Partridge et al. (Abstract 3368), patients reported that the average time between early symptoms of an exacerbation, usually experienced as shortness of breath, and peak symptoms was 5.1 days. During this time, patients increased their use of SABA by an average of fourfold relative to a period without an imminent exacerbation. While this up-titration of SABA demonstrates that patients actively manage their symptoms, the authors concluded that patients are using the wrong strategy. They stated that in an interval of five days, up-titration of both ICS and LABA, which was rarely reported by patients in INSPIRE, would be expected to yield a greater benefit than up-titrating only a SABA.

In other data from INSPIRE presented separately by van der Molen et al. (Abstract P1825), the desire of patients to assume control of their symptoms was emphasized. In these findings, they reported that more than 60% of patients strongly agreed with the statement “I am confident to intervene early;” another 25% (total 87%) agreed somewhat with the statement. While 73% of patients in INSPIRE reported suboptimal control of asthma by acknowledging some limitation of activities despite chronic maintenance therapy, the overall data suggest most patients are willing to be more aggressive in self-management if given appropriate instruction.

These survey results are of particular relevance when evaluated in the context of new data suggesting combination therapy of an ICS and LABA are effective for reducing the risk of exacerbations in both asthma and COPD. In asthma, one of several recently completed large studies testing this premise was presented by Rabe et al. (Abstract P3866). Investigators compared different strategies to reduce the risk of exacerbations in asthma patients already taking an ICS and a LABA for maintenance combined in a single inhaler. The full results were published just prior to this meeting (Rabe et al. Lancet 2006;368:744-53). In this multicentre 12-month study, 3394 patients receiving a combination maintenance therapy of the ICS budesonide and the LABA formoterol were randomized to control exacerbations with terbutaline as needed; formoterol as needed; or additional inhalations of budesonide/formoterol as needed.

SMART: Flexible Dosing

With the evaluation carried out by several measures, the best control over the 12 months of the study was provided by using additional inhalations of budesonide/formoterol as needed, a strategy that has been identified by the acronym SMART (Symbicort for both Maintenance and Reliever Therapy). For example, the rate of exacerbations per 100 patients per year was 37, 29, and 19 in the as-needed SABA group, the as-needed formoterol group (P<0.01 vs. as-needed SABA) and the as-needed budesonide/formoterol group (P<0.0001 vs. as-needed SABA or as-needed formoterol), respectively. SMART was also associated with a significant reduction in night-time awakenings (P=0.018 vs. formoterol and P=0.0025 vs. terbutaline) as well as a significant reduction in exacerbations of any kind (P<0.0001 vs. formoterol or terbutaline).

Similar results were demonstrated in two other studies evaluating SMART. In a multinational trial called COMPASS (Comparison versus higher fixed-dose of Symbicort and Seretide), presented by Kuna et al. (Abstract P1228), there were three arms consisting of: a single-inhaler combination of fluticasone/salmeterol with terbutaline as needed; a single-inhaler combination of budesonide/formoterol with terbutaline as needed; or a single-inhaler combination of budesonide/formoterol with additional inhalations of budesonide/formoterol as needed to control symptoms (SMART).

SMART was associated with a significant reduction in severe exacerbations vs. either of the two other arms (P<0.0048 vs. budesonide/formoterol with terbutaline and P<0.001 vs. fluticasone/salmeterol plus terbutaline). Patients randomized to SMART had 41% fewer days on oral steroids relative to budesonide/formoterol plus terbutaline and 45% fewer days relative to fluticasone/ salmeterol plus terbutaline. All of the treatments were well tolerated.

The other large study was conducted in Canada and presented by Sears et al. (Abstract 3601). In this study, 1538 patients were randomized to SMART or conventional best practice based on current treatment guidelines. Over six months of follow-up, the 43% reduction in the mean number of hospitalizations or emergency room visits (4.4 vs. 7.8 per 100 patients treated for one year; P=0.07) favouring SMART approached statistical significance. SMART was associated with a significant reduction in total dose of ICS (P<0.001) and reliever medication use (P=0.0036) relative to conventional best practice.

Protection against exacerbations appears to provide a relative cost advantage when compared to other strategies. In the Canadian study, an analysis indicated that the costs of SMART were 23% lower (P<0.0001) than those of conventional therapy, mainly due to reduction in risk of exacerbations. In a cost-analysis of the COMPASS study, presented separately from the efficacy data by Price et al. (Abstract P1274), significant savings were also reported. Specifically, the authors calculated that switching 100 patients to SMART from fluticasone/salmeterol would prevent seven exacerbations over six months for a savings of more than $15,000 (CDN). Relative to budesonide/formoterol with terbutaline as needed, a switch of 100 patients would be expected to prevent four exacerbations over six months for a savings of more than $10,000 (CDN).

Synergy of a Single Inhaler

The ability to use budesonide/formoterol for both maintenance and reliever management of asthma may be unique to this combination. In particular, due to the longer half-life of salmeterol, in a combination therapy of fluticasone/salmeterol, multiple as-needed inhalations would be expected to generate an unacceptable risk of side effects. These pharmacologic characteristics preclude its use as a rescue treatment in addition to its maintenance.

A recent study has shown that a combination fluticasone/salmeterol has potential to improve outcome in COPD. In a study called TORCH (Towards a Revolution in COPD Health) presented by Calverley et al. (Abstract E311), 6112 patients with COPD were randomized to receive combination therapy of fluticasone/salmeterol, fluticasone alone, salmeterol alone, or placebo over a period of three years. The ICS/LABA combination was associated with a 17.5% reduction in the risk of death from any cause relative to placebo. The difference relative to placebo was not significant for either fluticasone alone or salmeterol alone. The fluticasone/salmeterol combination was also associated with a significant relative improvement in quality of life. This is likely a class effect but no studies evaluating budesonide and formoterol with mortality as an end point have been published.

