Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study

Figures & data

Figure 1 Study design.

Abbreviations: CPRD, Clinical Practice Research Datalink; GP, general practitioner; OCS, oral corticosteroid; OPCRD, Optimum Patient Care Research Database; SCS, systemic corticosteroid.

Table 1 Outcomes evaluated after the index date in each risk cohort

Outcome	Definition applied after the index date (during follow-up period)a
Type 2 diabetes mellitus	• Diagnosis of type 2 diabetes mellitus and/or
	• One or more prescriptions for antidiabetic medicationb and/or
	• HbA1c value ≥6.5%
Cardio-/cerebrovascular disease	• Myocardial infarction, heart failure, or stroke diagnosis
Myocardial infarction	• Myocardial infarction diagnosis
Heart failure	• Heart failure diagnosis
Cerebrovascular accident	• Cerebrovascular accident diagnosis
Dyslipidemia	• Dyslipidemia diagnosis and/or total cholesterol reading >6.5 mmol/L, and/or low-density lipoprotein reading >4 mmol/L, and/or triglyceride reading ≥2.3 mmol/L
Hypertension	• Hypertension diagnosis
Weight gain	• An increase in BMI of ≥1 kg/m^2 compared with the last BMI in the 5 years before the index date
Osteoporosis diagnosis	• Osteoporosis diagnosis
Osteoporosis and osteoporotic fracture	• Osteoporosis diagnosis AND
	• Likely osteoporotic fracture (hip, wrist, or vertebral fracture)
Glaucoma	• Glaucoma diagnosis and/or treatment for glaucoma
Cataract	• Cataract diagnosis or surgery for cataract
Renal impairment	• Chronic kidney disease stage 3a+ diagnosis, or eGFR <60 mL/min/1.72 m^2, or dialysis or renal transplant
Peptic ulcer	• Peptic ulcer diagnosis
Depression/anxiety	• Depression/anxiety diagnosis or depression/anxiety diagnosis and prescription of antidepressants
Sleep apnea	• Sleep apnea diagnosis and/or referral to sleep clinic and use of a continuous positive airway pressure device
Pneumonia	• Pneumonia diagnosis

Notes:

a Diagnoses were defined as diagnostic Read codes recorded after the index date. See Table S1 for exclusion criteria specific to each risk cohort.

b Patients with a diagnosis of polycystic ovary syndrome (PCOS) and ≥1 metformin prescriptions in the follow-up period were excluded because metformin is given as treatment for PCOS.

Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate.

