h ps://doi.o g/10.1177/1179545X17704660
C ea i e Commons Non Comme cial CC BY-NC: This a icle is dis ibu ed unde he e ms o he C ea i e Commons A ibu ion-NonComme cial
4.0 License (h p://www.c ea i ecommons.o g/licenses/by-nc/4.0/) which pe mi s non-comme cial use, ep oduc ion and dis ibu ion o he wo k wi hou
u he pe mission p o ided he o iginal wo k is a ibu ed as speci ied on he SAGE and Open Access pages (h ps://us.sagepub.com/en-us/nam/open-access-a -sage).
Clinical Medicine Insigh s:
Blood Diso de s
Volume 10: 1–8
© The Au ho (s) 2017
Rep in s and pe missions:
sagepub.co.uk/jou nalsPe missions.na
DOI: 10.1177/1179545X17704660
In oduc ion
Venous h omboembolic e en s (VTEs), such as deep enous
h ombolysis and pulmona y embolism (PE), a e po en ially
a al complica ions o o hopedic su ge y, whose incidence may
each 30% o he pa ien s unde going knee o hip eplace-
men .1 Fu he mo e, non a al e en s a e equen and a e asso-
cia ed wi h signi ican mo bidi y. The de elopmen and clinical
Th ombop ophylaxis Wi h Apixaban in
Pa ien s Unde going Majo O hopedic Su ge y:
Me a-Analysis and T ial-Sequen ial Analysis
Daniel Caldei a1,2,3, Filipe B Rod igues1,3,4, Faus o J Pin o5,
Joaquim J Fe ei a1,3 and João Cos a1,3,6,7
1Labo a ó io de Fa macologia Clínica e Te apêu ica, Faculdade de Medicina, Uni e sidade de
Lisboa, Lisboa, Po ugal. 2Ca diology Depa men , Hospi al Ga cia de O a, Almada, Po ugal.
3Clinical Pha macology Uni , Ins i u o de Medicina Molecula , Lisboa, Po ugal. 4Hun ing on’s
Disease Cen e, Ins i u e o Neu ology, Uni e si y College London, London, UK. 5Ca diology
Depa men , CCUL, CAML, Faculdade de Medicina, Uni e sidade de Lisboa, Lisboa, Po ugal.
6Cen e o E idence-Based Medicine (CEMBE), Faculdade de Medicina, Uni e sidade de
Lisboa, Lisboa, Po ugal. 7Coch ane Po ugal, Faculdade de Medicina, Uni e sidade de Lisboa,
Lisboa, Po ugal.
ABSTRACT
BACkgROUnd: Venous h omboembolism (VTE) is a po en ially a al complica ion o o hopedic su ge y, and un il ecen ly, ew an i h om-
bo ic compounds we e a ailable o pos ope a i e h ombop ophylaxis. The in oduc ion o he non– i amin K an agonis s o al an icoagu-
lan s (NOAC), including apixaban, has ex ended he he apeu ic a mamen a ium in his ield. The e o e, es ima ion o NOAC ne clinical
bene i in compa ison wi h he es ablished ea men is needed o in o m clinical decision making.
OBjeCTi eS: Sys ema ic e iew o assess he e icacy and sa e y o apixaban 2.5 mg wice a day e sus low-molecula -weigh hepa ins
(LMWH) o h ombop ophylaxis in pa ien s unde going knee o hip eplacemen .
dATA SOURCeS: MEDLINE, Embase, and CENTRAL we e sea ched om incep ion o Sep embe 2016, o he sys ema ic e iews, e e -
ence lis s, and expe s we e consul ed.
STUdy eligiBiliTy CRiTeRiA, PARTiCiPAnTS, And inTeR enTiOn: All majo o hopedic su ge y andomized con olled ials com-
pa ing apixaban 2.5 mg wice daily wi h LMWH, epo ing h ombo ic and bleeding e en s.
dATA exTRACTiOn: Two independen e iewe s, using a p ede e mined o m.
