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* From the Department of Respiratory Medicine (Dr. Cazzola), Unit of Pneumology and Allergology, Antonio Cardarelli Hospital, Naples, Italy; and the Department of Respiratory Diseases (Dr. Dahl), University Hospital Aarhus, Aarhus, Denmark.
Correspondence to: Mario Cazzola, MD, FCCP, Via del Parco Margherita 24, 80121 Napoli, Italy; e-mail mcazzola{at}qubisoft.it
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Abstract |
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 TOP Abstract IntroductionUse of Long-Acting ß2...Use of Corticosteroids in...Pharmacologic Rationale for...Inhaled Combination Therapy With...Systemic Adverse Effects Using...Need for Further StudiesConclusionsReferences |
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levels, and protease/antiprotease imbalance). They are also able to reduce the total number of bacteria adhering to the respiratory mucosa in a concentration-dependent manner without altering the bacterial tropism for mucosa, and to preserve ciliated cells. Several clinical trials support the concept of inhaled combination therapy with LABAs and corticosteroids in stable COPD patients. This type of therapy not only improves airflow obstruction but also provides clinical benefits, as manifested by sustained reduction in overall symptoms, improvements in health-related quality of life, and reductions in exacerbations. All of these effects are very important because, despite recent advances in our understanding of COPD and its treatment, therapy remains suboptimal for a considerable number of patients.
Key Words: inhaled corticosteroids • long-acting ß2-agonists
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Introduction |
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TOPAbstractIntroductionUse of Long-Acting ß2...Use of Corticosteroids in...Pharmacologic Rationale for...Inhaled Combination Therapy With...Systemic Adverse Effects Using...Need for Further StudiesConclusionsReferences |
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,4 which are generally considered to be important mediators in neutrophil recruitment. Oxidative stress and an imbalance between proteases and antiproteases in the lung also have been implicated in the pathophysiology of the condition.4
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The Global Initiative for Chronic Obstructive Lung Disease guidelines1 are more cautious in suggesting the use of corticosteroids. They state that regular treatment with inhaled corticosteroids (ICSs) should be prescribed only for symptomatic COPD patients with a documented spirometric response to corticosteroids or in those with an FEV1 < 50% of predicted values, and repeated exacerbations requiring treatment with antibiotics and/or oral corticosteroids.
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Use of Long-Acting ß2-Agonists in COPD |
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LABAs can usefully be prescribed for the combined bronchodilator treatment of COPD.1213 In particular, the addition of a LABA to an anticholinergic compound appears to be more efficacious than adding a short-acting ß2-agonist (SABA) in stable patients with COPD.14
In addition to prolonged bronchodilatation, LABAs exert other additive effects that may be of clinical relevance in COPD15 (Table 1 ). For example, data indicate that LABAs can increase the level of cyclic adenosine 3'5'-monophosphate (cAMP) in neutrophils, thereby inhibiting neutrophil adhesion, accumulation, and activation, and inducing apoptosis.15 In particular, salmeterol inhibits neutrophil adhesion to bronchial epithelial cells.16 Formoterol inhibits chemotaxis to platelet-activating factor17 over the concentration range 10–7 to 10–4 mol/L. Neutrophil activation also was attenuated, as evidenced by reductions in the release of superoxide,18 IL-8,19 and bacterial permeability-increasing protein,20 which are not associated with the SABA albuterol. However, in general, these effects were only significant at relatively high concentrations (ie, > 10–6 mol/L) and were not reversed by propranolol, suggesting that they were not mediated by ß2-adrenoceptors. The end result is a possible reduction in the number and activation status of neutrophils in airway tissue and in the airway lumen21 (Table 2 ). LABAs also may decrease the number of neutrophils that adhere to the vascular endothelium at sites of inflammation and may reduce the amount of plasma leakage,22 but the relevance of these findings to COPD patients is unclear. It is noteworthy that glucocorticoids have been shown to increase high-affinity ß-agonist binding in human neutrophils.23 It is also possible that LABAs may increase the peripheral deposition of ICSs, thus enhancing their antiinflammatory activity.24
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Use of Corticosteroids in COPD |
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Impact of Corticosteroids on Inflammation in COPD
Some studies25262728 have indicated that these agents apparently do not exert a major influence on inflammatory cells and mediators in the sputum of stable patients with COPD, but other reports2930313233343536 have suggested that treatment with corticosteroids may induce biological responses that may be associated with changes in some clinical outcomes and endoscopic findings in these patients (Table 3
).
