RESEARCH ARTICLE Open Access
P os a e cance -speci ic su i al among
wa a in use s in he Finnish Randomized
S udy o Sc eening o P os a e Cance
Pe e T. T. Kinnunen
1*
, Teemu J. Mu ola
1,2
, Ki si Talala
3
, Kimmo Taa i
4
, Teu o L. J. Tammela
1,2
and Anssi Au inen
5
Abs ac
Backg ound: Venous h omboembolic e en s (VTE) a e common in cance pa ien s and associa ed wi h highe
mo ali y. In i o h ombosis and an icoagula ion migh be in ol ed in umo g ow h and p og ession. We s udied
he associa ion o wa a in and o he an icoagulan use as an i h ombo ic medica ion and p os a e cance (PCa)
dea h in men wi h he disease.
Me hods: The s udy included 6,537 men diagnosed wi h PCa du ing 1995-2009. In o ma ion on an icoagulan use
was ob ained om a na ional eimbu semen egis y. Cox eg ession wi h adjus men o age, PCa isk g oup,
p ima y he apy and use o o he medica ion was pe o med o compa e isk o PCa dea h be ween wa a in use s
wi h 1) men using o he ypes o an icoagulan s and 2) non-use s o an icoagulan s. Medica ion use was analyzed
as a ime-dependen a iable o minimize immo al ime bias.
Resul s: In o al, 728 men died om PCa du ing a median ollow-up o 9 yea s. Compa ed o an icoagulan non-
use s, pos -diagnos ic use o wa a in was associa ed wi h an inc eased isk o PCa dea h (o e all HR 1.47, 95% CI 1.
13-1.93). Howe e , his was limi ed o low-dose, low-in ensi y use. O he wise, he isk was simila o an icoagulan
non-use s. Addi ionally, we ound no isk di e ence be ween wa a in and o he ypes o an icoagulan s.
P e-diagnos ic use o wa a in was no associa ed wi h he isk o PCa dea h.
Conclusions: We ound no educ ion in isk o PCa dea h associa ed wi h wa a in use. Con e sely, he isk was
inc eased in sho - e m use, which is p obably explained by a highe isk o h ombo ic e en s p omp ing wa a in
use in pa ien s wi h e minal PCa.
Keywo ds: P os a e cance , Wa a in, An icoagulan , Su i al, Coho
Backg ound
Venous h omboembolism (VTE) has been p oposed as
p ognos ic ac o in p os a e cance (PCa). VTE is
common in cance pa ien s and associa ed wi h poo
p ognosis, isk o dea h is 8- old highe in cance pa ien
wi h VTE [1–3]. This applies o PCa as well [4].VTE in
PCa pa ien s has been associa ed wi h mo e han 6- old
mo ali y in bo h symp oma ic and inciden al enous
h omboembolic diseases [5]. Thus,an icoagulan d ugs
could ha e an impac on PCa p ognosis by educing
dea hs om VTE.Fu he mo e, an icoagulan s, including
wa a in, ha e shown p omising an i umo p ope ies
in i o [6–10] mainly in lung and b eas cance .
P e ious ai ly small s udies on an icoagulan use and
PCa su i al ha e epo ed di e ing esul s [11–13]. A
po en ial explana ion could be con ounding by indica-
ion; pa ien s wi h an ad anced cance a e a inc eased
isk o VTE [14], hus mo e o en p esc ibed an icoagu-
lan s compa ed o people wi hou cance . We conduc ed
a e ospec i e, popula ion-based coho s udy o assess
he associa ion o p e- and pos -diagnos ic use o
wa a in and o he an icoagulan s wi h PCa su i al in
he Finnish Randomized S udy o Sc eening o P os a e
Cance (FinRSPC) [15].
* Co espondence: [email p o ec ed]
1
Uni e si y o Tampe e, Facul y o Medicine and Li e Sciences, Tampe e,
Finland
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Kinnunen e al. BMC Cance (2017) 17:585
DOI 10.1186/s12885-017-3579-8
Me hods
S udy coho
FinRSPC includes 80,458 men aged 55-67 yea s a base-
line (i.e. a FinRSPC andomiza ion). A e exclusion o
p e alen PCa cases, he men we e andomized du ing
1996-1999 ei he o PSA sc eening a ou -yea in e als
( he sc eening a m) o o no in e en ion ( he con ol
a m). All men we e ollowed ia Finnish Cance Regis y,
which co e s 99% o cance s diagnosed in Finland [16].
This s udy included 6,537 inciden PCa cases diagnosed
du ing 1996-2013. Clinical in o ma ion included Gleason
g ade and TNM s age (a ailable o 97.3% and 97.7% o
he cases, espec i ely).
PCa cases we e s a i ied in o low/in e media e- isk
and high- isk g oups acco ding o he de ini ion o he
Eu opean Associa ion o U ology (EAU) [17]. All M1
cases we e included in he high- isk g oup.
In o ma ion on dea hs was ob ained om he S a is ics
Finland, which assigns o icial causes o dea h based on
manda o y dea h ce i ica es, co e ing all dea hs in
Finland [18]. The accu acy o in o ma ion on PCa dea hs
was asce ained by he FinRSPC cause o dea h commi -
ee wi h an excellen conco dance be ween o icial
causes o dea h and he cause o dea h commi ee
assignmen s o PCa (kappa 0.95) [15]. Only dea hs wi h
PCa (ICD-10 code C61) as he p ima y cause o dea h
we e ega ded as PCa dea hs.
A sensi i i y analysis wi h PCa as an in e media e
cause o dea h was also pe o med.
