Risk of COPD Exacerbations Associated with Statins versus Fibrates: A New User, Active Comparison, and High-Dimensional Propensity Score Matched Cohort Study

Figures & data

Table 1 Selected Baseline Characteristics of the Eligible Cohort

	Before Matching (n=134,909)			After hd-PS Matching (n=127,855)
	Statins (n=110,726)	Fibrates (n=24,183)	Standardized Difference^a	Statins (n=103,735)	Fibrates (n=24,120)	Standardized Difference^a
Variables				n=24,120^b	n=24,120^b
Demographics
Age, mean (SD)	67.6 (11.8)	63.9 (12.6)	0.31	63.9 (12.0)	63.9 (12.5)	<0.01
Male, n (%)	64,110 (57.9)	15,291 (63.2)	0.11	15,229 (63.1)	15,239 (63.2)	<0.01
COPD duration, mean (SD)	595.4 (592.3)	507.1 (513.8)	0.16	499.0 (516.5)	507.4 (514.1)	0.02
Mean dose of the index prescriptions
Index dose (ddd/day), mean (SD)	0.7 (0.4)	0.8 (0.4)	0.16	0.8 (0.5)	0.8 (0.4)	<0.01
Resource utilization, mean (SD)
Number of outpatient visits	42.9 (26.7)	42.8 (28.1)	<0.01	43.1 (27.7)	42.8 (28.1)	0.01
Number of outpatient visits due to cardiovascular disease^c	8.7 (8.7)	8.0 (8.6)	0.08	8.1 (8.7)	8.0 (8.6)	0.01
Number of outpatient visits due to respiratory diseases	3.4 (6.2)	3.2 (5.8)	0.04	3.3 (6.0)	3.2 (5.8)	0.01
Number of outpatient visits due to COPD	4.6 (5.8)	4.2 (5.5)	0.08	4.2 (5.3)	4.2 (5.5)	<0.01
Number of hospitalizations	0.6 (1.4)	0.5 (1.4)	0.05	0.5 (1.7)	0.5 (1.3)	<0.01
Number of hospitalizations due to cardiovascular disease^c	0.4 (0.8)	0.3 (0.8)	0.14	0.3 (0.7)	0.3 (0.7)	0.01
Number of hospitalizations due to respiratory diseases	0.1 (0.5)	0.1 (0.5)	0.04	0.1 (0.4)	0.1 (0.5)	<0.01
Number of hospitalizations due to COPD	0.3 (0.6)	0.1 (0.5)	0.11	0.1 (0.5)	0.1 (0.5)	<0.01
Number of cholesterol test ordered	1.8 (1.5)	1.6 (1.6)	0.08	1.6 (1.4)	1.6 (1.6)	<0.01
Number of triglyceride test ordered	1.7 (1.5)	1.7 (1.6)	<0.01	1.7 (1.5)	1.7 (1.6)	<0.01
Pneumonia and influenza vaccination, n (%)	30,383 (27.4)	5917 (24.5)	0.07	5877 (24.4)	5911 (24.5)	<0.01
Comorbidities, n (%)
Hypertension	75,699 (68.4)	15,906 (65.8)	0.06	16,020 (66.4)	15,871 (65.8)	<0.01
Ischemic heart disease	37,259 (33.7)	6107 (25.3)	0.19	6042 (25.1)	6100 (25.3)	<0.01
Myocardial infarction	5221 (4.7)	296 (1.2)	0.21	307 (1.3)	296 (1.2)	<0.01
Coronary revascularization	5507 (5.0)	238 (1.0)	0.24	255 (1.1)	238 (1.0)	<0.01
Cardiac dysrhythmia	16,050 (14.5)	2724 (11.3)	0.10	2709 (11.2)	2720 (11.3)	<0.01
Congestive heart failure	17,007 (15.4)	2785 (11.5)	0.11	2803 (11.6)	2781 (11.5)	<0.01
Cereborvascular disease	20,945 (18.9)	3693 (15.3)	0.10	3746 (15.5)	3683 (15.3)	0.01
Peripheral vascular disease	3152 (2.9)	747 (3.1)	0.01	738 (3.1)	745 (3.1)	<0.01
Hyperlipidemia	72,648 (65.6)	17,143 (70.9)	0.11	17,085 (70.8)	17,088 (70.9)	<0.01
Diabetes mellitus	39,944 (36.1)	9310 (38.5)	0.05	9387 (38.9)	9281 (38.5)	0.01
Asthma	26,451 (23.9)	5006 (20.7)	0.08	5044 (20.9)	4999 (20.7)	0.01
Pneumonia, influenza, or acute bronchitis	58,514 (52.9)	12,998 (53.8)	0.02	13,036 (54.1)	12,953 (53.7)	0.01
Acute bronchiectasis	3621 (3.3)	570 (2.4)	0.06	408 (1.7)	409 (1.7)	<0.01
Tuberculosis	2002 (1.8)	410 (1.7)	0.01	573 (2.4)	570 (2.4)	<0.01
Medications, n (%)
ACEI s/ARBs	57,274 (51.7)	10,927 (45.2)	0.13	10,943 (45.4)	10,908 (45.2)	<0.01
β blockers	42,512 (38.4)	9154 (37.9)	0.01	9296 (38.5)	9126 (37.8)	0.02
Calcium channel blockers	62,226 (56.2)	12,677 (52.4)	0.08	12,714 (52.7)	12,656 (52.5)	0.01
Diuretics	37,312 (33.7)	7288 (30.1)	0.08	7368 (30.6)	7268 (30.1)	0.01
Other anti-hypertensive agents	13,771 (12.4)	3065 (12.7)	0.01	3117 (12.9)	3057 (12.7)	0.01
Nitrates	27,457 (24.8)	4032 (16.7)	0.20	4119 (17.1)	4027 (16.7)	<0.01
Anti-arrhythmic agents	7,658 (6.9)	1097 (4.5)	0.10	1117 (4.6)	1093 (4.5)	0.01
Digoxin	5,751 (5.2)	1278 (5.3)	<0.01	1303 (5.4)	1271 (5.3)	0.01
Aspirin	48,791 (44.1)	8436 (34.9)	0.19	8446 (35.0)	8420 (34.9)	<0.01
Clopidogrel	12,143 (11.0)	1022 (4.2)	0.26	1027 (4.3)	1021 (4.2)	<0.01
Warfarin	2,944 (2.7)	374 (1.6)	0.08	362 (1.5)	374 (1.6)	<0.01
Insulin	10,369 (9.4)	2189 (9.1)	0.01	2184 (9.1)	2179 (9.0)	<0.01
Oral anti-diabetic agents	32,995 (29.8)	7716 (31.9)	0.05	7772 (32.2)	7687 (31.9)	0.01
Inhaled short-acting bronchodilators	83,741 (75.6)	19,506 (80.7)	0.12	19,412 (80.5)	19,454 (80.7)	<0.01
Inhaled long-acting bronchodilators	19,140 (17.3)	2710 (11.2)	0.18	2780 (11.5)	2710 (11.2)	0.01
Inhaled corticosteroids;	18,253 (16.5)	2648 (11.0)	0.16	2695 (11.2)	2647 (11.0)	0.01
Oral bronchodilators	79,607 (71.9)	17,117 (70.8)	0.03	17,061 (70.7)	17,067 (70.8)	<0.01
Oral corticosteroids	56,001 (50.6)	11,654 (48.2)	0.05	11,606 (48.1)	11,617 (48.2)	<0.01
Antibiotics	81,371 (73.5)	17,746 (73.4)	<0.01	17,795 (73.8)	17,692 (73.4)	0.01

