Exposure to antimuscarinic medications for treatment of overactive bladder and risk of lung cancer and colon cancer

Figures & data

Figure 1 Inclusion of study population to the study cohort.

Table 1 Demographics and clinical characteristics of study subjects, both exposed and unexposed individuals

Variables	Exposed	Unexposed	da
Total number of individuals	164,000	1,446,472
Age at index (years)			0.08
Mean (SD)	67 (15)	66 (15)
Median (q1–q3)	69 (60–78)	68 (58–77)
Follow-up time (months)			0.00
Mean (SD)	47 (24)	47 (24)
Median (q1–q3)	47 (27–68)	47 (27–68)
Sex, n (%)
Women	93,440 (57.0)	785,928 (54.3)	0.05
Men	70,560 (43.0)	660,544 (45.7)	−0.05
Index year, n (%)
2006–2008	71,057 (43.3)	625,357 (43.2)	0.00
2009–2010	48,060 (29.3)	421,824 (29.2)	0.00
2011–2012	44,883 (27.4)	399,291 (27.6)	0.00
Education (highest completed), n (%)
Mandatory or less (≤9 years)	39,815 (24.2)	366,988 (25.4)	−0.03
Upper secondary (10–12 years)	55,416 (33.8)	494,258 (34.2)	−0.01
Higher education (>12 years)	35,168 (21.4)	319,865 (22.1)	−0.02
No educational data	33,601 (20.6)	265,361 (18.3)	0.06
Income (quartiles from overall population), n (%)
q1	41,137 (25.1)	361,367 (25.0)	0.00
q2	44,442 (27.1)	358,064 (24.8)	0.05
q3	41,222 (25.2)	361,277 (25.0)	0.00
q4	36,918 (22.5)	365,587 (25.3)	−0.07
Diagnosis of overactive bladder, n (%)	9,093 (5.5)	16,882 (1.2)	0.24
Comorbid conditions, n (%)
Cerebrovascular disease	12,538 (7.6)	82,593 (5.7)	0.08
COPD	4,657 (2.8)	33,544 (2.3)	0.03
Diabetes mellitus (type 1 or 2)	19,278 (11.8)	141,221 (9.8)	0.06
Hypertension	74,840 (45.6)	563,678 (39.0)	0.13
Inflammatory bowel disease	1,632 (1.0)	11,524 (0.8)	0.02
Peptic ulcer disease	2,716 (1.7)	16,776 (1.2)	0.04
Obesity	957 (0.6)	4,577 (0.3)	0.04
Incidence rate difference per 100,000 person-years
Lung cancer	−44.9 (95% CI: −53.3, −36.5)		–
Colon cancer	−26.1 (95% CI: −35.8, −16.3)		–

Note:

a Standardized difference.

