Abstract: Tiotropium plus LABA/ICS versus tiotropium We included six studies (1902 participants) with low risk of bias that compared tiotropium in addition to inhaled corticosteroid and long-acting beta2-agonist combination therapy versus tiotropium alone. We found no statistically significant differences in mortality between treatments (odds ratio (OR) 1.80, 95% confidence interval (CI) 0.55 to 5.91; two studies; 961 participants) as well as in the all-cause hospitalisations (OR 0.84, 95% CI 0.53 to 1.33; two studies; 961 participants). The effect on exacerbations was heterogeneous among trials and was not meta-analysed. Health-related quality of life measured by St. George’s Respiratory Questionnaire (SGRQ) showed a statistically significant improvement in total scores with use of tiotropium + LABA/ICS compared with tiotropium alone (mean difference (MD) -3.46, 95% CI -5.05 to -1.87; four studies; 1446 participants). Lung function was significantly different in the combined therapy (tiotropium + LABA/ICS) group, although average benefit with this therapy was small. None of the included studies included exercise tolerance as an outcome. A pooled estimate of these studies did not show a statistically significant difference in adverse events (OR 1.16, 95% CI 0.92 to 1.47; four studies; 1363 participants), serious adverse events (OR 0.86, 95% CI 0.57 to 1.30; four studies; 1758 participants) and pneumonia (Peto OR 1.62, 95% CI 0.54 to 4.82; four studies; 1758 participants). Tiotropium plus LABA/ICS versus LABA/ICS One of the six studies (60 participants) also compared combined therapy (tiotropium + LABA/ICS) versus LABA/ICS therapy alone. This study was affected by lack of power; therefore results did not allow us to draw conclusions for this comparison. This review update includes three additional studies and provides new low quality evidence supporting the finding that tiotropium + LABA/ICS-based therapy improves the disease-specific quality of life. The current evidence is insufficient to support the benefit of tiotropium + LABA/ICS-based therapy for mortality, hospital admission or exacerbations (moderate and low quality evidence). Compared with use of tiotropium alone, tiotropium + LABA/ICS-based therapy does not seem to increase undesirable effects nor serious non-fatal adverse events.

Plain-language summary: This review found six studies, involving 1902 participants, comparing the long-term efficacy and side effects of tiotropium combined with combination inhalers for treatment of patients with COPD. Not all of the people included in these studies had COPD that was severe enough to be recommended for combined therapy according to current guidelines. Current evidence shows potential benefits of treatment with tiotropium in addition to inhaled corticosteroid and long-acting beta2-agonist combination therapy through increased health-related quality of life and a small improvement i n lung function in patients receiving this combined therapy. However, this evidence does not allow us to draw conclusions about the effects of these treatments on mortality, hospitalisation for all causes and exacerbations. The frequency of serious and non-serious adverse events was not increased in either of the two groups. Overall, we assessed the evidence presented in this review to be of moderate or low quality, which means we are reasonably confident in some of the findings, but less confident in others.