STUdy APPRAiSAl And SynTheSiS MeThOdS: The Coch ane ool o assess isk bias was used by wo independen au ho s. Re Man
so wa e was used o es ima e pooled isk a io (RR) and 95% con idence in e als (95% CI) using andom-e ec s me a-analysis. T ial
sequen ial analysis (TSA) was pe o med in s a is ical signi ican esul s o e alua e whe he cumula i e sample size was powe ed o he
ob ained e ec . O e all con idence in cumula i e e idence was assessed using he G ading o Recommenda ions Assessmen , De elop-
men , and E alua ion (GRADE) Wo king G oup me hodology.
ReSUlTS: Fou s udies compa ing apixaban 2.5 mg wice daily wi h LMWH we e included, wi h a o al o 11.828 pa ien s (55% unde going
knee and 45% hip eplacemen ). The o e all isk o bias ac oss s udies was low. In compa ison wi h LMWH (all egimens), apixaban showed
a signi ican ly lowe isk o VTE e en s and o e all mo ali y combined (RR: 0.63, 95% CI: 0.42-0.95, I2 = 84%, n = 8346), bu no o majo
VTE e en s (RR: 0.62, 95% CI: 0.32-1.19, I2 = 63%, n = 9493), o o symp oma ic VTE e en s and VTE- ela ed mo ali y combined (RR: 1.14,
95% CI: 0.68-1.90, I2 = 0%, n = 11 879). T ial sequen ial analysis showed ha he isk educ ion ob ained o VTE and mo ali y was based
on unde powe ed cumula i e sample size and e ec dimension. Subg oup analysis acco ding o LMWH egimens showed ha apixaban
educed he isk o VTE e en s and o e all mo ali y, and majo VTE e en s, when compa ed wi h LMWH once daily, wi hou di e ences
be ween apixaban and LMWH wice daily.
COnClUSiOnS: The e is low o mode a e e idence ha in pa ien s unde going knee o hip eplacemen , apixaban seems equally e ec i e
and sa e o LMWH wice a day. When compa ed wi h LMWH once a day, apixaban seems a supe io h ombop ophylaxis op ion. Howe e ,
he esul s a e unde powe ed which p ecludes de ini e answe s ega ding he ue ne clinical bene i o apixaban e sus LMWH in his clini-
cal con ex .
keyWORdS: Venous h omboembolism, non– i amin K o al an icoagulan s, apixaban, hepa in, low-molecula -weigh , sys ema ic e iew
ReCei ed: No embe 07, 2016. ACCePTed: Ma ch 13, 2017.
PeeR Re ieW: Fou pee e iewe s con ibu ed o he pee e iew epo . Re iewe s’
epo s o aled 351 wo ds, excluding any con iden ial commen s o he academic edi o .
TyPe: Re iew
FUnding: The au ho (s) ecei ed no inancial suppo o he esea ch, au ho ship, and/o
publica ion o his a icle.
deClARATiOn OF COnFliCTing inTeReSTS: The au ho (s) decla ed no po en ial
con lic s o in e es wi h espec o he esea ch, au ho ship, and/o publica ion o his
a icle.
CORReSPOnding AUThOR: Daniel Caldei a, Labo a ó io de Fa macologia Clínica e
Te apêu ica, Faculdade de Medicina, Uni e sidade de Lisboa, A . P o . Egas Moniz,
Lisboa 1649-028, Po ugal. Email: dgcaldei a@ho mail.com
704660BDX0010.1177/1179545X17704660Clinical Medicine Insigh s: Blood Diso de sCaldei a e al
esea ch-a icle2017
2 Clinical Medicine Insigh s: Blood Diso de s
launch o new o al an icoagulan s also called non– i amin K
an agonis o al an icoagulan s (NOACs) has inc eased he lim-
i ed a senal o an i h ombo ic he apeu ic op ions a ailable o
pos su gical h ombop ophylaxis o pa ien s unde going
o hopedic su ge ies.2
Non– i amin K an agonis o al an icoagulan s selec i ely
inhibi h ombin o ac o Xa, and hei o al egimen and
absence o egula hemos a ic pa ame e s e alua ion ep esen
a signi ican ad ancemen o an i h ombo ic ea men com-
pa ed wi h pa en e al an icoagulan s such as low-molecula -
weigh hepa in (LMWH) and i amin K an agonis s. As
occu s wi h any pa ien ea ed wi h an icoagulan s, he main
objec i e is o o e he ea men ha p o ides he bes ne
clinical bene i ou come, ha is, which concedes he bes bal-
ance be ween h omboembolism p e en ion and wi h minimal
bleeding isk.3
The aim o his wo k was o assess he e icacy and sa e y o
apixaban (a Xa inhibi o ) a 2.5 mg wice a day ( he Eu opean
Medicines Agency and Food and D ug Adminis a ion–
app o ed dosage in VTE p e en ion in o hopedic pa ien s) in
compa ison wi h LMWH o h ombop ophylaxis in pa ien s
unde going knee o hip eplacemen o help in o ming he
p ocess o clinical decision making.
