Escalation to single- or multiple-inhaler triple therapy (SITT; MITT) is a recommended option for patients with asthma who remain uncontrolled by medium-dose inhaled corticosteroid/long-acting β2-agonist; however, characterization of elderly users of triple therapy is limited. This real-world cohort study describes demographics and clinical characteristics of elderly patients with asthma with and without comorbid chronic obstructive pulmonary disease (COPD) who are new users of triple therapy, and asthma treatment patterns preceding triple therapy initiation.
Methods
This retrospective cohort study used administrative claims data from the Optum Clinformatics Data Mart database. Eligible patients were ≥ 65 years of age with asthma or with asthma and comorbid COPD who initiated either triple therapy with single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI; 100/62.5/25 μg) or MITT between September 18, 2017 and September 30, 2020. Demographics, clinical characteristics, healthcare resource utilization, healthcare costs, and asthma treatment patterns were described in the 12-month period before triple therapy initiation (baseline period).
Results
In total, 15,557 patients were included. Among FF/UMEC/VI initiators with asthma (N = 635) mean age was 73.3 years and 66.6% were female. During the baseline period, > 75% of patients used controller therapy, > 92% used rescue medications, 27.9% experienced ≥ 1 asthma-related exacerbation, with mean annual exacerbation rate of 0.42, and mean all-cause healthcare costs were $23,407. Patients with asthma initiating MITT and patients with asthma and comorbid COPD initiating FF/UMEC/VI or MITT had similar characteristics, healthcare resource utilization, healthcare costs, and asthma treatment patterns to FF/UMEC/VI initiators with asthma.
Conclusions
Triple therapy is often initiated following use of other asthma controller medications in real-world practice. Substantial rescue medication use and high disease and economic burden among this elderly patient population suggest that their asthma was not adequately controlled prior to triple therapy initiation. This retrospective study provides an early profile of elderly patients with asthma in the USA.
Prior Presentation: An abstract based on this study was previously presented as a poster presentation at the American Academy of Allergy Asthma & Immunology (AAAAI) Annual Meeting, 25–28 February 2022, Phoenix, Arizona, USA.
Key Summary Points
Why carry out this study?
There is a paucity of real-world data on the characteristics of patients aged ≥ 65 years with asthma, a population that may not be well represented in clinical trials as a result of higher prevalence of comorbidities.
This study aimed to characterize the profile of elderly patients with asthma with or without comorbid chronic obstructive pulmonary disease (COPD) who initiated triple therapy in the USA.
What was learned from this study?
This retrospective study described an important early profile of real-world clinical characteristics and treatment patterns of new elderly users of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) or multiple-inhaler triple therapy (MITT). In the year prior to triple therapy initiation, patients in the four cohorts assessed had broadly similar characteristics.
Controller medication use prior to escalation to triple therapy indicated that patients’ asthma was likely uncontrolled.
Further real-world analyses are warranted to better understand current asthma management among elderly patients and how it may be improved to reduce the economic burden of this disease and improve clinical outcomes.
Introduction
Asthma places a major clinical and economic burden in the USA. It affects approximately 25 million people [1] and is a leading cause of mortality [2], and between 2008 and 2013 it accounted for $50 billion in medical costs and $32 billion in losses due to absenteeism and mortality [3]. These costs have been predicted to grow in the future, in particular in relation to uncontrolled asthma [4]. For adult patients who remain symptomatic on at least medium-dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) dual therapy, the Global Initiative for Asthma (GINA) report recommends add-on therapy with a supplementary long-acting muscarinic antagonist (LAMA) controller as a treatment option, administered either as single- or multiple-inhaler triple therapy (SITT or MITT, respectively) [5].
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In real-world studies, MITT use was associated with lower adherence and persistence rates among patients with asthma [6‐8], which may be due to different dosing regimens or devices required for MITT delivery [5]. Additionally, a retrospective cohort study of MITT for asthma between 2014 and 2017 found that 90% of patients initiating MITT (mean age 56 years) used prior asthma controller therapy [6]. Furthermore, high healthcare resource utilization (HCRU) and exacerbation rates suggested that patients had substantial disease burden and unmet needs prior to MITT initiation [6]. SITT, for the maintenance treatment of asthma in adults, is available as an ICS/LAMA/LABA combination of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) at two doses (100/62.5/25 μg and 200/62.5/25 μg) administered via the dry-powder ELLIPTA single-inhaler [9]. SITT may simplify asthma management, with demonstrated efficacy compared with FF/VI dual therapy in patients with asthma and with overlapping asthma and chronic obstructive pulmonary disease (COPD) [10].
Patient characteristics and treatment patterns among a commercially insured population of adults (aged ≥ 18 years) with asthma using off-label FF/UMEC/VI has previously been reported in a US claims database study [11]. However, there is a paucity of real-world data on the characteristics of elderly patient populations (aged ≥ 65 years) with asthma. The prevalence of asthma in this population in the USA is estimated to be approximately 7–9% [12] and is thought to be underdiagnosed as a result of underreporting [13]. The highest mortality rates associated with patients with asthma are observed among adults aged ≥ 65 years [14]. Comorbidities, including COPD and obesity, increase with age [14], and this may play a role in the lack of representation of elderly patients in current asthma clinical trials [15, 16]. Overlapping diagnostic criteria can lead to some patients presenting with symptoms of both asthma and COPD [5], and prevalence for these overlapping conditions has been estimated in the range of 12–55% in different studies [17]. Also, prescribed medications for the management of comorbidities may exacerbate asthma [14], resulting in increased disease burden. This expected increase highlights the importance of characterizing the elderly asthma population in a real-world setting to ensure patients can benefit from the newest and most effective treatments [18]. Here, we expand on the current understanding of real-world use of triple therapy in the USA and establish the profile of elderly patients with asthma or asthma and comorbid COPD who initiated triple therapy in the form of single-inhaler FF/UMEC/VI (100/62.5/25 μg) or MITT.
