Long-acting beta(2)-agonist in addition to tiotropium versus either tiotropium or long-acting beta(2)-agonist alone for chronic obstructive pulmonary disease

BackgroundLong-acting bronchodilators comprising long-acting beta(2)-agonists and the anticholinergic agent tiotropium are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and long-acting beta2-agonists for the treatment of chronic obstructive pulmonary (COPD) disease are unclear.ObjectivesTo assess the relative effects of treatment with tiotropium in addition to long-acting beta(2)-agonist compared to tiotropium or long-acting beta2-agonist alone in patients with chronic obstructive pulmonary disease.Search methodsWe searched the Cochrane Airways Group Specialised Register of trials and clinicaltrials.gov up to January 2012.Selection criteriaWe included parallel group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to long-acting beta2-agonist against tiotropium or long-acting beta2-agonist alone for patients with chronic obstructive pulmonary disease.Data collection and analysisTwo review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials.Main resultsFive trials were included in this review, mostly recruiting participants with moderate or severe chronic obstructive pulmonary disease. All of them compared tiotropium in addition to long-acting beta(2)-agonist to tiotropium alone, but only one trial additionally compared a combination of the two types of bronchodilator with long-acting beta2-agonist (formoterol) alone. Two studies used the long-acting beta2-agonist indacaterol, two used formoterol and one used salmeterol.Compared to tiotropium alone (3263 patients), treatment with tiotropium plus long-acting beta2-agonist resulted in a slightly larger improvement in the mean health-related quality of life (St George's Respiratory Questionnaire (SGRQ) MD -1.61; 95% CI -2.93 to -0.29). In the control arm, tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with both treatments the improvement was a fall of 6.1 units from baseline (on average). High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).The secondary outcome of pre-bronchodilator FEV1 showed a small mean increase with the addition of long-acting beta2-agonist (MD 0.07 L; 95% CI 0.05 to 0.09) over the control arm, which showed a change from baseline ranging from 0.03 L to 0.13 L on tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There were wide confidence intervals around these outcomes and moderate heterogeneity for both exacerbations and withdrawals.The results from the one trial comparing the combination of tiotropium and long-acting beta2-agonist to long-acting beta2-agonist alone (417 participants) were insufficient to draw firm conclusions for this comparison.Authors' conclusionsThe results from this review indicate a small mean improvement in health-related quality of life for patients on a combination of tiotropium and long-acting beta2-agonist compared to tiotropium alone, but it is not clear how clinically important this mean difference may be. Hospital admission and mortality have not been shown to be altered by adding long-acting beta(2)-agonists to tiotropium. There were not enough data to determine the relative efficacy and safety of tiotropium plus long-acting beta2-agonist compared to long-acting beta2-agonist alone. There were insufficient data to make comparisons between the different long-acting beta2-agonists when used in addition to tiotropium

