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Statins and the Risk of Cancer after Heart Transplantation
Georg Marcus Fröhlich, Kaspar Rufibach, Frank Enseleit, Mathias Wolfrum, Michelle von Babo,
Michelle Frank, Reto Berli, Mathias Hermann, Johannes Holzmeister, Georg Noll, Thomas F.
LГјscher and Frank Ruschitzka
Circulation. published online July 3, 2012;
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright В© 2012 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/early/2012/06/28/CIRCULATIONAHA.111.081059
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DOI: 10.1161/CIRCULATIONAHA.111.081059
Statins and the Risk of Cancer after Heart Transplantation
Running title: Fröhlich et al.; Statins and cancer after heart transplantation
Georg Marcus Fröhlich, MD1; Kaspar Rufibach, PhD2; Frank Enseleit, MD1;
Mathias Wolfrum, MD1; Michelle von Babo, BSc1; Michelle Frank, MD1; Reto Berli, MD1;
Mathias Hermann, MD1; Johannes Holzmeister, MD1; Georg Noll, MD1;
Thomas F. LГјscher, MD1; Frank Ruschitzka, MD1
1
Cardiovascular
Ca
rdi
rd
diova
iova
v scul
ulaar
ul
ar Center,
Center, Cardiology, Univers
University
sit
ity Hospital Zuric
Zurich;
icch;
h 2Di
Division
Div
vision of Biostatistics,
Institut
Institute
utee for
for Social
S ciial and
So
and Preventive
Pre
P
reve
re
vent
ve
n iv
nt
ivee Medicine,
Meedi
dici
c ne
ci
ne,, University
Univ
iv
ver
ersi
sity
si
ty of
of Zurich,
Zu
uri
r ch
h, Zurich,
Zuri
Zu
rich
ch,, Sw
ch
Swit
Switzerland
itze
zerl
ze
r an
rl
andd
Correspondence:
Corr
rrespo
p nd
po
nden
ence:
Georg
Geor
Ge
o g Marcus
Marc
rcus
us Fröhlich,
Frö
Г¶hllic
i h, MD
MD
Cardiovascular Center Cardiology
Heart Failure/Transplantation Clinic
University Hospital Zurich
Rämistrasse 100
CH-8091 Zurich, Switzerland
Tel: +41 44 255 1111
Fax: +41 44 255 4401
E-mail: [email protected]
Journal Subject Codes: [11] Other heart failure; [112] Lipids; [27] Other Treatment
1
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DOI: 10.1161/CIRCULATIONAHA.111.081059
Abstract:
Background - While newer immunosuppressive agents, like mTOR inhibitors, have lowered the
occurrence of malignancies after transplantation, cancer is still the leading cause of death late
after heart transplantation. Statins may impact on clinical outcomes beyond their lipid-lowering
effects. The aim of the present study was to delineate whether statin therapy impacts on cancer
risk and total mortality after heart transplantation.
Methods and Results - 255 patients who underwent heart transplantation at the University
Hospital Zurich between 1985 and 2007 and survived the first year were included. The primary
outcome measure was the occurrence of any malignancy, the secondary endpoint overall
survival.
urvival. During follow-up, a malignancy was diagnosed in 108 patients (42%). The
The cumulative
cu
umu
mula
lati
la
tive
v
incidence
ncidence of tumors 8 years after transplantation was reduced in patients receiving a statin (34%
vs.13%,
vs
s.113%
3%, 95%
95% CII 0.25-0.43
00.2
.25-0.43 vs. 0.07-0.18, p<0.003).
p<0.0003). Statin use was
waas associated
asso
sooci
ciat
a ed with improved
cancer-free
and
overall
survival
Cox-regression
model
ca
ancer-free
ncc
an
nd ov
over
ral
a l su
surv
rviv
ivaal
iv
al ((both
both
bo
t pp<0.0001).
th
<0.0
000
01). A Co
ox-re
x-regr
grres
esssion m
o el aanalyzing
od
naly
na
lyzi
zing
zi
ngg tthe
h ttime
he
ime tto
im
o
tumor
umo
morr fo
fformation
rm
mat
atio
ionn with
with orr without
w th
wi
houut statin
stat
st
a in
at
n therapy,
tthe
hera
he
rapy,
ra
y, adjusted
aaddjuuste
teed for
for age,
age, male
mal
alee gender,
geend
ndeer,
er ty
type
pe ooff
cardiomyopathy
cardiomyop
patthy and
and immunosuppressive
iimm
m un
mm
unos
o up
os
uppr
p es
pr
essiive
v therapy
tthe
hera
he
rapy
ra
py (including
(inc
n lu
udi
d ng switch
swi
witc
t h too mTOR
mTO
m
TOR
TO
R inhibitors
inhi
in
hibi
hi
b to
bi
t rs or
tacrolimus) demonstrates a superior survival in the statin group. Statins reduced the hazard of
occurrence of any malignancy by 67% (HR 0.33, 95% CI 0.21-0.51, p<0.0001).
Conclusions - Although it is not possible to adjust for all potential confounders due to the very
long follow-up period, this registry suggests, that statin use is associated with improved cancerfree and overall survival after cardiac transplantation. These data will have to be confirmed in a
prospective trial.
Key words: cholesterol; heart transplantation; statins; transplantation; malignancy
2
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DOI: 10.1161/CIRCULATIONAHA.111.081059
Introduction
Newer immunosuppressive regimens like mTOR inhibitors or tacrolimus have not only steadily
reduced the incidence of acute rejection, but also of post-transplant malignancy1-3. However,
malignancy still is an important cause of long-term mortality in transplant recipients4. The
incidence of malignancy has been estimated at 20% after 10 years of chronic
immunosuppression5, and the relative risk may increase 100-fold for specific cancers in
comparison to the general population6. Heart transplant patients are at particular risk of
developing posttransplant malignancies that is increased up to four-fold compared to renal
transplant recipients.6-11 Indeed, cancer is now a leading cause of death late after heart
transplantation
ransplantation12.
