Relationship of COPD Exacerbation Severity and Frequency on Risks for Future Events and Economic Burden in the Medicare Fee-For-Service Population

Figures & data

Figure 1 Attrition Diagram and Study Timeline. The attrition diagram presents the inclusion and exclusion criteria used to select the study patient population with a COPD diagnosis date in 2015. The study timeline includes a 12-month look back period in 2014; baseline history of exacerbations in YR1; and post-index exacerbations in YR2 and YR3.

Table 1 Unadjusted and Adjusted Rate Ratios for Overall, Moderate and Severe Exacerbations in Post-Index YR2 and YR3 by Baseline YR1 Exacerbation Category

	YR2		YR3
Exacerbation Baseline Category* (YR1)	Unadjusted Model: RR (95% CI)	Adjusted** Model: RR (95% CI)	Unadjusted Model: RR (95% CI)	Adjusted** Model: RR (95% CI)
Overall Exacerbations
Cat A (Ref)	1.00	1.00	1.00	1.00
Cat B	2.06 (2.05–2.08)	1.47 (1.45–1.48)	1.89 (1.87–1.90)	1.37 (1.36–1.38)
Cat C	5.0 (4.97–5.04)	2.55 (2.52–2.57)	4.16 (4.12–4.19)	2.17 (2.15–2.19)
Cat D	2.01 (1.97–2.05)	1.45 (1.42–1.48)	1.90 (1.87–1.94)	1.40 (1.37–1.43)
Cat E	6.88 (6.81–6.94)	2.85 (2.82–2.88)	5.75 (5.69–5.81)	2.47 (2.44–2.49)
Moderate Exacerbations
Cat A (Ref)	1.00	1.00	1.00	1.00
Cat B	2.11 (2.10–2.13)	1.48 (1.47–1.49)	1.92 (1.91–1.93)	1.38 (1.37–1.39)
Cat C	5.22 (5.18–5.26)	2.62 (2.60–2.64)	4.30 (4.27–4.33)	2.22 (2.20–2.23)
Cat D	1.70 (1.67–1.73)	1.26 (1.24–1.29)	1.63 (1.60–1.66)	1.24 (1.21–1.26)
Cat E	6.06 (6.00–6.12)	2.58 (2.55–2.61)	5.11 (5.06–5.16)	2.25 (2.22–2.27)
Severe Exacerbations
Cat A (Ref)	1.00	1.00	1.00	1.00
Cat B	1.74 (1.73–1.76)	1.32 (1.3–1.33)	1.68 (1.67–1.7)	1.29 (1.26–1.34)
Cat C	3.65 (3.61–3.68)	1.96 (1.93–1.98)	3.35 (3.32–3.38)	1.92 (1.91–1.99)
Cat D	3.99 (3.91–4.07)	2.38 (2.33–2.43)	3.44 (3.37–3.51)	2.29 (2.21–2.43)
Cat E	12.11 (11.99–12.23)	4.36 (4.31–4.42)	9.38 (9.28–9.47)	4.12 (4.09–4.32)

