ONLINE SUPPLEMENTARY
Statin use and risk of non-melanoma skin cancer: a nationwide study in Denmark
Data sources
Drug exposure classification
Supplementary analyses
Supplementary references
Code list
Supplementary Tables
Sidsel Arnspang1, Anton Pottegård1,2, Søren Friis3, Ole Clemmensen4, Klaus Ejner Andersen5, Jesper
Hallas1,2, David Gaist6
1
Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, J.B. Winsløws Vej 19,
2.sal , 5000 Odense C, Denmark
2
Department of Clinical Chemistry & Pharmacology, Odense University Hospital, J.B. Winsløws Vej 19,
2.sal , 5000 Odense C, Denmark
3
Danish Cancer Society Research Centre, Strandboulevarden 49, 2100 Copenhagen Ø, Denmark; Faculty of
Health, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark; and Department of Public
Health, University of Copenhagen, Copenhagen, Denmark.
4
Department of Clinical Pathology, Odense University Hospital, J.B. Winsløws Vej 15, 5000 Odense C,
Denmark
5
Department of Dermatology and Allergy Centre, Odense University Hospital, Institute of Clinical Research,
Faculty of Health Sciences, University of Southern Denmark, Sdr. Boulevard 29, 5000 Odense C, Denmark
6
Department of Neurology, Odense University Hospital, Institute of Clinical Research, Faculty of Health
Sciences, University of Southern Denmark, Sdr. Boulevard 29, 5000 Odense C, Denmark
22nd June 2014
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DATASOURCES
Our study was based on information from the following nationwide Danish registries: the Danish
Cancer Registry (DCR) (Gjerstorff 2011), the Danish Civil Registration System (Pedersen 2011),
the Danish National Prescription Registry (Kildemoes 2011), the Danish National Patient Register
(DNPR) (Lynge 2011), and registries in Statistics Denmark (Thygesen 2011, Thygesen 2014).
Cancer diagnoses in the DCR are recorded according to the International Classification of
Diseases, version 10 (ICD-10), and the ICD for Oncology (ICD-O-3) for topography and
morphology codes. Linkage to the Danish Pathology Registry has ensured a virtually complete
registration of BCC in the DCR since 2004 (Bjerregaard 2011). Diagnoses of BCC and SCC were
ascertained on the basis of the ICD-10 diagnosis for NMSC and the specific ICD-O-3 codes for
SCC and BCC (Code list).
Controls were selected from the entire Danish population using the Civil Registration System
(Pedersen 2011) and risk-set sampling (Rothman 2008), i.e., the controls had to be alive and at risk
for a first diagnosis of BCC/SCC at the time the corresponding case was diagnosed (index date).
The Civil Registration System is continuously updated and includes data on vital status and
migration.
Information on highest educational level achieved by study subjects according to annually
updated information was retrieved from registries at Statistics Denmark (Jensen 2011).
Information on use of statins and other drugs was obtained from the National Prescription
Registry, which contains information on all prescriptions dispensed at community pharmacies in
Denmark since 1995 (Kildemoes 2011). For each prescription, the Prescription Registry records
date and a full description of the dispensed product, including the anatomical therapeutic code
(ATC) (WHO 2012) and the number of defined daily doses (DDD) in each package. One DDD
represents the typical daily dose required by an adult when the drug is used for its main indication
(WHO 2012). Drugs used for the same indication are thus in principle equipotent when measured in
DDD.