Importantly, HMG-CoA-reductase-inhibitors (statins) initiated after heart transplantation
exert
ex
xerrt be
bene
beneficial
neefi
fici
cial eeffects
ci
ffects on the incidence of cardiac
ff
cardia
iacc aallograft
ia
llograft reject
rejection,
cttio
i n,, tr
transplant
tra
an
ansplant
vasculopathy
13,14
14
and
an
nd survival rat
rates.
tes.
es 13,
IIntriguingly,
ntri
ntri
rigu
guin
gu
ingl
in
gly,
y, iin
n no
non-transplant
on-trran
nspllannt ppatients,
attie
ienntss,
s, sst
statin
tatin intake
inttakke
in
ke is
is associated
asso
as
soociiat
a ed
e with
with
itth a
1
decreased
decr
de
crea
cr
ease
ea
s d risk
se
risk of
of malignancies
maliignnancie
mali
ies such
ie
such aass ly
lymphoma
ymp
mpho
ho
oma155, brea
bbreast
rea
east
st1166,o
,ovarian
,ova
vaariian17
, ccolorectal
olo
ore
r ct
c all1188, lung
lu
ungg and
aan
nd
nd
19,20
20
pancreatic can
an
nce
cerr19
. Wh
W
While
ilee el
il
eelevated
evat
ev
a ed
at
e pplasma
lasm
la
smaa ch
sm
cholesterol
hol
o es
este
t ro
te
ol le
leve
levels
v ls hhave
ve
av
ve be
been
en aassociated
ssoc
ss
ocia
oc
iate
ia
tedd with the
te
cancer
development of skin, colon or prostate cancer21-24, it is matter of a still ongoing debate whether
the potential benefit of statins in cancer may be explained by its cholesterol-lowering or potential
pleiotropic, particularly immunomodulatory effects.25,26
To the best of our knowledge, up to date no data exist on the impact of statin use or
cholesterol levels on cancer risk in immunosuppressed patients. Hence, the aim of this study was
to evaluate the influence of statin therapy and cholesterol levels beyond the role of
immunosuppression on the development of malignancies and total mortality.
3
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DOI: 10.1161/CIRCULATIONAHA.111.081059
Methods
Study design and patient sample
We evaluated all patients 18 years of age or older, who underwent heart transplantation at the
University Hospital Zurich between 1985 and 2007 and survived the first year after
transplantation. Statin therapy was initiated usually three to twelve months after transplantation
in patients transplanted after year 1995. Statin therapy was recorded on a daily basis from heart
transplantation until the occurrence of malignancy or the end of the follow-up period. Follow-up
was performed until December 2010.
All patients who received a statin were assigned to the statin group. Further, detailed
information
inhibitors
nformation of immunosuppressive therapy including switch to mTOR inhibitor
rs orr ttacrolimus,
accro
roli
limu
li
m s,
mu
s
lipid
ipid status as well as episodes of rejections were recorded. Rejection was defined according to
International
Society
Transplantation
(ISHLT)
criteria,
nteern
rnat
atio
at
iona
io
nall So
na
oci
cieety
ety for Heart and Lung Transp
pla
lanntation (ISHLT
T) crit
iter
eriia,
er
ia based on findings in
the
he re
regular en
endomyocardial
ndo
domy
myoc
my
ocaardi
dial
di
al bbiopsies
iops
io
psie
i s (>
ie
> IISHLT
SH
HLT
T IB
B - occ
occurred
cccurre
urreed in nn=205,
=205,, 881%
=205
1%
% - an
andd IS
ISHL
ISHLT
H T > II HL
occurred
separately)
oc
ccu
curr
rred
rr
e in
ed
in n=167,
n=16
n=
16
67,, 666%
6% - aaree sshown
hown
ho
wn ssep
epar
ep
arat
ar
atelly)
at
y 2277. On
Only
nly
y bbi
biopsy
iops
iops
psyy pr
prov
proven
oven
ov
en
n rejections
rej
ejec
ecti
ec
tiion
o s > 1 month
mont
mo
nthh
after the previous
prev
vio
ious
u bbiopsy
us
i ps
io
p y we
were
re ccounted
ount
ou
nted
nt
ed
d aass a de nnovo
ovoo rrejection.
ov
e ec
ej
ecti
tion
ti
on..
on
Immunosuppressive therapy followed a standardized protocol in all patients and was
recorded after 12 months, when levels of immunosuppressive drugs were in a steady state.
Presence of malignancy was ruled out prior to transplantation in all patients according to the
guidelines of the ISHLT.27-29
Study endpoints
The primary outcome measure was the time from HTX to the occurrence of any malignancy,
defined as the detection of any malignant tumor. For this endpoint, the competing event “death
from non-malignant cause” was considered.
4
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DOI: 10.1161/CIRCULATIONAHA.111.081059
Secondary endpoints were overall survival and time to tumor occurrence for which we
additionally distinguished between skin vs. non-skin malignancies. “Non-skin” malignancies
included lymphoma, multiple myeloma, tumors of bladder, lung, gastrointestinal system, kidneys
and of unknown origin. Further, we investigated whether high cholesterol is an independent risk
factor for the occurrence of a malignancy or of the competing endpoint of death from a nonmalignant cause.
