Re
Po
Ca diol.
2018;37(10):859---863
www. e po ca diol.o g
Re is a
Po uguesa
de
Ca diologia
Po uguese
Jou nal
o
Ca diology
REVIEW
ARTICLE
P o on
pump
inhibi o s
and
he
isk
o
se e e
ad e se
e en s
---
A
ca dio ascula
bombshell?夽
Nelson
Cunhaa,∗,
An ónio
Ped o
Machadob
aSe ic¸o
de
Ca diologia,
Hospi al
Uni e si á io
de
San a
Ma ia
(CHLN),
Cen o
Académico
de
Medicina
de
Lisboa
e
CCUL,
Faculdade
de
Medicina,
Uni e sidade
de
Lisboa,
Lisboa,
Po ugal
bSe ic¸o
de
Medicina
I
B,
CHLN
-
Hospi al
de
San a
Ma ia,
Lisboa,
Po ugal
Recei ed
20
Sep embe
2017;
accep ed
8
Oc obe
2017
KEYWORDS
P o on
pump
inhibi o s;
Ni ic
oxide;
Acu e
co ona y
synd ome;
S oke
Abs ac
P o on
pump
inhibi o s
a e
cu en ly
one
o
he
mos
p esc ibed
pha macological
classes
in
de eloped
coun ies,
gi en
hei
e ec i eness
and
sa e y
p o ile,
which
has
un il
now
been
conside ed
a o able.
Howe e ,
in
ecen
yea s,
se e al
pape s
ha e
been
published
ha
associa e
p olonged
use
o
hese
d ugs
wi h
a
wide
ange
o
ad e se
e ec s,
posing
doub s
abou
hei
sa e y.
Among
he
ad e se
e ec s
desc ibed
is
an
inc eased
isk
o
ca dio ascula
e en s.
This
ela ionship
was
i s
desc ibed
in
subjec s
a e
acu e
co ona y
synd ome
due
o
he
in e e ence
o
p o on
pump
inhibi o s
in
he
cy och ome
P450
2C19
and
he
con e sion
o
clopidog el
o
i s
ac i e
me aboli e.
Mo e
ecen
s udies
ha e
also
epo ed
his
ela ionship
wi h
he
use
o
an ipla ele
agen s
ha
do
no
depend
on
cy och ome
P450
2C19
ac i a ion.
The
p oposed
mechanism
is
inhibi ion
o
dime hyla ginine
dime hylaminohyd olase,
a
physiological
inhibi o
o
asymme ic
dime hyla ginine,
which
inc eases
plasma
concen a ions
o
he
la e
enzyme,
leading
o
lowe
le els
o
ni ic
oxide.
By
e iewing
in
his
a icle
he
ela ionship
be ween
he
use
o
p o on
pump
inhibi o s
and
inc eased
isk
o
ca dio ascula
and
ce eb o ascula
e en s,
he
au ho s
aim
o
ale
he
medical
communi y
o
he
po en ially
ha m ul
e ec s
o
hese
d ugs,
and
ecommend
he
se ing
o
a
mo a o ium
on
hei
p olonged
use.
©
2018
Sociedade
Po uguesa
de
Ca diologia.
Published
by
Else ie
Espa˜
na,
S.L.U.
This
is
an
open
access
a icle
unde
he
CC
BY-NC-ND
license
(h p://c ea i ecommons.o g/licenses/by-
nc-nd/4.0/).
夽Please
ci e
his
a icle
as:
Cunha
N,
Machado
AP.
Inibido es
da
bomba
de
p o ões
e
o
isco
de
e en os
ad e sos
g a es
---
uma
bomba
ca dio ascula ?.
Re
Po
Ca diol.
2018;37:859---863.
∗Co esponding
au ho .
E-mail
add ess:
[email p o ec ed]
(N.
Cunha).
2174-2049/©
2018
Sociedade
Po uguesa
de
Ca diologia.
Published
by
Else ie
Espa˜
na,
S.L.U.
This
is
an
open
access
a icle
unde
he
CC
BY-NC-ND
license
(h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
860
N.
Cunha,
A.P.
Machado
PALAVRAS-CHAVE
Inibido es
da
bomba
de
p o ões;
Óxido
ní ico;
Sínd ome
co oná ia
aguda;
Aciden e
ascula
ce eb al
Inibido es
da
bomba
de
p o ões
e
o
isco
de
e en os
ad e sos
g a es
---
uma
bomba
ca dio ascula ?
