Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid.

BACKGROUND: Asthma is a common respiratory disease among both adults and children and short acting inhaled beta-2 agonists are used widely for 'reliever' bronchodilator therapy. Long acting beta-2 agonists (LABA) were introduced as prospective 'symptom controllers' in addition to inhaled corticosteroid 'preventer' therapy (ICS). In this updated review we have included studies in which patients were either not on ICS as a group, or in which some patients, but not all, were on ICS to complement previous systematic reviews of studies where LABA was given in patients uniformly receiving ICS. We have focussed particularly on serious adverse events, given previous concerns about potential risks, especially of death, from regular beta-2 agonist use. OBJECTIVES: This review aimed to determine the benefit or detriment on the primary outcome of asthma control with the regular use of LABA compared with placebo, in mixed populations in which only some were taking ICS and in populations not using ICS therapy. SEARCH STRATEGY: We carried out searches using the Cochrane Airways Group trial register, most recently in October 2005. We searched bibliographies of identified RCTs for additional relevant RCTs and contacted authors of identified RCTs for other published and unpublished studies. SELECTION CRITERIA: All randomised studies of at least four weeks duration, comparing a LABA given twice daily with a placebo, in chronic asthma. Selection criteria to this updated review have been altered to accommodate recently published Cochrane reviews on combination and addition of LABA to ICS therapy. Studies in which all individuals were uniformly taking ICS were excluded from this review. DATA COLLECTION AND ANALYSIS: Two reviewers performed data extraction and study quality assessment independently. We contacted authors of studies for missing data. MAIN RESULTS: Sixty-seven studies (representing 68 experimental comparisons) randomising 42,333 participants met the inclusion criteria. Salmeterol was used as long-acting agent in 50 studies and formoterol fumarate in 17. The treatment period was four to nine weeks in 29 studies, and 12 to 52 weeks in 38 studies. Twenty-four studies did not permit the use of ICS, and forty permitted either inhaled corticosteroid or cromones (in three studies this was unclear). In these studies between 22% and 92% were taking ICS, with a median of 62%. There were significant advantages to LABA treatment compared to placebo for a variety of measurements of airway calibre including morning peak expiratory flow (PEF), evening PEF and FEV1. They were associated with significantly fewer symptoms, less use of rescue medication and higher quality of life scores. This was true whether patients were taking LABA in combination with ICS or not. Findings from SMART (a recently published surveillance study) indicated significant increases in asthma related deaths, respiratory related deaths and combined asthma related deaths and life threatening experiences. The absolute increase in asthma-related mortality was consistent with an increase of around one per 1250 patients treated with LABA for six months, but the confidence intervals are wide (from 700 to 10,000). Post-hoc exploratory subgroups suggested that African-Americans and those not on inhaled corticosteroids were at particular risk for the primary end-point of death or life-threatening asthma event. There was also a suggestion of an increase in exacerbation rate in children. Pharmacologically predicted side effects such as headache, throat irritation, tremor and nervousness were more frequent with LABA treatment. AUTHORS' CONCLUSIONS: LABA are effective in the control of chronic asthma in the "real-life" subject groups included. However there are potential safety issues which call into question the safety of LABA, particularly in those asthmatics who are not taking ICS, and it is not clear why African-Americans were found to have significant differences in comparison to Caucasians for combined respiratory-related death and life threatening experiences, but not for asthma-related death.

Action plans for chronic obstructive pulmonary disease.

BACKGROUND: The effectiveness of action plans as treatment for chronic obstructive pulmonary disease (COPD) is not known. OBJECTIVES: To assess the efficacy of action plans in the management of COPD. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register, CENTRAL, MEDLINE, CINAHL and the National Research Register of Ongoing Trials. We also searched reference lists of identified studies. The search was completed in August 2004. SELECTION CRITERIA: Randomised controlled trials of action plans in COPD. Studies with a primary diagnosis of asthma excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Investigators were contacted for additional information when necessary. Study results were combined in meta-analyses using the Cochrane Collaboration software RevMan. MAIN RESULTS: There was evidence of a positive effect of action plans on self-management knowledge. The mean difference (MD) for recognition of a severe exacerbation was 2.50; 95% confidence interval 1.04 to 3.96, for self-action in severe exacerbations MD 1.50; 95% confidence interval 0.62 to 2.38 and the use of antibiotics MD 6.00; 95% confidence interval 2.68 to 9.32. There was also evidence of a positive effect on the initiation of antibiotics (odds ratio (OR) 10.16; 95% confidence interval 2.02 to 51.09) and/or oral steroids (OR 6.58; 95% confidence interval 1.29 to 33.62). However, there was no evidence of significant effects on healthcare utilisation, health-related quality of life, lung function, functional capacity, symptom scores, mortality, anxiety, or depression. No trials used as outcomes: number of exacerbations, length of exacerbations, or days lost from work. AUTHORS' CONCLUSIONS: This review shows there is evidence that action plans aid people with COPD in recognising and reacting appropriately to an exacerbation of their symptoms via the self-initiation of antibiotics or steroids. Further research needs to be completed with more comprehensive outcomes measures in order to ascertain whether this results in significantly decreased morbidity and/or mortality.

