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Original Research: COPD |

Safety of Long-Acting β-Agonists in Stable COPD*: A Systematic Review FREE TO VIEW

Gustavo J. Rodrigo, MD; Luís J. Nannini, MD; Roberto Rodríguez-Roisin, MD
Author and Funding Information

*From the Departamento de Emergencia (Dr. Rodrigo), Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay; Sección Neumonología (Dr. Nannani), Hospital G. Baigorria, Universidad Nacional de Rosario, Santa Fe, Argentina; and Servei de Pneumologia (Institut del Tòrax) [Dr. Rodríguez-Roisin], Hospital Clínic, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS Ciber Enfermedades Respiratorias), Universitat de Barcelona, Barcelona, Spain.

Correspondence to: Gustavo J. Rodrigo, MD, Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Av. 8 de Octubre 3020, Montevideo 11600, Uruguay; e-mail: gurodrig@adinet.com.uy



Chest. 2008;133(5):1079-1087. doi:10.1378/chest.07-1167
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Background: Some studies have suggested that use of long-acting β2-agonists (LABAs) leads to an increased risk for adverse events in patients with stable COPD. The purpose of this review was to assess the safety, and secondarily the efficacy of LABAs.

Methods: The authors conducted a systematic review with metaanalysis of randomized clinical trials (≥ 1 month in duration) in the published literature that have compared LABAs with placebo or anticholinergics in stable poorly reversible and reversible COPD.

Results: MEDLINE, EMBASE, CINAHL, and the Cochrane Controlled Trials Register were searched to identify 27 studies. LABAs reduced severe exacerbations compared with placebo (relative risk [RR], 0.78; 95% confidence interval [CI], 0.67 to 0.91). There was no significant difference between LABA and placebo groups in terms of respiratory deaths (RR, 1.09; 95% CI, 0.45 to 2.64). Use of LABAs with inhaled corticosteroids reduced the risk of respiratory death compared with LABAs alone (RR, 0.35; 95% CI, 0.14 to 0.93). Patients receiving LABAs showed significant benefits in airflow limitation measures, health-related quality of life, and use of rescue medication. Finally, tiotropium decreased the incidence of severe COPD exacerbations compared with LABAs (RR, 0.52; 95% CI, 0.31 to 0.87).

Conclusion: This review supports the beneficial effects of the use of LABAs in patients with stable moderate-to-severe COPD, and did not confirm previous data about an increased risk for respiratory deaths. Also, our analysis suggests the superiority of tiotropium over LABAs for the treatment of stable COPD patients.

Figures in this Article

Treatment guidelines12 indicate that inhaled bronchodilators are the standard of care in COPD patients. Short-acting inhaled bronchodilators (short-acting β2-agonists [SABAs] and anticholinergics) are recommended for the relief of symptoms on an as-needed basis, whereas long-acting inhaled bronchodilators (long-acting β2-agonists [LABAs] or tiotropium) in a regularly scheduled regimen or short-acting agents are recommended as first-line therapy in symptomatic patients with moderate-to-severe COPD. Although the consensus with regard to the central role of inhaled bronchodilators as first-line therapy is unanimous worldwide with the highest scientific level of evidence, several questions remains concerning different aspects of management. Of particular concern is the evidence that LABA use could lead to an increased risk for adverse events and respiratory deaths in patients with asthma and COPD.4 However, previous reviews36 presented very restrictive inclusion criteria and several shortcomings that affect the validity of their conclusions. Thus, these reviews studied only cardiovascular effects from patients with asthma and COPD that compare SABAs and LABAs,3 included only poorly reversible COPD patients,56 and did not assess outcomes such as COPD exacerbations requiring withdrawal and respiratory mortality.56 Additionally, one review4 performed its analysis on redundant data. Consequently, to clarify these issues, we performed a systematic review to assess the safety, as the primary end point outcome, and secondarily the efficacy of the use of LABAs in patients with COPD compared with placebo and anticholinergics.

Search Strategy and Selection Criteria

The search was conducted using three strategies. Firstly, we queried MEDLINE (1966 to April 2007), EMBASE (1974 to April 2007), and CINAHL (1982 to April 2007) databases using the following medical subject headings, full text, and key word terms: long-acting β2 adrenoceptor agonist OR salmeterol OR formoterol OR eformoterol AND COPD OR COPD OR chronic bronchitis OR emphysema. Secondly, a search of the Cochrane Controlled Trials Register (CENTRAL; first quarter 2007) was completed using the above search strategy to identify any additional trials. Thirdly, references from included studies, reviews, and texts were searched for citations. Trials published solely in abstract form were excluded.

