A Pint of Sweat Will Save a Gallon of Blood: A Call for Randomized

DOI: 10.1161/CIRCULATIONAHA.113.007549
A Pint of Sweat Will Save a Gallon of Blood:
A Call for Randomized Trials of Anticoagulation in End Stage Renal Disease
Running title: Granger et al.; A Call for Randomized Trials of Anticoagulation
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Christopher B. Granger, MD1; Glenn M. Chertow, MD, MPH2
1
Duke Clinical Research Institute, Durham, NC; 2Stanford University School off M
Medicine,
edi
dicine,
Universsitty,
y Stanford, CA
Stanford University,
Address
Add
dress for Correspondence:
Corr
Co
rresp
rr
ponden
nden
nce
ce::
Christopher
Chhri
r st
stop
opphe
herr B.
B Granger,
Graang
nger
er,, MD
D
Duke
Duke C
Clinical
lini
li
nica
ni
call Re
ca
Rese
Research
sear
se
arch
ar
ch IInstitute
nsti
ns
titu
ti
tute
tu
te
DUMC
DUMC 3409
340
4099
Durham, NC 27705
Tel: 919-668-8900
Fax: 919-668-7056
E-mail: [email protected]
Journal Subject Codes: Anticoagulants:[184] Coumarins, Stroke:[53] Embolic stroke,
Treatment:[118] Cardiovascular pharmacology
Key words: Editorial, atrial fibrillation, end-stage renal disease, stroke, randomized controlled
trial
1
DOI: 10.1161/CIRCULATIONAHA.113.007549
Approximately 430,000 patients were receiving maintenance dialysis in the United States in
20111. Compared to the general population, atrial fibrillation is far more common2 and
associated with a much higher risk of stroke in the dialysis population3. Thus, there is an
important need to define and apply strategies to reduce stroke in patients receiving dialysis with
atrial fibrillation.
Warfarin for atrial fibrillation is one of the most successful treatments in all of medicine,
preventing nearly two-thirds of strokes in the general atrial fibrillation population4.
Approximately one-fifth of all strokes are related to atrial fibrillation, and these strokes are more
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frequently disabling or fatal than strokes associated with other conditions. It is now well
established that impaired kidney function is associated with increased risks of stroke
str
trrok
okee an
andd of
bleeding associated with the use of anticoagulation5. Patients with mild-to-moderate chronic
ki
idnney ddisease
isea
is
e se aand
ea
nd aatrial
trial fibrillation experience gr
ggreater
eater relative aand
n abs
nd
bssolute
ol benefits from
kidney
absolute
warfarin
w
arrfarin
rf
thera
therapy
apy6. D
Despite
espi
pite
pi
te tthe
he llack
acck of eevidence
videencce dderived
erriveed
ed ffrom
ro
om ra
rand
randomized
ndom
nd
miz
izeed clinical
clin
linica
nicall trials
trria
ials
l in
ls
in the
th
he
dialysis
dial
di
alys
al
ysis
ys
i ppopulation,
is
opul
op
u at
ul
atiion,
n, K
Kidney
idne
id
n y Di
ne
D
Disease:
seas
se
asee:
as
e: IImproving
mpro
mp
rovving
ro
ng Glo
G
Global
lobal
a O
al
Outcomes
ut ome
utco
mess (K
(KD
(KDIGO)
DIGO
GO)) cl
GO
clin
clinical
inic
icaal
ic
al ppractice
ract
ra
c ic
ct
icee
guidelines published
pubbliishhed in
in 2006
20067 rec
recommended
ecom
ec
omme
om
meend
nded
ed
d that
tha
hatt warfarin
warf
wa
r arrin be
rf
be used
used
e as
as per
per American
Amer
Am
eric
er
ican
ic
an Heart
Heart
Association guidelines for atrial fibrillation with the caveat that “dialysis patients are at increased
risk for bleeding and careful monitoring should accompany intervention.”
Since then, several observational studies have questioned the benefit of warfarin for
stroke prevention, particularly when balancing the risks of bleeding in this population8. Using
data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS), Wizeman
and colleagues found that warfarin use was independently associated with a higher risk of stroke,
particularly in patients over age 75 where the risk was twice as high with warfarin2. A second
large observational study used data from Fresenius Medical Care North America and found that
2
DOI: 10.1161/CIRCULATIONAHA.113.007549
warfarin was associated with nearly twice the risk of stroke after adjustment for comorbidities9.