Oral corticosteroids for stable chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common chronic lung disorder, usually related to cigarette smoking, representing a major and increasing cause of morbidity and mortality. It is defined "as a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases". The use of corticosteroids for their anti-inflammatory effects has been suggested. OBJECTIVES: To assess the effects of oral corticosteroids on the health status of patients with stable COPD. SEARCH STRATEGY: Searches of the Cochrane Airways Group Specialised Register and MEDLINE were carried out in December 2003 and 2004. Review articles and bibliographies were searched. SELECTION CRITERIA: Randomised controlled prospective studies in adults with stable COPD ( post-bronchodilator FEV1 <80% of predicted, FEV1/FVC <70%) and a history of smoking, excluding known asthmatics, in which oral steroid use was compared with placebo and use of co-interventions was matched in both groups. DATA COLLECTION AND ANALYSIS: Data was extracted independently by two reviewers. All trials were combined using Review Manager (version 4.2.7). MAIN RESULTS: From 459 titles 24 studies met the inclusion criteria. Treatment lasted three weeks or less in 19 studies, high dose oral steroid was used in 21 studies and subjects had moderate or severe COPD in 15 studies. There was a significant difference in FEV1 after two weeks treatment, WMD 53.30 ml; 95% confidence interval 22.21 to 84.39 favouring oral steroid use compared to placebo when 14 studies with available data (n=396) were combined, with no significant heterogeneity. There was a significant increase in odds for individual patient FEV1 response greater than 20% from baseline with high dose oral steroid treatment compared to placebo, OR 2.71; 95% CI 1.84 to 4.01 (9 studies) . It would be necessary to treat 7 patients (95% CI 5 to 12) with oral corticosteroids to achieve one extra case of increasing FEV1 by more than 20%, with a placebo group risk of 0.13. All differences in health-related quality of life were less than the minimum clinically important difference. There were small statistically significant advantages for functional capacity and respiratory symptom of wheeze with oral steroid treatment but no significant difference in risk of withdrawal from study due to an exacerbation or rate of serious exacerbations over 2 years with low dose oral steroid treatment. There was an increased risk of adverse effects, including increased blood glucose, adrenal suppression and reduced serum osteocalcin. AUTHORS' CONCLUSIONS: There is no evidence to support the long-term use of oral steroids at doses less than 10-15 mg prednisolone though some evidence that higher doses (>/= 30 mg prednisolone) improve lung function over a short period. Potentially harmful adverse effects e.g.. diabetes, hypertension, osteoporosis would prevent recommending long-term use at these high doses in most patients.

Long-acting beta2-agonists in asthma: an overview of Cochrane systematic reviews.

According to major asthma management guidelines, long-acting beta2-agonists (LABAs) should be used only when asthma remains symptomatic in patients already receiving regular inhaled corticosteroids (ICSs). A large Cochrane systematic review provides evidence that LABAs are safe and beneficial in control of asthma; sub-group analyses indicating that this is true when ICSs are used and in their absence. Two other Cochrane systematic reviews have found that LABAs are more effective than regular short-acting beta2-agonists, and are as effective as theophylline with fewer side-effects. These reviews support guidelines in the use of LABA as additional therapy when asthma is inadequately controlled by ICS at moderate dose. However, guidelines may be too conservative, and more studies in stable mild asthma comparing their use and safety with placebo and ICS are required.

Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: COPD is a common condition, mainly related to smoking. The burden of the disease is increasing and it is projected to rank fifth in 2020 for the world-wide burden of disease. Acute exacerbations of COPD, usually related to superimposed infection occur commonly and systemic corticosteroids are widely used in their management in combination with other treatments including antibiotics, oxygen supplementation and bronchodilators. OBJECTIVES: To determine the efficacy of corticosteroids, administered either parenterally or orally, on the outcome in patients with acute exacerbations of COPD. SEARCH STRATEGY: Searches were carried out using the Cochrane Airways Group COPD RCT register with additional studies sought in the bibliographies of randomised controlled trials and review articles. Authors of identified randomised controlled trials were contacted for other published and unpublished studies. The last search was carried out in August 2004. SELECTION CRITERIA: Randomised controlled trials comparing corticosteroids, administered either parenterally or orally, with appropriate placebo. Other interventions e.g. bronchodilators and antibiotics were standardised. Clinical studies of acute asthma were excluded. DATA COLLECTION AND ANALYSIS: Data was extracted independently by two reviewers. Outcome data was sent to authors for verification. All trials were combined using Review Manager (version 4.2.4) for analyses. MAIN RESULTS: Ten studies were identified that fulfilled the inclusion criteria. There were significantly fewer treatment failures within thirty days in patients given corticosteroid treatment, odds ratio 0.48; 95% confidence interval 0.34 to 0.68 and Hazard Ratio 0.78; 95% confidence interval 0.63 to 0.97. It would have been necessary to treat 9 patients (95%CI 6 to 14) with systemic corticosteroids to avoid one treatment failure in this time period. There was no significant difference in mortality. The early FEV1, up to 72 hours, showed a significant treatment benefit, weighted mean difference 140 mls (95% confidence interval 80-200 mls), although this benefit was not found for later time points. There was a significant improvement in breathlessness and blood gases between 6 - 72 hours after treatment. There was an increased likelihood of an adverse drug reaction with corticosteroid treatment, odds ratio 2.29; 95% confidence interval 1.55 to 3.38. Overall one extra adverse effect occurred for every 6 people treated (95% CI 4 to 10). The risk of hyperglycaemia was significantly increased, odds ratio 5.48; 95% confidence interval 1.58 to 18.96. AUTHORS' CONCLUSIONS: Treatment of an exacerbation of COPD with oral or parenteral corticosteroids significantly reduces treatment failure and the need for additional medical treatment . It increases the rate of improvement in lung function and dyspnoea over the first 72 hours, but at a significantly increased risk of an adverse drug reaction.

Inhaled long acting beta agonists for stable chronic asthma.

BACKGROUND: Asthma is a common respiratory disease among both adults and children and short acting inhaled beta-2 agonists are used widely for 'reliever' bronchodilator therapy. Long acting beta-2 agonists were introduced as prospective 'symptom controllers' in addition to inhaled corticosteroid 'preventer' therapy (ICS). OBJECTIVES: This review aimed to determine the benefit or detriment on the primary outcome of asthma control with the regular use of long acting inhaled beta-2 agonists compared with placebo. SEARCH STRATEGY: We carried out searches using the Cochrane Airways Group trial register, most recently in October 2002. We searched bibliographies of identified RCTs for additional relevant RCTs and contacted authors of identified RCTs for other published and unpublished studies. SELECTION CRITERIA: All randomised studies of at least two weeks duration, comparing a long acting inhaled beta-agonist given twice daily with a placebo, in chronic asthma. DATA COLLECTION AND ANALYSIS: Two reviewers performed data extraction and study quality assessment independently. We contacted authors of studies for missing data. MAIN RESULTS: Eighty five studies met the inclusion criteria, 56 parallel group and 29 cross over design. Salmeterol xinafoate was used as long acting agent in 60 studies and formoterol fumarate in 25. The treatment period was two to four weeks in 32 studies, and 12 to 52 weeks in 53 studies. 34 study groups used concurrent inhaled corticosteroid treatment, 21 studies did not permit their use and 35 permitted either inhaled corticosteroid or cromones. There were significant advantages to long acting beta-2 agonist treatment compared to placebo for a variety of measurements of airway calibre including morning peak expiratory flow (PEF) (weighted mean difference (WMD) 26.78 L/min 95%CI 20.36 to 33.20), evening PEF (WMD 19.17 L/min 95%CI 11.63 to 26.73). They were associated with significantly fewer symptoms, less use of rescue medication and higher quality of life scores. The risk of exacerbation was lower in adults using regular inhaled corticosteroids. REVIEWER'S CONCLUSIONS: Long acting beta-2 agonists are effective in the control of chronic asthma, and the evidence supports their use in addition to inhaled corticosteroids, as emphasised in current guidelines. Further research is needed on their use in children under 12 and in mild asthmatics not taking ICS.