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Statin use and risk for ovarian cancer: a Danish nationwide casecontrol study
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Data sources
Supplementary analyses
Supplementary references
Supplementary Tables 1 and 2
Louise Baandrup1, Christian Dehlendorff1, Søren Friis1, Jørgen H. Olsen1 and
Susanne K. Kjær1,2
1
Danish Cancer Society Research Centre, Danish Cancer Society, Copenhagen, Denmark
2
The Gynaecologic Clinic, Juliane Marie Centre, Rigshospitalet, University of Copenhagen,
Denmark
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Data sources
The Danish Cancer Registry (Gjerstorff, 2011) has recorded incident cancers on a
nationwide basis since 1943 and ensures accurate and virtually complete ascertainment of
cancer cases. Cancer diagnoses 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.
The Civil Registration System (Pedersen, 2011) contains continuously updated information
on date of birth, death, emigration and changes in address for all Danish residents from 1968
to the present.
The Danish Prescription Registry (Kildemoes et al, 2011) holds detailed information on all
prescription drugs dispensed at pharmacies in Denmark since 1995. The data include type
of drug according to the Anatomical Therapeutic Classification (ATC) (WHO, 2011), quantity
dispensed and date of dispensing. Dosing schedule and indication(s) are not available. The
quantity of each prescription is given as the strength and number of the pharmaceutical entity
(typically tablets) and the defined daily dose (DDD) (WHO, 2011).
The National Patient Register (Lynge et al, 2011) contains information on all hospitalizations
for somatic conditions since 1977 and all outpatient consultations since 1995. Diagnoses are
coded according to the ICD-8 from 1977–1993, and ICD-10 from 1994 onwards. Surgical
procedures are classified according to the Danish Classification of Surgical Procedures and
Therapies (Danish Board of Health, 1973) until the end of 1995 and thereafter according to
the Nordic Classification of Surgical Procedures (NOMESCO).
Registries in Statistics Denmark on education and income (Baadsgaard et al, 2011; Jensen
et al, 2011)
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The Danish Fertility Database (Blenstrup et al, 2011) contains data on reproductive variables
for all women in Denmark aged 13–49 years from 1980 to the present.
Supplementary analyses
Stratification according to type of statin (lipophilic / hydrophilic)
Among all statin users, 87.6% were exclusive users of lipophilic statins and 12.4% were ever
users of hydrophilic statins. Restricting the overall analyses to exclusive use of lipophilic
statins yielded risk estimates of epithelial ovarian cancer and histological types close to those
of the main analysis (Supplementary Table 2). Likewise, the odds ratios (ORs) for epithelial
and serous ovarian cancer according to duration and intensity of exclusive lipophilic statin
use were also similar to those of the main analysis (data not shown). Ever use of hydrophilic
statins was associated with ORs for epithelial and serous ovarian cancer of 1.08 (95%
confidence interval (CI) =0.82–1.42) and 1.24 (95% CI=0.91–1.69), respectively (data not
shown). The low prevalence of hydrophilic statin use precluded meaningful evaluation of
duration, intensity and associations with the three other histological types.
Family history of ovarian and breast cancer
Using the Civil Registration System (Pedersen, 2011) and the Danish Cancer Registry
(Gjerstorff, 2011), we assessed the family history of ovarian and breast cancer for women
born after 1953. Within the subgroup of these women, additional adjustment for family history
of ovarian or breast cancer did not materially change the ORs for epithelial ovarian cancer
associated with statin use (data not shown).
Oral contraceptives and hormonal replacement therapy
Elderly women in our study population might have been misclassified as non-users of oral
contraceptives and hormonal replacement therapy (HRT) if they had used these agents
before 1995. We repeated the analyses with restriction to women born after 1953, i.e.,
women aged 42 years or younger in 1995, for whom we assumed to have complete
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information on HRT use and fair information on oral contraceptive use. The results of this
sensitivity analysis were close to those of the main analyses, indicating that residual
confounding by use of these agents did not constitute a major limitation of our study.
Stratification by age and menopausal status
We evaluated potential effect measure modification by age in five age categories (30–39,
40–49, 50–59, 60–69, and 70–84) and of menopausal status (“pre/perimenopausal”, ≤ 50
years; “postmenopausal”, > 50 years) by including interaction terms between statin use and
age or menopausal status, respectively. We found no statistical significant interactions (on
multiple scales) with age (p interaction = 0.26) or menopausal status (p interaction = 0.33).