In o ma ion on an icoagulan usage
In o de o ob ain in o ma ion on an icoagulan d ug
pu chases du ing 1995-2009, he s udy coho was
linked o a na ional medica ion eimbu semen da abase
main ained by he Finnish Social Insu ance Ins i u ion
(SII) using he unique pe sonal iden i ica ion code as he
key. As a pa o he na ional heal h insu ance ha
co e s all Finnish ci izens, SII p o ides eimbu semen s
o pu chases o physician-p esc ibed d ugs [19].The e-
imbu semen is 50-100 % depending on he indica ion
and se e i y o he condi ion. In Finland, an icoagulan
d ugs a e a ailable only h ough physicians’p esc ip-
ion, hus all an icoagulan pu chases in ou pa ien se -
ing a e egis e ed by he da abase. D ugs used du ing
hospi al inpa ien pe iods a e no egis e ed.
All 13 an icoagulan d ugs used in ou pa ien se ing
du ing he s udy pe iod we e iden i ied based on hei
ATC codes (Addi ional ile 1: Table S1). Addi ionally, we
ob ained in o ma ion on choles e ol-lowe ing d ugs,
an idiabe ic and an ihype ensi e d ugs, aspi in and
o he NSAIDs and alpha-blocke s. We also collec ed
in o ma ion on p ima y he apy o PCa ( adical p os a-
ec omy, ex e nal beam adia ion he apy (EBRT), ho -
monal he apy o ac i e su eillance/wa ch ul wai ing).
O he medica ion se ed as a p oxy o co-mo bidi ies,
as hey may in luence su i al [20–25].
The in o ma ion om he Na ional Ca e Regis e o
Heal h Ca e main ained by he Na ional Ins i u e o
Heal h and Wel a e included p o ided diagnoses o
condi ions se ing as indica ions o an icoagulan use:
a ial ib illa ion (ICD-10: I48), enous h omboembol-
ism (all eco ded I82 diagnoses in he s udy popula ion),
pulmona y embolism (ICD-10: I26.0, I26.9) and h om-
bocy osis. The egis e co e s all o Finland and egis e s
all diagnoses made du ing in- and ou -pa ien hospi al
isi s du ing 1996-2014, bu does no co e diagnoses
om p ima y ca e [26]. Addi ionally, we s a i ied he
analysis by Cha lson Como bidi y Sco e [27] calcula ed on
basis o he egis e ed diagnoses o subg oup analysis.
S a is ical analysis
Cox p opo ional haza ds eg ession was used o calcu-
la e haza d a ios (HR) and 95% con idence in e als
(CIs) o PCa dea h. Follow-up s a ed a PCa diagnosis
and con inued un il dea h, emig a ion om Finland o
Janua y 1
s
, 2015, whiche e was i s . Time me ic was
yea s and mon hs since he PCa diagnosis.
We used wo di e en model adjus men s. The i s
Cox eg ession model was adjus ed o age only and he
second o age, EAU umo isk g oup and o he
medica ions. The analysis was pe o med sepa a ely o
p e-diagnos ic and pos -diagnos ic use o wa a in and
addi ionally o o he ypes o an icoagulan s. Sepa a e
compa isons we e pe o med be ween all an icoagulan
use s and non-use s o es ima e he o e all e ec o
an icoagulan usage, and be ween wa a in use s and
men using non-wa a in an icoagulan s o es ima e
speci ic e ec s o wa a in wi h simul aneous con ol o
con ounding by indica ion.
Fo each man in he s udy coho , he o al annual
amoun o medica ion pu chases was calcula ed o each
calenda yea , and hen sepa a ely o p e- and pos -
diagnos ic use. S anda diza ion o doses be ween di e -
en an icoagulan s was pe o med by di iding he annual
o al millig am amoun wi h he s anda d De ined Daily
Dose (DDD) as lis ed by he WHO [28]. Each yea wi h
egis e ed an icoagulan pu chases, ega dless o he
amoun , was conside ed a yea o usage. The in ensi y o
he use was calcula ed by di iding he cumula i e annual
doses wi h he numbe o yea s o usage.
P e-diagnos ic medica ion use was analyzed as a ime-
independen a iable, and cumula i e p e-diagnos ic
an icoagulan usage beginning om 1995 was s a i ied
by e iles. Pos -diagnos ic use was analyzed as a ime-
dependen a iable; he usage s a us and cumula i e use
we e upda ed sepa a ely o each yea o ollow-up,
beginning om he yea o diagnosis.
Kinnunen e al. BMC Cance (2017) 17:585 Page 2 o 9
All men we e ca ego ized as non-use s un il he
po en ial i s an icoagulan pu chase. A e he i s
pu chase, he s a us was changed in o a use , which was
main ained o each yea wi h eco ded pu chases. Men
who discon inued he pu chases du ing he ollow-up
we e kep as e e -use s. In analysis o wa a in use s
compa ed o non-wa a in use s, men we e ca ego ized
as wa a in use s each yea wi h eco ded wa a in
pu chases, e en i hey had used o he ypes o an icoag-
ulan s. Only o yea s wi h eco ded an icoagulan
pu chases wi hou wa a in use, we e hey eco ded as
non-wa a in use s.
Long- e m impac o iming o pos -diagnos ic an i-
coagulan use was e alua ed in lag- ime analysis, whe e
an icoagulan exposu e was lagged 1 o 3 yea s o wa d
om he ac ual yea o usage i.e. i s e ec was igno ed
o ha du a ion om he i s exposu e.
Compe ing isks analysis using Fine and G ay
eg ession me hod wi h non-PCa dea h and majo
h omboembolic diseases as he compe ing cause o
dea h was pe o med.
All s a is ical analyses we e ca ied ou using IBM
SPSS S a is ics 22.0. All s a is ical es s a e wo-sided.
Resul s
Popula ion cha ac e is ics
Du ing he median ollow-up o 9 yea s a e PCa diag-
nosis 2,296 men died, o whom 728 om PCa (Table 1).
The median ollow-up om he diagnosis o PCa dea h
was 3.9 yea s among men wi h no pos -diagnos ic an i-
coagulan use, 4.8 yea s among wa a in use s and 5.8
yea s in use s o o he an icoagulan s. High-g ade
cance s we e almos equally dis ibu ed in hese sub-
ca ego ies. Dis ibu ion o backg ound cha ac e is ics
a e p esen ed in Table 1.
