Effects of inhaler therapy on mortality in patients with tuberculous destroyed lung and airflow limitation

Figures & data

Figure 1 Study flow chart.

Abbreviation: LAMA, long-acting muscarinic antagonist.

Table 1 Baseline characteristics of patients with airflow limitation according to LAMA usage over 360 days

	LAMA group*	Non-LAMA group	P-value
Number of patients	177 (25.9)	506 (74.1)
Age, years	63.9±10.0	61.3±11.5	0.004
Male gender	132 (74.6)	339 (67.0)	0.061
Body mass index, kg/m^2	21.7±3.4	22.0±3.4	0.272
Ever smoker	113 (63.8)	291 (57.5)	0.140
mMRC dyspnea scale			<0.001
−0	27 (15.3)	196 (38.9)
−1	69 (39.2)	166 (32.9)
−2	44 (25.0)	80 (15.9)
−3	24 (13.6)	45 (8.9)
−4	12 (6.8)	17 (3.4)
Charlson Comorbidity Index	1.4±1.1	1.5±1.4	0.496
Concomitant asthma	35 (19.8)	55 (10.9)	0.003
ICS/LABA usage over 360 days	177 (18.8)	23 (2.9)	<0.001
Pulmonary function tests
FEV1, % predicted	40.7±13.0	54.1±20.2	<0.001
FVC, % predicted	63.1±16.0	71.1±19.4	<0.001
FEV1/FVC ratio, %	48.0±11.1	54.9±10.9	<0.001
DLco, % predicted	56.7±22.1	71.5±20.2	<0.001
Respiratory admission within 2 years	30 (16.9)	47 (9.3)	0.006
X-ray severity (0–6)	3.3±1.3	2.9±1.3	<0.001
Long-term oxygen therapy	30 (16.9)	29 (5.7)	<0.001

Notes: Data are presented as mean ± SD or number of patients (%), unless otherwise indicated.

* LAMA group included patients who were prescribed the tiotropium inhaler for ≥360 days during the follow-up period.

Abbreviations: DLco, diffusing capacity for carbon monoxide; ICS/LABA, inhaled corticosteroid/long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist.

Table 2 Baseline characteristics of patients with airflow limitation according to ICS/LABA usage over 360 days

	ICS/LABA group*	Non-ICS/LABA group	P-value
Number of patients	171 (25.0)	512 (75.0)
Age (years)	61.9±10.8	62.0±11.4	0.930
Male gender	119 (69.6)	352 (68.8)	0.837
Body mass index, kg/m^2	21.9±3.6	21.9±3.4	0.969
Ever smoker	107 (62.6)	297 (58.0)	0.293
mMRC dyspnea scale			<0.001
−0	22 (12.9)	201 (39.4)
−1	59 (34.7)	176 (34.5)
−2	47 (27.6)	77 (15.1)
−3	29 (17.1)	40 (7.8)
−4	13 (7.6)	16 (3.1)
Charlson Comorbidity Index	1.3±1.1	1.5±1.5	0.017
Concomitant asthma	52 (30.4)	38 (7.4)	<0.001
LAMA usage over 360 days	107 (62.6)	70 (13.7)	<0.001
Pulmonary function tests
FEV1, % predicted	40.2±13.0	54.1±20.0	<0.001
FVC, % predicted	62.8±16.8	71.1±19.1	<0.001
FEV1/FVC ratio, %	47.6±10.8	54.9±11.0	<0.001
DLco, % predicted	61.4±23.1	70.1±20.7	0.003
Respiratory admission within 2 years	25 (14.6)	52 (10.2)	0.110
X-ray severity (0–6)	3.3±1.4	2.9±1.3	<0.001
Long-term oxygen therapy	31 (18.1)	28 (5.5)	<0.001

Notes: Data are presented as mean ± standard deviation or number of patients (%), unless otherwise indicated.

* ICS/LABA group included patients who were prescribed the fluticasone propionate/salmeterol or budesonide/formoterol inhaler for ≥360 days during the follow-up period.

Abbreviations: DLco, diffusing capacity for carbon monoxide; LAMA, long-acting muscarinic antagonist; ICS/LABA, inhaled corticosteroid/long-acting beta-2 agonist.