Methods
Study Design
This retrospective cohort study used medical and pharmacy claims data from the Optum Clinformatics™ Data Mart (CDM) database. Index date was defined as the date of first pharmacy claim for single-inhaler FF/UMEC/VI (100/62.5/25 μg), or the date of first overlapping days of supply with all three components of MITT during the identification period if no pharmacy claims for single-inhaler FF/UMEC/VI (from September 18, 2017 to September 30, 2020) (Fig. 1).
Fig. 1
Study design. aIndex date was defined as date of first FF/UMEC/VI pharmacy claim, or date of first overlapping days of supply with all three components of MITT. COPD chronic obstructive pulmonary disease, FF fluticasone furoate, MITT multiple-inhaler triple therapy, UMEC umeclidinium, VI vilanterol
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The 12 months prior to index date were defined as the baseline period, during which patients’ demographics and clinical characteristics were assessed. Additionally, the baseline period was stratified into four 3-month intervals from index date to 12 months prior to triple therapy initiation and was used to evaluate treatment patterns and blood eosinophil (EOS) levels (Fig. 1). The post-index period was not used to evaluate any study endpoints.
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MITT was defined as the concomitant use of two different inhalers in the form of ICS/LABA + LAMA or ICS + LAMA/LABA, or three different inhalers in the form of ICS + LAMA + LABA. MITT users were identified on the basis of an overlap of ≥ 1 day of supply of all three triple therapy components, using an algorithm based on previous studies [19‐21].
Data Source
This study used de-identified data from the Optum CDM database (data ranging from January 1, 2015 to September 30, 2020) [22]. The database contains 15–19 million annual lives of United Health Group members in all census regions in the USA. It also includes laboratory tests and results, historical data on patient demographics, insurance coverage, dates of eligibility and death, claims for inpatient (IP) and outpatient (OP) visits, pharmacy claims, and costs of services.
Study Population
Patients were required to be aged ≥ 65 years at index and have ≥ 1 dispensing of single-inhaler fixed-dose FF/UMEC/VI 100/62.5/25 μg or ≥ 1 overlapping day of supply with all three MITT controller medications (ICS, LABA, and LAMA), ≥ 12 months of continuous health insurance coverage prior to index date, and ≥ 1 medical claim with a primary or secondary diagnosis of asthma during the baseline period or at index.
Patients were classified into four mutually exclusive cohorts based on their index date medication and diagnosis during baseline period. The four patient cohorts were new elderly users of FF/UMEC/VI with asthma; new elderly users of MITT with asthma; new elderly users of FF/UMEC/VI with asthma and comorbid COPD; and new elderly users of MITT with asthma and comorbid COPD. Asthma and COPD diagnosis codes were defined by the International Classification of Diseases (ICD), Tenth Revision (Table S1) [23]. Patients in the asthma and comorbid COPD cohorts were required to have ≥ 1 medical claim with a diagnosis of COPD during the baseline period or at index. Patients initiating both FF/UMEC/VI and MITT during the identification period were classified into the FF/UMEC/VI cohort.
Patients were excluded from this study if they had ≥ 1 dispensing of FF/UMEC/VI and ≥ 1 overlapping day of supply with all three components of MITT at index. Patients were excluded from the FF/UMEC/VI cohort if they had ≥ 1 dispensing of FF/UMEC/VI during the baseline period, excluded from the MITT cohort if they had ≥ 1 overlapping day of supply with all three components of MITT during the baseline period, and excluded from the asthma cohort if they had ≥ 1 medical claim with a primary or secondary diagnosis of COPD during the eligibility period.
Study Endpoints
The primary objective of this study was to describe the demographic and clinical characteristics during the baseline period of new elderly users of FF/UMEC/VI with asthma and to describe patterns of asthma medication use preceding the initiation of FF/UMEC/VI. The secondary objectives of this study were to describe the demographics, clinical characteristics, and treatment patterns during the baseline period among new elderly users of MITT with asthma, and among new elderly users of FF/UMEC/VI or MITT with asthma and comorbid COPD. The combinations of medications comprising patients’ triple therapy regimen at index were reported among MITT users.
Data Analyses
Demographic information was evaluated at index, and clinical characteristics and treatment patterns were evaluated during the baseline period.
All results were summarized by patients’ treatment regimen, FF/UMEC/VI or MITT, and disease condition, asthma or asthma and comorbid COPD. Baseline characteristics, including blood EOS levels, and treatment patterns were reported using descriptive statistics, including mean and standard deviation (SD) for continuous variables and frequencies and proportions for categorical variables.
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Overall exacerbations were defined as asthma-related IP or emergency department (ED) visit (IP/ED-defined exacerbation), or asthma-related ED or OP visit with a systemic corticosteroid (SCS) dispensing (including oral corticosteroids [OCS]) within ± 5 days (SCS-defined exacerbation). If ≥ 2 exacerbations were observed within 14 days of each other for a single patient, they were considered as one exacerbation and classified according to highest severity.
