Re
Po
Ca diol.
2013;32(4):303---310
Re is a
Po uguesa
de
Ca diologia
Po uguese
Jou nal
o
Ca diology
www. e po ca diol.o g
ORIGINAL
ARTICLE
Digoxin
in
ad anced
hea
ailu e
pa ien s:
A
ques ion
o
hy hm
Elisabe e
Jo ge∗,
Rui
Bap is a,
Hélia
Ma ins,
Fá ima
Sa ai a,
Susana
Cos a,
Hen ique
Viei a,
Lou enc¸o
Coelho,
Ped o
Mon ei o,
Fá ima
F anco,
Luís
A.
P o idência
Hospi ais
da
Uni e sidade
de
Coimb a
e
Clínica
Uni e si á ia
de
Ca diologia
da
Faculdade
de
Medicina
da
Uni e sidade
de
Coimb a,
Coimb a,
Po ugal
Recei ed
6
Oc obe
2011;
accep ed
5
No embe
2012
A ailable
online
23
Ma ch
2013
KEYWORDS
Ad anced
hea
ailu e;
Digoxin;
A ial
fib illa ion;
P ognosis
Abs ac
Backg ound:
The
impac
o
digoxin
on
ou comes
o
pa ien s
wi h
ad anced
hea
ailu e
(HF)
emains
unce ain
and
i s
e ec
may
be
di e en
o
pa ien s
in
a ial
fib illa ion
(AF)
o
sinus
hy hm
(SR).
Objec i es:
To
de e mine
he
impac
o
digoxin
on
ou comes
o
ad anced
HF
pa ien s
and
o
assess
whe he
p ognosis
di e s
in
pa ien s
in
AF
and
SR.
Me hods:
A
o al
o
268
consecu i e
pa ien s
admi ed
o
an
in ensi e
ca e
uni
wi h
decom-
pensa ed
HF
we e
e alua ed.
Pa ien s
we e
di ided
in o
wo
g oups:
A
---
pa ien s
wi h
AF
(n=89),
and
B
---
pa ien s
in
SR
(n=179).
Fo
each
g oup
we
compa ed
pa ien s
medica ed
and
no
medica ed
wi h
digoxin.
A
mean
ollow-up
o
3.3
yea s
was
pe o med.
Resul s:
Addi ion
o
digoxin
o
con empo a y
s anda d
HF
he apy
showed
no
impac
on
mo al-
i y
o
pa ien s
in
g oup
B
(all-cause
mo ali y
in
ollow-up:
19.1%
s.
22.5%,
p=0.788).
Rega ding
g oup
A,
we
obse ed
significan ly
lowe
medium- e m
mo ali y
o
pa ien s
on
digoxin
he apy
(18.6%
s.
46.6%,
p=0.048).
Digoxin
he apy
did
no
influence
eadmissions
o
decompensa ed
HF.
Among
AF
pa ien s,
no
di e ences
we e
ound
ega ding
demog aphic,
clinical,
echo-
ca diog aphic
and
labo a o y
a iables
be ween
pa ien s
medica ed
and
no
medica ed
wi h
digoxin.
Conclusions:
Digoxin
he apy
may
imp o e
he
p ognosis
o
ad anced
HF
pa ien s
wi h
AF
unde
op imal
medical
he apy.
Howe e ,
no
benefi
o
digoxin
was
demons a ed
o
pa ien s
in
SR.
These
esul s
may
help
o
imp o e
pa ien
selec ion
o
digoxin
he apy.
©
2011
Sociedade
Po uguesa
de
Ca diologia
Published
by
Else ie
España,
S.L.
All
igh s
ese ed.
∗Co esponding
au ho .
E-mail
add ess:
[email p o ec ed]
(E.
Jo ge).
0870-2551/$
–
see
on
ma e
©
2011
Sociedade
Po uguesa
de
Ca diologia
Published
by
Else ie
España,
S.L.
All
igh s
ese ed.
h p://dx.doi.o g/10.1016/j. epc.2012.11.007
304
E.
Jo ge
e
al.
PALAVRAS-CHAVE
Insuficiência
ca díaca
a anc¸ada;
Digoxina;
Fib ilhac¸ão
au icula ;
P ognós ico
Digoxina
na
insuficiência
ca díaca
a anc¸ada:
uma
ques ão
de
i mo
Resumo
In oduc¸ão:
O
impac o
p ognós ico
da
digoxina
na
insuficiência
ca díaca
(IC)
a anc¸ada
pe -
manece
mal
escla ecido.
A
ele ância
da
e apêu ica
digi álica
pode
se
di e en e
na
fib ilhac¸ão
au icula
(FA)
ela i amen e
ao
i mo
sinusal
(RS).
Objec i os:
De e mina
o
impac o
p ognós ico
da
digoxina
na
IC
e
e ifica
se
es e
é
di e en e
consoan e
se
encon em
em
FA
ou
em
RS.
Mé odos:
Es uda am-se
268
doen es
in e nados
numa
unidade
de
cuidados
in ensi os
po
IC
descompensada.
Di idiu-se
a
populac¸ão
em
dois
g upos:
A
---
89
doen es
em
FA;
g upo
B
---
179
doen es
em
RS.
Pa a
cada
g upo
compa a am-se
os
doen es
medicados
com
os
não
medicados
com
digoxina.
