Practical considerations when prescribing a long-acting muscarinic antagonist for patients with COPD

Figures & data

Table 1 Double-blind, randomized, placebo-controlled studies of LAMA therapy with durations of at least 6 months

Study	Duration	N	Baseline FEV1 % predicteda	Treatments	Concomitant maintenance treatment for COPD
Tiotropium (via HandiHaler^® device)
Casaburi et al (2002)^Citation18	1 year ×2b	921	39c	Tiotropium 18 μg qd Placebo (3:2)	Theophylline; ICS/OCS
Donohue et al (2002)^Citation19	6 months	623	40c	Tiotropium 18 μg qd Salmeterol 50 μg bid Placebo (1:1:1)	ICS/OCS
Niewoehner et al (2005)^Citation20	6 months	1,829	36 (≤60 predicted)c	Tiotropium 18 μg qd Placebo (1:1)	Study treatment given in addition to LABA or LABA/ICS
Chan et al (2007)^Citation21	48 weeks	913	39 (≤65 predicted)c	Tiotropium 18 μg qd Placebo (2:1)	Study treatment given in addition to LABA or LABA/ICS
Tashkin et al (2008) (UPLIFT)^Citation22	4 years	5,993	48 (GOLD II–IV)	Tiotropium 18 μg qd Placebo (1:1)	Study treatment given in addition to LABA or LABA/ICS
Troosters et al (2014)^Citation23	24 weeks	457	66 (GOLD II)	Tiotropium 18 μg qd Placebo (1:1)	OCS (up to 2 weeks for acute exacerbations)
Tiotropium (via Respimat^® device)
Bateman et al (2010)^Citation24	1 year ×2b	1,990	45–47	Tiotropium 5 μg qd Tiotropium 10 μg qd Placebo (1:1:1)	ICS/OCS; theophylline
Bateman et al (2010)^Citation25	1 year	3,991	45	Tiotropium 5 μg qd Placebo (1:1)	Study treatment given in addition to LABA or LABA/ICS
Glycopyrronium
D’Urzo et al (2011) (GLOW1)^Citation26	26 weeks	822	54–55 (GOLD II–IV)	Glycopyrronium 50 μg qd Placebo (2:1)	ICS at stable dose; OCS and/or SABA for exacerbations
Kerwin et al (2012) (GLOW2)^Citation27	52 weeks	1,066	56 (GOLD II–IV)	Glycopyrronium 50 μg qd Tiotropium 18 μg qd OL Placebo (2:1:1)	ICS at stable dose; OCS and/or SABA for exacerbations
Umeclidinium
Donohue et al (2013)^Citation28	24 weeks	1,532	47–48 (GOLD II–IV)	Umeclidinium/vilanterol 62.5/25 μg qd Umeclidinium 62.5 μg qd Vilanterol 25 μg qd Placebo (3:3:3:2)	ICS at stable dose
Aclidinium
Jones et al (2012) (ATTAIN)^Citation29	24 weeks	828	57 (GOLD II/III)	Aclidinium 200 μg bid Aclidinium 400 μg bid Placebo (1:1:1)	ICS; theophylline; OCS; oxygen therapy
Singh et al (2014) (ACLIFORM)^Citation30	24 weeks	1,729	54 (GOLD II/III)	Aclidinium/formoterol 400/12 μg bid Aclidinium/formoterol 400/6 μg bid Aclidinium 400 μg Formoterol 12 μg bid Placebo (2:2:2:2:1)	ICS; theophylline; OCS; oxygen therapy
D’Urzo et al (2014) (AUGMENT)^Citation31	24 weeks	1,692	53–55	Aclidinium/formoterol 400/12 μg bid Aclidinium/formoterol 400/6 μg bid Aclidinium 400 μg bid Formoterol 12 μg bid Placebo (1:1:1:1:1)	Stable doses of theophylline, ICS, or systemic corticosteroids permitted

Notes: In all studies, use of other anticholinergics/muscarinic antagonists was not permitted.

a Postbronchodilator FEV₁, unless otherwise stated.

b Two 1-year studies were evaluated.

c Reference does not specify if this is pre- or postbronchodilator FEV₁.

