Clinical and Economic Consequences of Inhaled Corticosteroid Doses and Particle Size in Triple Inhalation Therapy for COPD: Real-Life Study

Figures & data

Table 1 Baseline Characteristics of Study Subjects, COPD Classification and Medication Administered During Follow-Up by Study Groups

Inhaled ICS Doses	Low	Medium		High	Total	p
Number of Patients, %	N=849 (38.9%)	N=612 (28.0%)		N=724 (33.1%)	N=2185 (100%)
Sociodemographic features
Mean age, years	71.6 (11.8)	72.5 (11.4)		72.8 (10.5)	72.3 (11.3)	0.094
Age Range, years
40–64	27.3%	23.5%		21.3%	24.3%
65–74	29.2%	28.9%		29.0%	29.1%
≥ 75	43.5%	47.5%		49.7%	46.7%	0.049
Sex (male)	80.7%	82.4%		80.4%	81.1%	0.619
Overall comorbidity
Mean of diagnoses	3.6 (1.9)	3.7 (1.9)		3.7 (1.9)	3.7 (1.9)	0.413
Mean Charlson Index	1.6 (1.5)	1.8 (1.5)		1.7 (1.5)	1.7 (1.5)	0.332
1	32.0%	30.4%		30.7%	31.1%
2	19.1%	21.4%		19.3%	19.8%
3+	24.6%	26.5%		27.5%	26.1%	0.334
Associated comorbidities
Hypertension	60.1%	61.6%		61.9%	61.1%	0.731
Diabetes mellitus	26.3%	28.1%		27.1%	27.0%	0.737
Dyslipidaemia	55.0%	51.1%		55.1%	54.0%	0.258
Obesity	33.7%	33.5%		34.0%	33.7%	0.982
Active smoker	23.1%	23.2%		21.0%	22.4%	0.528
Ischemic heart disease	16.5%	19.8%		17.8%	17.8%	0.271
Cerebrovascular accident	11.2%	13.1%		11.0%	11.7%	0.443
Heart failure	23.2%	27.1%		24.0%	24.6%	0.210
Kidney failure	10.5%	11.3%		11.6%	11.1%	0.767
Depressive syndrome	13.3%	15.2%		13.3%	13.8%	0.509
Malign neoplasm	14.1%	14.2%		15.3%	14.6%	0.768
Asthma	13.0%	11.4%		12.7%	12.4%	0.664
COPD Severity
GOLD II (moderate)	64.8%	57.8%		59.7%	61.1%
GOLD III (severe)	34.0%	37.2%		42.8%	37.0%
GOLD IV (very severe)	1.2%	2.0%		2.5%	1.8%	0.029
Other parameters/variables
Time from diagnosis, years	15.3 (6.4)	15.9 (6.0)		16.3 (5.8)	15.8 (6.1)	0.011
BMI, kg/m^2	29.1 (5.2)	29.1 (5.0)		28.7 (4.8)	29.0 (5.0)	0.229
FEV1, %	60.7 (13.2)	58.6 (13.5)		54.9 (14.3)	58.2 (13.9)	<0.001
Blood eosinophils, cells/µL	185 (112)	186 (125)		182 (103)	184 (119)	0.527
Mean ICS dose	284.5 (83.1)	475.5 (67.1)		986.7 (121.5)	570.7 (317.1)	0.001

Notes: Values expressed as percentage or mean (SD: standard deviation), p: statistical significance.

Abbreviations: ICS, inhaled corticosteroids; GOLD, Global Initiative for Chronic Obstructive Lung Disease; BMI, body mass index, kg/m²; FEV₁, forced expiratory volume in the first second.

Figure 1 Study flow diagram. A retrospective observational study was carried out, made from the review of medical records (computerized databases, with anonymised and dissociated data) of patients diagnosed with COPD.

Abbreviation: ICS, inhaled corticosteroid.

