Impact of bronchodilator therapy on exercise tolerance in COPD

Figures & data

Table 1 Impact of short-acting bronchodilators on exercise capacity

Study	Dose of study drug	Study design	N	Baseline FEV1 (% pred.)	Change in resting lung volume	Change in exercise dyspnea (Borg score)	Changes in exercise performance
							Walking	CWR cycling	Progressive cycling	Other
Short-acting β2-agonists
Salbutamol
Porto et al^Citation48	400 μg	Single-dose, randomized	16	41%	Δ IC P = 0.001a	–	–	–	–	Incremental Arm Exercise: Δ IC, NSb
Aliverti et al^Citation47	5 mg nebulized	Single-dose, crossover	18	40.6%	Δ FEV1P < 0.001a Δ FRC P < 0.01a Δ IC P < 0.001a	NSa	–	NSa	–	–
Oga et al^Citation46	400 μg	Single-dose, crossover	67	44.2%	Δ FEV1P < 0.001a Δ FVC P < 0.001a	P < 0.001a	–	Δ endurance time 29 s (+15%) P < 0.001a	–	–
Procaterol
Shioya et al^Citation50	20 μg qid	52-week, randomized	20	48.1%	Δ FEV1P < 0.05b Δ FVC P < 0.05b	P < 0.05b	6MWD: Δ 42 m (+10%) P < 0.05b	–	–	–
Sukisaki et al^Citation51	20 μg	Single-dose, crossover	19	38.5%	Δ FEV1 NSa	NSb	SWT: Δ 37 m (P = 0.001b)	–	–	–
Short-acting anticholinergics
Ipratropium
O’Donnell et al^Citation57	500 μg nebulized	Single-dose, crossover	16	90%	Δ FEV1P < 0.05a Δ FVC P < 0.05a Δ TLC NSa Δ FRC P < 0.05a Δ IC NSa	NSa	–	NSa	–	–
Pepin et al^Citation56	500 μg nebulized	Single-dose, crossover	14	50%	Δ FEV1P < 0.001a	–	SWT: Δ 144 m (P = 0.03) 6MWD: NS	–	–	–
Pepin et al^Citation7	500 μg nebulized	Single-dose, crossover	17	56%	Walk and Cycle: Δ FEV1P < 0.001a	NS	SWT: Δ endurance time 2 mins 44 s (P < 0.01a)	NSa	–	–
Akkoca et al^Citation55	40 μg qid	2 week, crossover	10	69%	Δ FEV1 NSb Δ FVC NSb Δ TLC NSb Δ FRC NSb Δ IC NSb	–	–	–	Δ W max = NSb Δ endurance time 1 min 18 s P < 0.05b	–
Saey et al^Citation12	500 μg nebulized	Single-dose	18	38%	Δ FEV1P < 0.05a,b Δ IVC P < 0.0001a Δ FRC P < 0.01a Δ RV P < 0.001a	–	–	Δ endurance time 1 min 58 s (+37%) P = 0.06a	–	–
Oga et al^Citation46	80 μg	Single-dose, crossover	67	44.2%	Δ FEV1P < 0.001a Δ FVC P < 0.001a	P < 0.001a	–	Δ endurance time 27 s (+14%) P < 0.001a	–	–
Liesker et al^Citation53	80 μg tid	1 week, crossover	34	55.6%	Δ FEV1P < 0.0001a Δ IVC P < 0.0001a Δ FVC NSa Δ FRC P < 0.01a Δ RV P < 0.001a	NSa	–	–	Δ endurance time 46 s P < 0.0001a	–
Wadbo et al^Citation54	80 μg tid	12 weeks, parallel	183	33.6%	Δ FEV1P < 0.05a Δ FVC P < 0.05a	NSa	SWT: NSa	–	–	–
Rennard et al^Citation52	36 μg qid	12 weeks, parallel	405	–	Δ FEV1P < 0.05a Δ FVC P < 0.05a	NSa	6MWD: NSa	–	–	–
Oxitropium
Shioya et al^Citation50	200 μg qid	52-week, randomized	20	49.4%	Δ FEV1 NSb Δ FVC NSb	NSb	6MWD: NSb	–	–	–
Oga et al^Citation58	400 μg	Single-dose, crossover	38	40.8%	Δ FEV1P < 0.001a Δ FVC P < 0.01a	Δ 0.2 P < 0.05a (PCE test only)	6MWD: Δ 6 m (+1%) P < 0.05a	Δ endurance time 34 s (+18%) P < 0.001a	Δ Wmax 3 W P < 0.01a	–

a Active drug versus placebo;

b Active drug versus baseline.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FRC, forced residual capacity; IC, inspiratory capacity; FVC forced vital capacity; CWR, constant work rate; PCE, progressive cycle ergometry; CWR, constant work rate; 6MWD, 6 minute walk distance; SWT, shuttle walk test; NS, not significant.

