Prevalence of bleeding secondary to anticoagulation and mortality in patients with atrial fibrillation admitted with SARS-CoV-2 infection
Abstract
Supplementary data associated with this article can befound, in the online version, at https://doi.org/10.1016/j.medcli.2021.06.015
Full text
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Medicina
Clínica
158
(2022)
569–575
w
w
w.else ie .es/medicinaclinica
O iginal
a icle
P e alence
o
bleeding
seconda y
o
an icoagula ion
and
mo ali y
in
pa ien s
wi h
a ial
fib illa ion
admi ed
wi h
SARS-CoV-2
in ec ion
Rica do
Rubini-Cos aa,b,1,
F ancisco
Be múdez-Jiméneza,b,c,1,
Rica do
Ri e a-Lópeza,b,
Elena
Sola-Ga cíaa,b,
Hadi
Nagib-Rayab,d,
Edua do
Mo eno-Escoba b,d,
Miguel
Ángel
López-Zú˜
nigae,
Adela
B iones-T a és ,
F ancisco
Sanz-He e ag,
Jose
Miguel
Sequí-Saba e h,
Juan
Luis
Rome o-Cab e ai,
Ja ie
Maíllo-Secoj,
Felipe
Fe nández-Vázquezj,
Ma ía
Ri adenei a-Ruizk,
Lucas
López-Vale ol,
Ca los
Gómez-Na a om,
Jose
An onio
Apa icio-Gómezm,
Miguel
Ál a ez
Lópeza,b,
Luis
Te cedo a,b,
Ma ía
Molina-Jiméneza,b,
Rosa
Macías-Ruiza,b,
Juan
Jiménez-Jáimeza,b,∗
aSe icio
de
Ca diología,
Hospi al
Gene al
Uni e si a io
Vi gen
de
las
Nie es,
A da.
de
las
Fue zas
A madas
2,
18014
G anada,
Spain
bIns i u o
de
In es igación
Biosani a ia
IBS,
Uni e sidad
de
G anada,
Hospi al
Real,
A enida
del
Hospicio,
s/n,
18010
G anada,
Spain
cCen o
Nacional
de
In es igaciones
Ca dio ascula es
Ca los
III
(CNIC),
Melcho
Fe nández
Almag o,
3,
28029
Mad id,
Spain
dSe icio
de
Ca diología,
Hospi al
Clínico
San
Cecilio,
A .
del
Conocimien o,
s/n,
18016
G anada,
Spain
eSe icio
de
Medicina
In e na,
Hospi al
Uni e si a io
de
Jaén,
A .
del
Ejé ci o
Espa˜
nol,
10,
23007
Jaén,
Spain
Se icio
de
U gencias,
Conso cio
Hospi al
Gene al
Uni e si a io
de
Valencia,
A .
de
les
T es
C eus,
2,
46014
Valencia,
Spain
gSe icio
de
Neumología,
Conso cio
Hospi al
Gene al
Uni e si a io
de
Valencia,
A .
de
les
T es
C eus,
2,
46014
Valencia,
Spain
hSe icio
de
Reuma ología,
Hospi al
Uni e si a io
Reina
So ía,
A .
Menendez
Pidal,
s/n,
14004
Có doba,
Spain
iSe icio
de
Medicina
In e na,
Hospi al
Uni e si a io
Reina
So ía,
A .
Menendez
Pidal,
s/n,
14004
Có doba,
Spain
jSe icio
de
Ca diología,
Hospi al
Uni e si a io
de
León,
Al os
de
na a,
s/n,
24071
León,
Spain
kSe icio
de
Ca diología,
Hospi al
Uni e si a io
Vi gen
Maca ena,
D .
Fed iani,
3,
41009
Se illa,
Spain
lHospi al
Uni e si a io
de
Cas ellón,
A inguda
de
Benicàssim,
128,
12004
Cas ellón,
Spain
mSe icio
de
Ca diología,
Hospi al
Uni e si a io
To ecá denas,
He mandad
de
Donan es
de
Sang e,
s/n,
04009
Alme ía,
Spain
a
i
c
l
e
i
n
o
A icle
his o y:
Recei ed
27
Ap il
2021
Accep ed
21
June
2021
A ailable
online
15
July
2021
Keywo ds:
COVID-19
A ial
fib illa ion
Majo
bleeding
Mo ali y
An icoagula ion
a
b
s
a
c
In oduc ion
and
pu pose:
A ial
fib illa ion
(AF)
is
common
in
pa ien s
admi ed
wi h
se e e
COVID-
19.
Howe e ,
he e
is
limi ed
da a
abou
he
managemen
o
ch onic
an icoagula ion
he apy
in
hese
pa ien s.
We
assessed
he
an icoagula ion
and
incidence
o
majo
ca dio ascula
e en s
in
hospi alized
pa ien s
wi h
AF
and
COVID-19.
Me hods:
We
e ospec i ely
in es iga ed
all
consecu i e
pa ien s
wi h
AF
admi ed
wi h
COVID-19
be ween
Ma ch
and
May
2020
in
9
Spanish
hospi als.
We
selec ed
a
con ol
g oup
o
non-AF
pa ien s
consecu i ely
admi ed
wi h
COVID-19.
We
compa ed
baseline
cha ac e is ics,
incidence
o
majo
bleed-
ing,
h ombo ic
e en s
and
mo ali y.
We
used
p opensi y
sco e
ma ching
(PSM)
o
minimize
po en ial
con ounding
a iables,
as
well
as
a
mul i a ia e
analysis
o
p edic
majo
bleeding
and
dea h.
Resul s:
305
pa ien s
admi ed
wi h
AF
and
COVID-19
we e
included.
A e
PSM,
151
AF
pa ien s
we e
ma ched
wi h
151
con ol
g oup
pa ien s.
Du ing
admission,
low-molecula -weigh
hepa in
was
he
p incipal
an icoagulan
and
he
incidence
o
majo
bleeding
and
mo ali y
we e
highe
in
he
AF
g oup
[16
(10.6%)
s
3
(2%),
p
=
0.003;
52
(34.4%)
s
35
(23.2%),
p
=
0.03,
espec i ely].
The
mul i a ia e
analysis
showed
he
p esence
o
AF
as
independen
p edic o
o
in-hospi al
majo
bleeding
and
mo ali y
in
COVID-19
pa ien s.
In
AF
g oup,
a
seconda y
mul i a ia e
analysis
iden ified
high
le els
o
D-dime
as
independen
p edic o
o
in-hospi al
majo
bleeding.
