The safety of long-acting β₂-agonists in the treatment of stable chronic obstructive pulmonary disease

Figures & data

Table 1 Study selectiona

	FOR	SLM	IND
Retrieved (total)	154	225	42
Excluded	144	216	38
Acute (eg, single dose)	30	30	6
Already listed (eg, pooled studies)	2	1	–
No LABA as single treatment arm	–	10	–
No LABA as single treatment, no placebo	–	5	–
No placebo	9	20	–
Not relevant	50	65	7
Of other interest (eg, meta-analysis)	1	2	2
Other (eg, journal club)	1	2	–
Review	9	9	7
Secondary study report	–	20	–
Too short	23	28	14
Too short, no single treatment arm, no placebo	–	1	–
Too short, no placebo	19	23	2
Included	10	9	4b

Notes:^aOnly single reasons included here although articles may have qualified for exclusion for multiple reasons

^btwo of these studies also feature in the FOR and SLM columns.

Abbreviations: FOR, formoterol; SLM, salmeterol; IND, indacaterol; LABA, long-acting β₂-agonist.

Table 2 Effect of treatment on COPD exacerbations (as efficacy outcome)

Reference	Exclusion criteria for asthma	ICS allowed^a (% of patients)	n (LABA/PBO)	Exacerbations (LABA vs PBO)
FOR 9, 10, or 12 μg bid
Rossi et al^Citation68	Current or childhood asthma according to American Thoracic Society criteria	Y(47)	211/220	~32%vs~4l%ofdays(mild)^b 7% vs 8% of days (moderate) 32% vs 34% of pts (additional therapy) 10 vs 20 hospitalizations
Szafranski et al^Citation69	History of asthma and/or seasonal allergic rhinitis before the age of 40 years	N	201/205	1.84 vs 1.87 per pt-yr (severe)
Calverley et al^Citation31	History of asthma/seasonal allergic rhinitis before the age of 40 years	N	255/256	154 vs 96 days (time to first exacerbation) 1.85 vs 1.80 per pt-yr (total) 0.91 vs 1.14 per pt-yr (oral steroids)
Campbell et al^Citation70	History of asthma or seasonal allergic rhinitis	Y(47)	215/217	16.3% vs 15.7% of pts (≥ 1 severe)
Tashkin et al^Citation71	History of asthma or seasonal allergic rhinitis before the age of 40 years	N	284/300	1.098 vs I.I 10 per pt-yr (all) 1.104 vs 1.068 per pt-yr (oral steroids)
Vogelmeier et al^Citation72	Not stated	Y	210/209	24.9% vs 33.9% “bad days”^b 2.4% vs 4.7% “exacerbation days”^b 8.1 % vs 14.4% of pts (additional therapy) 0.5% vs 1.4% (hospitalizations)
Rennard et al^Citation73	History of asthma or seasonal allergic rhinitis before the age of 40 years	N	495/481	~0.75 vs ~0.88 per pt-yr
Dahl et al^Citation39	History of asthma	Y(5I)	435/432	3 1.5% vs 36.3% of pts (≥ 1 exacerbation) 0.56 vs 0.74 per yr^b
Doherty et al^Citation74	Current diagnosis of asthma	N	243/236	40% vs 46% of pts (total) 18% vs 25% of pts (moderate/severe as first event)
Tashkin et al^Citation75	Current diagnosis of asthma; increase in FEV1 ≥400 mL post-salbutamol	N	209/212	ND
FOR 24 μg bid
Rossi et al^Citation68	Current or childhood asthma according to American Thoracic Society criteria	Y(47)	214/220	~34%vs~4l%"baddays"^b 4% vs 8% of days (moderate)^b 23% vs 34% of pts (additional therapy) 5 vs 20 hospitalizations
SLM 50 μg bid
Mahler et al^Citation76	Current diagnosis of asthma	N	160/181	No significant difference (time to first)
Chapman et al^Citation77	Not stated	Y(68)	201/207	26% vs 33% of pts (> 1 exacerbation) 13% vs 18% of pts (oral steroids)
Calverley et al^Citation78	Not stated	N	372/361	1.04 vs 1.30 per pt-yr (total)^b 0.54 vs 0.76 per pt-yr (oral steroids)^b
Brusasco et al^Citation79	Patients with a history of asthma, allergic rhinitis, atopy, or with an increased total eosinophil count	ND	405/400	35% vs 39% of pts (≥ 1 exacerbation) 24.1 vs 25.0 "exacerbation days" per pt-yr 13.8% vs 14.5% of pts (oral steroids) 5% vs 5% of pts (hospitalization) 1.23 vs 1.49 per pt-yr (total) 0.17 vs 0.15 per pt-yr (hospitalization)
Hanania et al^Citation80	Current diagnosis of asthma	N	177/185	No significant differences (number or time to first)
Stockley et al^Citation81	Not stated	Y(54)	316/318	0.58 vs 0.83 per pt-yr (moderate/severe)^b
Calverley et al^Citation7	Increase in FEV1 with salbutamol < 10% of predicted value; diagnosis of asthma	N	1521/1524	0.97 vs 1.13 per pt-yr (moderate/severe)^b 0.64 vs 0.80 per pt-yr (systemic steroids)^b 0.16 vs 0.19 per pt-yr (hospitalization)^b
Kornmann et al^Citation40	History of asthma	Y(46)	333/335	34.1% vs 38.1% "days of poor COPD control"
IND I50 μg od
Donohue et al^Citation41	History of asthma	Y(38)	416/418	17.3% vs 21.8% of pts (≥ 1 exacerbation) Hazard ratio 0.69^b (time to first) 0.50 vs 0.72 per pt-yr^b
Kornmann et al^Citation40	History of asthma	Y(45)	330/335	34.1% vs 38.1% "days of poor COPD control"
Chapman et al^Citation42	History of asthma	Y(34)	144/124	0.39 vs 0.54 per pt-yr^b
IND 300 μg od
Dahl et al^Citation39	History of asthma	Y(56)	437/432	32.8% vs 36.3% of pts (≥1 exacerbation) Hazard ratio 0.77^b (time to first) IND 300, 0.60 vs 0.74 per pt-yr
Donohue et al^Citation41	History of asthma	Y(37)	416/418	18.3% vs 21.8% of pts (≥ 1 exacerbation) Hazard ratio 0.74 (time to first) 0.53 vs 0.72 per pt-yr
Chapman et al^Citation42	History of asthma	Y(34)	146/124	0.38 vs 0.54 per pt-yr^b
IND 600 μg od
Dahl et al^Citation35	History of asthma	Y(53)	428/432	29.3% vs 36.3% of pts (≥ 1 exacerbation) Hazard ratio 0.69^b (time to first) 0.57 vs 0.74 per pt-yr^b

