A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD

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Abstract

The aim of this pilot study was to explore the relative efficacy in terms of improvement in symptoms and lung function of combining fluticasone propionate/salmeterol combination (FSC) and tiotropium in patients with severe-to-very severe stable COPD. Ninety patients were randomized to receive 3 months of treatment in one of three treatment groups: (1) FSC 500/50 μg Diskus, 1 inhalation twice daily+placebo Handihaler 1 inhalation once-daily daily; (2) tiotropium 18 μg Handihaler, 1 inhalation once daily+placebo Diskus, 1 inhalation twice daily; (3) FSC 500/50 μg Diskus, 1 inhalation twice daily+tiotropium 18 μg Handihaler, 1 inhalation once-daily daily. Patients attended the clinic before and after 1 month, 2 months, and 3 months of treatment for evaluations of pulmonary function, and dyspnea, which was assessed using a visual analog scale (VAS). Also the supplemental salbutamol use was measured. Eighty-one patients completed the 3-month treatment period: 26 patients receiving FSC, 26 patients receiving tiotropium, and 29 patients receiving FSC+tiotropium. Patients were withdrawn for COPD exacerbation. Improvements in trough FEV1 with all treatments medications were observed by the first month when trough FEV1 had improved significantly above baseline by 74 mL (p<0.05) in the tiotropium group, by 117 mL (p<0.05) in the FSC group and by 115 mL (p<0.05) in FSC+tiotropium group. At the end of the study, trough FEV1 had improved significantly above baseline by141 mL (p<0.05) in the tiotropium group, by 140 mL (p<0.05) in the FSC group and by 186 mL (p<0.05) in FSC+tiotropium group. The difference between FSC and tiotropium appeared to decrease, that between FSC and FSC+tiotropium appeared to increase and that between tiotropium and FSC+tiotropium remained almost similar with study duration. Our results suggest that adding FSC and tiotropium may provide benefits in symptomatic patients with severe-to-very severe stable COPD.

Introduction

The Global Initiative for Obstructive Lung Disease (GOLD) guidelines, which were updated in July 2003, highlighted the role of long-acting bronchodilators in symptomatic management of all stages of chronic obstructive pulmonary disease (COPD) [1]. They also warranted that regular treatment with inhaled corticosteroids is only appropriate for symptomatic COPD patients with an FEV1<50% predicted (Stage III: severe COPD; and Stage IV: very severe COPD) and repeated exacerbations requiring treatment with antibiotics or oral corticosteroids.

Afterwards, Tashkin and Cooper [2] emphasized the advantage of tiotropium on long-acting β2-agonists, and suggested a single long-acting bronchodilator plus an as-needed, short-acting agent in moderate disease (stage II of the GOLD classification [1]), the combination of long-acting anticholinergic and long-acting β2-adrenergic therapy with progression of disease severity, with or without the addition of inhaled corticosteroids for patients with frequent exacerbations or inadequate symptom control despite optimal treatment with bronchodilators alone (stage III/IV). In effect, some papers have documented the advantage for COPD patients in combining long-acting anticholinergic and long-acting β2-adrenergic agents [3], [4], [5], [6]. Other papers [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15] have clearly shown that both long-acting β2-agonists and inhaled corticosteroids have an important role in COPD, which increases when the two drugs are combined in the same therapeutic regimen.

Unfortunately, although tiotropium has entered the market with a wide and solid documentation of its efficacy in stable COPD, the interesting comparison of the combination inhaler with a long acting β2-agonist and an inhaled corticosteroid versus tiotropium has not yet been undertaken [16]. Moreover, we do not know if there is a real advantage in administering a long-acting β2-agonist/inhaled corticosteroid combination together with tiotropium for treating severe-to-very severe COPD.

For this reason, the current study was designed to compare the efficacy and safety of 12 weeks’ therapy with fluticasone propionate/salmeterol combination (FSC) and tiotropium with that of individual treatments alone in patients with severe-to-very severe stable COPD.

Section snippets

Patients and methods

Ninety patients with well-controlled COPD were enrolled. All were 50 years of age or older, and were current or former smokers with a 20 pack-year or more history. Inclusion criteria required a baseline FEV1 of less than 50% of predicted, and a post-bronchodilator FEV1/FVC<70% following salbutamol 400 μg according with the GOLD criteria of severity [1]. Exclusion criteria were as follows: current evidence of asthma as primary diagnosis; unstable respiratory disease requiring oral/parenteral

Results

Eighty-one patients completed the 3-month treatment period: 26 patients receiving FSC, 26 patients receiving tiotropium, and 29 patients receiving FSC+tiotropium. Patients were withdrawn for COPD exacerbation resulting in hospitalization or even treatment with an oral corticosteroid. There was no significant difference among the baseline spirometric values of the three treatment groups (FEV1, p>0.05)).

Significant (p<0.05) improvements in trough FEV1 above baseline with all treatments

Discussion

In this study, the improvement in pulmonary function, expressed as a change in FEV1, did not differ between tiotropium and FSC, but the simultaneous administration of the two treatments provided greater improvements in through FEV1 compared to therapy with the other two therapeutic regimens. This is an intriguing finding, but our data do not allow to establish if the improvements in lung function caused by combining fluticasone propionate/salmeterol and tiotropium in severe-to-very severe COPD

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