Conclusions:
AF
pa ien s
admi ed
wi h
COVID-19
ep esen
a
popula ion
a
high
isk
o
bleeding
and
mo ali y
du ing
admission.
I
seems
ad isable
o
indi idualize
an icoagula ion
he apy
du ing
admission,
conside ing
pa ien
specific
bleeding
and
h ombo ic
isk.
©
2021
Else ie
Espa˜
na,
S.L.U.
All
igh s
ese ed.
Abb e ia ions:
LMWH,
low-molecula -weigh
hepa in;
PSM,
p opensi y
sco e
ma ching;
VTE,
enous
h omboembolism.
∗Co esponding
au ho .
E-mail
add ess:
[email p o ec ed]
(J.
Jiménez-Jáimez).
1Bo h
au ho s
con ibu ed
equally.
h ps://doi.o g/10.1016/j.medcli.2021.06.015
0025-7753/©
2021
Else ie
Espa˜
na,
S.L.U.
All
igh s
ese ed.
R.
Rubini-Cos a,
F.
Be múdez-Jiménez,
R.
Ri e a-López
e
al.
Medicina
Clínica
158
(2022)
569–575
Palab as
cla e:
COVID-19
Fib ilación
au icula
Hemo agia
mayo
Mo alidad
An icoagulación
P e alencia
de
hemo agia
secunda ia
a
an icoagulación
y
mo alidad
en
pacien es
con
fib ilación
au icula
ing esados
po
in ección
po
SARS-CoV-2
e
s
u
m
e
n
An eceden es
y
obje i os:
La
fib ilación
au icula
(FA)
es
ecuen e
en
pacien es
ing esados
po
COVID-19
g a e.
Sin
emba go,
los
da os
sob e
el
manejo
de
la
an icoagulación
c ónica
en
es os
pacien es
son
escasos.
Analizamos
la
an icoagulación
y
la
incidencia
de
episodios
ca dio ascula es
mayo es
en
pacien es
con
FA
ing esados
po
la
COVID-19.
Mé odos:
Re ospec i amen e,
se
iden ifica on
odos
los
pacien es
con
FA
ing esados
po
la
COVID-19
en e
ma zo
y
mayo
de
2020,
en
9
hospi ales
espa˜
noles.
Se
seleccionó
un
g upo
con ol
de
pacien es
ing esados
consecu i amen e
po
la
COVID-19
sin
FA.
Se
compa a on
las
ca ac e ís icas
basales,
inci-
dencia
de
hemo agias
mayo es,
episodios
ombó icos
y
mo alidad.
Pa a
educi
po enciales
ac o es
de
con usión
se
ealizó
un
empa ejamien o
po
pun uación
de
p opensión,
así
como
un
análisis
mul i a ian e
pa a
p edeci
hemo agia
mayo
y
mo alidad.
Resul ados:
Se
incluye on
305
pacien es
con
FA
ing esados
po
la
COVID-19.
T as
el
empa ejamien o
po
pun uación
de
p opensión,
151
pacien es
con
FA
ue on
empa ejados
con
151
con oles.
Du an e
el
ing eso,
la
hepa ina
de
bajo
peso
molecula
ue
el
p incipal
an icoagulan e
y
la
incidencia
de
hemo agia
mayo
y
mo alidad
ue
mayo
en
el
g upo
de
FA
(16[10,6%]
s.
3[2%],
p
=
0,003;
52[34,4%]
s.
35[23,2%],
p
=
0,03,
espec i amen e).
El
análisis
mul i a ian e
demos ó
la
p esencia
de
FA
como
p edic o
indepen-
dien e
de
sang ados
y
mo alidad
in ahospi ala ia
en
los
pacien es
con
la
COVID-19.
En
el
g upo
de
FA,
un
segundo
análisis
mul i a ian e
iden ificó
alo es
ele ados
de
díme o-D
como
p edic o
independien e
de
hemo agia
mayo
in ahospi ala ia.
Conclusiones:
Los
pacien es
con
FA
ing esados
po
la
COVID-19
ep esen an
una
población
de
al o
iesgo
de
sang ado
y
mo alidad
du an e
el
ing eso.
Pa ece
ecomendable
indi idualiza
la
an icoagulación
du an e
el
ing eso,
conside ando
el
iesgo
específico
de
sang ado
y
ombosis.
©
2021
Else ie
Espa˜
na,
S.L.U.
Todos
los
de echos
ese ados.
In oduc ion
The
co ona i us
disease
2019
(COVID-19)
pandemic
caused
by
he
se e e
acu e
espi a o y
synd ome-co ona i us-2
(SARS-CoV-
2)
has
apidly
sp ead
h oughou
he
wo ld
causing
significan
mo bidi y
and
mo ali y.1Se e al
s udies
ha e
epea edly
sugges ed
ha
p e-exis ing
ca dio ascula
como bidi ies
a e
asso-
cia ed
wi h
a
wo se
p ognosis
COVID-19.2–5 Specifically,
a ial
fib illa ion
(AF)
has
been
epo ed
as
a
common
condi ion
in
pa ien s
admi ed
wi h
se e e
o ms
o
COVID-19.3,6,7 I
has
been
sugges ed
ha
AF
migh
be
an
independen
p edic o
o
mo al-
i y
o
hese
pa ien s.8Howe e ,
unde lying
ae iology
o
his
high
mo ali y
a es
a e
no
well
es ablished.
On
he
basis
o
possible
d ug-d ug
in e ac ions,
he
Ame ican
Hea
Associa ion
(AHA)
and
he
Eu opean
Socie y
o
Ca diology
(ESC)
ag ee
on
he
ecommenda ion
o
hepa in
as
he
an icoagu-
lan
o
choice
in
hospi alized
COVID-19
pa ien s
wi h
AF
who
a e
ecei ing
p io
an icoagula ion.9,10 Ce ainly,
he
sys ema ic
an i-
coagula ion
wi h
hepa in
is
he
mos
common
s a egy
adop ed
by
he
physicians
in
his
clinical
scena io.
Howe e ,
he e
a e
no
da a
ega ding
he
di e en
an icoagula ion
he apies
in
hese
pa ien s
and
he
incidence
o
po en ial
ou comes,
especially,
h ombo ic
and
majo
bleedings.
The
p ima y
aim
o
his
s udy
was
o
assess
he
incidence
haem-
o hagic
and
h ombo ic
e en s,
mo ali y
and
he
an icoagula ion
egimen
in
a
mul icen ic
coho
o
pa ien s
wi h
AF
admi ed
wi h
COVID-19.
