The Utilization and Safety of Umeclidinium and Umeclidinium/Vilanterol in UK Primary Care: A Retrospective Cohort Study

Figures & data

Figure 1 Study design. ^aAmong patients who discontinued index medication, all person-time from the discontinuation date up to the censoring date, or up to the date of resumption of the index medication (if applicable), was classified as not currently exposed.

Abbreviations: GP, general practitioner; LABD, long-acting bronchodilator; UMEC, umeclidinium; UMEC/VI, umeclidinium/vilanterol.

Table 1 Demographic Characteristics and Comorbidities at Baseline in the Primary Care Cohort

Characteristics	UMEC (n=3875)	UMEC/VI (n=2224)	Other LABD (n=32,809)
Age at index, mean years (SD)	68.8 (10.8)	69.0 (10.7)	65.7 (14.9)
Age category, years, n (%)
<18 years	0 (0)	0 (0)	609 (1.9)
18−34 years	16 (0.4)	6 (0.3)	600 (1.8)
35−64 years	1237 (31.9)	686 (30.8)	11,863 (36.2)
≥65 years	2622 (67.7)	1532 (68.9)	19,737 (60.2)
Female, n (%)	1984 (51.2)	1055 (47.4)	16,723 (51.0)
Smoking status, n (%)
Current smoker	1656 (42.7)	883 (39.7)	13,107 (39.9)
Ex-smoker	1886 (48.7)	1152 (51.8)	14,435 (44.0)
Never smoker	332 (8.6)	188 (8.5)	4947 (15.1)
Missing^a	1 (0)	1 (0)	320 (1.0)
BMI mean kg/m^2 (SD)	27.9 (6.5)	28.4 (6.4)	28.0 (6.7)
Underweight (<18.5 kg/m^2), n (%)	189 (4.9)	82 (3.7)	1367 (4.2)
Normal (18.5−24.9 kg/m^2), n (%)	1162 (30.0)	615 (27.7)	9680 (29.5)
Overweight (25.0−29.9 kg/m^2), n (%)	1228 (31.7)	732 (32.9)	9987 (30.4)
Obese (≥30 kg/m^2), n (%)	1244 (32.1)	770 (34.6)	10,326 (31.5)
Missing^a, n (%)	52 (1.3)	25 (1.1)	1449 (4.4)
Comorbidities^b, n (%)
Cardiovascular disease	2510 (64.8)	1453 (65.3)	19,711 (60.1)
Prescription for a beta-blocker	707 (18.2)	485 (21.8)	6391 (19.5)
Pneumonia	284 (7.3)	160 (7.2)	2312 (7.0)
Gastroesophageal disease	890 (23.0)	525 (23.6)	7440 (22.7)
Diabetes	753 (19.4)	410 (18.4)	5863 (17.9)
Kidney disease	826 (21.3)	438 (19.7)	5883 (17.9)
Cancer	564 (14.6)	313 (14.1)	4287 (13.1)
“Moderate” COPD exacerbations in the previous year^c
Rate per 1000 person-years (95% CI)	1091 (1058, 1124)	769 (734, 807)	830 (820, 840)
0 events, n (%)	1826 (47.1)	1257 (56.5)	17,629 (53.7)
1 event, n (%)	984 (25.4)	563 (25.3)	8535 (26.0)
≥2 events, n (%)	1065 (27.5)	404 (18.2)	6645 (20.3)
Dyspnea, mean (SD)	2.8 (1.0)	2.7 (0.9)	2.6 (1.0)
MRC grade 1, n (%)	196 (6.5)	100 (5.9)	1643 (9.2)
MRC grade 2, n (%)	1070 (35.5)	680 (40.4)	7091 (39.8)
MRC grade 3, n (%)	1018 (33.7)	585 (34.8)	5586 (31.4)
MRC grade 4, n (%)	629 (20.8)	278 (16.5)	2935 (16.5)
MRC grade 5, n (%)	105 (3.5)	40 (2.4)	545 (3.1)
Missing^a, n (%)	1186 (30.6)	599 (26.9)	12,200 (37.2)
FEV1 % predicted, mean (SD)	58.1 (19.2)	60.0 (19.0)	59.8 (19.4)
Mild, Grade 1 (≥80%), n (%)	329 (12.2)	226 (13.9)	2882 (14.0)
Moderate, Grade 2 (≥50% to <80%), n (%)	1427 (53.1)	915 (56.3)	11,312 (54.9)
Severe, Grade 3 (≥30% to <50%), n (%)	768 (28.6)	401 (24.7)	5266 (25.6)
Very severe, Grade 4 (<30%), n (%)	165 (6.1)	83 (5.1)	1149 (5.6)
Missing^a, n (%)	1186 (30.6)	599 (26.9)	12,200 (37.2)
FEV1/FVC ratio, mean (SD)	58.9 (15.9)	60.4 (14.1)	62.1 (15.6)
<70%, n (%)	1752 (79.1)	1130 (77.8)	12,866 (72.1)
≥70%, n (%)	464 (20.9)	323 (22.2)	4975 (27.9)
Missing^a, n (%)	1659 (42.8)	771 (34.7)	14,968 (45.6)

