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

Munich, Germany / September 2-6, 2006

In asthma as in chronic obstructive pulmonary disease (COPD), the immediate goal of an effective therapeutic regimen is to prevent acute exacerbations, a goal that also has important implications for inhibiting progressive bronchial dysfunction. The reason is that acute airway restriction and hyperreactivity drive the inflammatory response and, ultimately, airway remodelling. Asthma and COPD are very different diseases with fundamentally different pathophysiologic cues and risks, but both can benefit from treatment with inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs). The evidence that combination therapy of an ICS and a LABA yield tighter control than either agent used separately in patients who are candidates for both has been accumulating through a series of studies, many of which were published in the past few months.

Combination Strategies: Implications for Outcome

According to Dr. Bo Lundbäck, Unit for Lung and Allergy Research, National Institute for Environmental Medicine, Karolinska Institute, Stockholm, Sweden, “The combination inhalers help to keep patients free from symptoms and exacerbations. This is the key in asthma management. It is important not just for patient well- being, but it provides an opportunity to reduce the risk of bronchial hyperreactivity and inflammation, which has important implications for long-term outcome.”

The focus of his remarks were on asthma, but other experts, including Dr. Alvar Agusti, Head, Pulmonary Section, Hospital Universitario Son Dureta, Palma de Mallorca, Spain, made similar statements about COPD. The opportunity to better prevent exacerbations not only has immediate implications for keeping patients out of the hospital but may directly influence long-term outcome. “By employing bronchodilators to control hyperinflation, there is growing evidence that you reduce the inflammatory response. By using steroids for inflammation, you appear to reduce the risk of hyperinflation. This is why a single combination of these two agents is attractive in COPD,” Dr. Agusti told the audience.

A series of studies demonstrating a high degree of efficacy and safety led to the development of the two currently available ICS/LABA combinations. One of these devices combines the ICS budesonide with the LABA formoterol, the other combines the ICS fluticasone with the LABA salmeterol. New data, including an analysis of the two inhalers for control of asthma, have confirmed and extended the evidence that these devices are highly effective and may provide protection against long-term progression of both asthma and COPD. The improved quality of life, including the reduction in the number of inhalers required to maintain disease control, provide an advantage independent of the improvement in disease control.

Managing Exacerbations

The most notable of the new data testing the role of these devices may be the double-blind comparison of the two devices in an asthmatic population. The study not only compared the two currently available combination inhalers but, more importantly, also tested the strategy of employing one device for both maintenance and reliever therapy. In this study, called COMPASS (COMPArison versus higher fixed dose of Symbicort and Seretide), 3335 patients with moderate to severe asthma were randomized to one of three treatment groups: fluticasone/salmeterol 250/50 µg b.i.d. plus terbutaline permitted as needed to control acute symptoms; budesonide/formoterol in a dose of 320/9 µg b.i.d. plus terbutaline as needed; or budesonide/formoterol 160/4.5 µg plus additional as-needed budesonide/formoterol with the same device to control acute symptoms. This latter approach, now tested in a series of clinical studies, is known by the acronym SMART (Symbicort for Maintenance And Reliever Therapy). The patients were followed over a period of six months.

“The reduction in the number of severe exacerbations with SMART over the fixed-dose combinations was nearly 40%, and was accompanied by a 40% reduction in the number of days in which oral steroids were required,” indicated Dr. Piotr Kuna, Department of Pneumology and Allergy, Medical University of Lodz, Poland. “The results of the study validate the concept of SMART for control of both persistent and acute symptoms. As an alternative to conventional fixed-dose combinations of ICS and LABAs with rescue therapy, this approach is simple, effective, well-tolerated and cost-effective.”

In this study, slightly more than 1100 patients were randomized to each of the three treatment arms. Study patients’ mean age was 38 years with a range of 12 to 83 years. The median time since diagnosis of asthma was 10 years. The mean forced expiratory volume in one second (FEV1) at baseline was approximately 73% of predicted value. During a two-week run-in before randomization, patients were taking a mean 2.3 inhalations of short-acting beta agonists (SABAs) per day.