Included studies met the following criteria: (1) target population: adult patients aged > 35 years with stable COPD satisfying American Thoracic Society/European Respiratory Society, or Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria12; (2) intervention: inhaled LABAs (delivered via metered-dose inhaler or dry powder) vs placebo or inhaled ipratropium bromide or inhaled tiotropium (with or without the additional use of SABAs); patients treated with LABAs as monotherapy or with a combination of LABAs and inhaled corticosteroids (ICS) were included in the analysis; (3) length of treatment: studies of at least 4 weeks in duration; (4) design: randomized (parallel group or cross-over) controlled trials without language restriction; and (5) primary outcomes: severe COPD exacerbations (all episodes that required withdrawal from the trial or hospitalization), all-cause mortality (death from any cause), and respiratory deaths (deaths due to a respiratory event such as COPD exacerbation, pneumonia or respiratory failure). Secondary outcome measures were mean change from baseline of postbronchodilator FEV1, mean change from baseline in the St. George Respiratory Questionnaire (SGRQ),,7 and need for rescue bronchodilator.

Data Abstraction and Validity Assessment

Titles, abstracts, and citations were independently reviewed by two reviewers (G.J.R. and L.J.N.). Both reviewers independently assessed studies for inclusion based on the criteria for population, intervention, study design, and outcomes. Any disagreement over study inclusion was resolved by consensus. The methodologic quality of each trial was evaluated using the 5-point scale (0 = worst to 5 = best) describe by Jadad et al.8

Data Analysis

Binary outcomes were pooled using common relative risks (RRs) and 95% confidence intervals (CIs). Trials that reported no respiratory deaths were included in an analysis of the absolute risk difference. If pooled-effect estimates for dichotomous outcomes were significantly different between groups, we calculated the number needed to treat (NNT). For continuous outcomes, the weighted mean difference (WMD) [for variables using the same unit of measure] and 95% CI were calculated. The results of the subgroups were compared using the interaction test.9We tested for heterogeneity by using the DerSimonian and Laird Q statistic. We also measured heterogeneity by using the I2 test.10 Values of 25%, 50%, and 75% represent low, moderate, and high heterogeneity, respectively. When heterogeneity was low, the data were combined by mean of a fixed-effects model11; otherwise, a random-effects model was used. We performed a sensitivity analysis using the method of combine data (fixed vs random model). Subgroup analysis included study duration, reversibility to salbutamol (> 15% reversibility of FEV1 after a small dose of SABA), use of different LABAs, and concomitant use of ICS. The fail-safe N test was used to adjust for publication bias,12 which computes the number of negative trials that would be needed to reverse the overall probability obtained from our combined test to a value greater than our critical value for statistical significance. A p value < 0.05 using a two-tailed test was taken as being of significance. The metaanalysis was performed using software (Review Manager 4.2, Cochrane Review Manager; Cochrane Collaboration; Oxford, UK), and analyses were intention-to-treat when possible.

A total of 27 randomized controlled trials1340 met inclusion criteria and were selected for analysis (Fig 1 ). Two studies42 were excluded from analysis because they included results for patients enrolled in previous trials. Thus, Brusasco et al16 presented combined results of Donohue et al41 and a similar unpublished trial, and van Noord et al37 reported the same data from the study of Rutten van Molken et al.42 All trials were of good quality (Jadad score > 2). The main characteristics of these studies are described in Table 1 . Data for 20,527 patients (72% male) with 26,389 patient-years of follow-up were available for metaanalysis (mean age, 63.3 ± 10.3 years). All studies enrolled patients with stable COPD that met moderate-to-severe GOLD criteria,1 (stages 2 and 3) [average baseline FEV1, 43% of predicted]. Eighteen studies,1315,2023,2526,2829,3233,3539 allowed the concomitant use of ICS (percentage of patient's range, 12 to 88%). Details on studies according to different comparisons and outcomes are shown in Table 2 .

