Twenty-nine RCTs were included in the review (36,657 patients; range 79 to 6112). Eighteen RCTs reported randomisation, 16 reported concealment of allocation, 14 reported blinding, 20 were intention-to-treat time periods and 20 RCTs had more than 20% drop-outs. Ten treatment combinations were included in the primary mixed treatment comparison and 15 were included in the secondary mixed treatment comparison analysis.
The primary analysis favoured inhaled glucocorticosteroids plus long-acting bronchodilators plus long-acting muscarinic antagonist (absolute treatment effect 0.82, 95% CI 0.57 to 1.15), and also the addition of roflumilast to long-acting muscarinic antagonist (absolute treatment effect 0.75, 95% CI 0.53 to 1.02) and to long-acting bronchodilators (absolute treatment effect 0.81, 95% CI 0.58 to 1.10). The combination of roflumilast plus a long-acting muscarinic antagonist showed the largest treatment effects compared with the other treatments and had the highest probability of being the best first-line treatment (45%).
The secondary analyses suggested that the highest probability of reductions in exacerbations was found with roflumilast plus inhaled glucocorticosteroids plus long-acting bronchodilators plus long-acting muscarinic antagonist. The secondary analysis again favoured inhaled glucocorticosteroids plus long-acting muscarinic antagonist plus long-acting bronchodilators (absolute treatment effect 0.63, 95% CI 0.54 to 0.73) and indicated that the addition of roflumilast may further reduce exacerbations (absolute treatment effect 0.53, 95% CI 0.43 to 0.64). These findings were robust to the sensitivity analyses.