The role of combination therapy with corticosteroids and long-acting β₂-agonists in the prevention of exacerbations in COPD

Figures & data

Table 1 Long-term effect of combination therapy in COPD

Study	Treatment (μg bid)a	N	Duration (weeks)	Baseline FEV1(% pred)	Primary outcome(s)
Fluticasone/salmeterol (FSC)
Hanania et al 2003	FSC 250/50	178	24	41%	Changes in FEV1
	FP 250	183		42%
	SAL 50	177		42%
	PLA	185		42%
Mahler et al 2002	FSC 500/50	165	24	41%	Changes in FEV1
	FP 500	168		41%
	SAL 50	160		40%
	PLA	181		41%
Calverley et al 2003a (TRISTAN study)	FSC 500/50	358	52	45%	Changes in FEV1
	FP 500	374		45%
	SAL 50	372		44%
	PLA	361		44.2
Budesonide/formoterol (BFC)
Szafranski et al 2003	BFC 400/12	208	52	36%	Changes in FEV1
	BUD 400	198		37%
	FORM 12	201		36%
	PLA	205		36%	Number of exacerbations
Calverley et al 2003b	BFC 400/12	254	52	36%	Changes in FEV1
	BUD 400	257		36%
	FORM 12	255		36%
	PLA	256		36%	Time to first exacerbation

a All doses are reported as metered doses.

Abbreviations: BFC, budesonide/formoterol combination; BUD, budesonide; FORM, formoterol; FP, fluticasone propionate; FSC, fluticasone/salmeterol combination; PLA, placebo; SAL, salmeterol.

Table 2 Absolute and relative risk reductions for exacerbations of COPD requiring medical intervention with number needed to treat in three randomized and double-blind multinational trials

Treatment	12 month frequency of exacerbation (mean rate/patient/year)		Absolute risk reduction	Relative risk reduction (combination vs LABA)	NTT	Reference
	combination therapy	LABA only
Fluticasone/salmeterol (TRISTAN, n = 1456)	0.97	1.04	0.07	0.067 (6.7%)	14	Calverley et al 2003a
Budesonide/formoterol (n = 812)	1.42	1.84	0.42	0.23 (23%)	2.4	Szafranski et al 2003
Budesonide/formoterol (n = 1002)	1.38	1.85	0.47	0.25 (25%)	2.1	Calverley et al 2003b

Data from Cazzola 2006.

Abbreviations: LABA, long-acting β₂-agonist; NNT, number needed to treat.

Table 3 Definitions of COPD exacerbation used in combination therapy studies

Study	Definition
Hanania et al 2003	Defined by treatment, with moderate exacerbations requiring treatment with antibiotics and/or corticosteroids, and severe exacerbations requiring hospitalization)
Mahler et al 2002	Defined by treatment (mild = increased use of salbutamol; moderate = use of either oral antibiotics and/or corticosteroids; severe = hospitalization)
Calverley et al 2003a (TRISTAN study)	Worsening of COPD symptoms that required treatment with antibiotics, oral corticosteroids, or both
Szafranski et al 2003	Mild: a day with ≥ 4 inhalations of reliever medication above the mean run-in use; severe: requirement for oral steroids and/or antibiotics and/or hospitalization due to respiratory symptoms
Calverley et al 2003b	Event requiring medical intervention (oral antibiotics and/or corticosteroids or hospitalization) due to respiratory symptoms

Figure 1 Total severe exacerbation rate.

Notes: PLA, placebo; LABA, salmeterol 50 μg bid or formoterol 12 μg bid; ICS, fluticasone propionate 500 μg bid or budesonide 400 μg bid; LABA/ICS, salmeterol 50 μg/fluticasone 500 μg bid or formoterol 12 μg/budesonide 400 μg bid. * difference between combination treatment and single compound treatment and/or PLA statistically significant (p<0.05); § difference between single compound treatment and PLA statistically significant (p<0.05). Data from Calverley et al 2003a (TRISTAN); Calverley et al 2003b; Szafranski et al 2003.

Figure 2 Rate of exacerbations requiring oral corticosteroids.

Notes: PLA, placebo; LABA, salmeterol 50 μg bid or formoterol 12 μg bid; ICS, fluticasone propionate 500 μg bid or budesonide 400 μg bid; LABA/ICS, salmeterol 50 μg/fluticasone 500 μg bid or formoterol 12 μg/budesonide 400 μg bid. * difference between combination treatment and single compound treatment and/or PLA statistically significant (p<0.05); § difference between single compound treatment and PLA statistically significant (p<0.05). Data from Calverley et al 2003a (TRISTAN); Calverley et al 2003b; Szafranski et al 2003.

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