Realizou-se
um
seguimen o
clínico
com
a
du ac¸ão
mediana
de
3,3
anos.
Resul ados:
A
digoxina
não
e e
impac o
na
mo alidade
dos
doen es
com
IC
a anc¸ada
que
se
encon a am
em
RS
(mo alidade
a
3,3
anos:
19,1%
e sus
22,5%,
p
=
0,788),
adicionada
à
e apêu ica
médica
o imizada.
Nos
doen es
em
FA
obse ou-se
uma
educ¸ão
significa i a
da
mo alidade
nos
doen es
medicados
com
digoxina
(18,6%
e sus
46,6%,
p
=
0,048).
A
digoxina
não
al e ou
a
axa
de
ein e namen os
po
IC
descompensada.
No
g upo
A
não
se
e ifica am
di e enc¸as
en e
os
doen es
medicados
e
não
medicados
com
digoxina
ela i amen e
aos
pa âme os
demog áficos,
clínicos,
ecoca diog áficos
ou
labo a o iais.
Conclusão:
Es e
es udo
suge e
que
a
digoxina
pode
melho a
o
p ognós ico
dos
doen es
com
IC
a anc¸ada
e
FA,
sob
e apêu ica
médica
op imizada.
Con udo,
es a
não
demons ou
bene ício
nos
doen es
em
RS.
Es es
esul ados
podem
con ibui
pa a
uma
melho
selec¸ão
dos
doen es
a
medica
com
digoxina,
o imizando
a
elac¸ão
isco/bene ício
des a
e apêu ica.
©
2011
Sociedade
Po uguesa
de
Ca diologia.
Publicado
po
Else ie
España,
S.L.
Todos
os
di ei os
ese ados.
In oduc ion
Despi e
mo e
han
200
yea s
o
esea ch,
he
ole
o
digoxin
in
hea
ailu e
he apy
emains
con o e sial.
The
Ame i-
can
College
o
Ca diology
and
Ame ican
Hea
Associa ion
(ACC/AHA)
guidelines
o
he
managemen
o
pa ien s
wi h
hea
ailu e
(HF)
ecommend
he
use
o
digoxin,
unless
con-
aindica ed,
o
pe sis en
symp oms
a e
op imal
medical
he apy.1Digoxin
use
is
also
endo sed
by
he
Eu opean
Soci-
e y
o
Ca diology
guidelines.2Al hough
widely
accep ed,
hese
ecommenda ions
a e
de i ed
mainly
om
sho - e m
s udies
assessing
non-mo ali y
ou comes.3 --- 8 The
Digi alis
In es iga o
G oup
(DIG)
s udy,9a
la ge
andomized
ial,
showed
no
impac
on
all-cause
o
ca dio ascula
mo al-
i y
wi h
digoxin
in
oligosymp oma ic
male
HF
pa ien s
in
sinus
hy hm
(SR).
Howe e ,
a
educ ion
in
hospi aliza ions
due
o
wo sening
HF
and
an
imp o emen
in
quali y
o
li e
we e
epo ed.10 Two
o he
ials
showed
ha
wi hd awal
o
digoxin
esul ed
in
wo sening
HF
symp oms.6,7 Al hough
mo e
han
90%
o
pa ien s
we e
ecei ing
angio ensin-
con e ing
enzyme
inhibi o s
(ACEIs)
in
he
DIG
ial,9 he
use
o
be a-blocke s
and
aldos e one
an agonis s
was
no
epo ed
and
likely
was
e y
limi ed.
Simila ly,
imp o ed
ou comes
a e
also
seen
wi h
ca diac
de ices,
which
a e
now
widely
used
in
HF
pa ien s.
A
ecen ly
published
s udy
sugges s
no
benefi
o
digoxin
in
ad anced
HF
pa ien s
on
con empo a y
medical
he apy.11 In
his
epo ,
HF
pa ien s
in
SR
ea ed
wi h
digoxin
had
a
wo se
p ognosis
han
hose
who
we e
no .
Howe e ,
his
did
no
appea
o
be
ue
o
pa ien s
in
a ial
fib illa ion
(AF).
In
pa ien s
wi h
AF,
he
beneficial
ole
o
digoxin
is
widely
accep ed,
mainly
o
op imize
en icula
a e
con ol,
and
he
Ca edilol
A ial
Fib illa ion
E alua ion
(CAFE)
s udy
sugges s
ha
he e
may
be
syne gis ic
benefi s
be ween
digoxin
and
ca edilol.11
In
ou
s udy,
we
sough
o
de e mine
he
impac
o
digoxin
he apy
in
ad anced
HF
pa ien s
on
op imal
con-
empo a y
medical
he apy,
and
o
assess
whe he
p ognosis
di e s
acco ding
o
he
p esence
o
AF.
Me hods
Pa ien
popula ion
and
da a
collec ion
This
single-cen e
s udy
included
268
consecu i e
pa ien s
admi ed
o
an
in ensi e
ca e
uni
be ween
Janua y
2003
and
June
2006
due
o
decompensa ed
HF
in
New
Yo k
Hea
Associa ion
(NYHA)
class
III
o
IV.
S anda dized
eco ds
we e
used
o
desc ibe
he
s udy
popula ion
in
e ms
o
clinical
and
demog aphic
cha ac e is ics,
ca dio ascula
isk
ac o s
and
como bidi ies.