Me hods
P o ocol and egis a ion
This sys ema ic e iew was epo ed in line wi h P e e ed
Repo ing I ems o Sys ema ic Re iews and Me a-Analyses
(PRISMA) guidelines.4 Repo ing o s a is ical da a ollowed
S a is ical Analyses and Me hods in he Published Li e a u e
(SAMPL) guidelines.5
Eligibili y c i e ia
We adop ed a me hodology simila o p e iously published
a icles.6–8 All phase 3 andomized con olled ials (RCTs)
compa ing apixaban agains LMWH in pa ien s submi ed o
majo o hopedic su ge y we e included. All published RCTs
we e conside ed o inclusion i espec i e o backg ound he -
apy, ea men du a ion, o ollow-up. Only ials epo ing
h ombo ic e en s and/o a al and non a al bleeding e en s
we e included. Ou ou comes o in e es we e as ollows: isk o
VTE and all-cause mo ali y (p ima y e icacy ou come),
majo VTE, symp oma ic VTE and VTE- ela ed mo ali y,
majo bleeding (p ima y sa e y ou come), and su ge y si e
bleeding. We used he In e na ional Socie y o Th ombosis
and Haemos asis de ini ion o majo bleeding.9
In o ma ion sou ces and sea ch me hod
Reco ds o po en ially eligible s udies we e iden i ied h ough
an elec onic sea ch o bibliog aphic da abases om incep ion
o Sep embe 2016 (MEDLINE, Embase, and CENTRAL a
Coch ane Lib a y). Sea ch s a egy de ails a e p o ided in
Supplemen a y Da a 1. No language es ic ions we e applied.
We sc eened, c oss-checked, and iden i ied sys ema ic e iews
and me a-analyses e alua ing NOACs, as well as e e ence lis s
o epo s o po en ial eligible s udies.
S udy selec ion, da a collec ion p ocess, and da a
i ems
Ti les and abs ac o eco ds ob ained om he sea ch p ocess
we e sc eened by 2 in es iga o s (D.C. and F.B.R.). Doub s
and disag eemen s we e sol ed by consensus. Whene e needed
a hi d elemen was consul ed (J.C.). Selec ed s udies we e
assessed in ull ex o de e mine i s app op ia eness o inclu-
sion. Da a om included s udies we e independen ly ex ac ed
by 2 au ho s (D.C. and F.B.R.) o a p epilo ed elec onic o m.
Re ie ed da a i ems we e as ollows: s udy design, yea o pub-
lica ion, pa ien s’ cha ac e is ics, in e en ions es ed, s udies’
ou comes, and da a o equi ed ou comes. Da a we e double-
checked o so wa e en y be o e analyses by an addi ional
au ho (J.C.).
Risk o bias in indi idual s udies
We used he Coch ane ool o assessing isk o bias o
included s udies.10 The 6 p ede ined speci ic domains o anal-
ysis we e as ollows: andom sequence gene a ion, alloca ion
concealmen , blinding o pa icipan s and pe sonnel, blinding
o ou come assessmen , incomple e ou come da a, and selec-
i e epo ing. Fo -p o i bias domain was added. Two inde-
penden e iew au ho s (D.C. and F.B.R.) pe o med c i ical
assessmen s o each domain o he isk o bias ool. Any disa-
g eemen was sol ed by discussion be ween he 2 e iewe s
and, i necessa y, eached consensus wi h he pa icipa ion o
a hi d e iewe (J.C.). The isk o bias was quali a i ely e al-
ua ed as high, unclea , o low isk. Risk o bias g aphs we e
de i ed om hese ools.
