Double bronchodilation in chronic obstructive pulmonary disease: a crude analysis from a systematic review

Figures & data

Figure 1 Flow chart of included–excluded studies.

Abbreviations: ACLI/FOR, aclidinium/formoterol; IND/GLY, indacaterol/glycopyrronium; TIO/OLO, tiotropium/olodaterol; UMEC/VIL, umeclidinium/vilanterol.

Table 1 Efficacy outcomes for double combinations versus placebo by the end of triala

Variables	IND/GLY	UMEC/VIL	ACLI/FOR	TIO/OLO
Lung function
FEV1 5 minutes post morning dose (mL)	290	NAb	108–128	NAb
Peak FEV1 (mL)	330	224	298–334	339
Trough FEV1 (mL)	189–219	122–243	130–152	162–207
FEV1 AUC0–24 (mL)	320	NAb	NAb	280
Symptoms
Dyspnea (TDI)	1.09–1.37	0.7–1.2	1.3–1.44	1.20–2.05
TDI increase ≥1 point (%)	10.6–17.8	8	16.2–21.6	NAb
TDI increase ≥1 point (OR)	2.78	1.3–2	2.54–2.8	NAb
HRQL (SGRQ)	−3.01 to −4.7	−2.02 to −5.51	NS to −4.36	−4.56 to −4.89
SGRQ increase ≥4 points (%)	NSc	10–11	19.5	19.2–21.9
SGRQ increase ≥4 points (OR)	NSc	1.5–2	2.3	2.2–2.5
Rescue medication (puffs/day)	−0.73 to −1.43	−0.6 to −1.2	−0.66 to −0.91	NAb
Endurance test (seconds)	60	NS to 69.4	NAb	54.9–78.6
Endurance SWT (seconds)	NAb	NAb	NAb	NSc
Exacerbations
Number of all exacerbations (RR)	NAb	NAb	NS to 0.76	NAb
Time to first exacerbation, all (HR)	0.7	0.5–0.6	0.72	NAb
Number of moderate-to-severe exacerbations (RR)	NAb	NAb	NS to 0.71	NAb
Time to first moderate-to-severe exacerbation (HR)	0.7	NAb	0.70	NAb

Notes:

a Data expressed as the minimum and maximum average value from all trials analyzed.

b Outcomes with no information in any of the trials evaluated.

c Outcomes with nonsignificant results in all available trials.

Abbreviations: ACLI/FOR, aclidinium/formoterol; AUC_0–24, area under the curve from 0 to 24 hours post morning dose; FEV₁, forced expiratory volume in the first second; HR, hazard ratio; HRQL, heath-related quality of life; IND/GLY, indacaterol/glycopyrronium; NA, not available; NS, not significant; OR, odds ratio; RR, rate ratio; SGRQ, St George’s Respiratory Questionnaire; SWT, shuttle walking test; TDI, transitional dyspnea index; TIO/OLO, tiotropium/olodaterol; UMEC/VIL, umeclidinium/vilanterol.

Table 2 Efficacy outcomes for double combinations versus their LAMA by the end of triala

Variables	IND/GLY	UMEC/VIL	ACLI/FOR	TIO/OLO
Lung function
FEV1 5 minutes post morning dose (mL)	130	NAb	92	79
Peak FEV1 (mL)	130	67–94	121–124	111
Trough FEV1 (mL)	70–90	22–52	NSc	NS–79
FEV1 AUC0–24 (mL)	120	NAb	NAb	111
Symptoms
Dyspnea (TDI)	NSc	NSc	NS–0.44	0.35–0.61
TDI increase ≥1 point (%)	NSc	NSc	NSc	NAb
TDI increase ≥1 point (OR)	NAb	NSc	NSc	NAb
HRQL (SGRQ)	NS to −2.8	NSc	NSc	−1.23 to −2.49
SGRQ increase ≥4 points (%)	NSc,*	NAb	NSc	7.9–11.4
SGRQ increase ≥4 points (OR)	NSc,*	NSc	NSc	1.53–1.58
Rescue medication (puffs/day)	−0.66 to −0.81	−0.6	−0.36	−0.55
Endurance test (seconds)	NAb	NAb	NAb	NSc
Endurance SWT (seconds)	NAb	NAb	NAb	NAb
Exacerbations
Number of all exacerbations (RR)	0.85	NAb	NSc	NAb
Time to first exacerbation, all (HR)	NSc	NSc	NSc	NAb
Number of moderate-to-severe exacerbations (RR)	0.88	NAb	NSc	NAb
Time to first moderate-to-severe exacerbation (HR)	NAb	NAb	NSc	NSc

Notes:

a Data expressed as the minimum and maximum average value from all trials analyzed.

b Outcomes with no information in any of the trials evaluated.

c Outcomes with nonsignificant results in all available trials.

* Significant differences favoring the double bronchodilation until week 52.

Abbreviations: ACLI/FOR, aclidinium/formoterol; AUC_0–24, area under the curve from 0 to 24 hours post morning dose; FEV₁, forced expiratory volume in the first second; HR, hazard ratio; HRQL, heath-related quality of life; IND/GLY, indacaterol/glycopyrronium; LAMA, long-acting muscarinic antagonist; NA, not available; NS, not significant; OR, odds ratio; RR, rate ratio; SGRQ, St George’s Respiratory Questionnaire; SWT, shuttle walking test; TDI, transitional dyspnea index; TIO/OLO, tiotropium/olodaterol; UMEC/VIL, umeclidinium/vilanterol.