The
eco ds
also
showed
HF
e iology,
hemodynamic
s a us
on
admission,
labo a o y
pa ame-
e s,
elec oca diog aphic
and
echoca diog aphic
da a,
and
ea men .
Renal
dys unc ion
was
defined
as
c ea inine
clea ance
o
<60
ml/min
calcula ed
by
he
Cockc o ---Gaul
o mula.
Ischemic
ca diomyopa hy
was
defined
as
le
en-
icula
dys unc ion
associa ed
wi h
significan
co ona y
disease
(>70%
s enosis
in
a
leas
one
majo
epica dial
co o-
na y
a e y
and/o
>50%
le
main
s enosis).
In
he
mino i y
o
pa ien s
wi hou
co ona y
angiog aphy
(4%)
he
diagnos-
ic
c i e ion
o
ischemic
hea
disease
was
p io
myoca dial
in a c ion
(his o y
o
in a c ion
o
in a c
sca
on
ECG).
Non-
ischemic
ca diomyopa hy
was
defined
as
le
en icula
dys unc ion
in
he
absence
o
he
abo e
al e a ions.
Co o-
na y
angiog aphy
was
pe o med
in
70%
o
his
g oup;
an
Digoxin
in
ad anced
hea
ailu e
pa ien s
305
Table
1
Gene al
cha ac e is ics
o
he
s udy
popula ion.
(%)
Sinus
hy hm
(n=179)
A ial
fib illa ion
(n=89)
SR
s.
AF
No
digoxin
Digoxin
To al
p
No
digoxin
Digoxin
To al
p
p
Male
62.8
76.5
73.2
0.078
95.7
69.7
76.4
0.012
0.600
Anemia
28.1
16.5
19.3
0.145
15.8
19.1
18.2
0.749
0.855
Dyslipidemia
54.8
35.5
39.7
0.051
52.4
28.0
35.2
0.500
0.524
COPD
18.2
13.5
14.6
0.503
26.3
31.3
68.8
0.736
0.114
Diabe es
36.4
29.1
30.8
0.427
26.3
36.4
33.8
0.425
0.651
S oke
10.0 6.0 6.9
0.449
5.3
6.7
6.3
0.832
0.860
PAD 13.8 15.5 15.1 0.825 5.6 15.9
12.9
0.270
0.689
Dialysis
2.4 2.9 2.8 0.666 0.0 4.5 3.4
0.141
0.968
Thy oid
d.
6.5
11.4
10.3
0.423
0.0
29.4
22.1
0.011
0.023
Li e
d.
0.0
5.9
4.6
0.179
5.6
0.0
1.6
0.111
0.291
AF:
a ial
fib illa ion;
COPD:
ch onic
obs uc i e
pulmona y
disease;
d:
disease;
PAD:
pe iphe al
a e ial
disease;
SR:
sinus
hy hm.
ischemia
s ess
es
(s ess
echoca diog aphy,
myoca dial
pe usion
scanning
o
pe usion
magne ic
esonance
imag-
ing)
was
a ailable
in
he
emainde ,
which
e ealed
no
sig-
nifican
al e a ions.
A
mean
clinical
ollow-up
o
40
mon hs
was
pe o med.
Clinical
da a
we e
collec ed
du ing
pa ien s’
isi s
o
he
ou pa ien
clinic
o
by
elephone
in e iew.
The
occu ence
o
eadmission
due
o
decompensa ed
HF
and
dea h
was
eco ded.
Medical
eco ds
we e
e iewed
o
con-
fi m
and
o
ob ain
addi ional
in o ma ion.
The
popula ion
was
di ided
in o
wo
g oups,
acco ding
o
he
p esence
o
AF:
g oup
A
---
89
pa ien s
wi h
AF
and
g oup
B
---
179
pa ien s
in
sinus
hy hm.
A
p e iously
defined
subg oup
analysis
was
pe o med
in
pa ien s
in
SR
s.
AF.
Fo
each
g oup
pa ien s
medica ed
and
no
medica ed
wi h
digoxin
we e
compa ed.
Endpoin s
The
p ima y
endpoin
was
long- e m
all-cause
mo ali y
and
he
seconda y
endpoin
was
a
combined
ou come
o
mo al-
i y
and
ehospi aliza ion
due
o
decompensa ed
HF.
S a is ical
analysis
The
s a is ical
analysis
was
pe o med
wi h
SPSS
13.0
o
Windows
(SPSS
Inc.,
Chicago,
Ill.).
The
esul s
we e
exp essed
as
means
±
s anda d
de ia ion
o
con inuous
a iables
and
as
equencies
and
pe cen ages
o
ca ego ical
a iables.
The
equencies
o
he
ca ego ical
a iables
in
he
wo
g oups
we e
compa ed
by
he
chi-squa e
es
o
Fishe ’s
exac
es .
Con inuous
a iables
we e
compa ed
using
he
S uden ’s
unpai ed
es
(no mal
a iables)
and
he
Mann---Whi ney
U
es
(non-no mal
a iables).
Kaplan---Meie
su i al
analysis
and
he
B eslow
es
we e
used
o
compa e
he
g oups
in
e ms
o
cumula i e
su i al.
A
alue
o
p<0.05
was
conside ed
s a is ically
significan .