Risk o PCa dea h by p e-diagnos ic use o wa a in and
o he an icoagulan s
In gene al, when compa ed o an icoagulan non-use s,
he e was no clea associa ion be ween p e-diagnos ic
use o wa a in and PCa dea h in ei he age-adjus ed o
mul i a iable-adjus ed analysis (mul i a iable-adjus ed
HR 1.15, 95% CI 0.88-1.49). No s a is ically signi ican
isk ends by cumula i e amoun o du a ion o use
we e obse ed (Table 2). Howe e , p e-diagnos ic use o
wa a in o 5 yea s o mo e was associa ed wi h a bo -
de line signi ican isk inc ease in he mul i a iable-
adjus ed model (HR 1.49, 95% CI 0.97-2.28).
When use s o o he an icoagulan s we e used as he
e e ence g oup, wa a in use was no associa ed wi h
PCa dea h. No isk ends by cumula i e use we e obse -
e ei he (Table 2).
Risk o PCa dea h by pos -diagnos ic an icoagulan use
In he analysis o pos -diagnos ic use o wa a in, he
o e all isk o PCa dea h was signi ican ly highe
among wa a in use s in compa ison o an icoagulan
non-use s (mul i a iable-adjus ed HR 1.47, 95% CI
1.13-1.93) (Table 3). The isk associa ion was s on-
ges in low-dose usage (<200 DDD) (mul i a iable-ad-
jus ed HR 2.50, 95% CI 1.86-3.36). Sho - e m (1 yea
o less)/low-in ensi y use (<128 DDD/yea ) o
wa a in was simila ly associa ed wi h an inc eased
isk o PCa dea h. As he cumula i e amoun s in-
c eased and he du a ion o usage ex ended o 2 yea s
o mo e, he isk inc ease was a enua ed and was no
longe s a is ically signi ican .
The isk PCa dea h was simila o wa a in and o he
an icoagulan s (mul i a iable-adjus ed HR 1.01, 95% CI
0.71-1.44). In he s a i ied analysis, sho - e m use o
wa a in was associa ed wi h an inc eased isk o PCa
dea h, bu again he isk inc ease was smalle in high-
in ensi y use (Table 3).
Lag- ime analysis
In o de o e alua e long- e m e ec s o wa a in use
and minimize bias due o h ombo ic e en s igge ing
he p esc ip ion, we pe o med an analysis lagging
wa a in use by one, wo and h ee yea s, i.e. ela ing i
o e en s a leas 1-3 yea s la e han he exposu e o
allow o la ency. The isk inc ease compa ed o an i-
coagulan non-use s was dec eased al eady in he ana-
lysis lagged by one yea , bu emained non-signi ican ly
ele a ed (Table 3). The isk inc ease no ed in low-dose
usage was ound in he 1-yea lagged analysis, bu a e
2-yea lag- ime i was only bo de line signi ican ( wo-
yea lag- ime o ≤200 DDD HR 1.34, 95% CI 0.99-1.83).
In gene al, ex ending he lag- ime o wo o h ee yea s
did no subs an ially al e he esul s compa ed o one-
yea lag- ime analysis.
Lag- ime analysis o wa a in use ela i e o usage o
o he an icoagulan d ugs was no subs an ially al e ed
compa ed wi h he non-lagged esul s. No isk inc ease
among sho - e m use s o dec eased isk among high-
in ensi y use s was ound in he lagged analysis (Table 3).
Subg oup analyses
No clea isk modi ica ion by any backg ound a iable
was p esen be ween p e-diagnos ic wa a in use and
isk PCa dea h (Fig. 1). The same applied also o
pos -diagnos ic use and isk o PCa dea h (Fig. 2).
E ec modi ica ion was no ound when compa ing
wa a in usage o o he ypes o an icoagulan s in
p e- and pos -diagnos ic se ing (Addi ional ile 2:
Figu e S1 and Addi ional ile 3: Figu e S2)
Kinnunen e al. BMC Cance (2017) 17:585 Page 3 o 9
Table 1 Popula ion cha ac e is is o he s udy popula ion acco ding o p e- and pos -diagnos ic an icoagulan usage s a us
P e-diagnos ic s a us Pos -diagnos ic s a us
No an icoagula ion Wa a in O he an icoagulan s No an icoagula ion Wa a in O he an icoagulan s
n o men in he s udy popula ion 5601 570 366 4485 1074 978
Mean age a diagnosis 67 70 70 67 68 67
PCa dea hs 624 (11.1%) 65 (11.4%) 39 (10.7%) 509 (11.3%) 121 (11.3%) 98 (10.0%)
Median age a dea h (yea s) 73 76** 76** 72 75** 74**
Median ollow-up om diagnosis o
PCa dea h (yea s)
4.5 4.5 4.5 3.9 4.8 5.8
EAU p os a e cance isk-g oup
b
High-g ade 1661 (29.6%) 181 (31.8%) 109 (29.8%) 1353 (30.2%) 330 (30.7%) 268 (27.4%)
Low-/In e media e-g ade 3940 (70.3%) 389 (68.2%) 257 (70.2%) 3132 (69.8%) 744 (69.3%) 710 (72.6%)
P ima y he apy
a
Radical p os a ec omy 1575 (28.1%) 38 (6.7%)** 39 (10.7%)** 1141 (25.4%) 203 (18.9%)** 308 (31.5%)**
EBRT 2019 (36.0%) 255 (44.7%) 149 (40.7%) 1647 (36.7%) 444 (41.3%) 332 (33.9%)
Ho monal ea men 2197 (39.2%) 303 (53.2%)** 169 (46.2%)** 1814 (40.4%) 490 (45.6%)** 365 (37.3%)**
Ac i e su eillance o wa ch ul wai ing 957 (17.1%) 113 (19,8%) 82 (22.4%) 796 (17.7%) 195 (18,2%) 161 (16.5%)
Use o o he medica ion
S a in use s 2443 (43.6%) 346 (60.7%)** 270 (73.8%)** 1825 (40.7%) 607 (56.5%)** 627 (64.1%)**
An i-diabe ic d ug use s 1024 (18.3%) 158 (27.7%)** 92 (25.1%) 780 (17.4%) 277 (25.8%)** 217 (22.2%)**
An i-hype ensi e d ug use s 3868 (69.1%) 540 (94.7%)** 340 (92.9%)** 2966 (66.1%) 998 (92.9%)** 784 (80.2%)**
NSAID use s 4806 (85.8%) 487 (85.4%) 343 (93.7%)** 3800 (84.7%) 935 (87.1%) 901 (92.1%)**
Alpha-blocke use s 2509 (44.8%) 320 (56.1%)** 203 (55.5%)** 2017 (45.0%) 536 (49.9%) 479 (49.0%)
Aspi in use s 623 (11.1%) 91 (16.0%) 174 (47.5%)** 393 (8.8%) 151 (14.1%)** 344 (35.2%)**
Reco ded diagnoses o :
A ial ib illa ion 404 (7.2%) 303 (53.2%)** 27 (7.4%) 129 (2.9%) 571 (53.2%)** 34 (3.5%)
Th ombo ic ac o s* 198 (3.5%) 93 (16.3%)** 36 (9.8%) 88 (2.0%) 169 (15.7%)** 70 (7.2%)**
Cha lson Como bidi y Sco e
0 3469 (61.9%) 226 (39.6%)** 127 (34.7%)** 2955 (65.9%) 449 (41.8%)** 418 (42.7%)**
1 1093 (19.5%) 147 (25.8%) 113 (30.9%) 822 (18.3%) 272 (25.3%)** 259 (26.5%)**
2 1039 (18.6%) 197 (34.6%)** 126 (34.4%)** 708 (15.8%) 353 (32.9%)** 301 (30.8 %)**
** P o di e ence compa ed o non-use s < 0.001. Calcula ed wi h Chi-squa e es
a
P ima y ea men modali ies no mu ually exclusi e
b
Ca ego ized acco ding o c i e ia o he Eu opean Associa ion o U ology (EAU) as o 2015
Kinnunen e al. BMC Cance (2017) 17:585 Page 4 o 9
Sensi i i y analysis
As pa o sensi i i y analyses, use s o any an icoagu-
lan s including wa a in we e compa ed o non-use s.
The e was a bo de line signi ican isk inc ease among
p e-diagnos ic use s o an icoagulan s (mul i a iable-ad-
jus ed HR 1.19, 95% CI 0.96-1.48) (Addi ional ile 4:
Table S2).
In analysis o pos -diagnos ic use, he isk was inc eased
(HR 1.58, 95% CI 1.27-1.97), bu no appa en isk ends
by cumula i e amoun o du a ion we e obse ed. In he
lag- ime analyses, no s a is ically signi ican isk inc ease
was p esen (Addi ional ile 4: Table S3).
No clea e ec modi ica ion was obse ed o p e- no
pos -diagnos ic use o all an icoagulan s (Addi ional ile 5:
Figu e S3 and Addi ional ile 6: Figu e S4).
Compe ing isk analysis
In a Fine-G ay eg ession analysis wi h non-PCa dea hs
as compe ing cause o dea h, no isk di e ence was
obse ed be ween use s o wa a in and o he an icoagu-
lan s (HR 0.95, 95% CI 0.74-1.24). The indings we e
simila when dea hs caused by pulmona y embolism o
s oke we e analyzed as he compe ing causes o dea h
(HR 0.95, 95% CI 0.73-1.23).
Discussion
Sho - e m and low-dose wa a in use a e he diagnosis
was associa ed wi h inc eased isk o PCa dea h compa ed
o an icoagulan non-use s. Howe e , in analyses allowing
o lag- ime, he isk was a enua ed a e one yea and
disappea ed in 2-yea o 3-yea lag- ime analysis. This
sugges s ha he isk inc ease occu s only o a sho ime
pe iod a e s a ing d ug use. We ound no s a is ically
signi ican isk di e ence be ween use s o wa a in and
o he ypes o an icoagulan s. Addi ionally, we ound no
associa ion be ween p e-diagnos ic use o wa a in and
PCa su i al. Al hough he indica ion o an icoagulan
ea men did no modi y he isk associa ion, i is likely
ha he sho - e m inc eased isk is explained by
h ombo ic e en s as indica ions o an icoagula ion. In
epidemiological li e a u e his phenomenon whe e
pha maceu ical d ug is p esc ibed o ea ly mani es a ion
o ye un-diagnosed disease is e e ed o as ‘p o opa hic
bias’[29].
P e ious s udies on wa a in and PCa mo ali y a e
spa se. To da e, h ee published s udies ha e assessed
he associa ion be ween PCa su i al and use o i amin
K an agonis s [11–13]. Tagalakis e al. ound an
inc eased isk o PCa dea h associa ed wi h one-yea o
e e -use o wa a in in a e PCa diagnosis [11]. Ou
s udy is consis en wi h an inc eased isk associa ed wi h
sho - e m use. In con as o Tagalakis e al., we we e
able o e alua e cumula i e amoun s and in ensi y o use
and ound ha high-dose o long- e m use a e no
associa ed wi h isk inc ease.