Hospitalizations

The total number of severe exacerbations—defined as need for hospitalization or for three or more days of oral steroids—was approximately 200 in the fluticasone/salmeterol group, 170 in the fixed-dose budesonide/formoterol group and 125 in the SMART group (Figure 1). The relative reduction in severe exacerbations for SMART was 39% (P<0.001) relative to fluticasone/salmeterol and 28% (P=0.0048) relative to the fixed-dose budesonide/formoterol group. Oral steroid use was required for 618 days in the SMART group vs.1044 days in the fixed-dose group and 1132 days in the fluticasone/salmeterol group, representing a 45% reduction (statistical significance not reported) in days on oral steroids. In addition, the average daily ICS dose in beclomethasone equivalents was slightly lower in the SMART patients vs. the other treatment groups (753 µg/day vs. 1000 µg/day for fluticasone and 1000 µg/day for the fixed-dose group).

Figure 1. Severe Exacerbations over Six Months

Although there was no arm evaluating a maintenance and acute reliever strategy using fluticasone/salmeterol, this approach is precluded by the prolonged occupation of beta receptors by salmeterol. Formoterol has a relatively rapid onset of action but also a shorter duration of receptor occupancy. This shorter occupancy circumvents the risk of adverse events associated with prolonged action of the beta receptor, while the more rapid onset permits formoterol to be part of an acute reliever therapy if patients are instructed to take additional puffs of the inhaler when they experience early symptoms of an exacerbation. The difference in onset of action among LABA drugs has been documented in controlled studies, including one published by K. Richter et al. in the European Respiratory Journal (2002;19:865-871), which associated formoterol with greater bronchodilation than salmeterol at all timepoints between 5 and 60 minutes, according to Dr. Peter J. Barnes, Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, London, UK. He suggested that the overall onset of action of salmeterol is about 20 to 30 minutes slower than that of formoterol, precluding its use as an acute reliever agent.

“The pharmacokinetics of formoterol permits this agent to be use in a flexible way, including as an acute reliever therapy. The difference [with other LABAs] is critical. Salmeterol could never be dosed on an as-needed basis because of the unacceptable risk of cumulative adverse events,” Dr. Barnes reported.

INSPIRE Survey

Tightening control of asthma symptoms has long been identified as a critical goal in the effort both to prevent exacerbations leading to emergency room visits or the need for oral steroids and to inhibit disease progression that is thought to be associated with frequent exacerbations. A large survey called INSPIRE (INternational aSthma Patient Insight Research) study has substantiated the premise that patients are able and willing to adjust maintenance therapy in response to fluctuations in disease activity. In the INSPIRE survey of 3415 patients in 11 countries, the mean time between onset of signs and warnings of an exacerbation and onset of peak symptoms was reported to be 5.1 days, which is a sufficient period to permit patients to alter their regimen in time to regain control of disease without resorting to excessive and often ineffective dependence on SABAs. The survey also revealed that 88% of patients were confident that they could manage their own asthma if given an appropriate treatment plan.

“Patients do recognize the early signs of an exacerbation, and patients do feel confident to self- manage their symptoms. The problem is that they are choosing the wrong medications,” indicated Dr. Martyn R. Partridge, Department of Respiratory Medicine, Charing Cross Hospital, London, UK. Providing an overview of the INSPIRE results, Dr. Partridge reported that although patients recognize the onset of an impending exacerbation, the almost uniform response was to uptitrate their SABA rather than to uptitrate maintenance therapies. For example, he indicated that patients reported little change in their dose of ICS to prevent an exacerbation.

The INSPIRE survey included participants in Canada, where a recent study was conducted to test SMART as an alternative to conventional care to improve clinical control. Presented by Dr. Malcolm Sears, Department of Medicine, McMaster University, Hamilton, Ontario, the study randomized 1538 patients to SMART (budesonide/formoterol 160/4.5 µg b.i.d. with additional puffs permitted as needed) or conventional best practice, which permitted physician choice of strategy and did not exclude the fixed-dose combination of budesonide/formoterol. Outcomes were compared over six months.

Less Steroid Use, Better Control

Reported Dr. Sears, “Compared with conventional best practice in patients with persistent asthma, SMART achieved similar or improved clinical control but was associated with significantly less reliever medication [P=0.0036] and a significantly lower total ICS dose [P<0.0001]. The 43% reduction in hospitalizations or emergency room visits was just short of statistical significance [P=0.07].” He also noted that a cost analysis found that total management costs were 23% lower (P<0.0001) in the SMART arm.

Fig
s of Oral Steroid Use

<img413|center>

In COPD, there are also new data supporting the use of of an ICS/LABA therapeutic combination, and these include objective benefits on long-term lung function. Most notable of the studies presented at the ERS was TORCH (Towards a Revolution in COPD Health). In TORCH, 6112 patients were randomized to one of four study groups: fluticasone 500 µg b.i.d; salmeterol 50 µg b.i.d.; fluticasone/salmeterol 500/50 µg b.i.d.; or placebo. The primary outcome of the study, evaluated at three years, was all-cause mortality.

According to Dr. Peter Calverley, Department of Medicine, University Hospital Aintree, Clinical Sciences Centre, Liverpool, UK, “The fixed-dose combination reduced the risk of dying at any time in the three years by 17.5% relative to placebo (P=0.052), which was an absolute risk reduction of 2.6%. Mortality did not differ significantly in the groups receiving salmeterol or fluticasone alone relative to placebo.”

Times Is of the Essence

A similar study has not yet been conducted with the fixed-dose of budesonide/formoterol combination, but the rapid onset of action of formoterol relative to salmeterol has the potential to build on these benefits. In a placebo-controlled crossover trial conducted in 88 patients with moderate to severe COPD who were randomized to single doses of fluticasone/salmeterol, budesonide/formoterol, the fast-acting bronchodilator salbutamol or placebo, budesonide/formoterol had a faster onset of bronchodilatory effect than fluticasone/salmeterol. The effect was about the same as that observed with salbutamol. All treatment groups were more effective than placebo.

“The rapid bronchodilatory effect may provide better control and improve patient’s adherence to treatment,” reported Dr. Anne Lindberg, Department of Medicine, Sunderby Central Hospital, Luleå, Sweden. Commenting on these data, Dr. Partridge drew a similar conclusion: “Speed of onset is as important in COPD as it is in asthma, especially in the morning when patients often require a rapid onset of bronchodilatory effect.”

Exploring Treatment Synergy

In both COPD and asthma, there is preliminary evidence that delivering ICS and LABAs simultaneously has greater additive benefits or possibly synergism relative to the delivery of these compounds separately. However, it is suspected that the relative contribution of the two agents is different in the two diseases. In asthma, the ICS is considered to be the backbone of a strategy to control the inflammation, while the LABA prevents the bronchorestriction, a major component of the inflammatory response. In COPD, the LABA may play a more important role in preventing the events that trigger worsening inflammation, such as dyspnea and abnormal gas exchange, while the ICS plays a more adjunctive role in controlling the inflammatory process.

“Both components appear to be important in the two diseases, but their relative contribution to disease control differs,” commented Dr. Eric Bateman, Professor of Respiratory Medicine, University of Cape Town, South Africa. “However, in both cases, I think we see that the medicines work better when given together than when given separately in those individuals who are candidates for both.”

The evidence that single-dose inhalers may provide better protection against lung remodelling in asthma and COPD suggests that they may be named specifically in future guidelines as a tool for tighter disease control. Dr. Bateman, focusing on asthma, commented that the recent data with combination therapy “challenge the way this has been managed. The new data suggest that tighter control can be achieved with sustained therapy, and this has implications for long-term outcome.”

Summary

The fixed-dose combinations of an ICS and a LABA appear to provide a substantial step forward in the options to achieve long-term control of both asthma and COPD. While the convenience of a single inhaler over multiple inhalers in a management program is obvious, new data suggest that these devices improve outcomes, including a reduction in severe exacerbations in asthma, and a reduction in COPD mortality. Due to differences in the compounds they contain, the available fixed-dose combination inhalers do not appear to be interchangeable. In asthma, several studies presented at this year’s ERS have now confirmed the efficacy and safety of budesonide/formoterol combination inhaler within a strategy aimed at providing both reliever and maintenance control.