Resul s
Gene al
cha ac e is ics
o
he
s udy
g oups
The
baseline
cha ac e is ics
o
he
s udy
popula ion
a e
lis ed
in
Table
1.
O
he
o al
popula ion
hospi alized
due
o
ad anced
HF
du ing
he
s udy
pe iod,
33.2%
(89/268)
p esen ed
wi h
AF.
These
pa ien s
we e
olde
(62.4±12.8
s.
55.1±15.4
yea s;
p<0.001),
wi h
highe
le
en icula
ejec ion
ac ion
(LVEF)
(31.0%
s.
26.0%,
p=0.003)
and
a
highe
p e alence
o
al ula
disease
as
HF
e iology
(3.4%
s.
13.6%;
p<0.001).
The
p e alence
o
hy oid
disease
was
highe
in
AF
pa ien s
(22.1%
s.
10.3%;
p=0.023).
Among
he
AF
pa ien s,
he e
we e
no
significan
di e -
ences
be ween
pa ien s
wi h
o
wi hou
digoxin
ega ding
demog aphic
pa ame e s
such
as
age
o
gende .
We
obse ed
a
highe
p e alence
o
dyslipidemia
in
pa ien s
no
med-
ica ed
wi h
digoxin
(64.7%
s.
31.7%,
p=0.039),
bu
no
di e ences
we e
ound
be ween
he
g oups
ega ding
o he
ca dio ascula
isk
ac o s
o
como bidi ies.
Analy-
sis
o
hemodynamic,
labo a o y
and
echoca diog aphic
da a
on
admission
showed
no
significan
di e ences
in
blood
p essu e,
hea
a e,
diu esis
a e,
LVEF,
se um
sodium,
po assium,
hemoglobin
and
B- ype
na iu e ic
pep ide
(BNP)
le els,
ca diac
ou pu ,
peak
VO2o
pulmona y
a e y
sys-
olic
p essu e
(Table
2).
Dila ed
ca diomyopa hy
was
mo e
equen
in
pa ien s
on
digoxin
he apy
(86.8%
s.
13.2%,
p=0.032)
and
ischemic
ca diomyopa hy
was
mo e
p e alen
in
pa ien s
wi hou
his
he apy
(37.5%
s.
62.5%,
p<0.001),
as
shown
in
Table
3.
Conce ning
g oup
B,
no
di e ences
we e
ound
be ween
pa ien s
wi h
o
wi hou
digoxin
ega ding
demog aphic
pa ame e s,
ca dio ascula
isk
ac o s
o
como bidi ies.
LVEF
was
significan ly
lowe
in
pa ien s
on
digoxin
he apy
(25.0%
s.
30.0%,
p=0.003)
and
admission
c ea inine
was
also
lowe
(1.4±0.6
s.
1.7±1.1
mg/dl;
p=0.028)
(Table
2).
Dila ed
ca diomyopa hy
was
mo e
equen
in
pa ien s
on
digoxin
he apy
(57.4%
s.
35.7%,
p=0.014)
(Table
3).
The apy
Medica ions
on
admission,
du ing
hospi al
s ay
and
a
dis-
cha ge
a e
desc ibed
in
Table
4.
AF
pa ien s
we e
mo e
o en
medica ed
wi h
amioda one
(42.5%
s.
21.0%,
p=0.001)
and
wa a in
(50.7%
s.
23.1%,
p=0.001)
on
admission
and
a
discha ge
(61.8%
s.
43.3%;
p=0.004
and
65.2%
s.
34.1%;
p=0.001,
espec i ely,
o
amioda one
and
wa a in)
and
he
p esc ip ion
o
be a-blocke s
was
significan ly
lowe
306
E.
Jo ge
e
al.
Table
2
Hemodynamic,
echoca diog aphic
and
labo a o y
da a.
Sinus
hy hm
(n=179)
A ial
fib illa ion
(n=89)
SR
s.