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These findings seem to support the use of ICSs in treating COPD, although long-term treatment with ICSs must be associated with a high risk of adverse systemic effects and involves unnecessary expense.37 Unfortunately, however, clinical trials on the effects of corticosteroids in COPD have reported conflicting results. Consequently, there is considerable controversy concerning the utility of these agents for the long-term treatment of patients with COPD.3738
Clinical Effects of Corticosteroids in COPD
Negative Findings:
Some trials394041 have seemed to indicate that only those patients with an asthmatic component to their disease appear to benefit from corticosteroids. Thus, in the study by Chanez and colleagues,39 12 of 25 unselected patients in whom COPD had been clinically diagnosed responded to a daily oral dose of prednisolone, 1.5 mg/kg body weight, for 15 days, with an increase in FEV1 of at least 12% from the baseline value and an absolute value of 200 mL, measured at the end of treatment. By comparison with nonresponders, responders had a significantly larger number of eosinophils and higher levels of eosinophil cationic protein in their BAL fluid, and the responders also had a thicker reticular basement membrane than the nonresponders. Pizzichini and colleagues40 reported that an improvement in QOL score and FEV1 after a short-term course of prednisone therapy in smokers with chronic obstructive bronchitis was paralleled by a significant reduction in eosinophilia and eosinophil activation, as indicated by sputum eosinophil cationic protein levels, but not by changes in neutrophils or neutrophil proteases. Patients without sputum eosinophilia did not show clinical benefit from short-term prednisone therapy. Nishimura and colleagues,41 in a trial of patients with COPD, found a significant improvement in FEV1 in a minority of patients (5 of 30 patients) receiving 3,000 µg per day beclomethasone dipropionate over a 4-week treatment period. However, some of these responders showed a positive response to the bronchodilator challenge, as well as an elevated serum IgE level or eosinophil count, which is suggestive of the presence of an asthmatic component to their airflow obstruction.
Besides, four large studies (ie, the European Respiratory Society Study on COPD [EUROSCOP]42; the Copenhagen City Lung Study43; the Inhaled Steroids in Obstructive Lung Disease trial44; and the American Lung Health-245) have demonstrated that these agents did not have any worthwhile effect on the rate of decline in FEV1 when asthma was rigorously excluded (Table 4 ), indicating that there is no effect of ICSs on the progressive inflammatory disease process.37
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and IL-8, which are elevated in patients with COPD.37 Moreover, a population-based cohort study46 documented that ICS use after hospitalization for COPD was not found to reduce mortality and morbidity, but this study had only 979 persons and could not estimate the benefit with great precision.
Positive Findings:
Notwithstanding these negative findings, evidence is accumulating to support the therapeutic use of corticosteroids, at least in patients with more advanced COPD.47 For example, it was reported that treatment with an ICS for > 3 months improved prebronchodilator airflow obstruction and oxygenation while decreasing dyspnea in patients with moderate-to-severe COPD.48 Reductions in exacerbation severity were seen in another study49 of patients with moderately severe disease who were treated for 6 months with an inhaled glucocorticoid. The Inhaled Steroids in Obstructive Lung Disease study44 reported that, in patients with moderate-to severe-disease, 3 years of regular treatment with an ICS resulted in fewer exacerbations, a reduced rate of decline in health status, and higher FEV1 values than did placebo treatment. A recent systematic review50 of randomized placebo-controlled trials has demonstrated a beneficial effect of ICSs in reducing rates of COPD exacerbations. These agents also can extend survival in patients with COPD.51 Furthermore, the withdrawal of ICS therapy has been shown to lead to deterioration in ventilatory function and to increased exercise-induced dyspnea in patients with severe irreversible airway obstruction.52
All these findings lend support to the use of ICSs in stable patients with COPD, and a convincing demonstration of the effectiveness of these agents in COPD patients has come from the COPE study (an investigation of COPD in the Department of Palmonology, Enschede, the Netherlands).53 This study showed that the discontinuation of therapy with ICSs was associated with a more rapid onset and a higher risk of recurrence of exacerbations, and with a significant deterioration in aspects of health-related QOL, in the majority of patients.53 However, 40% of subjects in the COPE study experienced no untoward effect from the withdrawal of ICSs.53 This finding indicates that there is an urgent need to identify which subgroups of COPD patients respond well to prolonged inhaled glucocorticoid therapy.
This is not an easy task, since COPD comprises various diseases, which may differ in their pathologic, clinical, and functional features, and in the biological phenomena that cause and maintain airway inflammation. There also may be differences between the baseline disease state (ie, in the absence of a current exacerbation) and the disease state during an acute exacerbation, and differences according to the degree of airway obstruction or history of cigarette smoking. Nevertheless, since very few therapies offer significant benefits to patients with COPD, and since ICSs are potentially beneficial in the treatment of this disease (Table 5 ), the use of these agents remains a possible therapeutic approach to stable patients with COPD. Therefore, until a test is developed that can distinguish potential corticosteroid responders from nonresponders, it is worthwhile giving all patients with COPD a trial (3 to 6 months) of an ICS to determine whether or not they respond.54
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Pharmacologic Rationale for Combining a LABA and an ICS in COPD |
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, and leukotrieneB4, protease/antiprotease imbalance, and mucosal edema), as well as structural changes (eg, glandular hypertrophy and goblet cell hyperplasia) [Fig 2
]. Furthermore, when a LABA is added to an ICS, it has the potential for countering some of the possible negative effects of the corticosteroid.