All-cause and asthma-related HCRU were reported as percent of patients with ≥ 1 HCRU event. All-cause and asthma-related healthcare costs were reported as costs incurred and were inflation-adjusted to $US 2020 based on the US Medical Care component of the consumer price index. Asthma-related IP, ED, or OP visits used to define exacerbations, HCRU, and costs were identified as claims with a primary diagnosis of asthma.
Asthma medication use was described as the proportion of patients taking each class of medication during the 12-month baseline period and over 3-month intervals starting from the index date to 12 months pre-index. Daily ICS and ICS/LABA doses were calculated from pharmacy claims.
All analyses were conducted using SAS Enterprise Guide, Version 7.15 (SAS Institute, Cary, NC). All results presented in this study were analyzed descriptively, and no comparative analyses between patient groups were conducted.
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Ethics Approval and Informed Consent
This study used de-identified claims data; therefore, this study did not require institutional review board (IRB) approval. GSK complies with laws and regulations to ensure data privacy and appropriate use of de-identified datasets for research, including the Health Insurance Portability and Accountability Act of 1996 (HIPAA), to protect sensitive patient health information from being disclosed without the patient’s consent or knowledge. No direct subject contact or primary collection of individual human subject data occurred, and no patient identifiers are reported.
Results
Study Population
Of the 78,397 patients initiating treatment with FF/UMEC/VI or MITT between September 18, 2017 and September 30, 2020, there were 15,557 patients aged ≥ 65 years who met the eligibility criteria and were included in this study (Fig. 2). In total, 7307 new elderly users of FF/UMEC/VI were included, of whom 635 (8.7%) were classified into the asthma cohort and 6672 (91.3%) into the asthma and comorbid COPD cohort. Overall, 8250 new elderly users of MITT were included, of whom 1395 (16.9%) and 6855 (83.1%) were classified into the asthma cohort and asthma and comorbid COPD cohort, respectively (Fig. 2).
Fig. 2
Patient disposition. COPD chronic obstructive pulmonary disease, FDA Food and Drug Administration, FF fluticasone furoate, ICS inhaled corticosteroid, LABA long-acting β2-agonist, LAMA long-acting muscarinic antagonist, MITT multiple-inhaler triple therapy, UMEC umeclidinium, VI vilanterol
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New Elderly Users of FF/UMEC/VI or MITT with Asthma
Baseline Demographics and Clinical Characteristics
Baseline demographics, clinical characteristics, asthma-related exacerbations, and all-cause and asthma-related HCRU and healthcare costs of new elderly users of FF/UMEC/VI with asthma are presented in Table 1. Mean (SD) age of patients was 73.3 (5.8) years, 423 (66.6%) were female, and 565 (89.0%) had a Medicare insurance plan. Overall, 177 patients (27.9%) had ≥ 1 and 57 (9.0%) had ≥ 2 asthma-related exacerbations during baseline, with an annual mean exacerbation rate of 0.42 per patient per year (PPPY). In terms of all-cause HCRU, 67 patients (10.6%) had ≥ 1 hospitalization and 634 patients (99.8%) had ≥ 1 OP visit during baseline. Mean (SD) total all-cause healthcare costs were $23,407 ($33,531) during baseline, of which $3109 ($6072) were total asthma-related healthcare costs (Table 1).
Table 1
Baseline demographics and clinical characteristics
Asthma
Asthma and comorbid COPD
FF/UMEC/VI
(N = 635)
MITT
(N = 1395)
FF/UMEC/VI
(N = 6672)
MITT
(N = 6855)
Age (years),a mean (SD)
73.3 (5.8)
72.3 (5.5)
75.0 (6.3)
74.9 (6.4)
Female,an (%)
423 (66.6)
1023 (73.3)
4201 (63.0)
4569 (66.7)
Insurance plan type,an (%)
Medicare
565 (89.0)
1199 (85.9)
6341 (95.0)
6476 (94.5)
Commercial
70 (11.0)
196 (14.1)
331 (5.0)
379 (5.5)
Patients with ≥ 1 asthma-related exacerbation during baseline,bn (%)
Overall
177 (27.9)
537 (38.5)
1455 (21.8)
1835 (26.8)
SCS-defined
154 (24.3)
450 (32.3)
981 (14.7)
1118 (16.3)
IP/ED-defined
36 (5.7)
127 (9.1)
590 (8.8)
926 (13.5)