In a coho s udy including 12,186 men wi h PCa, bu
no in o ma ion on s age no e idence was ound o an
associa ion be ween PCa dea h and p e-diagnos ic use o
wa a in du ing a mean ollow-up o 3.7 yea s [12]. In a
sensi i i y analysis pos -diagnos ic use was associa ed
wi h an inc eased isk o PCa dea h. E alua ion o cumu-
la i e amoun s, du a ion no in ensi y o use o pos -
Table 2 P e-diagnos ic use o wa a in compa ed o an icoagulan non-use s and wa a in usage in compa ison wi h o he
an icoagulan d ugs s a i ied by De ined Daily Doses (DDD), du a ion and in ensi y o usage
n o dea hs Age-adjus ed Mul i a iable-adjus ed
Wa a in compa ed o non-use s
None 624 Re Re
Any 65 1.11 (0.85-1.44) 1.15 (0.88-1.49)
Amoun o wa a in use
≤200 DDD 24 0.98 (0.65-1.48) 0.97 (0.64-1.47)
201-796 DDD 18 1.09 (0.68-1.74) 1.19 (0.74-1.91)
>796 DDD 23 1.31 (0.86-1.99) 1.37 (0.90-2.09)
Du a ion o wa a in use
≤1 yea 20 0.91 (0.53-1.56) 0.72 (0.42-1.24)
2-4 yea s 22 0.96 (0.57-1.61) 0.87 (0.52-1.47)
5 o mo e yea s 23 1.33 (0.80-2.23) 1.16 (0.69-1.94)
In ensi y o wa a in use
≤114 DDD/yea 21 0.95 (0.56-1.62) 0.79 (0.47-1.35)
115-200 DDD/yea 24 1.09 (0.65-1.81) 0.94 (0.57-1.57)
>200 DDD/yea 20 1.10 (0.64-1.89) 0.96 (0.56-1.65)
Age-adjus ed and mul i a iable-adjus ed haza d a ios (95% CI) ela ed o all PCa dea hs
Kinnunen e al. BMC Cance (2017) 17:585 Page 5 o 9

diagnos ic use was no possible. Conco dan ly, we ob-
se ed no isk inc ease o p e-diagnos ic wa a in use.
Compa ed o he p e ious s udy, we had highe o PCa
dea hs and we e able o e alua e cumula i e amoun o
pos -diagnos ic use. We ound a isk inc ease only o
some subg oups.
A hi d s udy o Pa k e al. [13] was limi ed o 247 pa-
ien s wi h me as a ic PCa ecei ing doce axel chemo-
he apy, and included only 17 LMWH use s and 12
wa a in use s. LMWH was associa ed wi h an imp o ed
su i al, whe eas wa a in was no . In ou la ge and
mo e comp ehensi e s udy, we ound no e idence o
imp o ed su i al among men using o he ypes o
an icoagulan s.
In i o s udies ha e sugges ed ha he coagula ion
cascade and h ombocy es migh be in ol ed in umo
g ow h and p og ession, and ha an icoagulan d ugs
could in heo y imp o e p ognosis [6–10]. Howe e ,
in epidemiologic s udies, con ounding by indica ion
dilu es his po en ial e ec , as ad anced cance is
associa ed wi h an inc eased isk o h ombosis and
consequen ly wi h likelihood o ini ia ing an icoagu-
lan ea men . We con olled o such bias by com-
pa ing use s o di e en ypes o an icoagulan s and
pe o ming a compe ing isk analysis. We ound no
signi ican isk di e ence, which does no suppo he
pu a i e bene icial e ec o wa a in o any o he
an icoagulan s.
Table 3 Pos -diagnos ic use o wa a in compa ed o an icoagulan non-use s and sepe a ely o use s o o he ypes o an icoagu-
lan s s a i ied by De ined Daily Doses (DDD), du a ion and in ensi y o usage
n o dea hs Age-adjus ed Mul i a iable-adjus ed 1-yea lag- ime 2-yea lag- ime 3-yea lag- ime
Wa a in compa ed o non-use s
None 509 Re Re Re Re Re
Any 121 1.46 (1.12-1.90) 1.47 (1.13-1.93) 1.12 (0.85-1.48) 1.12 (0.85-1.48) 1.08 (0.83-1.41)
Amoun o wa a in use
≤200 DDD 63 2.47 (1.84-3.31) 2.50 (1.86-3.36) 1.45 (1.04-2.02) 1.34 (0.99-1.83) 1.26 (0.94-1.70)
200-667 DDD 32 0.87 (0.53-1.42) 0.88 (0.54-1.46) 0.85 (0.52-1.41) 0.76 (0.44-1.32) 0.76 (0.43-1.36)
>667 DDD 26 0.97 (0.56-1.68) 1.02 (0.59-1.78) 1.05 (0.60-1.83) 1.15 (0.67-1.97) 1.04 (0.58-1.85)
Du a ion o wa a in use
≤1 yea 56 2.03 (1.47-2.81) 2.04 (1.47-2.83) 1.26 (0.89-1.78) 1.25 (0.91-1.71) 1.15 (0.85-1.57)
2-4 yea s 44 1.28 (0.88-1.87) 1.30 (0.89-1.90) 1.11 (0.73-1.69) 0.87 (0.53-1.42) 0.93 (0.56-1.54)
5 o mo e yea s 21 0.95 (0.49-1.85) 1.05 (0.54-2.04) 1.06 (0.56-1.99) 1.37 (0.76-2.47) 1.22 (0.66-2.26)
In ensi y o wa a in use
≤128 DDD/yea 45 1.92 (1.34-2.74) 1.91 (1.34-2.74) 1.31 (0.91-1.88) 1.35 (0.98-1.86) 1.21 (0.89-1.66)
128-200 DDD/yea 51 1.74 (1.24-2.45) 1.77 (1.25-2.50) 1.13 (0.74-1.74) 0.93 (0.57-1.51) 0.94 (0.57-1.56)
>200 DDD/yea 25 0.73 (0.40-1.33) 0.78 (0.43-1.43) 0.99 (0.58-1.69) 0.97 (0.56-1.69) 0.99 (0.56-1.77)
Wa a in compa ed o o he an icoagulan d ugs
Non-wa a in an icoagulan use s 98 Re Re Re Re Re
Wa a in use s 121 1.13 (0.79-1.61) 1.01 (0.71-1.44) 0.93 (0.64-1.35) 1.02 (0.70-1.48) 0.93 (0.65-1.33)