DRUG EXPOSURE CLASSIFICATION
We retrieved prescription data from 1995 to the index date for both cases and controls. In the
main analyses, we evaluated statin use in a 10-year time-window prior to the index date. We disregarded statin prescriptions redeemed within the last year before the index date, in order to avoid
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potential selective prescribing of statins among cases close to the NMSC diagnosis (Rothman
2008). Based on the number of statin prescriptions dispensed during the 10-year period (i.e., 1-10
years) prior to index date, statin use was classified as ever use (≥2 statin prescriptions; ATC group
C10AA) or non-use (0 or 1 prescription for statins). We further defined duration of statin use based
on the dates of prescription and number of days covered by the individual prescriptions. The
coverage of each prescription was calculated as the sum of tablets for the prescription plus a grace
period of 25% of the dispensed tablets. We used the sum of tablets as this measure has been shown
to concord highly with the prescribed daily dose for statins (Kanstrup 2004). The grace period was
introduced to allow some degree of non-compliance. The arbitrarily chosen length of the grace
period corresponds to an approximate adherence of 80%. A continuous treatment period lasted for
as long as consecutive prescriptions were presented within the time-window defined by the
coverage of the preceding prescription. For study subjects with more than one treatment period, the
durations of separate treatment periods were added. The cumulative duration of use was categorised
into four mutually exclusive strata: <1, 1 to <3, 3 to <5, and ≥5 years. We also classified statin use
by the total number of DDDs presented during the 10-year period prior to the index date: 1-199,
200-499, 500-999, 1000-1999, ≥2000 DDD. We defined intensity of statin use as the cumulative
number of DDDs of statins prescribed to a study subject divided by the number of days between the
first and last eligible statin prescription plus 60 days. Furthermore, we classified statins as lipophilic
(simvastatin, lovastatin, fluvastatin, atorvastatin, and cerivastatin) and hydrophilic (pravastatin and
rosuvastatin).
Exposure to the potential confounder drugs was defined as ≥2 prescriptions during the 10-year
time period prior to the index date, with the exception of non-aspirin NSAID use, which was
classified in three categories, i.e., non-use (0-1 prescriptions), low use (2-9 prescriptions), or high
use (≥10 prescriptions).
SUPPLEMENTARY ANALYSES
We performed a number of supplementary analyses in which we:
(i) stratified by gender, age, and NSAID use to explore possible effect measure modification,
(ii) restricted the sample to subjects with index dates during 2008-2009, thus expanding the
exposure period to 12 years prior to index date and examining effects of long-term statin
exposure defined as 5+ years and 10+ years,
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(iii) evaluated the influence of i) including exposure within one year prior to index date and ii)
expanding the lag-period to 2 years prior to index date.
All analyses were performed using Stata Release 13.0 (StataCorp, College Station, TX, USA). The
study was approved by the Danish Data Protection Agency and Statens Serum Institut. Ethical
approval is not required for purely registry based studies according to Danish law (Thygesen 2011).
SUPPLEMENTARY REFERENCES
Bjerregaard B, Larsen OB (2011) The Danish Pathology Register. Scand J Public Health
39(Suppl): 72-4
Jensen VM, Rasmussen AW (2011) Danish education registers. Scand J Public Health 39(7 Suppl):
91-94
Kanstrup H, Lassen JF, Heickendorff L, Lauritzen T, Larsen ML (2004) Quality of lipid-lowering
therapy in patients with ischaemic heart disease: a register-based study in 3477 patients. J Intern
Med 255: 367-372
Kildemoes HW, Toft Sørensen H, Hallas J (2011) The Danish National Prescription registry. Scand
J Public Health 39(7 Suppl): 38–41
Lynge E, Sandegaard JL, Rebolj M (2011) The Danish National Patient Register. Scand J Public
Health 39(7 Suppl): 30–33
Thygesen LC, Daasnes C, Thaulow I, Brønnum-Hansen H (2011) Introduction to Danish
(nationwide) Registers on Health and Social Issues: Structure, Access, Legislation, and Archiving.