AF
To al
No
digoxin
Digoxin
p
To al
No
digoxin
Digoxin
p
p
Age,
yea s
55.08
±
15.43
55.35
±
16.04
55
±
15.29
0.898
62.36
±
12.81
64.09
±
12.99
61.76
±
12.8
0.456
<0.001
LVEF,
%
0.26
±
0.1
0.30
±
0.12
0.25
±
0.08
0.003
0.31
±
0.12
0.31
±
0.13
0.30
±
0.12
0.746
0.003
SBP,
mmHg
113.95
±
23.64
119.15
±
27.49
112.43
±
22.28
0.146
117.08
±
23.74
120.43
±
26.6
116.29
±
23.18
0.561
0.540
DBP,
mmHg
68.93
±
14.74
72.53
±
16.35
67.87
±
14.14
0.105
70.37
±
16.36
73.93
±
13.6
69.53
±
16.94
0.369
0.727
HR,
bpm
84.72
±
20.3
84.79
±
19.32
84.7
±
20.65
0.981
89.19
±
21.38
86.21
±
19.03
89.9
±
22
0.566
0.011
Admission
C ,
mg/dl
1.42
±
0.74
1.68
±
1.13
1.35
±
0.58
0.028
1.59
±
0.97
1.66
±
0.67
1.57
±
1.04
0.749
0.353
Discha ge
C ,
mg/dl
1.42
±
0.68
1.59
±
0.88
1.37
±
0.61
0.106
1.46
±
0.84
1.61
±
0.69
1.42
±
0.88
0.438
0.704
Na+,
mmol/l
136.89
±
5.32
138.34
±
3.68
136.5
±
5.63
0.082
135.97
±
5.64
136.33
±
6.99
135.88
±
5.31
0.783
0.047
K+,
mmol/l
4.38
±
0.72
4.43
±
0.7
4.36
±
0.73
0.600
4.28
±
0.64
4.03
±
0.77
4.35
±
0.59
0.090
0.403
Hb,
g/dl
13.19
±
2.14
12.79
±
1.89
13.29
±
2.2
0.267
13.4
±
2.22
12.96
±
2.46
13.5
±
2.17
0.435
0.489
BNP,
pg/ml
1354.25
±
1251.43
1408.58
±
1242.94
1339.22
±
1259.98
0.804
1000.83
±
909.93
1004.75
±
1186.02
999.74
±
834.34
0.987
0.140
PASP,
mmHg
50.67
±
16.47
40.55
±
17.17
48.77
±
18.65
0.187
47.59
±
11.56
65
±
18.91
53.24
±
19.2
0.232
0.153
VO2,
ml/kg/min
17.25
±
4.38
18.28
±
4.26
17.04
±
4.4
0.290
15.59
±
4.37
17.07
±
2.84
15.25
±
4.63
0.366
0.081
CI,
l/min/m22.04
±
0.51
2.23
±
0.48
1.99
±
0.51
0.164
2.15
±
1.12
2.85
±
2.3
1.96
±
0.41
0.082
0.672
Hospi al
s ay,
days
5.94
±
4.37
7.02
±
6.23
5.60
±
3.55
0.062
6.84
±
4.67
6.09
±
4.28
7.11
±
4.8
0.371
0.032
Blood
glucose,
mg/dl
130.01
±
60.01
143.74
±
70.41
125.70
±
55.96
0.089
139.74
±
55.45
135.77
±
49.72
141.08
±
57.55
0.701
0.282
BNP:
B- ype
na iu e ic
pep ide;
CI:
ca diac
index
by
he
Fick
me hod;
C :
c ea inine;
DBP:
dias olic
blood
p essu e;
Hb:
hemoglobin;
HR:
hea
a e;
LVEF:
le
en icula
ejec ion
ac ion;
PASP:
pulmona y
a e y
sys olic
p essu e;
SBP:
sys olic
blood
p essu e;
VO2:
peak
oxygen
up ake.
Digoxin
in
ad anced
hea
ailu e
pa ien s
307
Table
3
E iology
o
hea
ailu e.
(%)
Sinus
hy hm
(n=179)
A ial
fib illa ion
(n=89)
SR
s.
AF
No
digoxin Digoxin
To al
p
No
digoxin
Digoxin
To al
p
p
Dila ed
35.7
57.4
52.2
0.014
21.7
60.0
50.0
0.002
0.730
Res ic i e
2.4
0.0
0.6
0.072
8.7
1.5
3.4
0.104
0.074
Hype ophic
0.0
1.5
1.1
0.428
0.0
3.1
2.3
0.395
0.500
Ischemic
47.6
34.6
37.6
0.127
52.2
15.4
25.0
0.001
0.400
Val ulopa hy 0.0
4.4
3.4
0.165
8.7
15.4
13.6
0.422
<0.001
AF:
a ial
fib illa ion;
SR:
sinus
hy hm.
(57.3%
s.
83.2%;
p=0.001)
compa ed
wi h
pa ien s
in
SR.
In
AF
pa ien s,
spi onolac one
p esc ip ion
on
admission
was
highe
in
pa ien s
on
digoxin
he apy
(58.5%
s.
25.0%;
p=0.011),
bu
no
di e ences
we e
ound
ega ding
o he
p io
medica ions
o
discha ge
he apy.
Rega ding
SR
pa ien s,
we
obse ed
ha
pa ien s
on
digoxin
he apy
we e
mo e
o en
medica ed
wi h
spi ono-
lac one,
u osemide
and
wa a in
p io
o
hospi al
admission
(67.0%
s.
38.2%;
p=0.03;
88.0%
s.
67.6%;
p=0.006;
27.5%
s.
8.8%;
p=0.024,
espec i ely)
and
a
discha ge
(91.9%
s.
62.8%;
p=0.001;
99.3%
s.
93.0%;
p=0.016;
39.0%
s.
18.6%;
p=0.014,
espec i ely).
Long- e m
p ognosis
Abou
one-fi h
(21.1%)
o
pa ien s
unde wen
hea
ans-
plan a ion
du ing
he
ollow-up
pe iod.
Addi ion
o
digoxin
o
con empo a y
s anda d
HF
he apy
showed
no
impac
on
long- e m
mo ali y
in
pa ien s
wi h
ad anced
HF
and
SR
(19.1%
s.
22.5%,
p=0.788)
(Figu e
1).
Rega ding
AF
pa ien s,
we
obse ed
significan ly
lowe
long- e m
mo ali y
in
pa ien s
on
digoxin
he apy
(18.6%
s.
46.6%,
p=0.048)
(Figu e
2).
Digoxin
he apy
did
no
influence
he
composi e
endpoin
o
all-cause
mo ali y
and
ead-
missions
o
decompensa ed
HF,
in
he
o al
popula ion
o
s a ified
by
AF/SR.