Study groups
The outcome of patients receiving statin therapy was compared to patients without statins. Each
day on statin treatment was recorded and patients were divided into subgroups who received
statins
tatins for more than 50% of the follow-up compared to with patients with less than
th
han
n 50%
50% of
of
follow-up. Patients were divided into a low-dose group (equivalent simvastatin dose of 10-30
mg)
high-dose
simvastatin
mg).
mg
g) an
andd a hi
hig
gh-d
dose
ose group (equivalent simvastat
atin
at
i dose of 40-80
in
0m
mg)
g).30 T
The decision to put
patients
pati
ien
e ts on a “h
“high-dose”
hig
i h-do
dose
do
see” st
stat
statin
atin
at
in tthe
therapy
herrap
he
rapy w
was
ass bbased
asedd oon
n ccholesterol
holeestter
hole
erool
ol vvalues
alue
al
uees > 5.5
5.5 mm
mmol/l
mol
ol/l
/l ((n=24,
n=24
n=
24,
4
16%
16
6% of patients
pattie
ient
ntss on statin).
ssta
taati
tinn).
n).
Furthermore,
Furthe
heerm
rmor
ore,
or
e, ppat
patients
attient
ntss we
nt
were
ere aassigned
s ig
ss
igne
nedd to
ne
o ttwo
wo ggro
groups
r up
ro
upss ba
base
based
sedd onn their
se
the
heir
ir mean
mea
m
e n fa
ea
fast
fasting
stin
st
ingg total
in
cholesterol (TC) of all cholesterol measurements after three months after HTX, i.e. in a „highcholesterol group“ (TC • 5.5 mmol/l) and a „low-cholesterol group“ (TC < 5.5 mmol/l),31 as
lipid levels change due to immunosuppressive therapy after HTX.32
Statistical analyses
Statistical analysis was performed using “R” Software and Stata 11.2 (StataCorp, College
Station, TX).33 The survival analysis was performed using the R-package survival34 Cumulative
incidence curves are computed using the package “cmprsk”.34 Nominal variables are presented
as absolute (n) and relative frequency (%). To assess differences in nominal variables between
5
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DOI: 10.1161/CIRCULATIONAHA.111.081059
groups we used either Chi2 or Fisher's exact test, whichever was appropriate. Continuous
variables are presented as median and interquartile range (25-75 percentile) within brackets. To
assess differences between groups, the Mann-Whitney U-test was used. To assess time-to-event
endpoints with competing events, we computed cumulative incidence curves and provide
estimates of the cumulative incidences at 8, 10, and 12 years including 95% confidence intervals.
Cumulative incidence curves were compared between groups according to the method of Gray.35
For the primary outcome measure “freedom from malignancy”, the competing events
“occurrence of skin malignancy”, “non-skin malignancy”, “death from non-malignant cause”,
and “censored” (denoted “event-free survival”) were distinguished.
h ccovariates
he
ovar
ov
aria
ar
iate
ia
tes
Cox regression models were used to analyze the independent influence off the
“statin-group” on malignancy formation, where we adjusted these models for age, sex,
un
nde
derl
rlyi
rl
ying
yi
ng
g hhe
eartt ddis
i ease, conventional immunos
is
sup
u pression and cchange
h ng
ha
ge to
to mTOR inhibitors or
underlying
heart
disease,
immunosuppression
acrrolimus (mT
mTOR
OR aand
n ttacrolimus
nd
accro
roli
limu
li
muss as
as ttime-dependent
im
me-ddeppenddent co
co-v
-vaariiate
tess).
tacrolimus
(mTOR
co-variates).
ass
sses
esss whether
whettheer the
whet
the relative
reela
lati
tivve
ti
ve risk
rissk reduction
reduuct
re
c ion off tthe
he statin
sstaati
t n therapy
th
her
eraapy
py iiss in
ind
depe
depe
pend
nden
nd
en
nt of
o
To assess
independent
leeve
vels
ls and
and
n of
of interactions
in
nte
tera
r ct
ctio
ions
io
ns between
bbet
etwe
et
ween
we
en statin
ssta
tati
ta
tinn therapy
ti
t errapy and
th
and cholesterol
ccho
hole
ho
leest
ster
erol
er
ol values,
vval
alue
al
ues,
ue
s, a Cox
Cox
cholesterol levels
regression model with cholesterol (cholesterol as nominal co-variate В•5.5 mmol/l vs. <5.5
mmol/l ) and the “statin-groups” was determined. Kaplan-Meier estimates and log-rank tests for
overall survival and median follow-up were computed using inverted Kaplan-Meier estimate.
Confidence intervals for median time to event were computed using the method by Brookmeyer
and Crowley.36 A significance level of Д® = 0.05 was adopted throughout the study and all
confidence intervals are computed using a confidence level of 95%.
Ethics committee approval
The study was approved by the ethics committee of the University of Zurich, Zurich Switzerland.
6
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DOI: 10.1161/CIRCULATIONAHA.111.081059
Results
Patient characteristics
All 255 patients who underwent heart transplantation at the University Hospital Zurich between
1985 and 2007 and survived the first year were included (Table 1). The median follow-up for
event-free survival from cancer was 12.6 years (25th-75th percentile 11.0 – 14.0 years, Table 1).
During follow-up 94 patients (37%) died, of whom 29 patients (11%) died due to a malignancy.
The groups did not differ with regard to age, gender, mean cholesterol values, rejections per
patient per year and CMV risk (Table 2).
Cumulative incidences of occurrence of neoplasia were 21% (95% CI 0.16 – 0.26%) at
0.25
25 – 0.36%)
0 36
0.
36%)
%)
eight years follow-up, 27% (95% CI 0.21 – 0.32%) at ten years and 30% (95% CII 0.25
at twelve years. Cumulative incidences of skin malignancies were 11% (95% CI 0.07 – 0.15%) aat
eiigh
ht years
year
ye
arrs follow-up,
follow
fo
ow
w-up,
-u 15% (95% CI 0.11 – 0.20%)
0.20
0%)
%) at ten years and
and
n 17%
7% (95% CI 0.12 – 0.21%)
eight
welve years.
yearrs.
s Cu
C
umulat
umu
atiive
ive in
inci
cide
deence
nces ooff th
he comp
mpetin
mp
in
ng en
ndpoi
oint
nt ““death
deaath fr
de
rom nnon-malignant
on-m
on
- al
-m
a ig
gnaantt
att tw
twelve
Cumulative
incidences
the
competing
endpoint
from
caaus
use”
e” w
erre 12%
12% (9
(955 % CI 00.08
.088 – 0.