Table 2 HRs and 95% CIs for the end points, overall, by sex and cumulative DDD

	N	Unadjusted HR (95% CI)	Base adjusted HR (95% CI)a	Fully adjusted HR (95% CI)b
Lung cancer
Overall	9,053
Unexposed	8,394	1 (reference)	1 (reference)	1 (reference)
Exposed	659
<1 year	234	0.91 (0.79–1.04)	0.86 (0.76–0.99)	0.86 (0.75–0.98)
1–4 years	347	0.66 (0.59–0.74)	0.64 (0.57–0.71)	0.63 (0.56–0.70)
≥4 years	78	0.47 (0.37–0.59)	0.44 (0.35–0.55)	0.43 (0.34–0.55)
Sex
Men	4,907
Unexposed	4,571	1 (reference)	1 (reference)	1 (reference)
Exposed	336
<1 year	128	0.92 (0.77–1.10)	0.89 (0.74–1.07)	0.90 (0.75–1.08)
1–4 years	168	0.63 (0.54–0.73)	0.61 (0.52–0.72)	0.62 (0.53–0.72)
≥4 years	40	0.52 (0.38–0.71)	0.50 (0.36–0.69)	0.51 (0.37–0.70)
Women	4,146
Unexposed	3,823	1 (reference)	1 (reference)	1 (reference)
Exposed	323
<1 year	106	0.92 (0.75–1.12)	0.83 (0.68–1.02)	0.81 (0.66–0.99)
1–4 years	179	0.72 (0.62–0.83)	0.66 (0.56–0.76)	0.64 (0.54–0.74)
≥4 years	38	0.42 0.31–0.59)	0.39 (0.28–0.54)	0.37 (0.26–0.51)
DDDsc
≤90	340	1 (reference)	1 (reference)	1 (reference)
91–180	103	0.97 (0.77–1.21)	0.96 (0.76–1.20)	0.96 (0.76–1.20)
181–364	83	1.03 (0.81–1.32)	1.01 (0.79–1.28)	1.01 (0.79–1.29)
≥365	133	0.83 (0.68–1.02)	0.82 (0.67–1.00)	0.82 (0.67–1.00)
Colon cancer
Overall	10,448
Unexposed	9,537	1 (reference)	1 (reference)	1 (reference)
Exposed	911
<1 year	263	0.96 (0.85–1.09)	0.91 (0.80–1.03)	0.91 (0.80–1.03)
1–4 years	508	0.86 (0.79–0.95)	0.81 (0.74–0.89)	0.81 (0.74–0.88)
≥4 years	140	0.64 (0.54–0.76)	0.61 (0.51–0.72)	0.61 (0.51–0.73)
Sex
Men	5,556
Unexposed	5,102	1 (reference)	1 (reference)	1 (reference)
Exposed	454
<1 year	141	0.98 (0.82–1.16)	0.94 (0.80–1.12)	0.94 (0.79–1.13)
1–4 years	250	0.85 (0.75–0.97)	0.81 (0.71–0.93)	0.81 (0.71–0.93)
≥4 years	63	0.61 (0.47–0.79)	0.60 (0.46–0.78)	0.60 (0.46–0.78)
Women	4,892
Unexposed	4,435	1 (reference)	1 (reference)	1 (reference)
Exposed	457
<1 year	122	0.97 (0.80–1.17)	0.87 (0.72–1.05)	0.87 (0.72–1.05)
1–4 years	258	0.90 (0.79–1.02)	0.80 (0.70–0.91)	0.80 (0.70–0.91)
≥4 years	77	0.68 (0.54–0.86)	0.61 (0.49–0.78)	0.62 (0.49–0.78)
DDDsc
≤90	472	1 (reference)	1 (reference)	1 (reference)
91–180	148	1.01 (0.84–1.22)	0.99 (0.82–1.20)	0.99 (0.82–1.20)
181–364	118	1.05 (0.86–1.29)	1.02 (0.83–1.25)	1.02 (0.83–1.25)
≥365	173	0.74 (0.62–0.89)	0.73 (0.61–0.87)	0.73 (0.61–0.87)

Notes:

a Adjusted for the matching variables age, sex, and county of residence.

b Adjusted for age, sex, and county of residence, income, education, and the smoking proxy variable.

c Only including the exposed individuals.

Abbreviation: DDD, defined daily dose.

Table S1 ATC codes used to identify medications in the PDR used as disease proxies

Diseases	ATC codes
Hypertension	C02, C03, C07AA01-C07AA06, C07AA08, C07AA27, C07AB, C07Ag, C08, and C09
Diabetes mellitus	A10
Obesity	A09

Abbreviation: ATC, Anatomic Therapeutic Chemical classification system; PDR, Prescribed Drug Register.

Table S2 HR and 95% CIs for the end points, overall using 6-month and 12-month lag time, and by inclusion year using no lag time