Patients with ≥ 2 asthma-related exacerbations during baseline,bn (%)
Asthma-related healthcare costs, $US 2020,b,c mean (SD)
Total costs (medical + pharmacy)
3109 (6072)
5079 (10,328)
5301 (10,753)
6943 (18,411)
Total medical costs
1365 (5190)
1977 (8795)
2157 (9814)
3822 (18,037)
Total pharmacy costs
1744 (2775)
3102 (4753)
3144 (3974)
3121 (3319)
All-cause healthcare costs, $US 2020,b,c mean (SD)
Total costs (medical + pharmacy)
23,407 (33,531)
25,123 (32,615)
48,304 (63,391)
54,230 (70,280)
Total medical costs
16,219 (29,082)
17,162 (28,330)
39,697 (60,546)
45,431 (67,384)
Total pharmacy costs
7188 (12,863)
7961 (13,479)
8607 (14,525)
8799 (14,472)
Quan-CCI, mean (SD)b
2.13 (1.74)
1.97 (1.48)
3.03 (2.14)
3.19 (2.22)
Asthma-related comorbidities,bn (%)
GERD
280 (44.1)
586 (42.0)
3001 (45.0)
3272 (47.7)
Allergic rhinitis
247 (38.9)
623 (44.7)
1948 (29.2)
1928 (28.1)
Obesity
182 (28.7)
399 (28.6)
2143 (32.1)
2325 (33.9)
URTI
177 (27.9)
406 (29.1)
1733 (26.0)
1715 (25.0)
Sinusitis
166 (26.1)
398 (28.5)
1302 (19.5)
1314 (19.2)
Obstructive sleep apnea
135 (21.3)
353 (25.3)
1879 (28.2)
2006 (29.3)
Anxiety disorders
132 (20.8)
268 (19.2)
1944 (29.1)
2040 (29.8)
Depressive disorders
130 (20.5)
280 (20.1)
1931 (28.9)
2218 (32.4)
Pneumonia
74 (11.7)
165 (11.8)
1745 (26.2)
2043 (29.8)
Acute respiratory failure
14 (2.2)
59 (4.2)
1144 (17.1)
1473 (21.5)
Eosinophilic disorders
2 (0.3)
22 (1.6)
28 (0.4)
46 (0.7)
Elixhauser comorbidities,bn (%)
Hypertension
496 (78.1)
1038 (74.4)
5755 (86.3)
5925 (86.4)
Diabetes
231 (36.4)
396 (28.4)
2612 (39.1)
2874 (41.9)
Obesity
182 (28.7)
399 (28.6)
2143 (32.1)
2325 (33.9)
Cardiac arrhythmias
148 (23.3)
295 (21.1)
2625 (39.3)
2943 (42.9)
Renal failure
112 (17.6)
209 (15.0)
1795 (26.9)
1946 (28.4)
Peripheral vascular disorders
99 (15.6)
210 (15.1)
2336 (35.0)
2453 (35.8)
Valvular disease
95 (15.0)
194 (13.9)
1687 (25.3)
1723 (25.1)
Congestive heart failure
77 (12.1)
148 (10.6)
2194 (32.9)
2482 (36.2)
RA/CVD
74 (11.7)
133 (9.5)
766 (11.5)
841 (12.3)
Solid tumor without metastasis
63 (9.9)
128 (9.2)
1041 (15.6)
980 (14.3)
Deficiency anemias
53 (8.3)
100 (7.2)
989 (14.8)
989 (14.4)
Liver disease
39 (6.1)
101 (7.2)
610 (9.1)
674 (9.8)
Pulmonary circulation disorder
38 (6.0)
78 (5.6)
1042 (15.6)
1055 (15.4)
Blood EOS levelsb
Patients with ≥ 1 test, n (%)
245 (38.6)
493 (35.3)
2753 (41.3)
2512 (36.6)
Number of tests, mean (SD)
1.83 (1.22)
1.74 (1.12)
2.16 (1.94)
2.24 (2.50)
EOS levels among patients with ≥ 2 tests, cells/µL
EOS level of first test, mean (SD)
263.6 (190.6)
270.9 (287.5)
274.9 (450.5)
265.7 (293.1)
EOS level of last test, mean (SD)
286.9 (228.2)
279.3 (286.9)
274.0 (414.4)
256.7 (303.5)
High EOS level 0–3 months prior to index date, n (%)d
27 (24.8)
51 (23.0)
273 (21.9)
258 (22.3)
High EOS level 10–12 months prior to index date, n (%)d
20 (20.2)
35 (19.0)
231 (19.7)
235 (22.6)
COPD chronic obstructive pulmonary disease, CVD collagen vascular disease, ED emergency department, EOS eosinophil, FF fluticasone furoate, GERD gastroesophageal reflux disease, IP inpatient, MITT multiple-inhaler triple therapy, OP outpatient, PPPY per patient per year, Quan CCI Quan–Charlson Comorbidity Index, RA rheumatoid arthritis, SCS systemic corticosteroid, SD standard deviation, UMEC umeclidinium, URTI upper respiratory tract infection, $US United States dollar, VI vilanterol
aEvaluated on index date
bEvaluated during 12-month baseline period, excluding index date
cCosts were inflation-adjusted to $US 2020 using the US Medical Care consumer price index (Bureau of Labor Statistics, US Department of Labor)
dHigh EOS level indicated by ≥ 400 cells/µL
The most common asthma-related comorbidities were gastroesophageal reflux disease (GERD) (44.1%), allergic rhinitis (38.9%), obesity (28.7%), and upper respiratory tract infection (URTI) (27.9%). The most common baseline Elixhauser comorbidities were hypertension (78.1%), diabetes (36.4%), and obesity (28.7%) (Table 1).
During the 12-month baseline period, 245 patients (38.6%) had ≥ 1 EOS blood test. The proportion of patients with high EOS levels (≥ 400 cells/μL) increased to 24.8% in the 0–3 months prior to index from 20.2% in the 10–12 months prior (Table 1).
