Comparative Associations Between Measures of Anti-cholinergic Burden and Adverse Clinical Outcomes

Wen-Han Hsu; Yu-Wen Wen; Liang-Kung Chen; Fei-Yuan Hsiao

doi:10.1370/afm.2131

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Figure 1
Study design.
NHI=National Health Insurance.

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Table 1

Baseline Characteristics and Health Care Use of Study Cohort, Overall and Stratified by Age

Characteristic	Overall (N=116,043)	Aged 65–74 Years (n=78,993)	Aged 75–84 Years (n=32,282)	Aged ≥85 Years (n=4,768)
Female, No. (%)	57,523 (49.57)	38,788 (49.10)	15,933 (49.36)	2,802 (58.77)
Charlson Comorbidity Index
Total sample, mean (SD)	1.17 (1.36)	1.13 (1.34)	1.27 (1.40)	1.16 (1.39)
Female, mean (SD)	1.13 (1.36)	1.12 (1.35)	1.19 (1.38)	1.06 (1.33)
Male, mean (SD)	1.20 (1.36)	1.14 (1.33)	1.34 (1.42)	1.30 (1.45)
Comorbidities
Hypertension, No. (%)	44,278 (38.16)	29,692 (37.59)	12,916 (40.01)	1,670 (35.03)
Diabetes, No. (%)	20,852 (17.97)	15,017 (19.01)	5,364 (16.62)	471 (9.88)
Dyslipidemia, No. (%)	15,065 (12.98)	11,344 (14.36)	3,481 (10.78)	240 (5.03)
Coronary artery disease, No. (%)	23,475 (20.23)	15,151 (19.18)	7,378 (22.85)	946 (19.84)
Congestive heart failure, No. (%)	7,064 (6.09)	4,082 (5.17)	2,513 (7.78)	469 (9.84)
Cerebrovascular disease, No. (%)	14,915 (12.85)	8,803 (11.14)	5,255 (16.28)	857 (17.97)
Dementia, No. (%)	2,873 (2.48)	1,202 (1.52)	1,293 (4.01)	378 (7.93)
Depression, No. (%)	3,278 (2.82)	2,246 (2.84)	931 (2.88)	101 (2.12)
Psychosis/schizophrenia, No. (%)	3,185 (2.74)	1,481 (1.87)	1,331 (4.12)	373 (7.82)
Parkinson disease, No. (%)	2,491 (2.15)	1,311 (1.66)	1,012 (3.13)	168 (3.52)
Arthritis, No. (%)	32,979 (28.42)	22,147 (28.04)	9,526 (29.51)	1,306 (27.39)
Osteoporosis, No. (%)	10,217 (8.80)	6,623 (8.38)	3,086 (9.56)	508 (10.65)
Use of ambulatory care, annually
Number of visits, mean (SD)	24.44 (19.92)	23.82 (19.41)	26.06 (20.95)	23.64 (20.60)
Use of all drugs, monthly
Number of drugs used, mean (SD)	2.47 (2.40)	2.36 (2.35)	2.75 (2.50)	2.40 (2.33)
≥1 drug, No. (%)	74,408 (64.12)	49,260 (62.36)	22,105 (68.47)	3,043 (63.82)
≥5 drugs, No. (%)	18,178 (15.66)	11,422 (14.46)	6,040 (18.71)	716 (15.02)
≥10 drugs, No. (%)	1,005 (0.87)	630 (0.80)	344 (1.07)	31 (0.65)
Use of anticholinergic drugs
ARS
Score^a per month, mean (SD)	0.26 (0.57)	0.24 (0.56)	0.29 (0.61)	0.26 (0.56)
Use of ≥1 drug per year, No. (%)	43,301 (37.31)	28,665 (36.29)	12,839 (39.77)	1,797 (37.69)
ACB
Score^a per month, mean (SD)	0.60 (0.92)	0.57 (0.89)	0.69 (0.97)	0.64 (0.94)
Use of ≥1 drug per year, No. (%)	69,619 (59.99)	46,024 (58.26)	20,706 (64.14)	2,889 (60.59)
DBI-Ach
Score^b per month, mean (SD)	0.04 (0.09)	0.04 (0.09)	0.04 (0.10)	0.04 (0.09)
Use of ≥1 drug per year, No. (%)	43,301 (37.31)	28,665 (36.29)	12,839 (39.77)	1,797 (37.69)

ACB = Anticholinergic Cognitive Burden scale; ARS = Anticholinergic Risk Scale; DBI-Ach = Drug Burden Index - Anticholinergic component.
↵a ARS and ACB scores were calculated as the sum of the rankings for all prescribed drugs, with higher scores indicating greater anticholinergic burden.
↵b DBI-Ach score ranges from 0 to 1, with 0.5 indicating that an individual is exposed to an anticholinergic drug at the minimum recommended daily dose.