Exacerbations

Fourteen studies comparing LABA with placebo evaluated the incidence of severe COPD exacerbations. The overall cumulative incidence was 7.5% in the LABA group and 10.8% in the placebo group, with a significant exacerbation rate reduction of 3.3% (95% CI, 1.9 to 4.8) [Fig 2 ]. The RR reduction was similar with a fixed model (RR, 0.78; 95% CI, 0.67 to 0.91) or a random model (RR, 0.80; 95% CI, 0.69 to 0.92). The NNT was 30 (95% CI, 20 to 52). The fail-safe N test, which is the number of unpublished studies with null results needed to negate the current finding, was 23. When examining trials in which patients showed > 15% reversibility to salbutamol, there were no significant differences in the effects of formoterol vs salmeterol on exacerbations. When examining trials using salmeterol, there were no significant differences in effects between studies enrolling patients with poorly reversible and reversible obstruction (Table 3 ). Also, we did not find a significant difference between patients treated with LABAs vs placebo with the two arms exposed or not exposed to ICS. Because many studies1819,27,3031,34 allowed the concomitant use of ICS, we performed an additional analysis including only trials that truly examine monotherapy without ICS (2,447 patients). Thus, like the previous analysis, there was no significant difference between the LABA-without-ICS group compared with the same intervention with concomitant ICS group.

Mortality

Thirteen studies14,1617,20,30,3235 reported all-cause mortality during the length of protocol. The analysis of the trials that reported one or more deaths did not show significant differences between LABA and placebo (RR, 0.90; 95% CI, 0.76 to 1.06; p = 0.20; I2 = 0%; fixed-effects model). When trials,23,27,29,31 that did not report any death were incorporated in the analysis, LABAs patients presented an absolute risk reduction of 1.6% (95% CI, 0.8 to 2.4) [LABAs mortality rate, 4.9%; placebo, 6.5%]. There were no significant differences between salmeterol and formoterol subgroups and patients exposed or not exposed to ICS (Table 4 ).

Of a total of 12 studies, only 5 studies14,1618,34 displayed at least one or more respiratory deaths. Data from one study34 was obtained by personal communication with the authors. The remaining studies20,23,27,2932 did not present deaths. The analysis of the first five trials did not find significant difference between LABA and placebo groups (Fig 3 ) [RR, 1.09; 95% CI, 0.45 to 2.64; random model]. The conclusion was unchanged when we use a fixed model (RR, 1.11; 95% CI, 0.84 to 1.47). The fail-safe N was 14. When data from the studies that did not report any respiratory deaths were included in the analysis, there was no difference in the absolute risk reduction between both groups (RR, − 0.1%; 95% CI, − 0.7 to 0.5). There were 98 reported respiratory deaths in 4,316 patients in the LABAs group and 88 deaths in 3,733 patients in the placebo group (LABA and placebo rates, 2.27% and 2.35%, respectively). There were no significant differences between salmeterol vs placebo and formoterol vs placebo subgroups, and between LABA-treated patients vs placebo (both study arms exposed to ICS) and LABA vs placebo (both study arms not exposed to ICS) [Table 5 ]. Finally, the analysis of two studies,17,33 that compared LABAs as monotherapy with LABA plus ICS showed a significant decrease in the rate of respiratory deaths favoring the LABA-plus-ICS group (RR, 0.35; 95% CI, 0.14 to 0.93; p = 0.03; I2 = 0%).

Secondary Outcomes

Thirteen studies showed that the mean change from baseline of postbronchodilator FEV1 was greater in patients treated with LABAs (WMD, 0.13 L; 95% CI, 0.10 to 0.15; p = 0.0001, I2 = 92%; random-effect model) compared with placebo. Patients reversible to salbutamol who were treated with salmeterol showed a significantly greater increase in mean change FEV1 from baseline compared with poorly reversible patients treated with the same agent (0.18 L; 95% CI, 0.14 to 0.22; vs 0.10 L; 95% CI, 0.07 to 0.13; p = 0001).

Twelve studies examined the mean change from baseline in the SGRQ. The mean total SGRQ score of patients who received LABAs decreased significantly compared with placebo (WMD, − 3.26; 95% CI, − 4.57 to −1.96; p = 0.0001; I2 = 83%; random- effects model), indicating an improvement in quality of life. COPD patients treated with formoterol presented a greater reduction in the mean total SGRQ score (WMD, − 4.81; 95% CI, − 7.28 to − 2.33) compared with patients who received salmeterol (− 2.06; 95% CI, − 3.39 to − 0.73; p = 0.05).

