Association between poor therapy adherence to inhaled corticosteroids and tiotropium and morbidity and mortality in patients with COPD

Figures & data

Table 1 Baseline characteristics of patients using ICSs (including combined preparations)

Characteristics	Overall	Adherence category: first 6 months of ICS use				p-value
	ICSs (n=635)	Optimal use, ≥75–≤125% (n=365)	Suboptimal use, ≥50–<75% (n=92)	Underuse, <50% (n=75)	Overuse, >125% (n=103)
Age (years), mean (SD)	67.1 (9.7)	66.2 (9.5)	69.1 (10.3)	67.1 (9.8)	68.5 (9.6)	0.035
Sex (male), n (%)	377 (59.4)	221 (60.5)	61 (66.3)	39 (52.0)	56 (54.4)	0.187
Smoking status, n (%)
Current smoker	176 (27.7)	86 (23.6)	25 (27.2)	21 (28.0)	44 (42.7)	0.002
Ex-smoker	459 (72.3)	279 (76.4)	67 (72.8)	54 (72.0)	59 (57.3)
Lung function, mean (SD)
FEV1 (L)	1.4 (0.56)a	1.4 (0.55)	1.3 (0.66)	1.3 (0.59)	1.3 (0.46)	0.035
FEV1 % predicted	51.2 (18.4)a	52.3 (17.7)	49.4 (20.5)	50.1 (21.1)	49.7 (16.8)	0.379
FEV1/VC ratio	43.5 (13.3)a	43.5 (12.3)	42.7 (14.2)	45.6 (16.1)	42.8 (13.8)	0.483
mMRC, mean (SD)b	1.8 (1.26)	1.6 (1.2)	2.0 (1.3)	2.2 (1.3)	2.0 (1.3)	0.000
Tiotropium use, n (%)	440 (69.3)	265 (72.6)	70 (76.1)	40 (53.3)	65 (63.1)	0.002
Comorbidities, n (%)
Heart failure	100 (15.8)	52 (14.2)	19 (20.7)	11 (14.7)	18 (17.5)	0.460
Myocardial infarction	26 (4.1)	8 (2.2)	8 (8.7)	4 (5.3)	6 (5.8)	0.016
Diabetes mellitus	36 (5.7)	16 (4.4)	5 (5.4)	5 (6.7)	10 (9.7)	0.220

Notes:

a Lung function measurements of 634 patients (one patient with optimal use missing).

b mMRC data available for optimal use (n=328), suboptimal use (n=86), underuse (n=68), and overuse (n=97).

Abbreviations: ICS, inhaled corticosteroid; SD, standard deviation; FEV₁, forced expiratory volume in 1 second; FEV₁% predicted, percentage of predicted forced expiratory volume in 1 second; VC, vital capacity; mMRC, modified Medical Research Council.

Table 2 Baseline characteristics of patients using tiotropium

Characteristics	Overall	Adherence category: first 6 months of tiotropium use				p-value
	Tiotropium (n=505)	Optimal use, ≥75–≤125% (n=360)	Suboptimal use, ≥50–<75% (n=64)	Underuse, <50% (n=36)	Overuse, >125% (n=45)
Age (years), mean (SD)	66.0 (9.8)	65.9 (9.4)	67.1 (11.1)	64.0 (11.1)	66.8 (9.8)	0.443
Sex (male), n (%)	310 (61.4)	222 (61.7)	38 (59.4)	21 (58.3)	29 (64.4)	0.932
Smoking status, n (%)
Current smoker	149 (29.5)	94 (26.1)	24 (37.5)	14 (38.9)	17 (37.8)	0.073
Ex-smoker	356 (70.5)	266 (73.9)	40 (62.5)	22 (61.1)	28 (62.2)
Lung function, mean (SD)
FEV1 (L)	1.4 (0.56)	1.4 (0.56)	1.4 (0.53)	1.7 (0.66)	1.3 (0.46)	0.021
FEV1% predicted	51.7 (17.7)	51.9 (17.7)	51.1 (16.0)	57.1 (21.1)	47.1 (16.3)	0.090
FEV1/VC ratio	43.5 (12.8)	43.4 (12.5)	43.2 (13.2)	47.9 (16.3)	51.7 (17.7)	0.097
mMRC, mean (SD)a	1.71 (1.2)	1.59 (1.8)	1.93 (1.17)	2.00 (1.37)	2.15 (1.41)	0.007
ICS use, n (%)	440 (87.1)	316 (87.8)	55 (85.9)	30 (83.3)	39 (86.7)	0.876
Comorbidities, n (%)
Heart failure	86 (17.0)	67 (18.6)	4 (6.3)	7 (19.4)	8 (17.8)	0.108
Myocardial infarction	18 (3.6)	10 (2.8)	3 (4.7)	1 (2.8)	4 (8.9)	0.161
Diabetes mellitus	35 (6.9)	21 (5.8)	4 (6.3)	6 (16.7)	4 (8.9)	0.100

Note:

a mMRC data available for optimal use (n=334), suboptimal use (n=59), underuse (n=33), and overuse (n=39).

