Budesonide/Formoterol vs. Salmeterol/Fluticasone in COPD
Aims: This analysis was designed to provide a comparison between budesonide/formoterol and salmeterol/fluticasone for the relative incidence of pneumonia adverse events, pneumonia serious adverse events and pneumonia-related mortality in patients being treated for chronic obstructive pulmonary disease.
Methods: An initial literature search revealed no suitable head-to-head trials between budesonide/formoterol and salmeterol/fluticasone and therefore a systematic review was conducted to find randomised controlled trials providing data for input into an adjusted indirect comparison of the two combination treatments using placebo as a common comparator. The Bucher adjusted indirect comparison method was used to calculate odds ratios and 95% confidence intervals.
Results: Eight salmeterol/fluticasone trials and four budesonide/formoterol trials were identified as being relevant for the analyses. The proportion of patients experiencing a pneumonia adverse event was significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.47; 95% confidence interval, 0.28–0.80). The proportion of patients experiencing a pneumonia serious adverse event was also significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.41; 95% confidence interval, 0.19–0.86). However, there were too few events to draw any firm conclusions on pneumonia-related mortality.
Conclusions: The results of the indirect comparison support the hypothesis that budesonide/formoterol is associated with fewer pneumonia events than salmeterol/fluticasone in chronic obstructive pulmonary disease. The limitations of the analysis are that the results from a single study, TORCH, have a large bearing on the overall findings of the analysis, and that there is heterogeneity in the length and the dosing of the included studies, although it does not appear that heterogeneity affected the reported results. Another important limitation is the lack of predefined diagnostic standards for pneumonia in these studies.
Inhaled corticosteroid (ICS) treatment is commonly used in chronic obstructive pulmonary disease (COPD), particularly as add-on therapy to long-acting bronchodilators. The addition of ICS treatment has been shown to improve exacerbation outcomes and quality of life in patients with a forced expiratory volume in 1 s (FEV1) value < 50% predicted and a history of repeated exacerbations. ICS treatments are usually combined with a long-acting beta-2 agonist (LABA) in a combination inhaler for convenience of administration. However, the TORCH study results showed a statistically significant increase in the probability of the occurrence of non-fatal pneumonia when patients were treated with a study medication containing fluticasone propionate, relative to other treatments. This observation was also seen in the INSPIRE study, in which the combination inhaler salmeterol/fluticasone was compared with the inhaled long-acting anticholinergic bronchodilator tiotropium.
Subsequently, several groups have performed systematic reviews comparing pneumonia rates in patients being treated for COPD, the results of which can be used to explore whether the increased pneumonia rates reported are a class effect. When analysed at a class level, ICS therapy in patients with COPD has been linked to an increased risk of pneumonia, but not to an increased risk of all-cause mortality or pneumonia-related mortality. However, a recent publication by Sin et al. suggested that inhaled budesonide-containing therapy was not linked to an increased risk of pneumonia adverse events (AEs).
These findings seem to indicate that different ICS therapies have different pharmacological effects, with resulting differences in the rates of pneumonia AEs and serious adverse events (SAEs), but more work is required to better elucidate the relationships. The previous systematic reviews included data from patients with COPD who were treated with an ICS alone or in combination with an LABA. In clinical practice, ICS treatments are usually combined with an LABA in a single inhaler; therefore, this analysis focused on pneumonia with such combination treatments. Specifically, a systematic review was conducted to compare the two most commonly used LABA/ICS combination treatments: budesonide/formoterol (Symbicort®; AstraZeneca, Luton, UK) and salmeterol/fluticasone (Seretide®; GlaxoSmithKline, Uxbridge, UK).
This analysis was designed to address the question: 'In patients with COPD, how does treatment with budesonide/formoterol compare against treatment with salmeterol/fluticasone in terms of the relative incidences of pneumonia AEs, pneumonia SAEs and pneumonia-related mortality?'
Abstract and Introduction
Abstract
Aims: This analysis was designed to provide a comparison between budesonide/formoterol and salmeterol/fluticasone for the relative incidence of pneumonia adverse events, pneumonia serious adverse events and pneumonia-related mortality in patients being treated for chronic obstructive pulmonary disease.
Methods: An initial literature search revealed no suitable head-to-head trials between budesonide/formoterol and salmeterol/fluticasone and therefore a systematic review was conducted to find randomised controlled trials providing data for input into an adjusted indirect comparison of the two combination treatments using placebo as a common comparator. The Bucher adjusted indirect comparison method was used to calculate odds ratios and 95% confidence intervals.
Results: Eight salmeterol/fluticasone trials and four budesonide/formoterol trials were identified as being relevant for the analyses. The proportion of patients experiencing a pneumonia adverse event was significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.47; 95% confidence interval, 0.28–0.80). The proportion of patients experiencing a pneumonia serious adverse event was also significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.41; 95% confidence interval, 0.19–0.86). However, there were too few events to draw any firm conclusions on pneumonia-related mortality.
Conclusions: The results of the indirect comparison support the hypothesis that budesonide/formoterol is associated with fewer pneumonia events than salmeterol/fluticasone in chronic obstructive pulmonary disease. The limitations of the analysis are that the results from a single study, TORCH, have a large bearing on the overall findings of the analysis, and that there is heterogeneity in the length and the dosing of the included studies, although it does not appear that heterogeneity affected the reported results. Another important limitation is the lack of predefined diagnostic standards for pneumonia in these studies.
Introduction
Inhaled corticosteroid (ICS) treatment is commonly used in chronic obstructive pulmonary disease (COPD), particularly as add-on therapy to long-acting bronchodilators. The addition of ICS treatment has been shown to improve exacerbation outcomes and quality of life in patients with a forced expiratory volume in 1 s (FEV1) value < 50% predicted and a history of repeated exacerbations. ICS treatments are usually combined with a long-acting beta-2 agonist (LABA) in a combination inhaler for convenience of administration. However, the TORCH study results showed a statistically significant increase in the probability of the occurrence of non-fatal pneumonia when patients were treated with a study medication containing fluticasone propionate, relative to other treatments. This observation was also seen in the INSPIRE study, in which the combination inhaler salmeterol/fluticasone was compared with the inhaled long-acting anticholinergic bronchodilator tiotropium.
Subsequently, several groups have performed systematic reviews comparing pneumonia rates in patients being treated for COPD, the results of which can be used to explore whether the increased pneumonia rates reported are a class effect. When analysed at a class level, ICS therapy in patients with COPD has been linked to an increased risk of pneumonia, but not to an increased risk of all-cause mortality or pneumonia-related mortality. However, a recent publication by Sin et al. suggested that inhaled budesonide-containing therapy was not linked to an increased risk of pneumonia adverse events (AEs).
These findings seem to indicate that different ICS therapies have different pharmacological effects, with resulting differences in the rates of pneumonia AEs and serious adverse events (SAEs), but more work is required to better elucidate the relationships. The previous systematic reviews included data from patients with COPD who were treated with an ICS alone or in combination with an LABA. In clinical practice, ICS treatments are usually combined with an LABA in a single inhaler; therefore, this analysis focused on pneumonia with such combination treatments. Specifically, a systematic review was conducted to compare the two most commonly used LABA/ICS combination treatments: budesonide/formoterol (Symbicort®; AstraZeneca, Luton, UK) and salmeterol/fluticasone (Seretide®; GlaxoSmithKline, Uxbridge, UK).
This analysis was designed to address the question: 'In patients with COPD, how does treatment with budesonide/formoterol compare against treatment with salmeterol/fluticasone in terms of the relative incidences of pneumonia AEs, pneumonia SAEs and pneumonia-related mortality?'
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