Stratification by history of ischaemic cardio- or cerebrovascular disease
We also evaluated potential effect measure modification by history of ischaemic cardio- or
cerebrovascular disease. Ever use of statins was associated with a slightly higher OR for
epithelial ovarian cancer among women with a history of ischaemic cardio- or
cerebrovascular disease (OR=1.23, 95% CI=0.98–1.55) as compared with women without
such history (OR=0.96, 95% CI=0.83–1.10) (p interaction = 0.06) (data not shown). We have
no ready explanation for this finding. Additional evaluation of these results might have been
possible in a comparison of statin use with use of non-statin lipid-lowering drugs (Friis et al,
2005), however, use of the latter declined dramatically during the study period, and the
statistical precision of this comparison was too poor to provide meaningful results.
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Supplementary references
Baadsgaard M, Quitzau J (2011) Danish registers on personal income and transfer
payments. Scand J Public Health 39(7 Suppl): 103–105,
doi:10.1177/1403494811405098
Blenstrup LT, Knudsen LB (2011) Danish registers on aspects of reproduction. Scand J
Public Health 39(7 Suppl): 79–82, doi:10.1177/1403494811399957
Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, de Craen AJ, Knopp
RH, Nakamura H, Ridker P, van Domburg R, Deckers JW (2009) The benefits of
statins in people without established cardiovascular disease but with cardiovascular
risk factors: meta-analysis of randomised controlled trials. BMJ 338: b2376,
doi:10.1136/bmj.b2376
Danish Board of Health. Operations- og behandlingsklassifikation [Danish Classification of
Surgical Procedures and Therapies] (1973, 1980, 1988). Schultz Grafisk A/S:
Copenhagen, 1st, 2nd, 3rd edn.
Friis S, Poulsen AH, Johnsen SP, McLaughlin JK, Fryzek JP, Dalton SO, Soerensen HT,
Olsen JH (2005) Cancer risk among statin users: a population-based cohort study. Int
J Cancer 114: 643–647, doi:10.1002/ijc.20758
Gjerstorff ML (2011) The Danish Cancer Registry. Scand J Public Health 39(7 Suppl): 42–45,
doi:10.1177/1403494810393562
Jensen VM, Rasmussen AW (2011) Danish Education Registers. Scand J Public Health 39(7
Suppl): 91-94, doi:10.1177/1403494810394715
Kildemoes HW, Sorensen HT, Hallas J (2011) The Danish National Prescription Registry.
Scand J Public Health 39(7 Suppl): 38–41, doi:10.1177/1403494810394717
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Lynge E, Sandegaard JL, Rebolj M (2011) The Danish National Patient Register. Scand J
Public Health 39(7 Suppl): 30–33, doi:10.1177/1403494811401482
NOMESCO. Nordic Classification of Surgical Procedures. Available at
http://medinfo.dk/sks/brows/php
Pedersen CB (2011) The Danish Civil Registration System. Scand J Public Health 39(7
Suppl): 22–25, doi: 10.1177/1403494810387965
WHO (2010) Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC
Classification and DDDs Assignment 2011: Oslo
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Supplementary Table 1. Codes used in the analysis a
The Danish Cancer Register
ICD-10
Ovarian cancer
DC56
ICD-O-3
Serous ovarian cancer
84413, 84603, 84613, 90143
Mucinous ovarian cancer
84703, 84713, 84803, 84813, 90153
Endometroid ovarian cancer
83803, 83813, 85703, 89333, 89803
Clear cell ovarian cancer
83103, 83133, 84903
Danish Prescription
Registryb
Anathomical Therapeutic Classification codes
Lipophilic statins
Simvastatin
C10AA01
Lovastatin
C10AA02
Fluvastatin
C10AA04
Atorvastatin
C10AA05
Cerivastatin
C10AA06
Hydrophilic statins
Pravastatin
C10AA03
Rosuvastatin
C10AA07
Other drugs
Paracetamol
N02BE01
Low-dose aspirin
B01AC06
Oral contraceptives
G03A
Hormonal replacement therapy
G03C, G03D, G03F, G03HB01
Fertility drugsc