Combining an ICS and a LABA in a single inhaler is a logical development in patients who require both types of compounds to control asthma or COPD. While the convenience of a single inhaler is one advantage, the most recent data suggest that these combination therapies permit new treatment strategies with the potential to improve outcome. Although more studies are needed, it is reasonable to hypothesize that single inhalers may play a role in tighter inhibition of inflammation, a driving force for disease progression.

Summary

A series of studies with single inhalers that combine an ICS and a LABA suggest that these devices not only improve the convenience of maintenance therapy for asthma and COPD but also health outcomes. In asthma, a single-inhaler combination of budesonide and formoterol, used for both maintenance therapy and prevention of acute exacerbations, has demonstrated a reduction in severe exacerbations compared to a fixed-dose strategy with a combination inhaler plus an additional rescue medication. In COPD, a single ICS/LABA combination inhaler of fluticasone and salmeterol has been associated with a mortality benefit. Based on these study findings, a paradigm shift in routine control of progressive respiratory diseases can be foreseen.-

[3368] - Suboptimal asthma control in patients receiving long-term maintenance therapy

M. R. Partridge, T. van der Molen, S. E. Myrseth, W. Busse (London, United Kingdom; Groningen, Netherlands; Brussels, Belgium; Madison, United States of America)

Aim: To investigate patients’ perceptions of medication use and asthma control in adults receiving regular maintenance therapy in the International Asthma Patient Insight Research (INSPIRE) study.

Methods: Standardised interviews were conducted in 3415 asthma patients receiving inhaled corticosteroids in Europe, the USA, Canada and Australia. Therapy use, worsenings (i.e. symptoms becoming hindering/bothersome) and asthma control (6-item Asthma Control Questionnaire [ACQ-6]; item concerning forced expiratory volume in 1 s omitted; scale 0–6) were evaluated. Patients were classified as well controlled (ACQ-6 mean score 0–0.74), not well controlled (score 0.75–1.5) or uncontrolled (score >1.5). Interim results for European patients only were presented previously.

Results: In total, 73% of patients used a long-acting beta2-agonist, administered via a combination (61%) or separate inhaler (12%); however, over two-thirds (72%) of patients had suboptimal asthma control and only 28% were well controlled. Moreover, 74% of patients used their rescue inhaler every day (1–2 and 3 inhalations/day in 38% and 37% of patients, respectively). Uncontrolled patients had an average of 16.2 worsenings in the last year versus 7.4 and 6.3 for not well controlled and well controlled patients, respectively. Overall, 51% of patients had 1 asthma-related unscheduled medical intervention in the last year (mean 3.1/patient/year).

Conclusion: Asthma control is suboptimal in the majority of patients despite longterm maintenance treatment. Even well controlled patients experience frequent worsenings.

Comment on Abstract 3368

In this large survey of 3415 asthmatic patients using a maintenance therapy that included ICS for a mean of 16 years since the time of diagnosis, suboptimal symptom control was reported by the majority (73%) of respondents. The survey also found that the median time between the onset of early symptoms and the peak effects of an exacerbation averaged 5.1 days, suggesting an important window of opportunity to up-titrate therapy in order to limit the severity of an exacerbation. Although patients currently respond to symptoms of an exacerbation by upregulating SABAs, more potent therapies may be more effective.

Questions and Answers with author Dr. Martin Partridge

Q: Almost 75% of patients on maintenance therapy that included ICS still reported limitations in activity. Are current therapies insufficiently effective?

A: I think that there is evidence that current therapies can achieve good control of asthma in the majority of patients. The problem is that patients are not getting the right medications in the right doses, particularly in adjusting doses to fluctuations in disease activity.

Q: Did the interval of time between recognition of early signs of an exacerbation and peak symptoms of an exacerbation surprise you?

A: I am not sure it is surprising, but it is important. It demonstrates that the majority of patients do recognize early warning signs of an exacerbation at a point that they may be able to adjust therapy to limit the severity. This has important implications for educating patients on strategies to improve control.

Q: Your data suggest that patients already respond to signs of an exacerbation by up-titrating their SABAs. Perhaps exacerbations once started cannot be aborted?

A: SABAs relieve symptoms by dilating the airways, but they do not have a significant effect on the disease process. The data show that patients do adjust their therapies in response to signs of an exacerbation, but the problem is that they are changing the wrong medicines. The average window of time appears to be enough to upregulate therapies that work to control disease, such as ICS with LABAs.

Q: How important are the results of this survey?

A: These results suggest that we should be considering new strategies for treatment and patient education that would place more emphasis on intervention at the first sign of asthma symptoms to improve control. More data are needed, but this approach might not only reduce the acute burden of asthma but also limit the risk of lung remodelling over the long term.

[P1825] - Delayed adjustment in maintenance therapy in patients with worsening asthma symptoms

T. van der Molen, M. R. Partridge, S. E. Myrseth, W. Busse (Groningen, Netherlands; London, United Kingdom; Brussels, Belgium; Madison, United States of America)

Aim: To evaluate asthma variability and its impact on disease management and patient attitudes to treatment in a global study of patients’ perceptions.

Methods: The International Asthma Patient Insight Research (INSPIRE) study comprised standardised interviews in 3415 adults with inhaled corticosteroid-treated asthma recruited by clinicians in Europe, the USA, Canada and Australia. Questions concerned therapy use, asthma worsenings (i.e. symptoms becoming hindering/bothersome) and attitudes to self-management. Interim data on European patients only were presented previously.

Results: Overall, 73% of patients used a long-acting beta2-agonist, delivered via a combination (61%) or separate inhaler (12%). Eighty-eight per cent of patients were confident they could manage their own asthma without visiting their doctor and 61% recognised early signs of a worsening (e.g. shortness of breath/getting breathless). The mean time from onset to peak symptoms and from peak symptoms to recovery was 5.1 and 6.2 days, respectively. Rescue therapy use increased 4-fold during worsenings. Inhaled corticosteroid use increased to a much lesser extent and only when the worsening reached its peak. When symptoms decreased, patients reduced their medication intake.