Table 2 Impact of long-acting bronchodilators on exercise capacity

Study	Dose of drug	Study design	N	Baseline FEV1 (% pred.)	Change in resting lung volume	Change in exercise dyspnea		Changes in exercise performance
						Borg score	CRQ or TDI/BDI score	Walking	CWR cycling	Progressive cycling
Long-acting β2-agonists
Salmeterol
Brouillard et al^Citation77	50 μg	Single dose, 5-visit (≥48 h, ≤4 days apart), crossover	20	52%	Δ FEV1P< 0.0001a ΔFVC P < 0.0001a Δ IC NSa Δ FRC NSa Δ RV P < 0.05a	Δ Borg score 5.6 P = 0.006a (Isotime)	–	SWT: Δ 160 m P = 0.02a Δ endurance time 1 min 57 s P = 0.02a	–	–
Stockley et al^Citation76	50 μg bid	12-month, parallel	426	46.1%	Δ FEV1P < 0.0001a Δ FVC P < 0.01a Δ SVC P < 0.05a Δ IC P < 0.05a	NSa	–	SWT: Δ 30 m P = 0.04a	–	–
O’Donnell et al^Citation75	50 μg bid	8-week, parallel	123	39.5%	Δ FEV1P < 0.05a Δ FVC P < 0.05a Δ FRC P < 0.05a Δ RV P < 0.05a Δ IC P < 0.05a	NSa	–	–	NSa	–
Man et al^Citation74	50 μg bid	2-week, crossover	16	31.1%	Δ FEV1 NSa Δ VC NSa Δ IC P < 0.05a Δ RV NSa	Δ Borg score 0.84 (P = 0.02a) (Isotime)	–	Treadmill endurance test: NSa	–	–
O’Donnell et al^Citation73	50 μg bid	2-week, crossover	23	42%	Δ FEV1P < 0.01a Δ FVC P < 0.01a Δ FRC P < 0.01a Δ RV P < 0.01a Δ IC P < 0.01a	NSa	–	–	Δ endurance time 1 min 36 s (+58%) P = 0.018a	–
Gupta et al^Citation72	50 μg bid	8-week, parallel	33	–	Δ FEV1P < 0.05b Δ FVC P < 0.05b	–	TDI: P < 0.01a	6MWD: NSa	–	–
Rennard et al^Citation52	42 μg bid	12-week, parallel	405	–	Δ FEV1P < 0.05a Δ FVC P < 0.05a	NSa	–	6MWD: NSa	–	–
Weiner et al^Citation71	50 μg bid	18-week, parallel	23	33%	Δ FEV1 NSb	NSb	–	6MWD NSb	–	–
	50 μg bid+ exercise		17	35%		NSb		6MWD: Δ 42 m (+17%) < 0.05b
	50 μg bid + exercise + inspiratory muscle training		11	35%		P < 0.01b		6MWD: Δ 50 m (+20%) P < 0.05b
Formoterol
Cazzola et al^Citation70	12 μg bid	5-day, crossover	22	14%–56%	Δ FEV1P < 0.05b Δ IC P < 0.05b	Δ Borg score −1.7 P = 0.005b (pre-last dose) −1.8 P = 0.001b (post-last dose)	–	6MWD: Δ 53.6m P = 0.006b 12MWD: Δ 59.9 m P = 0.018b	–	–
Neder et al^Citation69	12 μg bid	2-week, crossover	21	38.8%	Δ IC P < 0.05a Δ EELV P < 0.05a Δ RV P < 0.05a	NSa	–	–	Δ 2 min 10 s P = 0.052	–
Akkoca et al^Citation55	12 μg bid	2 week, crossover	10	69%	Δ FEV1 NS Δ FVC NS Δ FEV1/FVC P < 0.05b Δ TLC NS Δ FRC NS Δ IC NS	–	–	–	–	Δ TTE 45 s P < 0.05b
Wadbo et al^Citation54	18 μg bid	12-week, parallel	183	33.3%	Δ FEV1P < 0.05a Δ FVC P < 0.05a	NS	–	SWT: NS	–	–
Aalbers et al^Citation68			Total 692	54%		–	–	SWT:	–	–
	4.5 μg bid	12-week, parallel	144	53.1%	Δ FEV1P < 0.01a			NSa
	9 μg bid		136	54.4%	Δ FEV1P < 0.05a			NSa
	18 μg bid		150	54.7%	Δ FEV1P < 0.001a			NSa
Liesker et al^Citation53	4.5 μg bid	1-week, crossover	34	–	Δ FEV1P < 0.05a Δ FRC P < 0.05a Δ FVC NSa Δ IVC P < 0.05a Δ RV P < 0.05a	NS	–	–	–	Δ TTE 44 s P < 0.0001a
	9 μg bid		34	–	Δ FEV1P < 0.05a Δ FRC P < 0.05a Δ FVC NSa Δ IVC P < 0.05a Δ RV P < 0.05a	NS	–	–	–	34 s P < 0.01a
	18 μg bid		34	–	Δ FEV1P < 0.05a Δ FRC P < 0.05a Δ FVC NSa Δ IVC P < 0.05a Δ RV P < 0.05a	NS	–	–	–	23 s P < 0.05a
Long-acting Anticholinergics
Tiotropium
Ambrosino et al^Citation83	18 μg qd	4-week, parallel	117	42.5%	Δ FEV1P ≤ 0.05	–	TDI: NSa	6MWD: NSa	–	–
	18 μg qd + rehabilitation	25-week (including 8 weeks’ rehabilitation), parallel	117	42.5%	Δ FEV1P ≤ 0.05	–	At end of PR (Week 13): 3.60 units P = 0.001a At Week 25: NSa	Week 13: NSa Week 25: NSa	–	–
Travers et al^Citation82	18 μg qd	7–10 day, crossover	18	40%	Δ FEV1P < 0.01a Δ RV P < 0.01a Δ FRC P < 0.01a	NS	–	–	NSa	–
Okudan et al^Citation81	18 μg qd	Single-dose, crossover	44	–	–	NS	–	6MWD: Δ 14.6 m (+4%) P < 0.05a	–	–
Verkindre et al^Citation80	18 μg qd	12-week, parallel	46	34.7%	Δ FVC P < 0.05a Δ IC P < 0.05a	NSa	TDI: NSa	SWT: Δ 36 m P < 0.05a	–	–
Casaburi et al^Citation79	18 μg qd	4-week, parallel	55	34%	Δ FEV1P < 0.01a Δ FVC P < 0.001a	–	TDI: NSa	Treadmill endurance test: NSa	–	–
	18 μg qd + rehabilitation	25-week (8 weeks’ rehabilitation) parallel	55	34%	Δ FEV1P < 0.01a Δ FVC P < 0.001a	NSa	1.67 units P < 0.01a	Δ 6 min 36 s P < 0.05a	–	–
Maltais et al^Citation78	18 μg qd	6-week, parallel	131	43.1%	Δ FEV1P < 0.001a Δ FVC P < 0.001a Δ SVC P < 0.001a Δ IC P < 0.001a Δ FRC P < 0.001a Δ RV P < 0.001a Δ TLC P < 0.01a	Δ 1.05 P < 0.001a (Isotime)	–	–	Δ 3 min 54 s (+ 41%) P < 0.001a	–
O’Donnell et al^Citation18	18 μg qd	6-week, parallel	96	42%	Δ FEV1P < 0.001a Δ FVC P < 0.0001a Δ IC P < 0.05a Δ RV P < 0.001a Δ FRC P < 0.001a	Δ 0.9 P < 0.01a (Isotime)	–	–	Δ 1 min 45 s (+ 21%) P < 0.01a	–