Baseline demographics, clinical characteristics, asthma-related exacerbations, and all-cause and asthma-related HCRU and healthcare costs of new elderly users of MITT with asthma are also presented in Table 1. Mean (SD) age was 72.3 (5.5) years; 1023 (73.3%) were female; 1199 (85.9%) had a Medicare insurance plan. Overall, 537 patients (38.5%) had ≥ 1 and 180 (12.9%) had ≥ 2 asthma-related exacerbations during baseline, with an annual mean exacerbation rate of 0.59 PPPY. In terms of all-cause HCRU, 191 patients (13.7%) had ≥ 1 hospitalization and 1394 patients (99.9%) had ≥ 1 OP visit during baseline. Mean (SD) total all-cause healthcare costs were $25,123 ($32,615) during baseline, of which $5079 ($10,328) were total asthma-related healthcare costs (Table 1).
The most common asthma-related and Elixhauser comorbidities were the same as those for patients initiating FF/UMEC/VI. During the 12-month baseline period, 493 patients (35.3%) had ≥ 1 EOS blood test; the proportion of those with high EOS levels (≥ 400 cells/μL) increased to 23.0% in the 0–3 months prior to index from 19.0% in the 10–12 months prior (Table 1).
Treatment Patterns
Of those elderly patients with asthma who were new users of FF/UMEC/VI, 478 (75.3%) had previous controller medication use during the 12-month baseline period (Table 2). The most common controller medication class was ICS/LABA (52.6%), followed by LTRA, ICS, LAMA and MITT. Most patients (92.1%) used ≥ 1 rescue medication during baseline, of which the most common were antibiotics, SCS, and short-acting β2-agonist (SABA) (Table 2).
Table 2
Baseline respiratory medication use
Asthma
Asthma and comorbid COPD
FF/UMEC/VI
(N = 635)
MITT
(N = 1395)
FF/UMEC/VI
(N = 6672)
MITT
(N = 6855)
Controller medications,an (%)
Any use of controller medication
478 (75.3)
1342 (96.2)
5656 (84.8)
6425 (93.7)
ICS/LABA
334 (52.6)
1095 (78.5)
3986 (59.7)
4453 (65.0)
LTRA
281 (44.3)
778 (55.8)
2552 (38.2)
2733 (39.9)
ICS
76 (12.0)
227 (16.3)
852 (12.8)
1059 (15.4)
LAMA
58 (9.1)
362 (25.9)
1531 (22.9)
2451 (35.8)
MITT
48 (7.6)
–
1356 (20.3)
–
LAMA/LABA
21 (3.3)
49 (3.5)
948 (14.2)
566 (8.3)
Biologics
12 (1.9)
45 (3.2)
110 (1.6)
119 (1.7)
Methylxanthines
6 (0.9)
18 (1.3)
154 (2.3)
139 (2.0)
LABA
4 (0.6)
11 (0.8)
109 (1.6)
151 (2.2)
Mast cell stabilizers
0 (0.0)
1 (0.1)
1 (0.0)
5 (0.1)
PDE-4 inhibitors
0 (0.0)
0 (0.0)
132 (2.0)
64 (0.9)
Rescue medications,an (%)
Any use of rescue medications
585 (92.1)
1339 (96.0)
6446 (96.6)
6606 (96.4)
Antibiotics
477 (75.1)
1049 (75.2)
5512 (82.6)
5557 (81.1)
SCSb
422 (66.5)
1001 (71.8)
5263 (78.9)
5243 (76.5)
SABA
422 (66.5)
1059 (75.9)
4914 (73.7)
5201 (75.9)
SABA/SAMA
62 (9.8)
167 (12.0)
1747 (26.2)
1863 (27.2)
SAMA
14 (2.2)
40 (2.9)
362 (5.4)
366 (5.3)
AMR,c,d mean (SD)
0.75 (0.26)
0.75 (0.24)
0.69 (0.29)
0.66 (0.29)
AMR asthma medication ratio, COPD chronic obstructive pulmonary disease, FF fluticasone furoate, ICS inhaled corticosteroid, LABA long-acting β2-agonist, LAMA long-acting muscarinic antagonist, LTRA leukotriene receptor antagonist, MITT multiple-inhaler triple therapy, OCS oral corticosteroid, PDE phosphodiesterase, SABA short-acting β2-agonist, SAMA short-acting muscarinic antagonist, SCS systemic corticosteroid, SD standard deviation, UMEC umeclidinium, VI vilanterol
aEvaluated during 12-month baseline period, excluding index date
bSCS category of rescue medications included OCS
cEvaluated during 12-month baseline period, including index date
dAMR measures the “units” of controller medications dispensed divided by the sum of the units of controller and rescue medications dispensed
The proportion of patients using LTRA increased to 34.3% in the 0–3 months prior to index from 26.5% in the 10–12 months prior (Fig. 3a). Likewise, the proportions of patients using ICS/LABA or ICS as controller medication increased slightly in the 0–3 months prior to index (30.4% or 5.5%) compared with the 10–12 months prior (30.2% or 4.4%). The proportion of patients using SCS increased to 39.5% in the 0–3 months prior to index from 27.2% in the 10–12 months prior, and similar increases were observed for patients using SABA or antibiotics as rescue medication (Fig. 4a).