In
addi ion,
we
p e end
o
iden i y
clinical
o
analy i-
cal
independen
p edic o s
o
majo
bleeding
and
mo ali y
du ing
admission.
Pa ien s
and
me hods
Popula ion
and
s udy
design
A
case–con ol
mul icen ic
s udy
was
pe o med
in
9
e ia y
e e al
hospi als
om
Spain.
All
pa ien s
wi h
p e ious
o
newly
diagnosed
AF
admi ed
wi h
confi med
SARS-CoV-2
in ec ion
be ween
Ma ch
1s
and
May
31s ,
2020,
we e
e ospec i ely
iden ified.
Confi med
SARS-CoV-2
in ec ion
was
defined
as
a
pos-
i i e
nasopha yngeal
polyme ase
chain
eac ion
and/o
posi i e
se ological
es .
Pa ien s
wi hou
a
p e ious
diagnosis
o
AF
we e
conside ed
as
newly
diagnosed
AF
and
all
we e
confi med
by
ECG
a
admission.
We
included
a
con ol
g oup
o
COVID-19
pa ien s
admi ed
du ing
he
same
pe iod
wi hou
AF.
The
con ol
g oup
was
ob ained
om
he
admi ed
COVID-19
pa ien
da abase
o
he
coo dina o
cen e,
which
was
p o ided
by
he
Medical
Reco ds
Depa men ,
and
he
pa ien s
we e
consecu i ely
included
by
admission
da e
un il
eaching
he
same
numbe
o
AF
g oup,
305
pa ien s.
Pa ien s
we e
ollowed
up
a
mean
o
7
±
1.6
mon hs
a e
hospi aliza ion,
by
e ision
o
medical
digi al
eco ds
o
by
elephone
con ac
when
necessa y.
The
Local
E hics
Commi ee
o
he
coo dina o
cen e
app o ed
he
s udy
p o ocol.
Da a
collec ion
and
ou comes
Baseline
cha ac e is ics,
hospi aliza ion
da a
and
ou comes
du ing
admission
and
ollow-up
we e
analyzed.
Local
elec onic
medical
eco ds
se ed
as
sou ce
da a,
which
we e
ex ac ed
by
each
cen e
esea che
and
cen alized
o
he
s udy
coo dina o
in
an
anonymized
da abase.
Baseline
in es iga ions
comp ised
p e ious
como bidi ies,
including
AF-ca dio ascula
isk
ac o s
wi h
a
pa icula
ocus
on
an i h ombo ic
he apy
(an icoagulan
and
an ipla ele ).
The
diag-
nosis
o
p e ious
AF
was
checked
in
medical
eco ds
and
wi h
ECG,
and
new
onse
AF
cases
we e
iden ified
wi h
he
admission
ECG.
Du ing
admission,
in e na ional
no malized
a io
(INR),
pla ele
coun ,
se um
biochemical
pa ame e s,
an i h ombo ic
he apy,
SARS-CoV-2
d ugs
ea men
(hyd oxychlo oquine,
azi h omycin,
lopina i / i ona i ,
da una i /cobicis a ,
emdesi i )
and
in ensi e
ca e
uni
(ICU)
admission,
we e
eco ded.
I
di e en
an icoagu-
lan
egimens
we e
p esc ibed
du ing
admission,
we
conside ed
as
he
p incipal
an icoagulan
ha
p esc ibed
du ing
>50%
o
he
hospi aliza ion
pe iod.
570
R.
Rubini-Cos a,
F.
Be múdez-Jiménez,
R.
Ri e a-López
e
al.
Medicina
Clínica
158
(2022)
569–575
Table
1
Baseline
and
clinical
cha ac e is ics
du ing
admission
o
AF
and
con ol
g oup
pa ien s,
be o e
and
a e
p opensi y
sco e
ma ching.
Va iable
To al
(n
=
610)
Be o e
PSM
A e
PSM
AF
(n
=
305)
No-AF
(n
=
305)
p
AF
(n
=
151)
No-AF
(n
=
151)
p
Baseline
cha ac e is ics
–
no.
(%)
Age,
mean
(SD)
–
y
72.9
(14.3)
79
(10.3)
66.8
(15.2)
<0.001
74.6
(11.0)
75.1
(12.0)
0.086
Male
sex
337
(55.2)
163
(53.4)
174
(57)
0.37
82
(54.3)
51
(53.6)
0.9
HBP
415
(68) 244
(80) 171
(56.1)
<0.001
115
(76.2)
105
(69.5)
0.19
DM
194
(31.9)
117
(38.4)
77
(25.2)
0.001
46
(30.5)
46
(30.5)
1
Dyslipidemia
216
(35.4)
123
(40.3)
93
(30.5)
0.011
63
(41.7)
8
(38.4)
0.56
Obesi y
96
(15.7)
68
(22.3)
28
(9.2)
<0.001
24
(15.9)
19
(12.6)
0.41
CKD
105
(17.5)
73
(23.9)
34
(11.1)
<0.001
28
(18.5)
25
(16.6)
0.65
DBADLa204
(33.4)
133
(43.6)
71
(23.3)
<0.001
46
(30.5)
50
(33.1)
0.62
Alcoholism
29
(4.8) 18
(5.9) 11
(3.6) 0.183 8
(5.3) 8
(5.3) 1
PVD
100
(16.4) 54
(17.7)
46
(15.1)
0.382
29
(19.2)
23
(15.2)
0.36
Hepa opa hy
34
(5.6)
22
(7.2)
12
(3.9)
0.078
7
(4.6)
8
(5.3)
0.79
Recen
s okeb5
(0.8)
5
(1.6)
0
0.06
2
(1.3)
0
0.49
S uc u al
hea
diseasec185
(30.5)
147
(48)
38
(12.5)
0.001
69
(46)
23
(15.3)
0.001
Mi al
s enosisd3
(0.5)
3
(1)
0
0.24
1
(0.7)
0
1
Mechanical
hea
al e
6
(1)
5
(1.6)
1
(0.3)
0.21
3
(2)
1
(0.7)
0.62
P io
majo
bleeding
39
(6.4)
28
(9.2)
11
(3.6)
0.005
8
(5.3)
8
(5.3)
1
P io
s oke
98
(16.1)
73
(23.9)
25
(8.2)
<0.001
17
(11.3)
19
(12.6)
0.72
CHA2DS2-VASc
(SD) 3.5
(2) 4.4
(1.7) 2.6
(1.9)
<0.001
3.7
(1.6)
3.3
(1.8)
0.339
Admission
–
no.