.0
00.16%)
16
6%) aatt ei
eigh
ghtt yea
gh
yyears
ears
ars fo
fol
llow
llow
ow-u
-u
up,
p 113%
3%
% ((95%
955% CII 00.09
.09
09 – 0.
0.1
17%)
%)
cause”
were
eight
follow-up,
0.17%)
nd 116%
6% ((95
95
5%C
.122 – 0.
.1
0.21
21%)
21
%) aatt tw
twel
elve
el
ve yyears.
ears
ea
rs.
rs
at ten years aand
CII 00.12
0.21%)
twelve
Impact of statin therapy on malignancy formation and mortality
Of the 151 patients on statin therapy, 83 patients (57%) received low-dose (equivalent to
simvastatin 10-30 mg) and 61 (42%) a high dose statin therapy (equivalent to 40-80 mg
simvastatin). In seven patients detailed information on statin dose was lacking. Statin intake was
recorded on a daily basis in the statin study population: Patients were on statin therapy for a
median of 64% (25th-75th percentile: 42 – 93%) of the follow-up time (time to occurrence of
cancer). During follow-up, a malignancy was diagnosed in 108 patients (42%). Patients on statin
therapy were more likely to survive without occurrence of malignancies (p < 0.003, Figure 1).
7
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DOI: 10.1161/CIRCULATIONAHA.111.081059
Patients in the statin group were at a lower risk of malignancy formation compared to the
non-statin group (13% vs. 34%, CI 0.07 – 0.18 vs. 0.25 – 0.43 ) at eight years after
transplantation, (18% vs. 39%, CI 0.12 – 0.24 vs. 0.30 – 0.49) 10 years after transplantation and
(22% vs. 42% , CI 0.15 – 0.28 vs. 0.33 – 0.52; p<0.003. Figure 1) 12 years of follow-up.
“Non-malignant cause of death” is a competing endpoint: statin use was associated with a
reduction of risk to die from a non-malignant cause compared to the non-statin group, (7% vs.
19%, CI 0.03 – 0.11 vs. 0.12 – 0.27) eight years after transplantation, (9% vs. 19%, CI 0.04 –
0.13 vs. 0.12 – 0.27) 10 years after transplantation and (11% vs. 24%, CI 0.06 – 0.16 vs. 0.16 –
0.32; p = 0.02; Figure 1) twelve years of follow-up.
Similarly, statin use was associated with a reduced risk of developing non
non-skin
n-sk
skkin
malignancies (4% vs. 18%, CI 0.01 – 0.07 vs. CI 0.11 – 0.26) eight years after
f transplantation, 10
years
after
transplantation
0.12
year
ye
arss af
ar
aft
ter tr
ter
tra
ansp
sppla
lant
n ation (5% vs. 20%, CI 0.02
2 – 00.09
.09 vs. CI 0.1
12 – 0.
00.28)
28 and twelve years of
28)
follow-up
while
was
folllow-up (7%
% vvs.
s. 22%
222% vs.,
vs , CI 0.03
0.0
0 03 – 0.11
0.111 vs.
0.
vs. CI 0.14
0. – 00.30;
.330; pp=0.04;
=0.04;
=0.0
4; Figure
Figu
Fi
gure
re 22),
), w
hile
hi
le tthere
here
he
ree w
as
no difference
ddif
iffe
if
fere
fe
renc
ncee for
nc
for occurrence
occu
occu
urr
rren
e ce of
en
of skin
skin malignancies
mal
alig
igna
ig
nanc
na
nccie
i s between
be wee
betw
eenn the
th
he statin
sttattin and
and the
thee non-statin
nnon
o -s
on
-sta
tati
ta
tinn grou
ggroup
rou
up
(p=0.2,
p=0.2, Figure
Figu
ure 22).
)..
Patients receiving statins for more than 50% of the follow-up time had a lower risk of
malignancy occurrence compared to patients who received a statin for less than 50% of followup time (p=0.02). This benefit persisted at eight years (16% vs. 25%; CI 0.08 – 0.23 vs. 0.18 –
0.32), ten years (21% vs. 31%; CI 0.13 – 0.29 vs. 0.23 – 0.38) and twelve years of follow-up
(25% vs. 34%, CI 0.16 – 0.34 vs. 0.26 – 0.41; Figure 3).
Moreover, patients on statin treatment В• 50% of the follow-up time were less likely to die
from a non-malignant cause auf death compared to patients receiving statins less than 50% of the
follow-up time (p-value: 0.007; Figure 3). Importantly, this benefit persisted eight years (7% vs.
8
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DOI: 10.1161/CIRCULATIONAHA.111.081059
15%; CI 0.02 – 0.13 vs. 0.09 – 0.20), 10 years (7% vs. 17%, CI 0.02 – 0.13 vs. 0.11 – 0.22) and
12 years after transplantation (8% vs. 21%, CI 0.03 – 0.14 vs. 0.15 – 0.27).
A Cox-regression model analyzing the time to tumor formation with or without statin
therapy, adjusted for age, male gender, type of cardiomyopathy and immunosuppressive therapy
demonstrates a lower hazard for tumor in the statin group. (Table 3).
Overall survival was improved in patients on statin therapy vs. the control group
(p<0.0001; Figure 4). Statin dose was not associated with malignancy occurrence (p=0.44).
