Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C for the Trial of Inhaled Steroids and long-acting beta2 agonists study group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2003;361:449-56
Overall Study Question
These investigators compared placebo with salmeterol alone, fluticasone alone and the combination (Advair) in patients with chronic obstructive pulmonary disease. Outcomes evaluated included FEV1, use of relief medication, symptom scores of breathlessness and cough, night time awakenings, number of acute exacerbations and a health status questionnaire – St. George’s Respiratory Questionnaire (SGRQ).
1465 patients with COPD with a mean age of 63. Seventy three percent were male, 50% were smokers, 50% had a previous use of inhaled corticosteroids and 40% had a previous use of a long acting beta-agonist.
All patients stopped there inhaled corticosteroids and long acting beta-agonist for two weeks if they were receiving these agents. Patients were then randomized to placebo, 50 mcg salmeterol, 500 mcg fluticasone or the combination twice daily.
The trial was continued for 52 weeks.
Shaded areas indicate statistically different from the combination group
No differences in side effects were found between the groups.
How does this study contribute to the drug therapy of patients patients with COPD?
This study suggests the combination of salmeterol and fluticasone provides little if any clinically important benefit over the use of the use of single agent therapy alone. Only cough and breathlessness were statistically significantly different from the combination therapy when compared to either single agent therapies alone. The absolute differences were 0.1 on a 3 point scale. The clinical importance of this is debatable as there was no clinically important differences between the groups in the SGRQ; including placebo.
Interestingly, the authors concluded that “because inhaled long-acting ß2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function, with no greater risk of side-effects than that with use of either component alone, this combination treatment should be considered for patients with COPD” and on editorialist stated “the TRISTAN study reported … in today’s Lancet is an important addition which should drive the clinical approach to COPD” and that “the combination was superior to individual components for these other features, among which were exacerbation frequency, symptoms of dyspnoea and cough, supplemental medication use, and health status (although not all of the differences were statistically significant)”
Other studies of inhaled corticosteroids have shown little or no clinical benefit in patients with COPD