Systematic review comparing LABA, olodaterol, and indacaterol: limitations

Dear editor Roskell et al present a systematic review comparing the long-acting beta2 agonists (LABA), olodaterol, and indacaterol in the July edition of the International Journal of Chronic Obstructive Pulmonary Disease.1 The end-points compared for the two LABAs were: change from baseline in trough forced expiratory volume in 1 second (FEV1) at week 12; quality of life analyzed by change from baseline in St George’s Respiratory Quotient (SGRQ; total score and proportion of responders) at week 12; transition dyspnea index (TDI), analyzed by change from baseline at week 12; use of rescue medication, analyzed by change from baseline in average number of puffs per day; and proportion of patients experiencing at least one exacerbation, analyzed in trials with a treatment duration of 24 weeks or longer reporting data for this outcome. The authors conclude that olodaterol and indacaterol have similar efficacy in patients with COPD. The findings of this systematic review were questionable for several reasons, which were mostly related to missing data, the difference in the concomitant medication allowed between the trials of olodaterol and indacaterol, and the differences in COPD severity in the patient populations of the trials of the two LABAs. It should also be noted that four of the eight olodaterol trials were of a 6-week duration only,2,3 while all indacaterol studies had a follow-up of at least 12 weeks. Regarding data sources, this systematic review was limited to articles published from 1 January 1990 through to 5 August 2011. However, data from several indacaterol studies published in this period were not included in the analysis. The excluded data were: TDI data from the INSIST trial;4 rescue medication data from the INTRUST 1 and 2 trials5; data on FEV1, SGRQ (total score and responders data) and TDI from the QBA149B1302 study;6 and TDI data from study QBA149B2354.7 Furthermore, data from some of the indacaterol studies were taken from other network meta-analyses8,9 instead of directly from the primary publications of the trials, which would explain the differences between some of the results in individual trial publications and the supplementary material. The authors state that olodaterol and indacaterol were compared under “similar trial conditions”; however the difference in the use of concomitant medication between the trials of the two LABAs makes this statement also questionable. Concomitant maintenance bronchodilator use was allowed in most of the olodaterol trials. In six out of eight trials,2,10,11 patients were allowed a long-acting muscarinic agent (LAMA; tiotropium). A short-acting muscarinic agent (SAMA; ipratropium) and/or a xanthine (theophylline) were also allowed in all olodaterol trials as well as the rescue medication with short-acting beta2 agonist (SABA).2,3,10,11 In ten out of the twelve indacaterol trials (INTRUST 1 and 2 excluded), patients were not allowed any concomitant bronchodilator except for the rescue medication with SABA.4–7,12–18 Inhaled corticosteroids (ICS) were allowed in the trials of indacaterol and olodaterol. This heterogeneity in trial design would have affected the results and conclusions of the meta-analysis. While some subgroup analyses were carried out to account for concomitant LAMA medication, these were limited to two subgroup analyses: one subgroup analysis of change from baseline of trough FEV1 in patients who were “LAMA-free”; and another of patients who were allowed “LAMA add-on therapy”. Moreover, data were missing from these analyses; the LAMA-free analysis only included studies 1222.39 and 1222.40 of olodaterol3 and did not include those patients who were LAMA-free in studies 1222.11, 1222.12, 1222.13, 1222.14, 1222.24, and 1222.25,2,10,11 therefore excluding relevant sources of data. Furthermore, no other subgroup analyses taking concomitant medications into account were carried out for any other outcomes such as TDI, SGRQ scores or response, rescue medication, or exacerbations. Data from the studies INTENSITY,14 INSIST,4 and B13026 trials were not included in the Forest plot tables analyzing change in baseline FEV1 (LAMA-free and LAMA add-on analyses), as well as for the TDI, SGRQ, and SGRQ responders analyses. No explanation was given for this omission. The differences found in disease severity between the trial populations of olodaterol and indacaterol were also a concern. Patients with COPD disease severity ranging from moderate to very severe COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] stages II–IV)19 were included in the olodaterol trials, whereas the indacaterol trials included patients with moderate-to-severe COPD (GOLD stages II/III)19 only. As the authors acknowledge in the Discussion section of their paper, the olodaterol trials were not stratified for disease severity and therefore, the differences in patient populations and possible lung function response by disease severity could not be addressed in the meta-analysis. The Methods section in the Abstract states that the systematic review was carried out to evaluate the efficacy and safety of olodaterol and indacaterol; however, no safety data were presented. To conclude, the extent of the missing data from these analyses, the variation in concomitant medication allowed within the trials of the two LABAs, as well as the difference in disease severity between the trial populations, make it difficult to draw any meaningful conclusions regarding the relative efficacy of olodaterol and indacaterol.