Resumo
Os
inibido es
da
bomba
de
p o ões
são
a ualmen e
uma
das
classes
a macológicas
mais
p esc i as
nos
países
desen ol idos,
dada
a
sua
e icácia
e
pe il
de
segu anc¸a
a é
en ão
conside ado
a o á el.
Con udo
ao
longo
dos
úl imos
anos,
êm
sido
publicados
á ios
abalhos
que
associam
o
uso
p olongado
des es
á macos
a
uma
panóplia
de
e ei os
ad e sos,
colocando
dú idas
ace ca
da
sua
segu anc¸a.
En e
os
e ei os
ad e sos
desc i os,
salien a-se
o
aumen o
do
isco
de
e en os
ca dio ascula es.
Es a
elac¸ão
oi
p imei amen e
desc i a
nos
indi íduos
após
sín-
d ome
co oná ia
aguda
pela
in e e ência
dos
inibido es
da
bomba
de
p o ões
no
ci oc omo
P450
2C19
e
a
con e são
do
clopidog el
em
me aboli o
a i o.
No
en an o,
abalhos
mais
ecen es
desc e em
es a
elac¸ão
ambém
com
o
uso
de
an iag egan es
que
não
dependem
da
a i ac¸ão
pelo
ci oc omo
P450
2C19.
O
mecanismo
p opos o
é
pela
inibic¸ão
da
dime ila ginina
dime ilaminohid olase,
inibido
isiológico
da
dime ila ginina
assimé ica,
aumen ando
assim
as
concen ac¸ões
plasmá icas
des a
úl ima
enzima
e
po
sua
ez
aduzindo-se
em
ní eis
mais
eduzidos
de
óxido
ní ico.
Os
au o es
ao
e e
nes e
a igo
a
elac¸ão
en e
o
uso
de
inibido es
da
bomba
de
p o ões
e
o
isco
ac escido
de
e en os
ca dio
e
ce eb o ascula es,
p e endem
ale a
a
comunidade
cien í ica
pa a
os
po enciais
e ei os
ne as os
des es
á macos
e
ecomendam
a
colocac¸ão
de
uma
mo a ó ia
à
sua
u ilizac¸ão
p olongada.
©
2018
Sociedade
Po uguesa
de
Ca diologia.
Publicado
po
Else ie
Espa˜
na,
S.L.U.
Es e ´
e
um
a igo
Open
Access
sob
uma
licenc¸a
CC
BY-NC-ND
(h p://c ea i ecommons.o g/licenses/by-
nc-nd/4.0/).
In oduc ion
P o on
pump
inhibi o s
(PPIs)
we e
he
six h
mos
p esc ibed
pha macological
class
in
Po ugal
in
2015,
wi h
6.99
million
uni s
sold,
and
he
eigh h
in
alue
(41.2
million
eu os
a
wholesale
p ices),
acco ding
o
da a
om
S a is ics
Po u-
gal,
he
na ional
s a is ics
ins i u e.
Fac o s
con ibu ing
o
his
high
consump ion
include
hese
d ugs’
e icacy
in
ea ing
dyspepsia,
pep ic
ulce ,
gas oesophageal
e lux
disease
and
e osi e
esophagi is,
a
sa e y
p o ile
ha
has
been
conside ed
a o able,
he
all
in
p ices
as
gene ic
e sions
en e ed
he
ma ke ,
inap-
p op ia e
p esc ibing
and
use
o
pe iods
exceeding
hose
ecommended,
and
ebound
acid
hype sec e ion.1 --- 3
The
ebound
e ec ,
in
which
dyspepsia
ecu s
a e
wi hd awal
o
ea men ,
and
which
leads
o
dependence,
is
one
o
he
main
easons
o
ch onic
use
o
PPIs
in
a
la ge
and
g owing
numbe
o
pa ien s.
