Impact of roflumilast on exacerbations of COPD, health care utilization, and costs in a predominantly elderly Medicare Advantage population

Figures & data

Table 1 Exacerbation type definitions and identification algorithm

Exacerbation type (ranked by decreasing severity)	Identification method
Inpatient hospitalized exacerbation (a variation of criteria used by Lindenauer et al^Citation13)	Presence of an inpatient hospital stay with a principal diagnosis of COPD with acute exacerbation (ICD-9-CM codes 491.21, 491.22, 493.22), emphysema (ICD-9-CM, 492.8), or if they had a principal diagnosis of respiratory failure (ICD-9-CM codes 518.81, 518.82, 518.84) combined with a secondary diagnosis of COPD with acute exacerbation or emphysema.
Exacerbation requiring an emergency room visit^Citation14	Presence of an emergency room visit with a primary diagnosis of COPD (ICD-9-CM code 491.x, 492.x, or 496.x).
Ambulatory exacerbation identified by qualifying diagnosis^Citation14	Presence of an office or outpatient non-emergency room visit with any of the following ICD-9-CM diagnosis codes in the first position: 136.3, 466–466.19, 480–486, 487.0, 490, 491.21, 491.22, 493.02, 493.12, 493.22, 493.92, 494.1, 506.0–506.3, 507–507.8, 511.0–511.1, 512–512.8, 517.1, 518.0, 518.81, 518.82, 518.84, 770.84.
Ambulatory exacerbation identified by qualifying antibiotic^Citation14	Presence of a pharmacy claim for the following oral antibiotics commonly used for respiratory infections amoxicillin, beta-lactamase inhibitors, second or third-generation cephalosporins, macrolides, or doxycycline.
Ambulatory exacerbation identified by qualifying systemic steroid^Citation14	Presence of a pharmacy claim for systemic steroids (oral, intramuscular, or intravenous).

Abbreviations: COPD, chronic obstructive pulmonary disease; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.

Table 2 Baseline demographics of subjects initiated on roflumilast and subjects not initiated on roflumilast

Trait	Roflumilast-treated group n=500	Non-roflumilast-treated group n=60,145	P-valuea
Age, years, mean (SD)	69.7 (8.3)	72.3 (9.1)	<0.0001
Age category, n (%)
40–49	7 (1.40%)	1,064 (1.77%)	<0.0001
50–59	50 (10.00%)	4,711 (7.83%)
60–69	181 (36.20%)	14,540 (24.17%)
70–79	204 (40.80%)	26,165 (43.50%)
80–89	58 (11.60%)	13,665 (22.72%)
Sex, female, n (%)	271 (54.20%)	33,758 (56.10%)	0.3870
Race/ethnicity, n (%)
White	451 (90.20%)	52,948 (88.03%)	0.1471
Black	39 (7.80%)	5,265 (8.75%)
Hispanic	2 (0.40%)	974 (1.62%)
Other	8 (1.60%)	958 (1.59%)
Geographic region, n (%)
Northeast	11 (2.20%)	954 (1.59%)	0.0825
Midwest	111 (22.20%)	13,674 (22.74%)
South	354 (70.80%)	40,985 (68.14%)
West	24 (4.80%)	4,532 (7.54%)
Low income subsidy, n (%)	243 (48.60%)	15,052 (25.03%)	<0.0001

Notes:

a Continuous variables compared via Wilcoxon rank sum test, categorical variables compared via Chi-square or Fisher’s exact test, as appropriate.

Abbreviation: SD, standard deviation.

Table 3 Baseline comorbid conditions of subjects initiated on roflumilast and subjects not initiated on roflumilast