Abbreviations: SD, standard deviation; FEV₁, forced expiratory volume in 1 second; FEV₁% predicted, percentage of predicted forced expiratory volume in 1 second; VC, vital capacity; mMRC, modified Medical Research Council; ICS, inhaled corticosteroid.

Table 3 ICSs that were investigated

Medication	Months used, median (IQR)
Ciclesonide (n=22)	23.5 (15.8–35.5)
Fluticasone (n=73)	25.7 (12.5–34.9)
Formoterol/budesonide (n=91)	31.2 (15.9–36.5)
Salmeterol/fluticasone (n=493)	27.4 (13.2–34.7)
Budesonide (n=44)	28.2 (17.4–36.7)
Beclomethasone (n=44)	15.7 (7.5–31.7)
Formoterol/beclomethasone (n=8)	9.3 (4.0–16.5)

Abbreviations: ICS, inhaled corticosteroid; IQR, interquartile range.

Table 4 Univariate and multivariate Cox regression analyses with time-varying coefficients of therapy adherence to ICSs

	Adherence category/confounder	Univariate			Multivariate
		HR	95% CI	p-value	HR	95% CI	p-value
Hospital admission	Suboptimal use	1.3	0.9–1.8	0.135	1.2	0.8–1.8	0.382
	Underuse	1.0	0.7–1.4		0.8	0.5–1.2
	Overuse	1.4	1.0–2.0		1.2	0.8–1.7
	FEV1% predicted				0.5	0.4–0.7	<0.001
	Age				1.0	1.0–1.0	0.295
	mMRC				1.4	1.2–1.5	<0.001
	MI				1.9	1.1–3.4	0.032
Pneumonia	Suboptimal use	1.1	0.7–1.7	0.918	1.0	0.6–1.6	0.940
	Underuse	1.2	0.8–1.8		1.1	0.7–1.7
	Overuse	1.1	0.7–1.7		0.9	0.6–1.5
	FEV1% predicted				0.7	0.5–1.0	0.007
	Age				1.0	1.0–1.0	0.026
	MI				1.9	1.1–3.5	0.047
Mortality	Suboptimal use	2.5	1.5–4.2	,0.001	2.9	1.7–5.1	<0.001
	Underuse	5.0	3.2–7.6		5.3	3.3–8.5
	Overuse	1.2	0.6–2.3		0.9	0.4–2.1
	FEV1% predicted				0.3	0.2–0.5	<0.001
	Age				1.1	1.0–1.1	<0.001
	mMRC				1.2	1.0–1.4	0.009
	Tiotropium use				1.2	0.8–1.8	0.635

Note: Optimal use set as reference category.

Abbreviations: ICS, inhaled corticosteroid; HR, hazard ratio; FEV₁% predicted, percentage of predicted forced expiratory volume in 1 second; mMRC, modified Medical Research Council; MI, myocardial infarction.

Table 5 Univariate and multivariate Cox regression analyses with time-varying coefficients of therapy adherence to tiotropium

	Adherence category/confounder	Univariate			Multivariate
		HR	95% CI	p-value	HR	95% CI	p-value
Hospital admission	Suboptimal use	3.1	2.1–4.5	<0.001	3.0	2.0–4.5	<0.001
	Underuse	1.8	1.2–2.9		1.9	1.2–3.1
	Overuse	2.4	1.5–3.8		1.8	1.1–3.2
	FEV1% predicted				0.5	0.4–0.7	<0.001
	mMRC				1.4	1.2–1.6	<0.001
Pneumonia	Suboptimal use	2.3	1.3–3.9	0.014	2.2	1.2–4.0	0.018
	Underuse	1.5	0.8–2.8		1.7	0.9–3.2
	Overuse	2.2	1.1–4.4		2.3	1.2–4.7
	FEV1% predicted				0.6	0.3–0.9	0.001
	mMRC				1.2	1.0–1.4	0.057
Mortality	Suboptimal use	4.1	2.4–7.3	<0.001	3.9	2.1–7.5	<0.001
	Underuse	5.6	3.4–9.1		6.4	3.8–10.8
	Overuse	1.7	0.7–4.4		1.1	0.3–3.7
	FEV1% predicted				0.3	0.2–0.5	<0.001
	mMRC				1.2	1.0–1.5	0.060

Note: Optimal use set as reference category.

Abbreviations: HR, hazard ratio; FEV₁% predicted, percentage of predicted forced expiratory volume in 1 second; mMRC, modified Medical Research Council.