a Notes: ^aData were presented as absolute values. ^bOne initiator of statins: one randomly sampled initiator of fibrates in each matched subset. ^cCardiovascular disease included hypertension, ischemic heart disease, myocardial infarction, coronary revascularization, cardiac dysrhythmia congestive heart failure, cereborvascular disease, and peripheral vascular disease.

Abbreviations: ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; COPD, chronic obstructive pulmonary disease; hd-PS, high-dimensional propensity score.

Figure 1 Flowchart of the study cohort assembly.

Abbreviation: COPD, chronic obstructive pulmonary disease.

Table 2 Follow-Up, Event Rates, and Risk of COPD Exacerbations Comparing Statins with Fibrates

	Before Matching(n=134,909)		After PS Matching(n=128,517)		After hd-PS Matching (n=127,855)
Variables	Statins	Fibrates	Statins	Fibrates	Statins	Fibrates
Number of patients	110,726	24,183	104,367	24,150	103,735	24,120
Number of events	1,735	244	1,507	244	1,436	242
Total person-days at risk	19,551,431	4,302,410	18,471,866	4,296,470	18,367,883	4,291,170
Mean follow-up days, mean (SD)	176.6	177.9	177.0	177.9	177.1	177.9
Incidence rate per 1,000 person-years (95% CI)^a	32.41 (30.92–33.97)	20.71 (18.27–23.48)	23.14 (20.55–26.06)	20.74 (18.30–23.52)	22.03 (19.50–24.89)	20.60 (18.16–23.36)
HR (95% CI)^a	Ref	1.56 (1.37–1.79)	Ref	1.10 (0.96–1.26)	Ref	1.08 (0.94–1.24)

Notes: ^aData were weighted by matching ratio in the PS and hd-PS matching analyses.

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; hd-PS, high-dimensional propensity score; HR, hazard ratio; PS, propensity score.

Figure 2 Kaplan–Meier curves for the probability of free of COPD exacerbations within 180 days after the index date (A) Kaplan–Meier curves before matching. (B) Kaplan–Meier curves after hd-PS matching^{a. a}Data were weighted by matching ratio in the hd-PS matching analysis.