Table 2 Incidence of Exacerbations and Pneumonia According to Inhaled Corticosteroid (ICS) Dose

Inhaled ICS Doses	Low	Medium	High	Total	p
Number of Patients	N=849	N=612	N=724	N=2185
Follow-up period (one year)
Mean (SD) number of exacerbations	0.5 (1.0)	0.6 (1.2)	0.6 (1.2)	0.6 (1.1)	0.062
% Patients with 0 exacerbation	72.6%	70.3%	69.6%	70.9%
% Patients with ≥1 exacerbation	26.4%	28.7%	30.4%	29.0%	0.047
1	16.5%	16.7%	18.4%	17.2%
2	6.1%	4.4%	4.6%	5.1%
3+	4.8%	8.7%	7.5%	6.8%	0.024
Mean nb (SD) number of mod exacerbation	0.4 (0.8)	0.5 (0.9)	0.5 (1.0)	0.4 (0.9)	0.257
% Patients with 0 mod exacerbation	72.8%	71.1%	70.9%	71.7%
% Patients with ≥1 mod exacerbation	26.2%	28.9%	29.1%	28.3%	0.044
1	19.4%	19.0%	21.3%	19.9%
2	3.8%	4.1%	1.7%	3.2%
3+	4.0%	5.9%	6.2%	5.3%	0.149
Mean nb (SD) of severe exacerbation	0.1 (0.3)	0.1 (0.4)	0.1 (0.4)	0.1 (0.4)	0.003
% Patients with 0 severe exacerbation	93.3%	90.8%	88.8%	91.1%
% Patients with ≥1 severe exacerbation	6.7%	9.2%	11.2%	8.9%	0.014
1	6.0%	7.2%	8.8%	7.3%
2	0.7%	2.0%	2.3%	1.6%	0.014
Time to first exacerbation, days
Mean (SD)	142.6 (98.9)	140.3 (95.1)	123.8 (82)	135.5 (92.5)	0.047
Median (P25 - P75)	132 (112–152)	130 (111–149)	116 (99–133)	130 (119–141)
Mean (SD) nb of pneumonias	0.0 (0.2)	0.0 (0.2)	0.1 (0.3)	0.1 (0.2)	0.002
% Patients with pneumonia	3.4%	4.2%	6.9%	4.7%	0.041
Death (% patients)	9.8%	11.4%	12.4%	11.1%	0.238
Medication use (% patients)
Oral corticosteroids	21.8%	23.5%	26.4%	25.3%	<0.001
Chronic use of oral corticosteroids	5.2%	7.5%	10.9%	8.1%	0.044
Systemic antibiotics	22.5%	25.7%	27.9%	23.8%	0.020
Beta-2 short-acting agonists	94.0%	92.0%	92.3%	92.9%	0.256
Xanthines	9.9%	8.7%	9.5%	9.4%	0.723
Leukotriene receptor antagonists	2.0%	2.1%	1.7%	1.9%	0.806
Home oxygen therapy	11.5%	11.4%	14.0%	12.3%	0.259
Duration of treatment (ICS), in months	10.3 (2.3)	10.5 (2.4)	10.1 (2.2)	10.4 (2.3)	0.748
Treatment changes	1.9 (0.2)	1.8 (0.2)	1.9 (0.2)	1.9 (0.2)	0.681

Note: Values expressed as percentage or mean.

Abbreviations: SD, standard deviation; p, statistical significance; P, percentile; IC, inhaled corticosteroids.