Trait	Roflumilast-treated group n=500	Non-roflumilast-treated group n=60,145	P-valuea
DCCI score, mean (SD)	2.63 (1.84)	2.61 (2.31)	0.8569
Comorbidity, n (%)
Myocardial infarction	60 (12.00%)	5,956 (9.90%)	0.1182
Congestive heart failure	120 (24.00%)	10,553 (17.55%)	0.0002
Peripheral vascular disease	70 (14.00%)	8,000 (13.3%)	0.6468
Cerebrovascular disease	53 (10.60%)	8,112 (13.49%)	0.0596
Dementia	8 (1.60%)	740 (1.23%)	0.4123
Chronic pulmonary disease	485 (97.00%)	39,431 (65.56%)	<0.0001
Connective tissue disease	23 (4.60%)	3,193 (5.31%)	0.4812
Peptic ulcer disease	11 (2.20%)	1,089 (1.81%)	0.5159
Mild liver disease	7 (1.40%)	606 (1.01%)	0.3623
Diabetes without complications	160 (32.00%)	20,217 (33.61%)	0.4468
Diabetes with complications	27 (5.40%)	7,039 (11.70%)	<0.0001
Paraplegia and hemiplegia	3 (0.60%)	521 (0.87%)	0.8055
Renal disease	64 (12.80%)	11,739 (19.52%)	0.0002
Cancer (including leukemia and lymphoma)	52 (10.40%)	7,146 (11.98%)	0.3078
Moderate or severe liver disease	2 (0.40%)	249 (0.41%)	1.0000
Metastatic carcinoma	1 (0.20%)	820 (1.36%)	0.0175
Acquired immunodeficiency syndrome	2 (0.40%)	98 (0.16%)	0.1997
Respiratory tract cancer	16 (3.20%)	1,490 (2.48%)	0.3011
Cystic fibrosis	0 (0.00%)	24 (0.04%)	1.0000
Fibrosis from tuberculosis	0 (0.00%)	4 (0.01%)	1.0000
Bronchiectasis	31 (6.20%)	1,128 (1.88%)	<0.0001
Pneumoconiosis	16 (3.20%)	1,076 (1.79%)	0.0181
Pulmonary fibrosis	50 (10.00%)	2,693 (4.48%)	<0.0001
Pulmonary tuberculosis	1 (0.20%)	86 (0.14%)	0.5136
Pulmonary sarcoidosis	2 (0.40%)	49 (0.08%)	0.0664

Notes:

a Continuous variables compared via Wilcoxon rank sum test, categorical variables compared via Chi-square or Fisher’s exact test, as appropriate.

Abbreviations: DCCI, Deyo-Charlson Comorbidity Index; SD, standard deviation.

Table 4 Baseline COPD treatment medications of subjects initiated on roflumilast and subjects not initiated on roflumilast

Trait	Roflumilast-treated group n=500	Non-roflumilast-treated group n=60,145	P-valuea
COPD medication class of interest, n (%)b
Short-acting β2-agonists	449 (89.80%)	25,608 (42.58%)	<0.0001
LABA	55 (11.00%)	658 (1.09%)	<0.0001
ICS + LABA combination product	345 (69.00%)	12,629 (21.00%)	<0.0001
Anticholinergics (short-acting)	259 (51.80%)	9,424 (15.67%)	<0.0001
LAMA	308 (61.60%)	7,216 (12.00%)	<0.0001
Methylxanthines	90 (18.00%)	1,404 (2.33%)	<0.0001
Oral/intravenous corticosteroids	446 (89.20%)	34,643 (57.60%)	<0.0001
ICS	99 (19.80%)	3,389 (5.63%)	<0.0001
Antibiotics	477 (95.40%)	53,503 (88.96%)	<0.0001
Long-term oxygen use	330 (66.00%)	10,607 (17.64%)	<0.0001
Combination regimen of interest, n (%)
ICS + LABA + LAMA combinationc	253 (50.60%)	4,057 (6.75%)	<0.0001

Notes:

a Categorical variables compared via Chi-square or Fisher’s exact test, as appropriate;

b not mutually exclusive;

c ICS + LABA + LAMA combination use indicates that a member utilized each of these drug classes at least once during the pre-index period. Concomitant use was not required. Use of individual drug classes (ICS, LABA, and/or LAMA) is reflected under COPD medication class of interest.

Abbreviations: COPD, chronic obstructive pulmonary disease; LABA, long-acting β-agonist; ICS, inhaled corticosteroids; LAMA, long-acting muscarinic antagonist.