Fig. 3
a–d Baseline treatment patterns of controller medications. aBiologics include omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab; bMonths prior to index date. COPD chronic obstructive pulmonary disease, FF fluticasone furoate, ICS inhaled corticosteroid, LABA long-acting β2-agonist, LAMA long-acting muscarinic antagonist, LTRA leukotriene receptor antagonist, MITT multiple-inhaler triple therapy, PDE phosphodiesterase, UMEC umeclidinium, VI vilanterol
Fig. 4
a–d Baseline treatment patterns of rescue medications. aSCS category of rescue medications included OCS. COPD chronic obstructive pulmonary disease, FF fluticasone furoate, MITT multiple-inhaler triple therapy, OCS oral corticosteroid, SABA short-acting β2-agonist, SCS systemic corticosteroid, UMEC umeclidinium, VI vilanterol
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Similar to patients initiating FF/UMEC/VI, a high proportion (96.2%) of elderly patients with asthma initiating MITT had previous controller medication use during the 12-month baseline period (Table 2). The most common controller and rescue medication classes used during baseline were the same as those for patients initiating FF/UMEC/VI (Table 2).
The proportion of patients using ICS/LABA increased to 63.6% in the 0–3 months prior to index from 35.8% in the 10–12 months prior, while those using LTRA increased to 45.1% in the 0–3 months prior to index from 26.7% in the 10–12 months prior (Fig. 3b). There was an increase in rescue medication use in the 0–3 months prior to index from the 10–12 months prior for all medications (Fig. 4b).
New Elderly Users of FF/UMEC/VI or MITT with Asthma and Comorbid COPD
Baseline Demographics and Clinical Characteristics
Baseline demographics and clinical characteristics for new elderly users of FF/UMEC/VI or MITT with asthma and comorbid COPD were generally similar during the baseline period (Table 1). In total, 21.8–26.8% of patients in each cohort had ≥ 1 and 5.8–8.3% had ≥ 2 asthma-related exacerbations during baseline (Table 1).
The most common asthma-related and Elixhauser comorbidities were similar to those presented for patients with asthma (Table 1).
At least one all-cause IP stay during baseline was observed for 2679 patients (40.2%) initiating FF/UMEC/VI and 3250 patients (47.4%) initiating MITT. Mean (SD) all-cause healthcare costs were $48,304 ($63,391) for elderly patients initiating FF/UMEC/VI and $54,230 ($70,280) for those initiating MITT. Asthma-related healthcare costs were $5301 ($10,753) for patients initiating FF/UMEC/VI and $6943 ($18,411) for those initiating MITT (Table 1).
Treatment Patterns
Most patients in each cohort had previous controller medication use in the 12 months prior to index (84.8% and 93.7% of those initiating FF/UMEC/VI and MITT, respectively) (Table 2). The most common controller medication classes used were ICS/LABA, LTRA, and LAMA and rescue medication classes were SCS, SABA, and SABA/short-acting muscarinic antagonist (SAMA) (Table 2). Treatment patterns over the 12-month baseline period stratified into 3-month intervals were similar in both cohorts. Generally, the proportion of patients using asthma controller (Fig. 3c, d) or rescue medication (Fig. 4c, d) increased in the 0–3 months prior to index versus the 10–12 months prior.
Triple Therapy Treatment Patterns at Index Among MITT Initiators With and Without Comorbid COPD
The most common combination of triple therapy at index was ICS/LABA + LAMA (94.0% and 88.8%) among new users of MITT with asthma with and without comorbid COPD, respectively (Table 3). The most frequently used formulation was medium-dose ICS/LABA, followed by high-dose ICS/LABA, for both cohorts. An overview of triple therapies on the index date can be found in Table 4.
Table 3
Triple therapy patterns on the index date for elderly patients initiating treatment with MITT
Asthma
(N = 1395)
Asthma and comorbid COPD
(N = 6855)
ICS/LABA + LAMA, n (%)
1311 (94.0)
6085 (88.8)
ICS/LABA daily dosea
Low
1783 (12.8)
1060 (15.5)
Medium
68,273 (48.9)
3564 (52.0)
High
451 (32.3)
1461 (21.3)
Dispensing days of supply,b mean (SD)
25.8 (19.2)
26.2 (19.3)
ICS + LAMA + LABA, n (%)
5 (0.4)
116 (1.7)
ICS daily dosea
Low
1 (0.1)
11 (0.2)
Medium
1 (0.1)
7 (0.1)
High
0 (0.0)
0 (0.0)
Dispensing days of supply,b mean (SD)
16.8 (7.4)
15.6 (12.1)
ICS + LAMA/LABA, n (%)
79 (5.7)
654 (9.5)
ICS daily dosea
Low
38 (2.7)
324 (4.7)
Medium
10 (0.7)
80 (1.2)
High
17 (1.2)
69 (1.0)
Dispensing days of supply,b mean (SD)
22.9 (14.8)
21.5 (16.2)
COPD chronic obstructive pulmonary disease, ICS inhaled corticosteroid, LABA long-acting β2-agonist, LAMA long-acting muscarinic antagonist, MITT multiple-inhaler triple therapy, SD standard deviation
aDaily ICS and ICS/LABA dose was calculated from pharmacy claims as follows: (strength of dose × quantity dispensed × number of actuations per inhaler)/(package size × number of inhalations per day × days of medication supplied)
bDispensing days of supply were calculated as the overlapping days of supply between each MITT component
Table 4
Triple therapy components on the index date for elderly patients initiating treatment with MITT
Asthma
(N = 1395)
Asthma and comorbid COPD
(N = 6855)
ICS/LABA + LAMA, n (%)
1311 (99.9)