Notes: *Category A (0 exacerbations) is reference category for statistical analysis. Category B, 1 moderate; Category C, ≥2 moderate; Category D, 1 severe; Category E, ≥2 exacerbations (≥1 being severe). Overall Exacerbations: **Generalized linear model with logit link function adjusted for the following YR1 characteristics: Age, gender, race, region, Medicare Part D Low-Income Subsidy status, original reason for Medicare enrollment, pre-index comorbidities (asthma, cancer, cerebrovascular disease, congestive heart failure, connective tissue disease, dementia, depression, gastroesophageal reflux disease, history of COPD, HIV/AIDS, hyperlipidemia, hypertension, liver disease, myocardial infarction, paraplegia, peptic ulcer, peripheral vascular disease, pneumonia, pulmonary embolism, renal disease, sleep apnea, urinary tract infection), inhaled corticosteroids, long-acting beta agonists, long-acting muscarinic agonist, respiratory antibiotics, oxygen use, systemic corticosteroids. Moderate Exacerbations: **Generalized linear model with logit link function adjusted for the following YR1 characteristics: Age, gender, race, region, Medicare Part D Low-Income Subsidy status, original reason for Medicare enrollment, pre-index comorbidities (asthma, cancer, cerebrovascular disease, connective tissue disease, dementia, depression, diabetes, gastroesophageal reflex disease, history of COPD, HIV/AIDS, hyperlipidemia, hypertension, liver disease, paraplegia, peripheral vascular disease, pneumonia, pulmonary hypertension, renal disease, sleep apnea, tobacco use, urinary tract infection), inhaled corticosteroids, long-acting beta agonists, long-acting muscarinic agonist, respiratory antibiotics, oxygen use, systemic corticosteroids. Severe Exacerbations: **Generalized linear model with logit link function adjusted for the following YR1 characteristics: Age, gender, race, region, Medicare Part D Low-Income Subsidy status, original reason for Medicare enrollment, pre-index comorbidities (asthma, cancer, cerebrovascular disease, connective tissue disease, dementia, depression, diabetes, gastroesophageal reflex disease, heart failure, history of COPD, HIV/AIDS, hyperlipidemia, hypertension, liver disease, myocardial infarction, paraplegia, peptic ulcer, peripheral vascular disease, pneumonia, pulmonary embolism, pulmonary hypertension, renal disease, sleep apnea, tobacco use, urinary tract infection), inhaled corticosteroids, long-acting beta agonists, long-acting muscarinic agonist, respiratory antibiotics, oxygen use, systemic corticosteroids.

Table 2 Unadjusted and Adjusted All-Cause Costs (A) and Cost Ratios (B) for Exacerbation Categories B–E versus Category a in Post-Index YR2 and YR3 by Baseline YR1 Exacerbation Category

Costs
A.	YR2		YR3
BASELINE CATEGORY YR1	Unadjusted	Adjusted	Unadjusted	Adjusted
Cat A (Ref)	$26,544	$25,084	$28,883	$24,282
Cat B	$26,657	$24,007*	$29,104**	$23,600*
Cat C	$30,192*	$25,067	$32,664*	$24,583**
Cat D	$38,564*	$26,505*	$41,789*	$26,344*
Cat E	$43,774*	$26,633*	$46,557*	$26,399*
Cost Difference Compared to Baseline Category A
	YR2		YR3
BASELINE CATEGORY YR1	Unadjusted	Adjusted	Unadjusted	Adjusted
Cat A (Ref)	$-	$-	$-	$-
Cat B	$113	$(1077)^§	$221	$(682)^§
Cat C	$3647	$(18)^§	$3780	$301
Cat D	$12,019	$1421	$12,906	$2062
Cat E	$17,230	$1548	$17,674	$2117
Cost Ratios
B.	YR2		YR3
Exacerbation Baseline Category^† YR1	Unadjusted Model: Cost Ratio (95% CI)	Adjusted^†† Model: Cost Ratio (95% CI)	Unadjusted Model: Cost Ratio (95% CI)	Adjusted** Model: Cost Ratio (95% CI)
All Exacerbations
Cat A (Ref)	1.00	1.00	1.00	1.00
Cat B	1 (1.00–1.01)	0.96 (0.95–0.96)	1.01 (1.00–1.01)	0.97 (0.97–0.98)
Cat C	1.13 (1.13–1.14)	1.00 (0.99–1.01)	1.13 (1.12–1.14)	1.01 (1.01–1.02)
Cat D	1.46 (1.44–1.48)	1.06 (1.04–1.07)	1.45 (1.43–1.47)	1.08 (1.07–1.10)
Cat E	1.65 (1.63–1.66)	1.06 (1.05–1.07)	1.61 (1.59–1.62)	1.09 (1.08–1.10)