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Effect of Long-Acting ß-Agonists on Corticosteroids
In addition to the beneficial effects of corticosteroids on LABA activity, LABAs also may enhance the effects of corticosteroids. It has been observed in vitro, using primary human lung fibroblasts and vascular smooth muscle cells, that LABAs induce glucocorticoid receptor (GR) translocation from the cell cytosol to the nucleus and enhance GR-glucocorticoid response element binding in the absence of ligand.59 Preliminary reports in vivo have confirmed this finding.60 It seems likely, therefore, that LABAs may be able to induce GR nuclear translocation and that this may prime the receptor to be more responsive to a concomitant or subsequent challenge with glucocorticoids (Fig 3). LABAs also may increase the sensitivity of the molecular pathways that are utilized by corticosteroids to suppress inflammation, including their action on histone acetylation and deacetylation,6162 or through effects on the activation of transcription factors, such as nuclear factor (NF)-
B.63 Recently, it has been documented64 that the combination of glucocorticoids and LABAs synchronizes the activation of the GR and CCAAT-enhancer binding protein (C/EBP)-, which belongs to a family of transcription factors that are involved in the differentiation process of numerous tissues. This action results in a faster and more prolonged activation of p21(Waf1/Cip1) compared with each drug given alone. In particular, when administered alone, formoterol and budesonide activate the two transcription factors with different potency and kinetics. The combined administration of the two drugs leads to a simultaneous activation of the GR and C/EBP-, resulting in a synergistic stimulatory effect on p21(Waf1/Cip1) promoter activity. Furthermore, when administered together, the drugs are effective at concentrations that are ineffective when either drug is administered alone. These data lend support to the idea that the combined application of the two drugs has a beneficial effect that is greater than that of increasing the dose of either drug alone, at least in asthma.6566
Role of LACA/ICS Interactions in COPD
At present, the role of these interactions in COPD patients cannot be clearly defined. GR does not interact only with C/EBP-, but also affects the action of other transcription factors, such as activating protein 1, cAMP responsive element-binding protein, and the inhibitor of NF-B.67686970 A direct interaction with the GR also has been shown for the signal transducer and activator of transcription 3 and 5.7172 These findings suggest that we must also investigate the possibility of an interaction between glucocorticoids and LABAs at these levels, and evaluate the potential impact on COPD management.
In Vitro Interactions of LABA and ICS Useful in COPD
Examples of interaction between these two classes of drugs that might be useful in COPD patients include the synergistic inhibition by glucocorticoids and LABAs of TNF--induced IL-8 release from cultured human airway smooth muscle cells63 and alveolar macrophages in patients with COPD,73 and the capacity of corticosteroids to counteract the enhancement of LABAs on TNF--induced IL-8 production in cultured human bronchial epithelial cells.74 These effects are mediated through the ß2-adrenoceptor into a signal transduction pathway that does not involve the GR, but other interactions between glucocorticoid and ß2-agonist cannot be excluded.74 The inhibition of transcription factors, such as NF-B, by ß-agonists may occur as a result of an increase in the levels of the inhibitor of NF-B. One study75 of monocytic THP-1 cells stimulated with lipopolysaccharide showed that ß-agonists could inhibit TNF- and IL-8 production, and that the effect was related to increased cytoplasmic concentrations of IB-, possibly through its decreased degradation. Elevated cAMP levels can inhibit NF-B-mediated gene transcription in human monocyte and endothelial cells.76 cAMP regulates cytokine gene expression by induction of the cAMP-mediated transcriptional repressor in human thymocytes.77 The inhibitory effects mediated by induction of the cAMP-mediated transcriptional repressor may be related to its ability to bind (ie, mask) a wide range of cyclic adenosine monophosphate response element and activating protein-1 motifs and/or its ability to inactivate certain transcription complexes via protein-protein interactions.76 In any case, IL-8 is a potent chemoattractant and an activator for neutrophils, and this may result in a persistent inflammatory cycle by establishing a positive feedback loop. Reductions in neutrophil number and function could reduce the severity of disease and the degree of airflow obstruction in patients with COPD.63
Another important finding is the capacity of both ICSs and LABAs to reduce the total number of bacteria adhering to the respiratory mucosa in a concentration-dependent manner without altering the bacterial tropism for mucosa, and to preserve ciliated cells.78 ICSs and LABAs, when administered together at low concentrations, exhibited a synergistic effect with respect to the preservation of ciliated cells, showing a trend toward reduced damage and a significant preservation of the number of ciliated cells compared to either agent alone at the same concentrations. This result may have clinical significance as it is thought that ciliated cells are the most sensitive to damage by bacterial infection.79 It is well-known that airway colonization and chronic infection contribute to progressive pulmonary damage in COPD patients via the action of proinflammatory substances in what is known as the "vicious circle theory"80 (Fig 4 ). Recently, the synergistic effects of salmeterol and fluticasone in human rhinovirus-induced proinflammatory cytokine production have been documented.81 Rhinoviruses are implicated in many acute exacerbations of COPD, perhaps by inducing proinflammatory cytokines.82
