Risk of Death and Cardiovascular Events Following an Exacerbation of COPD: The EXACOS-CV US Study

Figures & data

Figure 1 Study design.

Figure 2 Study population.

Table 1 Baseline Patient Demographic Characteristics and Healthcare Resource Utilization by Cohort

Patient Demographics	1-AECOPD	0-AECOPD Comparator	Standardized Mean Difference
	N=145,838	N=249,703
Age on index, mean (SD)	63 (12)	64 (12)	0.11
Female, N (%)	80,813 (55.4)	127,861 (51.2)	0.08
Region, N (%)
Northeast	22,191 (15.2)	42,877 (17.2)	0.05
Midwest	43,003 (29.5)	71,167 (28.5)	0.02
South	50,241 (34.4)	79,212 (31.7)	0.06
West	30,403 (20.8)	56,447 (22.6)	0.04
Neighborhood urbanicity, N (%)
Urban	74,993 (51.4)	133,426 (53.4)	0.04
Semi-urban	37,531 (25.7)	64,184 (25.7)	0.00
Rural	33,314 (22.8)	52,093 (20.9)	0.05
Neighborhood socioeconomic status quartile, N (%)
1 (0–25%)	27,505 (18.9)	42,821 (17.1)	0.04
2 (26–50%)	40,257 (27.6)	65,555 (26.3)	0.03
3 (51–75%)	41,036 (28.1)	71,448 (28.6)	0.01
4 (76–100%)	37,040 (25.4)	69,879 (28.0)	0.06
Insurance coverage, N (%)
Commercial	109,677 (75.2)	186,017 (74.5)	0.02
Medicare advantage	22,695 (15.6)	38,588 (15.5)	0.00
Other	13,466 (9.2)	25,098 (10.1)	0.03
Duration of baseline period (months), mean (SD)	56 (37)	57 (37)	0.00
Duration of COPD^a, N (%)
0 days	93,643 (64.2)	84,536 (33.9)	0.64
1 day - <3 months	12,990 (8.9)	105,985 (42.4)	0.83
3 months - <6 months	6,754 (4.6)	22,565 (9.0)	0.18
6 months - <2 years	21,769 (14.9)	32,522 (13.0)	0.05
2 years or longer	10,682 (7.3)	4095 (1.6)	0.28
Baseline health care utilization, N (%)
≥ 1 hospitalization	49,576 (34.0)	88,908 (35.6)	0.03
≥ 1 outpatient visit	143,979 (98.7)	248,776 (99.6)	0.10
≥ 1 pulmonologist visit	39,314 (27.0)	73,229 (29.3)	0.05
≥ 1 cardiologist visit	70,562 (48.4)	132,203 (52.9)	0.09

Notes: ^aDuration of COPD is defined as the time from the incident COPD diagnosis until the first exacerbation in the 1-AECOPD cohort or the assigned index date in the 0-AECOPD comparator cohort. Patients who contributed to both the 0-AECOPD and 1-AECOPD groups are represented in counts for each group.

Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; SD, standard deviation.

