Blood Eosinophil Counts, Withdrawal of Inhaled Corticosteroids and Risk of COPD Exacerbations and Mortality in the Clinical Practice Research Datalink (CPRD)

Figures & data

Figure 1. Flow chart showing the selection of eligible patients.

Table 1. Baseline characteristics of COPD patients by blood eosinophil counts

Baseline characteristics		Blood eosinophil counts
	Total (n = 48,157)	<0.34 × 10^9 cells/L (n = 39,486)	≥0.34 × 10^9 cells/L (n = 8671)
Females	22,081 (45.9)	19,042 (48.2)	3,039 (35.0)
Mean age (years, SD)	68.4 (10.9)	68.3 (10.9)	68.6 (10.8)
Age category (years)
40–59	10,175 (21.1)	8,406 (21.3)	1,769 (20.4)
60–79	29,942 (62.2)	24,481 (62.0)	5,461 (63.0)
80+	8,040 (16.7)	6,599 (16.7)	1,441 (16.6)
BMI at index date (kg/m^2)
Underweight (BMI < 18.0 kg/m^2)	2,418 (5.0)	2,068 (5.2)	350 (4.0)
Normal weight (BMI 18.5–25.0 kg/m^2)	16,225 (33.7)	13,414 (34.0)	2,811 (32.4)
Overweight (BMI 25.0–30.0 kg/m^2)	15,503 (32.2)	12,583 (31.9)	2,920 (33.7)
Obese (BMI ≥ 30.0 kg/m^2)	12,696 (26.4)	10,359 (26.2)	2,337 (27.0)
Missing BMI	1,315 (2.7)	1,062 (2.7)	253 (2.9)
Smoking status
Never	4,998 (10.4)	4,114 (10.4)	884 (10.2)
Current	20,528 (42.6)	16,922 (42.9)	3,606 (41.6)
Former	22,585 (46.9)	18,411 (46.6)	4,174 (48.1)
Missing	46 (0.1)	39 (0.1)	7 (0.1)
Drug use (in the past 6 months)
SABAs	27,091 (56.3)	22,022 (55.8)	5,069 (58.5)
LABAs	4,297 (8.9)	3,459 (8.8)	838 (9.7)
SAMAs	4,004 (8.3)	3,262 (8.3)	742 (8.6)
LAMAs	8,563 (17.8)	7,041 (17.8)	1,522 (17.6)
ICS	13,441 (27.9)	10,972 (27.8)	2,469(28.5)
Xanthine derivatives	359 (0.7)	281 (0.7)	78 (0.9)
Antipsychotics	555 (1.2)	463 (1.2)	92 (1.1)
History of co-morbidities
Cardiovascular disease	10,196 (21.2)	8,253 (20.9)	1,943 (22.4)
Diabetes Mellitus	5,945 (12.3)	4,716 (11.9)	1,229 (14.2)
Anxiety	7,142 (14.8)	5,974 (15.1)	1,150 (13.3)
Osteoporosis	2,951 (6.1)	2,512 (6.4)	439 (5.1)
Any cancer (except non-melanoma skin cancer)	7,196 (14.9)	5,935 (15.0)	1,261 (14.5)
Chronic liver disease	147 (0.3)	118 (0.3)	29 (0.3)

Data are n (%) or mean (SD). SD: standard deviation; COPD: chronic obstructive pulmonary disease; BMI: body mass index; SABAs: short-acting β-2 agonists; LABAs: long-acting β-2 agonists; SAMAs: short-acting muscarinic antagonists; LAMAs: long-acting muscarinic antagonists; ICS: inhaled corticosteroids.

Table 2. Risk of moderate-to-severe exacerbations with ICS use stratified by absolute and relative eosinophil counts among COPD patients.