Table 3 Resource Use and Costs by Study Groups

Inhaled ICS Doses	Low	Medium	High	Total	p
Number of Patients, %	N=849	N=612	N=724	N=2185
Resource use
Medical visits, primary care	14.5 (9.1)	15.3 (10.1)	15.5 (10.9)	15.0 (10.0)	0.133
Laboratory tests	0.5 (0.9)	0.6 (1.0)	0.7 (1.1)	0.6 (1.0)	0.007
Conventional radiology	0.4 (1.2)	0.6 (1.7)	0.6 (1.6)	0.5 (1.5)	0.015
Complementary tests	0.4 (1.3)	0.4 (1.0)	0.5 (1.3)	0.4 (1.2)	0.466
Days of hospitalization	0.1 (0.3)	0.1 (0.4)	0.1 (0.4)	0.1 (0.3)	0.013
Medical visits, hospitals	3.5 (3.1)	3.8 (3.5)	3.9 (3.3)	3.7 (3.3)	0.030
Emergency visits, hospitals	2.7 (2.0)	3 (2.2)	3.0 (2.2)	2.9 (2.1)	0.001
Gross costs (€)
Costs in primary care	1561 (536)	1569 (591)	1757 (631)	1628 (591)	<0.001
Medical visits	334 (210)	351 (232)	356 (250)	346 (230)	0.133
Laboratory tests	19 (32)	21 (34)	24 (37)	21 (34)	0.007
Conventional radiology	19 (58)	30 (78)	26 (76)	24 (70)	0.015
Complementary tests	36 (108)	34 (86)	41 (113)	37 (104)	0.466
Medications	1154 (397)	1133 (391)	1309 (435)	1199 (416)	0.001
Costs, specialized care	730 (985)	887 (1249)	914 (1229)	835 (1149)	0.003
Days of hospitalization	179 (701)	268 (907)	298 (908)	243 (835)	0.013
Medical visits	236 (212)	262 (235)	263 (222)	252 (222)	0.030
Emergency visits	315 (237)	357 (261)	354 (256)	339 (251)	0.001
Health costs	2291 (1313)	2456 (1674)	2670 (1670)	2.463 (1550)	<0.001
Corrected cost model (€)*				Difference
Costs in primary care	1573	1558	1749	177	<0.001
95% CI	1522–1622	1497–1618	1695–1803
Costs in specialized care	811	843	876	65	0.654
95% CI	717–904	729–956	774–977
Total health costs	2383	2401	2625	242	0.024
95% Ci	2256–2510	2247–2554	2488–2761

Notes: Values expressed as mean. *ANCOVA model: Contrasts are based on pairwise comparisons between estimated marginal means.

Abbreviations: SD, standard deviation; p, statistical significance; CI, confidence interval; IC, inhaled corticosteroids.

Table 4 Baseline Characteristics of Patients by Study Groups

Type of Particles	Extrafine	Non-Extrafine	p
Number of Patients, %	N=462 (31.6%)	N=999 (68.4%)
Sociodemographic features
Mean age, years	72.5 (11.5)	71.8 (11.7)	0.301
Range: 40–64 years	25.3%	25.9%
65–74 years	26.8%	30.1%
≥ 75 years	47.8%	43.9%	0.320
Sex (male)	81.4%	81.4%	0.999
Overall comorbidity
Mean diagnoses	3.6 (1.8)	3.7 (1.9)	0.521
Mean Charlson Index	1.7 (1.5)	1.7 (1.5)	0.955
1	33.8%	30.2%
2	19.7%	20.2%
3+	24.9%	25.6%	0.367
Associated comorbidities
Hypertension	62.3%	60.0%	0.387
Diabetes mellitus	27.1%	27.0%	0.991
Dyslipidaemia	55.4%	52.5%	0.292
Obesity	34.2%	33.3%	0.745
Active smoker	22.9%	23.2%	0.906
Ischemic heart disease	17.1%	18.2%	0.604
Cerebrovascular accident	11.7%	12.1%	0.817
Heart failure	24.9%	24.8%	0.978
Kidney failure	10.2%	11.1%	0.591
Depressive syndrome	13.9%	14.2%	0.854
Malign neoplasm	14.5%	14.0%	0.804
Asthma	14.7%	11.2%	0.058
COPD Severity
GOLD II (moderate)	61.3%	62.2%
GOLD III (severe)	37.0%	36.4%
GOLD IV (very severe)	1.7%	1.4%	0.861
Other parameters/variables
Time from diagnosis, years	16 (6.3)	15.4 (6.0)	0.083
BMI, kg/m^2	29.3 (5.2)	29 (5.1)	0.385
FEV1, %	59.3 (13.3)	60.1 (13.4)	0.269
Blood eosinophils, cells/µL	181 (102.3)	185 (112.5)	0.678
Mean ICS dose	375.5 (121.5)	369.4 (121.4)	0.419

Note: Values expressed as percentage or mean.

Abbreviations: SD, standard deviation; p, statistical significance; GOLD, Global Initiative for Chronic Obstructive Lung Disease; BMI, body mass index, kg/m²; FEV₁, forced expiratory volume in the first second.