Conclusion: Patients consistently adjust their medication in response to asthma variations, but adjustment in maintenance therapy is delayed in response to a worsening. The period from warning signs to peak symptoms provides a window of opportunity for improved self-management.

Comment on Abstract P1825

In a separate analysis of the same survey presented by Partridge et al. (Abstract 3368), an emphasis was placed on evidence that asthmatic patients express a strong interest in managing their symptoms. Approximately 90% reported that they are “very confident” or “quite confident” to self-manage asthma, and more than 60% of the patients agreed with the statement “I am confident to intervene early.” Most of the remaining patients agreed somewhat. In addition, approximately 70% of patients agreed strongly or somewhat that they are prepared to adjust their dose of ICS in response to symptoms. However, the survey also demonstrated that most patients now adjust their SABAs in response to increasing symptoms, but ICS were less likely to be adjusted and were generally adjusted only after peak symptoms of an exacerbation.

Questions and Answers with author Dr. Thys van der Molen

Q: What were the goals of this survey?

A: We wanted to look at a patient population already on maintenance therapy and assess the current degree of control and to evaluate whether there are overlooked opportunities to improve symptom management. Patients’ ability to respond to exacerbations was a particular focus.

Q: What was the most important finding?

A: I think the fact that 68% of patients were able to recognize early signs of a worsening, and that these signs or warnings are detected a mean of five days before peak symptoms, has a lot to tell us about whether we might be missing a chance to modify treatment more effectively in response to impending exacerbations.

Q: Are physicians concerned about patients upregulating potent therapies such as ICS?

A: Patients with asthma know very well the patterns of their disease, and I think that is revealed in this survey. Eighty-eight per cent of patients said that they were confident that they could manage their own asthma without visiting a doctor. I think with proper education, patients can be given the tools to achieve better control of their disease than what is typically done now.

Q: What about the patients who do not recognize early warning signs of an exacerbation?

A: Self-management is not for all patients. Some patients do not feel comfortable adjusting therapies or may not be suitable for making appropriate decisions. These patients are typically easy to recognize, but for the large proportion of patients who are willing and able to adjust their medication in response to disease activity, there may be an opportunity to prevent or minimize exacerbations and improve long-term control.

[P3866] - A new combination therapeutic approach challenging the current dogma of using inhaled corticosteroids as maintenance only to control asthma

K. F. Rabe, T. Atienza, P. Magyar, P. Larsson, C. Jorup, U. G. Lalloo (Leiden, Netherlands; Quezon City, Philippines; Budapest, Hungary; Lund, Sweden; Durban, South Africa)

Background: Budesonide/formoterol (B/F; Symbicort®), used as maintenance and reliever therapy (SMART), can reduce asthma exacerbations and improve symptom control compared with fixed-dosing regimens. This study investigated the contribution of both monocomponents of as needed B/F to asthma control in symptomatic patients receiving B/F maintenance therapy by comparing the efficacy and safety of three different reliever strategies.

Methods: In this 12-month, double-blind study, 3394 inhaled corticosteroid-treated patients (age 12 years; forced expiratory volume in 1 s 50–100% predicted) who were symptomatic on B/F 160/4.5 µg bid plus as needed terbutaline (T) during run-in were randomised to the same maintenance therapy plus one of three as needed medications: B/F 160/4.5 µg, F 4.5 µg or T 0.4 mg.

Results: The time to first severe asthma exacerbation (primary endpoint) was prolonged with B/F vs F (P=0.0048) and with F vs T (P=0.0051). The rate of severe exacerbations was 19, 29 and 37 per 100 patients/year with B/F, F and T, respectively (B/F vs both groups, P<0.001; F vs T, P=0.0012). Improvements in hospitalisation/emergency room treatment rates, night-time awakenings caused by asthma, symptoms, rescue medication use and lung function all favoured B/F vs F or T. All treatments were well tolerated.

Conclusion: Both budesonide and formoterol administered in the same inhaler as needed for relief contribute to improved asthma control in patients receiving budesonide/formoterol maintenance therapy. These findings challenge the current treatment paradigm that relies on ICS as maintenance therapy alone to control asthma.

Comment on Abstract P3866

This large study demonstrates that a combination therapy of budesonide, an ICS, and formoterol, a LABA, can be employed as both maintenance therapy and for rapid symptom relief. In the study design, the single-inhaler combination for maintenance and acute relief, identified as SMART, was not only compared to a conventional strategy of budesonide/formoterol plus LABA as needed but also to a budesonide/formoterol single-inhaler combination with formoterol for as-needed relief. Although formoterol is a rapidly acting LABA, the superior effect of the combination inhaler for both maintenance and relief demonstrates that the ICS and the LABA are needed to provide optimal protection against exacerbations.

Questions and Answers with author Dr. Klaus F. Rabe

Q: What is the main conclusion of this study?

A: A combination therapy of budesonide/formoterol for maintenance plus additional budesonide/formoterol as needed to control symptom, a strategy called SMART, reduces the risk of severe exacerbations and hospitalizations or emergency room visits better than the conventional approach of adding SABAs as needed. It is also important that we showed that the combination of the ICS and LABA was superior to the LABA alone, because this shows both are active in reducing the risk of exacerbations.

Q: Several outcomes were evaluated. Were they all consistent?

A: The SMART regimen performed better than the other two arms for every outcome we evaluated and in most cases, the difference was statistically significant. This included all exacerbations, hospitalizations and emergency room visits, night-time awakenings, and morning peak expiratory volume.

Q: Would you anticipate similar results with other single-inhaler combinations of an ICS and a LABA?