Impact of cholesterol levels on malignancy formation and mortality
In 239 of 255 patients serial cholesterol measurements, obtained at least three months after HTX,
were available (median number of 5.5 cholesterol values (min. 3 – max. 13). In a Cox-regression
Co
ox-re
regr
gres
gr
essi
es
sion
model analyzing the event free survival in patients with or without statin therapy and cholesterol
levels
co-variates,
statin
eveels (В•5.5
((В•
В•5.5
5.5 mmol/l
mmol
mmol
ol//l
/l vs. <5.5. mmol/l) as co-varia
iaates, the benefit of sta
ati
tinn therapy
t erapy (p= 0.0009, HR
th
0.43,
was
independent
cholesterol
0.43
3, 95% CI 00.26-0.71)
.266-0.
.2
0 71) wa
as in
inde
depe
pend
pe
nd
dennt off pplasma
lasm
ma cho
hole
ho
lessteerol llevels
evel
elss (p
p = 00.76,
.76,
.7
6, H
HR
R 11.09,
.09
9, 995%
5%
CII 0.26-1.92).
therapy
and
values
the
00.2266 1.
1.92
92)).
92
). No
No significant
sign
si
gniffic
gn
ican
antt interactions
in
nte
tera
racctio
ra
ctio
ons between
bbeetwe
ween
we
en
n sstatin
tattin th
ta
ther
erap
apyy an
ap
nd cho
ccholesterol
holes
olesste
t ro
roll va
valu
luees
es oon
n th
he
developmentt of tumors
increased
risk
“nontum
umor
orrs were
weere detected
ddet
etec
et
ecte
ec
teed (p=0.72).
(p=0
(p
=0
0.7
.72)
2 . But,
2)
But,, there
tthe
heere was
wass an
an in
incr
crea
cr
ease
ea
sedd ri
se
isk ffor
or “no
n nmalignant cause of death” in the high cholesterol group (p=0.0003). In the high cholesterol
group, patients on statin therapy had an improved survival as compared to those patients without
statin (p=0.0003).
Discussion
We here demonstrate that statin use is associated with a substantial reduction of cancer risk and
all-cause mortality in heart transplantation recipients. With a follow-up of up to 25 years it is not
possible to adjust away all the differences in therapy and especially during the recent era when
9
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DOI: 10.1161/CIRCULATIONAHA.111.081059
statins were used compared to the previous era in which there was more intense
immunosuppression with agents more likely to cause malignancy.
Over the last three decades the development of tumors in transplant recipients steadily
decreased by the introduction of newer immunosuppressive drugs, like mTOR inhibitors or
tacrolimus.3,12 However, while the one year survival rate improved dramatically since the early
era of organ transplantation due to more targeted immunosuppression and optimized strategies to
prevent severe acute organ rejections, overall long term survival did not further improve over the
last 20 years12. Long-term outcome after cardiac transplantation is still limited by graft
atherosclerosis and particularly by the risk of developing cancer, which remains a leading cause
6,9,11,12
9,11
,11,12
11,12
of death after 15 years, modern immunosuppressive therapies notwithstanding.6,9
Hence,
Henc
He
nce,
nc
e tthe
e,
observed 67% hazard reduction to develop cancer associated with the use of statins in the presen
present
study
tud
dy is of
of pa
part
particular
r iccul
ular
a clinical relevance. Importa
Importantly,
ant
ntly
y, the benefits ooff st
statins
tat
atin
ins were observed on top
in
off the
the use of modern
mode
mo
dern
de
n immunosuppressive
iimm
mm
mun
unos
osup
os
uppr
preess
pr
essive therapy
thherapy
y – mTOR
mTO
TOR
TO
R inhibitors,
innhib
nhib
bittor
ors, iin
n pa
par
particular.
rticul
rti
icular
ar.
ar
These
Thes
Th
esee findings
es
finndi
fi
ndings
ingss are
are
r inn line
l ne with
li
wiith
w
ith results
resu
re
sult
su
lts from
lt
from
m recent
reccen
nt case-control
casee-c
case
- on
ontr
trol
tr
ol studies
stu
tu
udiies
e in
in nonnonimmunosuppressed
mmunosupp
pppre
ress
s ed patients
ss
pat
a ie
i ntts indicating
indi
in
dica
di
cati
ca
tiing
n that
tha
hatt statin
stat
st
a in
at
i use
usee is aassociated
ssoc
ss
ocia
oc
iaate
tedd wi
w
with
th a rred
reduction
e uc
ed
ucti
tion
ti
on ooff the risk off
colon18, lung19 and pancreatic cancer20. In addition, a potential for statins as adjuvant therapy has
been suggested, as statins reduce proliferation and increase apoptosis in women with high grade
breast cancer16. Similarly, statins induce apoptosis of ovarian cancer cells and synergize with
doxorubicin17.
Moreover, the reduction of cancer risk in heart transplant recipients receiving statins was
paralleled by a substantial reduction of total mortality. This confirms and extends findings of
previous studies of Kobashigawa et al. that pravastatin improves survival after heart
transplantation particularly due to a reduction in graft atherosclerosis14. While the survival
10
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DOI: 10.1161/CIRCULATIONAHA.111.081059
benefit associated with the use of statins had been subsequently been confirmed by other groups
and other statins, data on cancer risk had not been reported37-39. Since the benefits of statins on
mortality and cancer risk in the present study were independent of cholesterol lowering, potential
mechanisms associated with the inhibition of the mevalonate HMG-Coenzyme A reductase
pathway beyond cholesterol lowering alone should be considered. Indeed, statins downregulate
the synthesis of dolichol, ubiquinol farnesol and geranylgeraniol40,41, all of which are associated
with cell transformation42, cell proliferation43 and angiogenesis44. Moreover, statins induce
apoptosis via activation of caspase and mitochondrial pathways45 and modulate cell migration by
down-regulating chemokine secretion and receptor expression in a geranylgeranylation
dependent mechanism.40,46,47 In addition, statins suppress several adhesion molec
molecules
eccul
ules
e iin
n or
orga
organ
gann
ga
tissue
issue and leukocytes such as ICAM-1 or VCAM-148 regulate metalloproteinases and several
cy
yto
oki
kinnes
nes that
that
a are
ree permissive
ppeermissive for tumor growth.49 A
As inhibition off me
m
metalloproteinases
taall
llooproteinases might
cytokines
50
prev
prevent
ven
e t cell tra
transformation
rans
nssfo
orm
mat
atio
ionn50
io
aand
nd sstatins
taati
tin
ns may
ns
y rreduce
eduuce
uce ttumor
umor
um
orr fformation
orm
or
mation
mat
on ass we
well
ell aass graf
ggraft
raf
aftt
51,52
51
52
rejection.
