Early response to inhaled bronchodilators and corticosteroids as a predictor of 12-month treatment responder status and COPD exacerbations

Figures & data

Table 1 Demographic and clinical characteristics of patients who received budesonide/formoterol, formoterol alone, or placebo in the 0–2-month responder analysis, and budesonide/formoterol or formoterol alone in the 12-month response and 2–12-month exacerbation rate analysesa

Characteristics	0–2-month response analysis (n=2,331)	12-month response analysis (n=1,799)	Exacerbation rate analysis (n=2,360)
Age, years	63.1 (9.2)	63.1 (9.2)	63.1 (9.2)
Male, n (%)	1,526 (65.5)	1,122 (62.4)	1,496 (63.4)
BMI, kg/m^2	26.8 (5.7)	26.7 (5.9)	26.6 (5.8)
Time since first symptoms, months	127.2 (84.8)	126.5 (85.3)	125.6 (85.2)
FEV1 parameters
Prebronchodilator, % predicted	34.2 (9.7)	34.7 (10.4)	34.4 (10.3)
Prebronchodilator,b L	1.0 (0.4)	1.0 (0.4)	1.0 (0.4)
Reversibility, % predicted	5.5 (5.9)	5.4 (5.6)	5.4 (5.6)
Postbronchodilator, % predicted	39.7 (11.9)	40.0 (12.4)	39.9 (12.4)
Prebronchodilator FEV1/FVC, %	47.6 (10.4)	47.0 (10.8)	46.8 (10.7)
Smoking history
Median, pack-years	40.0	43.0	42.0
Former smokers, n (%)	1,343 (57.6)	1,091 (60.6)	1,410 (59.8)
Current smokers, n (%)	988 (42.4)	708 (39.4)	950 (40.3)
SGRQ total score,b points (range)	54.9 (6.7–100.0)	56.1 (6.2–100.0)	55.8 (6.2–100.0)
Reliever use, no of inhalations (range)	3.7 (0.0–32.5)	4.8 (0.0–33.8)	4.5 (0.0–33.8)
COPD severity (GOLD grades),c n (%)
II (moderate)	436 (18.7)	386 (21.6)	497 (21.2)
III (severe)	1,364 (58.5)	981 (55.0)	1,288 (54.9)
IV (very severe)	522 (22.4)	414 (23.2)	555 (23.7)
Number of COPD maintenance medications,d n (%)
0	587 (25.2)	475 (26.5)	597 (25.4)
1	537 (23.0)	440 (24.6)	548 (23.3)
2	695 (29.8)	569 (31.8)	760 (32.3)
3	512 (22.0)	307 (17.1)	447 (19.0)

Notes: Data are given as mean (SD), unless otherwise stated.

a Assessments of FEV₁ and SGRQ were completed at baseline and month 2 (0–2-month responder analysis), and at baseline and months 2 and 12 (12-month responder and exacerbation rate analyses).

b Measured at randomization.

c GOLD COPD grades are defined as follows: grade II, postbronchodilator FEV₁ 50%–80% of predicted; grade III, postbronchodilator FEV₁ 30%–50% of predicted; and grade IV, postbronchodilator FEV₁ <30% of predicted.

d The number of COPD maintenance medications is defined as follows: 0, no maintenance treatment with LA or ICS (short-acting bronchodilators only); 1, one LA or ICS; 2, two LA or ICS; 3, three LA or ICS. All patients received short-acting β₂-agonists at inclusion so that a reversibility test could be conducted (GOLD classification based upon postbronchodilator FEV₁). The majority of patients with a prebronchodilator FEV₁ of 40%–50% had a postbronchodilator FEV₁ of ≥50%, thus classifying them as having moderate COPD. Patients were recruited if they displayed a prebronchodilator FEV₁ of ≤50%, but only postbronchodilator FEV₁ values are presented here.

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; LA, long-acting bronchodilator; SD, standard deviation; SGRQ, St George’s Respiratory Questionnaire.

Table 2 Demographic and clinical characteristics for all patients who received budesonide/formoterol, formoterol, or placebo, and by treatment group, in the two placebo-controlled trials included in the 0–2-month analysis

Characteristics	Total (n=2,331)	Budesonide/formoterol (n=771)	Formoterol (n=779)	Placebo (n=781)
Age, years	63.1 (9.2)	63.2 (9.0)	63.1 (9.3)	63.0 (9.3)
Male, n (%)	1,526 (65.5)	496 (64.3)	509 (65.3)	521 (66.7)
BMI, kg/m^2	26.8 (5.7)	26.6 (5.6)	26.8 (5.6)	27.0 (5.9)
Time since first symptoms, months	127.2 (84.8)	126.0 (84.0)	128.4 (85.1)	127.1 (85.3)
FEV1
Prebronchodilator, % predicted	34.2 (9.7)	33.3 (9.6)	34.1 (9.9)	35.1 (9.4)
Prebronchodilator, La	1.0 (0.4)	1.0 (0.4)	1.0 (0.4)	1.1 (0.4)
Reversibility, % predicted	5.5 (5.9)	5.4 (5.3)	5.3 (5.8)	5.8 (6.5)
Postbronchodilator, % predicted	39.7 (11.9)	38.8 (11.5)	39.4 (12.2)	41.0 (11.8)
Prebronchodilator FEV1/FVC, %	47.6 (10.4)	47.1 (10.4)	47.5 (10.5)	48.3 (10.3)
Smoking history
Median, pack-years	40.0	40.0	40.0	40.0
Former smokers, n (%)	1,343 (57.6)	455 (59.0)	437 (56.1)	451 (57.7)
Current smokers, n (%)	988 (42.4)	316 (41.0)	342 (43.9)	330 (42.3)
SGRQ total score,a points (range)	54.9 (6.7–100.0)	55.2 (6.7–100.0)	54.7 (16.4–97.4)	54.7 (8.8–96.9)
Reliever use, no of inhalations (range)	3.7 (0.0–32.5)	3.7 (0.0–21.6)	3.9 (0.0–32.5)	3.5 (0.0–28.0)
COPD severity (GOLD grades),b n (%)
II (moderate)	436 (18.7)	136 (17.6)	148 (19.0)	152 (19.5)
III (severe)	1,364 (58.9)	443 (57.5)	439 (56.4)	482 (61.7)
IV (very severe)	522 (22.4)	191 (24.8)	189 (24.3)	142 (18.2)
No of COPD maintenance medications,c n (%)
0	587 (25.2)	186 (24.1)	195 (25.0)	206 (26.4)
1	537 (23.0)	176 (22.8)	187 (24.0)	174 (22.3)
2	695 (29.8)	246 (31.9)	222 (28.5)	227 (29.1)
3	512 (22.0)	163 (21.1)	175 (22.5)	174 (22.3)

Notes: Data are given as mean (SD), unless otherwise stated.

a Measured at randomization.

b GOLD COPD grades are defined as follows: grade II, postbronchodilator FEV₁ 50%–80% of predicted; grade III, postbronchodilator FEV₁ <30%–50% of predicted; and grade IV, postbronchodilator FEV₁ <30% of predicted.

c The number of COPD maintenance medications is defined as follows: 0, no maintenance treatment with LA or ICS (short-acting bronchodilators only); 1, one LA or ICS; 2, two LA or ICS; and 3, three LA or ICS.

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; LA, long-acting bronchodilator; SD, standard deviation; SGRQ, St George’s Respiratory Questionnaire.

Table 3 Analysis of 2-month response rates in FEV₁ and SGRQ total score in patients who received budesonide/formoterol, formoterol alone, or placebo in the two placebo-controlled trials

	FEV1 responsea		SGRQ responseb
	OR (95% CI)	P-value	OR (95% CI)	P-value
Odds of achieving response vs nonresponse
Budesonide/formoterol	0.79 (0.68–0.92)		0.98 (0.84–1.15)
Formoterol	0.51 (0.43–0.60)		0.72 (0.62–0.85)
Placebo	0.36 (0.30–0.43)		0.69 (0.59–0.82)
Odds of achieving response with one treatment vs another
Budesonide/formoterol vs formoterol	1.56 (1.25–1.95)	<0.001	1.36 (1.09–1.70)	0.006
Budesonide/formoterol vs placebo	2.21 (1.75–2.79)	<0.001	1.42 (1.13–1.78)	0.002
Formoterol vs placebo	1.42 (1.12–1.81)	0.004	1.04 (0.83–1.31)	0.72

Notes:

a FEV₁ response was defined as an improvement in the FEV₁ of ≥100 mL.

b SGRQ response was defined as an improvement (ie, reduction) in SGRQ total score of ≥4 points.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; OR, odds ratio; SGRQ, St George’s Respiratory Questionnaire.

Figure 1 Cumulative distribution of (A) FEV₁ response and (B) SGRQ response at 2 months in patients who received budesonide/formoterol, formoterol alone, or placebo, by treatment, according to multiple cut-points.

Note: Vertical lines represent the predefined response cut-offs (+100 mL for FEV₁ and −4 points for SGRQ total score).
Abbreviations: BUD, budesonide; FEV₁, forced expiratory volume in 1 second; FORM, formoterol; SGRQ, St George’s Respiratory Questionnaire.

Table 4 Poisson regression analysis of exacerbation rates, by treatment, during months 2–12 in patients who received budesonide/formoterol or formoterol and who did and did not achieve FEV₁ and SGRQ response at 2 months

	FEV1a		SGRQb
	Estimates (95% CI)	P-value	Estimates (95% CI)	P-value
Treatment (rate)
Budesonide/formoterol responders	0.60 (0.50–0.71)	NA	0.69 (0.59–0.80)	NA
Budesonide/formoterol nonresponders	0.82 (0.72–0.95)	NA	0.77 (0.66–0.90)	NA
Formoterol responders	0.71 (0.59–0.86)	NA	0.85 (0.73–0.99)	NA
Formoterol nonresponders	1.02 (0.90–1.15)	NA	0.97 (0.84–1.11)	NA
Budesonide/formoterol vs formoterol	0.82 (0.71–0.96)	0.012	0.80 (0.69–0.92)	0.002
Response (ratio)
Responders vs nonresponders	0.71 (0.61–0.83)	<0.001	0.89 (0.77–1.03)	0.11
Budesonide/formoterol responders vs budesonide/formoterol nonresponders	0.72 (0.58–0.90)	0.004	0.90 (0.73–1.11)	0.31
Formoterol responders vs formoterol nonresponders	0.70 (0.56–0.87)	0.001	0.88 (0.73–1.07)	0.21
Budesonide/formoterol responders vs formoterol responders	0.84 (0.65–1.08)	0.17	0.81 (0.66–0.99)	0.04
Budesonide/formoterol nonresponders vs formoterol nonresponders	0.81 (0.68–0.96)	0.015	0.79 (0.65–0.97)	0.022
Interaction	1.04 (0.77–1.41)	0.81	1.02 (0.76–1.35)	0.92

Notes:

a FEV₁ response was defined as an improvement in FEV₁ of ≥100 mL.

b SGRQ response was defined as a reduction (ie, an improvement) in SGRQ total score of ≥4 points.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; NA, not applicable; SGRQ, St George’s Respiratory Questionnaire.

Figure 2 Exacerbation rates during months 2–12 in patients who received budesonide/formoterol or formoterol alone and who achieved (A) FEV₁ response and (B) SGRQ improvements above various thresholds at 2 months.

Note: Vertical lines represent the predefined response cut-offs (+100 mL for FEV₁ and −4 points for SGRQ total score).
Abbreviations: BUD, budesonide; FEV₁, forced expiratory volume in 1 second; FORM, formoterol; SGRQ, St George’s Respiratory Questionnaire.

Table 5 Poisson regression analysis of exacerbation rate from 2 to 12 months according to treatment type, baseline FEV₁, and SGRQ total score, and FEV₁ and SGRQ response at 2 months in patients who received budesonide/formoterol or formoterol

	Contrast/regression coefficient (95% CI)	P-value
FEV1a
2-month response (per 100 mL)	0.92 (0.89–0.96)	<0.001
Baseline FEV1 (per 100 mL increase)	0.91 (0.90–0.93)	<0.001
Budesonide/formoterol vs formoterolb	0.83 (0.73–0.96)	0.010
SGRQc
2-month response (per 4-point reduction)	0.95 (0.92–0.97)	<0.001
Baseline SGRQ total score (per 4-point reduction)	0.97 (0.95–0.98)	<0.001
Budesonide/formoterol vs formoterolb	0.82 (0.71–0.94)	0.006

Notes:

a FEV₁ response was defined as an improvement in FEV₁ of ≥100 mL.

b Randomized comparison.

c SGRQ response was defined as a reduction (ie, an improvement) in SGRQ total score of ≥4 points.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; NA, not applicable; SGRQ, St George’s Respiratory Questionnaire.