A: The LABA component of the combination is particularly important in regard to onset of action and duration of action. The longer half-life of salmeterol makes it difficult to employ on an as-needed basis because of the risk of component accumulation leading to a substantial increase in adverse events. In this study, the combination therapy was very well tolerated with no unexpected safety issues. In fact, fewer patients on the SMART regimen discontinued therapy due to asthma-related events than those receiving as-needed terbutaline.

Q: This study was published in The Lancet. Does this suggest that the results are considered to be important to a wide audience?

A: The results of this study validate the concept that SMART is effective for both maintenance and reliever therapy in patients with persistent asthma. As asthma is the most common respiratory disease worldwide, the identification of a new approach to treatment that appears to be superior to the conventional approach can be considered a significant development.

[P1228] - Budesonide/formoterol as maintenance and reliever therapy reduces asthma exacerbations versus a higher maintenance dose of budesonide/formoterol or salmeterol/fluticasone

P. Kuna, M. J. Peters, R. Buhl (Lodz, Poland; Concord, Australia; Mainz, Germany)

Background: Budesonide/formoterol (B/F; Symbicort®), used as maintenance and reliever therapy (SMART), improves daily symptom control and reduces exacerbations compared with the same maintenance dose of B/F plus standard reliever medication. This study evaluated the efficacy of SMART vs higher maintenance doses of combination therapy plus reliever.

Methods: This was a 6-month, randomised, double-blind study of symptomatic patients with asthma (n=3335; age 12 years; mean forced expiratory volume in 1 s 73% predicted; mean inhaled corticosteroid [ICS] dose 745 µg/day). The SMART group received B/F 160/4.5 µg bid plus additional doses of B/F 160/4.5 µg as needed. Comparator groups received B/F 320/9 µg bid or salmeterol/fluticasone (S/F) 50/250 µg bid plus terbutaline 0.5 mg as needed.

Results: Indicators of asthma control (symptoms, night-time awakenings and lung function) were similarly improved in all three groups. SMART prolonged the time to first severe asthma exacerbation vs fixed-dose B/F and S/F, and was associated with 28% and 39% fewer exacerbations, respectively (both P<0.01). The mean exacerbation rate was 12, 16 and 19 per 100 patients per 6 months in the SMART, B/F and S/F group, respectively. SMART-treated patients used 25% less ICS (beclomethasone equivalent) than patients in the fixed-dose groups.

Conclusion: SMART reduces asthma exacerbations and maintains symptom control at a reduced drug load compared with higher maintenance doses of budesonide/formoterol or salmeterol/fluticasone, thus offering a more effective and simple approach to asthma management.

Comment on Abstract P1228

This large multinational trial evaluated a combination therapy of budesonide 60/formoterol 4.5 mcg as both maintenance and reliever therapy in patients who required ICS for asthma control. This strategy, known by the acronym SMART, was compared to a single-inhaler combination of budesonide/formoterol 320/9 mcg b.i.d. plus terbutaline as needed and to a single-inhaler combination of fluticasone/salmeterol in a dose of 50/250 mcg b.i.d. plus terbutaline as needed. The SMART regimen reduced the incidence of severe asthma exacerbations and the use of oral steroids when compared to the other two strategies over a six-month period. In addition, patients on the SMART regimen used less total ICS than the comparator arms.

Questions and Answers with author Dr. Piotr Kuna

Q: The reduction in the risk of severe exacerbations was statistically significant, but was it clinically significant?

A: Relative to fluticasone/salmeterol, the SMART strategy reduced the total number of severe exacerbations, defined as a hospitalization, an emergency room visit, or the need for at least three days of oral steroids, by 39%. This is a substantial reduction. Relative to budesonide/formoterol, the reduction in severe exacerbations was 28%.

Q: Can this be entirely attributed to improved disease control?

A: The advantage of SMART was achieved even though patients in this arm reduced the number of days that they required oral steroids by about 40% relative to the other two groups. We also observed a reduction in the cumulative dose of ICS despite the reduction in the rate of severe exacerbations. Instructing patients to up-titrate their dose of budesonide/formoterol as a reliever therapy is an effective strategy.

Q: Do patients who are accustomed to using SABAs readily adjust to the SMART regimen?

A: This was not studied specifically, but the SMART regimen is very simple and would be expected to be easier to follow than conventional therapy using two or three inhalers for different medications. SMART reduces maintenance and reliever therapy to a single inhaler.

Q: What are the implications of the results?

A: The SMART treatment approach provides new insight into how to use the combination of ICS and LABA optimally. It challenges the current treatment paradigm for persistent asthma, which has been to go to as-needed SABAs to control acute symptoms.

[E3601] - Budesonide/formoterol maintenance and reliever therapy for asthma compared to conventional best practice: a randomised real-life study

M. R. Sears, L. P. Boulet, M. Laviolette, J. M. FitzGerald, T. R. Bai, N. Smiljanic-Georgijev, J. S. M. Lee (Hamilton, Quebec, Vancouver, Mississauga, Canada)

Aim: To study the effectiveness and safety of budesonide/formoterol (BUD/FORM; Symbicort®) Maintenance and Reliever Therapy (SMART) vs conventional best practice (CBP) in patients (pts) with persistent asthma.

Methods: This randomised, open-label, 6-month study was performed in 1538 adolescent and adult pts in Canada (mean age: 43 yrs; mean inhaled corticosteroid (ICS) dose: 568 µg/day). After 2 weeks on usual therapy, pts were randomised to BUD/FORM 160/4.5 µg 1 inhalation (inh) twice daily and as needed, or CBP (managed by the investigator). Severe exacerbations (defined as oral steroid use, emergency room (ER) visit or hospitalisation), reliever medication use and total ICS dose were analysed in all pts, and sputum eosinophil (EOS) counts in a subset (n=115).