Notes: ^aPercentages were calculated separately for those with missing and without missing data; ^bpatients who had ever had a diagnosis or who had a prescription for beta-blockers in the previous 12 months; ^caccording to primary care data.

Abbreviations: BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; LABD, long-acting bronchodilator; MRC, Medical Research Council; SD, standard deviation; UMEC, umeclidinium; UMEC/VI, umeclidinium/vilanterol.

Figure 2 Previous (A) and concomitant (B) use of inhaled COPD maintenance therapy at index in the primary care cohort.

Abbreviations: ICS, inhaled corticosteroids; LABA, long-acting β₂-agonist; LABD, long-acting bronchodilator; LAMA, long-acting muscarinic antagonist; OCS, oral corticosteroids; SABD, short-acting bronchodilator; UMEC, umeclidinium; UMEC/VI, umeclidinium/vilanterol.

Table 2 Diagnosis and Possible Off-Label Prescribing in the Primary Care Cohort (N=34,516)

Index Therapy	All New Users	COPD	Asthma	Other (Not COPD or Asthma)	Possible Off-Label Prescribing
All^a, n (%)	38,908	31,000 (79.7)	4876 (12.5)	3032 (7.8)	6385 (16.4)^b
UMEC, n (%)	3875	3604 (93.0)	130 (3.4)	141 (3.6)	271 (7.0)^c
UMEC/VI, n (%)	2224	2029 (91.2)	69 (3.1)	126 (5.7)	195 (8.8)^c
Other LABD, n (%)	32,809	25,367 (77.3)	4677 (14.3)	2765 (8.4)	5919 (18.0)^b
Other LAMA, n (%)	24,125	19,655 (81.5)	2327 (9.6)	2143 (8.9)	3980 (16.5)^b
Other LABA, n (%)	6218	3458 (55.6)	2278 (36.6)	482 (7.8)	1727 (27.8)^b
Other LABA/LAMA, n (%)	2466	2254 (91.4)	72 (2.9)	140 (5.7)	212 (8.6)^c

Notes: ^aPatients can qualify for cohort entry, disease or medication group more than once, which is reflected in the higher number new users than patients in the study; ^bdefined as all patients without a diagnosis code of COPD at any time, with the exception of a) patients with a diagnosis of asthma prescribed index tiotropium 2.5 µg, (other LAMA), if they entered the study on or after September 13, 2014, with a concurrent prescription for ICS/LABA; b) patients with a diagnosis of asthma prescribed an index other LABA and were receiving concomitant ICS at index date; ^cdefined as patients without a diagnosis of COPD only.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LABD, long-acting bronchodilator; LAMA, long-acting muscarinic antagonist; UMEC, umeclidinium; UMEC/VI, umeclidinium/vilanterol.

