Association Between Medication Adherence and Risk of COPD in Adult Asthma Patients: A Retrospective Cohort Study in Canada

Figures & data

Table 1 Cohort Characteristics by Asthma Medication Adherence Levels for the Patient at Baseline

Variables	Overall	Medication Adherence (MA) levels
		Low-Level (PDC<0.50)	Intermediate (PDC=0.5–0.79)	Optimal (PDC: ≥80%)	P-value
N	68,211	46,666 (68.4%)	9557 (14.0%)	11,988 (17.6%)
Socio-demographic
Mean age, (SD in years)	48.20 (18.63)	46.50 ±18.12	50.89 ±18.09	52.71 ±19.29	<0.0001
Male Sex	27,756(40.69)	18,306(39.23)	4136(43.28)	5314(44.33)	<0.0001
Obesity (BMI>30kg/m^2)	205(0.30)	134(0.29)	25(0.30)	46(0.40)	0.171
Tobacco/nicotine use	96(0.14)	59(0.10)	18(0.20)	19(0.20)	0.288
Charlson comorbidity index
Score=0	66,766 (97.90)	45,906(98.37)	9277(97.07)	11,583(96.62)	<0.0001
Score=1	1226 (1.80)	615(1.32)	251(2.63)	360(3.00)
Score ≥2	219(0.30)	145(0.31)	29(0.30)	45(0.38)
Clinical variables/outcomes
Sinusitis	108(0.16)	74(0.16)	15(0.16)	19(0.16)	0.999
URI	284(0.42)	174(0.37)	42(0.44)	68(0.57)	0.012
Asthma hospitalization	2701(3.96)	1760(3.77)	389(4.07)	552(4.60)	<0.0001
Emergency department visit	3158(4.63)	2295(4.92)	354(3.7)	509(4.25)	<0.0001
Asthma exacerbation	5585(8.19)	3871(8.30)	705(7.4)	1009(8.42)	0.007
Hospital stay [median (IQR)]	3.0(2–6)	3.0(2–6)	4(2–7))	4(2–7)	0.009
Asthma severity at baseline
Mild asthma	49,155(72.06)	33,730(72.28)	7205(75.39)	8220(68.57)	<0.0001
Moderate asthma	15,595(22.87)	10,776(23.09)	1851(19.37)	2968(24.76)
Severe asthma	3461(5.07)	2160(4.63)	501(5.24)	800(6.67)
Asthma medications prescribed
SABA only	14,037(20.58)	10,718(22.97)	1464(15.32)	1855(15.47)	<0.0001
ICS only	5842(20.58)	4220(9.04)	751(7.86)	871(7.27)	<0.0001
ICS/LABA combination	90(0.13)	57(0.12)	12(0.13)	21(0.18)	0.355
ICS+SABA only	39,451(57.84)	26,354(56.47)	5870(61.42)	7227(60.29)	<0.0001
ICS+LABA only	6639(9.73)	4003(8.58)	1148(12.01)	1488(12.41)	<0.0001
Others	2152(3.15)	1281(2.75)	324(3.39)	547(4.56)	<0.0001

Abbreviations: BMI, body mass index; URI, upper respiratory infections; SABA, short acting beta-2 agonist; LABA, long-acting beta-2 agonist; ICS/LABA, inhaled corticosteroids/long-acting beta-2 agonist; other medications included leukotriene receptor antagonists (LTRA) and theophylline; IQR, interquartile range; SD, standard deviation.

Figure 1 Adjusted survival curves for time-to incidence of COPD stratified by medication adherence (p<0.001).

Figure 2 Survival curves for time-to incidence of COPD stratified by asthma severity (p<0.001).

