Cardiovascular Events According to Inhaler Therapy and Comorbidities in Chronic Obstructive Pulmonary Disease

Figures & data

Figure 1 Flow diagram of the study population.

Figure 2 Study design.

Table 1 Baseline Characteristics of Cohort

	Total	LAMA/LABA	ICS/LABA	LAMA/LABA/ICS	p-value
Number	46,308	28,322	11,812	6174
Age (years)	68.5 10.1	68.8 9.5	67.6 11.3	68.9 10.3	<0.001**
Age distribution (years), N (%)					<0.001**
40–49	1766 (3.8)	728 (2.6)	808 (6.8)	230 (3.7)
50–59	7171 (15.5)	4092 (14.4)	2119 (17.9)	960 (15.5)
60–69	14,880 (32.1)	9593 (33.9)	3422 (29.0)	1865 (30.2)
70–79	15,978 (34.5)	10,220 (36.1)	3624 (30.7)	2134 (34.6)
80-	6513 (14.1)	3689 (13.0)	1839 (15.6)	985 (16.0)
Gender (male), N (%)	37,256 (80.5)	24,139 (85.2)	8204 (69.5)	4913 (79.6)	<0.001**
Co-morbidities during covariate assessment window, N (%)
Asthma (J45-46)	22,113 (47.8)	10,280 (36.3)	7790 (66.0)	4043 (65.5)	<0.001**
Hypertension (I10-15)	21,256 (45.9)	12,755 (45.0)	5181 (43.9)	3320 (53.8)	<0.001**
Diabetes mellitus (E10–E14)	10,773 (23.3)	6602 (23.3)	2524 (21.4)	1647 (26.7)	<0.001**
Tuberculosis (A15, A19, B90)	2292 (5.0)	1619 (5.7)	343 (2.9)	330 (5.3)	<0.001**
Diffuse interstitial lung disease (J84)	402 (0.9)	281 (1.0)	72 (0.6)	49 (0.8)	0.001**
Lung cancer (C33-C34)	829 (1.8)	641 (2.3)	101 (0.9)	87 (1.4)	<0.001**
Charlson Comorbidity Index score	3.0 2.4	3.0 2.5	2.8 2.3	3.1 2.3	<0.001**
Charlson Comorbidity Index score, N (%)					<0.001**
0 (CCI score = 0)	2721 (5.9)	1943 (6.9)	510 (4.3)	268 (4.3)
1 (CCI score = 1)	12,198 (26.3)	7185 (25.4)	3577 (30.3)	1436 (23.3)
2 (CCI score = 2)	9776 (21.1)	5788 (20.4)	2775 (23.5)	1213 (19.6)
3 (CCI score ≥ 3)	21,613 (46.7)	13,406 (47.3)	4950 (41.9)	3257 (52.8)

Note: A p-value less than 0.01 is marked by **. The percentage is provided in parentheses.

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

Table 2 Hospital Visit During Covariate Assessment Window

	Total	LAMA/LABA	ICS/LABA	LAMA/LABA/ICS	p-value
Inpatient hospitalization
▪ Respiratory related (J00-J99)
0	39,464 (85.2)	24,508 (86.5)	10,070 (85.2)	4886 (79.1)	<0.001**
1	4803 (10.4)	2763 (9.8)	1204 (10.2)	836 (13.5)
≥ 2	2041 (4.4)	1051 (3.7)	538 (4.6)	452 (7.3)
▪ Any reason
0	27,936 (60.3)	16,915 (59.7)	7667 (64.9)	3354 (54.3)	<0.001**
1	9471 (20.5)	5962 (21.1)	2124 (18.0)	1385 (22.4)
≥ 2	8901 (19.2)	5445 (19.2)	2021 (17.1)	1435 (23.2)
Emergency room visit
▪ Respiratory related (J00-J99)					<0.001**
0	42,317 (91.4)	26,020 (91.9)	10,913 (92.4)	5384 (87.2)
1	3206 (6.9)	1876 (6.6)	715 (6.0)	615 (10.0)
≥2	785 (1.7)	426 (1.5)	184 (1.6)	175 (2.8)
▪ Any reason
0	35,740 (77.2)	21,848 (77.1)	9472 (80.2)	4420 (71.6)	<0.001**
1	7148 (15.4)	4428 (15.6)	1580 (13.4)	1140 (18.5)
≥ 2	3420 (7.4)	2046 (7.2)	760 (6.4)	614 (9.9)

Note: A p-value less than 0.01 is marked by **. The percentage is provided in parentheses.