eje
ject
cttio
ion.
n.51,
Interestingly,
Intere
est
stin
in
ngl
gly,
y, tthe
he beneficial
ben
enef
en
e iccia
ef
iall effects
e feect
ef
c s of st
sstatins
a in
at
inss in
i the
the present
ppre
r se
re
sennt study
stud
st
udyy were
ud
were
r not
not only
onl
nlyy
independent of the immunosuppressive therapy but also of statin dose and cholesterol levels.
Even in the “high-cholesterol” subgroup (defined as a mean cholesterol value of more than 5.5
mmol/l), patients on statin therapy were at a lower risk of malignancy formation compared to
patients without statin treatment.
Is there a link between cholesterol levels and cancer development?
In patients after solid organ transplantation, data on the relation of cholesterol and statins on
clinical outcome are sparse. In the present study, no significant association of elevated
cholesterol values and cancer risk was detected. However, cholesterol is a major component of
11
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DOI: 10.1161/CIRCULATIONAHA.111.081059
the cell membrane and plays an important role in vesicular trafficking and cellular pathways. In
line with this concept, Zhuang et al. could demonstrate a decreased apoptosis rate in cholesterol
enriched prostate cancer cells53. Moreover, cholesterol levels influence the activity of
metalloproteinases that are actively involved in tumor promotion54-56 and could represent another
link between cholesterol and tumor growth. While an inverse association of cholesterol levels
and cancer risk had been reported previously57-59 more recent evidence suggest that this
observation may be due to reverse causation59. Therefore, a potential role of cholesterol in the
development of malignancies remains still elusive.
The role of newer immunosuppressive agents in malignancy formation
Transplant-related malignancies arise from a complex interplay of immunologicc aand
nd
d nnonon-on
mmunologic risk factors4. It still remains a matter of debate, however, whether the type of
immunologic
mmu
munnosu
nosuupp
p ress
sssiv
ivee regimen, total dosage and du
dura
rattion of treatm
men
e t orr tth
he degree of
immunosuppressive
duration
treatment
the
immunosuppression,
mmunosuppre
mu
ress
sssio
on,
n aare
ree rrel
relevant
elev
el
evaant
ev
an to de
determining
eteermiining can
ccancer
anceer
er rrisk.
iskk. P
is
Previous
reevi
viouus pu
publications
ub icaati
ubli
tion
onns de
demo
demonstrated,
mons
mo
nstr
t ated
tr
at
that
hat the
the risk
ris
riskk of
of pposttransplant
osstt
ttra
raansspl
p an
antt ma
mali
malignancies
lign
li
gnan
an
nciies iis li
link
linked
nkked
dw
with
itth azathioprine,
azat
azat
athi
h opri
hi
opri
rine
n , bbut
ne
ut not
not with
wiith newer
nneewer
ewer agents
ageent
ns
such
uch as myco
mycophenolate
oph
phen
en
nol
olat
atte mofetil
mo
ofe
feti
t l and
and sirolimus.
s ro
si
oli
limu
mus.
mu
s. 4 P
Preliminary
Pre
reli
re
liimi
m na
nary
ry llong-term
ongon
g teerm ddata
gataa su
at
supp
support
ppor
pp
ortt th
or
the use of
these newer agents, like mTOR inhibitors or tacrolimus, with potential antitumor properties and
lower cancer risk in transplant recipients12.
Limitations
It has to be acknowledged that it is not possible to adjust away all the differences in therapy over
a two decades follow-up and especially during the recent era when statins were more frequently
used compared to the previous era in which more intense immunosuppression was more likely to
cause malignancy. While retrospective analyses are subject to bias and confounding, randomized
clinical trials addressing the role of statins in cancer in immunosuppressed patients are still
12
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DOI: 10.1161/CIRCULATIONAHA.111.081059
lacking, which is mainly due to the long follow-up periods needed. Especially, the difference in
azathioprine use between the study groups could be an important confounder. However, in a Cox
regression model, azathioprine was not an independent risk factor for cancer in our study
population. Only 18% of patients were switched to mTOR inhibitors or tacrolimus over time.
Thus, cancer risk can be further reduced in the future with the use of newer immunosuppressive
drugs.
The sample size of the present study has to be weighed against the high event rate of
tumor occurrence and the long follow-up period of up to 25 years with a median follow-up for
overall survival of 14.4 years. Importantly, all patients included in the study underwent a rigid
heart
post-transplant follow-up schedule according to a standardized protocol in our he
earrt
transplantation
ransplantation clinic and had frequent check-ups at least on a half-yearly basis, which assured a
careful
patient
monitoring
While
ca
areefu
full pa
ati
tien
ent mo
en
mon
ni
nitoring
and early detection off malignancies.