(%)
C ea inine
(SD)e1.3
(1.1)
1.4
(1.3)
1.2
(0.9)
0.01
1.3
(1.16)
1.3
(0.8)
0.699
D-dime
(SD) 5028
(18501)
4280
(100001)
5744
(23963)
0.334
4733
(10192)
6150
(15308)
0.352
Pla ele
coun
(SD)e213529
(91165)
210767
(91299)
216291
(91098)
0.455
212490
(82950)
214880
(91239)
0.812
ICU
admission
59
(9.7)
32
(10.5)
27
(8.9)
0.493
24
(15.9)
16
(10.6)
0.174
Hyd oxychlo oquine
542
(88.9)
246
(80.7)
296
(97)
<0.001
131
(86.8)
144
(95.4)
0.009
Azi h omycin
511
(83.8)
217
(71.1)
294
(96.4)
<0.001
108
(71.5)
147
(97.4)
0.001
Da una i /cobicis a
37
(6.1)
16
(5.2)
21
(6.9)
0.396
12
(7.9)
13
(8.6)
0.83
Lopina i / i ona i
327
(53.6)
130
(42.6)
197
(64.6)
<0.001
79
(52.3)
82
(54.3)
0.72
PSM,
p opensi y
sco e
ma ching;
AF,
a ial
fib illa ion;
SD,
s anda d
de ia ion;
HBP,
high
blood
p essu e;
DM,
diabe es
melli us;
CKD,
ch onic
kidney
disease;
DBADL,
dependency
o
basic
ac i i ies
o
daily
li ing;
PVD,
pe iphe al
ascula
disease;
ICU,
in ensi e
ca e
uni .
aDBADL
was
conside ed
i
i
was
desc ibed
in
he
medical
his o y
o
o
ins i u ionalized
pa ien s.
bRecen
s oke
was
conside ed
i
i
occu ed
in
he
las
6
mon hs.
cNo e
ha
60
(19.7%)
(AF
g oup)
and
210
pa ien s
(68.8%)
(no-AF
g oup)
did
no
ha e
p e ious
echoca diog aphic
s udy.
dConside ed
i
mode a e
o
se e e
mi al
s enosis.
eA
admission.
Maximum
alue
du ing
admission.
Majo
ca dio ascula
e en s
du ing
admission
and
a
ollow-
up
we e
collec ed.
They
included
majo
bleeding,
dea h,
s oke
and
enous
h omboembolism
(VTE).
Majo
bleeding
was
defined
using
In e na ional
Classifica ion
o
Diseases-10 h
Re ision
codes
(including
lowe
and
uppe
gas oin es inal
bleeding,
in ac anial
haemo hage,
hema u ia,
hemop ysis
and
epis axis)
and
confi med
by
any
o
he
ollowing
c i e ia:
(1)
haemoglobin
d op
<7
g/dL
in
needing
o
any
ed
blood
cell
ans usion;
(2)
a
leas
wo
uni s
o
ed
blood
cell
ans usion
wi hin
48
h.
I
bleeding
was
suspec ed
wi hou
confi ma ion
o
an
ac i e
bleeding
sou ce,
we
conside ed
i
as
majo
bleeding
i
mee
c i e ia
(1)
o
(2).
VTE
included
pulmona y
embolism
(PE)
and
deep
ein
h ombosis
(DVT).
Synch onously
diagnosed
DVT
and
PE
in
he
same
pa ien
we e
conside ed
1
VTE
e en .
S oke
was
conside ed
in
case
o
es ablished
o
ansien
ischaemia
in
b ain.
The
p ima y
ou come
o
his
s udy
was
he
incidence
o
in-
hospi al
majo
bleeding.
Key
seconda y
ou comes
we e
in-hospi al
mo ali y
and
incidence
o
VTE
and
s oke.
In
discha ged
pa ien s,
addi ional
seconda y
ou comes
eco ded
du ing
ollow-up
we e
ou pa ien
mo ali y,
majo
haemo hage
and
h omboembolic
e en s
(VTE
and
s oke).
S a is ical
analysis
Nume ical
a iables
a e
exp essed
as
mean
and
s anda d
de ia ion
o ,
o
non-no mally
dis ibu ed
a iables,
as
median
[in e qua ile
ange].
Ca ego ical
a iables
a e
exp essed
as
abso-
lu e
and
ela i e
equencies
and
we e
con as ed
wi h
he
Pea son’s
chi-squa e
es
o
Fishe ’s
exac
es
in
cases
whe e
applicabili y
condi ions
we e
no
me .
Fo
he
quan i a i e
a i-
ables,
he
S uden ’s
- es
was
used
o
independen
samples
and
he
Mann–Whi ney
es
was
used
o
hose
a iables
wi h
a
non-
no mal
dis ibu ion.
A
p
alue
o
<0.05
was
conside ed
s a is ically
significan .
P opensi y
sco e
ma ching
(PSM)
was
u ilized
o
con-
ol
o
po en ial
con ounding
a iables.
In
o de
o
analyze
he
p ima y
ou come
and
p edic o s
o
i ,
we
pe o med
bo h
mul-
i a ia e
logis ic
eg essions
o
in-hospi al
majo
bleeding:
fi s ,
in
all
he
COVID-19
pa ien s;
and
second,
only
in
he
AF
coho .
In
addi ion,
we
conduc ed
a
mul i a ia e
analysis
o
he
key
sec-
onda y
ou come
in-hospi al
mo ali y
in
COVID-19
pa ien s.
All
he
mul i a ia e
logis ic
eg essions
we e
pe o med
be o e
he
PSM.
Baseline
di e ences
(p
<
0.10)
we e
in oduced
in
he
eg ession
model.
Kaplan–Meie
su i al
analysis
was
pe o med
o
mo al-
i y
du ing
ollow-up
in
he
discha ged
pa ien s
and
compa ed
wi h
he
Log-Rank
es .
Indi iduals
who
expe ienced
he
e en
we e
cen-
so ed
a
hei
e en
ime.
All
analyses
we e
conduc ed
using
SPSS
S a is ics
(IBM
SPSS
24.0,
A monk,
NY,
USA).