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Table 2

Anticholinergic Burden and Emergency Department Visits in Older Adults

Scale and Score	Emergency Department Visits

	Aged 65–74 Years (n = 287,693)			Aged 75–84 Years (n = 137,858)			Aged ≥85 Years (n = 16,830)

	No.	aOR^a (95% CI)	P Value	No.	aOR^a (95% CI)	P Value	No.	aOR^a (95% CI)	P Value
ARS^b
0 (ref)	214,635	1.00	–	101,410	1.00	–	12,926	1.00	–
1	22,426	1.90 (1.86–1.95)	<.001	13,014	1.85 (1.79–1.91)	<.001	1,590	1.61 (1.47–1.76)	<.001
2	22,753	1.55 (1.51–1.59)	<.001	10,359	1.54 (1.48–1.60)	<.001	1,047	1.34 (1.19–1.51)	<.001
3	17,616	1.65 (1.61–1.70)	<.001	8,351	1.56 (1.50–1.62)	<.001	827	1.38 (1.23–1.54)	<.001
≥4	10,263	2.04 (1.97–2.11)	<.001	4,724	1.94 (1.85–2.03)	<.001	440	1.73 (1.50–2.01)	<.001
ACB^b
0 (ref)	140,058	1.00	–	65,016	1.00	–	9,143	1.00	–
1	64,684	1.41 (1.37–1.45)	<.001	30,612	1.38 (1.35–1.41)	<.001	3,432	1.35 (1.28–1.44)	<.001
2	32,822	1.71 (1.66–1.75)	<.001	16,287	1.63 (1.59–1.68)	<.001	1,776	1.49 (1.38–1.61)	<.001
3	23,915	1.82 (1.78–1.87)	<.001	12,375	1.74 (1.69–1.79)	<.001	1,251	1.59 (1.46–1.74)	<.001
≥4	26,214	2.25 (2.19–2.31)	<.001	13,568	2.07 (2.00–2.14)	<.001	1,228	1.69 (1.54–1.85)	<.001
DBI-Ach^c
0 (ref)	214,636	1.00	–	101,411	1.00	–	12,926	1.00	–
0< score ≤0.5	56,873	1.68 (1.66–1.70)	<.001	28,900	1.60 (1.57–1.63)	<.001	3,110	1.55 (1.47–1.64)	<.001
0.5< score ≤1	16,184	2.02 (1.97–2.07)	<.001	7,547	1.87 (1.80–1.93)	<.001	794	1.98 (1.79–2.19)	<.001

aOR = adjusted odds ratio; ARS = Anticholinergic Risk Scale; ACB = Anticholinergic Cognitive Burden scale; DBI-Ach = Drug Burden Index - Anticholinergic component; ref=reference group.
Note: In multivariate generalized estimating equation models. Total sample for analysis was 442,381.
↵a Models were adjusted for sex and time-varying comorbidities (annually measured by Charlson Comorbidity Index; higher index indicates more comorbidities). For the ARS and ACB scales, we further adjusted defined daily dose of drugs with anticholinergic properties in the models to compare among the 3 scales.
↵b ARS and ACB scores were calculated as the sum of the rankings for all prescribed drugs, with higher scores indicating greater anticholinergic burden.
↵c DBI-Ach score ranges from 0 to 1, with 0.5 indicating that an individual is exposed to an anticholinergic medication at the minimum recommended daily dose.

