Elsevier

The Lancet

Volume 361, Issue 9356, 8 February 2003, Pages 449-456
The Lancet

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Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(03)12459-2Get rights and content

Summary

Background

Inhaled longacting β2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease (COPD), whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status. We postulated that a combination of these treatments would be better than each component used alone.

Methods

1465 patients with COPD were recruited from outpatient departments in 25 countries. They were treated in a randomised, double-blind, parallel-group, placebo-controlled study with either 50 μg salmeterol twice daily (n=372), 500 μg fluticasone twice daily (n=374), 50 μg salmeterol and 500 μg fluticasone twice daily (n=358), or placebo (n=361) for 12 months. The primary outcome was the pretreatment forced expiratory volume in 1 s (FEV1) after 12 months treatment' and after patients had abstained from all bronchodilators for at least 6 h and from study medication for at least 12 h. Secondary outcomes were other lung function measurements, symptoms and rescue treatment use, the number of exacerbations, patient withdrawals, and disease-specific health status. We assessed adverse events, serum cortisol concentrations, skin bruising, and electrocardiograms. Analysis was as predefined in the study protocol.

Findings

All active treatments improved lung function, symptoms, and health status and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pretreatment FEV1 significantly more than did placebo (treatment difference 133 mL, 95% CI 105–161, p<0·0001), salmeterol (73 mL, 46–101, p<0·0001), or fluticasone alone (95 mL, 67–122, p<0·0001). Combination treatment produced a clinically significant improvement in health status and the greatest reduction in daily symptoms. All treatments were well tolerated with no difference in the frequency of adverse events, bruising, or clinically significant falls in serum cortisol concentration.

Interpretation

Because inhaled long-acting β2 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.

Published online Jan 28, 2003 http://image.thelancet.com/extras/02art5284web.pdf

Introduction

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity worldwide. It is characterised by chronic progressive symptoms, airflow obstruction,1, 2 and impaired health status,3 which is worse in those who have frequent, acute episodes of symptom exacerbation.4 The aim of treatment is to prevent and control symptoms and exacerbations while improving lung function and health status.5, 6 Any new treatment approach should be judged against these endpoints.

Inhaled long-acting β2 agonists improve airflow obstruction, control of symptoms, and health status in patients with COPD over 3–4 months7, 8, 9, 10, 11, 12, 13, 14 and have several potentially beneficial non-bronchodilatory effects.15 The role of inhaled corticosteroids in COPD management is less certain.16 These drugs do not change the rate of decline in lung function,17, 18, 19, 20 but can increase postbronchodilator forced expiratory volume in 1 s (FEV1),17, 19 reduce the number of exacerbations,17, 18 and slow the rate of decline in health status.17 Whether long-acting β2 agonists and inhaled corticosteroids in combination will result in treatment effects that are better than those associated with either drug alone is not clear. Furthermore, we do not know whether improvements seen in the short term will be maintained during sustained treatment. To test our hypothesis, we did a randomised controlled trial over 1 year of combination treatment with salmeterol and fluticasone versus each of the components and placebo.

Section snippets

Patients

We recruited outpatients with COPD from 196 hospitals in 25 countries. All patients had a baseline FEV1 before bronchodilation that was 25–70% of that predicted, an increase of less than 10% of predicted FEV1 30 min after inhaling 400 μg salbutamol, and a prebronchodilator FEV1/forced vital capacity (FVC) ratio of 70% or less.21 Patients also had a history of at least 10 pack-years of smoking (ie, equivalent to 20 cigarettes smoked per day for 10 years), of chronic bronchitis, at least one

Results

We recruited 1974 patients from 196 centres in 25 countries, of whom 1465 received treatment (figure 1). Demographic data, baseline characteristics, and compliance did not differ between groups, but the withdrawal rate did. Significantly fewer patients withdrew from the combination and fluticasone groups than from placebo and salmeterol groups (Table 1). The main reason for differences in withdrawal was presence of adverse events. Patients in the combination group had a slightly higher mean

Discussion

Ideally, any new treatment for COPD should improve one or more of the endpoints outlined in the GOLD (Global Initiative for Chronic Obstructive Lung Disease) management protocol25—symptoms, health status, and frequency of exacerbation. These effects should be sustained and better than those of existing treatments. Many treatment trials in COPD have only lasted 3–6 months,18, 26 or if longer, they have compared only one active treatment with placebo. Our trial has compared commonly prescribed

References (33)

  • N Siafakas et al.

    Optimal assessment and management of chronic obstructive pulmonary disease (COPD)

    Eur Respir J

    (1995)
  • Global Initiative for Chronic Obstructive Lung Disease (GOLD)

    Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: NHLBI/WHO workshop report, NIH publication 2701

    (2001)
  • S Rennard et al.

    Use of a long-acting inhaled beta2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (2001)
  • G Boyd et al.

    An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD)

    Eur Respir J

    (1997)
  • M Taccola et al.

    Salmeterol versus slow-release theophylline in patients with reversible obstructive pulmonary disease

    Monaldi Arch Chest Dis

    (1999)
  • P Jones et al.

    Quality of life changes in COPD patients treated with salmeterol

    Am J Respir Crit Care Med

    (1997)
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