Resul s
Basal
clinical
ea u es
Th ee
hund ed
and
fi e
pa ien s
wi h
p e ious
o
newly
diag-
nosed
AF
admi ed
wi h
confi med
COVID-19
we e
included
and
ma ched
wi h
a
con ol
g oup
o
COVID-19
pa ien s
wi hou
AF.
Baseline
cha ac e is ics
o
bo h
g oups
a e
summa ized
in
Table
1.
Be o e
ma ching,
pa ien s
wi h
AF
we e
significan ly
olde
han
con ols,
wi h
a
simila
sex
dis ibu ion
and
mo e
p e alence
o
571
R.
Rubini-Cos a,
F.
Be múdez-Jiménez,
R.
Ri e a-López
e
al.
Medicina
Clínica
158
(2022)
569–575
p e ious
ca dio ascula
isk
ac o s.
In
he
AF
coho ,
mos
o
he
pa ien s
had
pe manen
AF
(61%),
wi h
lowe
p opo ions
o
pa oxysmal
(22%),
pe sis en
(5.2%)
o
newly
diagnosed
(11.8%).
Be o e
admission,
mos
o
he
pa ien s
we e
on
o al
an icoagu-
lan s
(Table
A.1).
Du ing
admission,
low-molecula -weigh
hepa in
(LMWH)
was
he
mos
commonly
used
an icoagulan
in
AF
pa ien s
(83%),
while
DOAC
(7.5%)
and
VKA
(2.6%)
we e
used
in
a
mino i y
o
pa ien s
(Table
A.2).
A e
con olling
o
possible
con ounding
ac o s
using
PSM,
151
pa ien s
wi h
AF
we e
ma ched
wi h
151
pa ien s
wi hou
AF
(Table
1).
Simila
p opo ions
o
AF
sub ypes
and
ca dio ascula
isk
ac o s
we e
ob ained
a e
ma ching
in
he
AF
coho ,
bu
a
highe
p opo ion
o
ca diac
disease
in
AF
pa ien s
s ill
emained
s a is ically
significan
(Table
1).
Rega ding
an icoag-
ulan
egimen
du ing
admission,
he e
we e
expec ed
di e ences
a e
PSM,
wi h
a
highe
p opo ion
o
AF
pa ien s
ecei ing
he a-
peu ic
doses
o
LMWH
han
non-AF
pa ien s.
Ou comes
du ing
admission
The
p ima y
ou come
in-hospi al
majo
bleeding
occu ed
in
37
(6%)
pa ien s:
30
(9.8%)
and
7
(2.3%)
in
he
AF
and
con ol
g oups,
espec i ely
(OR:
4.64,
95%
CI
2.00–10.74,
p
<
0.001).
This
finding
was
consis en
a e
he
PSM
[16
(10.6%)
s
3
(2%),
OR:
5.85,
95%
CI
1.67–20.51,
p
=
0.003]
ega dless
o
baseline
and
clinical
como -
bidi ies
(Fig.
1).
The
lis
o
majo
bleeding
episodes
in
AF
pa ien s
is
summa ized
in
Table
A.3.
AF
pa ien s
wi h
a
majo
bleeding
e en
du ing
admission
we e
compa ed
wi h
hose
wi h
no
majo
bleeding
(Table
2).
Dyslipidemia
and
obesi y
we e
mo e
common
in
AF
pa ien s
wi h
in-hospi al
majo
bleeding
(OR:
2.43,
96%
CI
1.12–5.24,
p
=
0.021;
OR:
2.61,
95%
CI
1.19–5.73,
p
=
0.014,
espec-
i ely).
No
majo
bleeding
occu ed
in
pa ien s
ea ed
wi h
DOACs.
The
mul i a ia e
analysis
iden ified
AF
as
independen
p edic o
o
in-hospi al
majo
bleeding
in
all
he
COVID-19
pa ien s
o
he
s udy
Table
2
Baseline,
clinical
cha ac e is ics
and
endpoin s
du ing
admission
o
AF
pa ien s
depending
on
he
p esence
o
majo
bleeding
du ing
admission.
Va iable
To al
(n
=
305)
No
bleeding(n
=
275)
Bleeding
(n
=
30)
p
Baseline
cha ac e is ics
–
no.
(%)
Age,
mean
(SD)
–
y
79
(10.3)
79.2
(10.3)
77
(9.2)
0.263
Male
sex
163
(53.4)
144
(52.4)
19
(63.3)
0.253
HBP
244
(80)
216
(78.5)
28
(93.3)
0.055
DM
117
(38.4) 102
(37.1) 15
(50) 0.167
Dyslipidemia
123
(40.3)
105
(38.2)
18
(60)
0.021
Obesi y
68
(22.3)
56
(20.4)
12
(40)
0.014
CKD
73
(23.9)
62
(22.5)
11
(36.7)
0.085
DBADLa133
(43.6)
123
(44.7)
10
(33.3)
0.232
Alcoholism
18
(5.9)
15
(5.5)
3
(10)
0.402
PVD
54
(17.7)
47
(17.1)
7
(23.3)
0.448
Hepa opa hy
22
(7.2) 19
(6.9)
3
(10)
0.464
Recen
s okeb5
(1.6)
4
(1.5)
1
(3.3)
0.406
S uc u al
hea
diseasec147
(48)
131
(47.6)
16
(53.3)
0.462
Mi al
s enosisd3
(1)
2
(0.7)
1
(3.3)
0.268
Mechanical
hea
al e
5
(1.6)
4
(1.5)
1
(3.3)
0.406
P io
majo
bleeding 28
(9.2) 23
(8.4) 5
(16.7)
0.173
P io
s oke
73
(23.9)
65
(23.6)
8
(26.7)
0.712
CHA2DS2-VASc
(SD)
4.4
(1.7)
4.3
(1.7)
4.6
(1.4)
0.423
An icoagulan
234
(76.7)
207
(75.3)
27
(90)
0.07
An ipla ele
38
(12.5)
33
(12)
5
(16.7)
0.557
A ial
fib illa ion
Newly
diagnosed
36
(11.8)
34
(12.4)
2
(6.7)
0.519
Pa oxysmal
67
(22)
61
(22.2)
6
(20)
Pe sis en
16
(5.2)
13
(4.7)
3
(10)
Pe manen
186
(61)
167
(60.7)
19
(63.3)
Admission
–
no.
