Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease

Summary

Background

The efficacy of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD) remains controversial because of a lack of placebo-controlled studies. We compared the effect of inhaled fluticasone propionate with placebo in the treatment of patients with COPD.

Methods

We used a randomised, double-blind, placebo-controlled design. We enrolled from 13 European countries, New Zealand, and South Africa, 281 outpatient current or ex-smokers, aged between 50 and 75 years. They had a forced expiratory volume in 1 s (FEV₁) of between 35% and 90% of predicted normal values, a ratio of FEV₁ to forced vital capacity of 70% or less and bronchodilator reversibility of less than 15%, as well as a history of chronic bronchitis. Patients were randomly assigned fluticasone propionate 500 μg (n=142) or placebo (n=139) twice daily via a metered-dose inhaler for 6 months. The main outcome measures were the number of patients who had at least one exacerbation by the end of treatment, the number and severity of exacerbations, clinic lung function, diary card symptoms and peak expiratory flow and 6 min walking distance.

Findings

51 (37%) patients in the placebo group compared with 45 (32%) in the fluticasone propionate group had had at least one exacerbation by the end of treatment (p=0·449). Significantly more patients had moderate or severe exacerbations in the placebo group than in the fluticasone propionate group (86% vs 60%, p<0·001). Diary-card and clinic morning peak expiratory flows improved significantly in the fluticasone propionate group (p<0·001, p=0·048, respectively), as did clinic FEV₁ (p<0·001), forced vital capacity (p<0·001), and mid-expiratory flow (p=0·01). Symptom scores for median daily cough and sputum volume were significantly lower with fluticasone propionate treatment than with placebo (p=0·004 and p=0·016, respectively). At the end of treatment, patients on fluticasone propionate had increased their 6 min walking distance significantly more than those on placebo (p=0·032). Fluticasone propionate was tolerated as well as placebo, with few adverse effects and without a clinically important effect on mean serum cortisol concentration.

Interpretation

Fluticasone propionate may be of clinical benefit in patients with COPD over at least 6 months. Inhaled corticosteroids may have an important role in the long-term treatment of COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is a heterogeneous group of disorders, consisting of chronic bronchitis, emphysema, and small-airways disease, which lead to progressive, largely irreversible airflow obstruction that may be accompanied by airway hyper-responsiveness.¹ COPD is characterised by cough, sputum production, and breathlessness associated with airflow obstruction. Patients generally have a progressive deterioration in lung function, which leads to substantial problems in their general health and quality of life, and eventual repiratory failure and early death.² COPD is one of the leading causes of death worldwide, with an increasing prevalence and mortality rate.³

The major risk factor is cigarette smoking, but the pathogenesis of COPD is not clear. Airway inflammation seems to be involved, as it is in asthma.⁴ Corticosteroids have proved to be valuable in the treatment of asthma and may, therefore, be beneficial in patients with COPD, although their role in the management of COPD is less well established.⁵ Short-term inhaled corticosteroids in COPD have had little effect on airway hyper-responsiveness or forced expiratory volume in 1 s (FEV₁), at doses that improve asthma.6, 7, 8, 9 Longer-term treatment has shown some benefit on lung function, but studies generally have not distinguished between COPD and asthma.10, 11 Exacerbations are an important clinical feature of asthma and COPD, and inhaled corticosteroids decrease their frequency and severity in asthma,10, 12 but this effect has not been proved in COPD.

Fluticasone propionate is effective and safe for patients with all grades of severity of asthma,12, 13, 14, 15 and has a therapeutic ratio superior to other inhaled corticosteroids.12, 16, 17 No clinical studies have assessed the effect of fluticasone propionate in COPD, although one study did show a reduction in neutrophil chemotactic activity and in the proteinase-antiproteinase ratio in the sputum of COPD patients treated for 8 weeks.¹⁸

We used a multicentre, double-blind, randomised, placebo-controlled design to investigate the efficacy and safety of fluticasone propionate in COPD patients.