Exacerbation heterogeneity in COPD: subgroup analyses from the FLAME study

Figures & data

Table 1 Prespecified and post hoc statistical analyses

Endpoint	Statistical analysis	Prespecified analysis	Post hoc analysis
Baseline demographic and clinical characteristics	Summaries by exacerbation history in the previous year		X
Rate of moderate/severe exacerbations	Subgroup analysis by exacerbation history in the previous year • 1 and ≥2 moderate/severe exacerbations	X
Rate of all (mild, moderate, severe) exacerbations	• GOLD 2017 Group D (≥2 exacerbations or ≥1 hospitalization due to exacerbations)*		X
	Subgroup analysis by previous treatment
	• ICS use at screening • LABA use at screening • LABA/ICS fixed-dose combination use at screening • LAMA use at screening • LABA/LAMA/ICS use at screening	X
		X
		X
		X
			X
	Analysis according to HCRU*
	• Requiring treatment with systemic corticosteroids and antibiotics • Requiring treatment with antibiotics • Requiring treatment with systemic corticosteroids alone • Requiring hospitalization • Rehospitalizations within 30 days after a severe exacerbation	X
		X
		X
		X
		X
Time to first moderate/severe exacerbation	Subgroup analysis by exacerbation history in the previous year
	• 1 and ≥2 moderate/severe exacerbations • GOLD 2017 Group D (≥2 exacerbations or ≥1 hospitalization due to exacerbations)		X
			X
Treatment with antibiotics and/or systemic corticosteroids	Pattern of treatment with antibiotics and/or systemic corticosteroids in patients with ≥2 exacerbations and ≥3 exacerbations during the treatment period		X
COPD deaths	Number and percentage	X

Note:

* Analysis performed only for rate of moderate/severe exacerbations.

Abbreviations: GOLD, Global Initiative for Chronic Obstructive Lung Disease; HCRU, health care resource use; ICS, inhaled corticosteroid; LABA, long-acting β2 agonist; LAMA, long-acting muscarinic antagonist.

Table 2 Patient demographics and clinical characteristics at baseline based on exacerbation history in the previous year (randomized set)

Patient characteristics	1 exacerbation (N=2,710)	≥2 exacerbations (N=649)	≥2 exacerbations or ≥1 hospitalization due to exacerbations (N=1,047)
Age (years)	64.5 (7.8)	64.7 (7.9)	64.8 (7.8)
Male, n (%)	2,094 (77.3)	461 (71.0)	791 (75.5)
Duration of COPD (years)	7.2 (5.4)	7.7 (5.5)	7.2 (5.3)
Current smoker, n (%)	1,088 (40.1)	243 (37.4)	403 (38.5)
Severity of COPD (GOLD 2015), n (%)
High risk and more symptoms (GOLD D)	1,864 (68.8)	649 (100.0)	1,047 (100.0)
Severity of airflow limitation (GOLD 2011–2014), n (%)
Moderate (GOLD 2)	928 (34.2)	193 (29.7)	298 (28.5)
Severe (GOLD 3)	1,561 (57.6)	392 (60.4)	636 (60.7)
Very severe (GOLD 4)	199 (7.3)	58 (8.9)	105 (10.0)
Post-bronchodilator FEV1 (L)	1.2 (0.3)	1.2 (0.3)	1.2 (0.3)
Post-bronchodilator FEV1, % predicted	44.3 (9.4)	43.1 (9.6)	42.6 (9.6)
Post-bronchodilator FEV1 reversibility (%)	22.2 (15.9)	23.1 (16.4)	22.6 (16.1)
Post-bronchodilator FEV1/FVC (%)	41.7 (9.7)	40.8 (10.3)	41.1 (10.3)
COPD medications at screening, n (%)
ICS alone or in combination	1,486 (54.8)	406 (62.6)	644 (61.5)
LAMA alone or in combination	1,614 (59.6)	421 (64.9)	660 (63.0)
LABA alone or in combination	1,794 (66.2)	462 (71.2)	722 (69.0)
LABA/LAMA/ICS use only	886 (32.7)	263 (40.5)	410 (39.2)
LABA/ICS use only	504 (18.6)	123 (19.0)	201 (19.2)
LABA/LAMA use only	276 (10.2)	62 (9.6)	88 (8.4)
LAMA+ICS use only	56 (2.1)	15 (2.3)	26 (2.5)
LABA use only	128 (4.7)	14 (2.2)	23 (2.2)
LAMA use only	396 (14.6)	81 (12.5)	136 (13.0)
Other	464 (17.1)	91 (14.0)	163 (15.6)
SGRQ-C total scorea	46.5 (15.6)	50.3 (16.4)	50.5 (16.3)
CAT scoreb	16.4 (6.9)	18.0 (7.2)	17.9 (7.3)
mMRC dyspnea scale, n (%)
Grade 2	1,969 (72.7)	441 (68.0)	703 (67.1)
Grade 3	690 (25.5)	180 (27.7)	300 (28.7)
Grade 4	46 (1.7)	28 (4.3)	44 (4.2)
Rescue medication use (puffs/day)	3.9 (3.8)	4.7 (4.3)	4.6 (4.3)
Urine cortisolc (ng/mL)	15.6 (23.3)	17.5 (18.9)	16.4 (17.1)

Notes: Data are presented as mean (SD) unless otherwise specified;

a On a scale of 0–100, with higher scores indicating worse health status;

b On a scale of 0–40, with higher scores indicating worse health status;

c Twenty-four hour urine cortisol measured in a total of 535 patients (IND/GLY 266, and SFC 269).

Abbreviations: CAT, COPD assessment test; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β₂ agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council; SGRQ-C, St George’s Respiratory Questionnaire for COPD.

Figure 1 Annualized rate of moderate or severe COPD exacerbations in different subgroups of patients based on prior exacerbations (full analysis set).

Abbreviations: IND/GLY, indacaterol/glycopyrronium; SFC, salmeterol/fluticasone.

Figure 2 Kaplan–Meier plot of time to first moderate or severe COPD exacerbation in different subgroups of patients based on prior exacerbations (full analysis set).

Notes: (A) Patients with history of 1 exacerbation in the previous year. (B) Patients with history of ≥2 exacerbations in the previous year. (C) Patients with history of ≥2 exacerbations or at least 1 exacerbation that led to hospitalization in the previous year.
Abbreviations: IND/GLY, indacaterol/glycopyrronium; SFC, salmeterol/fluticasone.

Figure 3 Annualized rate of moderate or severe COPD exacerbations based on previous treatment (full analysis set).

Abbreviations: ICS, inhaled corticosteroid; IND/GLY, indacaterol/glycopyrronium; LABA, long-acting β₂ agonist; LAMA, long-acting muscarinic antagonist; SFC, salmeterol/fluticasone.

Figure 4 Number and RR of moderate or severe COPD exacerbations according to HCRU with IND/GLY versus SFC during the treatment period.

Notes: *If an exacerbation satisfies multiple criteria (eg, required treatment with a medication and later required hospitalization), then the event is counted in each category (row) satisfied. Thus, the percentages do not add up to 100%.
Abbreviations: HCRU, health care resource utilization; IND/GLY, indacaterol/glycopyrronium; RR, rate ratio; SFC, salmeterol/fluticasone.