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Inhaled Combination Therapy With LABAs and Corticosteroids in Stable COPD Patients |
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Clinical Effects in Adding an ICS to a LABA
The results of a recent small study84 have indicated that the addition of budesonide amplifies the fast onset of action of formoterol, but does not induce systemic effects, in patients with COPD. It has been shown that glucocorticoids act on steroid receptors to increase ß2-adrenoceptor expression by augmenting the rate of ß2-adrenoceptor gene transcription.85 However, the glucocorticoid-induced increase in the accumulation of ß2-adrenoceptor messenger RNA could be detected at 15 min, the maximal accumulation occurred at 2 h, and the glucocorticoid-induced increase in ß2-adrenoceptor messenger RNA returned to the control level by 17 h. In contrast, the increase in the ß2-adrenoceptor values was slower, reaching a maximum between 17 and 24 h. These findings indicate that another type of interaction may underlie the rapid onset of action of combination therapy with formoterol and budesonide. It is likely that a nongenomic action of budesonide might explain this effect. Thus, it is possible that corticosteroids might induce a fall in intracellular Ca2+ that might result, in part, from the inhibition of Ca2+ entry through voltage-gated ion channels.86
The capacity of corticosteroids to prevent homologous down-regulation of ß2-adrenoceptor values and to induce an increase in the rate of synthesis of these receptors may be important when a patient is receiving regular treatment with LABAs. The addition of an ICS to a LABA was initially studied in a 3-month trial that enrolled 80 COPD patients. The association therapy progressively improved lung function over the 3-month period compared to long-acting bronchodilator treatment alone, although the difference was not statistically significant.87 However, the association of therapy with salmeterol (50 µg twice daily) with that with fluticasone (250 or 500 µg twice daily) allowed a significantly greater improvement in lung function after salbutamol therapy alone than salmeterol therapy (50 µg twice daily) alone. It is likely that this effect was due to the prevention of the homologous down-regulation of ß2-adrenoceptors and the induction of an increase in the rate of synthesis of receptors through a process of increased ß2-adrenoceptor gene transcription induced by fluticasone. This may be considered clinically important, because when airway obstruction becomes more severe the preferred therapeutic option is to add a fast-acting inhaled ß2-agonist as rescue medication to produce rapid relief of bronchospasm.
Combination Therapy With Salmeterol/Fluticasone
The value of regular combination therapy with LABAs and corticosteroids delivered via a single inhaler to COPD patients has been documented repeatedly (Table 6
). Since the overall goals for improving clinical outcomes are to reduce symptoms, especially dyspnea, to improve exercise capacity, to reduce exacerbations and the possible need for hospitalization, and to enhance health status,1 the different trials have not only evaluated the efficacy of combination therapy on lung function, but also its impact on these other clinical outcomes.
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A 52-week multicenter, randomized, double-blind, placebo-controlled trial (Trial of Inhaled Steroids and Long-Acting ß2-Agonists [TRISTAN])89 compared the safety and efficacy of the salmeterol, 50 µg twice daily/fluticasone propionate, 500 µg twice daily, combination with that of the individual drugs alone in 1,465 patients with COPD (mean FEV1, 45% predicted). Following a year of treatment with the salmeterol/fluticasone propionate combination, patients with COPD experienced significant and clinically meaningful improvements in health status, as measured by the St. George Respiratory Questionnaire (SGRQ), compared with placebo or fluticasone alone therapy. In addition, patients treated with combination therapy had greater reductions in symptom scores compared with all other treatments, and greater reductions in activity (limitation) scores compared with placebo and fluticasone therapy alone. These findings could have a real impact on the management of COPD. Patients with COPD have significant and measurable decreases in health status, which worsen with disease progression. The fatigue and emotional distress resulting from COPD symptoms such as dyspnea, cough, and phlegm production reduce the ability of patients to work or carry out their normal activities. As there is currently no cure for COPD, the goals of therapy are to prevent symptoms and exacerbations, to preserve lung function, and to maintain health status.