Abbreviations: bid, twice daily; FEV₁, forced expiratory volume in 1 second; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; OCS, oral corticosteroids; OL, open label; qd, once daily; SABA, short-acting β₂-agonist.

Table 2 Lung function in patients receiving LAMA therapy, compared with placebo, in double-blind, randomized, placebo-controlled studies ≥6 months in duration

Study	FEV1 at baseline (mL)		Trough FEV1 (mL)
	Treatment	Placebo	Δ vs placebo (at time point)	P-value
Tiotropium 18 µg qd (via HandiHaler^® device)
Casaburi et al (2002)^Citation18	1,000	1,040	120–150a (49 weeks)	<0.01
Donohue et al (2002)^Citation19	1,110	1,060	137 (24 weeks)	<0.0001
Niewoehner et al (2005)^Citation20	1,040	1,040	100 (6 months)	<0.001
Chan et al (2007)^Citation21	970	960	100 (48 weeks)a	<0.0001
Tashkin et al (2008) (UPLIFT)^Citation22	1,330	1,332	87–103 (over study period to 48 months)a	<0.001
Troosters et al (2014)^Citation23	1,950	1,900	140 (week 24)	<0.001
Kerwin et al (2012) (GLOW2)^Citation27	1,500	1,500	83 (week 12) 84 (week 26) 89 (week 52)	<0.001
Tiotropium 5 µg qd (via Respimat^® device)
Bateman et al (2010)^Citation24	1,066	1,058	127 (week 48)a	<0.0001
Bateman et al (2010)^Citation25	1,109	1,101	102 (week 48)a	<0.0001
Glycopyrronium 50 µg qd
D’Urzo et al (2011) (GLOW1)^Citation26	1,490	1,450	105 (week 12)a 113 (week 26)	<0.001
Kerwin et al (2012) (GLOW2)^Citation27	1,500	1,500	97 (week 12)a 134 (week 26) 108 (week 52)	<0.001
Umeclidinium 62.5 µg qd
Donohue et al (2013)^Citation28	NR	NR	115 (day 169)a	<0.001
Aclidinium 400 µg bid
Jones et al (2012) (ATTAIN)^Citation29	1,510	1,500	128 (week 24)a	<0.0001
Singh et al (2014) (ACLIFORM)^Citation30	1,400	1,420	117 (week 24)	<0.001
D’Urzo et al (2014) (AUGMENT)^Citation31	1,340	1,350	~101 (week 24)b	<0.0001

Notes: Results for FEV₁ are expressed as active treatment minus placebo values. All differences vs placebo are statistically significant unless otherwise indicated.

a Primary endpoint.

b Estimated from figure.

Abbreviations: bid, twice daily; FEV₁, forced expiratory volume in 1 second; LAMA, long-acting muscarinic antagonist; NR, not reported; qd, once daily.

Table 3 Effect on exacerbations in patients receiving LAMA therapy, compared with placebo, in double-blind, randomized, placebo-controlled studies ≥6 months in duration

