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Response

I appreciate the comments of Dr Anthony D’Urzo concerning the recent debate on the safety of β-agonist use in chronic obstructive lung disease (COPD).¹ I will respond to his comments here, but first I would like to point out that Dr D’Urzo has consultant arrangements with the pharmaceutical firms AstraZeneca and Novartis, has received grant support from AstraZeneca, and is on the speakers’ bureau for Schering-Plough.² It is possible that Dr D’Urzo’s comments are tempered by a serious bias toward promoting long-acting β-agonist use, especially that of formoterol, the long-acting β-agonist made by these companies.

As Dr D’Urzo pointed out, my recent analysis of β-agonist use in COPD³ did not include the TORCH study,⁴ but this is because it had not been published at that time. As I discussed in the debate rebuttal, this trial also showed an increase in respiratory deaths for β-agonist use compared with placebo, although it was not statistically significant. It is true that the TORCH trial found an 18% reduction in hospitalizations due to COPD,⁴ while previous studies found no reduction in COPD hospitalizations with β-agonist use.³ This is consistent with the evidence that β-agonists improve COPD symptoms but might increase respiratory mortality compared with placebo. It is important to compare these results with those of anticholinergic agents, which have been shown to reduce hospitalizations by 33% and respiratory mortality by 73%, compared with placebo.³

Another published analysis evaluated long-acting β-agonists in asthma and found a similar increase in respiratory mortality compared with placebo.⁵ This adverse effect of β-agonists in obstructive lung disease is thought to be due, in part, to tolerance that develops to β-agonist use over time, although I agree with Dr D’Urzo that other factors might be involved.⁶ As Dr D’Urzo points out, the FACET trial⁷ was not included in my previous analysis, but that is because it was not a placebo-controlled trial. He also suggests that these safety concerns in asthma have centred on salmeterol and not formoterol, but pooled trial data have found a significant and equal increase in asthma hospitalizations for both formoterol and salmeterol, compared with placebo.⁵

Dr D’Urzo is worried that my arguments are not supported by the best available evidence because my literature review is not comprehensive and that this might introduce a serious bias. He suggests that my review might "serve only to confuse family physicians who are far too busy looking after patients to carry out comprehensive literature searches of their own." A full literature review was not possible in this short position statement, but I would like to assure the readers that my meta-analyses have included all of the randomized placebo-controlled trials that were available when the reviews were completed. The fact that Canadian Family Physician invited a debate on whether β-agonists should be avoided in COPD should alert readers that there might be some serious concerns about their safety. I myself am a practising general internist caring for patients with COPD, and I have no ties to the pharmaceutical industry. I personally use anticholinergic agents instead of β-agonists as the bronchodilator of choice in the treatment of these patients.

	References

TOP References

 

1. Salpeter SR. Should we avoid β-agonists for moderate and severe chronic obstructive pulmonary disease? Yes [Debates]. Can Fam Physician 2007;53:1290-3. (Eng), 1294–7 (Fr).[Free Full Text]
2. D’Urzo TD. Control of airway inflammation. J Allergy Clin Immunol 2007;119:252-4.[Medline]
3. Salpeter SR, Buckley NS, Salpeter EE. Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD. J Gen Intern Med 2006;21:1011-9.[Medline]
4. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-89.[Abstract/Free Full Text]
5. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Long-acting beta-agonists increase severe asthma exacerbations and asthma-related deaths: meta-analysis of randomized controlled trials. Ann Intern Med 2006;144:904-12.[Abstract/Free Full Text]
6. Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular β2-agonist use in patients with asthma. Ann Intern Med 2004;140:802-13.[Abstract/Free Full Text]
7. Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O’Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997;337:1405-11. Erratum in: N Engl J Med 1998;338:139.[Abstract/Free Full Text]

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