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

Table 3 Cumulative Incidence of Cardiovascular Events During Observation Period

						Multiple Comparison with Bonferroni Correction
	Total	LAMA/LABA	ICS/LABA	Triple	p-value	LAMA/LABA vs ICS/LABA	LAMA/LABA vs Triple	ICS/LABA vs Triple
Cumulative incidence of cardiovascular events for 5 years, N (%)
Cardiovascular
Ischemic heart disease (I20 - I25)	1689 (3.7)	1057 (3.7)	364 (3.1)	268 (4.3)	<0.001**	0.004**	0.073	<0.001**
Myocardial infarction (I21 - I22)	362 (0.8)	212 (0.8)	97 (0.8)	53 (0.9)	0.575	1	1	1
Heart failure (I50)	584 (1.3)	313 (1.1)	142 (1.2)	129 (2.1)	<0.001**	1	<0.001**	<0.001**
Arrhythmia (I44 – I49)	943 (2.0)	541 (1.9)	200 (1.7)	202 (3.3)	<0.001**	0.423	<0.001**	<0.001**
Atrial fibrillation /flutter (I48)	314 (0.7)	176 (0.6)	57 (0.5)	81 (1.3)	<0.001**	0.286	<0.001**	<0.001**
Cerebrovascular
Hemorrhagic stroke (I60-I62)	206 (0.4)	114 (0.4)	62 (0.5)	30 (0.5)	0.213	0.273	1	1
Ischemic stroke (I63-I66)	1083 (2.3)	631 (2.2)	278 (2.4)	174 (2.8)	0.021*	1	0.016*	0.176

Notes: A p-value less than 0.05 is marked by* and a p-value less 0.01 by **. The percentage is provided in parentheses.

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

Figure 3 The annual incidence of cardiovascular events. (a) Annual incidence of ischemic heart disease. (b) Annual incidence of heart failure. (c) Annual incidence of arrhythmia. (d) Annual incidence of atrial fibrillation/flutter. The percentage is presented on top of each bar.

Table 4 Multivariable Analysis of Risk Factors for the Development of Ischemic Heart Disease and Heart Failure in COPD

Variables	Multivariable Cox Regression ANALYSIS
	Ischemic Heart Disease		Heart Failure
	Hazard Ratio (95% CI)	p-value	Hazard Ratio (95% CI)	p-value
Therapeutic intervention
LAMA/LABA therapy	1.08 (0.95 ─ 1.22)	0.242	0.93 (0.75 ─ 1.14)	0.471
LAMA/LABA/ICS therapy	1.22 (1.04 ─ 1.43)	0.014*	1.45 (1.14 ─ 1.84)	0.003**
ICS/LABA therapy	Ref.		Ref.
Age group (years)
40–49	Ref.		Ref.
50–59	1.19 (0.80 ─ 1.79)	0.389	6.49 (0.89 ─ 47.59)	0.066
60–69	1.78 (1.21 ─ 2.61)	0.003**	8.30 (1.16 ─ 59.62)	0.036*
70–79	1.84 (1.26 ─ 2.70)	0.002**	18.14 (2.54 ─ 129.68)	0.004**
80-	1.76 (1.19 ─ 2.62)	0.005**	35.78 (5.00 ─ 256.00)	<0.001**
Sex (male)	1.96 (1.68 ─ 2.29)	<0.001**	0.85 (0.70 ─ 1.04)	0.109
Asthma	0.87 (0.78 ─ 0.96)	0.006**	0.89 (0.75 ─ 1.06)	0.176
Hypertension	1.77 (1.59 ─ 1.97)	<0.001**	1.97 (1.62 ─ 2.40)	<0.001**
Diabetes mellitus	1.20 (1.07 ─ 1.35)	0.002**	1.09 (0.91 ─ 1.31)	0.363
Tuberculosis	0.84 (0.66 ─ 1.07)	0.164	0.77 (0.50 ─ 1.21)	0.261
Diffuse interstitial lung disease	1.24 (0.78 ─ 1.98)	0.364	0.88 (0.37 ─ 2.14)	0.785
Lung cancer	0.81 (0.57 ─ 1.15)	0.233	0.58 (0.3 ─ 1.13)	0.111
Charlson Comorbidity Index score
0 (CCI score = 0)	Ref.		Ref.
1 (CCI score = 1)	0.76 (0.59 ─ 0.96)	0.024*	0.85 (0.49 ─ 1.46)	0.553
2 (CCI score = 2)	0.85 (0.66 ─ 1.08)	0.184	0.77 (0.44 ─ 1.35)	0.362
3 (CCI score ≥ 3)	1.03 (0.81 ─ 1.31)	0.806	1.39 (0.82 ─ 2.36)	0.216
Inpatient hospitalization (any reason)
0	Ref.		Ref.
1	1.12 (0.99 ─ 1.28)	0.084	1.42 (1.14 ─ 1.77)	0.002**
≥2	1.11 (0.96 ─ 1.28)	0.174	1.27 (1.00 ─ 1.62)	0.053
Emergency room visit (any reason)
0	Ref.		Ref.
1	1.06 (0.92 ─ 1.22)	0.459	1.51 (1.21 ─ 1.89)	<0.001**
≥2	1.64 (1.38 ─ 1.95)	<0.001**	2.33 (1.79 ─ 3.02)	<0.001**