Abbreviations: COPD, chronic obstructive pulmonary disease; hd-PS, high-dimensional propensity score.

Table 3 Risk of COPD Exacerbations Comparing Statins with Fibrates, by Maximum Follow-Up Duration and Follow-Up Scheme

Maximum Follow-Up Duration	Crude HR (95% CI)	HR (95% CI) After PS Matching	HR (95% CI) After hd-PS Matching
	“First exposure carried forward” analysis
180 days (primary analysis)	1.56 (1.37, 1.79)	1.10 (0.96,1.26)	1.08 (0.94, 1.24)
365 days	1.45 (1.31, 1.60)	1.04 (0.94, 1.15)	1.02 (0.92, 1.13)
730 days	1.39 (1.29, 1.50)	1.02 (0.94, 1.11)	0.98 (0.90, 1.06)
No truncation at maximum follow-up duration^a	1.33 (1.26, 1.42)	1.01 (0.95,1.08)	0.98 (0.92, 1.04)
	“On-treatment” analysis
180 days	1.72 (1.45, 2.05)	1.16 (0.97, 1.38)	1.12 (0.93, 1.34)
365 days	1.65 (1.41, 1.93)	1.12 (0.95, 1.31)	1.07 (0.91, 1.27)
730 days	1.61 (1.39, 1.86)	1.09 (0.94, 1.27)	1.05 (0.90, 1.22)
No truncation at maximum follow-up duration^b	1.61 (1.39, 1.86)	1.09 (0.94, 1.26)	1.03 (0.89, 1.20)

a Notes: ^aThe mean follow-up duration was 1,393 days before matching. ^bThe mean follow-up duration was 247 days before matching.

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; hd-PS, high-dimensional propensity score; HR, hazard ratio; PS, propensity score.

Table 4 Risk of COPD Exacerbations Comparing Statins with Fibrates, by Type of Statins and Patient Characteristic

		Before Matching			After hd-PS Matching
		Events/Patients		Crude HR	Events/Patients		HR After hd-PS Matching
		Statins	Fibrates		Statins	Fibrates
Type of statins	Atorvastatin	730/44,258	244/24,183	1.65 (1.43–1.91)	681/42,847	224/20,302	1.08 (0.92–1.28)
	Rosuvastatin	427/22,908	244/24,183	1.87 (1.60–2.19)	420/22,703	209/16,232	1.07 (0.89–1.28)
	Simvastatin	261/19,173	244/24,183	1.35 (1.14–1.61)	261/19,173	143/13,967	1.28 (1.04–1.58)
	Other statins	317/24,387	244/24,183	1.29 (1.09–1.53)	317/24,387	206/18,348	0.93 (0.77–1.13)
Age	≥65	1,448/65,735	179/11,347	1.41 (1.20–1.64)	1,188/59,662	179/11,346	1.02 (0.87–1.21)
	<65	287/44,991	65/12,836	1.26 (0.96–1.65)	281/44,046	65/12,731	1.13 (0.85–1.51)
Sex	Male	1,364/64,110	169/15,291	1.95 (1.66–2.28)	1,120/58,571	169/15,205	1.13 (0.96–1.34)
	Female	371/46,616	75/8,892	0.94 (0.74–1.21)	346/44,970	75/8,886	0.84 (0.65–1.10)
Cardiovascular history	Yes	1560/88,605	207/18,044	1.55 (1.34 −1.79)	1,305/82,170	207/18,038	1.06 (0.91–1.23)
	No	175/22,121	37/6139	1.31 (0.92–1.87)	172/21,915	37/6,071	1.13(0.76–1.67)
Diabetes history	Yes	622/32,995	108/7716	1.36 (1.11–1.66)	555/31,451	108/7,712	0.98 (0.79–1.21)
	No	1,113/77,731	136/16,467	1.75 (1.46–2.09)	945/72,552	136/16,421	1.15 (0.96–1.39)
Cardiovascular and diabetes history	No	122/15,898	23/4638	1.55 (0.99–2.42)	120/15,629	23/4,546	1.25 (0.78–2.03)
Asthma history	Yes	933/26,451	100/5006	1.79 (1.45–2.20)	788/24,504	100/4,998	1.24 (0.997–1.53)
	No	802/84,275	144/19,177	1.27 (1.07–1.52)	703/79,809	144/19,143	0.97 (0.80–1.17)
Prior hospitalization due to COPD	Yes	1,063/12,313	127/1792	1.24 (1.03–1.49)	807/9,388	127/1,786	1.06 (0.87–1.28)
	No	672/98,413	117/22,391	1.31 (1.08–1.60)	635/94,570	117/22,359	1.03 (0.84–1.27)

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; hd-PS, high-dimensional propensity score; HR, hazard ratio.