Summa y measu es
All ou comes da a we e summa ized as dicho omous da a. The
e ec measu emen es ima e chosen was isk a io (RR)
because ela i e es ima es a e mo e simila ac oss s udies wi h
di e en designs, popula ions, and leng hs o ollow-up han
absolu e e ec s.11
Syn hesis esul s
We used Re Man 5.3.3 so wa e (The No dic Coch ane
Cen e, The Coch ane Collabo a ion, 2014) o s a is ical
analysis and o de i e o es plo showing he esul s o indi-
idual s udies and pooled analysis. We compa ed apixaban 2.5
mg wice a day wi h LMWH, h ough andom-e ec s me a-
analysis weigh ed by he Man el-Haenszel me hod o es ima e
Caldei a e al 3
pooled RR and 95% con idence in e als (95% CI).
He e ogenei y measu ed as he pe cen age o o al a ia ion
be ween s udies due o he e ogenei y was assessed h ough he
I2 es .12 We used andom-e ec s model independen ly o he
exis ence (I2 ⩾ 50%) o no o subs an ial he e ogenei y
be ween s udies’ esul s because we pooled esul s o s udies
wi h di e en designs and pa ien s’ cha ac e is ics. When sig-
ni ican di e ences we e ound, we also de e mined he num-
be needed o ea (NNT) and 95% CI aking in o accoun he
baseline isk (p opo ion o e en a e in con ol g oup).10
P especi ied sensi i i y (by excluding s udies a a highe isk o
bias) and/o subg oup (by conside ing di e en egimens o
LMWH) analyses we e pe o med o explain and explo e he
ou come es ima es po en ially associa ed wi h s a is ical and/o
clinical he e ogenei y.
T ial sequen ial analyses (TSAs) we e pe o med o p i-
ma y ou comes using TSA e sion 0.9 be a (Copenhagen T ial
Uni , Cen e o Clinical In e en ion Resea ch, Copenhagen,
Denma k, 2011) o explo e whe he cumula i e da a we e ade-
qua ely powe ed o e alua e ou comes.13,14 The equi ed in o -
ma ion size and he O’B ien-Fleming adjacen ial sequen ial
alpha spending moni o ing bounda ies we e calcula ed based
on a 2-sided 5% isk o a ype I e o , 20% isk o a ype II e o
(powe o 80%), isk educ ion based on pooled analysis, he
weigh ed incidence o e en s in he con ol g oup, and he e o-
genei y. Powe o he p ima y ou comes indings was in e -
p e ed i signi icance was eached wi h ei he a minimum
sample size o c ossing ial sequen ial alpha spending moni-
o ing bounda y.
Assessmen o con idence in cumula i e e idence
As ecommended by he G ading o Recommenda ions
Assessmen , De elopmen , and E alua ion (GRADE)
Wo king G oup me hodology,15,16 2 e iewe s independen ly
assessed all he c i ical ou comes in he ollowing domains:
isk o bias, inconsis ency, indi ec ness, imp ecision, and
publica ion bias. In case o disag eemen , he au ho s eached
consensus, consul ing an independen hi d e iew, i
necessa y. Fo his pu pose, we used he GRADEp o ile
(GRADEp o) so wa e ool, which was hen ex ac ed in o
he o m o a summa y o indings able o inclusion in o he
e iew manusc ip . We applied he s anda d de ini ions o he
quali y o e idence17 and explici c i e ia o ensu e he consis -
ency and ep oducibili y o GRADE judgmen s o each
domain and o all key compa isons o he c i ical ou comes
(Supplemen a y Da a 2).
Resul s
S udy selec ion
O e all, 1161 e e ences we e e ie ed om he elec onic
sea ch (425 MEDLINE, 492 Embase, and 244 CENTRAL).