6085 (99.8)
BUD/FOR + TIO
501 (38.2)
2579 (42.4)
FLU/SAL + TIO
463 (35.3)
2203 (36.2)
FF/VI + TIO
268 (20.4)
1078 (17.7)
MOM/FOR + TIO
79 (6.0)
225 (3.7)
ICS + LAMA/LABA, n (%)
79 (100.0)
654 (100.0)
FF + UMEC/VI
24 (30.4)
80 (12.2)
FP + UMEC/VI
19 (24.1)
186 (28.4)
BUD + UMEC/VI
7 (8.9)
110 (16.8)
FP + TIO/OLO
7 (8.9)
108 (16.5)
BUD + TIO/OLO
7 (8.9)
71 (10.9)
BEC + UMEC/VI
4 (5.1)
11 (1.7)
MOM + UMEC/VI
4 (5.1)
5 (0.8)
FF + TIO/OLO
2 (2.5)
61 (9.3)
CIC + UMEC/VI
2 (2.5)
4 (0.6)
MOM + TIO/OLO
1 (1.3)
3 (0.5)
CIC + TIO/OLO
1 (1.3)
0 (0.0)
FP + GLY/IND
1 (1.3)
0 (0.0)
BEC + TIO/OLO
0 (0.0)
12 (1.8)
BEC + GLY/IND
0 (0.0)
1 (0.2)
FF + GLY/IND
0 (0.0)
1 (0.2)
FP + ACL/FOR
0 (0.0)
1 (0.2)
ICS + LAMA + LABA, n (%)
5 (100.0)
116 (100.0)
BUD + FOR + TIO
2 (40.0)
44 (37.9)
BUD + ARF + TIO
1 (20.0)
50 (43.1)
FP + SAL + TIO
1 (20.0)
10 (8.6)
FP + ARF + TIO
1 (20.0)
3 (2.6)
BUD + SAL + TIO
0 (0.0)
4 (3.4)
FP + FOR + TIO
0 (0.0)
3 (2.6)
BEC + SAL + TIO
0 (0.0)
1 (0.9)
MOM + SAL + TIO
0 (0.0)
1 (0.9)
ACL aclidinium, ARF arformoterol, BEC beclomethasone, BUD budesonide, CIC ciclesonide, COPD chronic obstructive pulmonary disease, FF fluticasone furoate, FLU fluticasone, FOR formoterol, FP fluticasone propionate, GLY glycopyrrolate, ICS inhaled corticosteroid, IND indacaterol, LABA long-acting β2-agonist, LAMA long-acting muscarinic antagonist, MOM mometasone, OLO olodaterol, SAL salmeterol, TIO tiotropium, UMEC umeclidinium, VI vilanterol
Discussion
This retrospective cohort study provides important insights into the real-world clinical and economic burden of elderly patients with asthma with and without comorbid COPD in the USA who were new users of triple therapy in the form of FF/UMEC/VI or MITT.
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During 12-month baseline period, elderly patients initiating FF/UMEC/VI or MITT had broadly similar characteristics. However, among new users of MITT with asthma, a numerically higher proportion of patients were female and had a slightly higher prevalence of asthma-related exacerbations (overall and SCS-defined) than in other cohorts. Additionally, the condition of patients with asthma and comorbid COPD was generally more severe than those with asthma initiating the respective triple therapy, as evidenced by numerically higher rates of chronic diseases and asthma medication use and higher comorbidity burden, HCRU, and healthcare costs. Similarly, previous multicenter studies among patients ≤ 65 years of age found that patients with asthma and COPD had a higher comorbidity burden, all-cause healthcare costs, frequency of hospitalizations, and medication use than those with asthma [24, 25].
Comorbidity burden in elderly patients with asthma, with and without comorbid COPD, is of particular importance because patients may be prescribed other medications that may indirectly affect asthma control in the elderly population [26].
Controller and rescue medication use in the 12 months prior to triple therapy initiation was high among new elderly users of FF/UMEC/VI or MITT in the present study. Of those patients with asthma and comorbid COPD, a numerically higher proportion used LAMA and biologics as controller medications than in the cohorts of patients with asthma who initiated the respective triple therapy. This may be indicative of patients with asthma and comorbid COPD having more severe disease conditions. Overall, observations from this study suggest that triple therapy was initiated as a step-up from previous controller medication use, as recommended by asthma treatment guidelines [5], rather than as an initial therapy option in elderly patients. Among those patients with asthma initiating MITT, ICS/LABA (medium- or high-dose) + LAMA was the most common form of triple therapy used, also consistent with treatment guidelines [5]. This MITT combination was also the most common form of triple therapy for patients with asthma and comorbid COPD and is in line with GINA recommendations that patients with overlapping diagnoses criteria be treated for asthma first with the prescription of ICS and reassessed regularly to ensure the correct course of treatment is being followed [5].
In this study, almost one-quarter of all patients had high blood EOS levels (≥ 400 cells/µL) during baseline, with higher levels observed in the 0–3 months prior to triple therapy initiation than in the 10–12 months prior. High blood EOS levels are indicative of patients potentially being good candidates for biologic therapies [27, 28]; however, there is very low use of biologics among the patient cohorts in this study. Additionally, SCS use among patients was high in this study, ranging from 66.5% to 78.9% among the four cohorts. High levels of SCS use have previously been shown to be indicative of patients potentially being good candidates for biologics [29]. The use of biologics for the treatment of severe asthma has accelerated in recent years [30, 31], in particular in relation to their OCS-sparing ability [32] which aligns with GINA guidelines on the treatment of asthma [5]. As a result of the widely reported side effects of OCS use [33, 34], the use of biologics for the treatment of asthma in the elderly population may be of importance to explore.