Table 5 Description of Exacerbations and Pneumonia by ICS Particle Size Grouping

ICS Particle Size	Extrafine		Non-Extrafine	p
Number of Patients, %	N=462 (31.6%)		N=999 (68.4%)
Follow-up period (one year)
Total exacerbations, %	24.0%		30.4%	0.012
Mean (SD) number of exacerbations	0.5 (1.1)		0.5 (1.1)	0.172
% Patients with 0 exacerbation	76.0%		69.6%
1	12.8%		18.3%
2	5.4%		5.4%
3+	5.8%		6.7%	0.048
Moderate exacerbations, %	23.6%		29.9%	0.048
Mean (SD) number of exacerbations	0.4 (0.9)		0.5 (0.9)	0.165
% Patients with 0 exacerbation	76.4%		70.1%
1	15.4%		21.0%
2	3.9%		3.9%
3+	4.3%		5.0%	0.079
Severe exacerbations (hospitalization), %	6.5%		8.3%	0.078
Mean (SD) number of exacerbations	0.1 (0.3)		0.1 (0.3)	0.268
% Patients with 0 exacerbation	93.5%		91.7%
1	5.4%		7.0%
2	1.1%		1.3%	0.479
Time to first exacerbation
Mean (SD)	164.6 (99)		133.4 (95.2)	0.004
Median (P25 - P75)	160 (138–182)		126 (114–138)
% Patients with pneumonia	3.0%		4.3%	0.378
Mean (SD) nb of pneumonias	0.0 (0.2)		0.1 (0.2)	0.102
Deaths	9.7%		10.8%	0.534
Medication use
Oral corticosteroids	26.4%		25.3%	0.413
Chronic oral corticosteroid use	7.9%		8.3%	0.685
Systemic antibiotics	21.2%		23.2%	0.647
Beta-2 short-acting agonists	95.2%		92.2%	0.032
Xanthines	9.7%		9.2%	0.746
Leukotriene receptor antagonists	2.2%		2.0%	0.839
Home oxygen therapy	11.3%		11.6%	0.843
Duration of treatment (ICS), in months	10.5 (2.2)		10.1 (2.3)	0.799
Treatment changes	1.8 (0.1)		1.9 (0.2)	0.691

Note: Values expressed as percentage or mean.

Abbreviations: SD, standard deviation; p, statistical significance; P, percentile.

Table 6 Resource Use and Costs by ICS Particle Size Grouping

ICS Particle Size	Extrafine	Non-Extrafine	p
Number of Patients, %	N=462 (31.6%)	N=999 (68.4%)
Resource use
Medical visits, primary care	12.4 (8.5)	15.9 (9.8)	<0.001
Laboratory tests	0.5 (0.8)	0.6 (1.0)	0.075
Conventional radiology	0.2 (0.6)	0.6 (1.7)	<0.001
Complementary tests	0.4 (1.2)	0.4 (1.2)	0.396
Days of hospitalization	0.1 (0.3)	0.1 (0.3)	0.315
Medical visits, hospitals	2.8 (2.0)	4 (3.6)	<0.001
Emergency visits, hospitals	2.3 (1.2)	3.1 (2.4)	<0.001
Gross costs (€)
Costs in primary care	1368 (500)	1655 (562)	<0.001
Medical visits	285 (196)	366 (224)	<0.001
Laboratory tests	18 (28)	21 (34)	0.075
Conventional radiology	9 (28)	30 (78)	<0.001
Complementary tests	32 (101)	36 (98)	0.396
Medications	1025 (382)	1200 (388)	<0.001
Costs, specialized care	643 (905)	867 (1180)	<0.001
Days of hospitalization	186 (743)	230 (817)	0.315
Medical visits	190 (136)	273 (247)	<0.001
Emergency visits	267 (137)	364 (280)	<0.001
Health costs	2011 (1185)	2522 (1568)	<0.001
Corrected cost model (€)*
Costs in primary care	1376	1657	<0.001
95% CI	1313–1438	1614–1700
Costs in specialized care	714	856	0.061
95% CI	591–837	771–939
Health costs	2090	2513	<0.001
95% CI	1926–2252	2401–2624

Notes: Values expressed in mean. *ANCOVA model: Contrasts are based on pairwise comparisons between estimated marginal means.

Abbreviations: SD, standard deviation; p, statistical significance; CI, confidence interval.