(%)
C ea inine
(SD)e1.06
(0.8–1.48)
1.4
(1.3)
1.6
(1.1)
0.347
D-dime
(SD) 4280
(10001)
3936
(8281)
7657
(20255)
0.065
Pla ele
coun
(SD)e210767
(91299)
210145
(90115)
216466
(103030)
0.719
ICU
admission
32
(10.5)
27
(9.8)
5
(16.7)
0.222
Hyd oxychlo oquine
246
(80.7)
223
(81.1)
23
(76.7)
0.56
Azi h omycin
217
(71.1)
194
(70.5)
23
(76.7)
0.482
Da una i /cobicis a
16
(5.2)
15
(5.5)
1
(3.3)
1
Lopina i / i ona i
130
(42.6)
118
(42.9)
12
(40)
0.76
LMWH
253
(82.9)
228
(82.9)
25
(83.3)
0.953
The apeu ic
dose
79
(25.9)
71
(25.8)
8
(26.7)
0.92
P ophylac ic
dose
174
(57)
157
(57.1)
17
(56.7)
0.964
DOAC
23
(7.5)
23
(8.4)
0
0.145
VKA
8
(2.6)
7
(2.5)
1
(3.3)
0.568
No
an icoagula ion
21
(6.9)
17
(6.2)
4
(13.3)
0.138
Endpoin s
du ing
admission
S oke
1
(0.3)
1
(0.4)
0
1
Venous
h omboembolism
4
(1.3)
3
(1.1)
1
(3.3)
0.341
Exi us
116
(38)
103
(37.5)
13
(43.3)
0.529
SD,
s anda d
de ia ion;
HBP,
high
blood
p essu e;
DM,
diabe es
melli us;
CKD,
ch onic
kidney
disease;
DBADL,
dependency
o
basic
ac i i ies
o
daily
li ing;
PVD,
pe iphe al
ascula
disease;
ICU,
in ensi e
ca e
uni ;
LMWH,
low-molecula -weigh
hepa in;
DOAC,
di ec
o al
an icoagulan ;
VKA,
i amin
K
an agonis .
aDBADL
was
conside ed
i
i
was
desc ibed
in
he
medical
his o y
o
o
ins i u ionalized
pa ien s.
bRecen
s oke
was
conside ed
i
i
occu ed
in
he
las
6
mon hs.
cNo e
ha
56
(20.4%)
(no
bleeding
g oup)
and
4
pa ien s
(13.3%)
(bleeding
g oup)
did
no
ha e
p e ious
echoca diog aphic
s udy.
dConside ed
i
mode a e
o
se e e
mi al
s enosis.
eA
admission.
Maximum
alue
du ing
admission.
572
R.
Rubini-Cos a,
F.
Be múdez-Jiménez,
R.
Ri e a-López
e
al.
Medicina
Clínica
158
(2022)
569–575
Fig.
1.
Incidence
o
majo
ca dio ascula
e en s.
Incidence
o
majo
ca dio ascula
e en s
in
pa ien s
wi h
and
wi hou
AF
in
he
whole
sample
(panel
A)
and
a e
p opensi y
sco e
ma ching
analysis
(panel
B).
No e
he
significan
di e ence
be ween
bo h
g oups
in
majo
bleeding,
wi h
a
simila
a e
o
AF- ela ed
h omboembolic
complica ions.
(ns:
non
significan ;
***
means
p
<
0.001;
**
means
p
<
0.01
and
*
means
p
<
0.05).
Table
3
Mul i a ia e
analysis.
Independen
p edic ing
ac o s
o
in-hospi al
majo
bleeding
in
COVID-19
pa ien s.
Va iable
Odds
a io 95%
CI
p
Lowe
Uppe
A ial
fib illa ion
3.51
1.49
8.32
0.004
P io
majo
bleeding
2.83
1.06
7.56
0.038
ICU
admission
3.06
1.27
7.37
0.013
DM
2.01
1.01
4.03
0.048
CI,
confidence
in e al;
DM,
diabe es
melli us;
ICU:
in ensi e
ca e
uni .
(OR:
3.51,
95%
CI
1.49–8.32,
p
=
0.004),
as
well
as
p io
majo
bleed-
ing,
ICU
admission
and
diabe es
melli us
(Table
3).
The
a iable
“p io
an icoagulan
he apy”
was
closely
ela ed
o
he
p esence
o
AF
and
he e o e
was
excluded
o
he
eg ession
model.
A
sec-
onda y
mul i a ia e
analysis
was
pe o med
only
in
he
AF
coho ,
showing
high
D-dime
le els
as
an
independen
p edic ing
ac o
o
majo
bleeding
du ing
admission
(OR:
1.03,
95%
CI
1.003–1.06,
p
=
0.03)
(Table
A.4).
The
incidence
o
he
key
seconda y
ou come
in-hospi al
mo -
ali y
was
165
(27%)
and
i
was
significan ly
highe
in
he
AF
g oup
be o e
and
a e
PSM
[116
(38%)
s
49
(16.1%),
OR:
3.21,
95%
CI
2.19–4.70,
p
<
0.001;
52
(34.4%)
s
35
(23.2%),
OR:
1.74,
95%
CI
1.05–2.87,
p
=
0.03,
espec i ely]
(Fig.
2A
and
Table
A.5).
Mul i a ia e
analysis
showed
he
p esence
o
AF
as
an
indepen-
den
p edic ing
ac o
o
in-hospi al
mo ali y
(OR:
1.88,
95%
CI
1.19–2.94,
p
=
0.006)
as
well
as
male
sex,
olde
age,
ch onic
kid-
ney
disease
(CKD),
D-dime
and
absence
o
an icoagula ion
du ing
admission
(Table
4).
Howe e ,
he
p esence
o
majo
bleeding
du -
ing
admission
as
well
as
he
an icoagulan
he apy
wi h
LMWH
we e
no
independen ly
associa ed
wi h
he
inc eased
mo ali y
in
AF
pa ien s.
Finally,
he e
we e
no
di e ences
be ween
bo h
g oups
in
he
o he
key
seconda y
ou comes
o
s oke
and
VTE
e en s
du ing
admission.
Ne e heless,
he e
was
a
end
owa ds
a
lowe
inci-
dence
in
AF
g oup
(Fig.
1).
E en s
a
ollow
up
Respec i ely,
189
(62%)
and
256
(83.9%)
pa ien s
wi h
and
wi h-
ou
AF
we e
discha ged
a e
he
COVID-19
admission.
In
he
AF
g oup,
DOAC
he apy
was
he
mos
equen
an icoagulan
p e-
sc ibed
a
discha ge
(45.7%),
ollowed
by
AVK
(14.5%)
and
LMWH
(9.6%);
up
o
30.2%
we e
no
p esc ibed
any
an icoagulan .