Table
4
Medica ion
on
admission,
du ing
hospi al
s ay
and
a
discha ge.
Medica ion
Sinus
hy hm
(n=179)
A ial
fib illa ion
(n=89)
SR
s.
AF
No
digoxin
(%)
Digoxin
(%)
To al
(%)
p
No
digoxin
(%)
Digoxin
(%)
To al
(%)
p
p
Admission
ACEI
67.6
63.3
64.3
0.644
55.0
71.7
67.1
0.176
0.684
ARB
5.9
14.7
12.6
0.177
20.0
17.0
17.8
0.764
0.391
Be a-blocke
44.1
57.8
54.5
0.162
40.0
47.2
45.2
0.583
0.194
Spi onolac one
38.2
67.0
60.1
0.003
25.0
58.5
49.3
0.011
0.129
Digoxin
11.8
52.3
42.7
<0.001
10.0
67.9
52.1
<0.001
0.190
Fu osemide
67.6
88.0
83.1
0.006
85.0
88.7
87.7
0.670
0.378
Amioda one
17.6
22.0
21.0
0.585
45.0
41.5
42.5
0.788
<0.001
S a in
32.4
21.1
23.8
0.178
25.0
17.0
19.2
0.438
0.442
Wa a in
8.8
27.5
23.1
0.024
40.0
54.7
50.7
0.262
<0.001
In-hospi al
Dobu amine
14.3
18.5
17.5
0.528
8.7
21.2
18.0
0.178
0.926
Dopamine
9.5
11.1
10.7
0.772
17.4
9.1
11.2
0.278
0.901
No ad enaline
2.4
0.7
1.1
0.380
0.0
3.0
2.2
0.398
0.480
IV
amioda one
23.1
21.2
21.7
0.890
25.0
25.0
25.0
1.000
0.758
Le osimendan
67.4
81.5
78.1
0.053
56.5
80.0
73.9
0.028
0.443
Discha ge
ACEI
79.1
82.2
81.5
0.643
65.2
78.5
75.0
0.207
0.221
ARB
14.0
14.9
14.7
0.876
17.4
21.2
20.2
0.694
0.252
Be a-blocke
81.4
83.8
83.2
0.710
52.2
59.1
57.3
0.564
<0.001
Spi onolac one
62.8
91.9
84.9
<0.001
82.6
86.4
85.4
0.661
0.918
Fu osemide
93.0
99.3
97.8
0.016
100.0
98.5
98.9
0.553
0.527
Amioda one
38.1
44.9
43.3
0.440
47.8
66.7
61.8
0.109
0.004
S a in
46.5
31.6
31.7
0.075
26.1
22.7
23.6
0.744
0.054
Wa a in
18.6
39.0
34.1
0.014
65.2
65.2
65.2
0.995
<0.001
ACEI:
angio ensin-con e ing
enzyme
inhibi o ;
AF:
a ial
fib illa ion;
ARB:
angio ensin
ecep o
blocke ;
IV:
in a enous;
SR:
sinus
hy hm.

308
E.
Jo ge
e
al.
1.0
0.8
0.6
Cumula i e su i al
0.4
0.2
0.0
0.00
500.00
1000.00
1500.00
Time o dea h, days
2000.00
2500.00
Digoxin
No
Yes
No-censo ed
Yes-censo ed
Figu e
1
Cumula i e
40-mon h
su i al
in
pa ien s
in
sinus
hy hm
s a ified
acco ding
o
digoxin
medica ion.
Discussion
Despi e
ecen
ad ances
in
he apy,
HF
emains
associa ed
wi h
high
mo ali y
and
hospi aliza ion
a es,
as
we
epo
in
ou
con empo a y
coho .
Digoxin
is
he
oldes
HF
d ug
and
one
o
he
leas
expensi e.
The
ACC/AHA
HF
guide-
lines
ecommend
conside ing
adding
digoxin
in
pa ien s
wi h
pe sis ing
HF
symp oms
al eady
ea ed
wi h
diu e ics,
an
ACEI
(o
angio ensin
ecep o
blocke )
and
a
be a-blocke .1
1.0
Cumula i e su i al
0.8
0.6
0.4
0.2
0.0
0.00
500.00
1000.00
1500.00
Time o dea h, days
2000.00
2500.00
Digoxin
No
Yes
No-censo ed
Yes-censo ed
Figu e
2
Cumula i e
40-mon h
su i al
in
pa ien s
wi h
a ial
fib illa ion
s a ified
acco ding
o
digoxin
medica ion.
Howe e ,
he e
is
limi ed
e idence
on
he
ole
o
digoxin
in
pa ien s
on
backg ound
he apy
wi h
be a-blocke s
and
ACEIs.
The
landma k
DIG
s udy,
a
andomized
con olled
ial
o
digoxin
in
pa ien s
wi h
ch onic
HF
al eady
medica ed
wi h
diu e ics,
showed
ha
digoxin
had
no
impac
on
o e all
mo ali y,
bu
did
educe
he
a e
o
hospi aliza ions
due
o
HF.9Howe e ,
he
p esc ip ion
a e
o
be a-blocke s
was
no
epo ed
and,
a
he
ime
he
ial
was
conduc ed,
be a-
blocke s
we e
no
accep ed
as
s anda d
he apy
o
pa ien s
wi h
HF.