Nine studies showed data on the mean number of daytime puffs of salbutamol. LABA patients presented a significant decrease of salbutamol use (WMD, − 1.22; 95% CI, − 1.42 to − 1.02; I2 = 0%; p = 0.04; fixed-effects model). There were no differences between patients treated with salmeterol (WMD, − 1.08; 95% CI, − 1.37 to − 0.79) and formoterol (WMD, − 1.17; 95% CI, − 1.37 to − 0.97; p = 0.6).

Patients treated with LABAs showed a trend toward fewer exacerbations compared with those treated with ipratropium; however, the difference was not significant (RR, 0.83; 95% CI, 0.67 to 1.04; I2 = 12%; p = 0.11; fixed-effects model). None of the three ipratropium studies reported deaths of respiratory cause.

Compared with LABAs, tiotropium resulted in a decrease of 48% in the incidence of severe COPD exacerbations (RR, 0.52; 95% CI, 0.31 to 0.86; I2 = 0%; p = 0.01; fixed-effects model). The same three trials indicated that tiotropium increased the final change from baseline in mean FEV1 by 0.05 L (95% CI, 0.02 to 0.07; I2 = 57.6%; p = 0.0003; random-effects model). Although two studies1516 reported respiratory mortality data, only one displayed at least one death per group.

This review found that compared with placebo, LABAs reduced severe exacerbations by 21% (NNT = 30). More important, LABAs patients did not differ in all-cause mortality rate, and contrary to a previous review4 they did not present differences in the rate of all and respiratory mortality, compared with placebo patients (98 reported respiratory deaths in 4,316 patients in the LABA-treated group and 88 deaths in of 3,733 patients in the placebo group). The analysis including those studies without respiratory deaths showed a significant difference in the absolute risk reduction of all-cause mortality rate between both groups favoring LABAs (LABA mortality rate, 4.9%; placebo, 6.5%).

Although patients receiving LABAs showed statistically significant benefits in airflow limitation measures, quality of life, and use of rescue medication, the clinical relevance of these improvements remain elusive. Certainly, a FEV1 increase of 112 mL and a reduction of four units in the SGRQ total score have been indicated as threshold changes for clinically significant improvements.7,43 However, the spirometric and quality-of-life benefits are limited by the presence of a high heterogeneity among studies. When we stratified studies by reversibility to SABAs, reversible COPD patients displayed a significant greater increase in mean change FEV1 from baseline with salmeterol compared with poorly reversible patients.

With regard to the comparison with anticholinergics drugs, LABAs showed a nonsignificant trend toward fewer exacerbations compared with ipratropium. On the contrary, LABA treatment was associated with significantly more severe COPD exacerbations and a lesser increase in FEV1 from baseline compared with tiotropium. Although based on a small number of trials, these results suggest the superiority of tiotropium over LABAs for the treatment of stable COPD patients, findings akin to previous data.44

In the last few years, several systematic reviews36 on the safety and efficacy of LABAs in COPD patients have been published. However, they offer incomplete information on this topic. Thus, the four reviews did not assess outcomes such as severe COPD exacerbations and mortality.

Salpeter et al4 evaluated the safety and efficacy of β-agonists (SABAs and LABAs) compared with placebo and anticholinergics in stable COPD (22 trials with a minimum of 3 months in duration). Of those, only 12 studies compared LABAs with placebo or anticholinergics (7,449 patients). They found that β-agonist (SABA and LABA) reduced the risk of severe COPD exacerbations but were associated with a significant increase in respiratory deaths (RR, 2.47; 95% CI, 1.12 to 5.45) compared with placebo.