	Moderate-to-severe (n = 6767)*	IR (/1000PY)	Age and gender adjusted HR (95% CI)	Adjusted HR (95% CI)^a
Absolute eosinophil counts
Withdrawal from ICS
<0.34 × 10^9 cells/L	1625	49.2	0.55 (0.51–0.60)^c	0.72 (0.66–0.78)^c
≥0.34 × 10^9 cells/L	366	49.5	0.57 (0.50–0.64)	0.72 (0.63–0.81)
Continuous ICS users
<0.34 × 10^9 cells/L	3850	85.4	0.96 (0.89–1.03)	0.97 (0.91–1.05)
≥0.34 × 10^9 cells/L	926	87.7	Reference	Reference
Relative eosinophil counts
Withdrawal from ICS
<4.0%	1511	49.8	0.60 (0.55–0.65)^c	0.74 (0.68–0.80)^c
≥4.0%	480	47.5	0.58 (0.52–0.64)	0.73 (0.66–0.82)
Continuous ICS users
<4.0%	3652	86.9	1.04 (0.97–1.11)	1.01 (0.94–1.08)
≥4.0%	1124	82.2	Reference	Reference

ICS: inhaled corticosteroids; IR: incidence rate; HR: hazard ratio; CI: confidence interval; PY: person-years.

^a Adjusted for age, gender, smoking status, body mass index, alcohol use, history of heart failure, chronic liver disease, ischemic heart disease, use of antipsychotic, antidepressants, atopic dermatitis, use of oxygen, short-acting β-2 agonists, long-acting β-2 agonists, short-acting muscarinic antagonists, long-acting muscarinic antagonists, xanthine derivatives and oral corticosteroid 6 months prior to the start of an interval.

^b Wald’s statistics: Withdrawal of ICS with low eosinophil counts statistically significantly different (p<.05) from withdrawal of ICS with high eosinophil count.

^c Wald’s statistics: Withdrawal of ICS with low eosinophil counts statistically significantly different (p<.05) from continuous ICS use with low eosinophil count.

* Numbers of never ICS user with moderate-to-severe exacerbations not included.

Table 3. Risk of severe exacerbations with ICS use stratified by absolute and relative eosinophil counts among COPD patients.

	Severe exacerbations (n = 1177)*	IR (/1000PY)	Age and gender adjusted HR (95% CI)	Adjusted HR (95% CI)^a
Absolute eosinophil counts
Withdrawal of ICS
<0.34 × 10^9 cells/L	263	6.9	0.57 (0.47–0.70)^c	0.79 (0.64–0.97)^c
≥0.34 × 10^9 cells/L	63	7.4	0.61 (0.46–0.82)	0.82 (0.61–1.10)
Continuous ICS users
<0.34 × 10^9 cells/L	690	12.4	1.02 (0.86–1.21)	1.03 (0.87–1.23)
≥0.34 × 10^9 cells/L	161	12.1	Reference	Reference
Relative eosinophil counts
Withdrawal of ICS
<4.0%	248	7.1	0.62 (0.52–0.75)^c	0.82 (0.67–0.99)^c
≥4.0%	78	6.7	0.59 (0.45–0.77)	0.80 (0.61–1.04)
Continuous ICS users
<4.0%	656	12.6	1.10 (0.94–1.30)	1.06 (0.91–1.25)
≥4.0%	195	11.4	Reference	Reference

ICS: inhaled corticosteroids; IR: incidence rate; HR: hazard ratio; CI: confidence interval; PY: person-years.

^a Adjusted for age, gender, smoking status, body mass index, alcohol use, history of heart failure, chronic liver disease, diabetes mellitus, ischemic heart disease, osteoporosis, use of proton-pump inhibitors, antidepressants, oxygen, antipsychotics, statins, short-acting β-2 agonists, long-acting β-2 agonists, short-acting muscarinic antagonists, long-acting muscarinic antagonists, xanthine derivatives and oral corticosteroid 6 months prior to the start of an interval.

^b Wald’s statistics: Withdrawal of ICS with low eosinophil counts statistically significantly different (p<.05) from withdrawal of ICS with high eosinophil count.

^c Wald’s statistics: Withdrawal of ICS with low eosinophil counts statistically significantly different (p<.05) from continuous ICS use with low eosinophil count.

* Numbers of never ICS user with severe exacerbations not included.

Table 4. Risk of all-cause mortality with ICS use stratified by absolute and relative eosinophil counts among COPD patients.