Pa icipan s
in
he
DIG
ial
we e
male
ou pa ien s
wi h
ch onic
s able
HF
( he
majo i y
in
NYHA
class
I
o
II)
in
SR,
and
hus
did
no
eflec
eal-wo ld
HF
popula ions.9
Simila ly
o
he
DIG
ial,
we
did
no
see
a
su i al
benefi
in
ad anced
HF
pa ien s
in
sinus
hy hm.
Howe e ,
we
ailed
o
demons a e
a
educ ion
in
HF
hospi aliza ions,
p obably
due
o
lack
o
powe .
Ou
popula ion
is
significan ly
di e en
om
ha
o
he
DIG
ial,
wi h
mo e
se e e
pa ien s
hospi alized
o
decompensa ed
HF,
all
in
NYHA
class
III
o
IV
wi h
se e ely
dep essed
LVEF,
and
a
high
p e alence
o
como bidi ies.
The
se e i y
o
his
popula ion
is
highligh ed
by
he
signi -
ican
p opo ion
o
pa ien s
who
ul ima ely
p oceeded
o
hea
ansplan a ion.
Fu he mo e,
he
use
o
diu e ics,
ACEIs,
be a-blocke s
and
de ices
in
ou
s udy
popula ion
was
highe
han
in
o he
s udies
examining
he
ole
o
digoxin.
This
may
ha e
educed
he
independen
beneficial
e ec
o
digoxin
on
HF
eadmissions.
The
same
is
epo ed
in
a
subs udy
o
he
Valsa an
in
Hea
Failu e
T ial
(Val-
HeFT).12 In
a
coho
o
6800
pa ien s,
he
in es iga o s
also
ailed
o
show
any
hospi aliza ion
benefi
wi h
he
use
o
digoxin
he apy,
u he
suppo ing
ou
esul s.
One
ela-
i ely
ecen
e ospec i e
s udy
sugges s
ha
he e
was
no
benefi
wi h
digoxin
in
a
hea
ansplan
e e al
popula ion
o
455
pa ien s
wi h
ad anced
HF
ecei ing
con empo a y
medical
he apy.13 In
his
s udy,
digoxin
use
was
associa ed
wi h
inc eased
isk
o
he
p ima y
ou come
o
dea h,
u gen
ansplan a ion
o
en icula
assis
de ice
implan a ion,
and
he
isk
was
highe
in
pa ien s
in
SR
compa ed
wi h
AF.
Ou
s udy
sugges s
ha
digoxin
he apy
may
imp o e
he
i al
p ognosis
o
pa ien s
wi h
ad anced
HF
and
AF
unde
op imal
medical
he apy.
In
AF
pa ien s,
one
po en ial
mech-
anism
o
benefi
o
digoxin
is
simply
o
educe
en icula
a e,
he eby
limi ing
myoca dial
oxygen
consump ion,
a
concep
in
which
in e es
was
ecen ly
eawakened
wi h
he
publica ion
o
he
landma k
SHIFT
ial.14 The
idea
ha
be a-blocke s
migh
elimina e
he
need
o
digoxin
in
pa ien s
wi h
AF
and
HF
was
he
a ionale
o
he
CAFE
s udy.11 Howe e ,
a he
han
showing
ha
digoxin
is
edun-
dan ,
he
s udy
sugges ed
ha
he e
could
be
syne gis ic
benefi s
be ween
digoxin
and
ca edilol.
The e
a e
easons
o he
han
a e
con ol
why
digoxin
may
be
mo e
e ec i e
in
he
p esence
o
be a
blockade.
Be a-blocke s,
especially
nonselec i e
ones,
ha
a enua e
s ess-induced
educ ions
in
se um
po assium15 migh
neu-
alize
he
inc ease
in
sudden
dea h
associa ed
wi h
he
use
o
digoxin.
The
ino opic
e ec
o
digoxin
may
imp o e
ol-
e abili y
o
be a-blocke s,
enabling
highe
dose
i a ion.
Aldos e one
an agonis s
also
inc ease
se um
po assium,
educing
he
incidence
o
hypokalemia;
i
is
well
known
ha
sudden
dea h
educ ion
was
one
o
he
p ima y
mech-
anisms
o
mo ali y
educ ion
in
he
Randomized
Aldac one
Digoxin
in
ad anced
hea
ailu e
pa ien s
309
E alua ion
S udy
(RALES)16 and
he
EPHESUS
ial.17 Spi ono-
lac one
ended
o
exe
a
g ea e
educ ion
in
mo ali y
among
pa ien s
ea ed
wi h
digoxin.
Pos -hoc
analyses
o
he
DIG
ial
sugges
ha
digoxin
educed
mo ali y
a
low
(0.5---0.9
ng/ml)
se um
digoxin
con-
cen a ions
(SDC),
bu
had
no
e ec
a
highe
(≥1
ng/ml)
SDC.18 A
close
examina ion
o
he
Kaplan---Meie
su i al
plo s
in
he
DIG
ial
e eals
an
ea ly
mo ali y
educ-
ion
in
he
digoxin
g oup,
ollowed
by
a
la e
i ual
o e lap
o
he
plo s,
sugges ing
ha ,
al hough
he
ea ly
su i al
benefi
was
elimina ed
in
la e
yea s,
he e
was
no
inc ease
in
mo ali y.19 This
lack
o
a
long- e m
e ec
o
digoxin
on
mo ali y
may
be
due
o
use
o
open-labeled
digoxin
in
he
placebo
g oup,
and
a
cumula i e
e ec
o
he
use
o
high-dose
digoxin;
mo e
han
80%
o
he
pa icipan s
in
he
DIG
ial
we e
ecei ing
≥0.25
mg
o
digoxin
daily
o
ma ching
placebo,
which
was
highe
han
he
cu en ly
ec-
ommended
daily
dosage.18 In
ou
popula ion,
he
s anda d
daily
dose
was
0.125
mg,
wi h
a
majo i y
o
pa ien s
paus-
ing
on
weekends;
he
maximum
dose
p esc ibed
du ing
da a
collec ion
was
0.25
mg/day,
fi e
imes
a
week.