A e manual and au oma ic deduplica ion, 743 i les
and abs ac s we e sc eened o ull- ex e iew (Figu e 1).
Fou s udies wi h o e all 11 828 pa ien s unde going knee
(55%; 6496 pa ien s) o hip eplacemen (45%; 5332 pa ien s),
ea ed wi h apixaban 2.5 mg wice daily o LMWH
(2 s udies wi h enoxapa in 40 mg once daily, and 2 s udies
wi h enoxapa in 30 mg wice daily), we e selec ed o be
included.18–21 Thei main ea u es a e b ie ly cha ac e ized in
Table 1.
Risk o bias wi hin s udies
The o e all isk o bias ac oss s udies was low (Figu e 2). No
s udy had high o low isk o bias o e e y e alua ed domain.
One s udy (APROPOS18) did no epo he me hods o an-
domiza ion. All s udies used a cen alized me hod o pa ien
alloca ion. The blinding o pa icipan s, s udy pe sonnel, and
ou come assesso s was o low isk o bias ac oss RCTs. In a
single s udy (APROPOS), i was no possible o e alua e he
in luence o he imbalances p esen on some o ea men a m
in he s udy esul s. All s udies we e o high isk o o -p o i
bias because he s udies we e unded and sponso ed by he
Figu e 1. P e e ed Repo ing I ems o Sys ema ic Re iews and
Me a-Analyses (PRISMA) lowcha o s udies selec ion.
4 Clinical Medicine Insigh s: Blood Diso de s
companies who owned apixaban’s pa en , bu one (APROPOS),
whe e s udy unding was no decla ed.
Syn hesis o esul s
Apixaban 2.5 mg showed a 37% signi ican isk educ ion
(RR: 0.63, 95% CI: 0.42-0.95) o he composi e ou come o
all VTE e en s o mo ali y (Figu e 3) in compa ison wi h
LMWH. Acco ding o his es ima e, he NNT wi h apixaban
would be 26 pa ien s (95% CI: 16-190) o a weigh ed mean
pe iod o 73 days.
Howe e , he s a is ical he e ogenei y was e y high
(I2 = 84%) which can be pa ially a ibu ed o he di e en
egimens o LMWH (enoxapa in) in he con ol a ms. In
subg oup analysis, apixaban signi ican ly educed VTE
e en s o mo ali y compa ed wi h once-daily LMWH
egimens (RR: 0.50, 95% CI: 0.41-0.61; I2 = 68%), bu no
signi ican di e ence was ound when compa ing wi h
wice-daily LMWH egimens (RR: 0.96, 95% CI: 0.73-1.25,
I2 = 33%) (Table 2).
Rega ding TSA analysis, RR educ ion (RRR) o 37%
was assumed based on he RR o 0.63 ound in he me a-
analysis o VTE and all-cause mo ali y. The cumula i e
e idence eached 59% o minimum in o ma ion size equi ed
(14 138 pa ien s) adjus ed o he ob ained RRR and he e o-
genei y (Figu e 4). As s a is ical signi icance was ob ained
be o e he in o ma ion size has been eached, i was
impo an o e alua e whe he an adjus men o signi icance
bounda ies (O’B ien-Fleming bounda ies) o he sample size
s ill esul s in s a is ical signi ican es ima es. The TSA g aph
shows ha cumula i e es ima es we e no obus enough
o de e mine he p ema u e s a is ically signi ican esul s
(ie, he blue line did no c oss he do ed o ange line in
Figu e 4).
Conside ing he isk o majo VTE, he e we e no di e -
ences be ween apixaban and LMWH (RR: 0.62, 95% CI:
0.32-1.19) (Figu e 3). Simila o he esul s ound o he p i-
ma y e icacy ou come, subs an ial s a is ical he e ogenei y was
also no iced (I2 = 63%). Subg oup analysis acco ding o
LMWH egimens showed a signi ican isk educ ion in majo
VTE o apixaban compa ed wi h once-daily LMWH (RR:
0.45, 95% CI: 0.27-0.74; I2 = 0%), bu no signi ican di e -
ences when compa ed wi h wice-daily LMWH (RR: 0.91,
95% CI: 0.30-2.83; I2 = 48%).