Table 2 Baseline^a Patient Comorbidities and Medication Use by Cohort

Comorbidities and Medications	1-AECOPD	0-AECOPD Comparator	Standardized Mean Differences
	N=145,838	N=249,703
Comorbidities
Acute CV events^b	16,541 (11.3)	29,106 (11.7)	0.01
Cardiovascular disease	101,953 (69.9)	183,636 (73.5)	0.08
Hyperlipidemia	97,733 (67.0)	176,960 (70.9)	0.08
Hypertension	99,481 (68.2)	178,347 (71.4)	0.07
Type 2 diabetes	34,066 (23.4)	59,811 (24.0)	0.01
Serious lower respiratory infections	12,338 (8.5)	18,447 (7.4)	0.04
Asthma	38,720 (26.6)	54,511 (21.8)	0.11
Bronchiectasis	25,710 (17.6)	37,239 (14.9)	0.07
Interstitial lung disease	32,359 (22.2)	59,082 (23.7)	0.04
Pleural disease	37,169 (25.5)	64,708 (25.9)	0.01
Depression and/or anxiety	58,181 (39.9)	95,057 (38.1)	0.04
Any cancer^c	27,866 (19.1)	54,139 (21.7)	0.06
Quan-Charlson Comorbidity Index count, N (%)
0	36,938 (25.3)	26,418 (10.6)	0.39
1	46,743 (32.1)	103,730 (41.5)	0.2
2	16,137 (11.1)	25,819 (10.3)	0.02
3+	46,020 (31.6)	93,736 (37.5)	0.13
Prescription medications, N (%)
Antibiotics	126,274 (86.6)	193,197 (77.4)	0.24
Glucocorticoids^d	103,168 (70.7)	156,212 (62.6)	0.17
Immunosuppressants	88,477 (60.7)	124,137 (49.7)	0.22
Long-acting bronchodilators (LABA or LAMA)	36,375 (24.9)	46,329 (18.6)	0.16
Short-acting bronchodilators (SABA or SAMA)	76,324 (52.3)	98,812 (39.6)	0.26
Inhaled corticosteroids	36,516 (25.0)	47,564 (19.0)	0.14
Oral corticosteroids	82,579 (56.6)	116,287 (46.6)	0.2

Note: ^aBaseline period begins on start of continuous enrollment and ends the day before the index date unless otherwise specified. ^bAcute CV events occurred > 6 months prior to index date. ^cAny cancer includes all cancers except for basal cell carcinoma. ^dIncludes all formulations of glucocorticoids (oral, intravenous, etc). Patients who contributed to both the 0-AECOPD and 1-AECOPD groups are represented in counts for each group.

Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; CV, cardiovascular; NA, Not applicable; LAMA, long-acting muscarinic antagonists; LABA, long-acting beta2-agonists; SABA, short-acting beta 2-agonists; SAMA, short-acting muscarinic antagonists.

Table 3 Hazard Ratios of All-Cause Mortality by AECOPD Status, Overall, and by Patient Characteristic Subgroups

	1-AECOPD		0-AECOPD Comparator		Adjusted^a HR (95% CI)
	Cases	Person-Years	Cases	Person-Years
Full study population
All-cause mortality^b	3835	209,326.06	8446	462,440.03	1.25 (1.20, 1.30)
Subgroup
Duration follow-up^c
<30 days	456	10,510.61	597	19,931.20	1.79 (1.58, 2.04)
30 days to 90 days	508	18,411.96	821	36,907.80	1.55 (1.38, 1.73)
91 days to <6 months	481	24,038.32	880	49,423.27	1.39 (1.24, 1.56)
6 months to <1 year	665	39,555.51	1316	83,583.27	1.33 (1.21, 1.47)
1 year to <2 years	715	51,172.43	1755	115,198.95	1.15 (1.05, 1.25)
2 years to <3 years	389	30,184.78	1157	71,523.61	1.03 (0.92, 1.16)
3 or more years	621	35,452.44	1920	85,871.93	1.04 (0.95, 1.14)
Insurance Coverage
Commercial	882	158,432.42	1842	335,177.68	1.31 (1.20, 1.42)
Medicare advantage	1601	28,811.21	3386	69,207.75	1.28 (1.21, 1.37)
Other	1352	22,082.43	3218	58,054.60	1.15 (1.08, 1.23)
Urbanicity of home neighborhood
Urban	2072	110,420.53	4796	250,372.48	1.20 (1.14, 1.26)
Semi-urban	999	53,638.29	2207	118,672.84	1.29 (1.19, 1.39)
Rural	764	45,267.24	1443	93,394.72	1.33 (1.22, 1.46)
Neighborhood socioeconomic status quartile
1 (0–25%)	614	36,426.78	1263	73,990.72	1.26 (1.14, 1.39)
2 (26–50%)	1004	55,442.22	1988	117,592.75	1.39 (1.29, 1.51)
3 (51–75%)	1058	59,043.29	2443	132,946.24	1.22 (1.13, 1.31)
4 (76–100%)	1159	58,413.77	2752	137,910.33	1.16 (1.08, 1.25)
SABA dispensings in 1-year prior to index
None	2257	113,497.52	6163	296,876.75	1.23 (1.17, 1.29)
1 or more	1578	95,828.53	2283	165,563.28	1.30 (1.22, 1.39)
History of respiratory infections in the 1-year prior to index
None	2878	196,324.28	6699	432,742.01	1.23 (1.17, 1.28)
1 or more	957	13,001.77	1747	29,698.02	1.36 (1.25, 1.48)
History of acute CV events^d
Yes	1247	20,186.22	2558	51,775.05	1.27 (1.19, 1.37)
No	2588	189,139.83	5888	410,664.98	1.26 (1.20, 1.32)