The
con-
inued
use
o
high-dose
digoxin
in
elde ly
pa ien s,
wi h
de e io a ing
kidney
unc ion,
may
ha e
esul ed
in
highe
SDC
du ing
he
la e
yea s
o
he
DIG
ial.
The
benefi-
cial
e ec s
o
digoxin
a
low
SDC
a e
p ima ily
due
o
i s
e ec
on
he
neu oho monal
sys em.18 By
inhibi ing
he
sodium-po assium
adenosine
iphospha e
pump
in
enal
ubules
and
agal
a e en
fibe s,
digoxin
supp esses
bo h
he
enin-angio ensin-aldos e one
and
sympa he ic
ne ous
sys ems.18 Low
SDC
also
educes
he
isk
o
digoxin
oxic-
i y
and
associa ed
mo bidi y
and
mo ali y.18 Concomi an
he apy
wi h
be a-blocke s
and
aldos e one
an agonis s
and
use
o
lowe
doses
o
digoxin
could
adically
imp o e
he
isk/benefi
a io
o
digoxin.20
The
explana ion
o
di e en
ou comes
in
AF
and
SR
emains
elusi e.
In
ou
popula ion,
we
obse ed
significan ly
lowe
LVEF
in
pa ien s
in
SR
(26.0%
s.
31.0%,
p=0.003),
bu
no
o he
significan
di e ences
we e
ound
be ween
pa ien s
in
SR
and
AF.
Ou
s udy
has
se e al
limi a ions.
Fi s ,
his
obse a ional
e ospec i e
s udy
eflec s
a
single-cen e
expe ience
and
includes
a
ela i ely
small
numbe
o
pa ien s.
Second,
we
did
no
ha e
da a
o
SDC;
howe e ,
he
s anda d
dose
p esc ibed
was
0.125
mg/day
fi e
imes
a
week
and
he
maximum
dose
p esc ibed
du ing
da a
collec ion
was
0.25
mg/day,
and
we
know
ha
digoxin
dose
is
a
s ong
p e-
dic o
o
SDC.
Gi en
he
na u e
o
he
da a
se ,
we
we e
unable
o
asce ain
he
leng h
o
he apy
on
digoxin
be o e
he
index
HF
admission.
Thi d,
da a
ega ding
discon inu-
ing
o
s a ing
he apy,
o
op imiza ion
o
d ug
doses
du ing
ollow-up,
we e
no
a ailable.
P e ious
s udies
on
digoxin
in
pa ien s
wi h
ch onic
HF
epo ed
imp o emen s
in
LVEF,
HF
symp oms
and
exe cise
pe o mance.
In
ou
s udy,
hese
we e
no
measu ed,
and
hus
we
canno
exclude
po en ial
beneficial
e ec s
on
hese
so
endpoin s.
One
issue
wi h
e ospec i e
ou comes
analysis
is
always
whe he
o
no
he
mo e
se e e
pa ien s
p e e en ially
ecei ed
a
gi en
he -
apy.
Howe e ,
in
ou
popula ion
he e
we e
no
significan
di e ences
be ween
AF
pa ien s
wi h
o
wi hou
digoxin
ega ding
demog aphic
pa ame e s,
significan
como bidi-
ies,
o
hemodynamic,
labo a o y,
elec oca diog aphic
and
echoca diog aphic
da a
on
admission,
making
selec ion
bias
unlikely.
Conclusions
The
p esen
s udy
sugges s
ha
digoxin
may
imp o e
he
i al
p ognosis
o
AF
pa ien s
wi h
ad anced
HF
unde
op i-
mal
medical
he apy.
Digoxin
did
no
demons a e
benefi
in
pa ien s
in
SR.
These
esul s
may
help
o
imp o e
pa ien
selec ion
o
ea men
wi h
digoxin,
in
o de
o
achie e
a
be e
isk/benefi
a io
in
ad anced
HF
pa ien s.
Polypha -
macy
is
known
o
be
associa ed
wi h
an
inc eased
isk
o
ad e se
d ug
eac ions,
d ug
in e ac ions
and
poo
compli-
ance.
Thus,
o
mul iple
easons
o
bo h
e ficacy
and
sa e y,
whe he
o
no
digoxin
he apy
has
any
ole
in
he
cu en
managemen
o
ad anced
HF
needs
o
be
e alua ed.
Fu -
he
andomized
con olled
ials
a e
equi ed
o
find
ou
whe he
digoxin
has
a
ole
in
con empo a y
managemen
o
HF.
Conflic s
o
in e es
The
au ho s
ha e
no
conflic s
o
in e es
o
decla e.
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