Table 3 Efficacy outcomes for double combinations versus tiotropium by the end of triala

Variables	IND/GLY	UMEC/VIL	ACLI/FOR	TIO/OLO
Lung function
FEV1 5 minutes post morning dose (mL)	120	NAb	NAb	79
Peak FEV1 (mL)	130	72–95	NAb	111
Trough FEV1 (mL)	60–100	60–112	NAb	NS to 79
FEV1 AUC0–24 (mL)	110	NAb	NAb	110
Symptoms
Dyspnea (TDI)	0.49–0.51	NSc	NAb	0.35–0.61
TDI increase ≥1 point (%)	8.9–17.8	NAb	NAb	NAb
TDI increase ≥1 point (OR)	1.78	NSc	NAb	NAb
HRQL (SGRQ)	NS to −3.1	NS to −2.1	NAb	−1.23 to −2.49
SGRQ increase ≥4 points (%)	NS* to 7.3	NAb	NAb	7.9–11.4
SGRQ increase ≥4 points (OR)	NSc,*	NS to 1.4	NAb	1.53–1.58
Rescue medication (puffs/day)	−0.45 to −1.08	−0.5 to −0.7	NAb	−0.55
Endurance test (seconds)	NSc	NAb	NAb	NSc
Endurance SWT (seconds)	NAb	NAb	NAb	NAb
Exacerbations
Number of all exacerbations (RR)	0.86	NSc	NAb	NAb
Time to first exacerbation, all (HR)	NSc	NS to 0.5	NAb	NAb
Number of moderate-to-severe exacerbations (RR)	NSc	NAb	NAb	NAb
Time to first moderate-to-severe exacerbation (HR)	NSc	NAb	NAb	NSc

Notes:

a Data expressed as the minimum and maximum average value from all trials analyzed.

b Outcomes with no information in any of the trials evaluated.

c Outcomes with nonsignificant results in all available trials.

* Significant differences favoring the double bronchodilation until week 52.

Abbreviations: ACLI/FOR, aclidinium/formoterol; AUC_0–24, area under the curve from 0 to 24 hours post morning dose; FEV₁, forced expiratory volume in the first second; HR, hazard ratio; HRQL, heath-related quality of life; IND/GLY, indacaterol/glycopyrronium; NA, not available; NS, not significant; OR, odds ratio; RR, rate ratio; SGRQ, St George’s Respiratory Questionnaire; SWT, shuttle walking test; TDI, transitional dyspnea index; TIO/OLO, tiotropium/olodaterol; UMEC/VIL, umeclidinium/vilanterol.

Table 4 Efficacy outcomes for double combinations versus their own LABA by the end of triala

Variables	IND/GLY	UMEC/VIL	ACLI/FOR	TIO/OLO
Lung function
FEV1 5 minutes post morning dose (mL)	NSc	NAb	NSc	NSc
Peak FEV1 (mL)	120	88–116	116–138	120
Trough FEV1 (mL)	70	90–95	45–81.5	85–92
FEV1 AUC0–24 (mL)	120	NAb	NAb	115
Symptoms
Dyspnea (TDI)	NSc	NSc	NS to 0.47	0.42
TDI increase ≥1 point (%)	NSc	NAb	NSc	NAb
TDI increase ≥1 point (OR)	NAb	NSc	NSc	NAb
HRQL (SGRQ)	NSc	NSc	NSc	−1.693
SGRQ increase ≥4 points (%)	NSc	NAb	NSc	12.7
SGRQ increase ≥4 points (OR)	NAb	NSc	NSc	NAb
Rescue medication (puffs/day)	−0.31	NSc	NSc	−0.28
Endurance test (seconds)	NAb	NAb	NAb	NS to 46.6
Endurance SWT (seconds)	NAb	NAb	NAb	NAb
Exacerbations
Number of all exacerbations (RR)	NAb	NAb	NSc	NAb
Time to first exacerbation all (HR)	NAb	NSc	NSc	NAb
Number of moderate-to-severe exacerbations (RR)	NAb	NAb	NSc	NAb
Time to first moderate-to-severe exacerbation (HR)	NAb	NAb	NSc	0.83

Notes:

a Data expressed as the minimum and maximum average value from all trials analyzed.

b Outcomes with no information in any of the trials evaluated.

c Outcomes with nonsignificant results in all available trials.

Abbreviations: ACLI/FOR, aclidinium/formoterol; AUC_0–24, area under the curve from 0 to 24 hours post morning dose; FEV₁, forced expiratory volume in the first second; HR, hazard ratio; HRQL, heath-related quality of life; IND/GLY, indacaterol/glycopyrronium; LABA, long-acting β₂-agonist; NA, not available; NS, not significant; OR, odds ratio; RR, rate ratio; SGRQ, St George’s Respiratory Questionnaire; SWT, shuttle walking test; TDI, transitional dyspnea index; TIO/OLO, tiotropium/olodaterol; UMEC/VIL, umeclidinium/vilanterol.