Long-acting beta2-agonists for chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a respiratory disease that causes progressive symptoms of breathlessness, cough and mucus build-up. It is the fourth or fifth most common cause of death worldwide and is associated with significant healthcare costs.Inhaled long-acting beta2-agonists (LABAs) are widely prescribed to manage the symptoms of COPD when short-acting agents alone are no longer sufficient. Twice-daily treatment with an inhaled LABA is aimed at relieving symptoms, improving exercise tolerance and quality of life, slowing decline and even improving lung function and preventing and treating exacerbations. OBJECTIVES: To assess the effects of twice-daily long-acting beta2-agonists compared with placebo for patients with COPD on the basis of clinically important endpoints, primarily quality of life and COPD exacerbations. SEARCH METHODS: We searched the Cochrane Airways Group trials register, ClinicalTrials.gov and manufacturers' websites in June 2013. SELECTION CRITERIA: Parallel, randomised controlled trials (RCTs) recruiting populations of patients with chronic obstructive pulmonary disease. Studies were required to be at least 12 weeks in duration and designed to assess the safety and efficacy of a long-acting beta2-agonist against placebo. DATA COLLECTION AND ANALYSIS: Data and characteristics were extracted independently by two review authors, and each study was assessed for potential sources of bias. Data for all outcomes were pooled and subgrouped by LABA agent (formoterol 12 μg, formoterol 24 μg and salmeterol 50 μg) and then were separately analysed by LABA agent and subgrouped by trial duration. Sensitivity analyses were conducted for the proportion of participants taking inhaled corticosteroids and for studies with high or uneven rates of attrition. MAIN RESULTS: Twenty-six RCTs met the inclusion criteria, randomly assigning 14,939 people with COPD to receive twice-daily LABA or placebo. Study duration ranged from three months to three years; the median duration was six months. Participants were more often male with moderate to severe symptoms at randomisation; mean forced expiratory volume in 1 second (FEV1) was between 33% and 55% predicted normal in the studies, and mean St George's Respiratory Questionnaire score (SGRQ) ranged from 44 to 55 when reported.Moderate-quality evidence showed that LABA treatment improved quality of life on the SGRQ (mean difference (MD) -2.32, 95% confidence interval (CI) -3.09 to -1.54; I(2) = 50%; 17 trials including 11,397 people) and reduced the number of exacerbations requiring hospitalisation (odds ratio (OR) 0.73, 95% CI 0.56 to 0.95; I(2) = 10%; seven trials including 3804 people). In absolute terms, 18 fewer people per 1000 were hospitalised as the result of an exacerbation while receiving LABA therapy over a weighted mean of 7 months (95% CI 3 to 31 fewer). Scores were also improved on the Chronic Respiratory Disease Questionnaire (CRQ), and more people receiving LABA treatment showed clinically important improvement of at least four points on the SGRQ.The number of people who had exacerbations requiring a course of oral steroids or antibiotics was also lower among those taking LABA (52 fewer per 1000 treated over 8 months; 95% CI 24 to 78 fewer, moderate quality evidence).Mortality was low, and combined findings of all studies showed that LABA therapy did not significantly affect mortality (OR 0.90, 95% CI 0.75 to 1.08; I(2) = 21%; 23 trials including 14,079 people, moderate quality evidence). LABA therapy did not affect the rate of serious adverse events (OR 0.97, 95% CI 0.83 to 1.14; I(2) = 34%, moderate quality evidence), although there was significant unexplained heterogeneity, especially between the two formoterol doses.LABA therapy improved predose FEV1 by 73 mL more than placebo (95% CI 48 to 98; I(2) = 71%, low quality evidence), and people were more likely to withdraw from placebo than from LABA therapy (OR 0.74, 95% CI 0.69 to 0.80; I(2) = 0%). Higher rates of withdrawal in the placebo arm may reduce our confidence in some results, but the disparity is more likely to reduce the magnitude of difference between LABA and placebo than inflate the true effect; removing studies at highest risk of bias on the basis of high and unbalanced attrition did not change conclusions for the primary outcomes. AUTHORS' CONCLUSIONS: Moderate-quality evidence from 26 studies showed that inhaled long-acting beta2-agonists are effective over the medium and long term for patients with moderate to severe COPD. Their use is associated with improved quality of life and reduced exacerbations, including those requiring hospitalisation. Overall, findings showed that inhaled LABAs did not significantly reduce mortality or serious adverse events

Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis.