Table 3 Risk factors for mortality in tuberculous destroyed lung patients with airflow limitation

	Univariate analysis			Multivariate analysis
	HR	95% CI	P-value	HR	95% CI	P-value
Age, years	1.047	1.023–1.071	<0.001	1.059	1.032–1.087	<0.001
Male gender compared to female	1.979	1.104–3.547	0.022	1.239	0.576–2.666	0.583
Body mass index	0.876	0.813–0.943	<0.001	0.892	0.826–0.964	0.004
Ever smoker	1.509	0.926–2.460	0.099	1.024	0.543–1.933	0.941
mMRC dyspnea scale			0.326
0 (reference)	1.000
1	0.805	0.448–1.446	0.805
2	0.973	0.486–1.948	0.973
3	1.274	0.609–2.666	0.520
4	2.201	0.836–5.793	0.110
Charlson Comorbidity Index	1.553	1.374–1.756	<0.001	1.495	1.315–1.700	<0.001
Concomitant asthma	0.654	0.313–1.364	0.257
LAMA usage	0.609	0.326–1.135	0.118	0.405	0.211–0.776	0.006
ICS/LABA usage	0.951	0.568–1.592	0.848
FEV1, % predicted	0.984	0.971–0.997	0.015	0.985	0.970–1.001	0.062
X-ray severity (0–6)	1.329	1.120–1.578	0.001	1.244	1.004–1.541	0.045
Long-term oxygen therapy	2.146	1.176–3.916	0.013	1.301	0.686–2.466	0.420

Note: Cox proportional hazards analysis was performed.

Abbreviations: DLco, diffusing capacity for carbon monoxide; LAMA, long-acting muscarinic antagonist; ICS/LABA, inhaled corticosteroid/long-acting beta-2 agonist.

Table 4 Baseline characteristics of patients in LAMA and non-LAMA groups after propensity score matching

	Including patients with ICS/LABA usage				Excluding patients with ICS/LABA usage
	LAMA group	Non-LAMA group	P-value	SMD	LAMA group	Non-LAMA group	P-value	SMD
Number of patients
Age (years)	63.6±10.4	62.4±10.1	0.364	0.117	64.2±9.6	64.7±10.0	0.766	0.053
Male gender	90 (74.4)	87 (71.9)	0.772	0.056	50 (78.1)	51 (79.7)	>0.999	0.038
Body mass index (kg/m^2)	21.7±3.4	21.6±3.4	0.794	0.034	21.2±3.2	20.6±3.5	0.297	0.185
Ever smoker	78 (64.5)	76 (62.8)	0.894	0.034	42 (65.6)	45 (70.3)	0.705	0.101
mMRC dyspnea scale			0.778	0.172			0.903	0.182
−0	23 (19.0)	24 (19.8)			15 (23.4)	16 (25.0)
−1	42 (34.7)	49 (40.5)			25 (39.1)	28 (43.8)
−2	34 (28.1)	32 (26.5)			17 (26.6)	13 (20.3)
−3	15 (12.4)	12 (9.9)			5 (7.8)	4 (6.3)
−4	7 (5.8)	4 (3.3)			2 (3.1)	3 (4.7)
Charlson Comorbidity Index	1.4±1.1	1.5±1.4	0.796	0.033	1.5±1.2	1.4±1.2	0.829	0.038
Concomitant asthma	24 (19.8)	22 (18.2)	0.870	0.042	5 (7.8)	3 (4.7)	0.715	0.129
ICS/LABA usage over 360 days	53 (43.8)	54 (44.6)	>0.999	0.017	0	0
Pulmonary function tests
FEV1, % predicted	42.9±13.6	43.5±14.8	0.776	0.037	45.4±14.6	45.1±15.1	0.906	0.021
FVC, % predicted	63.9±16.0	65.2±18.6	0.556	0.076	64.5±16.4	63.8±18.3	0.823	0.040
FEV1/FVC ratio, %	49.8±11.0	48.8±10.7	0.478	0.091	52.2±11.1	51.8±10.8	0.822	0.040
DLco, % predicted	60.8±23.0	66.7±20.3	0.192	0.098	59.2±20.6	63.4±22.0	0.464	0.159
Respiratory admission within 2 years	15 (12.4)	12 (9.9)	0.683	0.079	7 (10.9)	8 (12.5)	>0.999	0.049
X-ray severity (0–6)	3.2±1.3	3.2±1.4	0.732	0.044	3.2±1.2	3.0±1.2	0.374	0.158
Long-term oxygen therapy	16 (13.2)	12 (9.9)	0.547	0.103	6 (9.4)	6 (9.4)	>0.999	0

Note: Data are presented as mean ± standard deviation or number of patients (%), unless otherwise indicated.

Abbreviations: DLco, diffusing capacity for carbon monoxide; ICS/LABA, inhaled corticosteroid/long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist; SMD, standardized mean differences.

Figure 2 Comparison of Kaplan–Meier survival curves between LAMA and non-LAMA groups.

Notes: (A) Before propensity score matching, (B) after propensity score matching, including patients with inhaled corticosteroid/long-acting beta-2 agonist (ICS/LABA) usage, (C) after propensity score matching excluding patients with ICS/LABA usage. P-value from log rank test.
Abbreviation: ICS/LABA, inhaled corticosteroid/long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist.