Study	Annual exacerbation rate (treatment vs placebo)			% patients with ≥1 exacerbation			Risk reduction Exacerbation in time to first type exacerbation (P-value)
	Placebo	Treatment	Treatment vs placebo (P-value)	Placebo	Treatment	Treatment vs placebo (P-value)
Tiotropium (via HandiHaler^® device)
Casaburi et al (2002)^Citation18	0.95	0.76	20% reduction (0.045)	42	36	14% reduction (<0.05)	NR (0.011)	All
Donohue et al (2002)^Citation19	NR	NR	NR	NR	NR	NR	NR	NR
Niewoehner et al (2005)^Citation20	1.05	0.85	NR (0.031)	32	28	OR =0.81a (0.037)	17% (0.028)	Moderate or severe
Chan et al (2007)^Citation21	0.92	0.88	NR (NS)	41	44	NR (NS)	NR	Moderate
Tashkin et al (2008) (UPLIFT)^Citation22	0.85	0.73	Relative risk =0.86 (<0.001)	68	67	NR (NS)	14% (<0.001)	Moderate
Troosters et al (2014)^Citation23	NR	NR	NR	NR	NR	NR	NR
Kerwin et al (2012) (GLOW2)^Citation27	NR	NR	NR (NS)	NR	NR	RR =0.80 (NS)	39% (0.001)	Moderate or severe
Tiotropium (via Respimat^® device)
Bateman et al (2010)b,^Citation24	1.91	0.93	NR (NS)	44	37	OR =0.75 (<0.01)	NR (<0.0001)	Moderate
Bateman et al (2010)^Citation25	0.87	0.69	Relative rate =0.79 (<0.0001)	43	35	HR =0.69 (<0.0001)	31%a (<0.0001)	Mild or moderate
Glycopyrronium 50 µg qd
D’Urzo et al (2011) (GLOW1)^Citation26	0.59	0.43	RR =0.72 (NS)	24	18	NR	31% (0.023)	Moderate or severe
	NR	NR	NR	NR	NR	NR	65% (0.022)	Severe
Kerwin et al (2012) (GLOW2)^Citation27	NR	NR	NR	0.80	0.54	RR =0.66 (0.003)	34% (0.001)	Moderate or severe
Umeclidinium 62.5 µg qd
Donohue et al (2013)^Citation28	NR	NR	NR	13	NR, 7%–9% in active groups	NR (NR)	~40% (<0.05)	Moderate or severe
Aclidinium 400 µg bid
Jones et al (2012) (ATTAIN)^Citation29	0.47	0.34	RR =0.72 (NS)	NR	NR	NR	NR	Moderate or severe
	0.60	0.40	RR =0.67 (<0.05)	NR	NR	NR	NR	All
Singh et al (2014) (ACLIFORM)^Citation30	0.36	0.29	NR (NS)	NR	NR	NR	NR	All (HCRU)
D’Urzo et al (2014) (AUGMENT)^Citation31	NR	NR	NR	NR	NR	NR	NR

Notes: Mild exacerbation defined as increase in symptoms for ≥2 days resulting in an increased use of short-acting bronchodilators and/or ICS. Moderate exacerbation defined as new/increased cough, sputum, sputum purulence, dyspnea, wheeze, or chest discomfort for ≥3 days requiring antibiotics and/or systemic steroids. Severe exacerbations defined as exacerbations leading to hospitalization. HCRU, Healthcare Resource Utilization (defined as an increase of COPD symptoms during ≥2 consecutive days that require a change in COPD treatment).

a Primary endpoint.

b Pooled analysis of two studies (difference in time to first exacerbation was not significant in one of the two studies).

Abbreviations: bid, twice daily; HR, hazard ratio; ICS, inhaled corticosteroid; LAMA, long-acting muscarinic antagonist; NR, not reported; NS, not statistically significant; OR, odds ratio; qd, once daily; RR, rate ratio.

Table 4 Dyspnea, health status, and rescue medication use in patients receiving LAMA therapy, compared with placebo, in double-blind, randomized, placebo-controlled studies ≥6 months in duration