A third study showed a higher risk of hemorrhagic stroke and no lower risk of ischemic stroke
with warfarin in hemodialysis using claims data from Medicare patients augmented with the
United States Renal Data System (USRDS)10. While another study from Denmark found a lower
risk of stroke with warfarin use for patients with atrial fibrillation receiving dialysis3 and data
included in the 2013 USRDS Annual Data Report found a lower risk of stroke in warfarintreated patients, there was enough uncertainty that the KDIGO summary in 2011 changed the
recommendation to not advise warfarin for stroke prevention in end stage renal disease11. This
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group highlighted the need for clinical trials of anticoagulants in advanced chronic kidney
disease (CKD) (stage 4 and 5, including persons on dialysis) as an area for future
ree res
research.
e eaarch.
rcch.
h Th
The
Canadian Cardiovascular Society Atrial Fibrillation Guidelines, likewise, no longer recommend
warf
wa
warfarin
rfar
rf
arrin ffor
or aatrial
tria
iaal fi
fibrillation for patients on dialysis
diaaly
lysiis12 and calledd fo
fforr ra
randomized
and
ndomized trials.
In thiss issue
issu
is
suee of Circulation,
su
Circ
Ci
rcul
ulat
ul
atio
ionn, Shah
S ah
Sh
h and
ndd coauthors
coauuth
uthors
rss have
hav
ve provided
prov
pr
oviide
dedd additional
ad
ddi
diti
tioonal
ti
onal data
dat
ataa to
to inform
inf
nfo
form
orm
this
his ddebate
ebat
eb
atee133. The
The authors
auth
auth
horrs id
ide
identified
enti
enti
tifi
fied
fi
ed ppatients
atieent
atie
ntss admitted
admi
ad
mittted to
mi
to hospitals
hosp
ho
sppit
ital
alls in Ontario
Onttar
ario
io
o aand
n Quebec
nd
Quebbecc wi
with
ith
h
atio
ionn an
io
andd an
anal
a yz
yzed
ed ooutcomes
utco
ut
co
omees ac
acco
cord
co
rdiing tto
rd
o su
ubs
bseq
eque
eq
uent
ue
n uuse
nt
se ooff wa
warf
rfar
arin
ar
in aand
nd according
atrial fibrillat
fibrillation
analyzed
according
subsequent
warfarin
to dialysis status. Among the 1626 patients on dialysis, nearly half were prescribed warfarin.
The authors found no reduction in stroke risk associated with warfarin use after adjusting for
other predictors (hazard ratio 1.14, 95% confidence interval (95% CI) 0.78 to 1.67), but a
significantly higher risk of bleeding (hazard ratio 1.44, 95% CI 1.13 to 1.85), similar to findings
reported by Winkelmayer et al10. The study by Shah et al included a broad population base,
adjusted for key determinants of stroke and bleeding (components of the CHADS2 and HASBLED scores), and employed propensity score adjustment to address confounding by indication.
But even with careful adjustment, observational studies are limited by the effects of unmeasured
3
DOI: 10.1161/CIRCULATIONAHA.113.007549
confounders and selection bias and are thus unreliable when attempting to estimate treatment
effects. There is evidence that this is the case in the analysis by Shat et al, where the 13%
relative reduction in stroke with warfarin in the population not treated with dialysis is an
underestimate compared with the more reliable 64% relative risk reduction seen in randomized
trials of this population.
While the balance of risks and benefits of warfarin appear favorable in patients with
mild-to-moderate CKD, too few patients with advanced CKD have been included in randomized
trials, including no patients with creatinine clearance of less than 25 ml/min in the trials of direct
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acting oral anticoagulants in atrial fibrillation14-17. A potential role of the direct acting oral
anticoagulants in patients with advanced CKD is supported by data showing con
consistent
nsist
stten
entt be
bene
benefits
nefi
ne
fitts
compared to warfarin in patients with moderate CKD14-18. Whether another strategy to prevent
tro
oke
ke,, left
left aatrial
t iall occluder
tr
occluder
cc
appropriate
ate
t ffor
or the dialysis
iss pop
population
pul
ulaation also requires
stroke,
devices19, is appropria
ffurther
urtther study. Tr
Tria
Trials
alss of
of st
sstatins
tat
atin
at
in
ns have
have shown
show
hown us
us tha
that
at tthe
he ddialysis
ialy
ialy
ysiis ppopulation
opula
pulati
tionn iss ssufficiently
ti
uffici
uffi
c en
ci
entl
tlyy di
tl
diff
different
ffer
ferren
e t
that
from
hat treatment
tre
reat
atme
ment
me
n effects
nt
effec
ffeccts may
may
a fundamentally
fun
un
nda
dame
mennta
me
ntally
al y differ
diffe
iffeer fr
rom
m tthose
ho
ose oobserved
bser
bs
errveed in
n tthe
he ggeneral
he
en
ner
eraal
al ppopulation
op
pullat
atio
io
on2200.
