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ASTHMA: Umesh G. Lalloo, Jóseph Malolepszy, Dezsó Kozma, Kamil Krofta, Jaro Ankerst, Bjørn Johansen, and Neil C. Thomson Budesonide and Formoterol in a Single Inhaler Improves Asthma Control Compared With Increasing the Dose of Corticosteroid in Adults With Mild-to-Moderate Asthma Chest 2003; 123: 1480-1487 [Abstract] [Full text] [PDF]

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Outcomes were biased towards budesonide/formoterol combination

Brian J Lipworth, Catherine Jackson   (17 June 2003)

Outcomes were biased towards budesonide/formoterol combination 17 June 2003
Brian J Lipworth, Professor of allergy and pulmonology Asthma and Allergy Research Group,Ninewells University Hospital,Dundee, Catherine Jackson Send letter to journal: Re: Outcomes were biased towards budesonide/formoterol combination b.j.lipworth{at}dundee.ac.uk Brian J Lipworth, et al.	The findings of Lalloo et al(1) are entirely predictable given the choice of smooth muscle responsive outcome measures which would always favour adding formoterol to a lower dose of budesonide.It can hardly be surprising that when adding in a 24/7 bronchodilator such as formoterol bid , that there will be greater improvements in peak flow and symptoms, as well as reduced reliever use, since these are highly sensitive to its effects on airway smooth muscle. One must also ask whether the observed mean difference in morning peak flow of 9 L/min is clinically relevant ,given that most peak flow meters are only calibrated to the nearest 10 L/min. It is also important to note that the patients were taking inhaled steroids in a daily dose of 200-500ug prior to enrolment, and were therefore on the plateau of the steroid dose response curve .Thus , one would always expect to see a better response when comparing the combination of budsonide 80ug/formoterol 4.5ug bid to budesonide 200ug bid alone .Moreover the initial run-in period on budesonide 100ug bid was not of sufficient duration to ensure a maximal response was attained over 2 weeks, as compared to the 12 week duration on randomised budesonide 200ug bid. The definition of a mild exacerbation was also based on formoterol responsive end points ,including peak flow,nighttime waking and reliever use,whcih would explain the apparent superiority of the combination nhaler.Further inspection of the data shows a 9% difference in the absolute number of mild exacerbations between the groups,which may be statistically significant but can hardly be considered as being clinically significant.Pointedly no differences were seen in severe exacerbations and no evalauation was made of any inflammatory outcome measures. For example in a study of mild to moderate asthmatics uncontrolled on budesonide 200ug daily, adding formoterol 9 ug bid to budesonide 200ug daily as compared to increasing the dose to 800ug,the former was associated with a significant worsening of sputum eosinophils and exhaled nitric oxide, while the latter was associated with a significant improvement of the same outcomes, despite an improvement in peak flow with the former(2).This points to a disconnect between lung function and inflammation when evaluating effects of combination inhalers. The study of Lalloo is yet another example of how the pharmaceutical industry is trying to influence guidelines with data on the putative benefits of using combination inhalers earlier on ,whereas in reality ,most patients with mild to moderate asthma can be adequately controlled on an optimsed dose of inhaled steroid as monotherapy. There are important economic issues for managed care when one considers the relative UK costs for 28 days of budesonide 200ug bid ($16.57) versus budesonide 80ug /formoterol 4.5ug bid ($24.64)- ie a 49% difference. It is therefore important to remember that long acting beta-2-agonists such as formoterol do not exhibit any clinically meaningful anti- inflammatory activity in vivo ,and consequently the biggest "bang for buck" in mild to moderate asthma will be achieved by optimising the dose and delivery of inhaled steroid in the first instance ,rather than choosing the more expensive option of a combination inhaler. However for more severe patients where airway calibre is more compromised, the use of a combination inhaler is a more rational treatment option. References (1)U G. Lalloo, J Malolepszy, D Kozma,et al.Budesonide and Formoterol in a Single Inhaler Improves Asthma Control Compared With Increasing the Dose of Corticosteroid in Adults With Mild-to -Moderate Asthma Chest 2003; 123: 1480-1487 (2) R.H. Green, C.E. Brightling, S. McKenna, et al . A placebo controlled comparison of formoterol,montelukast or higher dose of inhaled corticosteroids in subjects with symptomatic asthma despite treatment with inhaled corticosteroids. Thorax 2002;57(suppl 3):11,S31 Conflicts of interest: The asthma and allergy research group has received financial support from AstraZeneca for clinical trials ,equipment ,staff developement,attending and speaking at postgraduate educational meetings .