Table 2.
Summary of findings and strength of evidence
| Outcomes | No of trials | No/total No of patients | Effect size (95% CI)* | I2 | P | GRADE evidence |
|---|---|---|---|---|---|---|
| Triple therapy versus LAMA (10 trials) | ||||||
| Moderate to severe exacerbations | ||||||
| Rate of exacerbation | 5 | 2550/2020 | 0.71 (0.60 to 0.85) | 65.4 | 0 | Moderate |
| No of patients with ≥1 moderate to severe exacerbation | 5 | 1159/1176 | 0.74 (0.56 to 0.97) | 50.6 | 0.03 | Moderate |
| Time to first exacerbation | 3 | 2232/1695 | 0.69 (0.54 to 0.88) | 71.6 | 0.002 | Moderate |
| Rate of severe exacerbations | 4 | 1726/1730 | 0.58 (0.47 to 0.72) | 0 | 0 | High |
| All cause mortality | 4 | 2377/1851 | 0.71 (0.45 to 1.10) | 23.3 | 0.13 | Moderate |
| FEV1 trough (L) | 11 | 3483/2423 | 0.07 (0.06 to 0.08) | 0 | 0 | High |
| Safety | ||||||
| Adverse events | 6 | 2579/2046 | 0.98 (0.92 to1.04) | 0 | 0.57 | Moderate |
| Serious adverse events | 6 | 2773/2252 | 0.83 (0.71 to 0.98) | 0 | 0.03 | Moderate |
| Cardiovascular events | 2 | 1759/1232 | 0.77 (0.45 to 1.31) | 0 | 0.33 | Low |
| Pneumonia events | 4 | 2269/1754 | 1.30 (0.79 to 2.12) | 0 | 0.30 | Low |
| Quality of life | ||||||
| SGRQ score | 8 | 3063/2056 | −2.78 (−3.87 to −1.70) | 0 | 0 | High |
| Triple therapy versus LAMA and LABA (3 trials) | ||||||
| Moderate to severe exacerbations | ||||||
| Rate of exacerbation | 2 | 4915/2838 | 0.78 (0.70 to 0.88) | 46.3 | 0 | Moderate |
| No of patients with ≥1 moderate to severe exacerbation | 1 | 145/148 | 0.91 (0.78 to 1.07) | NA | NA | Low |
| Time to first exacerbation | 2 | 4915/2838 | 0.85 (0.79 to 0.91) | 0 | 0 | High |
| Rate of severe exacerbations | 3 | 5153/3090 | 0.68 (0.59 to 0.78) | 0 | 0 | High |
| All cause mortality | 3 | 5060/2986 | 0.77 (0.58 to 1.03) | 0 | 0.07 | Moderate |
| FEV1 trough (L) | 3 | 4275/2406 | 0.04 (0.02 to 0.07) | 27.1 | 0 | High |
| Safety | ||||||
| Adverse events | 3 | 5060/2986 | 1.00 (0.93 to 1.08) | 58.3 | 0.98 | Low |
| Serious adverse events | 3 | 5060/2986 | 0.94 (0.86 to 1.03) | 0 | 0.20 | Moderate |
| Cardiovascular events | 3 | 5060/2986 | 0.97 (0.84 to 1.12) | 27 | 0.70 | Low |
| Pneumonia events | 3 | 5060/2986 | 1.53 (1.25 to 1.87) | 19.7 | 0 | Moderate |
| Quality of life | ||||||
| SGRQ score | 3 | 4227/2386 | −1.81 (−2.57 to −1.04) | 0 | 0 | High |
| Triple therapy versus ICS and LABA (11 trials) | ||||||
| Moderate to severe exacerbations | ||||||
| Rate of exacerbation | 3 | 5749/5713 | 0.77 (0.66 to 0.91) | 64.0 | 0.003 | Moderate |
| No of patients with ≥1 moderate to severe exacerbation | 8 | 3872/3028 | 0.76 (0.62 to 0.93) | 48.1 | 0.008 | High |
| Time to first exacerbation | 2 | 4838/4814 | 0.84 (0.79 to 0.90) | 0 | 0 | High |
| Rate of severe exacerbations | 1 | 4151/4134 | 0.87 (0.75 to 1.00) | NA | 0.05 | Moderate |
| All cause mortality | 9 | 8023/6905 | 0.88 (0.69 to 1.13) | 0 | 0.33 | Low |
| FEV1 trough (L) | 12 | 6453/5348 | 0.11 (0.10 to 0.13) | 65.1 | 0 | Moderate |
| Safety | ||||||
| Adverse events | 10 | 8052/6931 | 1.02 (0.99 to 1.04) | 21.5 | 0.78 | Moderate |
| Serious adverse events | 9 | 8023/6905 | 1.01 (0.94 to 1.08) | 42.9 | 0.82 | Moderate |
| Cardiovascular events | 8 | 7904/6788 | 0.99 (0.89 to 1.11) | 0 | 0.92 | Moderate |
| Pneumonia events | 9 | 8023/6905 | 1.11 (0.97 to 1.28) | 2 | 0.13 | Moderate |
| Quality of life | ||||||
| SGRQ score | 11 | 6383/5293 | −1.81 (−2.28 to −1.35) | 0 | 0 | High |
| Fixed triple therapy versus separate triple therapy (2 trials) | ||||||
| Moderate to severe exacerbations | ||||||
| Rate of severe exacerbations | 2 | 1604/1065 | 0.97 (0.85 to 1.11) | 0 | 0.56 | Moderate |
| All cause mortality | 2 | 1604/1065 | 1.18 (0.59 to 2.38) | 0 | 0.64 | Moderate |
| FEV1 trough (L) | 2 | 1604/1065 | 0.01 (−0.02 to 0.04) | 58.6 | 0.52 | Low |
| Safety | ||||||
| Adverse events | 2 | 1604/1065 | 0.98 (0.91 to 1.05) | 0 | 0.51 | Moderate |
| Serious adverse events | 2 | 1604/1065 | 0.98 (0.79 to 1.22) | 0 | 0.88 | Moderate |
| Cardiovascular events | 2 | 1604/1065 | 1.16 (0.75 to 1.79) | 0 | 0.50 | Low |
| Pneumonia events | 2 | 1604/1065 | 0.88 (0.55 to 1.41) | 24.8 | 0.60 | Low |
| Quality of life | ||||||
| SGRQ score | 2 | 1553/1049 | 0.20 (−1.96 to 2.35) | 56.7 | 0.93 | Low |
LAMA=long acting muscarinic receptor antagonist; LABA=long acting β2 adrenoreceptor agonist; ICS=inhaled corticosteroids; FEV1=forced expiratory volume in 1 second; SGRQ=St George’s respiratory questionnaire; GRADE=grading of recommendations assessment, development, and evaluation; NA=not applicable.
*
Effect sizes are as follows: rate ratio for moderate to severe exacerbations rates; risk ratio for number of patients with ≥1 moderate to severe exacerbation, all cause mortality, and safety outcomes; hazard ratio for time to first exacerbation; and mean difference for FEV1 trough and SGRQ score.