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.

18th Annual Congress of the European Respiratory Society

Berlin, Germany / October 4-8, 2008

Asthma is thought to affect approximately 300 million individuals worldwide. Although asthma-related mortality has declined in developed countries in recent years, asthma is still associated with significant morbidity and the burden on health services—particularly in relation to hospitalization for exacerbations—is significant. In recent years, recognition of the associated morbidity and reduction in quality of life (QoL) has been one of the factors behind the development of the concept of “asthma control.” The various guidelines generally agree on what constitutes good or suboptimal control, but there is a grey area sometimes denoted as “satisfactory control” or “acceptable control” that is less well defined.

Achieving Overall Asthma Control in Moderate/Severe Asthma

A post-hoc analysis presented by Dr. Eric D. Bateman, Division of Pulmonology, Department of Medicine, University of Cape Town, South Africa, and Dr. Paul M. O'Byrne, Department of Medicine, McMaster University, Hamilton, Ontario, pooled results from two studies with budesonide/formoterol maintenance and reliever therapy. In the first study, budesonide/formoterol maintenance and reliever therapy (160/4.5 µg b.i.d. and as needed) was compared to 320/9 µg b.i.d. or salmeterol/fluticasone 25/125 µg b.i.d. plus short-acting b2-agonists (SABAs) as needed (Kuna et al. Int J Clin Pract 2007;61:725-36). In the second study, high-dose budesonide/formoterol maintenance and reliever therapy (2 x 160/4.5 µg b.i.d. and as needed) were compared with maximum-dose salmeterol/fluticasone 50/500 µg b.i.d. (Bousquet et al. Respir Med 2007;101;2437-46).

The level of control was determined using the validated five-item asthma control questionnaire (ACQ-5). A generally accepted but nevertheless somewhat arbitrary definition of well-controlled intermediate control and uncontrolled patients is ACQ-5 0.75, 0.76-1.49, and ACQ 1.5, respectively. In the pooled analysis, the number of well-controlled and intermediate controlled patients was similar, but a significantly higher percentage was uncontrolled for double-dose inhaled corticosteroids (ICS)/long-acting b₂-agonists (LABAs) + SABA (Figure 1).

An interesting subanalysis showed the close relationship between asthma control and exacerbation rates. The exacerbation rate of well-controlled and intermediate-controlled patients was less than half that of uncontrolled patients. The difference was even more striking when patients were analyzed by whether they were on high-dose ICS at study entry—1.030 exacerbations/patient/year for uncontrolled patients vs. 0.263 for well-controlled and intermediate-controlled patients.

Future Risk: Reducing Exacerbations

“Exacerbations represent the period of greatest risk of mortality, and a period of great concern and anxiety for patient, family and healthcare workers, and also the greatest component of cost of management asthma,” confirmed Dr. O’Byrne. However, exacerbations have also been linked to loss of lung function over time, particularly when they occur early on in the disease course (Sears et al. N Engl J Med. 2003 Oct 9;349(15):1414-22). Understandably, preventing exacerbations is now a central part of asthma management strategies.

Previous studies have shown that budesonide/formoterol maintenance and reliever therapy can reduce asthma exacerbation rates. This finding was further confirmed in an analysis presented by Dr.s. O’Byrne and Bateman in which six double-blind, placebo- controlled studies of budesonide/formoterol maintenance and reliever therapy and comparators were pooled to provide comparisons of this treatment with two- to fourfold higher fixed budesonide dose + SABA as needed (comparison A; n=3770), same fixed-dose budesonide/formoterol + SABA as needed (comparison B; n=3405), and higher fixed-dose ICS/LABA + SABA as needed (comparison C; n=4697).

For the three comparisons, the mean annualized rates of all asthma exacerbations were significantly lower for budesonide/formoterol maintenance and reliever therapy by between 29% and 43%. On analyzing exacerbation rates by patients receiving high-dose ICS at study entry, the differences remained large (37% for comparison A, 60% for comparison B and 44% for comparison C). Likewise, the mean annualized rates of hospitalization/visits to the emergency room for exacerbations also showed benefit for budesonide/formoterol maintenance and reliever therapy by between 27% and 35%.

From Clinical Trials to Clinical Practice

As Dr. Harrison, Nottingham University Hospitals Trust, UK, pointed out, “If a patient doesn’t meet the inclusion criteria [of a clinical trial], it doesn’t matter, you move on to the next patient; in real life, we don’t have that option, we have to treat everybody who comes to see us, regardless of prior treatment, lung function, and so on.” Consequently, the findings of randomized clinical trials cannot always be extended into “real-life” situations. However, a couple of studies of similar design have attempted to mirror clinical practice by comparing budesonide/formoterol maintenance and reliever therapy with conventional best practice (using any alternative Global Initiative for Asthma [GINA] step 2-4 maintenance therapy considered appropriate). The first study, presented by Demoly and colleagues, included patients from several European countries, Chile, and Canada (n=7747). The second, presented by Dahl and colleagues, included patients from Norway, Denmark and Finland (n=1835).

After a run-in phase, patients were randomized to either conventional best practice according to GINA guidelines or budesonide/formoterol maintenance and reliever therapy and followed for half a year. Treatment in the best practice arm could vary at the discretion of the investigator, whereas treatment in the budesonide/formoterol maintenance and reliever therapy arm remained unchanged. In the first study, the exacerbation rate was 15% lower in patients treated with budesonide/formoterol maintenance and reliever therapy (P=0.02) and the percentage of well controlled patients was higher (45% vs. 41%, P<0.01) while that of uncontrolled patients was lower (25% vs. 29%, P<0.01), as determined by ACQ-5 score. Also of note was that the mean daily dose of ICS in beclomethasone dipropionate equivalents was significantly lower with budesonide/formoterol maintenance and reliever therapy (732 µg vs. 1007 µg/day; P<0.0001). In the second study, the cumulative number of severe asthma exacerbations at the end of follow-up was 26% lower for budesonide/formoterol maintenance and reliever therapy, although this difference was not quite significant (P=0.058).

Summary

Approaches to asthma management are changing. A number of considerations should be taken into account when assessing the success of treatment. Good control is essential, not only for improving the QoL of the patients in the present, but also for reducing future risk of exacerbations and preserving lung function. Steroids are an essential part of asthma management, but they must be used wisely, as excessive doses may be associated with long-term problems and patient rejection. As presented at this year’s ERS congress, there is evidence that budesonide/formoterol maintenance and reliever therapy can provide good asthma control and reduce the rate of exacerbations while reducing the total steroid dose compared to other strategies.

Figure 1.