The prevention of exacerbations is a key goal for the effective management of COPD,1 since exacerbations are known to reduce QOL and are cost drivers in the treatment of COPD patients. Therefore, controlling exacerbations is important from both economic and patients’ perspectives. Subgroup analyses of the TRISTAN trial89 have been performed to determine the relative efficacy of the salmeterol, 50 µg twice daily/fluticasone, 500 µg twice daily, combination therapy in reducing exacerbations in COPD patients with FEV1 values of < 50% predicted at baseline (ie, the more severe subgroup) or FEV1 values of 
50% predicted at baseline (ie, the less severe subgroup). Exacerbations were defined a priori as a worsening of COPD symptoms that required treatment with antibiotics, oral corticosteroids, or both. Episodes that required corticosteroid treatment or hospital admission were noted separately. A total of 949 patients (65%) had a prebronchodilator FEV1 of < 50% predicted and were classified into the more severe subgroup, and 513 patients (35%) had FEV1 values of 50% predicted and were classified into the less severe subgroup. During the study, there was a higher incidence of exacerbations in the more severe subgroup compared with the less severe subgroup (567 patients [60%] vs 226 patients [44%], respectively). In the total population, the salmeterol/fluticasone combination treatment produced a significant reduction in the exacerbation rate of 25%, compared with placebo treatment. This reduction was 30% in the more severe subgroup, compared with a 10% reduction in the less severe subgroup. These effects of combination therapy were more pronounced when considering exacerbations requiring oral corticosteroids, which were reduced by 39% in the total population, 43% in the more severe subgroup, and 24% in the less severe subgroup. Salmeterol/fluticasone combination treatment also reduced the number of exacerbations requiring therapy with oral corticosteroids by 19%, compared with therapy with salmeterol alone, in the more severe subgroup. Although twice-daily therapy with salmeterol/fluticasone was effective in significantly reducing the number of exacerbations across both categories of disease severity, there was a trend for a larger reduction in exacerbations and exacerbations requiring oral corticosteroids in the more severe subgroup.
Recently, Dal Negro et al90 have compared therapy with salmeterol, 50 µg twice daily/fluticasone, 250 µg twice daily, via a single inhaler with therapy with salmeterol, 50 µg twice daily, alone and placebo in 52-week study that has enrolled a small group of ICS-naive patients with moderate COPD who had already been treated with theophylline, 400 mg per day, and SABAs on demand. The mean (± SD) number of exacerbations per year decreased from 3.5 ± 0.8 to 1.16 ± 0.75 in the salmeterol/fluticasone group (p < 0.001), from 3.0 ± 0.89 to 2.3 ± 0.81 in the salmeterol group (difference not significant), and from 3.16 ± 1.16 to 4.16 ± 0.75 in the placebo group (difference not significant). Patients receiving salmeterol/fluticasone therapy showed the highest mean improvement in FEV1 (mean increase, 6.6 ± 2.4%) over the baseline pretreatment value (p < 0.001), with FEV1 remaining unchanged after 52 weeks of treatment in the salmeterol group (mean increase, 0.3 ± 0.9%) and with a substantial decrease following placebo therapy (mean decrease, 2.6 ± 0.5; p < 0.001).
Combination Therapy With Formoterol/Budesonide
The effects of formoterol/budesonide combination treatment in COPD patients also have been investigated. In a 12-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study,91 812 adults with moderate-to-severe COPD (mean age, 64 years; mean FEV1, 36% predicted; median time since diagnosis, 5 years) received two inhalations twice daily of formoterol (6 µg)/budesonide (200 µg), budesonide (200 µg) alone, formoterol (6 µg) alone, or placebo. Formoterol/budesonide treatment increased FEV1 by 15% vs placebo, 9% vs budesonide alone, and 1% vs formoterol alone. Significant improvements in morning and evening peak expiratory flow (PEF) values were seen during the 12 months of therapy with formoterol/budesonide compared with all other treatment groups (adjusted mean change from run-in: morning PEF, 24, 16, and 12 L/min vs placebo, budesonide alone, and formoterol alone, respectively; evening PEF, 20, 15, and 11 L/min vs placebo, budesonide alone, and formoterol alone, respectively; all p < 0.001). These lung function improvements were maintained throughout the 12-month study. The improvement in lung function observed after formoterol/budesonide treatment must be considered to be important, but the greater capacity of formoterol/budesonide to decrease the mean total symptom score (p < 0.001 vs placebo; p < 0.001 vs budesonide alone; p = 0.103 vs formoterol alone), to increase the number of days free from shortness of breath by 12% vs placebo (p < 0.001), and to increase the number of awakening-free nights by 14% vs placebo (p < 0.001), each of which is equivalent to approximately 1 extra day/night per week, is likely to have a more substantial impact on health status. Formoterol/budesonide also significantly reduced the use of reliever medication by 1.3 and 0.7 inhalations per 24 h vs placebo and budesonide alone, respectively (both p < 0.001).
The sustained reduction in overall symptoms, including the number of sleep-disturbed nights, in patients with moderate-to-severe COPD was reflected in improvements in health-related QOL. Mean reductions from baseline were –3.9, –1.9, –3.6 and –0.03, respectively, after therapy with formoterol/budesonide, budesonide, formoterol, and placebo.91 Compared with treatment with placebo, treatment with formoterol/budesonide significantly improved the SGRQ total score (p = 0.009), and the symptom domain score (p < 0.001) and impact domain score (p = 0.006). Greater improvements were seen with formoterol/budesonide compared with the other active treatments, but these did not achieve statistical significance.