a Active drug versus placebo;

b Active drug versus baseline.

Abbreviations: EELV, end-expiratory lung volume; FEV₁, forced expiratory volume in 1 second; CRQ, chronic respiratory disease questionnaire; BDI, baseline dyspnea index; TDI, transition dyspnea index; FRC, forced residual capacity; IC, inspiratory capacity; FVC, forced vital capacity; VC, vital capacity; RV, residual volume; CWR constant work rate; IVC, inspiratory vital capacity; PCE, progressive cycle ergometry; 6MWD, 6 minute walk distance; SWT, shuttle walk test; TTE, Time to exhaustion (for PCE); NS, not significant; PR, pulmonary rehabilitation.

Table 3 Comparison of different classes of bronchodilators on exercise capacity

Study	Dose of drugs	Study design	N	Baseline FEV1 (% pred.)	Change in resting lung volumes	Change in exercise dyspnea (Borg score)	Changes in exercise performance
							Walking	CWR cycling	Progressive cycling
Oga et al^Citation46	80 μg ipratropium vs 400 μg salbutamol	Single-dose, crossover	67	44.2%	FEV1P < 0.003 in favor of salbutamol FVC P < 0.001 in favor of salbutamol	NS (P = 0.23)	–	CWR: NS (P = 0.71)	–
Comparision of short- and long-acting bronchodilators
Akkoca et al^Citation55	40 μg qid ipratropium vs formoterol 12 μg bid	2 weeks, crossover	10	69%	NS	–	–	–	PCE: NS
Liesker et al^Citation53	80 μg ipratropium tid vs. formoterol 4.5 μg bid, 9 μg bid, 18 μg bid	1 week, crossover	–	55.6%	NS	NS	–	–	PCE: Significant increase in TTE (23 s) in favor of ipratropium compared with 18 μg formoterol (but not 4.5 and 9 μg formoterol)
Wadbo et al^Citation54	80 μg tid ipratropium vs 18 μg bid formoterol	12 weeks, parallel	183	33.6% 33.3%	FEV1P < 0.05 at Wk 4 in favor of formoterol vs ipratropium (treatment differences NS at study end) FVC NS	NS	SWT: NS	–	–
Rennard et al^Citation52	36 μg qid ipratropium vs 42 μg bid salmeterol	12 weeks, parallel	405	–	NS	NS	6MWD: NS	–	–

Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PCE, progressive cycle ergometry; CWR, constant work rate; 6MWD, 6 minute walk distance; SWT, shuttle walk test; TTE, Time to exhaustion (for PCE); NS, not significant.

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