Abstract: We included 11 studies comprising 9839 participants in our quantitative analysis. Most studies included people with moderate to severe COPD, without recent exacerbations. One pharmaceutical sponsored trial that included only people with recent exacerbations was the largest study and accounted for 37% of participants. All but one study were sponsored by pharmaceutical companies, thus we rated them as having a high risk of 'other bias'. The unsponsored study was at high risk of performance and detection bias, and possible selective reporting. Five studies recruited GOLD Category B participants, one study recruited Category D participants, two studies recruited Category A/B participants, and three studies recruited participants regardless of category. Follow-up ranged from 6 to 52 weeks. Compared to the LABA+ICS arm, the results for the pooled primary outcomes for the LAMA+LABA arm were as follows: exacerbations, OR 0.82 (95% CI 0.70 to 0.96, P = 0.01, I2 = 17%, low quality evidence); serious adverse events (SAE), OR 0.91 (95% CI 0.79 to 1.05, P = 0.18, I2 = 0, moderate quality evidence); St. George's Respiratory Questionnaire (SGRQ) total score change from the baseline, MD -1.22 (95% CI -2.52 to 0.07, P = 0.06, I2 = 71%, low quality evidence); and trough forced expiratory volume in one second (FEV1) change from the baseline, MD 0.08 L (95% CI 0.06 to 0.09, P < 0.0001, I2 = 50%, moderate quality evidence). Compared to the LABA+ICS arm, the results for the pooled secondary outcomes for the LAMA+LABA arm were as follows: pneumonia, OR 0.57 (95% CI 0.42 to 0.79, P = 0.0006, I2 = 0%, low quality evidence); all-cause death, OR 1.01 (95% CI 0.61 to 1.67, P = 0.88, I2 = 0%, low quality evidence); and SGRQ total score change from the baseline of 4 points or greater (the minimal clinically important difference for the SGRQ is 4 points), OR 1.25 (95% CI 1.09 to 1.44, P = 0.002, I2 = 0%, moderate quality evidence). For the treatment of COPD, LAMA+LABA has fewer exacerbations, a larger improvement of FEV1, a lower risk of pneumonia, and more frequent improvement in quality of life as measured by an increase over 4 units or more of the SGRQ. These data were supported by low or moderate quality evidence generated from mainly participants with moderate to severe COPD in heterogeneous trials with an observation period of less than one year. Our findings support the recently updated GOLD guidance.

Plain-language summary: We included 11 studies involving 9839 participants comparing the benefits and harms of LAMA+LABA and LABA+ICS for the treatment of people with COPD. Although risk of serious side effects and death were not affected by the choice of treatment, compared to LABA+ICS, LAMA+LABA was associated with a lower risk of flare-ups, fewer episodes of pneumonia, larger improvement in how well the lungs work, and improved quality of life. Since most of the analysed studies were sponsored by pharmaceutical companies, we had to interpret the results carefully. However, we judged the included studies to be generally conducted in an acceptable manner. These data were supported by low or moderate quality evidence from trials in people with mainly moderate to severe COPD who were studied for less than one year.