Formoterol/budesonide therapy also produced clinically significant reductions in the number of exacerbations in patients with moderate-to-severe COPD.91 It reduced the number of severe exacerbations per patient per year by 24% vs placebo therapy (p = 0.035), by 23% vs formoterol therapy (p = 0.043), and by 11% vs budesonide therapy (p = 0.385). Moreover, budesonide/formoterol therapy also reduced the number of mild exacerbations compared with therapy with placebo (62%; p < 0.001), budesonide alone (35%; p = 0.022); and formoterol alone (15%; p = 0.403).
In another randomized, double-blind, active-controlled study, 1,022 patients (mean age, 64 years; FEV1, 0.99 L and 36% predicted) with moderate-to-severe COPD and a history of exacerbations had their condition optimized with therapy with formoterol, 12 µg twice daily, and oral prednisolone prior to being given formoterol (12 µg twice daily)/budesonide (400 µg twice daily), budesonide alone (400 µg twice daily), formoterol alone (12 µg twice daily), or placebo for 1 year.929394 The study, which has not been published yet, was designed to determine whether these treatments prevented COPD exacerbations. Formoterol/budesonide therapy was significantly better than that with long-acting ß2-agonists alone, corticosteroids alone, or placebo in maintaining the lung function improvement achieved after optimization.92 Mean FEV1 in the budesonide/formoterol group remained 14% above the value in the placebo group (p < 0.001), 11% above the value in the budesonide group (p < 0.001), and 5% above the value in the formoterol group (p < 0.01). Morning PEF in the budesonide/formoterol group was 18 L/min above the value in the placebo group (p < 0.001), 15 L/min above the value in the budesonide group (p < 0.001), and 7 L/min above the value in the formoterol group (p < 0.01). The value for evening PEF in the budesonide/formoterol group was 14 L/min above the value in the placebo group (p < 0.001), 12 L/min above the value in the budesonide group (p < 0.001), and 5 L/min above the value in the formoterol group (p = 0.056). For FVC, the value in the formoterol/budesonide group was 9% above that in the placebo group (p < 0.001), 8% above that in the budesonide group (p < 0.001), and 2% above that in the formoterol group. These changes, which occurred soon after treatment began, showed no sign of tachyphylaxis over the 12-month study period. Formoterol/budesonide therapy also improved SGRQ total score.93 In particular, it improved all domain scores vs placebo (p < 0.01), activity score by 3.6 vs budesonide therapy (p < 0.05) and 3.5 vs formoterol therapy (p < 0.05), and impact score by 5.7 vs budesonide (p < 0.001) and 3.7 vs formoterol (p < 0.05).
Interestingly, formoterol/budesonide therapy provided significantly better protection against exacerbations than either LABA alone, corticosteroid steroid alone, or placebo treatment.94 It prolonged the time to the first exacerbation requiring medical intervention (ie, hospitalization and/or the use of oral steroids/antibiotics) compared with therapy with budesonide alone (p < 0.05), formoterol alone (p < 0.01), or placebo (p < 0.05). The median durations to the first exacerbation were as follows: formoterol/budesonide, 254 days; budesonide alone, 178 days; formoterol alone, 154 days; and placebo, 96 days. Formoterol/budesonide therapy also reduced the risk of a first exacerbation by 29% vs placebo (p < 0.01), 30% vs formoterol alone (p < 0.01), and 23% vs budesonide alone (p < 0.05). Fewer exacerbations per patient per year were recorded in the formoterol/budesonide group (1.38) than in the budesonide alone group (1.60), the formoterol-alone group (1.85), or the placebo group (1.80). The reduction in the mean exacerbation rate, compared with placebo, was 11.6% in the budesonide-alone group (difference not significant), 3.0% in the formoterol-alone group (difference not significant), and 24% in the formoterol/budesonide group (p < 0.05). The numerically larger reduction in the formoterol/budesonide group suggests that synergy may occur. Furthermore, formoterol/budesonide treatment significantly reduced the mean number of oral steroid courses by 45% vs placebo (p < 0.001), 28% vs budesonide alone, and 30% vs formoterol alone (both p < 0.05). Budesonide therapy alone reduced the mean number of oral steroid courses by 23% vs placebo (p < 0.05).