Results: No differences between SMART and CBP were seen in time to first severe exacerbation (P=0.95) and severe exacerbation rate (19 vs 21 events/100 pts/yr; P=0.63). There were 43% fewer ER visits/hospitalisations with SMART vs CBP (4.4 vs 7.8 events/100 pts/yr; P=0.07). Mean as-needed use was reduced by 14% with SMART (0.94 vs 1.09 inh/day; P=0.0036) and the mean total ICS dose was reduced by 27% (748 vs 1023 µg/day beclomethasone equivalent; P<0.0001). Geometric mean sputum EOS counts remained within the range for controlled inflammation in both groups (run-in/treatment %’s: SMART 1.12/0.87, CBP 1.34/1.26; P=0.23). All treatments were well tolerated.

Conclusion: Budesonide/formoterol Maintenance and Reliever Therapy achieved similar or improved clinical control vs conventional best practice with a significantly lower total ICS dose and no increase in eosinophilic inflammation.

Comment on Abstract E3601

Support for the multinational trial published in The Lancet (see Abstract P1228) was provided by an open-label study conducted in Canada. The study randomized 1538 patients to SMART, which consisted of daily doses of 160 mcg budesonide and 4.5 mcg formoterol b.i.d. delivered by the same inhaler plus additional inhalations as needed to control symptoms, or to conventional best practice selected by physicians following published guidelines. The open-label trial, like the double-blind multinational trial, associated SMART with a 43% reduction in hospitalizations and emergency room visits relative to conventional best practice. This reduction fell just short of statistical significance (P=0.07), but it was achieved with 26% reduction (P<0.0001) in the total ICS dose. Adverse event rates were similar on the two treatment strategies, both of which were well tolerated.

Questions and Answers with author Dr. Malcolm Sears

Q: The title of the presentation emphasizes that the study was conducted in a real-life setting. What makes the design or selection of this study population more “real-life” than other studies?

A: The real-life nature of the study is highlighted by the fact that there was a broad study population, and that it was an open trial which was necessitated by the question being asked, namely, whether use of a single inhaler for maintenance and rescue therapy was as effective or more effective than use of any other therapy which the physician was free to choose.

Q: Some physicians may be concerned that patients employing budesonide/formoterol may increase their systemic exposure to ICS by overdosing this combination to control exacerbations. Although this study did not show that problem overall, do you think patients should be screened to show competency to employ the SMART regimen?

A: The results from several studies that have used budesonide/formoterol as maintenance and rescue therapy show that very few patients use more than one or two additional puffs per day. It is likely that when they do, the increased use of ICS is actually treating an impending exacerbation and, in many instances, reducing their need for oral steroids which would give a greater systemic exposure. Experience has been that the majority of patients find the SMART regimen very easy to understand and follow.

Q: You reported a 14% reduction in reliever medication in the SMART group. Were SABAs permitted in the SMART group? If so, under what circumstances (and were they defined in relationship to inadequate relief from up-titration of budesonide/formoterol)?

A: The SMART group used budesonide/formoterol combination therapy as their reliever medication. The 14% reduction was a comparison of the use of reliever medication in the conventional best practice group compared with the as-needed use of this combination of ICS/LABA. The frequency of taking a rescue dose of budesonide/formoterol combination compared with a rescue dose of SABA in the conventional group was 14% lower.

Q: Among your conclusions, you reported that SMART was associated with a lower ICS exposure, fewer hospitalizations, less use of reliever medication, and a lower cost. Do you consider any of these outcomes particularly important (as opposed to equally important) in considering placing asthmatic patients on a SMART protocol?

A: Regarding the importance of the outcomes, I would place reduction in hospitalizations and emergency room visits as being the most important, as exacerbations are not only the most feared by patients but also the most expensive and can be even life-threatening. Of secondary importance is the maintenance of control with lower ICS use, followed by less use of reliever medication. The lower cost is a consequence primarily of the reduction in hospitalizations together with the lesser use of ICS.

[P1274] - Budesonide/formoterol (B/F) as maintenance and relief for asthma improves efficacy and is cost-saving versus a higher maintenance dose of B/F or salmeterol/fluticasone (S/F)

D. Price, A. Wiren, P. Kuna (Aberdeen, United Kingdom; Lund, Sweden; Lodz, Poland)

Background: B/F (Symbicort®) as maintenance and reliever therapy (SMART) is a simplified management approach that addresses breakthrough symptoms with a rapid increase in controller medication. The costeffectiveness of SMART vs a higher fixed dose of B/F or S/F is unknown.

Methods: In this 6-month, double-blind study, symptomatic patients with asthma (n=3335; age 12 years) were randomised to: B/F 160/4.5 µg bid plus further doses as needed (prn) (SMART); B/F 320/9 µg bid plus terbutaline (T) prn; or S/F 50/250 µg bid plus T prn. An economic analysis applied 2004 UK and Australian unit costs to the pooled data. The effectiveness variable was the number of exacerbations/patient/6 months.

Results: The SMART-treated group experienced fewer severe exacerbations than both fixed-dose groups (P 0.0048 vs B/F and S/F). All treatments provided similar improvements in other asthma control markers. Study drug costs were lower in the SMART group (P 0.0014 vs B/F and S/F). By extrapolation, the results indicated that switching 100 patients to SMART from fixed-dose B/F for 6 months would prevent 4 severe exacerbations and would reduce healthcare costs by £7300 (95% CI: £4800–9500) or AUS$3500 (95% CI: $1500–8400). Likewise, switching from S/F would prevent 7 exacerbations and reduce costs by £8200 (95% CI: £5500–10,700) or AUS$15,400 (95% CI: $9700–21,100).

Conclusion: SMART is more effective in preventing asthma exacerbations than a higher maintenance dose of B/F or S/F and delivers direct cost savings.