Study	Treatments	TDI focal score		Health status (SGRQ)		Rescue medication
		Δ vs placebo	Responders (%) (treatment vs placebo)	Δ vs placebo	Responders (%) (treatment vs placebo)	use (treatment vs placebo)
Tiotropium (via HandiHaler^® device)
Casaburi et al (2002)^Citation18	Tiotropium 18 μg qd	0.8–1.1 P<0.001	42–47 vs 29–34 P<0.001	NR P<0.05	49 vs 30 Significant but P-value not given	3.2 vs 4.1 doses/day P<0.01
Donohue et al (2002)^Citation19	Tiotropium 18 μg qd	1.02 P=0.01	42 vs 26 P<0.01	−2.71 P<0.05	51 vs 42 P<0.05	−1.45 puffs/day vs placebo P<0.0001
Niewoehner et al (2005)^Citation20	Tiotropium 18 μg qd	NR	NR	NR	NR	NR
Chan et al (2007)^Citation21	Tiotropium 18 μg qd	NR	NR	−2.8 P<0.01	53 vs 44 NS	~6 fewer puffs/week vs placebo P<0.01
Tashkin et al (2008) (UPLIFT)^Citation22	Tiotropium 18 μg qd	NR	NR	−2.7 P<0.001	45–49 vs 36–41 P<0.001	NR
Troosters et al (2014)^Citation23	Tiotropium 18 μg qd	NR	NR	NR	NR	NR
Kerwin et al (2012) (GLOW2)^Citation27	Tiotropium 18 μg qd OL Week 26 Week 52	0.94 P=0.002 0.66 P=0.037	53.4 vs 44.2 P=0.032 NR	−2.52 P<0.05 −2.84 P=0.014	NR 59 vs 51 NS	NR −0.63 puffs/day P<0.01
Tiotropium (via Respimat^® device)
Bateman et al (2010)^Citation24	Tiotropium 5 μg qd	1.05 P<0.0001	56 vs 44 P<0.0001	−3.5 P<0.0001	51 vs 41 P<0.05	−0.6 occasions/day P<0.0001
Bateman et al (2010)^Citation25	Tiotropium 5 μg qd	NR	NR	−2.9 P<0.0001	50 vs 41 P<0.0001	NR
Glycopyrronium
D’Urzo et al (2011) (GLOW1)^Citation26	Glycopyrronium 50 μg qd	1.04 P<0.001	61 vs 48 P=0.001	−2.8 P=0.004	57 vs 46 P=0.006	−0.46 puffs/day P=0.005
Kerwin et al (2012) (GLOW2)^Citation27	Glycopyrronium 50 μg qd Week 26 Week 52	0.81 P=0.002 0.57 P=0.038	55 vs 44 P=0.01 NR	−3.38 P<0.001 −3.32 P<0.001	NR 54 vs 51 NS	NR −0.37 puffs/day P<0.05
Umeclidinium
Donohue et al (2013)^Citation28	Umeclidinium 62.5 μg qd	1.0 P≤0.001	53 vs 41 P≤0.01	−4.69 P≤0.001	44 vs 34 P≤0.01	−0.3 puffs/day NS
Aclidinium
Jones et al (2012) (ATTAIN)^Citation29	Aclidinium 400 μg bid	1.0 P<0.001	57 vs 46 P<0.01	−4.6 P<0.0001	57 vs 41 P<0.001	−0.95 puffs/day P<0.0001
Singh et al (2014) (ACLIFORM)^Citation30	Aclidinium 400 μg bid	0.9 P<0.01	57 vs 46 P<0.05	0.71 NS	NR	NR
D’Urzo et al (2014) (AUGMENT)^Citation31	Aclidinium 400 μg bid	0.98a P≤0.001	55 vs 37 P≤0.001	−4.23a P≤0.001	55 vs 39 P≤0.001	−0.68 from baseline with aclidinium (placebo NR) P<0.0001

Notes: All comparisons are vs placebo. Responder analyses represent percentages of patients with TDI score ≥1 or SGRQ improvement ≥4 points.

a Values are estimated from figures in the associated reference.

Abbreviations: bid, twice daily; LAMA, long-acting muscarinic antagonist; NR, not reported; NS, not statistically significant; OL, open label; qd, once daily; SAL, salmeterol; SGRQ, St George’s Respiratory Questionnaire; TDI, transition dyspnea index.