Table 2 Baseline characteristics of the matched treatment arms

	Non-SCS (n=24,117)	SCS (n=24,117)	SMD (%)
Sex, femalea	15,585 (65%)	15,585 (65%)	0.0
Age at index date (years)	43.9 (18.1)	48.7 (16.9)	27.4
18–40	11,958 (50%)	8,519 (35%)	23.5
41–60	7,072 (29%)	9,055 (38%)
61–80	4,342 (18%)	5,893 (24%)
>80	745 (3%)	650 (3%)
First SCS and matched non-SCS, median year (IQR)a	2,005 (9.0)	2,005 (9.0)	0.0
Available HES data linkagea	9,413 (39%)	9,413 (39%)	0.0
Body mass index (kg/m^2), n (% nonmissing)b	17,466 (72%)	16,810 (70%)	18.8
<18.5	435 (2%)	328 (2%)
≥18.5 to <25	6,996 (40%)	5,439 (32%)
≥25 to <30	5,511 (32%)	5,473 (33%)
≥30	4,524 (26%)	5,570 (33%)
Smoking status, n (% nonmissing)b	23,281 (97%)	23,587 (98%)	13.7
Current smoker	7,373 (32%)	8,604 (36%)
Ex-smoker	4,061 (17%)	4,773 (20%)
Nonsmoker	11,847 (51%)	10,210 (43%)
GINA stepc,d
No medication	2,302 (10%)	4,454 (18%)	2.4
Step 1	4,590 (19%)	3,970 (16%)
Step 2	9,512 (39%)	6,386 (26%)
Step 3	4,761 (20%)	4,972 (21%)
Step 4	2,952 (12%)	4,335 (18%)
High-dose ICS (mean dose >500 µg/day)b	1,029 (4%)	1,676 (7%)	11.7
FDC ICS/LABA: ICS daily dose (µg/day)c
0	7,109 (30%)	8,692 (36%)	2.4
>0–400	15,284 (63%)	12,792 (53%)
>400–800	1,357 (6%)	2,002 (8%)
>800	367 (2%)	631 (3%)
SABA (µg/day)c
0	5,062 (21%)	4,761 (20%)	7.3
1–100	4,247 (18%)	4,614 (19%)
101–200	6,214 (26%)	5,327 (22%)
201–400	4,558 (19%)	4,370 (18%)
>400	4,036 (17%)	5,045 (21%)
Infections treated with antibioticsc
0	20,476 (85%)	14,799 (61%)	49.0
1	2,343 (10%)	5,747 (24%)
2	868 (4%)	2,361 (10%)
≥3	430 (2%)	1,210 (5%)
Conditions recorded ever, before index date
Type 2 diabetes mellituse	1,223 (5%)	931 (4%)	5.9
Cardio-/cerebrovascular disease	1,037 (4%)	1,016 (4%)	0.4
Myocardial infarction	420 (2%)	458 (2%)	1.2
Heart failure	294 (1%)	255 (1%)	1.5
Cerebrovascular accident	471 (2%)	426 (2%)	1.4
Dyslipidemia	2,964 (12%)	3,211 (13%)	3.1
Hypertension	3,754 (16%)	4,145 (17%)	4.4
Osteoporosis	319 (1%)	383 (2%)	2.2
Osteoporosis or osteoporotic fracture	1,400 (6%)	1,565 (6%)	2.8
Glaucoma	258 (1%)	293 (1%)	1.4
Cataract diagnosis or surgery	727 (3%)	768 (3%)	1.0
Renal impairmentf	2,004 (8%)	2,204 (9%)	2.0
Peptic ulcer	427 (2%)	553 (2%)	3.7
Depression/anxiety	6,109 (25%)	7,088 (29%)	9.1
Sleep apnea	69 (0.3%)	71 (0.3%)	0.2
Pneumonia in the prior yearc	68 (0.3%)	117 (0.5%)	3.3
Charlson comorbidity indexg
0–4	10,778 (45%)	11,070 (46%)	5.6
5–8	10,325 (43%)	9,995 (41%)
9–12	827 (3%)	804 (3%)
13–16	829 (3%)	952 (4%)
≥17	1,358 (6%)	1,296 (5%)

Notes: Unless otherwise noted, data are n (%), mean (SD), or median (IQR). Percentages may not add up to 100 because of rounding.

a Matching variable.

b The closest body mass index within 5 years before and the smoking status closest to index date were included. High-dose ICS (fluticasone propionate–equivalent dose) refers to the last prescription before or on the index date.

c Variables assessed during the prior year (baseline). The ICS dose was the fluticasone propionate–equivalent dose.

d The GINA step was based on the last asthma medication(s) prescribed during the baseline year, including the index date. For the determination of GINA step in the SCS arm, “no medication” was defined as no asthma-related medication other than SCS prescribed at the index date. No patients were receiving biologics or at GINA step 5.

e Type 2 diabetes mellitus diagnostic Read code or HbA1c≥6.5% recorded twice or more.

f Stage 3a or higher at most recent assessment before the index date.

g Greater scores predict increased 10-year risk of mortality for people with multiple comorbidities.

Abbreviations: FDC, fixed-dose combination; GINA, Global Initiative for Asthma; HES, Hospital Episode Statistics; ICS, inhaled corticosteroid; LABA, long-acting β-agonist; SABA, short-acting β-agonist; SMD, standardized mean difference; SCS, systemic corticosteroid.