Unlike this previous review,4 we restricted the analysis to studies that compared only LABAs with placebo or anticholinergics. Additionally, we extended the search to those trials with a minimum of 1 month in duration. As a result, 17 new randomized trials with a total of 13,845 patients have been added. Our analysis confirms some previous findings. Thus, LABAs decrease severe COPD exacerbations and showed benefits in terms of airflow limitation measures, quality of life, and use of rescue medication compared with placebo. The decrease in the incidence of severe COPD exacerbations and the increase in FEV1 were greater with tiotropium than with LABAs. However, our findings did not identify any detrimental effect of LABAs on respiratory mortality. This finding disagrees with those by Salpeter et al.,4 In our analysis, we included five trials that reported respiratory deaths, three of which14,16,18 were included in the study of Salpeter et al.4 However, there were several differences between the study by Salpeter et al4 and our current analysis: (1) we included two trials, a new large one trial,17 and respiratory deaths data from a second study34 obtained through a personal communication with its authors; (2) we excluded the study by Donohue et al41 included in the review by Salpeter et al4 because the latter presented redundant data; (3) although Salpeter et al4 reported two respiratory deaths for the article by Boyd et al14 (one for each group), only the death that occurred in the placebo group had a respiratory cause (pneumonia). Also, the number of deaths by respiratory cause in the trial by Calverley et al18 was uncertain. In any case, whether or not this study is included the overall result was unchanged. When we added to the analysis seven additional studies20,23,27,2932 that did not report any death, increasing the denominator, there was no difference in the absolute risk increase among both groups. However, the exclusion of the trial of Calverley et al18 resulted in a pooled analysis based only in four studies.14,16,18,34 On this case, there was a nonsignificant difference between LABAs and placebo groups.

Strengths and Shortcomings

This study met most of the methodologic criteria suggested for scientific reviews.45 All of the included studies were randomized and double blinded, and combined with quite homogeneous clinical characteristics of the studied samples (namely GOLD stages 3 and 4). We also used the fail-safe N test to adjust for publication bias. Thus, it is unlikely that 23 studies and 14 studies (number of negative studies that would be required to reverse our conclusions regarding COPD exacerbations and mortality of respiratory cause, respectively) would be found with a more extensive literature search. This systematic review differs from others,36 in that it included poorly reversible and reversible COPD patients, accordingly to COPD definitions.12 Also, in this review we excluded two studies4142 that included data from patients enrolled in previous trials, avoiding double counting of patients. An important limitation was that only 12 studies (representing only 39% of total sample) reported findings regarding respiratory deaths, such that the vast majority of trials could not be included in the analysis of this outcome. Also, we need to bear in mind that 18 of 27 studies allowed the concomitant use of ICS in both the treatment and placebo arms, such that in the majority of studies there were not true placebo-controlled studies of LABA use in patients with COPD. However, sensitivity analysis according the concomitant use of ICS did not show significant differences between subgroups in outcomes like severe COPD exacerbations, all-cause deaths, and respiratory deaths. In the same way, an additional analysis including only trials that examine monotherapy without ICS did not show significant difference between LABAs compared with the same intervention with concomitant ICS in terms of severe COPD exacerbations. On the contrary, there are data that suggest a beneficial effect of ICS on respiratory mortality. Thus, the use of LABAs with ICS was associated with a significant decrease compared with LABAs alone (RR, 0.35; 95% CI, 0.14 to 0.93), although this analysis was based on only two studies.

Clinical Implications

This review supports the beneficial effects of the use of LABAs in patients with stable moderate and severe COPD. This benefit was evident in both poorly reversible and reversible patients. Compared to placebo, inhaled LABAs (salmeterol, 50 to 100 μg; formoterol, 4.5 to 18 μg bid) produce a 21% reduction of severe COPD exacerbations. Unlike a previous review,4 our analysis did not confirm an increased risk for respiratory deaths. Furthermore, this current study showed significant changes in favor of LABAs regarding lung function, quality of life, and use of daily rescue medication with SABAs. However, these effects are of uncertain clinical significance. The benefit on spirometric measure was greater in the subgroup of patients with reversibility to salbutamol. Except for health-related quality of life, in the remaining variables salmeterol and formoterol displayed equivalent effects. However in respect to both exacerbations and lung function, tiotropium showed a degree of superiority over LABAs.

Abbreviations: CI = confidence interval; ICS = inhaled corticosteroids; GOLD = Global Initiative for Chronic Obstructive Lung Disease; LABA = long-acting β2-agonist; NNT = number need to treat; RR = relative risk; SABA = short-acting β2-agonist; SGRQ = St. George Respiratory Questionnaire; WMD = weighted mean difference

Funding for this study came from salary support for Dr. Rodrigo. No sponsorship from institutions or pharmaceutical industry was provided to conduct this study.

Dr. Rodrigo has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, and Dr. Esteve SA, and consulted for CYDEX Inc. and Discovery Laboratories. Dr. Nannini has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of AstraZeneca and Altana. Dr. Rodriguez-Roisin has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Pfizer; consulted with several pharmaceutical companies with relevance to the topics discussed in the present article (Altana, AstraZeneca, Aventis, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Laboratorios Dr. Esteve SA, Novartis, Pfizer, Viechi and Zambon); serves on advisory boards for Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, and Procter & Gamble; has been sponsored for several clinical trials; and has received laboratory research support from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Laboratorios Dr Esteve SA, and Pfizer.