Table 1. Main cha ac e is ics o included s udies compa ing apixaban 2.5 mg wice daily e sus LMWH.
TRIALS PATIENTS ORTHOPEDIC
CONDITION
MEAN
AgE
LMWH (ENOXAPARIN) PRIMARy
OUTCOME
MEAN FOLLOW-
UP, D
APROPOS18 303aElec i e knee
eplacemen
67 30 mg bid Majo bleeding 42
ADVANCE-119 3195 Elec i e knee
eplacemen
66 30 mg bid VTE e en s and
all-cause mo ali y
72
ADVANCE-220 3057 Elec i e knee
eplacemen
67 40 mg od VTE e en s and
all-cause mo ali y
72
ADVANCE-321 5407 Elec i e hip
eplacemen
61 40 mg od (ex ended
p ophylaxis
egimen—35 d)
VTE e en s and
all-cause mo ali y
95
Abb e ia ions: bid, wice daily; LMWH, low-molecula -weigh hepa in; od, once daily; VTE, enous h omboembolism.
aFo he p e ended compa ison.
Figu e 2. Risk o bias g aph.
Caldei a e al 5
The o e all isk o symp oma ic VTE and VTE- ela ed
dea h, majo bleeding, and su ge y si e bleeding was no di e -
en be ween apixaban and LMWH (conside ing all egimens)
(Figu es 3 and 5).
The sensi i i y analyses excluded he APROPOS s udy
which was he only phase 2 ial and he only s udy wi h an
unclea isk o bias in 3 o he 7 i ems analyzed. Such sensi i -
i y analyses did no esul in any s a is ically signi ican esul s,
and s a is ical he e ogenei y did no change subs an ially o all
ou comes’ es ima es (Table 3).
Table 4 de ails he GRADE app oach o he quali y o he
a ailable e idence which was conside ed o be low o mode a e.
Discussion
The main indings o his e iew we e as ollows: (1) he e is
low o mode a e quali y e idence compa ing apixaban wi h
LMWH; (2) apixaban 2.5 wice daily dec eases he isk o
VTE o all-cause mo ali y, and majo VTE, mos ly due o he
esul s o ials compa ing apixaban wi h once-daily 30 mg
enoxapa in; (3) his isk educ ion is, howe e , unde powe ed
acco ding o he TSA analysis; (4) he isk o symp oma ic
VTE and VTE- ela ed dea h wi h apixaban was simila o
LMWH; (5) he e we e no signi ican di e ences be ween
bo h in e en ions conce ning majo bleeding and su ge y si e
bleeding e en s.
The in e p e a ion o cu en da a is no as op imis ic as
epo ed in a p e ious sys ema ic e iew.22 Despi e he o e all
s a is ical signi ican educ ion in he isk o VTE and all-
cause mo ali y, i seems easonable o assume ha his di e -
ence was mainly d i en by he isk o majo VTE, pa icula ly
in compa ison wi h he “Eu opean” once-daily egimen o
enoxapa in, which may be an impo an gain in he ca e
o hese pa ien s. I is impo an o s a e ha he signi icance
o such ou come and isk educ ion es ima es a e
Figu e 3. Fo es plo o e icacy ou comes.
Table 2. Subg oup analysis pe di e en egimens o LMWH in he con ol a ms.
OUTCOME RR (95% CI) FOR APIXABAN
VS LMWH 40 Mg OD; I2 (%)
RR (95% CI) FOR APIXABAN
VS LMWH 30 Mg BID; I2 (%)
P VALUE FOR RR
INTERACTION
All VTE o all-cause mo ali y 0.50 (0.41–0.61); I2 = 68 0.96 (0.73–1.25); I2 = 33 <.001
Majo VTE 0.45 (0.27–0.74); I2 = 0 0.91 (0.30–2.83); I2 = 48 .26
Symp oma ic VTE o VTE- ela ed dea h 0.92 (0.40–2.08); I2 = 0 1.31 (0.68–2.51); I2 = 0 .50
Majo bleeding 0.94 (0.51, 1.73); I2 = 30 0.50 (0.24–1.02); I2 = N/A .18
Su ge y si e bleeding 0.96 (0.56–1.65); I2 = 3 0.57 (0.24–1.35); I2 = N/A .31
Abb e ia ions: bid, wice daily; CI, con idence in e al; LMWH: low-molecula -weigh hepa in; N/A, no applicable; od, once daily; RR: isk a io; VTE: enous
h omboembolism.