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Table 3

Anticholinergic Burden and All-Cause Hospitalizations in Older Adults

Scale and Score	All-Cause Hospitalizations

	Aged 65–74 Years (n = 235,824)			Aged 75–84 Years (n = 118,907)			Aged ≥85 Years (n = 15,790)

	No.	aOR (95% CI)	P Value	No.	aOR (95% CI)	P Value	No.	aOR (95% CI)	P Value
ARS
0 (ref)	175,954	1.00	–	87,169	1.00	–	11,909	1.00	–
1	20,208	1.95 (1.91–2.00)	<.001	12,166	1.85 (1.79–1.92)	<.001	1,703	1.75 (1.59–1.93)	<.001
2	18,295	1.44 (1.40–1.48)	<.001	8,987	1.42 (1.36–1.48)	<.001	1,057	1.36 (1.21–1.53)	<.001
3	13,781	1.49 (1.45–1.53)	<.001	6,806	1.36 (1.31–1.41)	<.001	718	1.20 (1.07–1.36)	.002
≥4	7,586	1.69 (1.64–1.75)	<.001	3,779	1.62 (1.54–1.71)	<.001	403	1.58 (1.37–1.83)	<.001
ACB
0 (ref)	115,085	1.00	–	56,126	1.00	–	8,378	1.00	–
1	53,156	1.32 (1.26–1.38)	<.001	26,370	1.31 (1.27–1.35)	<.001	3,309	1.37 (1.29–1.46)	<.001
2	27,028	1.57 (1.50–1.64)	<.001	14,574	1.59 (1.54–1.64)	<.001	1,751	1.52 (1.40–1.65)	<.001
3	20,059	1.70 (1.63–1.77)	<.001	10,565	1.61 (1.55–1.66)	<.001	1,179	1.55 (1.41–1.70)	<.001
≥4	20,496	1.92 (1.85–2.00)	<.001	11,272	1.83 (1.77–1.89)	<.001	1,173	1.66 (1.51–1.83)	<.001
DBI-Ach
0 (ref)	175,954	1.00	–	87,173	1.00	–	11,909	1.00	–
0< score ≤0.5	47,217	1.61 (1.58–1.63)	<.001	25,312	1.56 (1.53–1.59)	<.001	3,116	1.62 (1.53–1.72)	<.001
0.5< score ≤1	12,653	1.79 (1.74–1.83)	<.001	6,422	1.74 (1.68–1.80)	<.001	765	1.95 (1.75–2.18)	<.001

aOR = adjusted odds ratio; ACB = Anticholinergic Cognitive Burden scale; ARS = Anticholinergic Risk Scale; DBI-Ach = Drug Burden Index - Anticholinergic component; ref=reference group.
Notes: In multivariate generalized estimating equation models. Total sample for analysis was 370,521. Refer to Table 2 notes for description of adjustment and scales.

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Table 4

Anticholinergic Burden and Fracture-Specific Hospitalizations in Older Adults

Scale and Score	Fracture-Specific Hospitalizations

	Aged 65–74 Years (n = 11,682)			Aged 75–84 Years (n = 6,567)			Aged ≥85 Years (n = 1,018)

	No.	aOR (95% CI)	P Value	No.	aOR (95% CI)	P Value	No.	aOR (95% CI)	P Value
ARS
0 (ref)	9,224	1.00	–	5,133	1.00	–	847	1.00	–
1	683	1.61 (1.47–1.76)	<.001	458	1.49 (1.33–1.66)	<.001	59	1.02 (0.75–1.39)	.88
2	832	1.64 (1.48–1.81)	<.001	443	1.56 (1.37–1.79)	<.001	47	0.99 (0.63–1.55)	.96
3	610	1.64 (1.49–1.81)	<.001	365	1.64 (1.43–1.87)	<.001	41	1.19 (0.79–1.78)	.41
≥4	333	1.96 (1.72–2.23)	<.001	168	1.73 (1.44–2.07)	<.001	24	1.65 (1.03–2.66)	.04
ACB
0 (ref)	6,915	1.00	–	3,707	1.00	–	651	1.00	–
1	2,231	1.10 (1.02–1.18)	.009	1,310	1.17 (1.07–1.28)	<.001	164	1.00 (0.84–1.20)	.97
2	939	1.13 (1.04–1.23)	.006	575	1.18 (1.05–1.31)	.004	89	1.18 (0.94–1.48)	.16
3	756	1.34 (1.23–1.46)	<.001	474	1.37 (1.22–1.54)	<.001	62	1.28 (0.98–1.67)	.07
≥4	841	1.71 (1.57–1.86)	<.001	501	1.62 (1.45–1.82)	<.001	52	1.18 (0.89–1.58)	.25
DBI-Ach
0 (ref)	9,224	1.00	–	5,133	1.00	–	847	1.00	–
0< score ≤0.5	1,941	1.45 (1.38–1.53)	<.001	1,171	1.43 (1.34–1.52)	<.001	134	1.13 (0.94–1.37)	.19
0.5< score ≤1	517	1.67 (1.52–1.84)	<.001	263	1.48 (1.30–1.68)	<.001	37	1.60 (1.15–2.23)	.006

aOR = adjusted odds ratio; ACB = Anticholinergic Cognitive Burden scale; ARS = Anticholinergic Risk Scale; DBI-Ach = Drug Burden Index - Anticholinergic component; ref=reference group.
Note: In multivariate generalized estimating equation models. Total sample for analysis was 19,267. Refer to Table 2 notes for description of adjustment and scales.

