This review concluded that indacaterol was expected to have similar effects on health status and breathlessness to salmeterol/fluticasone and similar effects on health status to formoterol/budesonide. It was also expected to be at least as good as formoterol/budesonide, and similar to salmeterol/fluticasone for lung function. These conclusions reflect the data presented and are appropriately cautious.

To compare efficacy of indacaterol (150μg and 300μg) to fixed-dose combination formoterol and budesonide and fixed-dose combination salmeterol and fluticasone for the treatment of chronic obstructive pulmonary disease.

MEDLINE and EMBASE were searched from 1989 to 2010 and full search strategies were reported in an appendix. Study documents for indacaterol studies were provided by Novartis.

Eligible randomised controlled trials (RCTs) compared indacaterol 150μg or 300μg, fixed-dose combinations of formoterol/budesonide and salmeterol/fluticasone with each other or placebo, in adults with chronic obstructive pulmonary disease. Outcomes of interest included trough forced expiratory volume in one second (FEV₁) reported predose values at 12 weeks and six months, St. George’s Respiratory Questionnaire total score at six months and transition dyspnoea index total score at six months.

All active therapies were compared with placebo and three studies directly compared indacaterol 150μg to indacaterol 300μg. No study directly compared other active treatments. The studies included patients 40 years of age or older with FEV₁/forced vital capacity of 0.70 or less and FEV₁ percent predicted less than 80% (indacaterol trials required patients to have a predicted FEV₁ 30% or above). Most studies were of patients who were current or ex-smokers with a smoking history of at least 10 years and most excluded patients with asthma or other respiratory or pulmonary diseases and other clinically significant diseases that may have affected treatment. Most studies were of predominantly Caucasian patients or reported study centres in Europe and North America.

Two reviewers independently assessed studies for inclusion.

The authors did not state that they assessed methodological quality.

Data were extracted on trough FEV₁ at 12 weeks and six months, St. George’s Respiratory Questionnaire total score at six months and transition dyspnoea index total score at six months. Only outcomes that were within two weeks of the time point of interest were extracted. For each outcome the difference in the change from baseline (or difference at follow-up adjusted for baseline) was extracted or calculated.

For indacaterol studies, only data from patients not using inhaled corticosteroids during the study were included.

The authors did not state how many reviewers performed the data extraction.

Bayesian network meta-analyses were undertaken for each outcome measure and for all studies and a sub-set that excluded the three Asian studies. Summary statistics were presented for the expected absolute and relative treatment effects, with 95% credible intervals (95% CrI). For each outcome, the probability that indacaterol was better than other treatments was also presented.

The following covariates (potential effect modifiers) were included simultaneously where possible, or in separate models where insufficient data were available: proportion of patients who were current smokers (as opposed to ex-smokers); proportion of patients with severe or very severe chronic obstructive pulmonary disease (as opposed to mild or moderate chronic obstructive pulmonary disease).

Eleven studies were identified from the literature search and four clinical trials of indacaterol were provided by Novartis. The total number of study participants was 10,211.

Trough FEV₁ at 12 weeks and six months:

In the analysis without covariates, all treatments were more effective than placebo. Indacaterol 150μg was associated with a greater change from baseline in FEV₁ at 12 weeks than fixed-dose combination formoterol and budesonide 9/160μg (difference in change from baseline 0.11L; 95% CrI 0.08 to 0.13) and than fixed-dose combination formoterol and budesonide 9/320μg (difference in change from baseline 0.09L; 95% CrI 0.06 to 0.11) and was comparable to fixed-dose combination salmeterol and fluticasone 50/250μg and 50/500μg. Similar results were observed for indacaterol 300μg at 12 weeks and indacaterol 150/300μg at six months. Results were not significantly altered by exclusion of the Asian studies. Adjusting for potential effect modifiers indicated that the comparison of indacaterol 150μg with fixed-dose combination formoterol and budesonide 9/320μg was sensitive to the proportion of patients with severe chronic obstructive pulmonary disease (difference became non-significant).

St. George’s Respiratory Questionnaire total score at six months:

Based on the analysis of all studies without covariates, all active treatments were more effective than placebo, with the exception of fixed-dose combination formoterol and budesonide 9/160μg which included zero in the credible intervals, and indacaterol 150μg resulted in comparable improvements in St. George’s Respiratory Questionnaire total score to fixed-dose combination salmeterol and fluticasone 50/500μg, fixed-dose combination formoterol and budesonide 9/160μg and formoterol/budesonide 9/320μg. Indacaterol 300μg resulted in lower scores than indacaterol 150μg, but was comparable to the alternative treatments. Excluding the Asian studies had minimal impact on the results, and no analyses adjusting for potential effect modifiers were possible.

Transition dyspnoea index total score at six months:

Based on the analysis of all studies without covariates, all active treatments were more effective than placebo. Lack of data precluded comparative estimates versus fixed-dose combination formoterol and budesonide. Indacaterol 150 and 300μg showed comparable transition dyspnoea index scores to fixed-dose combination salmeterol and fluticasone 50/250μg and fixed-dose combination salmeterol and fluticasone 50/500μg. Excluding the Asian studies produced similar results. No analyses adjusting for potential effect modifiers were possible.

Indacaterol monotherapy was expected to be at least as good as fixed-dose combination formoterol and budesonide (9/320 and 9/160μg) and similar to fixed-dose combination salmeterol and fluticasone (50/250 and 50/500μg) in terms of lung function (trough FEV₁). Indacaterol was also expected to have similar effectiveness to fixed-dose combination formoterol and budesonide (9/320 and 9/160μg) and fixed-dose combination salmeterol and fluticasone 50/500μg for health status outcomes (St. George’s Respiratory Questionnaire total) and to be similar to fixed-dose combination salmeterol and fluticasone (50/250 and 50/500μg) for breathlessness (transition dyspnoea index total).

The review stated a clear objective and defined appropriate inclusion criteria. Two bibliographic databases were searched, without language restriction, for relevant studies and additional data were supplied by the industry sponsor. Study selection incorporated measures to minimise error and/or bias, but it was not clear whether similar measures were applied to the data extraction process. No assessment of the methodological quality of included studies was provided. It was therefore not possible to fully assess the reliability of the data upon which the reported meta-analyses were based. The meta-analytic methods reported appeared robust.

The authors' conclusions reflected the data presented and were appropriately cautious.

Practice: The authors did not specify any recommendations for clinical practice.

Research: The authors did not specify any recommendations for future research.

Novartis Pharma AG.

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.