Amoun o wa a in use
≤200 DDD 63 1.85 (1.25-2.74) 1.63 (1.10-2.42) 1.15 (0.75-1.77) 1.19 (0.78-1.80) 1.06 (0.71-1.58)
200-667 DDD 32 0.65 (0.37-1.14) 0.58 (0.33-1.01) 0.68 (0.38-1.20) 0.67 (0.36-1.25) 0.64 (0.34-1.21)
>667 DDD 26 0.72 (0.39-1.33) 0.67 (0.36-1.23) 0.83 (0.45-1.55) 1.02 (0.56-1.87) 0.87 (0.46-1.64)
Du a ion o wa a in use
≤1 yea 56 1.52 (1.00-2.31) 1.33 (0.88-2.02) 1.00 (0.64-1.55) 1.11 (0.73-1.68) 0.97 (0.65-1.45)
2-4 yea s 44 0.96 (0.61-1.52) 0.85 (0.54-1.34) 0.88 (0.53-1.46) 0.77 (0.44-1.35) 0.78 (0.44-1.38)
5 o mo e yea s 21 0.71 (0.35-1.46) 0.69 (0.34-1.40) 0.84 (0.42-1.67) 1.22 (0.64-2.33) 1.02 (0.53-2.00)
In ensi y o wa a in use
≤128 DDD/yea 45 1.44 (0.93-2.24) 1.25 (0.80-1.95) 1.04 (0.66-1.64) 1.20 (0.78-1.83) 1.02 (0.68-1.53)
128-200 DDD/yea 51 1.31 (0.85-2.01) 1.16 (0.75-1.78) 0.90 (0.54-1.49) 0.82 (0.47-1.44) 0.79 (0.45-1.40)
>200 DDD/yea 25 0.55 (0.29-1.05) 0.51 (0.27-0.98) 0.79 (0.43-1.44) 0.86 (0.46-1.60) 0.83 (0.44-1.57)
Age-adjus ed, mul i a iable-adjus ed and lag- ime haza d a ios (95% CI) ela ed o all PCa dea hs. S a is ically signi ican esul s a e bolded
Kinnunen e al. BMC Cance (2017) 17:585 Page 6 o 9
Themains eng hso hiss udya e hela ge
popula ion-based coho as well as comp ehensi e
and ou abili y o use de ailed, na ionally comp ehen-
si e egis e -based in o ma ion on an icoagulan use
una ec ed by ecall bias. Being able o s udy la ge
popula ions h ough na ional egis ies allows us o
es ima e e en ela i ely uncommonly used d ugs such
as an icoagulan s as cance isk ac o . Ou s udy in-
cluded subs an ially mo e wa a in use s han in p e-
ious s udies. We we e able o analyze pos -diagnos ic
use o wa a in mo e comp ehensi ely han be o e.
We also pe o med lag- ime analyses o es ima e he
isk associa ions allowing o la ency and emo ing
e ec s limi ed o he immedia e pe iod ollowing i s
subsc ip ion. Fu he mo e, we had longe ollow-up
han in p e ious s udies.
Ou s udy also has some limi a ions. We we e no able
o adjus ou analysis o smoking, li e-s yle ac o s o
BMI which may be associa ed wi h isk o PCa dea h
[30–33]. Ne e heless, we we e able o adjus o Cha l-
son Como bidi y Index and his enabled adjus men o
co-exis ing mo bidi ies. Fu he mo e, ou s udy was no
andomized, and is hus p one o esidual con ounding.
Conclusion
In a popula ion-based se ing, wa a in o o he ypes o
an icoagulan s a e no associa ed wi h imp o ed PCa
p ognosis. Con e sely, in sho - e m use isk o PCa
dea h was inc eased, which is mos likely due o h om-
bosis caused by an ad anced cance , as he isk inc ease
was no obse ed in long e m.
Fig. 1 P e-diagnos ic subg oup analysis o wa a in usage compa ed o an icoagulan non-use s
Fig. 2 Pos -diagnos ic subg oup analysis o wa a in usage compa ed o an icoagulan non-use s
Kinnunen e al. BMC Cance (2017) 17:585 Page 7 o 9
Addi ional iles
Addi ional ile 1: Table S1. ATC codes o an icoagulan d ugs
included in he s udy. (DOCX 207 kb)
Addi ional ile 2: Figu e S1. P e-diagnos ic subg oup analysis be ween
use s o wa a in and o he an icoagulan d ugs. (DOCX 224 kb)
Addi ional ile 3: Figu e S2. Pos -diagnos ic subg oup analysis
be ween use s o wa a in and use s o o he an icoagulan d ugs.
(DOCX 224 kb)
Addi ional ile 4: Table S2. P e-diagnos ic analysis o combined
an icoagulan d ug usage s a i ied by numbe o De ined Daily
Doses (DDD), du a ion and in ensi y o usage. Age-adjus ed and
mul i a iable-adjus ed haza d a ios (95% CI) ela ed o all PCa dea hs.
Table S3. Pos -diagnos ic esul s o combined an icoagulan usage.
Age-adjus ed, mul i a iable-adjus ed and lag- ime haza d a ios (95%
CI) ela ed o all PCa dea hs. (DOCX 405 kb)
Addi ional ile 5: Figu e S3. Subg oup analysis o p e-diagnos ic
combined an icoagulan usage compa ed o non-use s. (DOCX 224 kb)
Addi ional ile 6: Figu e S4. Subg oup analysis o combined
an icoagulan usage compa ed o non-use s in pos -diagnos ic
se ing. (DOCX 224 kb)
Abb e ia ions
VTE: Venous h omboembolism; PCa: P os a e cance ; FinRSPC: he Finnish
Randomized S udy o Sc eening o P os a e Cance ; EAU: he Eu opean
Associa ion o U ology; SII: (Finnish) Social Insu ance Ins i u ion;
EBRT: ex e nal beam adia ion he apy; HR: Haza d a io; CI: Con idence
in e al; DDD: De ined Daily Dose
Acknowledgemen s
No applicable.