Comparison Between Combination Therapy With Salmeterol/Fluticasone and Formoterol/Budesonide
Apparently, there is no substantial difference between salmeterol/fluticasone and formoterol/budesonide in patients with COPD when these combinations are prescribed at the dosages recommended for this pathology, at least after acute administration.95
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Systemic Adverse Effects Using Combination Therapy With LABAs and Corticosteroids |
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Side Effects of Long-term Treatments With High-Dose ICSs
It is well-known that long-term treatments with high-dose ICSs have the potential to produce systemic adverse effects. Patients with COPD may be particularly vulnerable to these systemic effects as they are often elderly, immobile, and have poor nutrition, thus increasing the risk of osteoporosis.37 However, the results of different trials have been variable. In the Lung Health Study,45 a significantly lower bone density in the lumber spine and femur was observed, whereas the EUROSCOP study42 reported no difference between study arms. A recent Cochrane review96 of the effects on bone metabolism in COPD patients reported that there is no evidence of an effect of ICS treatment on bone mineral density or vertebral fracture when given at conventional doses for 2 or 3 years. Higher doses have been associated with biochemical markers of increased bone turnover, but data on bone mineral density and the incidence of fractures at these doses are not available. There is a need for further, even longer term, prospective studies of conventional and high doses of ICSs.
Elderly patients also may have an increased risk of developing cataracts, glaucoma, and diabetes.37 However, no differences in the rates of cataract were seen in the most important long-term trials.4243444549 In the EUROSCOP study,42 10% of patients developed skin bruising compared to 4% in the control group. It is generally accepted that any discussion of the use of high-dose ICSs in patients with COPD must weigh the real risk of systemic side effects against the minimal clinical value provided by this treatment.37
Side Effects of Combination Therapy With Salmeterol/Fluticasone
Although there is clear evidence that the concentration of ICSs can be reduced when combined with ß2-agonists, thus minimizing the risk of side effects,64 there is a real need to establish whether any side effects induced by combination therapy with LABAs and ICSs are outweighed by the clinical advantages.
The combined use of salmeterol and fluticasone propionate in a single formulation provides additive benefit in the treatment of COPD but with comparable safety to the individual components used alone.8889 The safety profile of salmeterol/fluticasone combination treatment was consistent with that observed with the administration of salmeterol plus fluticasone, and was not different from that for the monocomponents alone after a 12-week treatment period.87 The overall adverse event profile of the combination therapy showed no new or unexpected adverse events. There was no evidence that combination treatment with the salmeterol/fluticasone combination was associated with any increased risk of clinically relevant hypothalamic-pituitary-adrenal axis suppression (as assessed by cosyntropin stimulation testing) compared with treatment with fluticasone, salmeterol, or placebo alone. No unexpected cardiovascular effects, as assessed by Holter monitoring and routine ECG, were observed in those patients receiving salmeterol/fluticasone combination treatment compared with patients receiving salmeterol or placebo. In the TRISTAN study,89 all treatments were well-tolerated, although the percentage of patients with oropharyngeal candidiasis was higher in groups receiving fluticasone-containing treatment (placebo treatment, 2%; salmeterol treatment alone, 2%; fluticasone treatment alone, 7%; salmeterol/fluticasone combination treatment, 8%). The majority of patients (96%) had serum cortisol levels that were within the reference range or not significantly changed from baseline. The incidence of skin bruising was low and was comparable among treatment groups (placebo group, 6%; salmeterol alone group, 6%; fluticasone alone group, 7%; salmeterol/fluticasone combination group, 8%). ECG findings were unchanged by therapy.
Side Effects of Combination Therapy With Formoterol/Budesonide
Formoterol/budesonide therapy also was shown to be well-tolerated and to have a safety profile similar to that for therapy with placebo and the monocomponents in patients with moderate-to-severe COPD during 12 months of treatment.91 Most adverse events were reported for respiratory system disorders, particularly COPD (formoterol/budesonide group, 17%; placebo group, 26%; budesonide-alone group, 13%; and formoterol-alone group, 19%). No treatment-related patterns were discernible regarding death (26 deaths) or serious adverse events (number of serious adverse events per 1,000 treatment days: formoterol/budesonide group, 0.8; placebo group, 0.9; budesonide-alone group, 0.7; formoterol-alone group, 0.7). Discontinuations due to disease deterioration were highest in the placebo group (placebo group, 21%; formoterol/budesonide group, 10%; budesonide-alone group, 12%; formoterol-alone group, 14%), while the frequency of discontinuations due to other adverse events was similar in all groups (6 to 8%). No clinically important between-group differences were identified for laboratory or ECG measurements (including QTc prolongation).
Effect of LABA/ICS Combination Therapy on ß2-Adrenoceptor Tolerance
These clinical findings regarding combination treatment with both salmeterol/fluticasone and formoterol/budesonide are important. Tolerance generally develops to systemic ß2-mediated adverse effects, but it has been reported97 that concomitant therapy with inhaled budesonide resensitized the response of cardiac ß2-adrenoceptors to salbutamol in subjects who were receiving regular twice-daily formoterol therapy, which could suggest an increased propensity for the development of systemic ß2-mediated adverse effects. However, a previous study98 has demonstrated that the addition of the recommended dose of formoterol to ICS therapy did not induce significant nonpulmonary consequences, except tremor, which may sometimes be a limiting effect.