In
he
con ol
g oup,
mos
o
he
pa ien s
we e
no
an icoagula ed
a e
discha ge
(97.3%).
Table
4
Mul i a ia e
analysis.
Independen
p edic ing
ac o s
o
in-hospi al
mo ali y
in
COVID-19
pa ien s.
Va iable
Odds
a io
95%
CI
p
Lowe
Uppe
A ial
fib illa ion
1.88
1.19
2.94
0.006
Age
1.06
1.04
1.08
0.01
Male
sex
1.74
1.14
2.64
0.01
D-dime
1.02 1.01 1.04 0.002
CKD
2.31
1.43
3.72
0.001
An icoagula ion
du ing
admission
0.026
LMWHa1
–
–
–
No
an icoagula ion
3.80
1.40
10.30
0.01
DOAC
1.59
0.62
4.06
0.33
VKA
0.27
0.03
2.36
0.24
CI,
confidence
in e al;
CKD,
ch onic
kidney
disease;
DOAC,
di ec
o al
an icoagu-
lan ;
VKA,
i amin
K
an agonis .
aAn icoagula ion
wi h
low-molecula -weigh
hepa in
was
he
e e ence
o
com-
pa isons
wi h
o he
an icoagulan s.
Du ing
a
mean
ollow-up
pe iod
o
7
±
1.6
mon hs,
incidence
o
ou pa ien
majo
bleeding
was
simila
in
he
AF
g oup
compa ed
wi h
con ol
g oup
(4.8%
s
2.7%,
p
=
0.256),
as
well
as
s oke
(1.6%
s
1%,
p
=
0.65)
and
VTE
e en s
(0%
s
0.8%,
p
=
0.51).
In e es ingly,
a
significan ly
highe
ou pa ien
mo ali y
a e
was
s ill
p esen
among
pa ien s
wi h
AF
(Fig.
2B).
A
seconda y
mul i a ia e
analysis
was
pe o med
in
he
AF
coho
o
6-mon h
mo ali y,
showing
he
male
sex,
age,
dependency
o
basic
ac i i ies
o
daily
li ing
and
CKD
as
independen
p edic o s
o
highe
mo ali y
in
AF
pa ien s
(Table
A.6).
Discussion
Pa ien s
wi h
p e ious
o
newly
diagnosed
AF,
admi ed
wi h
SARS-CoV-2
in ec ion,
p esen
an
inc eased
isk
o
majo
bleeding,
as
well
as
an
ex emely
high
a e
o
mo ali y
du ing
admission
and
a
ollow
up
a e
discha ge,
wi h
a
low
a e
o
h omboem-
bolic
e en s,
which
was
simila
o
he
con ol
g oup.
These
wo s
ou comes
seem
o
be
independen
o
p e ious
clinical
s a us,
ca -
dio ascula
isk
ac o s
o
p io
ca dio ascula
and
bleeding
e en s.
Al hough
in
ou
s udy
we
desc ibe
a
high
incidence
o
majo
bleeding
in
pa ien s
wi h
AF,
we
did
no
iden i y
a
s a is ical
asso-
cia ion
be ween
any
an icoagulan
and
majo
bleeding
e en s.
Howe e ,
we
ecognize
ha
a
ele an
p opo ion
o
hese
pa ien s
ecei ed
he apeu ical
doses
o
LMWH,
wi h
a
esidual
use
o
DOACs.
In
ac ,
we
did
no
obse e
majo
bleeding
episodes
in
pa ien s
ea ed
du ing
admission
wi h
DOACs,
al hough
significan
573
R.
Rubini-Cos a,
F.
Be múdez-Jiménez,
R.
Ri e a-López
e
al.
Medicina
Clínica
158
(2022)
569–575
Fig.
2.
Mo ali y
in
pa ien s
wi h
AF
espec
o
he
con ol
g oup.
Panel
A
shows
he
di e ence
in
he
in-hospi al
mo ali y
in
he
whole
sample
o
pa ien s.
Panel
B
ep esen s
he
Kaplan–Mei
analysis
o
dea h
a e
discha ge
in
bo h
g oups.
di e ences
could
no
be
demons a ed
due
o
he
e ospec i e
and
no
andomized
design
o
ou
s udy.
Rega ding
mo ali y,
he e
we
sugges
ha
AF
in ol es
an
inde-
penden
poo
p ognosis
in
COVID-19
pa ien s
in
he
same
way
o
o he
ecen
s udies.8,11 Howe e ,
due
o
he
p e iously
men-
ioned
limi a ions,
we
canno
confi m
i
he
high
p opo ion
o
majo
bleeding
obse ed
in
AF
pa ien s
wi h
COVID-19
is
ela ed
o
hei
high
mo ali y
a e.
Se e al
s udies
ha e
been
epo ed
AF
as
a
equen
condi ion
in
pa ien s
admi ed
wi h
se e e
o ms
o
COVID-193,6–8 and
i
has
la ely
been
associa ed
wi h
an
inc eased
isk
o
un a ou able
ou -
comes
in
COVID-19
pa ien s.11 A
ema kable
finding
o
ou
esea ch
was
ha
he
absence
o
an icoagula ion
du ing
admission
was
independen ly
associa ed
wi h
a
highe
mo ali y
in
pa ien s
wi h
COVID-19,
bu
no
wi h
h ombo ic
e en s.
Al hough
a
p ope
an i-
coagula ion
and
a
lowe
mo ali y
in
COVID-19
pa ien s
has
been
es ablished
be o e,12–14 ou
da a
sugges
ha
some
o
hese
dea hs
migh
be
a ibu able
o
an
ad anced
COVID-19
disease
o
ex eme
agili y
ha
p e en
physicians
om
an icoagula ing
hem.
Al hough
pa ien s
wi h
AF
a e
a
popula ion
a
high
isk
o
wo se
ou comes
o
COVID-19,
he
isk
o
bleeding
e en s
and
he
sa es
an icoagula ion
he apy
has
no
been
es ablished
ye .