Comment on Abstract P1274

An economic analysis was conducted employing six-month data from the multinational study evaluating budesonide/formoterol in a single inhaler as both maintenance and reliever therapy (see Abstract P1228). Costs were calculated both for acquisition of medications and for costs of managing exacerbations, which were significantly reduced on the single-inhaler combination therapy of budesonide/formoterol as both maintenance and reliever therapy (called the SMART regimen) relative to a fixed-dose, single-inhaler combination therapy of either fluticasone/salmeterol or budesonide/formoterol plus terbutaline as needed. When calculated as a difference in cost from switching 100 patients to SMART from either of the other two strategies, the cost reductions ranged from more than $10,000 (CDN) to more than $15,000.

Questions and Answers with author Dr. David Price

Q: This study calculated lower costs from using a single inhaler of budesonide/formoterol for both maintenance and reliever therapy. What was the most important factor?

A: The main driver of costs was study medications, which were significantly lower on SMART than in either of the other fixed-dose strategies. While SMART was associated with a reduction in severe exacerbations, it is notable that this reduction was achieved with a lower overall load of medication.

Q: How significant were these cost differences? Are they likely to persist in different healthcare systems when the cost of drugs and exacerbations may vary?

A: SMART would still be a cost-saving treatment compared with fluticasone/salmeterol even after a substantial hypothetical increase in the price of budesonide/formoterol. An economic analysis demonstrated that the cost advantage persisted up to a 25% increase in the cost of budesonide/formoterol, which is the highest increase we evaluated. In this study, we looked at costs in the United Kingdom and Australia and found similar differences.

Q: Why did you evaluate costs in terms of switching 100 patients to SMART relative to the alternative regimens?

A: This was a reasonable approach for placing the costs in terms of an impact on a healthcare budget. A cost advantage from SMART cannot be anticipated in every patient because the advantage was a reduction in exacerbations among the study groups. We looked at the healthcare costs for one strategy vs. another in a population of patients with moderate to severe persistent asthma.

Q: Is it important to demonstrate a cost advantage for SMART?

A: Cost is a factor in healthcare decisions. In the context of the findings, which demonstrated that SMART was more effective than conventional therapy for preventing exacerbations, a cost analysis can reveal whether this is achieved with an increase in cost and the size of the increment. However, the cost analysis actually demonstrated that the more effective therapy is less expensive, which is not a common result.

[P1291] - Sustained asthma control can eliminate airway hyperreactivity: a 3 year study

B. Lundback, E. Ronmark, A. Lindberg, A. C. Jonsson, L. G. Larsson, D. Gor, M. James (Lulea, Stockholm, Sweden; London, United Kingdom)

Aim: It is widely accepted that guideline based asthma control as measured by the virtual abolition of symptoms, rescue use & exacerbations, can be achieved and maintained long term. In this study we examined whether the benefits of good asthma control also translate to a significant reduction in airway hyperreactivity (AHR) over time.

Methods: This was a two-phase study, comprising a 12-month, randomised, doubleblind period and a two-year open follow-up period reflecting a real-life setting, with the aim to provide freedom from asthma symptoms, exacerbations, rescue use, the need for sick leave, and to normalise patients’ lung function. Patients were randomised to receive salmeterol (SAL) 50, fluticasone propionate (FP) 250 or salmeterol/fluticasone propionate (SFC) 50/250, with the option to switch therapy in the open label phase. AHR was measured at randomisation and then yearly using methacholine challenge tests.

Results: 229 (81%) patients completed the study. At study end 73% of the subjects (168/229) were taking SFC to maintain their asthma, versus 21% (49/229) receiving FP & 5% (12/229) on SAL. 71% of patients on SFC and 46% on FP achieved full control of asthma. In controlled patients, AHR (PC20) decreased progressively from randomisation, 1 yr, 2 yrs & 3 yrs: SFC 0.45, 2.14, 2.42 & 4.09 mg/ml; FP 0.52, 1.29, 2.62 & 3.40 mg/ml (geometric medians). About 30% of controlled patients had a PC20 >8mg/ml, i.e. no AHR. Results for the SAL patients were inconclusive as only 2/12 had the 3 yr AHR tests.

Conclusion: Maintaining full asthma control over 3 years via stable-dosing progressively reduced AHR in most patients and eliminated AHR in one third of the patients. More patients benefited with SFC therapy.

Comment on Abstract P1291

It has been hypothesized that tight control of asthma can reduce the vicious cycle of inflammation and airway hyperreactivity that drives remodelling and disease progression. In this study, airway hyperreactivity was evaluated over three years in 229 patients, 73% of whom were taking a fixed-dose, single-inhaled combination of fluticasone and salmeterol (SFC) by the end of the study. In those on the fixed-dose combination therapy, 71% had complete control of symptoms vs. 46% of patients taking fluticasone alone. In those with tight control, regardless of therapy, airway hyperreactivity decreased progressively over the course of the trial. In one-third of patients with full symptom control, airway hyperreactivity was eliminated.

Questions and Answers with author Dr. Bo Lundback

Q: Does this study suggest that the progressive complications of asthma, such as bronchiectasis in late-stage disease, can be prevented with tight symptom control?

A: This study suggests that tight symptom control can reverse airway hyperreactivity, which is an important component of disease progression. The key message from this study is that if you keep patients free of symptoms and exacerbations at all times, you can reduce the hyperreactivity and inflammation that drives disease progression.

Q: Do you believe that this will lead to a change in long-term outcome?

A: In one-third of patients, airway hyperreactivity resolved completely. This suggests a potential for sustained remissions or even cure. What the findings are suggesting is that rather than short-term treatment adaptations in reaction to symptoms, we should be considering maintenance strategies that prevent symptoms in the first place.

Q: In this study, the single-inhaler combination therapy of an ICS and a LABA was more effective at sustained control than either component alone. Does this confirm that both components are needed for optimal maintenance treatment?

A: We saw additive protection against symptoms when the two agents were combined. We think that both agents are contributing to control of the underlying disease, including inflammation and hyperreactivity. It may be that together these are more effective at containing the vicious circle in which airway hyperreactivity promotes an inflammatory response and inflammation increases the risk of airway hyperreactivity.