Notes: ^aCox proportional hazards models were adjusted for the following baseline demographics, comorbidities, and medications: age, sex, urbanicity, region, insurance coverage, Index calendar year, SES, COPD duration, serious lower respiratory infections, congestive heart failure, hyperlipidemia, hypertension, Charlson Comorbidity Index, chronic kidney disease, pneumothorax, pulmonary edema, sleep apnea, cancer, alpha-1 antitrypsin deficiency, bronchiectasis, extrinsic allergic alveolitis, interstitial lung disease, pleural disease, sarcoidosis, acute CV events, CV procedures, antihistamines, lipid-lowering agents, antihypertensive agents, antiarrhythmics, antianginal agents, other CV agents (including letairis, ambrisentan, caduet, tracleer, etc.), anticoagulants, immunosuppressants, antidiabetics, antifungals, antivirals, ICS, oral corticosteroids, LABA, SABA, glucocorticoids, antibiotics, hospitalizations, outpatient visits, pulmonologist visits, and cardiologist visits. ^bAll-cause mortality data was derived from the National Death Index data. ^cFollow-up begins on the index date and continues until the patient is censored for the outcome, a subsequent AECOPD, death (if not the outcome), disenrollment from health plan, or end of the study period. ^dHistory of acute CV events is measured from the start of the study period until six months prior to the index date.

Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; ICS, inhaled corticosteroids; SABA, short-acting beta 2-agonists.

Table 4 30-Day Hazard Ratios of Acute CV Events and All-Cause Mortality According to AECOPD Severity and Number of AECOPD Using Data from Claims and the National Death Index

AECOPD Characteristic	Cases	Person-Years^a	Adjusted^b HR (95% CI)
	All-Cause Mortality
Severity of first AECOPD
No AECOPD	568	19,851.91	Ref
Moderate AECOPD	237	9186.69	1.22 (1.04, 1.43)
Severe AECOPD	196	1281.12	5.09 (4.30, 6.03)
Number of AECOPD
0-AECOPD Comparator	568	19,851.91	Ref
1-AECOPD	433	10,467.81	1.79 (1.58, 2.04)
1-AECOPD Comparator	65	5724.60	Ref
2-AECOPD	215	3732.56	3.35 (2.52, 4.46)
2-AECOPD Comparator	23	1062.84	Ref
3-AECOPD	230	2483.90	3.40 (2.20, 5.24)
	Acute CV events including events on the COPD diagnosis date
Severity of first AECOPD
No AECOPD	1475	19,851.91	Ref
Moderate	717	9,186.69	1.23 (1.12, 1.35)
Severe	232	1,281.12	1.93 (1.67, 2.22)
Number of AECOPD
0-AECOPD Comparator	1,475	19,851.91	Ref
1-AECOPD	949	10,467.81	1.34 (1.23, 1.46)
1-AECOPD Comparator	173	5724.60	Ref
2-AECOPD	370	3732.56	2.66 (2.21, 3.21)
2-AECOPD Comparator	46	1062.84	Ref
3 AECOPD	252	2483.90	2.19 (1.59, 3.02)
	Acute CV events excluding events on the COPD diagnosis date
Severity of first AECOPD
No AECOPD	1089	19,851.91	Ref
Moderate AECOPD	694	9186.69	1.63 (1.48, 1.80)
Severe AECOPD	206	1281.12	2.49 (2.14, 2.90)
Number of AECOPD
0-AECOPD Comparator	1089	19,851.91	Ref
1-AECOPD	900	10,467.81	1.74 (1.59, 1.91)
1-AECOPD Comparator	171	5724.60	Ref
2-AECOPD	370	3732.56	2.69 (2.23, 3.25)
2-AECOPD Comparator	46	1062.84	Ref
3 AECOPD	252	2483.90	2.19 (1.59, 3.02)

