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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Comparative efficacy of aclidinium versus glycopyrronium and tiotropium, as maintenance treatment of moderate to severe COPD patients: a systematic review and network meta-analysis

A Karabis, L Lindner, M Mocarski, E Huisman, and A Greening.

Review published: 2013.

CRD summary

This review of maintenance treatments for moderate-to-severe chronic obstructive pulmonary disease concluded that aclidinium, tiotropium and glycopyrronium were comparable and better than placebo with respect to improvements in lung function, health-related quality of life and dyspnoea at 12 and 24 week time points. The conclusions are moderately reliable with uncertainty relating to indirect comparison and heterogeneity.

Authors' objectives

To compare the efficacy of aclidinium versus tiotropium and glycopyrronium for maintenance treatment of moderate-to-severe chronic obstructive pulmonary disease (COPD).

Searching

MEDLINE, MEDLINE in process, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from July 1989 to October 2012 for publications in English. Search terms were reported. Conference abstracts dating back two years were screened.

Study selection

Eligible studies were randomised controlled trials with a duration of 10 weeks or more that compared the efficacy of aclidinium, glycopyrronium or tiotropium (eligible dose regimens stated in review) versus each other or placebo. Trial populations had to contain adults with chronic obstructive pulmonary disease (COPD as defined by a published guideline). Eligible outcomes were reported at 12 and 24 weeks (or within two weeks of these time points) and included trough forced expiratory volume in one second (FEV1), St George's Respiratory Questionnaire (SGRQ) total score and proportion of patients who achieved four or more unit change, Transition Dyspnea Index (TDI) focal score and the proportion of patients who achieved one or more point change.

All of the included trials were multicentre and had sometimes been performed across multiple continents. Patients were current or ex-smokers; most were male and aged 60 years or over. At baseline, the mean FEV percentage predicted at baseline ranged from 35% to 56%. All trials except one compared one drug with placebo. More than half of the trials administered tiotropium as the intervention drug (18µg once daily). Others administered tiotropium (5µg once daily), aclidinium (400µg twice daily) or glycopyrronium (50µg once daily). Trial duration ranged from 12 weeks to four years.

Two reviewers independently selected studies for inclusion; any disagreements were resolved by consensus.

Assessment of study quality

Trial quality was assessed using the Jadad Scale (maximum score of 5 indicating highest quality).

The authors did not state how many reviewers were involved in the quality assessment process.

Data extraction

Two reviewers independently extracted data on the outcomes. Any disagreements were resolved by consensus. Mean differences in change from baseline and standard error values were extracted or calculated for continuous outcomes; numbers of responders were extracted or calculated for dichotomous outcomes according to the intention-to-treat principle.

Methods of synthesis

Three series of Bayesian network meta-analyses were performed to estimate differences in change from baseline (CFB) or odds ratios, with 95% credible intervals. Fixed-effect and random-effects models were evaluated for each outcome. Generalised linear models with identity links and normal likelihood distributions were used for continuous outcomes. Logit links with binomial likelihood distributions were used for dichotomous outcomes. Markov chain Monte Carlo simulations were performed to estimate posterior densities for unknown parameters in each model. Where possible, potential confounding effects of certain patient characteristics (stated in the review) were adjusted for using treatment-by-covariate meta-regression models. A sensitivity analysis was performed by removal of studies which allowed concomitant use of long-acting β-agonists among patients. Further details of the synthesis were reported in the review.

Results of the review

Twenty-one randomised controlled trials were included in the review (22,542 patients reported in the text, range 100 to 5,993 per trial). Total Jadad Scale scores were 3 (eight trials), 4 (10 trials) or 5 (three trials).

Trough FEV1 (19 trials): Compared with placebo, all active treatment drugs were shown to be more efficacious (statistically and clinically) with point estimates above the minimal clinically important difference of 100mL (reported fully in the review). After 12 and 24 weeks, no statistically significant differences in trough FEV1 were found between aclidinium and tiotropium (5µg), tiotropium (18µg) and glycopyrronium (50µg).