Wher
re ar
aaree we
w in
in understanding
un
nde
ders
rsta
tand
ta
ndin
nd
ingg th
in
thee ef
effe
f ct
fe
c ooff wa
w
rfar
rf
arin
ar
in ffor
or aatrial
trria
iall fibrillation
fibr
fi
bril
br
illa
il
lati
tion
ti
on iin
n di
ddialysis
alysis
Where
effect
warfarin
patients? We have compelling evidence of benefit of warfarin for stroke prevention in atrial
fibrillation and evidence that the benefit is as great or greater in patients with moderate renal
impairment (Table 1). At the same time we have reasonably consistent findings from
observational studies that there are similar or higher stroke rates and higher bleeding rates with
warfarin in the dialysis population. Given the unreliability of using observational studies to
estimate treatment effects, the truth may be that oral anticoagulation provides important benefit.
But the study by Shah et al adds to the evidence that it is also possible that warfarin is harmful in
this setting. It is ironic that we are routinely treating many patients with renal disease and atrial
4
DOI: 10.1161/CIRCULATIONAHA.113.007549
fibrillation every day with great uncertainty as to benefit or harm without their consent, and at
the same time major regulatory and ethical barriers exist that prevent efficient enrollment of
patients into clinical trials that are needed to answer this (and other) important questions.
General George S. Patton, Jr. famously stated that “a pint of sweat will save a gallon of
blood.” Large-scale, randomized clinical trials require considerable effort and expense. Yet
given that atrial fibrillation in advanced CKD (and in end stage renal disease) is common and
consequential, placebo-controlled clinical trials comparing one or more anticoagulation strategies
in patients with atrial fibrillation are long overdue.
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Satellite
Conflict of Interest Disclosures: Dr. Chertow serves on the Board of Directorss ooff Sa
Sate
teell
llit
ie
it
Healthcare, Inc., a non-profit dialysis provider. Dr Granger discloses that, in thee past
pas
astt 3 years,
year
ye
ear
arss, he
he
has received compensation for research grants as well as from consulting/honaria from
BMS/Pfizer,
Boehringer
BM
MS/
S/Pf
Pfiz
Pf
izer
iz
er, Bo
er
Boeh
ehri
eh
ringer Ingelheim, Janssen, Bayer,
Baaye
y r, Daiitchi Sankyo,
Sank
nkkyo,, an
andd Sanofi-Aventis. Full
disclosure
available
discclo
di
losure iss av
vai
aila
labl
la
blle onn https://www.dcri.org/about-us/conflict-of-interest.
htt
t ps
ps:/
://w
:/
/www
/w
ww.d
.dcr
dcri.
i or
o g/
g ab
bouut-u
us/
s/co
conf
co
nfli
nf
lict
ct-o
ct
-o
off in
nter
terestt.
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iovanni
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M. Str
rippolli, P
h.D.
D , an
nd Jon
nathan C
Crai
aigg,
ai
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unssett fo
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7
DOI: 10.1161/CIRCULATIONAHA.113.007549
Table 1. Evidence of benefit vs. risk of warfarin for stroke prevention in atrial fibrillation.
Evidence favoring warfarin treatment
RCTs of warfarin in AF show overwhelming
benefit in reducing stroke
Evidence challenging warfarin treatment
ĺ
But patients on dialysis are fundamentally
different
RCTs show that patients with stage 3 CKD and
AF have more benefit from warfarin than patients
ĺ
with normal renal function, making it likely that
the benefit extends to ESRD
But no patients with more advanced kidney
disease have been included in RCTs of warfarin
and other oral anticoagulants in AF
But observational studies are hopelessly
confounded and cannot reliably estimate modest
treatment effects, nor can they define lack of
treatment effects
Observational studies, in aggregate, show
warfarin use is associated with higher risk of
bleeding and no reduction in stroke
ĸ
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
But risk of thrombosis and risk of stroke is higher
and therefore anticoagulation could be even more ĸ
important in dialysis patients
Platelet function is perturbed in ESRD; frequent
antibiotic use, dietary restrictions, impaired
nutritional status and drug-drug interactions
render anticoagulation unpredictable, placing
patients
p
atients at higher risk of bleeding
bleedin
ng
RCT=randomized clinical trial; CKD = chronic kidney disease; AF = atrial fibrillation; ESRD = eend
ndd sta
stage
taage rrenal
enal
en
al
disease
disease
8
A Pint of Sweat Will Save a Gallon of Blood: A Call for Randomized Trials of Anticoagulation
in End Stage Renal Disease
Christopher B. Granger and Glenn M. Chertow
Circulation. published online January 22, 2014;
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
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