Factors influencing treatment escalation from long-acting muscarinic antagonist monotherapy to triple therapy in patients with COPD: a retrospective THIN-database analysis

Figures & data

Table 1 Patient characteristics at baseline

Characteristic	All, n=14,866	Monotherapy,a n=8,384	Treatment escalation,b n=6,482
Age, years
Mean ± SD	68.4±10.7	68.8±10.9	67.8±10.5
Range	35–101	35–99	36–101
Sex, n (%)
Female	6,781 (45.6)	3,843 (45.8)	2,938 (45.3)
Male	8,085 (54.4)	4,541 (54.2)	3,544 (54.7)
LAMA therapy initiated, n (%)
Tiotropium HandiHaler	12,501 (84.1)	6,858 (81.8)	5,643 (87.1)
Tiotropium Respimat	1,183 (8)	611 (7.3)	572 (8.8)
Aclidinium	623 (4.2)	471 (5.6)	152 (2.3)
Glycopyrronium	487 (3.3)	376 (4.5)	111 (1.7)
Umeclidinium	87 (0.6)	79 (0.9)	8 (0.1)
ICS–LABAb stepped up to, n (%)
Fostair NEXThaler 200/6a	–	–	1 (0.02)
Flutiform 50/5a	–	–	1 (0.02)
Fostair NEXThaler 100/6	–	–	16 (0.25)
DuoResp Spiromax 320/9	–	–	19 (0.29)
Flutiform 250/5a	–	–	24 (0.37)
Relvar Ellipta 184 µga	–	–	34 (0.52)
Flutiform 125/5a	–	–	41 (0.63)
Seretide 50 Evohalera	–	–	64 (0.99)
Relvar Ellipta 92 µg	–	–	139 (2.1)
Symbicort 100/6 Turbohalera	–	–	154 (2.4)
Seretide 100 Accuhalera	–	–	178 (2.8)
Seretide 250 Accuhalera	–	–	399 (6.2)
Fostair 100/6	–	–	462 (7.1)
Seretide 125 Evohalera	–	–	508 (7.8)
Symbicort 200/6 Turbohaler	–	–	667 (10.3)
Symbicort 400/12 Turbohaler	–	–	915 (14.1)
Seretide 250 Evohalera	–	–	1,022 (15.8)
Seretide 500 Accuhaler			1,849 (28.5)
Time to treatment escalation, days
Mean ± SD	–	–	324.6±392.1
Range	–	–	1–2,080
Time to end of follow-up,c days
Mean ± SD	535.1±437.7	697.8±400.0	324.6±392.1
Range	0–2,080	0–1,193	1–2,080

Notes:

a Not licensed for COPD;

b for the monotherapy group, follow-up was measured up to 1,193 days to reflect a similar period to that of follow-up in the treatment-escalation group (calculated as the 95th percentile of distribution of the time to escalation);

c it may be inappropriate to compare across groups, owing to different lengths of follow-up. “–” indicates no data are available.

Abbreviations: ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist.

Figure 1 Cohort selection from THIN database of 8,676,730 patient records.

Note: ^a% of COPD diagnosis cohort.
Abbreviations: FDC, fixed-dose combination; ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist; THIN, The UK Health Improvement Network.

Table 2 Comorbidities recorded at any time during the study period

Comorbidity, n (%)	n=14,866
Hypertension	6,603 (44.4)
Chronic heart disease	3,036 (20.4)
Anxiety	2,969 (20)
Diabetes	2,174 (14.6)
Depression	1,967 (13.2)
Asthma	1,965 (13.2)
Cerebrovascular disease	1,695 (11.4)
Atrial fibrillation	1,464 (9.9)
Osteoporosis	1,174 (7.9)
Heart failure	990 (6.7)
Mental health disorders (QOF)	882 (5.9)
Obesity	826 (5.6)
Lung cancer	416 (2.8)
Rheumatoid arthritis	380 (2.6)
Epilepsy	337 (2.3)
Chronic kidney disease	247 (1.7)

Abbreviation: QOF, Quality and Outcomes Framework.

Figure 2 Cumulative time to treatment escalation.

Note: ^a% of all patients (n=14,866).