ma
W
Wh
ilee th
thee impact of
immunosuppression
malignancy
formation
remains
like
mmunosuppre
mu
ress
sssio
on on
on m
alig
al
ig
gnanc
nanccy fo
form
rm
matio
io
on rema
mainss chal
ma
cchallenging
hallleeng
ngiing
ing an
andd ddifferent
ifffe
ferrent
rentt ooptions
ptio
ptio
ionss llik
ike
k the
CD4,
agents
CD
D4, CD8,
CD8
C
D8,, CD16
C 16 or
CD
or CD20
CD20 cell
cel
e l count,
coun
co
unt,
t, the
the cumulative
ccum
umul
um
u atiive dose
ul
doose of
of the
t e immunosuppressive
th
immu
im
munnosu
nosuupp
ppre
ress
ssiive
ss
ive ag
gen
entts
ts oorr
60-62
62
the
rejections
have
he number ooff bi
bbiopsy
opsy
op
sy pproven
r ve
ro
venn re
reje
ject
je
c io
ct
ionss hhav
avee be
av
been
en
n pproposed
r po
ro
ose
sedd60
, th
thee nu
numb
number
mber
mb
e ooff se
er
seve
severe
vere
ve
r rejectionss
re
is increasingly considered to be a valuable approach to reflect the grade of immunosuppression,
as the dosing of the immunosuppressive drugs varies not only by body-weight but is also
depending on individual liver metabolization.63,64
In view of the potential viral aetiology of cancer in transplant recipients, it is noteworthy
that cytomegalovirus high-risk constellation (donor (D) +, recipient (R) Г­) was similar in the
statin and the control group.
In addition, the primary outcome measure of this study, i.e. the occurrence of malignancy,
might be influenced, by the occurrence of non-malignant events, cardiac death in particular.
13
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DOI: 10.1161/CIRCULATIONAHA.111.081059
Indeed, such events are known as competing risk events and the Kaplan–Meier estimation
procedure is not directly applicable under these conditions.65 As a consequence the cumulative
incidence function for the event of interest was calculated by appropriately accounting for the
presence of competing risk events.
Conclusion
Thus, in spite of limitations in adjusting for all potential confounders over a follow-up period of
up to 25 years, when factors related to the era of transplantation like overall intensity of
immunosuppression, and use of azathioprine might have changed, the results of the present study
uggest, that statin use is associated with a substantial reduction of cancer risk and
and
nd all-cause
all
ll-c
-cau
-c
ause
au
se
suggest,
mortality in heart transplantation recipients.
Whet
Wh
ethherr these
et
thes
th
ese benefits of statins are specific
speccif
i ic for heart transplant
tran
nsp
s laant recipients
r
Whether
who are at
part
tic
i ularly hig
ighh ri
iskk ooff ca
can
nce
cerr an
andd ca
cann bbee eextrapolated
xtrrapoolatedd to
xt
to aall
lll ppatients
attie
ientts on
on lon
onngg-te
term
rm
m
particularly
high
risk
cancer
long-term
mmu
muno
n su
no
supp
ppre
pp
ress
sssiv
ve th
herrap
apy (p
(par
arti
ar
ticu
ti
cula
cu
larl
r y ta
rl
tac
crol
olim
im
mus aand
nd
dm
mTO
TO
OR in
nhi
hibi
biito
tors
rs)) ne
need
e s to
ed
o bbee
immunosuppressive
therapy
(particularly
tacrolimus
mTOR
inhibitors)
needs
confirmed in
n llong-term
ongon
g teerm
gm rran
ndo
domi
mize
mi
zedd cl
ze
cclinical
inic
in
iccal ttrials.
r al
ri
a s.
s
randomized
Conflict of Interest Disclosures: Thomas F. LГјscher: receives research grants and honoraria
from Pfizer.
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Table 1. Patient characteristics. Categorical variables are presented as number of patients (%).
Continuous variables are presented as median with 25th – 75th percentiles in brackets. The
median follow-up for overall and event free survival is shown with 95% confidence intervals in
brackets.
n = 255
225 ((88))
51 (44 – 57)
106 (45)
129 (55)
Male, n ((%))
Age at time of transplantation (years)
schemic cardiomyopathy (n, %)
Ischemic
Non-ischemic cardiomyopathy (n, %)
CMV high risk constellation
(recipient
recipient negative/donor positive) (n, %)
Immunosuppressive
mmu
muno
mu
nosu
no
supp
su
pprresssiv
pp
ivee therapy
t erapy (n, %)
th
Calcineurin
Cal
Ca
lcineuri
lcin
rin
n iinhibitors
nhiibi
bito
tors
r
Ev
Everolimus
ver
e olimuss
Azathioprine
Az
Prednisone
Pr
red
e nisonee
Mycophenolic
Myco
My
coph
co
phen
ph
enol
en
olic
ol
ic acid
acidd
Swit
tch tto
o tacrolimus
t cr
ta
c ol
olim
imus
us ((n,%)
n %))
n,
Switch
S
wiitch
h to mT
mTOR
OR inhibitors
iinh
nhib
ibit
itor
ors (n
((n,%)
,%))
,%
Switch
Follow-up
Foll
Fo
llow
ow-u
up fo
forr fr
ffreedom
eedo
ee
dom
m from
from ccan
cancer
ance
cerr (yea
((years)
years
rs))
Tumors (n, % of all tumors)
Skin
Lymphoma
Unknown
Intestine
Brain
Bladder
Breast
Kidney
Follow-up for overall survival (years)
Cause of death (n, % of all patients)
Cancer (n, % of deaths)
Cardiovascular (n, % of deaths)
Infection (n, % of deaths)
Other (n, % of deaths)
Rejections ISHT >IB (per year)
Rejections > ISHT 2 (per year)
73 (31)
(98)
2247
47 ((98
9 )
2244 (1
(10)
0
179
79
9 ((71)
71))
71
2232
32
2 ((93)
93))
(62)
1155
15
5 (6
62)
18 (7)
7)
28 ((11)
11))
11
12.6
12
.6 (11.0
(11
(11
1.0 – 14.0)
114.