Pa adoxically,
he
d ugs
induce
he
symp oms
hey
a e
supposed
o
ea .4
The
de elopmen
o
dependence
may
explain
he
esul s
o
a
s udy
in
he
UK
showing
ha
he
o al
olume
o
PPIs
p esc ibed
ose
en old
in
ou
yea s,
wi h
epea
p e-
sc ip ions
accoun ing
o
77%
o
he
o al
in
he
las
yea
analyzed.5In
a
US
s udy,
PPIs
we e
p esc ibed
app op ia ely
in
only
35%
o
cases;
hey
we e
p esc ibed
o
gas op o ec-
ion
in
18%
and
in
36%
he e
was
no
documen ed
app op ia e
indica ion.6
PPIs
cause
hype gas inemia
and
achlo hyd ia.
In
he
sho
e m,
hype gas inemia
leads
o
hype acidi y,
wo sen-
ing
he
symp oms
o
gas oesophageal
e lux
and
dyspepsia,
when
ea men
is
wi hd awn.3,7 In
he
long
e m,
i
can
esul
in
en e och oma in-like
cell
hype plasia
and
pa ie al
cell
hype ophy,
leading
o
dyspepsia
and
inc easing
he
isk
o
ca cinoid
umo s.8
Despi e
he
widely
held
a o able
opinion
o
he
sa e y
o
PPIs,
esul s
published
in
ecen
yea s
ha e
aised
se ious
ques ions
conce ning
hei
p olonged
use.
A
g owing
numbe
o
s udies
and
edi o ials
ha e
begun
o
call
a en ion
o
he
associa ion
be ween
PPI
use
and
inc eased
isk
o
a
a ie y
o
condi ions.
These
include
Clos idium
di icile-associa ed
dia hea
and
en e ic
in ec ion
wi h
Campylobac e ,
Salmonella,
Shigella
and
Lis e ia9---11;
communi y-acqui ed
pneumonia12---14;
bone
ac u es,
pa icula ly
wi h
e y
long
ea men
pe iods15---17;
dose-dependen
inc eases
in
ex ahepa ic
cholangioca ci-
noma
and
ca cinoma
o
he
ampulla
o
Va e ,
duodenum,
jejunum
and
panc eas18---20;
esophageal
adenoca cinoma
in
indi iduals
wi h
Ba e ’s
esophagus21;
acu e
in e s i ial
neph i is22 and
ch onic
kidney
disease23;
and
a he o h om-
bo ic
ca dio ascula
e en s.24,25
P o on
pump
inhibi o s
and
isk
o
ca dio ascula
e en s
The
i s
epo s
o
an
inc eased
isk
o
ca dio ascula
e en s
associa ed
wi h
PPIs
came
om
s udies
on
pa ien s
wi h
a
his o y
o
acu e
co ona y
synd ome
ea ed
wi h
clopido-
g el.
These
s udies
ini ially
a ibu ed
his
ise
in
a es
o
ein a c ion
and
o he
acu e
co ona y
e en s
a e
hospi-
al
discha ge
o
he
educ ion
in
clopidog el’s
an ipla ele
e ec
caused
by
he
PPI
in e e ing
in
i s
con e sion
in
he
P o on
pump
inhibi o s
and
he
isk
o
se e e
ad e se
e en s
---
A
ca dio ascula
bombshell?夽861
li e
o
he
ac i e
me aboli e
by
blocking
he
cy och ome
P450
2C19
(CYP2C19).26,27
In
iew
o
he
con o e sy
su ounding
hese
ea ly
s ud-
ies,
a
sys ema ic
e iew
and
me a-analysis28 was
pe o med
examining
only
s udies
published
be ween
2012
and
2016.
This
con i med
ha
he
concomi an
use
o
clopidog el
and
PPIs
ollowing
co ona y
angioplas y
was
associa ed
wi h
highe
sho - e m
mo ali y
and
a
highe
long- e m
incidence
o
majo
ad e se
ca diac
e en s,
myoca dial
in a c ion
and
s en
h ombosis,
al hough
long- e m
mo -
ali y
was
no
signi ican ly
di e en .