Table 3 Univariate Cox regression analysis with significant (P<0.05) unadjusted predictors of treatment escalation

Characteristics	Univariate analysis, n=14,866
	HR	95% CI	P-value
Composite: COPD exacerbationsa	2.675	2.534–2.823	<0.0001
MRC grade (vs 1)			<0.0001
Grade 5	2.489	2.009–3.083	<0.0001
Grade 4	1.988	1.781–2.219	<0.0001
Grade 3	1.571	1.434–1.721	<0.0001
Grade 2	1.183	1.086–1.288	0.0001
Asthma	2.21	2.079–2.35	<0.0001
Elective secondary-care contact	1.466	1.371–1.569	<0.0001
Proactive COPD primary careb	1.303	1.275–1.332	<0.0001
Pneumonia	1.246	1.147–1.354	<0.0001
Number of cough symptomsc	1.209	1.183–1.236	<0.0001
Reactive COPD primary cared	1.191	1.1–1.29	<0.0001
Mental health disorders	1.187	1.075–1.311	0.0007
Depression	1.160	1.082–1.243	<0.0001
Number of sputum symptomse	1.149	1.108–1.193	<0.0001
Anxiety	1.125	1.06–1.194	0.0001
Number of short-acting bronchodilator prescriptions	1.041	1.038–1.045	<0.0001
Number of steroid prescriptions	1.026	1.023–1.028	<0.0001
Agef	0.997	0.995–1.00	0.0251
FEV1	0.979	0.976–0.982	<0.0001
Smoking status (vs never smoked)
Current	0.716	0.649–0.791	<0.0001
Ex	0.769	0.697–0.848	<0.0001

Notes: Data ordered by HR.

a Composite end point: if COPD emergency admission or AECOPD or LRTI or OCS + antibiotic occurred on the same day, 1 was assigned (otherwise 0). We used time-varying covariates (so patient had 0 assigned until the first occurrence of any of those). This has been validated in a previous paper.¹⁶

b COPD monitoring; disease monitoring by doctor; disease monitoring by nurse; shared-care disease monitoring; COPD 3-monthly, 6-monthly, and annual reviews; COPD followup; COPD health education; COPD-medication optimization; issue of COPD rescue pack or advance supply of steroid medication or antibiotic medication or deferred antibiotic therapy; COPD leaflet given, has COPD-care plan; has COPD-care pathway; has COPD clinical management plan; on COPD supportive care pathway; seen in COPD clinic.

c Number of consultations with code for cough: C/O – cough, dry cough, productive cough – clear sputum, productive cough – green sputum, productive cough – yellow sputum, productive cough NOS, coughing up phlegm, night cough present, chesty cough, bronchial cough, morning cough, evening cough, cough with fever, difficulty in coughing up sputum, cough symptom NOS, nocturnal cough/wheeze, cough aggravates symptom, cough swab, cough, cough with hemorrhage.

d Night visits; after-hours visits; follow-up visits; acute visits; home visits; hotel visits; nursing-home visits; residential home visits; twilight visits; visits by the practice, their cooperative, deputizing service, or local roster service; reactive surgery consultations; co-op surgery consultations; minor-injury service; medicine management; telephone consultation related to COPD.

e Number of consultations with code for sputum. C/O – sputum – symptom, sputum sample obtained, sputum examination, sputum sent for examination, sputum examination: abnormal; sputum: excessive – mucoid; sputum: mucopurulent; sputum: fetid/offensive, yellow sputum, green sputum, dark-green sputum, pale-green sputum, sputum appearance, brown sputum, white sputum, volume of sputum, copious sputum, profuse sputum, moderate sputum, grey sputum, sputum microscopy; sputum: pus cells present; sputum: organism on Gram stain, sputum microscopy NOS, sputum evidence of infection, sputum appears infected, sputum culture, sputum examination NOS, sputum sent for C/S, abnormal sputum, sputum abnormal – amount, sputum abnormal – color, sputum abnormal – odor, abnormal sputum – tenacious, abnormal sputum NOS, positive-culture findings in sputum, sputum clearance, difficulty in coughing up sputum, acute purulent bronchitis, chesty cough, bronchial cough, productive cough NOS, coughing up phlegm.

f HR relative to change to every 1-year difference in age.