4.0)
0)
61 (56)
18 (17)
9 (9)
7 (6)
6 (6)
3 (3)
2 (2)
2 (2)
13.7 (12.8 – 14.8)
94 (37)
29 (31)
49 (52)
9 (10)
7 (7)
0.3 (0.1-0.6)
0.1 (0-0.3)
20
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DOI: 10.1161/CIRCULATIONAHA.111.081059
Table 2. Characteristics of patients receiving statin therapy compared to those without statins.
Categorical variables are presented as number of patients (%). Continuous variables are
presented as median with 25th - 75th percentiles in brackets.
Statin therapy
(n=151)
134 (89)
52 (45–57)
125 (72-184)
Male, n (%)
Age at time of transplantation (years)
Follow-up for freedom from cancer (months)
Statin, n (%)
Simvastatin
No statin
(n=104)
91 (88)
50 (41-56)
75 (40-127)
p-value
0.84
0.70
0.55
35 (23)
Fluvastatin
Atorvastatin
6 (4)
28 (19)
Pravastatin
Statin related myopathy (all patients received high dose
statin therapy)
Discontinuation of statin therapy
82 (54)
5 (3)
2 (1)
Immunosuppressive
mmunosuppressive therapy (n, %)
Calcineurin inhibitors
Azathioprine
147 (97)
96 (64)
100 (9
(99)
9)
83 (83)
00.65
.65
65
0.002
Mycophenolic
Myco
My
coph
p en
ph
enol
olic
i aacid
cidd
ci
Baseline
Baaseli
line
li
ne cho
cholesterol
hole
lessterrol vval
le
values
a ues (mmol/l))
110 (74)
5.8 (4.9–6.1)
(4.9–
–6.
6 1)
45 (45)
5.5 ((5.0
5.0 – 6.7))
<0.001
0.50
(49)
699 (4
49)
(39)
337
7 (39
9)
Rejections
ISHLT
Rejeect
ctio
ionss IISH
SHLT
LT > IIB
B (perr yyear)
ea
ar)
(51)
711 ((5
51)
0.3
0.3 (0.1-0.6)
(0.1-0
(0
0.6
.6))
(61)
588 ((61
611)
0.22 (0–0.6)
(0–0
(0
–0.6))
0.17
0 17
0.
7
Rejections ISHLT
ISH
SH
HLT > 2 (per
(pe
perr year)
yeear
ar))
CMV high
hi h risk
i k constellation
ll i ((n,%)
%)
0.1
(0-0.3)
0 1 (0
0.
(0-0
-0.3))
-0
37 (26)
(0-0.4)
00.1
0.
1 (0
(0-0
-0.4
-0
.44)
36 (38)
0.23
00.08
08
54 (36)
32 (59)
54 (52)
29 (54)
Lymphoma
Unknown
7 (13)
6 (11)
11 (20)
3 (6)
Intestine
Brain
2 (4)
3 (6)
5 (9)
3 (6)
Bladder
Breast
2 (4)
0
1 (2)
2 (4)
Kidney
2 (4)
37 (15)
0
57 (22)
10 (4)
19 (8)
19 (8)
30 (12)
4 (2)
4 (2)
5 (2)
3 (1)
00.13
0.
1
13
Cause
transplantation
%))
Cause
Cau
us of trans
nspl
plaant
antatiion ((n,
n, %
Ischemic
sch
hem
e ic cardiomyopathy
cardiomyyop
yopathyy
Non-ischemic
Noonn is
isch
chem
micc cardiomyopathy
car
arddiom
myo
opaath
thyy
Tumors (n, % of all tumors within study group)
Skin
Cause of death (n, % of all patients)
Cancer (n, % of deaths)
Cardiovascular (n, % of deaths)
Infection (n, % of deaths)
Other (n, % of deaths)
21
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DOI: 10.1161/CIRCULATIONAHA.111.081059
Table 3. Hazard ratios and confidence intervals of a Cox regression model investigating the time
to tumor formation.
Statin therapy
Non-ischemic cardiomyopathy
Age (per year)
Male gender
Calcineurin-inhibitor therapy
Azathioprine therapy
Mycophenolate therapy
Switch to mTOR inhibitor (per year)
Switch to Tacrolimus (per year)
Hazard ratio
0.33
0.74
1.06
1.22
1.15
1.45
0.81
1.7
1.4
95% CI
0.21 – 0.51
0.48 – 1.14
1.04 – 1.10
0.45 – 3.3
0.11 – 12.4
0.87 – 2.4
0.47 – 1.37
0.34 -5.7
0.52 – 5.61
p-value
<0.0001
0.17
<0.0001
0.7
0.91
0.15
0.42
0.64
0.38
Figure Legends:
Figure 1. Cumulative incidence curves comparing tumor occurrence (p < 0.003) and death from
mali
ma
lign
li
gnan
gn
antt vs
an
vs.. no
onn-m
malignant origin (p = 0.02) in
n ppa
atients receivin
ng stat
attin therapy compared to
malignant
non-malignant
patients
receiving
statin
patients
pati
ien
e ts witho
without.
out
ut..
Figure 2. Cum
um
mul
u at
ativ
iv
ve in
nciide
d nc
n e of
o ““skin”
skkin
in” (p
p=0
0.2
2) vs.
vs ““non-skin”
nonno
n sk
nskin
in” ma
in
mali
lign
li
gnan
gn
anci
an
c ess ((p=0.04)
ci
p 0.
p=
0.04
0 ) in
Cumulative
incidence
(p=0.2)
malignancies
patients with statin - vs. no statin.
Figure 3. Cumulative incidence curves comparing tumor occurrence (p=0.02) and death from
malignant vs. non-malignant origin (p=0.007) in patients receiving statin therapy > 50% vs. <
50% of follow-up time. (TTC: time to cancer).
Figure 4. Overall survival of patients receiving statin therapy compared to patients without such
treatment (Log-rank p<0.0001).
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