Scandinavian Journal of Public Health 39(7 Suppl): 12–16
Thygesen LC, Ersbøll AK (2014) When the entire population is the sample: strengths and
limitations in register-based epidemiology. Eur J Epidemiol DOI: 10.1007/s10654-013-9873-0
[Epub ahead of print]
WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and
DDD assignment, 2013. Oslo, 2012
4
CODE LIST
Cancer codes
ICD-10
C44 – Non-melanoma skin cancer
ICD-0-3 morphology
Basal cell carcinoma
80903, 80913, 80923, 80933, 80943, 80953, 80973, 80983
Squamous cell carcinoma
80513, 80703, 80713, 80723, 80733, 80743, 80753, 80763, 80783, 80833, 80843
ATC codes
Statins
C10AA01 - Simvastatin
C10AA02 – Lovastatin
C10AA03 – Pravastatina
C10AA04 - Fluvastatin
C10AA05 – Atorvastatin
C10AA06 – Cerivastatin
C10AA07 – Rosuvastatina
Other drugs (covariates)
Aspirin – low-dose
B01AC06 – acetylsalicylic acid (75 mg, 100 mg, or 150 mg per tablet)
B01AC30 – acetylsalicylic acid (50 mg per tablet) in combination with dipyridamole
Non-aspirin nonsteroidal anti-inflammatory drugs
M01A (including Cox2 inhibitors), excluding M01AX
Antidiabetics
A10
Diuretics
C03A, C03EA01, C03EA13, C07B, C07D, C09BA, C09DA, C09XA52,
C09XA54 – thiazides
C03CA01 C03EB01 C03CA02 C03EB02 C03EA01 C03DA01 – other diuretics
Immunosuppressants
H02AB06 H02AB07 – glucocorticoids
L04AX01 – azathioprine
L01AA01, L04AA06, L04AD01, L04AD02, L04AX03 – other immunosuppressants
Hormone replacement therapy
G03CA03 G03CA04 G03CA53 G03CA57 G03CB01 G03CX01
G03FA01 G03FA12 G03FA10 G03FA11 G03FA15 G03FA17
G03FB11 G03FB05 G03FB06 G03FB01 G03FB09
G03DC02 G03DA02 G03DA04 G03DB08 G03DB01 G03DC03
Amiodarone
C01BD01
Antipsoriatics for topical use
D05AX
Hospital discharge codes
Diabetes
ICD-8: 249, 250
ICD-10: E10-E14
COPD
ICD-8: 49000 49100 49101 49103
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ICD-10: J42 J43 J44
Atopic dermatitis
ICD-8: 691
ICD-10: L20
Psoriasis
ICD-8: 69609 69610 69619
ICD-10: L40 M070 M071 M072 M073
Connective tissue disease (rheumatoid arthritis and other inflammatory polyarthropathies, polymyalgia
rheumatica, diffuse connective disease, sarcoidosis)
ICD-8: 135.99, 446, 712, 716, 734
ICD-10: D86, M05, M06, M08, M09, M30-M36
Moderate to severe renal disease (glomurelonephritis, nephropathies, and end-stage renal disease)
ICD-8: 403, 404, 580-583, 590.09, 593.19, 753.10-753.19, 792
ICD-10: I12, I13, N00-N05, N07, N11, N14, N17-N19, Q61
Organ transplant recipients
ICD-8 or NCSPb: Y9509, or NCSP procedure: 32209, 32219, 32229, 32240, 32250, 35609,
47270, 47279, 48840, 48849, 57480, 57490
ICD-10 or NCSPb: DZ940- DZ944, DZ948, DZ949 or NCSP procedure: KGDG, KFQA,
KFQB, KJJC, KJLE, KKAS
a
Classified as hydrophilic; other statins classified as lipophilic.
b
Nordic Classification of Surgical Procedures (NCSP) code.
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SUPPLEMENTARY TABLES
eTable 1. Characteristics of non-melanoma skin cancer cases and their matched controls
Gender
Male
Female
Age, median (interquartile range)
Schooling, number of years
7-10
11-12
≥13
Missing
History of a
Diabetesb
Psoriasisb
Atopic dermatitis
COPD
Connective tissue disease
Kidney disease
Charlson Comorbidity Index (CCI) score
0
1
2
≥3
Drug usec
Statin
Glucocorticoid
Azathioprine
Other immunosuppressant
Amiodarone
Thiazides
Other diuretics