Q: Do these findings support the use of a single inhaler that delivers both an ICS and a LABA?

A: The findings support protection against airway hyperreactivity by maintaining moderate to severe asthmatics on a stable regimen of both an ICS and a LABA. It may be that delivery of these components simultaneously does have added benefit—and treatment with a single inhaler is more convenient—but the key message appears to be a long-term benefit from a treatment regimen that maintains full asthma control over one that reduces symptoms but must be frequently supplemented with rescue therapy.

[P1231] - Ciclesonide 160 µg once daily compared with fluticasone propionate 250 µg twice daily in maintenance therapy of patients with stable asthma

M. Adler, J. Langan, J. B. Martinot, L. Croonenborghs, C. Gruss, C. Oedekoven (Harrow, Glasgow, United Kingdom; Namur, Veurne, Belgium; Konstanz, Germany)

Introduction: Ciclesonide (CIC) is a new-generation ICS that effectively improves lung function, asthma symptoms, and rescue medication use in patients with persistent asthma of all severity grades. We compared the efficacy of CIC 160µg/d and fluticasone propionate (FP) 500µg/d in asthma patients pretreated with FP 500µg/d or equivalent.

Methods: During the 2-week baseline period of this double-blind, parallel-group pilot study, ICS-pretreated patients with stable asthma (N=111, 17-75 y, FEV1 90% of predicted) were maintained on FP 250µg twice daily. After randomisation, 58 patients received CIC 160µg once daily (ex-actuator, HFA-MDI) and 53 patients received FP 250µg twice daily (500µg/d, ex-valve, MDI) for 12-weeks. Control of asthma symptoms and rescue medication use were of primary interest in this study.

Results: The median percentage of days without asthma symptoms was high and comparable between both treatment groups (CIC [98%], FP [98%]; P=0.82). Similar results were seen for the median percentages of days without rescue medication use (P=0.59) and days without nocturnal awakenings (P=0.66). The median percentage of days where patients neither experienced asthma symptoms nor needed rescue medication was high and similar between the CIC (97%) and FP (98%) groups (P=0.82). Lung function variables were maintained during the treatment period in both groups. For each group, two cases of asthma exacerbations were reported.

Conclusion: In this population of patients with stable asthma who are well maintained with FP 250µg twice daily (or equivalent), many of these patients may be switched to CIC 160µg once daily for maintenance therapy.

Comment on Abstract P1231

In this study, the goal was to evaluate the efficacy of a new-generation ICS called ciclesonide. After a baseline period of two to four weeks on 250 mcg fluticasone, 111 patients were randomized to remain on fluticasone or switch to 160 mcg ciclesonide once daily. The control of asthma symptoms was found to be similar over the 12-week study period. In the ciclesonide group, the median percentage of days without symptoms or need for rescue medication was 97%; in the fluticasone group, the median was 98%. The conclusion was that once-daily ciclesonide provides equivalent maintenance when compared to fluticasone b.i.d. and consequently might be a reasonable substitute in patients who wish to simplify therapy.

Questions and Answers with author Dr. Martin Adler

Q: In terms of micrograms, each once-daily dose of ciclesonide was lower than each of the twice-daily doses of fluticasone. Is this ICS more potent?

A: The major difference appears to be the size of the particles. Due to a relatively high fraction of respirable particles, more than 50% of the active agent reaches the lung on a metered-dose inhaler. This is substantially greater than that achieved with fluticasone.

Q: Is this the first study to compare ciclesonide directly with another ICS?

A: There have been a number of studies. In one study, patients with severe asthma who were being maintained on a high dose of beclomethasone were switched to ciclesonide. Although these patients were taking 1600 mcg of beclomethasone per day prior to the switch, they were effectively maintained on 800 mcg of ciclesonide per day.

Q: Was once-daily dosing with ciclesonide able to provide comparable 24-hour control of asthma?

A: In both groups, all patients were free of asthma-related nocturnal awakenings throughout the course of the study.

Q: Do you think ciclesonide will be primarily used in patients with severe disease?

A: So far, studies have found it to be safe and potent. It is being used in Europe in a broad spectrum of patients with asthma. Its chief advantage is that it appears to be effective in at least some patients as once-daily dosing.

[P1079] - Acute exacerbations of COPD (AECOPD) in the emergency department (ED): hospitalization criteria versus predictors of death

N. Roche, D. Soussan, M. Zureik, D. Perrotin, F. Neukirch, and investigators for the “Urgence BPCO 2003” Scientific Committee (Paris, France)

To identify predictors of outcome and describe pathways of care in patients visiting the ED with a diagnosis of AECOPD at entry, a prospective study was conducted in 103 French centres. 712 consecutive patients were recruited and the following variables were recorded: socio-demographic and anthropometric characteristics, smoking history and occupational risk factors, history of COPD (dyspnoea MRC grade at steady state, age at first symptoms, usual treatment and follow-up), clinical signs of severity (lower limb oedema, use of inspiratory and expiratory accessory muscles, confusion, cyanosis, asterixis), heart and respiratory rates, body temperature, pulsed oximetry. Outcomes were assessed: (i) at discharge from the ED (death in the ED, discharge home, hospitalization in an intensive care unit, hospitalization in a medical ward); and (ii) at the end of hospital stay (death during hospital stay, discharge home, discharge to an intermediate care facility). 628 patients were hospitalized and 59 died during hospital stay. Independent predictors of death during hospital stay in multivariate logistic regression analysis were age ( or < 70 years), number of clinical signs of severity (0, 1 or 2, 3 and more) and dyspnoea grade at steady state (0-1, 2-3, 4-5). Factors independently associated with the decision to hospitalize were age, heart rate and respiratory rate. Thus, criteria used to decide hospitalization are different from predictors of death, suggesting the need to rationalize hospitalization criteria by developing prediction rules.