Notes: *p<0.0001. **p<0.05. ^§Values in parentheses indicate lower costs compared to reference Category A. ^†Category A (0 exacerbations) is reference category for statistical analysis. Category B, 1 moderate; Category C, ≥2 moderate; Category D, 1 severe; Category E, ≥2 exacerbations (≥1 being severe). ^††Generalized linear model with gamma distribution and log link function, adjusted for the following YR1 characteristics: Age, gender, race, region, Medicare Part D Low-Income Subsidy status, original reason for Medicare enrollment, tobacco use, pre-index (asthma, cancer, cerebrovascular disease, congestive heart failure, connective tissue disease, dementia, depression, diabetes, gastroesophageal reflex disease, heart failure, history of COPD, HIV/AIDS, hyperlipidemia, hypertension, liver disease, myocardial infarction, paraplegia, peptic ulcer, peripheral vascular disease, pneumonia, pulmonary embolism, pulmonary hypertension, renal disease, sleep apnea, tobacco use, urinary tract infection), inhaled corticosteroids, long acting beta agonists, long acting muscarinic agonist, respiratory antibiotics, oxygen use, systemic corticosteroids.

Table 3 Patient (A) and Clinical (B) Characteristics at Index Diagnosis Date at Baseline YR1 for Overall Chronic Obstructive Pulmonary Disease Cohort and for Exacerbation Categories A–E

A: Patient Characteristics	Overall	Category A*	Category B	Category C	Category D		Category E
Unique Patients N (%)	1,492,108 (100)	921,530 (61.76)	318,786 (21.36)	151,686 (10.17)	26,029 (1.74)		74,077 (4.96)
Index Demographics
Age (years)
Mean (±SD)	70.9 (10.9)	71.3 (10.9)	70.4 (10.9)	69.8 (10.4)		72.6 (11.3)	70.1 (10.4)
Gender (%)
Female	58.6	56.5	61.2	62.6		62.4	64.6
Race (%)
White	86.4	85.6	87.3	88.9		82.4	86.6
Black	8.8	9.3	8.0	6.8		12.2	9.8
Hispanic	1.5	1.5	1.5	1.2		2.1	1.2
Other/Unknown	3.3	3.4	3.2	3.1		3.3	2.4
Region (%)
Northeast	18.3	18.8	17.4	16.3		18.8	19.4
Midwest	25.3	24.9	25.7	26.6		24.3	27.0
South	41.5	41.1	41.7	42.6		43.5	42.8
West	14.8	15.1	15.2	14.5		13.3	10.9
Other/Unkown	0.06	0.06	0.07	0.06		0.1	0.03
Dual Eligible Beneficiaries(%)
Yes	40.0	39.5	39.2	40.3		45.0	46.1
Low-Income Subsidy (%)
No	54.2	54.8	54.9	53.6		48.3	46.6
Medicare Entitlement (%)
Age ≥65 years	75.5	76.6	74.3	72.9		77.1	71.8
Disability/End-stage Renal Disease	24.5	23.4	25.7	27.1		22.9	28.2
B: Clinical Characteristics	Overall	Category A*	Category B	Category C		Category D	Category E
Index Comorbidities (%)
Deyo-Modified Charlson Comorbidity Index (CCI) Score
Mean (±SD)	4.0 (2.8)	4.1 (2.8)	3.7 (2.7)	3.6 (26)		5.0 (3.0)	4.6 (2.9)
Asthma	20.4	16.2	22.9	30.0		28.5	39.0
Anxiety or Depression	38.1	36.3	35.7	42.5		50.4	58.5
Cancer (Other than Skin and Lung Cancer)	38.0	38.0	36.7	39.7		38.7	40.0
Cerebrovascular Disease	22.9	24.1	20.7	18.9		28.7	24.6
Congestive Heart Failure	28.8	28.0	25.7	26.7		51.1	48.5
Diabetes Mellitus	37.5	38.3	33.4	35.0		49.6	45.0
Gastroesophageal Reflux Disease	40.7	39.3	38.6	44.6		50.2	55.6
Heart Failure	25.5	24.5	22.1	24.5		49.0	46.6
Hyperlipidemia	58.1	59.5	53.5	56.2		64.2	62.7
Hypertension	79.4	80.3	73.4	80.0		91.4	89.5
Myocardial Infarction	12.5	12.3	11.2	11.2		20.1	20.7
Peripheral VascularDisease	32.3	33.3	29.4	28.9		40.1	37.4
Pneumonia	18.6	13.7	18.7	26.3		48.5	53.6
Tobacco Dependence	52.3	48.9	49.7	59.6		69.5	84.8