Lung cancer
	n	Unadjusted HR (95% CI)	Base adjusted HR (95% CI)a	Fully adjusted HR (95% CI)b
6-month lag time
Overall	7,756
Unexposed	7,226	1 (reference)	1 (reference)	1 (reference)
Exposed	530
<1 year	176	0.74 (0.63–0.88)	0.70 (0.60–0.82)	0.70 (0.60–0.82)
1–4 years	311	0.68 (0.61–0.76)	0.65 (0.58–0.73)	0.64 (0.57–0.72)
≥4 years	43	0.36 (0.26–0.48)	0.33 (0.24–0.45)	0.33 (0.24–0.45)
12-month lag time
Overall	6,532
Unexposed	6,107	1 (reference)	1 (reference)	1 (reference)
Exposed	425
<1 year	139	0.64 (0.54–0.76)	0.62 (0.52–0.74)	0.62 (0.52–0.74)
1–4 years	258	0.66 (0.58–0.75)	0.63 (0.55–0.71)	0.61 (0.54–0.70)
≥4 years	28	0.34 (0.23–0.50)	0.31 (0.21–0.46)	0.30 (0.21–0.45)
Index year
2006–2008	5,663
Unexposed	5,237	1 (reference)	1 (reference)	1 (reference)
Exposed	426
<1 year	103	0.81 (0.66–0.99)	0.78 (0.63–0.95)	0.77 (0.62–0.94)
1–4 years	245	0.78 (0.68–0.89)	0.75 (0.66–0.86)	0.75 (0.66–0.86)
≥4 years	78	0.50 (0.40–0.63)	0.47 (0.37–0.60)	0.47 (0.37–0.59)
2009–2010	2,345
Unexposed	2,181	1 (reference)	1 (reference)	1 (reference)
Exposed	164
<1 year	74	1.02 (0.80–1.30)	0.97 (0.76–1.23)	0.97 (0.76–1.24)
1–4 years	90	0.56 (0.45–0.69)	0.53 (0.43–0.65)	0.51 (0.41–0.63)
≥4 years	0	–	–	–
2011–2012	1,045
Unexposed	976	1 (reference)	1 (reference)	1 (reference)
Exposed	69
<1 year	57	0.97 (0.74–1.28)	0.92 (0.70–1.21)	0.91 (0.69–1.20)
1–4 years	12	0.24 (0.14–0.43)	0.24 (0.14–0.42)	0.23 (0.13–0.42)
≥4 years	0	–	–	–
Colon cancer
	n	Unadjusted HR (95% CI)	Base adjusted HR (95% CI)a	Fully adjusted HR (95% CI)b
6-month lag time
Overall	9,094
Unexposed	8,315	1 (reference)	1 (reference)	1 (reference)
Exposed	779
<1 year	242	0.92 (0.80–1.05)	0.86 (0.75–0.98)	0.86 (0.75–0.98)
1–4 years	449	0.86 (0.78–0.95)	0.81 (0.73–0.89)	0.81 (0.73–0.89)
≥4 years	88	0.57 (0.46–0.70)	0.53 (0.43–0.66)	0.53 (0.43–0.66)
12-month lag time
Overall	7,768
Unexposed	7,120	1 (reference)	1 (reference)	1 (reference)
Exposed	648
<1 year	210	0.87 (0.76–1.01)	0.81 (0.70–0.93)	0.81 (0.71–0.94)
1–4 years	392	0.86 (0.77–0.95)	0.81 (0.73–0.90)	0.80 (0.72–0.89)
≥4 years	46	0.43 (0.32–0.58)	0.40 (0.30–0.54)	0.40 (0.30–0.54)
Index year
2006–2008	6,421
Unexposed	5,818	1 (reference)	1 (reference)	1 (reference)
Exposed	603
<1 year	109	0.81 (0.67–0.99)	0.78 (0.64–0.95)	0.78 (0.64–0.96)
1–4 years	354	1.08 (0.96–1.20)	1.01 (0.91–1.14)	1.01 (0.90–1.13)
≥4 years	140	0.70 (0.59–0.83)	0.66 (0.55–0.79)	0.66 (0.56–0.79)
2009–2010	2,796
Unexposed	2,573	1 (reference)	1 (reference)	1 (reference)
Exposed	223
<1 year	95	1.27 (1.03–1.58)	1.18 (0.95–1.47)	1.18 (0.95–1.46)
1–4 years	128	0.65 (0.54–0.78)	0.61 (0.51–0.73)	0.60 (0.50–0.73)
≥4 years	0	–	–	–
2011–2012	1,231
Unexposed	1,146	1 (reference)	1 (reference)	1 (reference)
Exposed	85
<1 year	59	0.91 (0.69–1.19)	0.84 (0.64–1.10)	0.85 (0.65–1.11)
1–4 years	26	0.42 (0.28–0.62)	0.39 (0.26–0.58)	0.39 (0.26–0.58)
≥4 years	0	–	–	–

Notes:

a Adjusted for the matching variables age, sex, and county of residence.

b Adjusted for age, sex, and county of residence, income, education, and the smoking proxy variable.

Table S3 HR and 95% CIs for the end points for tolterodine

	n	Unadjusted HR (95% CI)	Base adjusted HR (95% CI)a	Fully adjusted HR (95% CI)b
Lung cancer
Unexposed	4,423	1 (reference)	1 (reference)	1 (reference)
Exposed	348
<1 year	109	0.88 (0.72–1.07)	0.84 (0.69–1.03)	0.84 (0.69–1.03)
1–4 years	196	0.72 (0.62–0.83)	0.71 (0.61–0.82)	0.70 (0.61–0.82)
≥4 years	43	0.43 (0.30–0.60)	0.41 (0.29–0.58)	0.40 (0.28–0.57)
Colon cancer
Unexposed	5,126	1 (reference)	1 (reference)	1 (reference)
Exposed	512
<1 year	130	0.97 (0.81–1.17)	0.92 (0.77–1.11)	0.92 (0.77–1.11)
1–4 years	294	0.95 (0.84–1.07)	0.90 (0.80–1.02)	0.90 (0.80–1.02)
≥4 years	88	0.74 (0.59–0.94)	0.75 (0.59–0.95)	0.75 (0.59–0.95)

Notes:

a Adjusted for the matching variables age, sex, and county of residence.

b Adjusted for age, sex, and county of residence, income, education, and the smoking proxy variable.