Indacaterol on Dyspnea in COPD
We identified published studies between January 2007 and May 2012 from MEDLINE, EMBASE, and the Cochrane Controlled Trials Register (CENTRAL) databases using the terms indacaterol, long-acting ß2-agonist AND chronic obstructive pulmonary disease. We performed a search of relevant files from the Novartis trials results database (http://www.novctrd.com/ctrdWebApp/clinicaltrialrepository/public/login.jsp). We also performed a manual search of references cited in published original and review articles, and in clinical practice guidelines. Trials published solely in abstract form were excluded because they contain preliminary and rudimentary information and may not provide enough details to allow full analysis. Two reviewers (JNH and LD) then independently screened potentially relevant trials from titles and abstracts. Using the full texts as necessary, the two reviewers independently identified eligible articles for full review. Finally, we reviewed eligible articles to determine whether they qualified for meta-analysis. Differences were resolved by discussion.
To be included, studies had to meet all the following criteria: a) target population of stable COPD consistent with American Thoracic Society/European Respiratory Society or Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria; b) randomized placebo-controlled trials comparing indacaterol 75 μg, 150 μg, or 300 μg od with placebo; c) studies that followed patients for 12 weeks or more after randomization; d) studies that included assessment of dyspnea by transition dyspnea index (TDI) in outcome measures.
Two reviewers independently read each article that met inclusion criteria and performed data extraction using a pre-designed data collection form. Missing data were obtained from the manufacturer. Disagreement and uncertainty were solved by discussion. Consensus was reached for all data. Data extracted from each article included: first author's name and year of publication; study design; treatment arms; number of patients; treatment duration; baseline clinical characteristics including age, gender, smoking history, post-bronchodilator spirometry, and total score of the baseline dyspnea index (BDI). The outcome measure of TDI was recorded as total score and as the number of patients with TDI ≥ 1.
Dyspnea is often measured using the BDI and TDI, a tool recommended by regulatory authorities for inclusion in clinical trials of treatments for COPD. The BDI and TDI, as multidimensional instruments, each has three domains: functional impairment, magnitude of task, and magnitude of effort. The BDI domains measure baseline dyspnea severity, and are rated from 0 (severe) to 4 (unimpaired) and summed to provide a BDI total score of 0 to 12, with a lower score indicating more severe dyspnea. The TDI domains measure change from the baseline dyspnea index (BDI) over time, rated on a scale of +3 (major improvement) to −3 (major deterioration). The TDI has been shown to be valid, reliable and responsive. The minimum clinically important difference (MCID) for the TDI is an improvement from the BDI score of ≥1 unit.
Odds ratio (OR) for likelihood of achieving TDI score ≥1 after 12 weeks of treatment was used as a measure to compare indacaterol relative to placebo. We calculated pooled ORs with the DerSimonian-Laird random effects model, usually regarded as more appropriate than other statistical approaches when potential heterogeneity is present between studies. We performed separate analyses for indacaterol 75 μg versus placebo, indacaterol 150 μg versus placebo, and indacaterol 300 μg versus placebo. We calculated the 95% confidence intervals around the ORs, and assessed heterogeneity across studies with the chi-square test and I (p < 0.10, I > 25%). We then created forest plots of the individual studies and combined estimates. All analyses were performed with meta-analysis software (MetaAnalyst version beta 3.13, Tufts Medical Center, Boston, Massachusetts).
Methods
Data Sources and Selection Criteria
We identified published studies between January 2007 and May 2012 from MEDLINE, EMBASE, and the Cochrane Controlled Trials Register (CENTRAL) databases using the terms indacaterol, long-acting ß2-agonist AND chronic obstructive pulmonary disease. We performed a search of relevant files from the Novartis trials results database (http://www.novctrd.com/ctrdWebApp/clinicaltrialrepository/public/login.jsp). We also performed a manual search of references cited in published original and review articles, and in clinical practice guidelines. Trials published solely in abstract form were excluded because they contain preliminary and rudimentary information and may not provide enough details to allow full analysis. Two reviewers (JNH and LD) then independently screened potentially relevant trials from titles and abstracts. Using the full texts as necessary, the two reviewers independently identified eligible articles for full review. Finally, we reviewed eligible articles to determine whether they qualified for meta-analysis. Differences were resolved by discussion.
To be included, studies had to meet all the following criteria: a) target population of stable COPD consistent with American Thoracic Society/European Respiratory Society or Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria; b) randomized placebo-controlled trials comparing indacaterol 75 μg, 150 μg, or 300 μg od with placebo; c) studies that followed patients for 12 weeks or more after randomization; d) studies that included assessment of dyspnea by transition dyspnea index (TDI) in outcome measures.
Data Extraction
Two reviewers independently read each article that met inclusion criteria and performed data extraction using a pre-designed data collection form. Missing data were obtained from the manufacturer. Disagreement and uncertainty were solved by discussion. Consensus was reached for all data. Data extracted from each article included: first author's name and year of publication; study design; treatment arms; number of patients; treatment duration; baseline clinical characteristics including age, gender, smoking history, post-bronchodilator spirometry, and total score of the baseline dyspnea index (BDI). The outcome measure of TDI was recorded as total score and as the number of patients with TDI ≥ 1.
Baseline Dyspnea Index (BDI) and Transition Dyspnea Index (TDI)
Dyspnea is often measured using the BDI and TDI, a tool recommended by regulatory authorities for inclusion in clinical trials of treatments for COPD. The BDI and TDI, as multidimensional instruments, each has three domains: functional impairment, magnitude of task, and magnitude of effort. The BDI domains measure baseline dyspnea severity, and are rated from 0 (severe) to 4 (unimpaired) and summed to provide a BDI total score of 0 to 12, with a lower score indicating more severe dyspnea. The TDI domains measure change from the baseline dyspnea index (BDI) over time, rated on a scale of +3 (major improvement) to −3 (major deterioration). The TDI has been shown to be valid, reliable and responsive. The minimum clinically important difference (MCID) for the TDI is an improvement from the BDI score of ≥1 unit.
Statistical Analyses
Odds ratio (OR) for likelihood of achieving TDI score ≥1 after 12 weeks of treatment was used as a measure to compare indacaterol relative to placebo. We calculated pooled ORs with the DerSimonian-Laird random effects model, usually regarded as more appropriate than other statistical approaches when potential heterogeneity is present between studies. We performed separate analyses for indacaterol 75 μg versus placebo, indacaterol 150 μg versus placebo, and indacaterol 300 μg versus placebo. We calculated the 95% confidence intervals around the ORs, and assessed heterogeneity across studies with the chi-square test and I (p < 0.10, I > 25%). We then created forest plots of the individual studies and combined estimates. All analyses were performed with meta-analysis software (MetaAnalyst version beta 3.13, Tufts Medical Center, Boston, Massachusetts).
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