Notes:^aPatients permitted to continue on stable doses of inhaled corticosteroids; Significant difference favoring active over placebo treatment. “~” = estimated from graphical data.

Abbreviations: bid, twice daily; COPD, chronic obstructive pulmonary disease; FEV₁ forced expiratory volume in I second; FOR, formoterol; ICS, inhaled corticosteroids; IND, indacaterol; LABA, long-acting β₂-agonist; N, no; ND, not disclosed; od, once daily; PBO, placebo; pt, patient; SLM, salmeterol; Y, yes; yr, year.

Table 3 Reported safety outcomes (LABA versus PBO)

Study	Deaths (n)	SAEsa		AEs
		All	COPD	All	COPD
FOR 9, 10 or 12 μg bid
Rossi et al^Citation68	3 vs 0	11% vs 15%	ND	66% vs 67%	16% vs 15%
Szafranski et al^Citation69	6 vs 9	18% vs 18%	ND	ND	19% vs 26%
Calverley et al^Citation31	13 vs 5	85 vs 66 events	55 vs 38 events (29% vs 31%)	6 vs 5 events/1000 days	ND
Campbell et al^Citation70	2 vs 1	13 vs 9 pts	ND	3.8 vs 4.5 events/1000 days	ND
Tashkin et al^Citation71	1 vs 1	8% vs 8%	4% vs 4%	57% vs 51%	18% vs ND
vogelmeier et al^Citation72	0 vs 1	8%–10% vs ND	2% vs 3%	34% vs 39%	10% vs 16%
Rennard et al^Citation73	4 vs 4	18% vs 12%	8% vs 6%	60% vs 56%	17% vs 16%
Dahl et al^Citation39	3 vs 4	16% vs 11%	7% vs 5%	65% vs 62%	31% vs 35%
Doherty et al^Citation74	4 vs 2	8% vs 9%	2% vs 5%	38% vs 40%	ND
Tashkin et al^Citation75	3 vs 1	8% vs 6%	3% vs 3%	34% vs 32%	ND
FOR 24 μg bid
Rossi et al^Citation68	1 vs 0	7% vs 15%	ND	64% vs 67% pts	12% vs 15%
SLM 50 μg bid
Mahler et al^Citation76	0 vs 3	4%–7% overall	ND	73% vs 69%	ND
Chapman et al^Citation77	ND	ND	ND	72% vs 71%	20% vs 22%
Calverley et al^Citation78	ND	ND	ND	78%–81% overall	ND
Brusasco et alb,^Citation44,Citation79	6 vs 5	12% vs 14%	6% vs 6%	75% vs 77%	37% vs 41%
Hanania et al^Citation80	0 vs 0	3% vs 6%	ND	69% vs 64%	ND
Stockley et al^Citation81	6 vs 5	10% vs 12%	ND	45% vs 51%	ND
Calverley et al^Citation7	14 vs 15	40% vs 41%	ND	90% vs 90%	0.76 vs 0.92 per yr
Kornmann et al^Citation40	0 vs 3	6% vs 8%	1% vs 3%c	46% vs 47%	15% vs 19%
IND 150 μg od
Donohue et al^Citation41	1 vs 0	8% vs 8%	3% vs 2%	67% vs 64%	18% vs 22%
Kornmann et al^Citation40	1 vs 3	9% vs 8%	2% vs 3%c	51% vs 47%	18% vs 19%
Chapman et al^Citation42	0 vs 1	10% vs 11%	3% vs 2%	76% vs 68%	24% vs 27%
IND 300 μg od
Dahl et al^Citation39	1 vs 4	14% vs 11%c	4% vs 5%c	71% vs 62%	32% vs 35%
Chapman et al^Citation77	1 vs 1	12% vs 11%	3% vs 2%	77% vs 68%	27% vs 27%
Donohue et al^Citation41	0 vs 0	8% vs 8%	2% vs 2%	66% vs 64%	18% vs 22%
IND 600 μg od
Dahl et al^Citation39	0 vs 4	12% vs 11%c	3% vs 5%c	65% vs 62%	28% vs 35%

Notes: Percentages are % of patients. ^aDefined variably between the studies, eg, the studies with indacaterol include deaths

^badditional safety data from FDA.⁸²

^cdata supplied by Novartis Pharma AG.

Abbreviations: AE, adverse event; bid, twice daily; COPD, chronic obstructive pulmonary disease; FOR, formoterol; IND, indacaterol; LABA, long-acting β₂-agonist; ND, not disclosed; od, once daily; PBO, placebo; pt, patient; SAE, serious adverse event; SLM, salmeterol; yr, year.

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