PURPOSE: COPD is the only major chronic cause of death that is increasing globally. Our objective was to investigate whether salmeterol (SAL) and fluticasone propionate (FP) combined in a single formulation (FSC) could significantly impact survival.
METHODS: 6112 (intention to treat population) patients with moderate to severe COPD (<60% predicted FEV1) from 42 countries (mean age 65yrs, 76% males, 44% predicted post-bronchodilator FEV1; 3.7% reversibility to albuterol as % of predicted, 43% current smokers) were randomised to receive FP 500mcg (n=1534), SAL 50mcg (n=1521), FSC 500/50 (n=1533), or placebo (n=1524) bid via Diskus(R)in a 3 year double-blind study. Two interim analyses were carried out by an independent data monitoring board. The primary analysis was log-rank analysis of time to all-cause mortality (FSC vs placebo) at 156 weeks.
RESULTS: FSC reduced the risk of dying at any time by 18% compared with placebo (HR 0.825, 95% CI 0.68-1.00; p=0.052 adjusted for interim analyses; absolute rates 15.2% vs 12.6%; absolute reduction 2.6%). Supportive secondary analysis confirmed the result (Cox's proportional hazards: HR 0.811, 95% CI 0.67-0.98; p=0.031). Component arms were not significantly different from placebo (SAL HR 0.88, 95% CI 0.73-1.06; FP HR 1.06, 95% CI 0.89-1.27). There was also a trend to reduction in COPD-related mortality with FSC vs placebo (6.0% vs 4.7%, HR 0.78, 95% CI 0.57-1.06; p=0.107). No significant interaction with baseline FEV1 by GOLD stage was found (<30%, 30-50% and >50%; p= 0.402). Further, there were no interactions by smoking status, age, sex or BMI (all p>0.12).
CONCLUSION: FSC improves survival in this population of patients with COPD vs placebo over 3 years. This effect was not seen with the components alone.
CLINICAL IMPLICATIONS: FSC is the first intervention since oxygen and smoking cessation therapies that has been shown to improve survival in COPD. The improvement was comparable to that produced by statins in cardiovascular mortality, and represents an important step forward in the management of COPD.
DISCLOSURE: Peter Calverley, Grant monies (from industry related sources) This study is funded by a grant from GlaxoSmithKline. Departments of BC, CJ, PC, GF, JV, receive funding from GlaxoSmithKline for specific research projects; Employee JA and JY are employees of GlaxoSmithKline; Consultant fee, speaker bureau, advisory committee, etc. PJ, PC, BC, GF, CJ, JV and NP have been speakers and consultants for companies including GSK, Pfizer, AstraZeneca, Boehringer Ingelheim; Other JV's wife was until 2004 a GSK employee; Product/procedure/technique that is considered research and is NOT yet approved for any purpose, FSC 500/50 dose currently unlicensed for COPD in US.