Comment on Abstract P1079

Some of the most common criteria for hospitalizing patients for COPD are poor predictors of death, according to a prospective study conducted in 712 patients. Rather, this study found that easy-to-measure, objective clinical indicators of disease severity provide a far more sensitive predictor of a bad outcome and the need to consider hospital admission. The measures of disease severity found useful in this study were presence of lower limb edema, use of inspiratory and expiratory accessory muscles, confusion, cyanosis or asterixis. When combined with an age or < 70 years, these signs of disease severity were associated with a strong predictive value of death. In contrast, heart rate, body temperature, and respiratory rate were not good predictors. The data suggest that these signs may be organized into a more useful and reproducible methodology for selecting patients for hospitalization than clinical judgement.

Questions and Answers with author Dr. Nicholas Roche

Q: Does your study suggest that COPD patients who are at low risk for serious adverse events, particularly death, are now being hospitalized unnecessarily?

A: The data suggest that the wrong criteria are being used. According to the predictors we looked at, some patients are hospitalized who do not need hospitalization, but others are not being hospitalized despite a very high risk of adverse outcome, because physicians are not measuring the best indicators.

Q: Is clinical judgement insufficient when considering a hospital admission?

A: There has not been a prospective study that I am aware of to evaluate whether we are using criteria that are rational. Our study suggests that physicians are frequently measuring the wrong things. Again, the risk is not just hospitalizing someone who will not benefit from admission but not hospitalizing someone who is at a high risk of imminent death.

Q: You have identified criteria as predictors of a poor outcome. Will they be part of further studies assessing patients with acute exacerbations of COPD?

A: The findings are provocative, but we are now planning a prospective study to better test the hypothesis that we can identify more rational criteria for evaluating candidates for hospitalization. If the study supports these initial data, the advantages of a better methodology may include better patient care and lower costs.

Q: How easy is it to apply the criteria you identified in assessing COPD patients?

A: Very easy. All of the signs and symptoms that appear to be predictive can be assessed in a physician’s office within a few minutes. These are clinical signs that do not need any special equipment other than a stethoscope. If these criteria prove to be reproducible, this approach may not only provide a more rational basis on selecting patients for hospitalization but it should also be very easy to apply.

[E311] - The TORCH (TOwards a Revolution in COPD Health) study: salmeterol/fluticasone propionate (SFC) improves survival in COPD over three years

P. M. A. Calverley, G. T. Ferguson, J. A. Anderson, B. Celli, C. Jenkins, P. W. Jones, J. Vestbo, J. C. Yates, N. Pride (Liverpool, Greenford, London, Manchester, United Kingdom; Livonia, Boston, Research Triangle Park, United States of America; Sydney, Australia)

FEV1; 3.7% reversibility to salbutamol as % of predicted, 43% current smokers) were randomised to receive salmeterol (SAL) 50µg (n=1521), fluticasone propionate (FP) 500µg (1534), SFC 500/50 (1533), or placebo (PL) (1524) bd in a 3 year double-blind study. The primary analysis was log-rank of time to allcause mortality (SFC vs PL) at 156 weeks, adjusted for 2 interim analyses which were carried out by an independent data monitoring board. SFC reduced the risk of dying at any time in the three years by 17.5% vs PL (P=0.052) (absolute rates 15.2% vs 12.6%).

Table 1.

SAL and FP were not significantly different to PL (SAL HR 0.879, 95% CI 0.729- 1.061; FP HR 1.060, 95% CI 0.886-1.268). No significant interactions by baseline FEV1 (<30%, 30-50%, 50%), smoking, age or sex were found (all p 0.12). SFC is the first intervention since O2 and smoking cessation to improve survival in COPD.

Comment on Abstract E311

A study comparing salmeterol, fluticasone, and a single-inhaler combination of salmeterol/ fluticasone in patients with COPD associated the combination with a reduction in all-cause mortality over a three-year period. The risk of dying on the combination was reduced by 17.5% (P=0.052) relative to either of the components administered separately. The absolute risk reduction was 2.6%. This is the first study testing drug therapies that have employed mortality as the primary end point. The study also associated the fixed-dose, single-inhaler combination of the ICS and the LABA with a 25% reduction (P<0.001) in the risk of exacerbations relative to the individual components. The combination was also associated with a significant advantage for lung function and quality of life.

Questions and Answers with author Dr. Peter Calverley

Q: Is the magnitude of the benefit observed in this trial clinically significant?

A: This represents a substantial reduction in mortality that is comparable to smoking cessation in COPD or to the use of statins in patients with coronary heart disease. Any reduction in mortality in COPD is important because our options are so limited. This is the first intervention to demonstrate a mortality benefit since smoking cessation or the administration of oxygen.

Q: Which do you think is more important for the benefits seen in this trial, the ICS or the LABA?

A: I think they are both important and that they may work together. It may be important to administer these in the same inhaler because they have complementary actions, even though this was not demonstrated in this study. Although credit is given to the ICS for an anti-inflammatory effect that may slow disease progression, the LABA may also participate in inhibiting deterioration of lung function.

Q: Does protection against COPD come with any safety risks?

A: The combination of salmeterol/fluticasone was generally well tolerated. Although there was an increase in the rate of pneumonia in patients who received either salmeterol/fluticasone or fluticasone relative to salmeterol alone or placebo, there was no corresponding increase in mortality due to pneumonia. There was also no significant difference observed in the probability of total or non-traumatic bone fractures between study groups.

Q: How important is this study in terms of changing the approach to COPD?

A: TORCH is a landmark study. It suggests that we can offer treatment to the COPD patient that will improve outcome as well as reduce symptoms. This is a disease in which we need more treatment options. The morbidity and mortality from COPD has been increasing in most areas of the world, and it is on track to become the third leading cause of death worldwide within about 15 years.