Notes: ^aPerson-years were measured from Index date to censor date (earliest of dates of: first AECOPD event (for comparator cohort), subsequent AECOPD (for AECOPD cohorts), end of continuous enrollment, CV event, Death, Index date + 30 days, or Study end). ^bCox proportional hazards models were adjusted for the following baseline demographics, comorbidities, and medications: age, sex, urbanicity, region, insurance coverage, Index calendar year, SES, COPD duration, serious lower respiratory infections, congestive heart failure, hyperlipidemia, hypertension, Charlson Comorbidity Index, chronic kidney disease, pneumothorax, pulmonary edema, sleep apnea, cancer, alpha-1 antitrypsin deficiency, bronchiectasis, extrinsic allergic alveolitis, interstitial lung disease, pleural disease, sarcoidosis, acute CV events, CV procedures, antihistamines, lipid-lowering agents, antihypertensive agents, antiarrhythmics, antianginal agents, other CV agents (including letairis, ambrisentan, caduet, tracleer, etc.), anticoagulants, immunosuppressants, antidiabetics, antifungals, antivirals, ICS, oral corticosteroids, LABA, SABA, glucocorticoids, antibiotics, hospitalizations, outpatient visits, pulmonologist visits, and cardiologist visit.

Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; CV, cardiovascular; CI, Confidence Interval; HR, Hazard ratio; Ref, Reference Category.

Table 5 Hazard Ratios of Acute CV Events by Cohort Overall, by Follow-Up Time, and Individual CV Event, Including and Excluding CV Events Occurring on the COPD Diagnosis Date