Notes: A p-value less than 0.05 is marked by* and a p-value less than 0.01 by **.

Abbreviations: CI, confidence interval; LABA, long-acting β2-agonists; LAMA, long-acting muscarinic antagonists; ICS, inhaled corticosteroids; Ref, reference.

Table 5 Multivariable Analysis of Risk Factors for the Development of Arrhythmia in COPD

Variables	Multivariable Cox Regression Analysis
	Arrhythmia		Atrial Fibrillation/Flutter
	Hazard Ratio (95% CI)	p-value	Hazard ratio (95% CI)	p-value
Therapeutic intervention
LAMA/LABA therapy	1.09 (0.92 ─ 1.30)	0.301	1.23 (0.90 ─ 1.68)	0.192
LAMA/LABA/ICS therapy	1.72 (1.41 ─ 2.09)	<0.001**	2.31 (1.64 ─ 3.25)	<0.001**
ICS/LABA therapy	Ref.		Ref.
Age group (years)
40–49	Ref.		Ref.
50–59	1.00 (0.59 ─ 1.69)	0.989	1.28 (0.44 ─ 3.68)	0.649
60–69	1.21 (0.73 ─ 1.99)	0.456	1.38 (0.50 ─ 3.81)	0.536
70–79	2.03 (1.24 ─ 3.32)	0.005**	2.47 (0.91 ─ 6.75)	0.078
80-	3.05 (1.85 ─ 5.03)	<0.001**	3.35 (1.21 ─ 9.27)	0.020*
Sex (male)	1.15 (0.97 ─ 1.37)	0.098	1.24 (0.92 ─ 1.68)	0.156
Asthma	0.90 (0.79 ─ 1.04)	0.143	0.97 (0.76 ─ 1.23)	0.798
Hypertension	1.33 (1.16 ─ 1.54)	<0.001**	1.68 (1.30 ─ 2.17)	<0.001**
Diabetes mellitus	1.08 (0.93 ─ 1.26)	0.313	0.99 (0.77 ─ 1.28)	0.945
Tuberculosis	1.43 (1.10 ─ 1.85)	0.007**	1.04 (0.62 ─ 1.75)	0.892
Diffuse interstitial lung disease	2.00 (1.24 ─ 3.24)	0.005**	0.98 (0.32 ─ 3.07)	0.976
Lung cancer	1.01 (0.66 ─ 1.55)	0.971	1.13 (0.58 ─ 2.22)	0.720
Charlson Comorbidity Index score
0 (CCI score = 0)	Ref.		Ref.
1 (CCI score = 1)	0.87 (0.59 ─ 1.29)	0.497	0.56 (0.29 ─ 1.06)	0.077
2 (CCI score = 2)	1.19 (0.81 ─ 1.75)	0.390	0.77 (0.41 ─ 1.45)	0.419
3 (CCI score ≥ 3)	1.52 (1.04 ─ 2.22)	0.030*	1.23 (0.67 ─ 2.25)	0.501
Inpatient hospitalization (any reason)
0	Ref.		Ref.
1	1.10 (0.92 ─ 1.31)	0.299	0.98 (0.72 ─ 1.34)	0.898
≥2	1.06 (0.88 ─ 1.29)	0.534	1.19 (0.86 ─ 1.64)	0.291
Emergency room visit (any reason)
0	Ref.		Ref.
1	1.52 (1.28 ─ 1.81)	<0.001**	1.51 (1.12 ─ 2.03)	0.008**
≥2	1.75 (1.39 ─ 2.20)	<0.001**	1.49 (1.01 ─ 2.21)	0.047*

Notes: A p-value less than 0.05 is marked by* and a p-value less 0.01 by **.

Abbreviations: CI, confidence interval; LABA, long-acting β2-agonists; LAMA, long-acting muscarinic antagonists; ICS, inhaled corticosteroids; Ref, reference.