title: The use of long acting β₂-agonists, alone or in combination with inhaled corticosteroids, in chronic obstructive pulmonary disease (COPD): a risk-benefit analysis.
abstract: Chronic obstructive pulmonary disease (COPD) is a slowly progressive, largely non-reversible pulmonary disease which is characterised by airflow limitation. It is one of the few diseases with an increasing mortality rate and by 2020 it is predicted to be the third leading cause of death. The mainstays of current treatment are long acting β₂ agonists (LABAs) coupled with an increasing reliance on inhaled corticosteroids (ICS). Two LABAs (salmeterol and formoterol) are currently licensed for COPD both as monotherapy and in combination with ICS (fluticasone propionate (FP) and budesonide respectively). A comprehensive review of the risk-benefit of these medicines in COPD is provided here which concludes that there is limited efficacy for LABAs in COPD either alone or in combination with ICS and no overall modification of the disease process. However, where directly compared, combination therapy usually provides an advantage over monotherapy. Importantly the apparent effectiveness of treatment may significantly depend upon the outcome measure chosen with some measures possibly underestimating the extent of benefit. ICS benefit may also be greater in those patients who respond to treatment. Set against this benefit are recent concerns that a number of issues related to the clinical trial design such as prior use of ICS and different withdrawal rates between groups may be significantly influencing results. Furthermore there is no evidence of a dose response relationship with regard to ICS dose. A key issue with combination therapy is the excess risk of pneumonia conferred by the use of an ICS in this patient population. This risk does not appear to be proportional to the ICS dose but may differ between FP and budesonide. We conclude that further studies are required to identify the optimal dose of ICS, in terms of both risk and benefit, and to confirm their benefit in steroid naïve patients. Furthermore it will be important to determine whether the risk of pneumonia is apparent with both FP and budesonide and to identify factors which may predict steroid responsiveness in COPD.
authors.affiliation: Medicines and Healthcare Products Regulatory Agency, 151 Buckingham Palace Road, London SW1W9SZ , United Kingdom. Alison.Cave@mhra.gsi.gov.uk
authors.forename: Alison C
authors.initials: AC
authors.lastname: Cave
authors.forename: Martin M
authors.initials: MM
authors.lastname: Hurst
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000420:Albuterol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002985:Clinical Protocols; D002986:Clinical Trials as Topic; D003692:Delayed-Action Preparations / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004363:Drug Utilization / Q000639:trends; D004983:Ethanolamines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D000068759:Formoterol Fumarate; D006801:Humans; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D017063:Outcome Assessment, Health Care; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000401:mortality; D018570:Risk Assessment / Q000379:methods; D000068299:Salmeterol Xinafoate
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D003692:Delayed-Action Preparations; D004983:Ethanolamines; D018727:Muscarinic Antagonists; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000068759:Formoterol Fumarate