Figure S1 Comparison of Kaplan–Meier survival curves between patients with airflow limitation and without airflow limitation.

Note: P-value from Log rank test.

Table S1 Clinical course and medication history of patients in LAMA group and non-LAMA group

	Before propensity score matching			After propensity score matching (including patients with ICS/LABA usage)			After propensity score matching (excluding patients with ICS/LABA usage)
	LAMA group	Non-LAMA group*	P-value	LAMA group	Non-LAMA group**	P-value	LAMA group	Non-LAMA group***	P-value
Number of patients
Median follow-up duration, days	1,687 [1,048–2,352]	1,517 [863–2,479]	0.462	1,747 [1,085–2,446]	1,498 [973–2,465]	0.341	1,603 [928–2,424]	1,052 [622–1,930]	0.011
Mean follow-up duration, days	1,794.4±944.6	1,918.9±1,384.6	0.186	1,843.7±911.5	1,897.3±1,311.4	0.712	1,770.9±1,015.3	1,483.5 ±1,284.5	0.163
Death within 5-year	7 (4.0)	36 (7.1)	0.136	3 (2.5)	11 (9.1)	0.028	2 (3.1)	9 (14.1)	0.027
Median LAMA prescription duration, days (median)	940 [600–1,455]	90 [30–180]	<0.001	1,010 [605–1,435]	0 [0–50]	<0.001	845 [490–1,275]	0 [0–48]	<0.001
Mean LAMA prescription duration, days (mean)	1,047.3±494.4	114.6±91.9	<0.001	1,046.2±486.3	48.8±88.8	<0.001	901.3±39.7	454.3± 73.3	<0.001
MPR ≥ 80%	97 (54.8)	1 (0.7)*	<0.001	59 (48.8)	1 (2.2)**	<0.001	30 (46.9)	0	<0.001
MPR < 30%	13 (7.3)	134 (90.0)	<0.001	9 (7.4)	41 (89.1)	<0.001	7 (10.9)	18 (75.0)	< 0.001

Notes: Data are presented as median [interquartile range], mean ± standard deviation or number of patients (%).

* Among non-LAMA group before propensity score matching, 149 patients received LAMA inhaler <360 days. One patient received LAMA during 320 days (total follow-up period: 395 days).

** Among non-LAMA group after propensity score matching (including patients with ICS/LABA usage), 46 patients received LAMA inhaler <360 days. One patient received LAMA during 320 days (total follow-up period: 395 days).

*** Among non-LAMA group after propensity score matching (excluding patients with ICS/LABA usage), 24 patients received LAMA inhaler <360 days.

Abbreviations: LAMA, long-acting muscarinic antagonist; ICS/LABA, inhaled corticosteroid/long-acting beta-2 agonist; MPR, medication possession ratio.

Table S2 Baseline characteristics of patients in with or without airflow limitation groups

	With airflow limitation group	Without airflow limitation group	P-value
Number of patients	683 (55.8)	542 (44.2)
Age, years	62.0±11.2	56.4±13.5	<0.001
Male gender	471 (69.0)	300 (55.4)	<0.001
Body mass index, kg/m^2	21.9±3.4	21.5±3.6	0.032
Ever smoker	404 (59.2)	246 (45.4)	<0.001
mMRC dyspnea scale			<0.001
−0	223 (32.8)	333 (61.4)
−1	235 (34.6)	112 (20.7)
−2	124 (18.2)	66 (12.2)
−3	69 (10.1)	23 (4.2)
−4	29 (4.3)	8 (1.5)
Charlson Comorbidity Index	1.5±1.4	1.0±1.3	<0.001
Concomitant asthma	90 (13.2)	15 (2.6)	<0.001
LAMA usage over 360 days	171 (25.0)	23 (4.2)	<0.001
ICS/LABA usage over 360 days	177 (25.9)	31 (5.7)	<0.001
Pulmonary function tests
FEV1, % predicted	50.6±19.5	78.2±24.9	<0.001
FVC, % predicted	69.0±18.9	73.9±23.2	<0.001
FEV1/FVC ratio, %	53.1±11.4	80.5±0.08	<0.001
DLco, % predicted	67.8±21.6	75.7±26.4	<0.001
Respiratory admission within 2 years	77 (11.3)	67 (12.4)	0.557
X-ray severity (0 to 6)	3.0±1.3	2.3±1.5	< 0.001
Long-term oxygen therapy	59 (8.6)	31 (5.7)	0.052

Notes: Data are presented as mean ± standard deviation or number of patients (%), unless otherwise indicated. Airflow limitation group was defined as patients who had FEV₁/FVC <70%.

Abbreviations: LAMA, long-acting muscarinic antagonist; ICS/LABA, inhaled corticosteroid/long-acting beta-2 agonist; DLco, diffusing capacity for carbon monoxide.