Meta-analysis: Anticholinergics, but not β-agonists, reduce severe exacerbations and respiratory mortality in COPD

Cornell University, Итак, New York, United States
Journal of General Internal Medicine (Impact Factor: 3.42). 11/2006; 21(10):1011-9. DOI: 10.1111/j.1525-1497.2006.00507.x
Source: PubMed


Anticholinergics and beta2-agonists have generally been considered equivalent choices for bronchodilation in chronic obstructive pulmonary disease (COPD).
To assess the safety and efficacy of anticholinergics and beta2-agonists in COPD.
We comprehensively searched electronic databases from 1966 to December 2005, clinical trial websites, and references from selected reviews. We included randomized controlled trials of at least 3 months duration that evaluated anticholinergic or beta2-agonist use compared with placebo or each other in patients with COPD.
We evaluated the relative risk (RR) of exacerbations requiring withdrawal from the trial, severe exacerbations requiring hospitalization, and deaths attributed to a lower respiratory event.
Pooled results from 22 trials with 15,276 participants found that anticholinergic use significantly reduced severe exacerbations (RR 0.67, confidence interval [CI] 0.53 to 0.86) and respiratory deaths (RR 0.27, CI 0.09 to 0.81) compared with placebo. Beta2-agonist use did not affect severe exacerbations (RR 1.08, CI 0.61 to 1.95) but resulted in a significantly increased rate of respiratory deaths (RR 2.47, CI 1.12 to 5.45) compared with placebo. There was a 2-fold increased risk for severe exacerbations associated with beta2-agonists compared with anticholinergics (RR 1.95, CI 1.39 to 2.93). The addition of beta2-agonist to anticholinergic use did not improve any clinical outcomes.
Inhaled anticholinergics significantly reduced severe exacerbations and respiratory deaths in patients with COPD, while beta2-agonists were associated with an increased risk for respiratory deaths. This suggests that anticholinergics should be the bronchodilator of choice in patients with COPD, and beta2-agonists may be associated with worsening of disease control.

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Available from: Shelley R Salpeter
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    • "The results of the meta-analysis of Salpeter et al in 2006 conflict with our result [15]. They reported that 21 (1.6%) of 1320 beta-agonist administered patients had respiratory-related death, which is significantly higher than mortality of 0.7% (8 of 1084) among beta-agonist non-administered patients. "
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    ABSTRACT: Background Long-acting beta-agonists were one of the first-choice bronchodilator agents for stable chronic obstructive pulmonary disease. But the impact of long-acting beta-agonists on mortality was not well investigated. Methods National Emphysema Treatment Trial provided the data. Severe and very severe stable chronic obstructive pulmonary disease patients who were eligible for volume reduction surgery were recruited at 17 clinical centers in United States during 1988–2002. We used the 6–10 year follow-up data of patients randomized to non-surgery treatment. Hazard ratios for death by long-acting beta-agonists were estimated by three models using Cox proportional hazard analysis and propensity score matching were measured. Results The pre-matching cohort was comprised of 591 patients (50.6% were administered long-acting beta-agonists. Age: 66.6 ± 5.3 year old. Female: 35.4%. Forced expiratory volume in one second (%predicted): 26.7 ± 7.1%. Mortality during follow-up: 70.2%). Hazard ratio using a multivariate Cox model in the pre-matching cohort was 0.77 (P = 0.010). Propensity score matching was conducted (C-statics: 0.62. No parameter differed between cohorts). The propensity-matched cohort was comprised of 492 patients (50.0% were administered long-acting beta-agonists. Age: 66.8 ± 5.1 year old. Female: 34.8%. Forced expiratory volume in one second (%predicted) 26.5 ± 6.8%. Mortality during follow-up: 69.1%). Hazard ratio using a univariate Cox model in the propensity-matched cohort was 0.77 (P = 0.017). Hazard ratio using a multivariate Cox model in the propensity-matched cohort was 0.76 (P = 0.011). Conclusions Long-acting beta-agonists reduce mortality of severe and very severe chronic obstructive pulmonary disease patients.
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    • "Furthermore, the mortality for all causes and for respiratory causes in the salmeterol arm was lower, though not signifi cantly, than in the placebo arm. This large 3-year trial, therefore, in line with the previously mentioned shorter clinical trials, does not support the conclusion of the meta-analysis undertaken by Salpeter et al (2006b) whereas it supports the regular use of a LABA in COPD patients. The TORCH study, similarly to the previous clinical trial on salmeterol and SFC, did not report any adverse event related to the treatment with the LABA. "
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    ABSTRACT: COPD is characterized by progressive airflow obstruction which does not fully reverse to inhaled or oral pharmacotherapy. The management of patients with COPD has taken a totally new direction over the past 20 years, thank to the use of novel therapies aimed to improve and modify the natural history of COPD. Long-acting bronchodilators, including long-acting beta2-agonists (LABAs), were introduced several years ago in order to enhance improvements in lung function, health status related quality of life, and reduce the rate of exacerbations. These effects can be boosted by the combination of LABAs with long-acting anticholinergic, and/or with inhaled corticosteroids. Inhaled LABAs are commonly well tolerated although adverse effects such as tremor and palpitations are occasionally troublesome.
    Full-text · Article · Feb 2008 · International Journal of COPD
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    • "Four randomized placebo-controlled trails of the use of formoterol in COPD have demonstrated and peak expiratory flow improved lung function (FEV1 rates) and symptoms (symptom score and exacerbations) and decreased need for rescue medication (Dahl et al 2001; Aalbers et al 2002; Rossi et al 2002; Campbell et al 2005). Anticholinergic agents may reduce severe exacerbations and mortality in COPD when compared with beta2-agonists (Salpeter et al 2006). "
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    ABSTRACT: Formoterol is a beta2-agonist that has both short and long acting bronchodilator effects. Beta2-agonists used as bronchodilators have been synthesized as racemates that comprise (R,R) and (S,S)-enantiomers. Compounds that are beta2-selective derive their bronchodilator effect from an interaction between the (R,R)-enantiomer and the beta2-adrenoceptor. Arformoterol is the (R,R)-enantiomer and is distinguished from the more commonly used racemic (RR/S,S)-diasteriomer of formoterol. Overall literature on the use of arformoterol in COPD is very preliminary. There is some in vitro data that demonstrate significant bronchodilation and inhibition of inflammation with arformoterol, and these effects may be more pronounced than those caused by racemic formoterol. There are limited clinical trial data that demonstrate that arformoterol produces significant improvement in lung function in COPD; however, many of the subjects involved had marked baseline airway reversibility. Arformoterol has been very well tolerated in clinical trials and could potentially be used only once every 24 hours (due to its prolonged effect). It can only be given in nebulized form. Arformoterol can potentially be given with other inhaled medications.
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