β-Agonists: all the facts please

I would like to share my comments about the recent debate titled “Should we avoid β-agonists for moderate and severe chronic obstructive pulmonary disease?” (COPD) between Drs Salpeter and Aaron (Can Fam Physician 2007;53:1290-3 [Eng], 1294-7 [Fr]).

In support of the argument not to use β-agonists in the management of COPD, Salpeter leads the reader to believe that tolerance to β-agonists might be the underlying mechanism associated with adverse events when these medications are used to treat obstructive lung disease. Salpeter develops this theme using references to both asthma and COPD studies. Tolerance is a phenomenon observed with both short- and long-acting β-agonists1 and, to date, its importance within a clinical framework appears to be minimal.

In a meta-analysis carried out by Salpeter et al2 on the subject of tolerance to regular β–agonist use in patients with asthma there is no mention of the landmark Formoterol and Corticosteriod Establishing Therapy (FACET) trial3 where, despite the observation of tolerance to the bronchodilating effect of formoterol, the addition of formoterol to either low- or high-dose budesonide was associated with a reduction in severe exacerbations compared with budesonide use alone. Given her position on tolerance, it is important for Salpeter to reconcile these findings. I should note that current guidelines1,4 on asthma management recommend the addition of a long-acting β-agonist when asthma remains suboptimally controlled with inhaled corticosteroids for reasons outlined above.3 It is beyond the scope of this communication to address possible genetic factors that might influence β-receptor function and how this might be related to the phenomenon of tolerance. It is also important to note that safety concerns with respect to long-acting β-agonist use in asthma management centre on salmeterol use, as indicated in the reference list of the Salpeter debate.5

Given the established role of long-acting β-agonists as maintenance therapy in COPD, I was extremely surprised to see that Salpeter’s position was published without any mention of the Towards a Revolution in COPD Health (TORCH) study6—an issue addressed very appropriately by Dr Aaron. I cannot imagine that Dr Salpeter was not aware of the TORCH trial given its widespread international dissemination. The TORCH trial (despite some limitations) represents perhaps the longest and most robust randomized, placebo-controlled COPD trial to date and clearly demonstrated that salmeterol did not increase mortality compared with placebo. In fact, in the TORCH study,6 salmeterol reduced severe exacerbations requiring hospitalization as compared with placebo. Dr Salpeter should discuss these findings in relationship to her position.

Finally, many of the references included in Salpeter’s discussion include systemic reviews prepared by Salpeter. It is beyond the scope of this communication to outline important shortcomings of such studies, but it is relevant to note that unlike previous retrospective reports of reduced COPD mortality with inhaled corticosteroid use,7,8 the TORCH trial did not show a mortality benefit among patients using fluticasone compared with placebo. This type of discrepancy between the results of randomized, placebo-controlled trials and historical analyses underscores how misleading the latter might be.

I am concerned that Salpeter’s argument is not supported by the best available evidence because the literature review is not comprehensive— a limitation that introduces a serious bias. This might serve only to confuse family physicians who are far too busy looking after patients to carry out comprehensive literature searches of their own.

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