Comparison 1. Triple therapy versus LABA/LAMA combination.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Moderate‐to‐severe exacerbations (Rate)	5	15397	Rate Ratio (IV, Random, 95% CI)	0.74 [0.67, 0.81]
1.2 Moderate‐to‐severe exacerbations (Time‐to‐first)	5	15397	Hazard Ratio (IV, Random, 95% CI)	0.84 [0.77, 0.92]
1.3 Moderate‐to‐severe exacerbations (≥ 1 exacerbation)	3	6109	Odds Ratio (M‐H, Random, 95% CI)	0.80 [0.64, 0.99]
1.4 Moderate‐to‐severe exacerbations (Rate, stratified by eosinophil count)	5		Rate Ratio (IV, Random, 95% CI)	0.74 [0.67, 0.83]
1.4.1 High Eosinophils	5		Rate Ratio (IV, Random, 95% CI)	0.67 [0.60, 0.75]
1.4.2 Low Eosinophils	5		Rate Ratio (IV, Random, 95% CI)	0.87 [0.81, 0.93]
1.5 Moderate‐to‐severe exacerbations (Rate, stratified by baseline ICS use)	2		Rate Ratio (IV, Random, 95% CI)	0.75 [0.70, 0.82]
1.5.1 Baseline ICS Use	2		Rate Ratio (IV, Random, 95% CI)	0.75 [0.69, 0.82]
1.5.2 No Baseline ICS Use	2		Rate Ratio (IV, Random, 95% CI)	0.75 [0.62, 0.91]
1.6 Severe exacerbations (Rate)	4	14131	Rate Ratio (IV, Fixed, 95% CI)	0.75 [0.67, 0.84]
1.7 Severe exacerbations (Time‐to‐first)	2	7753	Hazard Ratio (IV, Random, 95% CI)	0.77 [0.67, 0.88]
1.8 All exacerbations (Rate)	1		Rate Ratio (IV, Fixed, 95% CI)	Totals not selected
1.9 Change in SGRQ	5	13879	Mean Difference (IV, Fixed, 95% CI)	‐1.65 [‐2.15, ‐1.15]
1.10 SGRQ, ≥ 4 decrease from baseline	4	14070	Odds Ratio (M‐H, Random, 95% CI)	1.35 [1.26, 1.45]
1.11 SGRQ, end of study	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.12 Pneumonia	5	15412	Odds Ratio (M‐H, Random, 95% CI)	1.59 [1.33, 1.89]
1.13 Pneumonia (Time‐to‐first)	3		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected
1.14 Serious adverse events, pneumonia	5	15412	Odds Ratio (M‐H, Fixed, 95% CI)	1.74 [1.39, 2.18]
1.15 Serious adverse event, all‐cause	5	15412	Odds Ratio (M‐H, Fixed, 95% CI)	0.95 [0.87, 1.03]
1.16 Change in E‐RS	2	2798	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐0.59, ‐0.00]
1.17 TDI, ≥ 1‐unit increase	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected
1.18 TDI (Focal score), over 24 weeks	3		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.19 Change in trough FEV1 (mL)	5	11352	Mean Difference (IV, Random, 95% CI)	38.68 [22.58, 54.77]
1.20 Trough FEV1, end of study (mL)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.21 FEV1 AUC 0 to 4 (mL), end of study	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.22 Change in trough FVC (mL)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.23 Death, all causes	5	15397	Odds Ratio (M‐H, Fixed, 95% CI)	0.70 [0.54, 0.90]
1.24 Death, all causes (Time‐to‐event)	3		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected
1.25 Death, cardiovascular causes	4	13865	Odds Ratio (M‐H, Fixed, 95% CI)	0.51 [0.34, 0.77]
1.26 Death, respiratory causes	3		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.27 Death, COPD‐related	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected