Clinical and Economic Impact of Long-Term Inhaled Corticosteroid Withdrawal in Patients with Chronic Obstructive Pulmonary Disease Treated with Triple Therapy in Spain

Figures & data

Table 1 Demographic Characteristics, Comorbidities, COPD Classification, and Other Variables in the 12-Month Pre-Index Period

Study Groups	Triple Therapy	ICS Withdrawal	Total	p-value
Number of patients, (%)	5740 (87.8)	801 (12.2)	6541 (100)
Demographic characteristics
Mean (SD) age, years	70.8 (10.8)	68.2 (11.2)	70.5 (10.8)	<0.001
Age range, %
40–64 years	27.3	35.1	28.3
65–74 years	32.3	33.0	32.3
≥75 years	40.4	32.0	39.4	<0.001
Male, %	71.0	70.4	70.9	0.750
General comorbidity
Mean (SD) Charlson index	2.2 (1.4)	2.0 (1.1)	2.2 (1.4)	0.001
Charlson index, %
1	41.4	45.3	41.9
2	28.5	25.0	28.1
3+	30.1	29.7	30.0	<0.001
Specific comorbidity, %
Hypertension	65.3	60.2	64.7	0.005
Diabetes mellitus	24.3	24.3	24.3	0.997
Dyslipidemia	54.4	43.6	53.1	<0.001
Obesity	16.9	17.6	17.0	0.628
Active smoker	15.1	11.5	14.7	0.006
Ischemic heart disease	15.2	13.5	15.0	0.191
Stroke	11.3	10.1	11.1	0.321
Heart failure	19.8	15.7	19.3	0.006
Kidney failure	13.0	12.0	12.9	0.423
Neoplasms	11.4	11.2	11.4	0.861
Asthma	12.7	11.0	12.5	0.169
Emphysema	10.3	9.1	10.2	0.292
Bronchiectasis	10.3	10.0	10.3	0.787
Classification/severity of COPD, %
GOLD II (moderate)	53.9	64.4	55.2
GOLD III (severe)	43.3	34.5	42.2
GOLD IV (very severe)	2.8	1.1	2.6	<0.001
Other parameters/variables
Mean (SD) time from diagnosis, years	18.9 (7.9)	16.4 (6.4)	18.6 (7.8)	<0.001
Mean (SD) BMI, kg/m^2	28 (3.9)	27.1 (4.7)	27.9 (4)	<0.001
Mean (SD) FEV1, %	52.2 (14)	55.8 (14.1)	52.6 (14)	<0.001
Mean (SD) blood eosinophils, cells/µL	212.7 (139.4)	172.7 (142)	207.8 (140.3)	<0.001
Blood eosinophils ≥300 cells/µL, %	18.4	13.5	17.8	0.001

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; SD, standard deviation.

Table 2 Medications Administered and Exacerbation Rate During the 12-Month Pre-Index Period

Study Groups	Triple Therapy	ICS Withdrawal	Total	p-value
Number of patients, (%)	5740 (87.8)	801 (12.2)	6541 (100)
Medication use, %
Oral corticosteroids	33.6	30.3	33.2	0.069
Chronic oral corticosteroids (>6 months)	10.6	8.2	10.3	0.042
Systemic antibiotics	26.6	24.6	26.4	0.219
Short-acting β2 agonists	93.3	89.3	92.8	<0.001
Xanthines	11.1	8.7	10.8	0.047
Leukotriene antagonists	2.8	2.5	2.8	0.619
Home oxygen therapy	11.1	9.9	10.9	0.308
Using LAMA, %
Tiotropium	71.4	69.9	71.2
Glycopyrronium	16.2	17.0	16.3
Others (aclidinium, umeclidinium)	12.4	13.1	12.5	0.807
Combination of LABA/ICS, %
Salmeterol/fluticasone propionate	55.5	51.7	55.0
Formoterol/budesonide	18.7	20.2	18.9
Vilanterol/fluticasone furoate	2.0	2.5	2.1
Formoterol/fluticasone propionate	1.4	1.2	1.4
Formoterol/beclomethasone	22.4	24.3	22.6	0.298
Dose of ICS, %
Low	38.8	43.2	39.4
Medium	28.2	29.7	28.4
High	33.0	27.1	32.3	0.003
Mean (SD) dose of ICS, mg	569.1 (314.4)	540.6 (301)	565.6 (312.9)	<0.001
Year before study entry
Patients with an exacerbation, %	35.2	31.2	34.7	0.028
Mean (SD) total exacerbations	0.6 (0.9)	0.4 (0.7)	0.5 (0.9)	0.016
Overall exacerbations, %
None	64.9	69.3	65.4
1	17.3	19.4	17.5
2	14.7	9.7	14.1
3+	3.1	1.6	2.9	<0.001
Patients with a moderate exacerbation, %	34.4	30.7	34.0	<0.001
Mean (SD) moderate exacerbations	0.4 (0.6)	0.4 (0.6)	0.4 (0.6)
Moderate exacerbations, %
None	65.6	69.3	66.0
1	29.5	26.3	29.1
2+	4.9	4.4	4.8	0.033
Severe exacerbations (hospital admission)
Mean (SD) severe exacerbations	0.2 (0.4)	0.1 (0.3)	0.1 (0.4)	<0.001
Severe exacerbations, %
None	84.5	91.8	85.4	<0.001
≥1	15.5	8.2	14.6	<0.001

Abbreviations: ICS, inhaled corticosteroids; LABA, long-acting β₂-agonists; LAMA, long-acting muscarinic antagonists; SD, standard deviation.

Table 3 Demographic Characteristics, Comorbidities, COPD Classification, and Other Variables in the 12-Month Pre-Index Period (After Propensity Score Matching)

Study Groups	Triple Therapy	ICS Withdrawal	Total	p-value	Standardized Differences
Number of patients, %	795	795	1590
Demographic characteristics
Mean (SD) age, years	68.7 (11.3)	68.4 (11.1)	68.5 (11.2)	0.654	0.023
Age range, %
40–64 years	34.8	34.6	34.7
65–74 years	33.5	33.2	33.3
≥75 years	31.7	32.2	31.9	0.977	0.005
Male, %	69.2	70.6	69.9	0.548	0.015
General comorbidity
Mean (SD) Charlson index	2.0 (1.3)	2.0 (1.2)	2 (1.2)	0.839	0.010
Charlson index, %
1	48.4	45.2	46.8
2	27.2	25.0	26.1
3+	24.4	29.8	27.1	0.482	0.078
Specific comorbidity, %
Hypertension	63.5	60.4	61.9	0.197	0.032
Diabetes mellitus	22.4	24.5	23.5	0.314	0.025
Dyslipidemia	47.3	43.9	45.6	0.174	0.034
Obesity	16.2	17.6	16.9	0.462	0.018
Active smoker	10.6	11.6	11.1	0.523	0.016
Ischemic heart disease	13.7	13.5	13.6	0.884	0.004
Stroke	8.6	10.2	9.4	0.263	0.028
Heart failure	15.7	15.8	15.8	0.945	0.002
Kidney failure	12.6	12.1	12.3	0.760	0.008
Neoplasms	10.2	11.2	10.1	0.519	0.018
Asthma	11.8	10.9	11.4	0.580	0.014
Emphysema	6.8	9.2	8.0	0.096	0.044
Bronchiectasis	8.3	10.1	9.2	0.224	0.030
Classification/severity of COPD, %
GOLD II (moderate)	62.4	64.2	63.3
GOLD III (severe)	36.2	34.7	35.5
GOLD IV (very severe)	1.4	1.1	1.3	0.722	0.020
Other parameters/variables
Mean (SD) time from diagnosis, years	16.1 (7.9)	16.5 (6.3)	16.3 (7.2)	0.225	0.061
Mean (SD) BMI, kg/m^2	27.4 (4.1)	27.1 (4.6)	27.3 (4.2)	0.142	0.038
Mean (SD) FEV1, %	54.4 (13.6)	55.7 (14.1)	55 (13.9)	0.081	0.094
Mean (SD) blood eosinophils, cells/µL	182.1 (103.4)	173.1 (142.4)	177.6 (124.5)	0.147	0.061
Blood eosinophils ≥300 cells/µL, %	13.6	13.6	13.6	0.999	0.001

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; SD, standard deviation.

Table 4 Medications Administered and Exacerbation Rate During the 12-Month Pre-Index Period (After Propensity Score Matching)

Study Groups	Triple Therapy	ICS Withdrawal	Total	p-value	Standardized Differences
Number of patients	795	795	1590
Medication use, %
Oral corticosteroids	28.8	29.9	29.4	0.620	0.012
Chronic oral corticosteroids (>6 months)	9.2	8.3	8.7	0.534	0.016
Systemic antibiotics	22.3	24.7	23.5	0.261	0.028
Short-acting β2 agonists	92.2	89.3	90.8	0.175	0.050
Xanthines	7.8	8.8	8.3	0.467	0.018
Leukotriene antagonists	2.0	2.5	2.3	0.613	0.017
Home oxygen therapy	8.8	9.9	8.9	0.045	0.038
Using LAMA, %
Tiotropium	70.6	69.8	70.2
Glycopyrronium	17.0	17.0	17.0
Others (aclidinium, umeclidinium)	12.5	13.2	12.8	0.914	0.018
LABA/ICS combination (retired), %
Salmeterol/fluticasone propionate	53.5	51.7	52.6
Formoterol/budesonide	18.6	20.4	19.5
Vilanterol/fluticasone furoate	1.5	2.5	2.0
Formoterol/fluticasone propionate	1.0	1.3	1.1
Formoterol/beclomethasone	25.4	24.2	24.8	0.502	0.046
Dose of ICS, %
Low	43.6	43.0	43.3
Medium	26.3	29.8	28.1
High	30.1	27.2	28.6	0.228	0.043
Mean (SD) dose of ICS, mg	550.0 (310.3)	541.1 (301.2)	545.6 (305.7)	0.561	0.029
Year before study entry
Patients with an exacerbation, %	30.9	30.2	30.6	0.913	0.003
Mean (SD) total exacerbations	0.5 (0.8)	0.4 (0.8)	0.4 (0.8)	0.560	0.029
Overall exacerbations, %
None	69.1	69.8	69.4
1	19.7	18.7	19.2
2	8.1	9.8	8.9
3+	3.1	1.7	2.4
Patients with a moderate exacerbation, %	30.7	30.2	30.4	0.754	0.021
Mean (SD) moderate exacerbations	0.4 (0.6)	0.4 (0.6)	0.4 (0.6)	0.540	0.057
Severe exacerbations, %
None	69.3	69.8	69.6
1	26.3	25.8	26.0
2+	4.4	4.4	4.4	0.821	0.044
Severe exacerbations (hospital admission)
Mean (SD) severe exacerbations	0.1 (0.3)	0.1 (0.3)	0.1 (0.3)	0.787	0.014
Number of severe exacerbations, %
None	91.3	91.7	91.5
≥1	8.7	8.3	8.5	0.755	0.007

Abbreviations: ICS, inhaled corticosteroids; LABA, long-acting β₂-agonists; LAMA, long-acting muscarinic antagonists; SD, standard deviation.

Table 5 Medication Administered, Exacerbations, and Other Variables During the 12-Month Follow-Up (After Propensity Score Matching)

Study Groups	Triple Therapy	ICS Withdrawal	Total	p-value
Number of patients	795	795	1590
Medication use, %
Oral corticosteroids	30.9	35.6	33.3	0.049
Chronic oral corticosteroids (>6 months)	8.3	9.2	8.7	0.534
Systemic antibiotics	25.2	31.9	28.6	0.003
Short-acting β2 agonists	92.7	95.7	94.2	0.010
Xanthines	8.2	11.4	9.8	0.028
Leukotriene antagonists	4.7	4.0	4.3	0.538
Home oxygen therapy	9.7	11.7	10.7	0.194
Exacerbations
Total patients with an exacerbation, %	31.4	36.6	34.0	0.030
Mean (SD) total exacerbations	0.4 (0.7)	0.5 (0.8)	0.5 (0.8)	0.018
Overall exacerbations
None	68.6	63.4	66.0
1	21.0	24.8	22.9
2	9.4	8.7	9.1
3+	1.0	3.1	2.1	0.009
Patients with a moderate exacerbation, %	31.4	34.1	32.8	0.251
Mean (SD) moderate exacerbations	0.3 (0.5)	0.4 (0.6)	0.4 (0.6)	0.011
Moderate exacerbations, %
None	68.6	65.9	67.2
1	30.2	27.9	29.1
2	0.9	6.2	3.5
3+	0.4	0.0	0.2	<0.001
Severe exacerbations (hospital admission), %	8.4	11.2	9.8	0.071
Mean (SD) severe exacerbations	0.1 (0.3)	0.1 (0.3)	0.1 (0.3)	0.044
Severe exacerbations, %
None	91.6	88.8	90.2
1	8.3	10.7	9.5
2	0.1	0.5	0.3	0.104
Pneumonia, %	3.6	3.3	3.5	0.583
Deaths, %	7.5	9.9	8.7	0.092
Time to first exacerbation, days
Mean (SD)	185.1 (100.3)	157.7 (100.5)	170.4 (101.2)	0.002
Median (P25–P75)	186 (102–270)	161 (59.7–244.7)	172 (79.0–258.0)
Treatment persistence
Percentage persistent on treatment, %	84.2	86.3	85.2	0.831
Mean (SD) persistence, days	331.3 (85.3)	335.8 (81)	333.6 (83.2)	0.277
Median (P25–P75) persistence, days	365 (365–365)	365 (365–365)	365 (365–365)

Abbreviations: ICS, inhaled corticosteroids; P, percentiles; SD, standard deviation.

Table 6 Health Resource Use and Costs (Mean/Patient/Year) During the 12-Month Follow-Up (After Propensity Score Matching)

Study Groups	Triple Therapy	ICS Withdrawal	Total	p-value
Number of patients	795	795	1590
Mean (SD) resource use
Primary care visits	8.6 (6.2)	10.4 (7.6)	9.5 (7.0)	<0.001
Specialist visits	0.8 (1.3)	1.1 (2.3)	0.9 (1.8)	0.004
Hospital emergency visits	0.6 (0.8)	1.0 (1.2)	0.8 (1.0)	<0.001
Days of hospital stay	0.9 (2.9)	1.9 (5.8)	1.4 (4.6)	<0.001
Laboratory tests	1.0 (0.9)	1.5 (1.3)	1.3 (1.1)	<0.001
Conventional radiology	1.1 (1.2)	1.6 (1.9)	1.3 (1.6)	<0.001
Axial tomography	0.5 (0.5)	0.9 (0.7)	0.7 (0.6)	<0.001
Magnetic nuclear resonance	0.4 (0.5)	0.6 (0.6)	0.5 (0.5)	<0.001
Other complementary tests	1.5 (1.0)	2.4 (1.5)	1.9 (1.4)	<0.001
Mean (SD) health costs (€)
Primary care visits	200 (144.1)	240.6 (175.7)	220.3 (161.9)	<0.001
Specialist visits	73.7 (115.7)	98.2 (210.2)	85.9 (170.1)	0.004
Hospital emergency visits	74.8 (96.2)	116.6 (141.7)	95.7 (122.8)	<0.001
Days of hospital stay	414.4 (1.414.6)	892.2 (2.802.8)	653.3 (2.232.1)	<0.001
Laboratory tests	33.7 (27.7)	48.9 (41.9)	41.3 (36.3)	<0.001
Conventional radiology	32 (33.6)	44.5 (55.5)	38.2 (46.3)	<0.001
Axial tomography	47.1 (48.0)	87.8 (67.1)	67.4 (61.8)	<0.001
Magnetic nuclear resonance	74.6 (87.5)	100.6 (99.9)	87.6 (94.8)	<0.001
Other complementary tests	71 (47.3)	111.3 (71.5)	91.1 (63.8)	<0.001
Respiratory medications	1150.2 (676.8)	1258.6 (417.3)	1204.4 (564.7)	<0.001
Total health costs	2171.5 (1821.4)	2999.3 (3159)	2585.4 (2610.7)	<0.001
Adjusted model (ANCOVA^a)			Difference
Health cost, mean	2130	2993	863	<0.001
95% CI	1.937–2.322	2.798–3.188

Notes: ^aANCOVA model: contrasts are based on peer comparisons between estimated marginal means; covariates: age, sex, time from diagnosis, Charlson index.

Abbreviations: ANCOVA, analysis of covariance; CI, confidence interval; ICS, inhaled corticosteroids; SD, standard deviation.