Figure Jump LinkFigure 1. Flowchart for identification of studies.Grahic Jump Location
Table Graphic Jump Location
Table 1. Characteristics of Included Studies*
* 

R = randomized; DB = double blind; PG = parallel group; CO = cross-over; MC = multicenter; NS = not stated; F = formoterol; S = salmeterol; IP = ipratropium; B = budesonide; PL = placebo; T = tiotropium.

Table Graphic Jump Location
Table 2. Studies That Report Data According to Different Comparisons and Outcomes
Figure Jump LinkFigure 2. Pooled RR for COPD exacerbations requiring withdrawal or hospitalization (with 95% CI) of eligible studies comparing inhaled LABAs with placebo (n = number of exacerbations; N = number of patients). Trials are stratified by type of LABA (salmeterol or formoterol) and reversibility to SABA (poorly reversible or reversible).Grahic Jump Location
Table Graphic Jump Location
Table 3. Comparisons Between RRs in COPD Exacerbations Stratified by LABA, Reversibility to Salbutamol, and Exposure to ICS
* 

From Higgins et al.10

Table Graphic Jump Location
Table 4. Comparisons Between RRs in All-Cause Mortality Stratified by LABA, and Exposure to ICS
* 

From Higgins et al.10

Figure Jump LinkFigure 3. Pooled RR for respiratory deaths (with 95% CI) of eligible studies comparing inhaled LABA with placebo; trials are stratified by type of LABA (salmeterol or formoterol). See Figure 2 for definition of abbreviations.Grahic Jump Location
Table Graphic Jump Location
Table 5. Comparisons Between RRs in Respiratory Deaths Stratified by LABA, and Exposure to ICS
* 

From Higgins et al.10

Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, updated 2007. Available at: www.goldcopd.com. Accessed April 2, 2008.
 
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Rennard, SI, Anderson, W, Zuwallack, R, et al Use of a long-acting inhaled β2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med2001;163,1087-1092. [PubMed]
 
Rossi, A, Kristufek, P, Levine, BE, et al Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD.Chest2002;121,1058-1069. [PubMed]
 
Szafranski, A, Cukier, A, Ramirez, A, et al Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease.Eur Respir J2003;21,74-81. [PubMed]
 
Stockley, RA, Chopra, N, Rice, L Addition of salmeterol to existing treatment in patients with COPD: a 12 month study.Thorax2006;61,122-128. [PubMed]
 
Ulrik, CS Efficacy of inhaled salmeterol in the management of smokers with chronic obstructive pulmonary disease: a single centre randomized, double blind, placebo controlled, crossover study.Thorax1995;50,750-754. [PubMed]
 
van Noord, JA, De Munck, DRAJ, Bantje, TA, et al Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive of ipratropium.Eur Respir J2000;15,878-885. [PubMed]
 
van Noord, JA, Aumann, JL, Janssens, E, et al Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD.Eur Respir J2005;26,214-222. [PubMed]
 
Wadbo, M, Lofdahl, CG, Larsson, K, et al Effects of formoterol and ipratropium bromide in COPD: a 3-month placebo-controlled study.Eur Respir J2002;20,1138-1146. [PubMed]
 
Calverley, PM, Boonsawat, W, Cseke, Z, et al Author's correction: maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease.Eur Respir J2004;24,1075
 
Donohue, JF, van Noord, JA, Bateman, ED, et al A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.Chest2002;122,47-55. [PubMed]
 
Rutten van Molken, M, Roos, B, van Noord, JA An empirical comparison of the St George's Respiratory Questionnaire (CRQ) and the Chronic Respiratory Disease Questionnaire (CRQ) in a clinical trial setting.Thorax1999;54,995-1003. [PubMed]
 
Redelmeir, DA, Goldstein, RS, Min, ST, et al Spirometry and dyspnea in patients with COPD: when small differences mean little.Chest1996;109,1163-1168. [PubMed]
 
Rodrigo, GJ, Nannini, LJ Tiotropium for the treatment of stable chronic obstructive pulmonary disease: a systematic review with meta-analysis.Pulm Pharmacol Ther2007;20,495-502. [PubMed]
 