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Table 5

Anticholinergic Burden and Incident Dementia in Older Adults

Scale and Score	Incident Dementia

	Aged 65–74 Years (n = 8,350)			Aged 75–84 Years (n = 5,637)			Aged ≥85 Years (n = 815)

	No.	aOR (95% CI)	P Value	No.	aOR (95% CI)	P Value	No.	aOR (95% CI)	P Value
ARS
0 (ref)	4,749	1.00	–	3,164	1.00	–	511	1.00	–
1	1,757	10.41 (9.67–11.21)	<.001	1,301	8.46 (7.76–9.22)	<.001	176	6.81 (5.30–8.76)	<.001
2	836	5.20 (4.73–5.73)	<.001	556	4.96 (4.41–5.58)	<.001	63	3.90 (2.74–5.55)	<.001
3	551	3.87 (3.51–4.27)	<.001	363	3.43 (3.05–3.87)	<.001	37	2.58 (1.78–3.75)	<.001
≥4	457	7.27 (6.48–8.16)	<.001	253	5.55 (4.76–6.46)	<.001	28	4.88 (3.08–7.74)	<.001
ACB
0 (ref)	3,301	1.00	–	2,187	1.00	–	366	1.00	–
1	1,617	3.13 (2.89–3.39)	<.001	1,091	2.76 (2.51–3.05)	<.001	166	2.51 (1.95–3.23)	<.001
2	777	3.62 (3.27–4.00)	<.001	581	3.30 (2.92–3.72)	<.001	82	2.44 (1.78–3.35)	<.001
3	1,196	7.17 (6.55–7.85)	<.001	817	5.81 (5.21–6.48)	<.001	98	4.48 (3.30–6.08)	<.001
≥4	1,459	10.01 (9.16–10.95)	<.001	961	7.44 (6.68–8.28)	<.001	103	5.16 (3.82–6.97)	<.001
DBI-Ach
0 (ref)	4,749	1.00	–	3,164	1.00	–	511	1.00	–
0< score ≤ 0.5	2,915	3.75 (3.57–3.93)	<.001	2,059	3.50 (3.30–3.70)	<.001	254	3.05 (2.59–3.60)	<.001
0.5< score ≤ 1	686	3.68 (3.39–3.99)	<.001	414	3.06 (2.75–3.39)	<.001	50	2.98 (2.21–4.03)	<.001

aOR = adjusted odds ratio; ARS = Anticholinergic Risk Scale; ACB = Anticholinergic Cognitive Burden scale; DBI-Ach = Drug Burden Index - Anticholinergic component; ref=reference group.
Note: In multivariate generalized estimating equation models. Total sample for analysis was 14,802. Refer to Table 2 notes for description of adjustment and scales.

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The Article in Brief

Comparative Associations Between Measures of Anticholinergic Burden and Adverse Clinical Outcomes

Fei-Yuan Hsiao , and colleagues

Background Anticholinergic burden is the cumulative effect of using multiple medications that block the effects of acetylcholine in the body. Medications with anticholinergic properties comprise 30 to 50 percent of all medications commonly prescribed to older adults. This is the first study to examine the association between long-term (10 years) anticholinergic burden and adverse clinical outcomes by comparing different measurement scales of anticholinergic burden.

What This Study Found Anticholinergic burden assessed with the Anticholinergic Cognitive Burden Scale consistently shows dose-response relationships with a variety of adverse outcomes. In a study of long-term associations between adverse clinical outcomes in older adults and three scales for anticholinergic burden, the ACB scale showed the strongest, most consistent dose-response relationships with risk of all four adverse outcomes studied: emergency department visits, all-cause hospitalizations, hospitalizations for fractures, and incident dementia.

Implications

The authors suggest that the ACB scale may be a useful tool to identify high-risk populations for future research.