Table 2 Patient Baseline Factors Associated with the Risk of COPD in Bivariate Analysis (18-Year Follow-Up)

Patient Factors	Hazard Ratio	95% CI	p-value
Age (years)	1.03	(1.031, 1.04)	<0.0001
Male Sex	1.27	(1.23, 1.33)	<0.0001
Charlson Comorbidity Index	1.45	(1.37, 1.54)	<0.0001
Asthma-related comorbidity
Sinusitis	0.53	(0.30, 0.94)	0.029
Upper respiratory diseases	1.41	(1.16, 1.73)	0.001
Asthma related hospitalization	1.18	(1.09, 1.28)	<0.0001
Emergency department visit	0.94	(0.85, 1.03)	0.203
Asthma exacerbation	1.08	(1.01, 1.15)	0.019
Length of stay (days)	1.38	(1.35, 1.40)	<0.0001
Tobacco use/nicotine dependence	1.78	(1.28, 2.46)	0.001
Obesity (BMI>30)	0.97	(0.75, 1.27)	0.846
Asthma severity
Mild	Ref
Moderate	1.52	(1.46, 1.58)	<0.0001
Severe	2.60	(1.54, 4.39)	<0.0001

Table 3 Propensity-Adjusted Association Between Medication Adherence, the Severity of Asthma and Incidence of COPD

Study Factors	5-Year		10-Year		Overall (18-Year)
	aHR(95% CI)	p-value	aHR(95% CI)	p-value	aHR(95% CI)	p-value
(A) Primary analysis: Adherence levels to all prescribed asthma medications combined
Adherence measured by PDC
Optimal-level	0.33(0.31, 0.35)	<0.0001	0.25(0.23, 0.28)	<0.0001	0.19(0.17, 0.24)	<0.0001
Intermediate	0.35(0.33, 0.37)	<0.0001	0.27(0.25, 0.30)	<0.0001	0.20(0.18, 0.23)	<0.0001
Low-level (or suboptimal)	Ref	n/a	Ref	n/a	Ref	n/a
Asthma Status
Severe	3.07(2.81, 3.35)	<0.0001	3.10(2.81, 3.44)	<0.0001	3.73(2.74, 5.09)	<0.0001
Moderate	1.65(1.57, 1.74)	<0.0001	1.53(1.43, 1.63)	<0.0001	1.68(1.49, 1.89)	<0.0001
Mild	Ref	n/a	Ref	n/a	Ref	n/a
(B) Secondary analysis*: Adherence asthma specific-medications
Adherence to ICS only
Optimal-level	0.32(0.29, 0.37)	<0.0001	0.32(0.28, 0.37)	<0.0001	0.33(0.27, 0.41)	<0.0001
Intermediate	0.39(0.35, 0.44)	<0.0001	0.39(0.35, 0.44)	<0.0001	0.39(0.32, 0.47)	<0.0001
Low-level	Ref	n/a	Ref	n/a	Ref	n/a
Adherence to combinations (ICS/LABA)
Optimal-level	0.29(0.25, 0.32)	<0.0001	0.26(0.22, 0.30)	<0.0001	0.25(0.20, 0.31)	<0.0001
Intermediate	0.40(0.35, 0.45)	<0.0001	0.37(0.33, 0.42)	<0.0001	0.30(0.26, 0.35)	<0.0001
Low-level	Ref	n/a	Ref	n/a	Ref	n/a

Notes: Table include adjusted hazard ratios (aHR) and 95% Confidence Interval (95% CI). Propensity adjusted analysis using Marginal Structural Cox model (inverse probability weighted cox model) which adjusted for both baseline covariates and time varying covariates and confounders. Optimal level = [PDC ≥ 0.80], Intermediate level= [0.50 ≤ PDC ≤ 0.79], low-level (or suboptimal) = [PDC <0.5]; ref=reference group; n/a= not applicable. *Analysis are adjusted for severity of asthma.

Abbreviations: ICS, inhaled corticosteroids; LABA, long-acting beta-2 agonist; MA, medication adherence; PDC, proportion of days covered.

Figure 3 Association between medication adherence and risk of COPD modified by asthma severity levels. aHR: adjusted hazard ratio; 95% CI: 95% confidence interval; Reference category for subgroup 1.1 is “low adherence*mild asthma”; *Reference category for subgroup 1.2 is “low adherence”.