On
he
basis
o
possible
d ug-d ug
in e ac ions
be ween
DOAC
and
VKA
wi h
empi ic
COVID-19
pha maco he apy
and
hei
po en ial
con-
sequences,
he
AHA
and
he
ESC
bo h
ag ee
on
he
ecommenda ion
o
hepa in
as
he
an icoagulan
o
choice
in
hospi alized
COVID-
19
pa ien s
wi h
AF,
who
a e
ecei ing
p io
an icoagula ion.9,10
In
he
p esen
s udy,
mos
o
he
pa ien s
wi h
AF
we e
ea ed
wi h
he apeu ic
doses
o
LMWH
du ing
admission,
wi h
low
le -
els
o
con inua ion
o
p io
an icoagula ion
wi h
DOAC
and
VKA.
This
s a egy
has
been
p e iously
named
as
b idging
he apy
and
is
associa ed
wi h
highe
isk
o
bleeding
wi h
no
significan
di e -
ence
in
mo ali y
o
h ombo ic
e en s,
especially
in
he
se ing
o
pe iope a i e
in asi e
p ocedu es.15–18
In
line
wi h
his
in o ma ion,
he e
we
desc ibe
a
high
incidence
o
majo
bleeding
in
AF
pa ien s
ecei ing
ull
LMWH
dosing
du ing
admission,
be o e
and
a e
con olling
o
con ounde s
wi h
PSM,
wi h
low
le els
o
h ombo ic
e en s.
In
con as ,
con ol
g oup
pa ien s
wi hou
AF
showed
lowe
incidence
o
majo
bleeding
be o e
and
a e
PSM,
wi h
a
highe
p opo ion
o
pa ien s
ecei ing
a
p ophylac ic
LMWH
dose.
Ano he
impo an
finding
o
ou
s udy
was
he
independen
associa ion
o
AF
wi h
in-hospi al
majo
bleeding
in
COVID-
19
pa ien s,
some hing
ha
has
no
been
p e iously
desc ibed.
This
no el
finding
should
be
aken
in o
accoun
and
i
sugges s
ha
p ecise
managemen
o
an icoagula ion
migh
educe
he
isk
o
bleeding.
Addi ionally,
we
obse ed
ha
high
le els
o
D-dime
we e
s ongly
associa ed
wi h
high
isk
o
majo
bleed-
ing
in
AF
pa ien s.
In e es ingly,
a
common
clinical
app oach
in
COVID-19
pa ien s
wi h
ele a ed
D-dime
le els
is
o
in ensi y
he
an icoagulan
doses
o
hepa in,
some hing
ha
migh
agg a a e
haemo hagic
complica ions,
especially
in
AF
pa ien s.
DOACs
ha e
epea edly
been
ound
o
be
sa e
and
mo e
e ec-
i e
han
VKA
an agonis s
in
he
ea men
o
non al ula
AF,
especially
in
olde
pa ien s.19,20 Taking
hese
da a
in o
accoun ,
and
he
low
and
simila
a e
o
h omboembolic
e en s
amongs
ou
s udy
g oups,
a
change
in
he
an icoagula ion
s a egy
in
he
COVID-19
pa ien s
wi h
AF
migh
be
conside ed,
gi ing
a
mo e
impo an
ole
o
DOACs.
Mo eo e ,
mos
o
he
d ugs
wi h
po en-
ial
in e ac ion
wi h
DOACs
ha e
been
p o en
o
be
ine ec i e
agains
COVID-19,
so
a e
used
less
and
less.
Al-Samka i
e
al.21 analyzed
he
a e
o
bleeding
and
h om-
bo ic
complica ions
in
a
la ge
mul icen e
coho
o
c i ically
ill
and
nonc i ically
ill
COVID-19
pa ien s,
showing
a
majo
bleeding
a e
o
2.3%.
He e,
we
desc ibe
a
highe
incidence
o
majo
bleed-
ing
e en s
among
pa ien s
wi h
AF.
Al hough
he
con ol
g oup
pa ien s
o
he
p esen
s udy
we e
e y
simila
o
he
pa ien s
o
hei
s udy,
ce ainly,
pa ien s
wi h
AF
in
ou
s udy
we e
olde ,
had
mo e
como bidi ies
and
he
majo i y
o
hem
we e
ea ed
wi h
LMWH
a
he apeu ic
dose,
han
hose
o
Al-Samka i
s udy.
All
hese
ac s
a e
likely
ela ed
wi h
his
highe
bleeding
a e.
Any-
way,
hese
po en ial
con ounding
a iables
we e
con olled
wi h
PSM;
hence,
he
an icoagula ion
egimen
seems
o
be
playing
an
impo an
ole.
In
summa y,
pa ien s
wi h
p io
o
newly
diagnosed
AF
admi -
ed
wi h
COVID-19
ep esen
a
popula ion
a
high
isk
o
majo
bleeding
and
mo ali y
du ing
he
hospi aliza ion.
I
seems
c i ical
o
indi idualize
an icoagula ion
he apy
du ing
admission,
consid-
e ing
pa ien
specific
isks
o
bleeding
and
VTE.
Limi a ions
The
non- andomized
na u e
o
he
s udy
limi s
he
conclusions
abou
he
influence
o
he
an icoagula ion
he apy
and
ou comes.
This
bias
is
pa ially
con olled
wi h
p opensi y
sco e
ma ching
s udy
ha
ha e
achie ed
e y
simila
s udy
g oups.
La ge
and
an-
domized
s udies
a e
equi ed
o
be e
cla i y
his
issue.
Da a
on
he
se e i y
o
he
SARS-CoV-2
in ec ion
we e
no
ully
collec ed.
The
high
mo ali y
a e
is
in
many
cases
mo e
due
o
he
COVID-19
in ec ion
a he
han
ca dio ascula
e en s.
Howe e ,
his
is
simi-
la
o
bo h
PSM
g oups
and
di e ences
ela ed
o
he
AF
condi ion
a e
s ill
p esen .
574
R.
Rubini-Cos a,
F.
Be múdez-Jiménez,
R.
Ri e a-López
e
al.
Medicina
Clínica
158
(2022)
569–575
Au ho s’
con ibu ions
All
o
he
au ho s
had
access
o
he
da a
and
pa icipa ed
in
he
p epa a ion
o
he
manusc ip .
E hical
conside a ions
The
s udy
p o ocol
was
app o ed
by
he
Local
E hics
Commi ee
o
he
coo dina o
cen e.
Funding
None
decla ed.
Conflic
o
in e es s
The
au ho s
decla e
ha
he e
is
no
conflic
o
in e es .
Appendix
A.
Supplemen a y
da a
Supplemen a y
da a
associa ed
wi h
his
a icle
can
be
ound,
in
he
online
e sion,
a
h ps://doi.o g/10.1016/j.
medcli.2021.06.015.
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