Abbreviations: AECOPD, acute exacerbation of COPD; C/O, complaining of; C/S, culture and sensitivity; FEV₁, forced expiratory volume in 1 second; LRTI, lower respiratory tract infection; MRC, Medical Research Council; NOS, not otherwise specified; OCS, oral corticosteroid.

Table 4 Multivariate analysis outcomes: predictors of treatment escalation

Characteristics	Multivariate Cox regression analysis, n=10,492
	HR	95% CI	P-value
COPD exacerbations: compositea	2.114	1.87–2.389	<0.0001
Asthma	1.948	1.695–2.238	<0.0001
MRC grade (vs 1)			<0.0001
2	1.167	1.005–1.355	0.043
3	1.403	1.189–1.656	<0.0001
4	1.757	1.42–2.174	<0.0001
5	1.923	1.135–3.258	0.0151
Proactive COPD primary careb	1.273	1.213–1.337	<0.0001
Reactive COPD primary carec	1.246	1.173–1.324	<0.0001
Elective secondary care contact	1.186	1.031–1.364	0.0171
Cough symptomsd	1.101	1.055–1.149	<0.0001
Number of SABA prescriptions	1.03	1.023–1.037	<0.0001
Age at index datee	0.994	0.989–0.999	0.0324
FEV1	0.98	0.977–0.983	<0.0001
Number of sputum symptomsf	0.907	0.833–0.988	0.0249
Smoking status (vs never smoked)
Current	0.544	0.424–0.7	<0.0001
Ex	0.702	0.552–0.892	0.0038

Notes: Multivariate analysis included 10,492 patients, of whom 4,591 received treatment escalation. Data are ordered by HR.

a Composite end point: if COPD emergency admission or AECOPD or LRTI or OCS + antibiotic occurred on the same day, 1 was assigned (otherwise 0). We used time-varying covariates (so patient had 0 assigned until the first occurrence of any of those). This has been validated in a previous paper.¹⁶

b COPD monitoring; disease monitoring by doctor; disease monitoring by nurse; shared-care disease monitoring; COPD 3-monthly, 6-monthly, and annual reviews; COPD follow-up; COPD health education; COPD-medication optimization; issue of COPD rescue pack or advance supply of steroid medication or antibiotic medication or deferred antibiotic therapy; COPD leaflet given, has COPD-care plan; has COPD-care pathway; has COPD clinical management plan; on COPD supportive care pathway; seen in COPD clinic.

c Night visits; after-hours visits; follow-up visits; acute visits; home visits; hotel visits; nursing-home visits; residential home visits; twilight visits; visits by the practice, their cooperative, deputizing service, or local roster service; reactive surgery consultations; co-op surgery consultations; minor-injury service; medicine management; telephone consultation related to COPD.

d Number of consultations with code for cough: C/O – cough, dry cough, productive cough-clear sputum, productive cough-green sputum productive cough-yellow sputum, productive cough not otherwise specified (NOS), coughing up phlegm, night cough present, chesty cough, bronchial cough, morning cough, evening cough, cough with fever, difficulty in coughing up sputum, cough symptom NOS, nocturnal cough/wheeze, cough aggravates symptom, cough swab, cough, cough with hemorrhage.

e HR relative to change to every 1 year difference in age.

f Number of consultations with code for sputum. C/O – sputum – symptom, sputum sample obtained, sputum examination, sputum sent for examination, sputum examination: abnormal, sputum: excessive – mucoid, sputum: mucopurulent, sputum: fetid/offensive, yellow sputum, green sputum, dark green sputum, pale green sputum, sputum appearance, brown sputum, white sputum, volume of sputum, copious sputum, profuse sputum, moderate sputum, grey sputum, sputum microscopy, sputum: pus cells present, sputum: organism on gram stain, sputum microscopy NOS, sputum evidence of infection, sputum appears infected, sputum culture, sputum examination NOS, sputum sent for C/S, abnormal sputum, sputum abnormal – amount, sputum abnormal – color, sputum abnormal – odor, abnormal sputum – tenacious, abnormal sputum NOS, positive culture findings in sputum, sputum clearance, difficulty in coughing up sputum, acute purulent bronchitis, chesty cough, bronchial cough, productive cough NOS, coughing up phlegm.