Table 5 Twelve-month baseline health care utilization, costs, and exacerbation frequency of subjects initiated on roflumilast and subjects not initiated on roflumilast

Measure	Roflumilast-treated group n=500	Non-roflumilast-treated group n=60,145	P-valuea
All-cause hospitalizations
Members with hospitalization, n (%)	298 (59.60%)	25,672 (42.68%)	<0.0001
Hospitalizations per member, mean (SD)	1.82 (3.46)	1.05 (2.93)	<0.0001
All-cause 30-day readmission
Members with 30-day readmit, n (%)	93 (18.60%)	7,040 (11.71%)	<0.0001
All-cause ER visits
Members with visit, n (%)	232 (46.40%)	23,337 (38.80%)	0.0005
Visits per member, mean (SD)	1.55 (3.51)	0.98 (2.31)	<0.0001
All-cause outpatient visits
Members with visit, n (%)	500 (100.00%)	60,051 (99.84%)	1.0000
Visits per member, mean (SD)	42.21 (29.16)	38.38 (31.54)	<0.0001
COPD-related hospitalizations
Members with hospitalization, n (%)	204 (40.80%)	4,745 (7.89%)	<0.0001
Hospitalizations per member, mean (SD)	0.90 (1.83)	0.11 (0.52)	<0.0001
COPD-related 30-day readmission
Members with 30-day readmit, n (%)	40 (8.00%)	434 (0.72%)	<0.0001
COPD-related emergency room visits
Members with visit, n (%)	87 (17.40%)	1,878 (3.12%)	<0.0001
Visits per member, mean (SD)	0.41 (1.41)	0.05 (0.34)	<0.0001
COPD-related outpatient visits
Members with visit, n (%)	482 (96.40%)	41,920 (69.70%)	<0.0001
Visits per member, mean (SD)	9.22 (8.56)	2.59 (3.74)	<0.0001
All-cause health care costs, mean (SD)
Total costs	$33,690.05 ($33,273.90)	$21,967.55 ($30,919.68)	<0.0001
Outpatient-related	$6,283.36 ($6,568.52)	$6,413.58 ($11,178.01)	<0.0001
Inpatient-related	$13,366.39 ($27,547.76)	$8,827.20 ($22,072.91)	<0.0001
ER-related	$790.03 ($1,885.93)	$533.23 ($1,375.83)	<0.0001
Pharmacy costs	$9,319.39 ($8,557.79)	$4,373.33 ($7,738.44)	<0.0001
COPD-related health care costs, mean (SD)
Total costs	$10,260.01 ($9,767.42)	$1,583.64 ($4,058.56)	<0.0001
Outpatient-related	$898.97 ($1,685.18)	$176.31 ($474.04)	<0.0001
Inpatient-related	$7,160.63 ($15,873.57)	$960.33 ($5,988.98)	<0.0001
ER-related	$226.55 ($769.76)	$26.36 ($213.14)	<0.0001
Pharmacy costs	$3,999.77 ($3,160.50)	$714.27 ($1,503.25)	<0.0001
Exacerbations
Severe, n (%)	187 (37.40%)	3,760 (6.25%)	<0.0001
Moderate-ER, n (%)	83 (16.60%)	1,752 (2.91%)	<0.0001
Moderate-outpatient by qualifying diagnosis, n (%)	319 (63.80%)	21,213 (35.27%)	<0.0001
Moderate-outpatient by qualifying steroid, n (%)	395 (79.00%)	30,739 (51.11%)	<0.0001
Any severity, n (%)	467 (93.40%)	42,182 (73.13%)	<0.0001
Number per member, mean (SD)	6.02 (5.04)	2.13 (2.84)	<0.0001

Notes:

a Continuous variables compared via Wilcoxon rank sum test, categorical variables compared via Chi-square or Fisher’s exact test, as appropriate. Currency is US dollars.

Abbreviations: SD, standard deviation; ER, emergency room; COPD, chronic obstructive pulmonary disease.

Table 6 Univariate difference-in-difference analyses of health care utilization, costs, and exacerbations for roflumilast (n=500) and non-roflumilast (n=60,145) groups