Table 3 On-Treatment Cardiovascular, Respiratory, and All-Cause Mortality Outcomes in New Users of UMEC/VI and UMEC in the Primary Care Cohort

Outcome	UMEC (n=3875; 3508.7 Person-Years^a)		UMEC/VI (n=2224; 1768.3 Person-Years^a)
	Total Events^b, n	IR per 1000 Patient-Years (95% CI)^c,d	Total Events^b, n	IR per 1000 Patient-Years (95% CI)^c.d
MI
All patients	27	6.9 (4.4, 10.2)	13	6.8 (3.5, 11.9)
With ICS use at index date	19	6.7 (3.9, 10.7)	0	0.0 (0.0, 21.6)
No ICS use at index date	8	7.4 (3.0, 15.3)	13	7.5 (3.9, 13.2)
Stroke
All patients	171	30.9 (25.3, 37.4)	84	30.5 (22.8. 39.8)
With ICS use at index date	113	26.7 (20.7, 33.9)	7	23.7 (6.5, 60.7)
No ICS use at index date	58	42.3 (30.1, 57.9)	77	31.2 (23.1, 41.2)
Newly diagnosed CHF^e
All patients	48	14.8 (10.9, 19.6)	18	11.0 (6.5, 17.4)
With ICS use at index date	35	14.9 (10.4, 20.7)	0	0.0 (0.0, 23.8)
No ICS use at index date	13	14.5 (7.7, 24.8)	18	12.2 (7.2, 19.2)
Pneumonia (primary care)
All patients	25	6.9 (4.4, 10.2)	6	3.4 (1.2, 7.4)
With ICS use at index date	21─24	Not calculated	2─5	Not calculated
No ICS use at index date	1─4	Not calculated	1─4	Not calculated
Moderate AECOPD^d
All patients	3409	979 (931, 1030)	1275	746 (687, 811)
With ICS use at index date	2919	1157 (1098, 1220)	231	1335 (1097, 1626)
No ICS use at index date	490	534 (467, 610)	1044	675 (617, 738)
Death (all causes)
All patients	105	29.9 (24.5, 36.2)	62	35.1 (26.9, 44.9)
With ICS use at index date	77	30.1 (23.7, 37.6)	5	29.3 (9.5, 68.3)
No ICS use at index date	28	29.6 (19.7, 42.8)	57	35.7 (27.0, 46.2)

Notes: ^aFollow-up time for the full cohort; ^bincludes first and subsequent events. Ranges are shown where <5 events were reported; ^cincidence based on first event only; ^dfor AECOPD, all events were included; ^epatients with prior history of CHF were excluded.

Abbreviations: AECOPD, acute exacerbations of COPD; CHF, congestive heart failure; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; IR, incidence rate; MI, myocardial infarction; UMEC, umeclidinium; UMEC/VI, umeclidinium/vilanterol.

Table 4 On-Treatment Cardiovascular, Respiratory, and All-Cause Mortality Outcomes in New Users of UMEC/VI and UMEC in the Linked Cohort