	All-cause mortality (n = 6008)*	IR (/1000PY)	Age and gender adjusted HR (95% CI)	Adjusted HR (95% CI)^a
Absolute eosinophil counts
Withdrawal from ICS
<0.34 × 10^9 cells/L	1763	45.5	0.94 (0.86–1.03)^c	1.14 (1.04–1.25)^b^,c
≥0.34 × 10^9 cells/L	415	47.4	0.93 (0.82–1.05)	1.08 (0.96–1.22)
Continuous ICS users
<0.34 × 10^9 cells/L	3125	54.3	1.13 (1.04–1.23)	1.14 (1.05–1.23)
≥0.34 × 10^9 cells/L	705	51.3	Reference	Reference
Relative eosinophil counts
Withdrawal of ICS
<4.0%	1676	47.0	1.08 (0.99–1.17)^b^,c	1.25 (1.15–1.36)^b
≥4.0%	502	42.4	0.91 (0.81–1.01)	1.08 (0.97–1.21)
Continuous ICS users
<4.0%	2997	55.8	1.30 (1.20–1.40)	1.25 (1.15–1.35)
≥4.0%	833	47.3	Reference	Reference

ICS: inhaled corticosteroids; IR: incidence rate; HR: hazard ratio; CI: confidence interval; PY: person-years.

^a Adjusted for age, gender, smoking status, body mass index, alcohol use, history of heart failure, chronic liver disease, ischemic heart disease, atopic dermatitis, diabetes mellitus, cancer, use of oxygen, statins, short-acting β-2 agonists, long-acting β-2 agonists, short-acting muscarinic antagonists, long-acting muscarinic antagonists, xanthine derivatives and oral corticosteroid use 6 months prior to the start of an interval.

^b Wald’s statistics: Withdrawal of ICS with low eosinophil counts statistically significantly different (p<.05) from withdrawal of ICS with high eosinophil count.

^c Wald’s statistics: Withdrawal of ICS low eosinophil counts statistically significantly different (p<.05) from continuous ICS use with low eosinophil count.

* Numbers of never ICS user who died not included.

Table 5. Risk of moderate-to-severe exacerbations with ICS use stratified by absolute and relative eosinophil counts among COPD patients censoring at any hospitalisation/A&E visit.

	Moderate-to-severe exacerbations (n = 6027)*	IR (/1000PY)	Age and gender adjusted HR (95% CI)	Adjusted HR (95% CI)^a
Absolute eosinophil counts
Withdrawal of ICS
<0.34 × 10^9 cells/L	1429	47.8	0.55 (0.51–0.60)^c	0.71(0.65–0.78)^c
≥0.34 × 10^9 cells/L	328	49.0	0.57 (0.50–0.65)	0.73(0.64-0.83)
Continuous ICS users
<0.34 × 10^9 cells/L	3440	83.4	1.09 (0.30–0.96)	0.98(0.91-1.06)
≥0.34 × 10^9 cells/L	830	85.7	Reference	Reference
Relative eosinophil counts
Withdrawal of ICS
<4.0%	1334	48.7	0.60 (0.56–0.66)^c	0.75(0.69-0.81)^c
≥4.0%	423	46.1	0.58 (0.52–0.65)	0.73(0.65-0.82)
Continuous ICS users
<4.0%	3270	85.3	1.06 (0.98–1.13)	1.02(0.95-1.10)
≥4.0%	1000	79.6	Reference	Reference

ICS: inhaled corticosteroids; IR: incidence rate; HR: hazard ratio; CI: confidence interval; PY: person-years; A/E: accident and emergency.

^a Adjusted for age, gender, smoking status, body mass index, alcohol use, history of heart failure, chronic liver disease, ischemic heart disease, use of antipsychotic, antidepressants, atopic dermatitis, oxygen, short-acting β-2 agonists, long-acting β-2 agonists, short-acting muscarinic antagonists, long-acting muscarinic antagonists, xanthine derivatives and oral corticosteroid 6 months prior to the start of an interval.

^b Wald’s statistics: Withdrawal of ICS with low eosinophil counts statistically significantly different (p<.05) from withdrawal of ICS with high eosinophil count.

^c Wald’s statistics: Withdrawal of ICS with low eosinophil counts statistically significantly different (p<.05) from continuous ICS use with low eosinophil count.

* Numbers of never ICS user not included in table.