Dear Editor

In his letter, Dr Devoy is questioning the strength of the conclusion in our publication regarding the clinical efficacy of salmeterol on dyspnea, quality of life and reductions of exacerbations. We had stated that the effects with long-acting ß2-adrenergic bronchodilators on COPD exacerbations and on other health outcomes has provided inconsistent results [1] We note that Dr Devoy’s argument is mostly based on two studies published very recently, one shortly before [2] and one at the same time [3] of our study, on one paper in press and four abstracts. We believe it is optimal to restrict comments only to the evidence arising from published full peer-reviewed papers. The recent study by Mahler et al.[2] referenced by Dr Devoy showed no difference between salmeterol and placebo regarding dyspnea, exacerbations, or health status. A similar lack of efficacy on these health outcomes was observed by Rennard et al.[4] Calverley et al.[3] showed slightly less exacerbations, but no effects with regard to quality of life and dyspnea. These findings do not change, but rather reinforce, our opinion that salmeterol treatment in COPD gave inconsistent results.

Dr Devoy further questions the definition of exacerbations of COPD used in our analysis, suggesting the use of health utilization or a combination of major and minor symptoms. There is no general consensus and a range of definitions have been used in the literature. Indeed, in at least three studies describing the effect of salmeterol on exacerbations, no definition at all is provided.[2,4,5] In our study, the definition of exacerbation has been pre-specified, includes a minimal time frame (3 days) to eliminate the misinterpretation of day to day variability and requires a minimum of two symptoms (new onset or increase in symptoms). Using this exacerbation definition, 88-91% of COPD exacerbations in this trial required the use of either antibiotics or oral corticosteroids or both, indicating that the clinicians involved considered the vast majority of these flare-ups to be clinically significant. The reduction seen with tiotropium in our study is also supported by the reductions in COPD exacerbations and associated hospitalizations observed in one-year trials, the later outcome (hospitalizations) being an important outcome with little debate.[6,7]

In conclusion the improvements in dyspnea, quality of life and exacerbations with tiotropium have been consistently demonstrated [6,7] whereas these outcomes with salmeterol are either absent or inconsistent at best.

References

(1) Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58:399-404 .

(2) Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T, Shah T. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Resp Crit Care Med 2002;166:1084-1091.

(3) Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvid A, Anderson J, Maden C. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2003;361:449-456.

(4) Rennard SI, Anderson W, ZuWallack R, Broughton J, Bailey W, Friedman M, Wisniewski M, Rickard K. Use of a long-acting inhaled B2-adrenergic agonist, salmeterol xinfoate in patients with chronic obstructive pulmonary disease. Am J Resp Crit Care Med2001;163:1087-92.

(5) Chapman KR, Arvidsson P, Chuchalin AG, Dhillon DP, Faurschou P, Goldstein RS, Kuipers AF. The addition of salmeterol 50 mcg bid to anticholinergic treatment in patients with COPD: a randomized placebo controlled trial. Can Respir J 2002;9:178-185.

(6) Casaburi R, Mahler DA, Jones PW, Wanner A, San Pedro G, ZuWallack RL, Menjoge SS, Serby CW, Witek TJ. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19(2):217-24.

(7) Vincken W, van Noord JA, Greefhorst APM, Bantje ThA, Kesten S, Korducki L, Cornelissen PJG. Improved health outcomes in patients with COPD during 1 yr’s treatment with tiotropium. Eur Respir J 2002;19(2):209-16.

Dear Editor

We would like to comment on strength of conclusions of the recent publication by Dr Brusasco et al,[1] particularly that no consideration is given to how the results compare to the balance of evidence that exists.

The paper’s conclusions imply superior efficacy of tiotropium over salmeterol in patients with COPD by emphasising endpoints in which tiotropium shows a difference compared with placebo, but salmeterol does not. However, as this combined analysis fails to show clinically relevant differences between salmeterol and tiotropium we believe such conclusions to be somewhat exaggerated.

We note that for certain endpoints, salmeterol in this analysis failed to show a difference compared with placebo. While these results were disappointing, they are not reflective of the wealth of evidence that exists from previous placebo-controlled studies of up to 12 months duration with salmeterol. These studies show significant improvements in lung function, quality of life, breathlessness and reliever use, and exacerbations compared with placebo/usual therapy.[2-9]

A recent meta-analysis of nine double-blind studies including over 3500 patients with COPD confirms that salmeterol has a significant and sustained bronchodilator effect with no evidence of tolerance compared with placebo, and significantly reduces the risk of exacerbations (22% reduction compared with placebo/usual therapy).[9,10]

Lastly, and we feel importantly, this study and analysis introduces a new definition of COPD exacerbations with no explanation for the rationale, nor a justification for the validity of this. Previous studies have either used health utilisation [2,11] (event measured is sufficiently important for the patient to seek medical help and the physician to feel the patient needs treatment), or exacerbations are defined by a combination of major and minor symptoms.[12,13] By not using any of these definitions, it is difficult for the clinician to evaluate any relative efficacy of tiotropium in reducing exacerbations, compared to other therapeutic agents currently available.

In conclusion, it is important to reflect on whether the findings of this study are supported by what we already know. We feel it is important to state that for this publication and for the results seen for salmeterol, this is clearly not the case.

References

(1) Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58:399-404.

(2) Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361:449–456.

(3) Mahler DA, Wire P, Horstman et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:1084-1091.

(4) Hanania NA, Knobil K, Watkins M, Wire P, Yates J, Darken P. The efficacy and safety of fluticasone propionate 250mcg/salmeterol 50mcg combined in the Diskus inhaler for the treatment of chronic obstructive pulmonary disease. Chest 2003;in press.

(5) Stockley RA, Chopra N. Salmeterol, added to usual therapy is an effective bronchodilator over 12 months of treatment in chronic obstructive pulmonary disease (COPD). Eur Respir J 2002;20 (suppl 38):241s.

(6) Stockley RA, Davies EA, Sondhi S, Rice L. Salmeterol provides sustained health status improvement over 12 months in patients with COPD. Eur Respir J 2002;20(suppl 38):241s.

(7) Jones PW, Bosh TK. Quality of life changes in COPD patients treated with salmeterol. Am J Respir Crit Care Med 1997;155:1283–1289.

(8) Boyd G, Morice AH, Pounsford JC, Siebert M, Peslis N, Crawford C. An evaluation of salmeterol in the treatment of chronic obstructive disease. Eur Respir J 1997;10(4):815–821.

(9) Stockley RA, Whitehead PJ, Williams MK, Hagan G. Serevent 50mcg bid significantly reduces moderate-severe exacerbations in patients with all severities of COPD. Am J Respir Crit Care Med 2003;167(7):A949.

(10) Stockley RA, Whitehead PJ, Williams MK, Hagan G. Serevent 50mcg bid significantly increases trough FEV1 in COPD up to 12 months without loss of effect. Am J Respir Crit Care Med 2003;167(7):A95.

(11) Szafranski W, Cukier A, Ramirez A et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003;21:74-81.

(12) Anthonisen RN, Manfreda J, Warren CPW, Hershfield ES, Harding GKM, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196-204.

(13) Seemungal TAR, Donaldson GC, Bhowmik A et al. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1608-1613.