	Including Acute CV Events Occurring on the COPD Diagnosis Date					Excluding Acute CV Events Occurring on the COPD Diagnosis Date
	1 AECOPD		0- AECOPD Comparator		Adjusted^a HR (95% CI)	1-AECOPD		0- AECOPD Comparator		Adjusted^a HR (95% CI)
	Cases	Person-Years	Cases	Person-Years		Cases	Person-Years	Cases	Person-Years
Full study population
All Serious acute CV events	5479	203,233.64	12,530	446,720.72	1.11 (1.07, 1.14)	5,430	203,233.64	12,144	446,720.72	1.14 (1.10, 1.18)
Follow-up Time
<30 days	949	10,467.81	1475	19,851.91	1.34 (1.23, 1.46)	900	10,467.81	1089	19,851.91	1.74 (1.59, 1.91)
30 days to 90 days	655	18,255.67	1204	36,630.84	1.29 (1.17, 1.42)	655	18,255.67	1204	36,630.84	1.29 (1.17, 1.42)
91 days to <6 months	632	23,731.84	1380	48,815.38	1.08 (0.98, 1.19)	632	23,731.84	1380	48,815.38	1.08 (0.98, 1.19)
6 months to <1 year	973	38,807.84	2107	81,972.55	1.14 (1.05, 1.23)	973	38,807.84	2107	81,972.55	1.14 (1.05, 1.23)
1 year to <2 years	1,022	49,679.00	2749	111,548.00	1.00 (0.92, 1.07)	1,022	49,679.00	2749	111,548.00	1.00 (0.92, 1.07)
2 years to <3 years	575	28,961.29	1599	68,200.85	1.04 (0.94, 1.14)	575	28,961.29	1599	68,200.85	1.04 (0.94, 1.14)
3 or more years	673	33,330.19	2016	79,701.19	1.00 (0.92, 1.10)	673	33,330.19	2016	79,701.19	1.00 (0.92, 1.10)
Short-term (30-day) incidence^b
MI	172	10,504.33	300	19,913.53	1.05 (0.86, 1.27)	154	10,504.33	199	19,913.53	1.43 (1.15, 1.78)
Ischemic stroke	62	10,509.93	140	19,923.47	0.95 (0.70, 1.29)	61	10,509.93	96	19,923.47	1.41 (1.01, 1.97)
Unstable angina	75	10,510.17	228	19,920.93	0.75 (0.57, 0.98)	73	10,510.17	203	19,920.93	0.84 (0.64, 1.11)
Acute heart failure	387	10,496.11	434	19,909.44	1.94 (1.69, 2.24)	372	10,496.11	332	19,909.44	2.46 (2.11, 2.87)
Pulmonary embolism	119	10,507.03	162	19,922.53	1.41 (1.11, 1.81)	114	10,507.03	123	19,922.53	1.81 (1.39, 2.36)
Cardiac arrhythmias	149	10,506.35	258	19,917.09	1.22 (0.99, 1.50)	140	10,506.35	182	19,917.09	1.64 (1.31, 2.07)
Atrial fibrillation and flutter	128	10,507.15	183	19,920.96	1.49 (1.18, 1.88)	120	10,507.15	129	19,920.96	2.01 (1.55, 2.60)
Other arrhythmias	25	10,512.00	83	19,927.27	0.63 (0.40, 1.00)	24	10,512.00	61	19,927.27	0.82 (0.50, 1.35)
CV death	52	10,512.83	76	19,931.20	1.63 (1.14, 2.35)	52	10,512.83	76	19,931.20	1.63 (1.14, 2.35)
Cardiac arrest	NR	NR	NR	NR	1.47 (0.48, 4.52)	NR	NR	NR	NR	1.71 (0.54, 5.46)

Notes: ^aCox proportional hazards models were adjusted for the following baseline demographics, comorbidities, and medications: age, sex, urbanicity, region, insurance coverage, Index calendar year, SES, COPD duration, serious lower respiratory infections, congestive heart failure, hyperlipidemia, hypertension, Charlson Comorbidity Index, chronic kidney disease, pneumothorax, pulmonary edema, sleep apnea, cancer, alpha-1 antitrypsin deficiency, bronchiectasis, extrinsic allergic alveolitis, interstitial lung disease, pleural disease, sarcoidosis, acute CV events, CV procedures, antihistamines, lipid-lowering agents, antihypertensive agents, antiarrhythmics, antianginal agents, other CV agents (including letairis, ambrisentan, caduet, tracleer, etc.), anticoagulants, immunosuppressants, antidiabetics, antifungals, antivirals, ICS, oral corticosteroids, LABA, SABA, glucocorticoids, antibiotics, hospitalizations, outpatient visits, pulmonologist visits, and cardiologist visits. ^bCV deaths from each individual CV cause are included in each category (eg, MI, ischemic stroke, pulmonary embolism, etc.) as well as separately under “CV death”. ^cAccording to Elevance Health policy, any cell with a value of 1 to 4 or any cell that allows a value of 1 to 4 to be derived from other reported cells or information cannot be reported.

Abbreviations: AECOPD, Acute exacerbation of chronic obstructive pulmonary disease; CI, confidence interval; CV, cardiovascular; HR, Hazard Ratio; MI, myocardial infarction, NR, not reportable^c.