Funding
Suppo ed by non- es ic ed compe i i e esea ch unding om he
Pi kanmaa Hospi al Dis ic 150640 o TJ Mu ola and non- es ic ed esea ch
g an om Pi kanmaa Cance Socie y o PTT Kinnunen. Academy o Finland
(g an 132385 and 260 931) and Cance O ganisa ions o Finland o A
Au inen, Compe i i e Resea ch unding o Pi kanmaa Hospi al Dis ic o TLJ
Tammela. No Funde o ganiza ion pa icipa ed in any pa o he s udy
design o collec ion, analysis o in e p e a ion o da a o w i ing he
manusc ip .
A ailabili y o da a and ma e ials
Pe mission o use he en i e da a has been g an ed pe sonally o his
speci ic s udy, hus we a e no allowed o make he en i e da a publicly
a ailable wi hou pe mission. Limi ed da a (i.e a iables used o he
analyses) can be ob ained upon easonable eques .
Each Adminis a o and In o ma ion Commissione o he used egis ies
p ocessed ou eques o use he da a and g an ed a pe sonal pe mission. I
desi ed, simila pe missions can be applied om he Finnish Social Insu ance
Ins i u ion (a ailable a : h p://www.kela. i/web/en/ esea ch) and he Na ional
Ins i u e o Heal h and Wel a e (a ailable a : h ps://www. hl. i/en/web/ hl i-
en/s a is ics/in o ma ion- o - esea che s).
Au ho s' con ibu ions
S udy Concep : KPTT, MTJ, AA. S udy Design: KPTT, MTJ, AA. Da a Acquisi ion:
KPTT, MTJ, TK, TK, TTLJ, AA. Quali y Con ol o Da a: KPTT, MTJ, TK, TK, TTLJ,
AA. All au ho s ha e ead and app o ed he manusc ip .
E hics app o al and consen o pa icipa e
The s udy has been app o ed by he E hical Commi ee o Pi kanmaa
Hospi al Dis ic (Commi ee’s e e ence numbe R10167). This s udy is based
on egis e da a collec ed ou inely o o he pu poses. Thus no in o med
consen is needed based on in e na ional p ac ices.
Consen o publica ion
No applicable.
Compe ing in e es s
We decla e he ollowing compe ing in e es s:
PTT Kinnunen: none, TJ Mu ola: Paid consul an o As ellas and Janssen-
Cilag, lec u e ees om As ellas, Janssen-Cilag, Abb ie and MSD, K Talala:
none, K Taa i: Consul ing ee om Abb ie, esea ch unding om Medi a ion,
a el suppo om As ellas, and O ion, TLJ Tammela: Paid consul an o
As ellas, , O ion Pha ma and Jansen-Cilag, A Au inen: lec u e ee om MSD,
paid consul an o Epid Resea ch Inc.
Publishe ’sNo e
Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in
published maps and ins i u ional a ilia ions.
Au ho de ails
1
Uni e si y o Tampe e, Facul y o Medicine and Li e Sciences, Tampe e,
Finland.
2
Depa men o U ology, Tampe e Uni e si y Hospi al, Tampe e,
Finland.
3
Finnish Cance Regis y, Helsinki, Finland.
4
Depa men o U ology,
Uni e si y o Helsinki and Helsinki Uni e si y Hospi al, Helsinki, Finland.
5
Uni e si y o Tampe e, Facul y o Social Sciences, Tampe e, Finland.
Recei ed: 10 Ap il 2017 Accep ed: 22 Augus 2017
Re e ences
1. Lyman GH. Venous h omboembolism in he pa ien wi h cance : ocus on
bu den o disease and bene i s o h ombop ophylaxis. Cance .
2011 Ap 1;117(7):1334–49.
2. P andoni P, Lensing AW, P ins MR. The na u al his o y o deep- ein
h ombosis. Semin Th omb Hemos . 1997;23(2):185–8.
3. Sø ensen HT, Mellemkjae L, Olsen JH, Ba on JA. P ognosis o cance s
associa ed wi h enous h omboembolism. N Engl J Med.
2000 Dec 21;343(25):1846–50.
4. Van Hemel ijck M, Adol sson J, Ga mo H, Bill-Axelson A, B a O, Ingelsson E,
e al. Risk o h omboembolic diseases in men wi h p os a e cance : esul s
om he popula ion-based PCBaSe Sweden. Lance Oncol.
2010 May;11(5):450–8.
5. Cha u edi S, Sidana S, Elson P, Kho ana AA, McC ae KR. Symp oma ic and
inciden al enous h omboembolic disease a e bo h associa ed wi h
mo ali y in pa ien s wi h p os a e cance . PLoS ONE. 2014;9(8):e94048.
6. Maa B. Selec i e mac ophage inhibi ion abolishes wa a in-induced
educ ion o me as asis. B J Cance . 1980 Feb;41(2):313–6.
7. B own JM. A s udy o he mechanism by which an icoagula ion wi h
wa a in inhibi s blood-bo ne me as ases. Cance Res.
1973 Jun;33(6):1217–24.
8. Bobek V, Boubelik M, Ko a ik J, Tal yno O. Inhibi ion o adhesion b eas
cance cells by an icoagulan d ugs and cime idine. Neoplasma.
2003;50(2):148–51.
9. McCulloch P, Geo ge WD. Wa a in inhibi ion o me as asis: he ole o
an icoagula ion. B J Su g. 1987 Oc ;74(10):879–83.
10. Mousa SA. An icoagulan s in h ombosis and cance : he missing link. Expe
Re An icance The . 2002 Ap ;2(2):227–33.
11. Tagalakis V, Tamim H, Blos ein M, Hanley JA, Kahn SR. Risk o p os a e
cance dea h in long- e m use s o wa a in: a popula ion-based case-
con ol s udy. Cance Causes Con ol. 2013 Jun;24(6):1079–85.