Outcome	UMEC (n=547; 374.7 Person-Years)		UMEC/VI (n=512; 365.6 Person-Years)
	Total Events^a, n	IR per 1000 Patient-Years (95% CI)^b,c	Total Events^a, n	IR per 1000 Patient-Years (95% CI)^b,c
MI
All patients	5	8.0 (1.7, 23.4)	1─4	Not calculated
With ICS use at index date	1─4	Not calculated	0	Not calculated
No ICS use at index date	1─4	Not calculated	1─4	Not calculated
Stroke
All patients	19	35.4 (18.9, 60.6)	13	16.5 (6.1, 36.0)
With ICS use at index date	14	31.1 (13.4, 61.4)	1─4	Not calculated
No ICS use at index date	5	45.5 (14.8, 106.3)	9─12	Not calculated
Newly diagnosed CHF^d
All patients	5	14.6 (4.7, 34.0)	7	20.5 (8.3, 42.3)
With ICS use at index date	5	21.0 (6.8, 49.0)	1─4	Not calculated
No ICS use at index date	0	0.0 (0.0, 35.2)	3─6	Not calculated
Pneumonia (primary and secondary care)
All patients	25	66.0 (42.3, 98.2)	18	47.3 (27.5, 75.7)
With ICS use at index date	21─24	Not calculated	1─4	Not calculated
No ICS use at index date	1─4	Not calculated	14─17	Not calculated
Moderate and severe AECOPD
All patients	554	1484 (1326, 1661)	421	1168 (1013, 1345)
With ICS use at index date	437	1658 (1471, 1869)	103	1931 (1426, 2616)
No ICS use at index date	117	1091 (830, 1434)	318	1027 (880, 1200)
Death (all causes)
All patients	18	48.0 (28.5, 75.9)	19	52.0 (31.3, 81.2)
With ICS use at index date	12	45.6 (23.6, 79.7)	1─4	Not calculated
No ICS use at index date	6	53.8 (19.7, 117.0)	15─18	Not calculated
Cardiovascular deaths
All patients	1─4	Not calculated	6	16.4 (6.0, 35.7)
With ICS use at index date	1─3	Not calculated	0	0.0 (0.0, 71.8)
No ICS use at index date	1─3	Not calculated	6	19.1 (7.0, 41.6)

Notes: ^aIncludes first and subsequent events. Ranges are shown where <5 events were reported; ^bincidence based on first event only; ^cfor AECOPD, all events were included; ^dpatients with prior history of CHF were excluded.

Abbreviations: AECOPD, acute exacerbations of COPD; CHF, congestive heart failure; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; IR, incidence rate; MI, myocardial infarction; UMEC, umeclidinium; UMEC/VI, umeclidinium/vilanterol.

Table 5 Treatment Patterns^a in the 12 Months Following Initiation of UMEC and UMEC/VI in the Primary Care Cohort

Treatment Pattern	UMEC (n=3240)		UMEC/VI (n=1822)
	n, (%)	Days to First Change, Mean (SD)	n, (%)	Days to First Change, Mean (SD)
No concomitant COPD maintenance therapy at index date
All patients	1047 (32.3)		1478 (81.1)
Continuous user	371 (35.4)	n/a	655 (44.3)	n/a
Augmenter	32 (3.1)	110.7 (65.6)	32 (2.2)	118.2 (72.0)
Immediate switcher	114 (10.9)	96.2 (66.7)	249 (16.8)	120.7 (88.9)
Discontinuer	530 (50.6)	106.5 (98.5)	542 (36.7)	111.3 (95.9)
True discontinuer	216 (40.8)	96.2 (98.2)	177 (32.7)	84.4 (89.7)
Discontinuer with drug hiatus	279 (52.6)	121.3 (100.7)	359 (66.2)	125.5 (96.5)
Discontinuer with latent switch	35 (6.6)	53.1 (41.0)	6 (1.1)	55.8 (31.5)
With concomitant COPD maintenance therapy at index date
All patients	2193 (67.7)		344 (18.9)
Continuous use of both drugs	1116 (50.9)	n/a	22 (6.4)	n/a
Discontinuation of index drug only	553 (25.2)	143.2 (105.9)	115 (33.4)	87.3 (81.8)
Discontinuation of concomitant drug only	364 (16.6)	114.7 (99.4)	148 (43.0)	68.4 (70.4)
Discontinuation of both drugs	160 (7.3)	125.4 (97.8)	59 (17.2)	87.3 (69.6)

Note: ^aAs defined in Supplementary Figure 1.

Abbreviations: COPD, chronic obstructive pulmonary disease; SD, standard deviation; UMEC, umeclidinium; UMEC/VI, umeclidinium/vilanterol.