Measure	Roflumilast-treated group			Non-roflumilast-treated group			Roflumilast change minus non-roflumilast change
	Pre-index period	Post-index period	Change	Pre-index period	Post-index period	Change	DIDa	P-valueb
All-cause utilization per 30 days, mean (SD)
Hospitalizations	0.1494 (0.2842)	0.1239 (0.2121)	−0.0255 (0.2264)	0.0866 (0.2410)	0.0792 (0.2441)	−0.0074 (0.2255)	−0.0181	0.0762
ER visits	0.1277 (0.2882)	0.1023 (0.2041)	−0.0254 (0.2262)	0.0807 (0.1902)	0.0657 (0.1579)	−0.0149 (0.1646)	−0.0105	0.3017
Outpatient visits	3.4692 (2.3965)	2.5558 (2.0372)	−0.9133 (1.9193)	3.1545 (2.5924)	2.4014 (2.1859)	−0.7531 (2.0756)	−0.1603	0.0637
COPD-related utilization per 30 days, mean (SD)
Hospitalizations	0.0740 (0.1503)	0.0557 (0.1093)	−0.0182 (0.1444)	0.0092 (0.0426)	0.0079 (0.0391)	−0.0013 (0.0441)	−0.0169	0.009
ER visits	0.0335 (0.1159)	0.0254 (0.0904)	−0.0081 (0.1153)	0.0040 (0.0277)	0.0035 (0.0244)	−0.0005 (0.0318)	−0.0076	0.1434
Outpatient visits	0.7575 (0.7032)	0.5075 (0.4967)	−0.2500 (0.6264)	0.2129 (0.3073)	0.1523 (0.2519)	−0.0606 (0.2945)	−0.1894	<0.0001
All-cause costs per 30 days, mean (SD)
Total costs	$2,769 ($2,734)	$2,484 ($2,883)	−$284 ($3,054)	$1,805 ($2,541)	$1,437 ($2,196)	−$367 ($2,563)	$84	0.5422
Outpatient-related costs	$516 ($539)	$404 ($530)	−$111 ($549)	$527 ($918)	$396 ($722)	−$130 ($844)	$19	0.4513
Inpatient-related costs	$1,098 ($2,264)	$1,072 ($2,366)	−$26 ($2,808)	$725 ($1,814)	$606 ($1,591)	−$119 ($2,122)	$93	0.4602
ER-related costs	$64 ($155)	$55 ($117)	−$9 ($137)	$44 ($113)	$36 ($91)	−$8 ($115)	−$1	0.8470
Pharmacy costs	$765 ($703)	$654 ($665)	−$111 ($497)	$359 ($636)	$269 ($513)	−$90 ($389)	−$21	0.3385
COPD-related costs per 30 days, mean (SD)
Total costs	$843 ($802)	$780 ($797)	−$62 ($850)	$130 ($333)	$110 ($280)	−$19 ($314)	−$43	0.2580
Outpatient-related costs	$74 ($52)	$43 ($119)	−$ 31 ($52)	$14 ($38)	$9 ($25)	−$4 ($40)	−$26	<0.0001
Inpatient-related costs	$588 ($1,304)	$447 ($1,015)	−$141 ($1,371)	$78 ($492)	$67 ($462)	−$11 ($593)	−$130	0.0346
ER-related costs	$18 ($63)	$14 ($53)	−$4 ($63)	$2 ($17)	$2 ($15)	$0 ($20)	−$4	0.1529
Pharmacy costs	$328 ($259)	$330 ($250)	$2 ($203)	$58 ($123)	$51 ($105)	−$7 ($70)	$9	0.2840
Exacerbations per 30 days, mean (SD)
Number of exacerbations	0.4955 (0.4144)	0.3382 (0.3006)	−0.1573 (0.3407)	0.1753 (0.2337)	0.1215 (0.1815)	−0.0538 (0.1819)	−0.1035	<0.0001
Number of severe exacerbations	0.0593 (0.1121)	0.0451 (0.0866)	−0.0143 (0.1064)	0.0068 (0.0313)	0.0056 (0.0261)	−0.0011 (0.0327)	−0.0131	0.0060
Number of moderate exacerbations, ER	0.0237 (0.0790)	0.0145 (0.0447)	−0.0091 (0.0693)	0.0029 (0.0185)	0.0024 (0.0155)	−0.0005 (0.0208)	−0.0087	0.0055
Number of moderate exacerbations, OP	0.1373 (0.1847)	0.0829 (0.1167)	−0.0544 (0.1517)	0.0487 (0.0878)	0.0318 (0.0646)	−0.0169 (0.0888)	−0.0375	<0.0001
Number of moderate exacerbations, steroid	0.2752 (0.3217)	0.1957 (0.2360)	−0.0794 (0.2611)	0.1169 (0.2053)	0.0816 (0.1556)	−0.0353 (0.1562)	−0.0442	0.0002

Notes:

a Roflumilast-treated group mean difference minus non-roflumilast-treated group mean difference; positive DID values favor non-roflumilast-treated group;

b t-test, unequal variances assumed. Currency is US dollars.

Abbreviations: DID, difference-in-difference; SD, standard deviation; ER, emergency room; COPD, chronic obstructive pulmonary disease; OP, outpatient.

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