title: The impact of inhaled corticosteroid and long-acting beta-agonist combination therapy on outcomes in COPD.
abstract: Chronic obstructive pulmonary disease (COPD) is an under-recognized cause of morbidity and mortality worldwide that imposes an ever increasing burden on the patient and society alike. The disease encompasses multiple structural and functional components of which inflammation is at the core of the disease, affecting the lungs and other organs. Consequently, current treatment strategies are aimed at treating both the symptoms and the pulmonary inflammation underlying the complex pathophysiology of COPD. Smoking cessation is the only intervention currently shown to slow disease progression in COPD and decrease all-cause mortality, aside from lung transplant, lung-volume reduction surgery and oxygen therapy in selective patients. However, this intervention is difficult to achieve and sustain because of the addictive and chronic relapsing nature of cigarette smoking. Pharmacotherapy with bronchodilating agents, including the beta 2-agonists, anticholinergics and methylxanthines, is central to the symptomatic management of all stages of COPD. While inhaled corticosteroids (ICS) are employed to reduce inflammation in more severe patients, their role as stand alone medication in COPD is not well defined. However, increasing evidence suggests that long-acting beta 2-agonists (LABAs) and ICS have complementary and synergistic effects, when delivered as combination therapy from a single inhaler. In this respect, two preparations comprising combinations of salmeterol+fluticasone propionate (SFC) and formoterol+budesonide (FBC) are currently available and employed for treatment of more severe disease. Several large-scale studies in patients with moderate-to-severe COPD have demonstrated that treatment with SFC and FBC leads to significantly greater improvements in lung function, exacerbations, health status and breathlessness, compared with placebo or monotherapy with the component drugs. In the recently published landmark study, Towards a Revolution in COPD Health (TORCH), regular treatment with SFC narrowly missed demonstrating a statistically significant benefit on the reduction in all-cause mortality over 3 years (17.5% reduction in risk, P=0.052), further emphasizing the clinical usefulness of LABA+ICS therapy in COPD. In view of this increasing evidence for the additional effectiveness of LABA+ICS combinations compared with the individual components, and the potential benefits of LABA+ICS on lung function, disease progression and potentially on all-cause mortality, initiation of LABA+ICS combination treatment early in the COPD disease process may be warranted.
  
  
  METHODS
  The studies discussed in this review were identified from systematic searches of Medline and the Cochrane Database, up to October 2007, for articles in English or with English abstracts describing randomized, double-blind, parallel-group/crossover trials of at least 24 weeks' duration. All searches were performed using the terms: chronic obstructive pulmonary disease, COPD, chronic obstructive airway disease, or COAD AND either salmeterol, formoterol, long-acting beta 2-adrenoceptor agonist, fluticasone propionate, budesonide, inhaled corticosteroids, or inhaled glucocorticosteroids. Additional relevant references were identified from the reference lists of selected papers. Only studies that compared a combined LABA+ICS therapy with its monotherapy components were selected for inclusion in this manuscript.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Asthma Clinical Research Center, Baylor College of Medicine, 1504 Taub Loop, Houston, TX 77030, USA. hanania@bcm.tmc.edu <hanania@bcm.tmc.edu>
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Hanania
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006305:Health Status Indicators; D006801:Humans; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D012129:Respiratory Function Tests; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D000318:Adrenergic beta-Agonists; D000893:Anti-Inflammatory Agents