Abbreviations: AECOPD, acute exacerbation of COPD; C/O, complaining of; C/S, culture and sensitivity; FEV₁, forced expiratory volume in 1 second; LRTI, lower respiratory tract infection; MRC, Medical Research Council; NOS, not otherwise specified; OCS, oral corticosteroid; SABA, short-acting bronchodilator.

Table 5 Treatment escalation per GOLD 2011/2013 and 2017 classification

Characteristic, n (%)	GOLD 2011/2013:^Citation1 patients with any FEV1 and MRC score during the last 12 months of study period	GOLD 2017:^Citation3 patients with any MRC score during the last 12 months of study period
	Treatment-escalation group, n=1,064	Treatment-escalation group, n=5,090
GOLD group
A	217 (20.4)	1,393 (27.4)
B	204 (19.2)	1,900 (37.3)
C	264 (24.8)	777 (15.3)
D	379 (35.6)	1,020 (20)
Predicted FEV1
<50%	388 (36.5)	–
≤50%	676 (63.5)	–
MRC score
1 or 2	481 (45.2)	2,170 (42.6)
≥3	583 (54.8)	2,920 (57.4)
Primary-care exacerbations
≤1	762 (71.6)	3,505 (68.9)
≥2	302 (28.4)	1,585 (31.1)
COPD emergency admissions
0	953 (89.6)	4,758 (93.5)
≥1	111 (10.4)	332 (6.5)
	Patients with any FEV1 measurement at any time during study period
	Treatment-escalation group, n=1,703
GOLD grade
1: FEV1 ≥80%	241 (14.2)
2: FEV1 50%–79%	907 (53.3)
3: FEV1 30%–49%	480 (28.2)
4: FEV1 <30%	75 (4.4)
Predicted FEV1
<50%	555 (32.6)
≥50%	1,148 (67.4)

Note: “–” indicates no data are available.

Abbreviations: FEV₁, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; MRC, Medical Research Council.

Figure 3 MRC breathlessness score in the treatment-escalation group.

Notes: (A) 12 Months from baseline (n=2,659) and (B) during the study and follow-up period (n=5,611). Median MRC scores at baseline were 2 and 3 during the study period.
Abbreviation: MRC, Medical Research Council.

Table S1 Covariates during the analyzed baseline period

Characteristic	Overall population, n=14,866
Smoking status, n (%)
Unknown	7 (0.1)
Current smoker	7,049 (47.4)
Ex-smoker	6,697 (45.1)
Never smoked	1,113 (7.5)
MRC score (categorical), n (%)
Unknown	6,466 (43.5)
Grade 1	1,437 (9.7)
Grade 2	3,730 (25.1)
Grade 3	2,134 (14.4)
Grade 4	925 (6.2)
Grade 5	174 (1.2)
MRC score (numeric)
Mean (SD)	2.4 (1)
FEV1, %
Mean (SD)	64 (17.9)
COPD severity, n (%)
Unknown	10,196 (68.6)
Mild	2,217 (14.9)
Moderate	1,993 (13.4)
Severe	444 (3)
Very severe	16 (0.1)
Respiratory hospital referral recorded, n (%)	997 (6.7)
Elective secondary care contact (COPD secondary care consultation or respiratory hospital referral), n (%)	2,911 (19.6)
Acute exacerbations of COPD, mean (SD)	0.3 (1.1)
COPD emergency admissions, mean (SD)	0.04 (0.3)
LRTI events, mean (SD)	2.8 (5.2)
Cough-related events, mean (SD)	1.9 (3.3)
Sputum-related events, mean (SD)	0.5 (1.6)
Oral corticosteroid prescriptions, mean (SD)	3.7 (14.7)
Oral antibiotics prescriptions, mean (SD)	9 (11.3)
Short-acting bronchodilator prescriptions, mean (SD)	14.7 (34.2)
COPD proactive primary care consultations, mean (SD)	1.5 (2.2)
COPD reactive primary care consultations, mean (SD)	1 (2.6)
Elective secondary care consultation, n (%)	2,068 (13.9)
Composite end point: exacerbations (COPD emergency admission or AECOPD or LRTI or OCS + antibiotic), n (%)	10,805 (72.7)

Abbreviations: AECOPD, acute exacerbation of COPD; FEV₁, forced expiratory volume in 1 second; LRTI, lower respiratory tract infection; MRC, Medical Research Council; OCS, oral corticosteroid.

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