Abstract: This review included 12 multicentre RCTs randomly assigning 9547 participants with stable COPD. All the studies were industry-sponsored and had similar inclusion criteria with relatively good methodological quality. All but one study included in the meta-analysis were double-blind and scored low risk of bias. The study duration ranged from four weeks to 52 weeks. Participants were more often males, mainly Caucasians, mean age ranging from 61.7 to 65.6 years, and with a smoking history of 10 or more pack years. They had moderate to severe symptoms at randomisation; the mean post-bronchodilator forced expiratory volume in one second (FEV1) was between 46% and 57.6% of the predicted normal value, and the mean St George's Respiratory Questionnaire score (SGRQ) ranged from 45.1 to 50.4 when reported. There was no difference between aclidinium and placebo in all-cause mortality (low quality) and number of patients with exacerbations requiring a short course of oral steroids or antibiotics, or both (moderate quality). Aclidinium improved quality of life by lowering the SGRQ total score with a mean difference of -2.34 (95% CI -3.18 to -1.51; I2 = 48%, 7 trials, 4442 participants) when compared to placebo. More patients on aclidinium achieved a clinically meaningful improvement of at least four units decrease in SGRQ total score (OR 1.49; 95% CI 1.31 to 1.70; I2 = 34%; number needed to treat (NNT) = 10, 95% CI 8 to 15, high quality evidence) over 12 to 52 weeks than on placebo. Aclidinium also resulted in a significantly greater improvement in pre-dose FEV1 than placebo with a mean difference of 0.09 L (95% CI 0.08 to 0.10; I2 = 39%, 9 trials, 4963 participants). No trials assessed functional capacity. Aclidinium reduced the number of patients with exacerbations requiring hospitalisation by 4 to 20 fewer per 1000 over 4 to 52 weeks (OR 0.64; 95% CI 0.46 to 0.88; I2 = 0%, 10 trials, 5624 people; NNT = 77, 95% CI 51 to 233, high quality evidence) compared to placebo. There was no difference in non-fatal serious adverse events (moderate quality evidence) between aclidinium and placebo. Compared to tiotropium, aclidinium did not demonstrate significant differences for exacerbations requiring oral steroids or antibiotics, or both, exacerbation-related hospitalisations and non-fatal serious adverse events (very low quality evidence). Inadequate data prevented the comparison of aclidinium to formoterol or other LABAs. Aclidinium is associated with improved quality of life and reduced hospitalisations due to severe exacerbations in patients with moderate to severe stable COPD compared to placebo. Overall, aclidinium did not significantly reduce mortality, serious adverse events or exacerbations requiring oral steroids or antibiotics, or both. Currently, the available data are insufficient and of very low quality in comparisons of the efficacy of aclidinium versus tiotropium. The efficacy of aclidinium versus LABAs cannot be assessed due to inaccurate data. Thus additional trials are recommended to assess the efficacy and safety of aclidinium compared to other LAMAs or LABAs.

Plain-language summary: The evidence was current to 7 April 2014. We included 12 studies involving 9547 COPD patients over a period of four to 52 weeks. These studies were sponsored by drug companies and were well designed. Both patients and the people doing the research did not know which treatment the patients were getting; although in one study one treatment was known to both parties. More men than women took part, and they were mostly Caucasians. They were in their 60s and had smoked a lot in their lives. These people had moderate to severe symptoms when they started treatment. Aclidinium did not reduce the number of people with flare-ups that need additional drugs. There was little or no difference in deaths or serious side effects between aclidinium and a dummy inhaler. Aclidinium inhalers improved quality of life more than the dummy inhalers. People who took aclidinium had fewer hospital admissions due to serious flare-ups. Based on our results, among 1000 COPD patients using a dummy inhaler over four weeks to one year 37 would have severe flare-ups needing hospital admission. Only 17 to 33 patients out of 1000 would require hospital admission if they were using aclidinium inhalers. We also set out to compare this new medication with tiotropium, which is already used to treat COPD. There were only two studies for this comparison thus we could not be sure how aclidinium compared to tiotropium. We also could not compare aclidinium with another well known inhaler that contains the drug formoterol because of unreliable data. For the comparison of aclidinium inhalers and dummy inhalers, we are confident that there are benefits in terms of the number of hospitalisations and patients' quality of life; we are less certain about the numbers of flare-ups needing additional drugs and serious side effects. We do not have enough information to assess any effect on the number of deaths. We did not have enough information to reliably compare aclidinium with tiotropium or formoterol.