Hormone replacement therapy
Aspirin, low-dose
Non-aspirin NSAID, number of
prescriptions
0-1
2-9
10+
Basal cell carcinoma
Cases
Controls
(n=38,484)
(n=384,756)
Squamous cell carcinoma
Cases
Controls
(n=3,724)
(n=37,188)
18,136 (47.1)
20,348 (52.9)
66 (57 - 76)
181,320 (47.1)
203,436 (52.9)
66 (57 - 76)
2,144 (57.6)
1,580 (42.4)
77 (67 - 84)
21,411 (57.6)
15,777 (42.4)
77 (67 - 84)
11,553 (30.0)
14,574 (37.9)
9,807 (25.5)
2,549 (6.6)
146,154 (38.0)
135,136 (35.1)
76,543 (19.9)
26,913 (7.0)
1,449 (38.9)
1,022 (27.4)
573 (15.4)
680 (18.3)
14,533 (39.1)
10,464 (28.1)
5,289 (14.2)
6,902 (18.6)
2,279 (5.9)
363 (0.9)
63 (0.2)
1,553 (4.0)
1,497 (3.9)
665 (1.7)
28,173 (7.3)
2,589 (0.7)
605 (0.2)
17,504 (4.5)
12,969 (3.4)
6,075 (1.6)
404 (10.8)
42 (1.1)
12 (0.3)
275 (7.4)
207 (5.6)
123 (3.3)
3,364 (9.0)
231 (0.6)
35 (0.1)
2,379 (6.4)
1,573 (4.2)
887 (2.4)
28,247 (73.4)
6,578 (17.1)
2,046 (5.3)
1,613 (4.2)
277,142 (72.0)
67,362 (17.5)
21,987 (5.7)
18,265 (4.7)
2,134 (57.3)
920 (24.7)
351 (9.4)
319 (8.6)
23,110 (62.1)
8,231 (22.1)
3,222 (8.7)
2,625 (7.1)
6,744 (17.5)
2,457 (6.4)
214 (0.6)
536 (1.4)
197 (0.5)
10,060 (26.1)
4,475 (11.6)
7,396 (19.2)
8,021 (20.8)
66,148 (17.2)
23,151 (6.0)
1,179 (0.3)
3,652 (0.9)
1,844 (0.5)
98,590 (25.6)
46,848 (12.2)
59,873 (15.6)
81,116 (21.1)
778 (20.9)
367 (9.8)
41 (1.1)
71 (1.9)
25 (0.7)
1,454 (39.0)
1,024 (27.5)
537 (14.4)
1,286 (34.5)
7,176 (19.3)
3,036 (8.2)
94 (0.3)
363 (1.0)
261 (0.7)
12,600 (33.9)
7,109 (19.1)
4,728 (12.7)
12,233 (32.9)
20,957 (54.5)
13,118 (34.1)
4,409 (11.5)
213,723 (55.5)
127,221 (33.1)
43,812 (11.4)
1,951 (52.4)
1,276 (34.3)
497 (13.3)
20,310 (54.6)
11,760 (31.6)
5,118 (13.8)
a
Based on Patient Registry data.
Based on Patient and Prescription Registry data.
c
Based on Prescription Registry data.
b
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eTable 2. Long-term exposure to statins (≥5 years) and risk of NMSC stratified by age and gender.
Cases
Controls
Exposed/Unexposed
Exposed/Unexposed
Adj ORa (95% CI)
– model 1
Adj ORb (95% CI)
– model 2
Basocellular carcinoma
All
1,418 / 31,740
13,806 / 318,608 1.04 (0.98-1.10)
1.10 (1.03-1.17)
Gender
Male
824 / 14,427
8,107 / 145,612
1.03 (0.96-1.12)
1.07 (0.98-1.16)
Female
594 / 17,313
5,699 / 172,996
1.04 (0.95-1.14)
1.14 (1.04-1.25)
Age group, years
<60
88 / 11,368
1,040 / 112,722
0.84 (0.68-1.05)
0.96 (0.76-1.21)
60-75
741 / 12,303
7,437 / 122,799
1.01 (0.93-1.09)
1.10 (1.00-1.20)
≥75
589 / 8,069
5,329 / 83,087
1.13 (1.03-1.24)
1.16 (1.06-1.28)
Squamous cell carcinoma
All
171 / 2,946
1,573 / 30,012
1.14 (0.96-1.35)
1.02 (0.85-1.22)
Gender
Male
108 / 1,648
1,080 / 16,792
1.05 (0.85-1.30)
0.95 (0.75-1.19)
Female
63 / 1,298
493 / 13,220
1.32 (1.00-1.75)
1.08 (0.88-1.58)
Age group, years
<60
7 / 321
44 / 3,357
1.69 (0.75-3.84)
0.99 (0.37-2.64)
60-75
65 / 966
632 / 9,731
1.08 (0.83-1.42)
0.93 (0.69-1.26)
≥75
99 / 1,659
897 / 16,924
1.15 (0.92-1.44)
1.07 (0.84-1.35)
a
Adjusted for age and gender
b
Adjusted for age, gender, years of schooling, history of atopic dermatitis, psoriasis, COPD, diabetes, CCIscore, and use of systemic glucocorticoids, azathioprine, other immunosuppressants, thiazides, other
diuretics, hormone replacement therapy, amiodarone, low-dose aspirin, or non-aspirin NSAID drugs
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