G03DA04, G03GA, G03GB02
Antidiabeticsc
A10A, A10B
National Patient Registry: hospital discharge codes
ICD-8 (1977–1993)
Infertilityc
628
Endometriosis
625.29–625.39
Diabetes mellitusc,d
Chronic obstructive pulmonary disease or
249, 250
asthmad
Ischaemic cardiovascular and cerebrovascular
491–493
disease d
410–414, 431–434, 440
ICD-10 (since 1994)
Infertilityc
N97
Endometriosis
Diabetes
N80
mellitusc,d
E10–E14
Chronic obstructive pulmonary disease or asthmad
Ischaemic cardiovascular and cerebrovascular
J41–46
diseased
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I20, I21, I23–I25, I61, I63, I64
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Supplementary Table 1. Codes used in the analysis (continued) a
National Patient Registry: procedure codes
Danish Classification of Surgical Procedures and Therapies (1977–1995):
Bilateral oophorectomy and salpingo-oophorectomy
60120, 60320
Tubal sterilization
60800, 60810, 60820, 60830, 60840
Hysterectomi
61000, 61020, 61040, 61100
Nordic Classification of Surgical Procedures (since 1996):
Bilateral oophorectomy and salpingo-oophorectomy
LAE20, LAE21, LAF10, LAF11
Tubal sterilization
Hysterectomi
LGA
KLCC10, KLCC11, KLCC20, KLCD00, LCD01,
KLCD04, KLCD10, KLCD11, KLCD30, KLCD31,
KLCD40, KLCD96, KLCD97, KLCE00, KLCE10,
KLCE20, KLCE96, KLEF13, KMCA33
Abbreviations: ICD = International Classification of Diseases; NSAIDs = nonsteroidal anti-inflammatory drugs.
a
All variables were defined 1 year before index date
b
Use was defined as ≥ 2 prescriptions on separate dates
c
A history of infertility or diabetes mellitus was defined as a composite measure of the hospital diagnosis and / or
prescription(s) for fertility drugs or antidiabetics.
d
The exposure window for the comorbid conditions was left truncated to 23 years before the index date to obtain the same
length of hospital history for all women in the study.
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Supplemetary Table 2. Risk for epithelial ovarian cancer and histological types by ever use of lipophilic
statins exclusively
Histological type by statin
use
Cases
Controls
3669
52 261
375
5646
2411
34 513
273
3998
593
8306
52
866
434
6023
25
476
231
3419
25
306
Age-matched OR
(95% CI)
Adjusted ORa
(95% CI)
Epithelial ovarian cancer
Non-use
Exclusive lipophilic statin use
b
1.00 (referent)
1.00 (referent)
0.94 (0.84–1.05)
0.97 (0.86–1.10)
1.00 (referent)
1.00 (referent)
0.97 (0.85–1.11)
1.00 (0.87–1.16)
1.00 (referent)
1.00 (referent)
0.83 (0.61–1.12)
0.83 (0.60–1.16)
1.00 (referent)
1.00 (referent)
0.69 (0.45–1.07)
0.72 (0.45–1.14)
1.00 (referent)
1.00 (referent)
1.29 (0.81–2.06)
1.42 (0.84–2.39)
Serous ovarian cancer
Non-use
Exclusive lipophilic statin useb
Endometroid ovarian cancer
Non-use
Exclusive lipophilic statin use
b
Mucinous ovarian cancer
Non-use
Exclusive lipophilic statin use
b
Clear cell ovarian cancer
Non-use
Exclusive lipophilic statin useb
Abbreviations: OR = odds ratio; CI = confidence interval
a
Adjusted for age (by matching), parity (0, 1, 2, ≥ 3), infertility (ever/never), endometriosis (ever/never), diabetes mellitus
(ever/never), chronic obstructive pulmonary disease or asthma (ever/never), hysterectomy (ever/never), tubal sterilization
(ever/never), education (basic, higher, vocational, unknown), income (low, medium, high), and use of oral contraceptives
(ever/never), hormonal replacement therapy (ever/never), paracetamol (ever/never), and low-dose aspirin (ever/never).
b
Among all statin users, 87.5% were users of exclusive lipophilic statins. Lipophilic statins include Simvastatin (C10AA01),
Atorvastatin (C10AA05), Lovastatin (C10AA02), Fluvastatin (C10AA04), and Cerivastatin (C10AA06).
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