Table 5 AEs in patients receiving LAMA therapy, compared with placebo, in double-blind, randomized, placebo-controlled studies ≥6 months in duration

Study	Treatments	Typical anticholinergic AEs (% patients)
		Dry mouth	Constipation	UTI
Tiotropium (via HandiHaler^® device)
Casaburi et al (2002)^Citation18	Tiotropium 18 μg qd/placebo	16/2.7	NR	NR
Donohue et al (2002)^Citation19	Tiotropium 18 μg qd/placebo	10/NR	NR	NR
Niewoehner et al (2005)^Citation20	Tiotropium 18 μg qd/placebo	NR	NR	NR
Chan et al (2007)^Citation21	Tiotropium 18 μg qd/placebo	3.5/3.6	NR	NR
Tashkin et al (2008) (UPLIFT)^Citation22	Tiotropium 18 μg qd/placebo	1.7/0.9a	1.6/1.3a	2.1/2.0a
Troosters et al (2014)^Citation23	Tiotropium 18 μg qd/placebo	1.3/0.9	NR	NR
Kerwin et al (2012) (GLOW2)^Citation27	Tiotropium 18 μg qd OL/placebo	1.5/1.9	NR	6.0/3.0
Tiotropium (via Respimat^® device)
Bateman et al (2010)^Citation24	Tiotropium 5 μg qd/placebo	7.2/2.1	NR	NR
Bateman et al (2010)^Citation25	Tiotropium 5 μg qd/placebo	3.1/1.4	NR	NR
Glycopyrronium
D’Urzo et al (2011) (GLOW1)^Citation26	Glycopyrronium 50 μg qd/placebo	NR	NR	NR
Kerwin et al (2012) (GLOW2)^Citation27	Glycopyrronium 50 μg qd/placebo	3.0/1.9	NR	2.7/3.0
Umeclidinium
Donohue et al (2013)^Citation28	Umeclidinium 62.5 μg qd/placebo	NR	NR	NR
Aclidinium
Jones et al (2012) (ATTAIN)^Citation29	Aclidinium 400 μg bid/placebo	NR	NR	0.7/0.7
Singh et al (2014) (ACLIFORM)^Citation30	Aclidinium 400 μg bid/placebo	NR	NR	NR
D’Urzo et al (2014) (AUGMENT)^Citation31	Aclidinium 400 μg bid/placebo	0.6/0.3	2.1/1.8	3.3/3.0

Notes:

a Incidence rate per 100 patient years.

Abbreviations: AEs, adverse events; bid, twice daily; LAMA, long-acting muscarinic antagonist; NR, not reported; OL, open label; qd, once daily; UTI, urinary tract infection.

Table 6 Inhalers used with LAMAs for COPD

Property of inhaler	HandiHaler^®9,101	Respimat^®8,102,103	Breezhaler^®10,101	Ellipta^®11,104,105	Genuair^®9,106
LAMA administered	Tiotropium	Tiotropium	Glycopyrronium	Umeclidinium	Aclidinium
Single dose or multidose	Single dose	Multidose	Single dose	Multidose	Multidose
Type	Dry powder	Soft mist (spray)	Dry powder	Dry powder	Dry powder
Resistance	High	Low	Low	Medium	Medium
Inhalations for each use	One capsulea	Two actuations	One capsuleb	One	One
Dose counter	N/A	Dose indicator shows approximately how much left	N/A	Yes (on opening cover)	Dose indicator (counts in intervals of 10)
Confirmation of dose	No (capsule is opaque but can be opened)	No	Yes (hear the click when the capsule is pierced and the whirring sound during inhalation; feel the lactose in the product; see the clear/empty capsule)	Yes (clicking sound when cover is opened and dose is ready; counter counts down by one)	Yes (green control window confirms that product is ready for inhalation – this turns back to red to confirm that full dose has been taken; clicking sound signals correct inhalation)
Locks when empty	N/A	Yes	N/A	No	Yes
Refillable	Yes (clean monthly; replace after 1 year)	No (replace if empty)	Yes within the same prescription. Each inhaler should be replaced after 30 days of use	No (replace if empty)	No (replace if empty)

Notes:

a Second inhalation required to ensure the capsule is empty.

b More than one inhalation may be required to empty the capsule; most people are able to empty the capsule with one or two inhalations.

Abbreviations: LAMA, long-acting muscarinic antagonist; N/A, not available.

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