Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease

Background Combination therapy (inhaled corticosteroids and long-acting beta(2)-agonists) and tiotropium are both used in the treatment of chronic obstructive pulmonary disease (COPD). There is uncertainty about the relative benefits and harms of these treatments. Objectives To assess the relative effects of inhaled combination therapy and tiotropium on patients with COPD. Search strategy We searched the Cochrane Airways Group Specialised Register of trials (March 2010) and reference lists of articles. We also contacted authors of the studies. Selection criteria We included only parallel, randomised controlled trials comparing inhaled combination corticosteroid and long-acting beta(2)-agonist against inhaled tiotropium bromide. Data collection and analysis Two authors independently assessed trials for inclusion and then extracted data on trial quality and outcome results. We contacted study authors for additional information. Discrepancies were resolved through discussion. Main results One large two year trial (INSPIRE) and two smaller, shorter trials (Dawber 2005; SCO40034) were found. The results from these trials were not pooled. The number of withdrawals from each arm of the INSPIRE trial was large and imbalanced and outcome data was not collected for patients who withdrew, raising concerns about the reliability of data from this study. In INSPIRE, there were more deaths on tiotropium than on fluticasone/salmeterol (Peto OR 0.55; 95% CI 0.33 to 0.93). This was a statistically significant difference, however the number of withdrawals from each of the arms was eleven times larger than the observed number of deaths for participants on fluticasone/salmeterol and seven times larger for participants on tiotropium. There were more all cause hospital admissions in patents on fluticasone/salmeterol than those on tiotropium in INSPIRE (Peto OR 1.32; 95% CI 1.04 to 1.67). There was no statistically significant difference in hospital admissions due to exacerbations, the primary outcome of INSPIRE. There was no significant difference in exacerbations in patients on fluticasone/salmeterol compared to tiotropium. Exacerbations requiring treatment with oral corticosteroids were less frequent in patients on fluticasone/salmeterol (Rate Ratio 0.81; 95% CI 0.67 to 0.99). Conversely exacerbations requiring treatment with antibiotics were more frequent in patients treated with fluticasone/salmeterol (Rate Ratio 1.19; 95% CI 1.02 to 1.38). There were more cases of pneumonia in patients on fluticasone/salmeterol than those on tiotropium (Peto OR 2.13; 95% CI 1.33 to 3.40). Confidence intervals for these outcomes do not reflect the additional uncertainty arising from unknown outcome data for patients who withdrew. Authors' conclusions Since the proportion of missing outcome data compared to the observed outcome data is enough to induce a clinically relevant bias in the intervention effect, the relative efficacy and safety of combined inhalers and tiotropium remains uncertain. Further large, long-term randomised controlled trials comparing combination therapy to tiotropium are required, including adequate follow-up of all participants randomised (similar to the procedures undertaken in TORCH and UPLIFT). Additional studies comparing alternative inhaled LABA/steroid combination therapies with tiotropium are also required.