6 Clinical Medicine Insigh s: Blood Diso de s
unde powe ed and u he in es iga ion would be equi ed o
de ini ely es ablish he ue e ec size o apixaban bene i .
Gómez-Ou es e  al23 in hei sys ema ic e iew sugges ed
ha he po en ial bene i s in bleeding isk (clinically ele an
Figu e 4. T ial sequen ial analysis o all enous h omboembolism e en s and all-cause mo ali y. RR indica es isk a io.
Figu e 5. Fo es plo o sa e y/bleeding ou comes. CI indica es con idence in e al; LMWH, low-molecula -weigh hepa in.
Table 3. Resul s o he sensi i i y analyses ha excluded he APROPOS s udy.
EXCLUDINg APROPOS OUTCOMES RR (95% CI) FOR APIXABAN VS LMWH I2 (%)
All VTE o all-cause mo ali y 0.63 (0.39–1.01) I2 = 89
Majo VTE 0.66 (0.31–1.39) I2 = 74
Symp oma ic VTE o VTE- ela ed dea h 1.20 (0.70–2.04) I2 = 0
Majo bleeding 0.76 (0.43, 1.33) I2 = 45
Su ge y si e bleeding 0.83 (0.53–1.31) I2 = 0
Abb e ia ions: CI, con idence in e al; LMWH, low-molecula weigh hepa in; RR, isk a io; VTE, enous h omboembolism.
Caldei a e al 7
bleeding) and po en ial p o h ombo ic e ec s (pa icula ly PE)
could be he esul om delaying he adminis a ion o apixaban
i s pos ope a i e dose o 18 hou s. Ou da a show ha majo
bleeding and su gical si e bleeding isks a e simila be ween
apixaban and enoxapa in egimens, and ha majo VTE was no
inc eased wi h apixaban, despi e he end owa d a p o ec i e
e ec . Fu he mo e, as occu s wi h all NOACs, he e is a signi i-
can dec ease in in ac anial hemo hage, and he pha macoki-
ne ic and pha macodynamic p o iles o hese d ugs,7 including
apixaban, disclose a p edic able an icoagulan e ec , he eby dis-
missing egula e alua ions o hemos a ic pa ame e s.
O e all, apixaban 2.5 mg wice daily seems o be a aluable
op ion o he h ombop ophylaxis o pa ien s unde going
elec i e knee o hip eplacemen .
The e a e s ill some unanswe ed ques ions, such as he
exis ence o no o ne clinical bene i s o apixaban compa ed
wi h LMWH wice daily (besides he in ac anial hemo hage
isk educ ion7), and he op imal iming o apixaban adminis-
a ion a e su ge y, as well as he op imal ea men du a ion
o each condi ion (knee o hip eplacemen ). I is s ill unknown
whe he using an ul aspeci ic ac o Xa/ h ombin es s o
LMWH moni o ing (4 hou s a e he adminis a ion) could
imp o e he ou comes in he con ol a m, as sugges ed o
some subg oups o pa ien s wi h enous h omboembolism.
The esul s o his e iew should be in e p e ed in line
wi h he limi a ions inhe en o sys ema ic e iews and
me a-analysis. The he e ogenei y in he an icoagula ion
du a ion and in con ols somehow impai s he obus ness o
he p esen ed da a. The compa a o s we e also di e en as
low-dose enoxapa in (30 mg) was gi en wice daily in 1 ial,
whe eas he emaining ials engaged o a once-daily 40 mg
o enoxapa in o h ombop ophylaxis. The ollow-up was
di e en acco ding o he condi ions ( ials ended ea lie in
he knee eplacemen s udies) as well as he measu emen o
ou comes ha equi ed examina ions such as enog aphy.