Although this study did not directly assess asthma control, some findings may suggest that elderly patients’ asthma was not adequately controlled during the baseline period. For example, most patients in our study used rescue medications prior to triple therapy initiation. In particular, there was high SCS use among all cohorts, contrary to guideline recommendations of no requirement for maintenance SCS to minimize long-term asthma risk [5]. Furthermore, approximately one-quarter of patients experienced ≥ 1 asthma-related exacerbation and a large proportion had high disease burden (including asthma-related and Elixhauser comorbidities, and ED and OP visits) during the baseline period. Taken together, these findings suggest that elderly patients with asthma with and without comorbid COPD initiating FF/UMEC/VI or MITT may represent an uncontrolled asthma population with persistent symptoms and unmet needs.
All-cause HCRU and healthcare costs assessed in this study suggest that elderly patients with asthma and comorbid COPD had higher HCRU, as assessed by IP stay and ED visits, than elderly patients with asthma only. HCRU and healthcare costs for all cohorts in this study were higher than those reported in a similar retrospective cohort study assessing an adult population (mean age < 65 years) [25], indicative of the high economic burden of elderly patients with asthma with and without comorbid COPD in the USA.
A primary strength of the current study is that this elderly population of patients represents a geographically diverse sample of the US population, which enhances generalizability of our findings regarding demographics, clinical characteristics, HCRU and healthcare costs, and treatment patterns. Furthermore, the present study utilized real-world data to assess new users of FF/UMEC/VI and MITT with asthma with and without comorbid COPD. Such data are currently scarce in the literature, possibly as a result of the higher prevalence of comorbidities that preclude patients ≥ 65 years from participating in randomized control trials.
Findings from this study are subject to some limitations. Medication data used in this study were derived from OP pharmacy claims; however, the presence of a dispensed medication does not indicate that the medication was consumed, adhered to, or taken by the patient as prescribed and does not provide any insight as to why patients initiated triple therapy. Additionally, medications not recorded in the claims data, including over-the-counter medications, drug samples, or those received during a hospitalization stay, were not available in the database and therefore were not accounted for in this analysis. Similar to other retrospective database analyses, administrative claims data may be vulnerable to coding inaccuracies, and thus, the presence of a diagnosis code on a medical encounter may not indicate presence of disease, which can consequently lead to misclassification of patients. Furthermore, asthma in the elderly is subject to under- or misdiagnosis [14, 35], and this may be the case for this study also. Finally, the data used in this study lacked information on specific clinical measures and patient characteristics (e.g., tobacco use, socioeconomic factors, symptoms) that are important to develop a full profile of elderly patients with asthma with and without comorbid COPD.
The results presented in the current study have limited generalizability to the broader US population beyond the study patient population, such as populations < 65 years of age or those with no or commercial insurance. Finally, the trends observed in this study represent the experiences of early adopters of triple therapy in patients with asthma with and without comorbid COPD; therefore, treatment patterns and patient characteristics may have changed over time.
Conclusion
This retrospective cohort study presented an important early profile of real-world clinical characteristics and treatment patterns of elderly patients with asthma with and without comorbid COPD who newly initiated FF/UMEC/VI or MITT in the USA. Elderly patients in real-world practice were found to have significant clinical and economic burden and were escalated from previous controller medication that likely did not adequately control their asthma. As asthma and COPD are not a single disease entity, but a descriptive term for clinical use that includes several different clinical phenotypes reflecting different underlying mechanisms, management strategy is a continuous assessment. LAMA or LABA add-on is in accordance with guidelines for adequate symptom control and further real-world analyses are warranted to better understand the asthma and comorbid COPD population.
Medical writing/Editorial Assistance
GSK was involved at all stages of the study, including study design, data collection, analysis and interpretation, and preparation of the report. The authors wish to acknowledge Michael Bogart, Carl Abbott, and Carlyne Averell, who were employed by GSK at the time of the study. Editorial support in the form of preparation of the first draft based on input from all authors and collation and incorporation of author feedback to develop subsequent drafts was provided by Evelin O. Szalai, PhD, and Jen Rouine, PhD, of Fishawack Indicia Ltd, UK, part of Avalere Health, and support for this assistance was funded by GSK.
Declarations
Conflict of Interest
Russell A. Settipane has received compensation from GSK for speaking, advisory board services, and serving as an independent contractor for clinical trial research. Guillaume Germain, Francois Laliberté, Malena Mahendran, Annalise Hilts, and Mei Sheng Duh are employees of Analysis Group, Inc., a consulting company that received research funds from GSK to conduct this study. Rosirene Paczkowski and Emmeline Burrows are employed by GSK and hold financial equities in GSK. ELLIPTA and DISKUS are owned by or licensed to the GSK Group of companies. Clinformatics is a trademark of OptumInsight, Inc.
Ethical Approval
This study complied with all applicable laws regarding subject privacy. No direct subject contact or primary collection of individual human subject data occurred. Study results were in tabular form and aggregate analyses that omit subject identification; therefore informed consent and ethics committee or institutional review board approval are not required. Any publications and reports will not include subject identifiers. Furthermore, this study used de-identified data that complied with the requirements of the Health Insurance Portability and Accountability Act (HIPAA).
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
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