Howe e ,
o he
ecen
s udies
ha e
associa ed
PPIs
no
only
wi h
wo se
clinical
ou comes
when
used
concomi an ly
wi h
clopidog el
in
high
ca dio ascula
isk
popula ions,
bu
also
wi h
educed
he apeu ic
bene i
o
o he
an ipla ele
agen s,
such
as
aspi in
and
icag elo ,
which
do
no
in ol e
ac i a ion
o
he
CYP2C19
isoenzyme,
sugges ing
ha
ano he
mechanism
is
a
wo k.29---31 This
appea s
o
be
co -
obo a ed
by
o he
s udies
showing
ha
all
membe s
o
he
PPI
pha macological
class,
e en
hose
wi h
a
minimal
e ec
on
CYP2C19,
inc ease
ca dio ascula
isk
in
pa ien s
wi h
acu e
co ona y
synd ome.24,26,30,32---34
Va ious
g oups
ha e
sugges ed
ha
his
inc eased
isk
is
mainly
due
o
educed
endo helial
p oduc ion
o
ni ic
oxide
(NO),
which
unc ions
as
an
endogenous
pla ele
inhibi o .
Thus,
he
e ec
o
PPIs
on
pla ele
agg ega ion
would
esul
om
hei
dele e ious
e ec
on
endo helial
unc ion.35
NO
eleased
by
endo helial
cells
plays
a
c ucial
ole
in
ascula
homeos asis,
ac ing
as
an
endogenous
asodila-
o
egula ing
local
ascula
one,
as
an
endogenous
pla ele
inhibi o
egula ing
pla ele
ac i i y,
and
h ough
i s
an ia he ogenic
ac ion
on
he
endo helium,
main aining
he
no mal
s uc u e
o
he
essel
wall.36
NO
syn hesis
in
essels
is
egula ed
by
endo helial
NO
syn hase,37 which
is
inhibi ed
by
ADMA
(asymme ic
dime hyla ginine),
such
ha
highe
le els
o
ADMA
educe
endo helial
NO
p oduc ion.38
Plasma
ADMA
concen a ions
a e
ele a ed
in
enal
ailu e,
co ona y
disease,
hype ension,
diabe es
and
p e-
eclampsia.
When
pa ien s
wi h
hese
condi ions
ake
PPIs,
ADMA
le els
in
endo helial
cells
ise
e en
mo e,
u he
inhibi ing
NO
syn hase,
educing
endo helial
NO
p oduc ion
and
exace ba ing
endo helial
dys unc ion.
As
he
bioa ail-
abili y
o
NO
diminishes,
condi ions
a o
he
p og ession
o
a he oscle osis
and
he
occu ence
o
a he o h ombo ic
e en s.25,39
PPIs
inc ease
plasma
ADMA
le els
and
educe
endo helial
NO
p oduc ion
by
inhibi ing
dime hyla ginine
dime hy-
laminohyd olase
(DDAH),
an
enzyme
ha
deg ades
ADMA.40
The
esea ch
g oup
ha
iden i ied
his
cascade
epo ed
ha
in
he
same
p eclinical
s udy
ADMA
le els
ose
by
a ound
30%
in
ex- i o
human
endo helial
cells
exposed
o
a
PPI
and
in- i o
se um
concen a ions
ose
by
abou
20%
in
mice
ecei ing
a
PPI.40
The
same
g oup
ecen ly
pe o med
a
p ospec i e
c osso e
pilo
s udy
in
21
indi iduals
(11
heal hy
and
10
wi h
es ablished
ca dio ascula
disease)
o
assess
in
i o
he
co ela ion
in
humans
be ween
PPI
use
and
ADMA
le els
and
endo helial
unc ion.
Al hough
PPI
use
did
no
signi i-
can ly
in luence
ascula
endo helial
unc ion,
highe
ADMA
le els
we e
obse ed
in
he
PPI
a m,
and
his
end
was
mo e
p onounced
among
subjec s
wi h
a
his o y
o
ascula
disease.41
Howe e ,
his
s udy
has
some
me hodological
laws,
pa -
icula ly
he
sho
ea men
pe iod
( ou
weeks
in
each
g oup)
and
he
small
sample
size,
which
would
be
unlikely
o
p o ide
esul s
wi h
s a is ical
signi icance.
Fu he mo e,
he
EndoPAT
echnique
used
in
he
s udy
o
assess
he
e ec
o
d ugs
on
ascula
unc ion
is
no
he
ideal
es
o
de ec
a ia ions
in
endo helial
unc ion
in
he
ea ly
s ages
o
clinical
d ug
ials,42 and
he
al e a ions
iden i ied
by
his
me hod
may
be
pa ly
NO-dependen .43 The
s udy
has
o he
limi a ions
ha
a e
beyond
he
scope
o
his
e iew.