12. O'Ro ke MA, Mu ay LJ, Hughes CM, Can well MM, Ca dwell CR. The e ec
o wa a in he apy on b eas , colo ec al, lung, and p os a e cance su i al:
a popula ion-based coho s udy using he Clinical P ac ice Resea ch
Da alink. Cance Causes Con ol. 2015 Ma ;26(3):355–66.
13. Pa k JC, P a z CF, Tes aye A, B odsky RA, An ona akis ES. The e ec o
he apeu ic an icoagula ion on o e all su i al in men ecei ing i s -line
doce axel chemo he apy o me as a ic cas a ion- esis an p os a e cance .
Clin Geni ou in Cance . 2015 Feb;13(1):32–8.
14. Ahlb ech J, Dickmann B, Ay C, Dunkle D, Thale J, Schmidinge M, e al.
Tumo g ade is associa ed wi h enous h omboembolism in pa ien s wi h
cance : esul s om he Vienna Cance and Th ombosis S udy. J Clin Oncol.
2012 No 1;30(31):3870–5.
15. Kilpeläinen TP, Tammela TL, Malila N, Hakama M, San i H, Mää änen L, e
al. P os a e cance mo ali y in he Finnish andomized sc eening ial.
J Na l Cance Ins . 2013 May 15;105(10):719–25.
Kinnunen e al. BMC Cance (2017) 17:585 Page 8 o 9
16. Teppo L, Pukkala E, Leh onen M. Da a quali y and quali y con ol o a
popula ion-based cance egis y. Expe ience in Finland. Ac a Oncol.
1994;33(4):365–9.
17. EAU isk g oup s a i ica ion, Table 4.2.2. A ailable a : h ps://u oweb.o g/
wp-con en /uploads/EAU-Guidelines-P os a e-Cance -2016.pd
18. The S a is ical Finland. A ailable a h p://www.s a . i/index_en.h ml
19. Ma ikainen J, Rajaniemi S. D ug eimbu semen sys ems in EU Membe
S a es, Iceland and No way. Helsinki: The Social Insu ance Ins i u ion,
Finland, Social secu i y and heal h epo s. 2002;54 A ailable a :
h ps://helda.helsinki. i/handle/10138/13
20. Flaha an EM, Benne K, Sha p L, Ba on TI. A coho s udy in es iga ing
aspi in use and su i al in men wi h p os a e cance . Ann Oncol.
2014 Jan;25(1):154–9.
21. Holmes S, G i i h EJ, Mus o G, Minuk GY. An ihype ensi e medica ions and
su i al in pa ien s wi h cance : a popula ion-based e ospec i e coho
s udy. Cance epidemiol. 2013 Dec;37(6):881–5.
22. Tan P, Wei S, Yang L, Tang Z, Cao D, Liu L, e al. The e ec o s a ins on
p os a e cance ecu ence and mo ali y a e de ini i e he apy: a
sys ema ic e iew and me a-analysis. Sci ep. 2016;6:29106.
23. Vei onmäki T, Mu ola TJ, Mää änen L, Taa i K, S enman U, Tammela TLJ, e
al. Use o non-s e oidal an i-in lamma o y d ugs and p os a e cance su i al
in he Finnish p os a e cance sc eening ial. P os a e.
2015 Sep;75(13):1394–402.
24. Kjellman A, F iis S, G ana h F, Gus a sson O, So ensen HT, Ak e O. T ea men
wi h inas e ide and p os a e cance su i al. Scand J U ol.
2013 Aug;47(4):265–71.
25. Randazzo M, Bea ice J, Hube A, G obholz R, Manka L, Wyle SF, e al.
In luence o me o min use on PSA alues, ee- o- o al PSA, p os a e cance
incidence and g ade and o e all su i al in a p ospec i e sc eening ial
(ERSPC Aa au). Wo ld J U ol. 2015 Aug;33(8):1189–96.
26. The Na ional Ca e Regis e o Heal h Ca e main ained by he Na ional
Ins i u e o Heal h and Wel a e. In o ma ion o easea che s a ailable a :
h ps://www. hl. i/en/web/ hl i-en/s a is ics/in o ma ion- o - esea che s
27. Cha lson ME, Pompei P, Ales KL, MacKenzie CR. A new me hod o classi ying
p ognos ic como bidi y in longi udinal s udies: de elopmen and alida ion.
J Ch onic Dis. 1987;40(5):373–83.
28. WHO ATC/DDD index 2016. A ailable a : h p://www.whocc.no/a c_ddd_
index/.
29. Ho wi z RI, Feins ein AR. The p oblem o "p o opa hic bias" in case-con ol
s udies. Am J Med. 1980;68(2):255–8.
30. Islami F, Mo ei a DM, Bo e a P, F eedland SJ. A sys ema ic e iew and
me a-analysis o obacco use and p os a e cance mo ali y and incidence
in p ospec i e coho s udies. Eu U ol. 2014 Dec;66(6):1054–64.
31. Dicke man BA, Ma k SC, Kosken uo M, Pukkala E, Mucci LA, Kap io J.
Alcohol in ake, d inking pa e ns, and p os a e cance isk and mo ali y: a
30-yea p ospec i e coho s udy o Finnish wins. Cance Causes Con ol.
2016 Sep;27(9):1049–58.
32. Da ies NM, Gaun TR, Lewis SJ, Holly J, Dono an JL, Hamdy FC, e al. The
e ec s o heigh and BMI on p os a e cance incidence and mo ali y: a
Mendelian andomiza ion s udy in 20,848 cases and 20,214 con ols om he
PRACTICAL conso ium. Cance Causes Con ol. 2015 No ;26(11):1603–16.
33. Fowke JH, McLe an DF, Gup a PC, He J, Shu X, Ramadas K, e al.
Associa ions o body mass index, smoking, and alcohol consump ion wi h
p os a e cance mo ali y in he Asia Coho Conso ium. Am J Epidemiol.
2015 Sep 1;182(5):381–3.
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