BACKGROUND: Pharmacological therapy for chronic obstructive pulmonary disease (COPD) is aimed at relieving symptoms, improving quality of life and preventing or treating exacerbations.Treatment tends to begin with one inhaler, and additional therapies are introduced as necessary. For persistent or worsening symptoms, long-acting inhaled therapies taken once or twice daily are preferred over short-acting inhalers. Several Cochrane reviews have looked at the risks and benefits of specific long-acting inhaled therapies compared with placebo or other treatments. However for patients and clinicians, it is important to understand the merits of these treatments relative to each other, and whether a particular class of inhaled therapies is more beneficial than the others. OBJECTIVES: To assess the efficacy of treatment options for patients whose chronic obstructive pulmonary disease cannot be controlled by short-acting therapies alone. The review will not look at combination therapies usually considered later in the course of the disease.As part of this network meta-analysis, we will address the following issues.1. How does long-term efficacy compare between different pharmacological treatments for COPD?2. Are there limitations in the current evidence base that may compromise the conclusions drawn by this network meta-analysis? If so, what are the implications for future research? SEARCH METHODS: We identified randomised controlled trials (RCTs) in existing Cochrane reviews by searching the Cochrane Database of Systematic Reviews (CDSR). In addition, we ran a comprehensive citation search on the Cochrane Airways Group Register of trials (CAGR) and checked manufacturer websites and reference lists of other reviews. The most recent searches were conducted in September 2013. SELECTION CRITERIA: We included parallel-group RCTs of at least 6 months' duration recruiting people with COPD. Studies were included if they compared any of the following treatments versus any other: long-acting beta2-agonists (LABAs; formoterol, indacaterol, salmeterol); long-acting muscarinic antagonists (LAMAs; aclidinium, glycopyrronium, tiotropium); inhaled corticosteroids (ICSs; budesonide, fluticasone, mometasone); combination long-acting beta2-agonist (LABA) and inhaled corticosteroid (LABA/ICS) (formoterol/budesonide, formoterol/mometasone, salmeterol/fluticasone); and placebo. DATA COLLECTION AND ANALYSIS: We conducted a network meta-analysis using Markov chain Monte Carlo methods for two efficacy outcomes: St George's Respiratory Questionnaire (SGRQ) total score and trough forced expiratory volume in one second (FEV1). We modelled the relative effectiveness of any two treatments as a function of each treatment relative to the reference treatment (placebo). We assumed that treatment effects were similar within treatment classes (LAMA, LABA, ICS, LABA/ICS). We present estimates of class effects, variability between treatments within each class and individual treatment effects compared with every other.To justify the analyses, we assessed the trials for clinical and methodological transitivity across comparisons. We tested the robustness of our analyses by performing sensitivity analyses for lack of blinding and by considering six- and 12-month data separately. MAIN RESULTS: We identified 71 RCTs randomly assigning 73,062 people with COPD to 184 treatment arms of interest. Trials were similar with regards to methodology, inclusion and exclusion criteria and key baseline characteristics. Participants were more often male, aged in their mid sixties, with FEV1 predicted normal between 40% and 50% and with substantial smoking histories (40+ pack-years). The risk of bias was generally low, although missing information made it hard to judge risk of selection bias and selective outcome reporting. Fixed effects were used for SGRQ analyses, and random effects for Trough FEV1 analyses, based on model fit statistics and deviance information criteria (DIC). SGRQ SGRQ data were available in 42 studies (n = 54,613). At six months, 39 pairwise comparisons were made between 18 treatments in 25 studies (n = 27,024). Combination LABA/ICS was the highest ranked intervention, with a mean improvement over placebo of -3.89 units at six months (95% credible interval (CrI) -4.70 to -2.97) and -3.60 at 12 months (95% CrI -4.63 to -2.34). LAMAs and LABAs were ranked second and third at six months, with mean differences of -2.63 (95% CrI -3.53 to -1.97) and -2.29 (95% CrI -3.18 to -1.53), respectively. Inhaled corticosteroids were ranked fourth (MD -2.00, 95% CrI -3.06 to -0.87). Class differences between LABA, LAMA and ICS were less prominent at 12 months. Indacaterol and aclidinium were ranked somewhat higher than other members of their classes, and formoterol 12 mcg, budesonide 400 mcg and formoterol/mometasone combination were ranked lower within their classes. There was considerable overlap in credible intervals and rankings for both classes and individual treatments. Trough FEV1 Trough FEV1 data were available in 46 studies (n = 47,409). At six months, 41 pairwise comparisons were made between 20 treatments in 31 studies (n = 29,271). As for SGRQ, combination LABA/ICS was the highest ranked class, with a mean improvement over placebo of 133.3 mL at six months (95% CrI 100.6 to 164.0) and slightly less at 12 months (mean difference (MD) 100, 95% CrI 55.5 to 140.1). LAMAs (MD 103.5, 95% CrI 81.8 to 124.9) and LABAs (MD 99.4, 95% CrI 72.0 to 127.8) showed roughly equivalent results at six months, and ICSs were the fourth ranked class (MD 65.4, 95% CrI 33.1 to 96.9). As with SGRQ, initial differences between classes were not so prominent at 12 months. Indacaterol and salmeterol/fluticasone were ranked slightly better than others in their class, and formoterol 12, aclidinium, budesonide and formoterol/budesonide combination were ranked lower within their classes. All credible intervals for individual rankings were wide. AUTHORS' CONCLUSIONS: This network meta-analysis compares four different classes of long-acting inhalers for people with COPD who need more than short-acting bronchodilators. Quality of life and lung function were improved most on combination inhalers (LABA and ICS) and least on ICS alone at 6 and at 12 months. Overall LAMA and LABA inhalers had similar effects, particularly at 12 months. The network has demonstrated the benefit of ICS when added to LABA for these outcomes in participants who largely had an FEV1 that was less than 50% predicted, but the additional expense of combination inhalers and any potential for increased adverse events (which has been established by other reviews) require consideration. Our findings are in keeping with current National Institute for Health and Care Excellence (NICE) guidelines

De Haas-Van Alphen Effect and Power Spectrum of Electrons of Conductivity of Some Hezagonal Metals under Pressure

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