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Another important point is the need to relate the short-term response to either ICSs or LABAs to a long-term benefit with inhaled combination therapy. This information is extremely important when we consider that only a positive response to a 2-week course of oral prednisolone (eg, 30 mg per day) or a 6-week course of ICSs (eg, beclomethasone, 500 µg twice daily, or equivalent) would justify the prescription of regular inhaled steroids to COPD patients, and that a limitation on the use of LABAs to patients with a demonstrable response to SABAs also has been recommended.101 It should be noted that formoterol/budesonide combination treatment was effective even in patients who had not been optimized with oral corticosteroid therapy.93
There is also a clear need for a study to examine whether adding a LABA to ICS therapy produces greater improvements in lung function and symptom control than increasing the ICS dose. On the other hand, we also need to know whether adding an ICS to a regular LABA treatment produces greater improvements in lung function and symptom control than increasing the dose of LABA alone. In other words, we need to know whether more integrated medical treatment can be more effective and safer than more aggressive therapy with the individual agent alone. Obviously, it is also important to investigate whether such integrated therapy can change the natural history of COPD.
Information on the economic impact of the various treatment options in COPD is also required. To date, few studies have examined the clinical and economic impact of treatments in COPD patients. One study102 has examined the use of a LABA in COPD patients, and has demonstrated that significant improvements in health and QOL may be obtained at a moderate cost. In another study,103 early intervention with an ICS resulted in significant health gains at a relatively low cost. We do not know whether the higher medication cost of combination therapy with a LABA and ICS, compared with monotherapy, is really justified from a pharmacoeconomic point of view for COPD patients. Looking at the results of studies that have been published in the literature or have been presented as abstracts to relevant international meetings,88899091929394 it is likely that the higher cost of medication is almost completely offset by savings in other costs, such as consultations and hospital admissions for treating exacerbations. Exacerbations are particularly important as they are major cost drivers, the costs varying considerably with the severity of the exacerbation. One study104 found that ß2-agonist therapy in conjunction with corticosteroid therapy resulted in improved health outcomes at a small increase in cost compared to ß2-agonist therapy alone. The addition of an ICS to a ß2-agonist resulted in net additional health-care costs of $201 per patient-year compared to therapy with a ß2-agonist alone, but more than half of the additional cost of adding the ICS was offset by a reduction in the costs of other health-care services. A recent health economic analysis105 comparing formoterol/budesonide therapy (12/400 µg, respectively, bid) with therapy with formoterol (12 µg bid), budesonide (400 µg bid), and placebo was performed on data from a 1-year multinational, prospective, randomized, parallel-group clinical study among 1,022 patients with COPD. The difference in total health-care costs (eg, hospitalizations, emergency department visits, general practitioner visits, study drugs, and concomitant medication use) associated with the different treatments was analyzed using Swedish unit costs. Health-care costs were numerically, but not statistically, significantly lower for formoterol/budesonide therapy (22,893 Swedish kronor [SEK] per year) compared with therapy with formoterol (33,211 SEK per year), budesonide (28,134 SEK per year), and placebo (29,207 SEK per year). The results were robust, as this pattern remained the same when applying UK unit costs (formoterol/budesonide therapy, £1,595 per year; formoterol, £2,577 per year; budesonide, £2,748 per year; placebo, £2,044 per year), and when analyzing subgroups of severe patients (FEV1 < 40% predicted) and European patients separately.
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The capacity of combination treatment to reduce exacerbations is particularly important. As correctly stressed by Calverley and coauthors,89 the low rate of acute episodes might be attributable to regression to the mean in the number of exacerbations or an effect of improved care associated with clinical trials, but suggests that a study of longer duration and with a larger number of participants would be needed to show a difference. Such long-term studies are underway. They will allow us to better evaluate the effect of such combination therapy on disease progression and mortality, and to determine the long-term tolerability of combination therapy in patients with COPD.
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B = nuclear factor-B; PEF = peak expiratory flow; QOL = quality of life; SABA = short-acting ß2-agonist; SEK = Swedish kronor; SGRQ = St. George Respiratory Questionnaire; TNF = tumor necrosis factor; TRISTAN = Trial of Inhaled Steroids and Long-Acting ß2-Agonists Dr. Cazzola has received fees for participating to Advisory Boards from Altana, AstraZeneca, and Novartis, for consulting from Chiesi Farmaceutici and GSK, and for speaking from AstraZeneca, Boehringer Ingelheim, GSK, Menarini Farmaceutici, Novartis, and Pfizer, and research-related grants from GSK. Dr. Dahl has received fees for participating in Advisory Boards from Altana, Boehringer-Ingelheim, and GSK, for speaking from Schering-Plough, MSD, and ALK-Abello, and research-related grants from Astra-Zeneca, GSK, ALK-Abello, Pfizer, Boehringer-Ingelheim, Novartis, Almirall, MSD, and UCB.
Received for publication June 25, 2003. Accepted for publication October 14, 2003.
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