Notes: *Category A (0 exacerbations) is reference category for statistical comparisons; all comparisons for each patient characteristic were significant at p<0.05. Category B, 1 moderate; Category C, ≥2 moderate; Category D, 1 severe; Category E, ≥2 exacerbations (≥1 being severe).

Figure 2 Changes in exacerbation Categories A-E for Baseline YR1 and Post-Index YR2 and YR3. Exacerbation rates are displayed in the Sankey diagram, which visualizes transition between the five exacerbation categories from YR1 to YR2 to YR3. The width at each time point is proportional to the number of patients in the category. Exacerbations were defined as 0 (Category A), 1 moderate (Category B); ≥2 moderate (Category C); 1 severe (Category D); ≥2 exacerbations, at least one being severe (Category E).

Figure 3 Moderate and Severe Exacerbation Rates Per 100-Patient-Years. The bar graph depicts the moderate and severe exacerbation rates per 100-patient-years for the overall cohort and by baseline exacerbation Categories A–E for post-index YR2 and YR3. Exacerbations were defined as 0 (Category A), 1 moderate (Category B); ≥2 moderate (Category C); 1 severe (Category D); ≥2 exacerbations, at least one being severe (Category E).

Figure 4 Percent of Patients with Single and Multiple Exacerbations. The bar graph depicts the percentage of patients with 1 and ≥2 exacerbations for the overall cohort and by baseline exacerbation Categories A-E for post-index YR2 and YR3. Exacerbations were defined as 0 (Category A), 1 moderate (Category B); ≥2 moderate (Category C); 1 severe (Category D); ≥2 exacerbations, at least one being severe (Category E).

Table 4 Percentage of Patients with COPD Receiving Treatment for Overall Cohort and Exacerbation Categories A–E at Baseline YR1 and Post-Index YR2 and YR3

Treatment Category*	Exacerbation Category
	Overall			Category A**			Category B			Category C			Category D			Category E
	YR1	YR2	YR3	YR1	YR2	YR3	YR1	YR2	YR3	YR1	YR2	YR3	YR1	YR2	YR3	YR1	YR2	YR3
Long-Acting Overall (%) (Maintenance Therapy)	49	47	47	42	40	40	54	51	51	70	66	65	52	45	46	79	73	72
ICS+LABA Dual	33	32	32	27	26	26	37	35	35	51	49	47	35	32	32	59	55	53
LAMA Mono	21	18	17	17	15	14	22	20	18	33	29	27	21	17	16	40	34	31
Open Triple (ICS+LAMA+LABA)	9	8	8	6	6	6	9	9	9	17	16	15	10	8	8	22	20	19
ICS Mono	8	7	7	6	6	6	9	8	8	13	11	11	9	7	7	14	13	13
LABA Mono	2	2	2	1	1	1	2	2	2	4	4	4	2	2	2	5	5	5
LABA+LAMA	2	4	5	2	3	5	2	4	6	4	6	8	2	3	5	4	5	8
Short-Acting Overall (%)	56	51	51	45	44	45	66	55	56	80	71	71	64	53	54	87	77	77
Systemic Corticosteroids Overall (%)	53	49	49	35	40	41	76	56	57	91	75	74	60	48	49	96	74	74
Patients with none of the following treatments: Long-Acting, Short-Acting, Systemic Corticosteriod (%)	20	24	24	28	30	30	8	18	19	3	8	9	14	24	24	1	6	7

Notes: Treatments are mutually exclusive; patients may have received more than one drug class. **Category A, 0 exacerbations; Category B, 1 moderate; Category C, ≥2 moderate; Category D, 1 severe; Category E, ≥2 exacerbations (≥1 being severe).

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