Moher, D, Cook, DJ, Eastwood, S, et al Improving the quality of reports of meta-analyses of randomized controlled trials: the QUOROM statement.Lancet1999;354,1896-1900. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Flowchart for identification of studies.Grahic Jump Location
Figure Jump LinkFigure 2. Pooled RR for COPD exacerbations requiring withdrawal or hospitalization (with 95% CI) of eligible studies comparing inhaled LABAs with placebo (n = number of exacerbations; N = number of patients). Trials are stratified by type of LABA (salmeterol or formoterol) and reversibility to SABA (poorly reversible or reversible).Grahic Jump Location
Figure Jump LinkFigure 3. Pooled RR for respiratory deaths (with 95% CI) of eligible studies comparing inhaled LABA with placebo; trials are stratified by type of LABA (salmeterol or formoterol). See Figure 2 for definition of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Characteristics of Included Studies*
* 

R = randomized; DB = double blind; PG = parallel group; CO = cross-over; MC = multicenter; NS = not stated; F = formoterol; S = salmeterol; IP = ipratropium; B = budesonide; PL = placebo; T = tiotropium.

Table Graphic Jump Location
Table 2. Studies That Report Data According to Different Comparisons and Outcomes
Table Graphic Jump Location
Table 3. Comparisons Between RRs in COPD Exacerbations Stratified by LABA, Reversibility to Salbutamol, and Exposure to ICS
* 

From Higgins et al.10

Table Graphic Jump Location
Table 4. Comparisons Between RRs in All-Cause Mortality Stratified by LABA, and Exposure to ICS
* 

From Higgins et al.10

Table Graphic Jump Location
Table 5. Comparisons Between RRs in Respiratory Deaths Stratified by LABA, and Exposure to ICS
* 

From Higgins et al.10

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Rennard, SI, Anderson, W, Zuwallack, R, et al Use of a long-acting inhaled β2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med2001;163,1087-1092. [PubMed]
 
Rossi, A, Kristufek, P, Levine, BE, et al Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD.Chest2002;121,1058-1069. [PubMed]
 
Szafranski, A, Cukier, A, Ramirez, A, et al Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease.Eur Respir J2003;21,74-81. [PubMed]
 
Stockley, RA, Chopra, N, Rice, L Addition of salmeterol to existing treatment in patients with COPD: a 12 month study.Thorax2006;61,122-128. [PubMed]
 
Ulrik, CS Efficacy of inhaled salmeterol in the management of smokers with chronic obstructive pulmonary disease: a single centre randomized, double blind, placebo controlled, crossover study.Thorax1995;50,750-754. [PubMed]
 
van Noord, JA, De Munck, DRAJ, Bantje, TA, et al Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive of ipratropium.Eur Respir J2000;15,878-885. [PubMed]
 
van Noord, JA, Aumann, JL, Janssens, E, et al Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD.Eur Respir J2005;26,214-222. [PubMed]
 
Wadbo, M, Lofdahl, CG, Larsson, K, et al Effects of formoterol and ipratropium bromide in COPD: a 3-month placebo-controlled study.Eur Respir J2002;20,1138-1146. [PubMed]
 
Calverley, PM, Boonsawat, W, Cseke, Z, et al Author's correction: maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease.Eur Respir J2004;24,1075
 
Donohue, JF, van Noord, JA, Bateman, ED, et al A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.Chest2002;122,47-55. [PubMed]
 
Rutten van Molken, M, Roos, B, van Noord, JA An empirical comparison of the St George's Respiratory Questionnaire (CRQ) and the Chronic Respiratory Disease Questionnaire (CRQ) in a clinical trial setting.Thorax1999;54,995-1003. [PubMed]
 
Redelmeir, DA, Goldstein, RS, Min, ST, et al Spirometry and dyspnea in patients with COPD: when small differences mean little.Chest1996;109,1163-1168. [PubMed]
 
Rodrigo, GJ, Nannini, LJ Tiotropium for the treatment of stable chronic obstructive pulmonary disease: a systematic review with meta-analysis.Pulm Pharmacol Ther2007;20,495-502. [PubMed]
 
Moher, D, Cook, DJ, Eastwood, S, et al Improving the quality of reports of meta-analyses of randomized controlled trials: the QUOROM statement.Lancet1999;354,1896-1900. [PubMed]
 
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