Table 3 Incidence of outcomes of interest in the matched non-SCS and SCS arms

Risk cohort	Non-SCS				SCS				IR difference (95% CI)	Unadjusted IR ratio (95% CI)
	N	Pt-yr	No. events	IR (per 100 pt-yr)	N	Pt-yr	No. events	IR (per 100 pt-yr)
Type 2 diabetes mellitus	21,808	166,756	1,025	0.615	21,808	183,458	1,921	1.047	0.432 (0.372–0.493)	1.70 (1.58–1.84)
Cardio-/cerebrovascular disease	22,112	169,323	826	0.488	22,112	185,195	1,774	0.958	0.470 (0.414–0.526)	1.96 (1.81–2.14)
Myocardial infarction	23,251	178,974	298	0.167	23,251	199,249	646	0.324	0.158 (0.126–0.189)	1.95 (1.69–2.24)
Heart failure	23,570	181,201	349	0.193	23,570	200,790	858	0.427	0.235 (0.200–0.270)	2.22 (1.96–2.52)
Cerebrovascular accident	23,228	178,454	451	0.253	23,228	198,519	823	0.415	0.162 (0.125–0.199)	1.64 (1.46–1.84)
Dyslipidemia	16,903	129,550	2,346	1.811	16,903	139,700	3,523	2.522	0.711 (0.600–0.822)	1.39 (1.32–1.47)
Hypertension	12,248	95,871	986	1.028	12,248	104,340	1,626	1.558	0.530 (0.431–0.629)	1.52 (1.40–1.64)
Weight gain (BMI increase ≥1 kg/m^2)	12,894	53,496	6,718	12.558	12,894	52,680	7,677	14.573	2.015 (1.572–2.458)	1.16 (1.12–1.20)
Osteoporosis diagnosis	23,422	179,971	382	0.212	23,422	198,056	964	0.487	0.274 (0.237–0.312)	2.29 (2.03–2.59)
Osteoporosis diagnosis and fracture	21,251	166,344	50	0.030	21,251	186,270	159	0.085	0.055 (0.040–0.071)	2.84 (2.05–3.98)
Glaucoma	23,424	180,109	273	0.152	23,424	201,118	433	0.215	0.064 (0.037–0.091)	1.42 (1.22–1.66)
Cataract	22,648	173,139	830	0.479	22,648	190,051	1,736	0.913	0.434 (0.380–0.488)	1.91 (1.75–2.07)
Renal impairment	20,137	152,844	1,758	1.150	20,137	162,698	3,215	1.976	0.826 (0.739–0.913)	1.72 (1.62–1.82)
Peptic ulcer	23,149	177,768	135	0.076	23,149	199,008	219	0.110	0.034 (0.015–0.054)	1.45 (1.16–1.81)
Depression/anxiety	7,961	62,801	1,257	2.002	7,961	66,924	1,554	2.322	0.320 (0.161–0.480)	1.16 (1.08–1.25)
Sleep apnea	23,980	184,930	84	0.045	23,980	207,072	205	0.099	0.054 (0.037–0.070)	2.18 (1.68–2.84)
Pneumonia	24,065	184,422	379	0.206	24,065	203,107	1,220	0.601	0.395 (0.356–0.435)	2.92 (2.60–3.29)

Abbreviations: BMI, body mass index; IR, incidence rate; pt-yr, patient-years; SCS, systemic corticosteroid.

Figure 2 HR (95% CI) for each adverse outcome in the SCS arms (vs non-SCS arms). The open squares represent unadjusted, and the closed squares, adjusted results. The adjusted HRs (95% CIs) are shown on the right. See Table S3 for list of confounders.

Abbreviations: BMI, body mass index; SCS, systemic corticosteroid.

Figure 3 (A–C) Adjusted hazard ratio (95% CI) for each adverse outcome in the SCS arms for categorized, cumulative SCS exposures, compared with the reference category of >0 to <0.5-g cumulative exposure. See Table S3 for list of confounders.

Abbreviations: BMI, body mass index; SCS, systemic corticosteroid.