The probabilities of aclidinium being a better treatment than these other drugs ranged from 41% to 59% at 12 weeks and from 48% to 72% at 24 weeks.

Health status according to SGRQ scores (14 trials): Compared with placebo, all active treatment drugs were associated with statistically significant improvements in SGRQ score (a lower score). One of the comparisons at 24 weeks (aclidinium versus placebo) demonstrated a clinically significant improvement exceeding four units (difference in CFB 4.63, 95% Crl -6.85 to -2.42). After 12 and 24 weeks, no statistically significant differences in SGRQ score were found between aclidinium and tiotropium (18µg) or glycopyrronium (50µg). At 24 weeks, aclidinium demonstrated a statistically significant reduction in SGRQ score compared with tiotropium (5µg) (difference in CFB -2.44, 95% Crl -4.82 to -0.05).

The probabilities of aclidinium being a better treatment than these other drugs ranged from 64% to 86% at 12 weeks and from 88% to 98% at 24 weeks.

Relief from dyspnoea according to TDI focal scores (10 trials): Compared with placebo, all active treatment drugs were associated with statistically significant improvements in TDI focal score (a higher score). One of the comparisons at 24 weeks (aclidinium versus placebo) demonstrated a clinically significant improvement of one unit (difference in CFB 1.00, 95% Crl 0.43 to 1.57). After 12 and 24 weeks, no statistically significant differences were shown between aclidinium and tiotropium (18µg) or glycopyrronium (50µg).

The probabilities of aclidinium being a better treatment than these other drugs ranged from 59% to 74%.

Similar results for the outcomes were shown in other scenario and covariate analyses. The proportions of patients who achieved the minimal clinically important difference of more than four units in SGEQ score and more than one unit in TDI score were statistically significantly higher for all active treatment drugs when they were each compared with placebo. All results were fully reported in the review.

Authors' conclusions

This network meta-analysis has predicted that aclidinium (400µg twice daily) would be better than placebo and comparable to tiotropium (5µg or 18µg once daily) and glycopyrronium (50µg once daily) for showing improvements in lung function, health-related quality of life and dyspnoea at 12 and 24 week time points.

CRD commentary

The review question was clear and supported by well-defined inclusion criteria. Relevant databases were searched for published and unpublished literature but only for those in English. The review processes of study selection and data extraction were performed in duplicate; this was not reported for the quality assessment processes. The quality of the included trials was assessed using suitable criteria although this tool has been criticised previously for missing out important quality domains. Overall, the results suggested that the quality of the studies was fairly high.

Study details were presented and revealed some clinical and methodological differences between the trials. The statistical methods of synthesis were appropriate with extensive sensitivity analysis particularly to explore possible confounding effects of certain study characteristics. The authors acknowledged that it was not possible to fully adjust for some characteristics because they were not always reported by individual trial papers. The lack of direct head-to-head comparisons meant that the network structure did not allow assessment of inconsistency so coherence and robustness of the results are uncertain.

The authors' conclusions reflect the evidence presented and are moderately reliable.

Implications of the review for practice and research

The authors did not state any implications for future practice and research.

Funding

Forest Research Institute, USA.

Bibliographic details

Karabis A, Lindner L, Mocarski M, Huisman E, Greening A. Comparative efficacy of aclidinium versus glycopyrronium and tiotropium, as maintenance treatment of moderate to severe COPD patients: a systematic review and network meta-analysis. International Journal of Chronic Obstructive Pulmonary Disease 2013; 8: 405-423. [PMC free article: PMC3772873] [PubMed: 24043936]

Indexing Status

Subject indexing assigned by CRD

MeSH

Pulmonary Disease, Chronic Obstructive; Humans; Administration, Oral; Tropanes; Glycopyrrolate; Scopolamine Derivatives

AccessionNumber

12013055521

Database entry date

28/11/2013

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 24043936

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