| Design | Double-blind, placebo-controlled RCT, four arms |
|---|---|
| Treatment | Salmeterol 50 microg plus fluticasone propionate 500 microg twice daily in a single inhaler |
| Control | Placebo, salmeterol alone, or fluticasone alone |
| Population | 6112 patients with COPD followed for three years |
| Follow-up | 3 years |
| Primary endpoint | Death from any cause, combination therapy versus placebo |
| Result | All-cause mortality 12.6% with combination versus 15.2% with placebo (HR 0.825, 95% CI 0.681 to 1.002, p=0.052) — a 17.5% relative reduction that missed the prespecified significance threshold. Exacerbations fell from 1.13 to 0.85 per year and health status and spirometry improved (p<0.001). Pneumonia was reported in 19.6% on combination therapy versus 12.3% on placebo (p<0.001). |
| Secondary endpoints | Exacerbation frequency, health status, spirometry |
The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance. There were significant benefits in all other outcomes among these patients.
The trial authors, in the published abstract
The trial that established both halves of the inhaled steroid argument in COPD: real reduction in exacerbations, real excess of pneumonia. The p=0.052 mortality result is the most over-interpreted number in respiratory medicine — it is not evidence of benefit, and it is not evidence of absence of benefit. The pneumonia signal recurred in IMPACT and shapes the case for LABA/LAMA first (FLAME).
Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007 Feb 22;356(8):775-89.