E en
so,
since
he e
is
a
endency
o
highe
ADMA
le els
wi h
PPI
use,
he e
appea s
o
be
a
need
o
s udies
wi h
mo e
ep esen a i e
popula ions
and
longe
ollow-up,
in
o de
o
ob ain
esul s
wi h
clinical
signi icance.
As
s a ed
abo e,
i
is
known
ha
ele a ed
plasma
ADMA
le els
a e
a
isk
ac o
o
ca dio ascula
mo bidi y
and
mo ali y,
in
bo h
pa ien s
wi h
ca dio ascula
disease
and
appa en ly
heal hy
indi iduals.44---50 The
la e
associa ion
is
hus
a
po en ially
se ious
public
heal h
p oblem
ha
should
be
in es iga ed.
On
he
assump ion
ha
PPIs
can
inc ease
le els
o
ADMA
e en
in
heal hy
indi iduals,
i
is
essen ial
o
assess
he
ela-
ionship
be ween
PPI
use
and
he
isk
o
a
i s
ca dio ascula
e en
in
he
popula ion
wi hou
known
ca dio ascula
dis-
ease.
The
olume
o
s udies
published
on
his
subjec
has
inc eased
ma kedly
in
ecen
yea s.
Examining
he
associ-
a ion
be ween
PPI
mono he apy
and
ca dio ascula
e en s
in
indi iduals
wi h
no
his o y
o
ca dio ascula
disease,
Sun
e
al.51 pe o med
a
me a-analysis
o
16
andomized
con olled
ials
including
7540
indi iduals
on
PPI
mono he -
apy
o
gas oesophageal
e lux
disease.
The
esul s
show
a
70%
inc eased
ca dio ascula
isk
in
pa ien s
aking
PPIs
( ela i e
isk
1.70,
95%
con idence
in e al
[CI]
1.13-
2.56,
p=0.01,
I2=0%),
an
associa ion
ha
appea ed
o
be
s onge
in
he
omep azole
and
long- e m
ea men
sub-
g oups.
The e
ha e
been
ew
s udies
on
he
associa ion
be ween
PPI
use
and
ca dio ascula
e en s
ha
included
s oke
in
he
combined
endpoin s24,30,31,52---55 and
only
one
assessed
ecu -
en
s oke
as
i s
p ima y
endpoin .
Wang
e
al.
acco dingly
pe o med
a
e ospec i e
analysis
based
on
a
na ionwide
da abase
o
assess
he
ela ion
be ween
isk
o
a
i s
ischemic
ce eb o ascula
e en
and
PPI
use
in
he
Taiwanese
popula ion.
They
compa ed
hospi aliza ions
wi h
a
p ima y
diagnosis
o
ischemic
s oke
in
indi iduals
wi h
and
wi h-
ou
cu en
PPI
use
a
a
1:1
a io.
PPI
use
was
associa ed
wi h
a
highe
isk
o
a
i s
ischemic
s oke,
independen ly
o
an ipla ele
he apy,
wi h
a
haza d
a io
o
1.36
(95%
CI
1.14-
1.620,
p=0.001).
The
associa ion
was
s onge
in
pa ien s
aged
<60
yea s.56
Conclusion
On
he
basis
o
he
esul s
o
he
abo e
s udies,
which
sugges
a
causal
ela ion
be ween
PPI
use
and
inc eased
isk
o
ca dio ascula
e en s,
en e ic
in ec ions,
pneumo-
nia,
ch onic
kidney
disease
and
cance ,
among
o he s,
he
862
N.
Cunha,
A.P.
Machado
au ho s
ecommend
a
leas
he
se ing
o
a
mo a o ium
on
hei
p olonged
use.
Wide
awa eness
o
hese
wo ying
da a
on
he
sa e y
o
long- e m
PPI
use
should
p omp
discussion
o
hei
use
(and
abuse)
in
Po ugal,
and
help
b ing
abou
mo e
a ional
p esc ibing
o
hese
d ugs.
Con lic s
o
in e es
The
au ho s
ha e
no
con lic s
o
in e es
o
decla e.
Re e ences
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e
al.
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e
al.
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o
a
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e
al.
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o
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4.
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ha
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apy
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he
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i
is
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o
ea .
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