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Inhaled Therapy and Mortality in COPD

Combination therapy with fluticasone plus salmeterol was associated with reduced mortality, but the difference was just short of statistical significance.

It is unclear whether inhaled corticosteroids and long-acting ß-agonists reduce mortality in patients with chronic obstructive pulmonary disease. In this industry-sponsored international trial (known as TORCH), researchers randomized more than 6000 COPD patients to receive inhaled salmeterol plus fluticasone (Advair 50/500), salmeterol (Serevent) alone, fluticasone (Flovent) alone, or placebo — all given twice daily. Enrollment criteria included a history of smoking, FEV₁ <60% of predicted, and reversibility with albuterol that was less than 10% of the patient's predicted FEV₁.

At 3 years, the following outcomes were noted:

• All-cause mortality (the primary endpoint) was 12.6% with combined therapy, 13.5% with salmeterol, 16.0% with fluticasone, and 15.2% with placebo. The difference between combined therapy and placebo did not quite reach significance (P=0.052).
  
• Combined therapy and salmeterol alone, but not fluticasone alone, significantly reduced the rate of hospitalization for COPD exacerbation.
  
• Pneumonia occurred more frequently in the two groups receiving fluticasone (about 19%) than in the placebo or salmeterol-alone groups (about 13%).
  
• Combined therapy was superior to both monotherapies — which, in turn, were superior to placebo — in reducing the number of moderate or severe COPD exacerbations and in mitigating the declines in FEV₁ and health status scores.
  

Comment: In this study of COPD patients, inhaled therapy with fluticasone plus salmeterol was associated with a 2.6 percentage-point reduction in mortality that just failed to reach statistical significance. In several respects, salmeterol monotherapy appeared superior to fluticasone monotherapy — an interesting outcome given the current controversy about potential harms with long-acting ß-agonists in asthma. How to interpret this trial will be debated for some time; for now, an editorialist concludes that combination therapy offers several advantages (but not clear-cut mortality reduction), that steroid monotherapy "should not be advocated," that salmeterol monotherapy "appears to be safe," and that the increased incidence of pneumonia with fluticasone requires further investigation.

— Allan S. Brett, MD

Published in Journal Watch General Medicine February 21, 2007

Citation(s):

Calverley PMA et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007 Feb 22; 356:775-89.

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• Medline abstract (Free)

Rabe KF. Treating COPD — The TORCH trial, P values, and the dodo. N Engl J Med 2007 Feb 22; 356:851-4.

• Original article (Subscription may be required)
• Medline abstract (Free)