These limi a ions may a leas pa ially explain o some
ex en he high s a is ical he e ogenei y ound in mos e icacy
ou comes. E en hough we conside he esul s a e eassu ing
o e icacy and sa e y.
Despi e he a ailable da a and p e ious me a-analysis, none
o hem had analyzed he powe o he signi ican esul s
ob ained in hei me a-analysis. The e o e, he me hods and
conclusions de i ed om TSA a e impo an o elucida ing
he obus ness o he da a ega ding apixaban e icacy in
pa ien s unde going majo elec i e o hopedic su ge ies such as
knee o hip eplacemen .
Conclusions
Apixaban 2.5 mg wice daily is a aluable and p ac ical op ion
o h ombop ophylaxis wi h bleeding isks simila o LMWH
and an e icacy likely o be be e han cu en enoxapa in
egimens.
Table 4. gRADE summa y o indings able—apixaban compa ed wi h LMWH o enous h omboembolism p ophylaxis a e majo o hopedic
su ge y.
OUTCOME
NO. OF PARTICIPANTS
(STUDIES)
RELATIVE EFFECT
(95% CI)
ANTICIPATED ABSOLUTE EFFECTS (95% CI)* QUALITy
WITHOUT APIXABAN WITH APIXABAN DIFFERENCE
All VTE and all-cause dea h
No. o pa icipan s: 8346
(4 RCTs)
RR: 0.63 (0.42–0.95) 10.5% 6.6% (4.4–9.9) 3.9% ewe (6.1
ewe -0.5 ewe )
⊕⊕
Lowa,b
Majo VTE
No. o pa icipan s: 9493
(4 RCTs)
RR: 0.62 (0.32–1.19) 1.6% 1.0% (0.5–1.9) 0.6% ewe (1.1
ewe -0.3 mo e)
⊕⊕
Lowa,b
Symp oma ic VTE and
dea h om VTE
No. o pa icipan s: 11 879
(4 RCTs)
RR: 1.14 (0.68–1.90) 0.5% 0.5% (0.3–0.9) 0.1% mo e (0.2
ewe -0.4 mo e)
⊕⊕⊕
Mode a eb
Majo bleeding
No. o pa icipan s: 11 828
(4 RCTs)
RR: 0.76 (0.43–1.33) 0.9% 0.7% (0.4–1.2) 0.2% ewe (0.5
ewe -0.3 mo e)
⊕⊕
Lowa,b
Su ge y si e bleeding
No. o pa icipan s: 11 828
(4 RCTs)
RR: 0.83 (0.53–1.31) 0.7% 0.6% (0.4–0.9) 0.1% ewe (0.3
ewe -0.2 mo e)
⊕⊕⊕
Mode a eb
Abb e ia ions: CI, con idence in e al; RCTs, andomized con olled ials; RR, isk a io; VTE, enous h omboembolism.
* The isk in he in e en ion g oup (and i s 95% con idence in e al) is based on he assumed isk in he compa ison g oup and he ela i e e ec o he in e en ion (and
i s 95% CI).
gRADE Wo king g oup g ades o e idence: high quali y, we a e e y con iden ha he ue e ec lies close o ha o he es ima e o he e ec ; mode a e quali y, we
a e mode a ely con iden in he e ec es ima e: he ue e ec is likely o be close o he es ima e o he e ec , bu he e is a possibili y ha i is subs an ially di e en ; low
quali y, ou con idence in he e ec es ima e is limi ed: he ue e ec may be subs an ially di e en om he es ima e o he e ec ; e y low quali y, we ha e e y li le
con idence in he e ec es ima e: he ue e ec is likely o be subs an ially di e en om he es ima e o e ec .
aS a is ical he e ogenei y supe io o 40%.
bMinimal in o ma ion size no me .
8 Clinical Medicine Insigh s: Blood Diso de s
Au ho Con ibu ions
DC con ibu ed o he concep and design, da a acquisi ion,
da a analysis, and in e p e a ion o he da a; w o e he i s
d a o he manusc ip ; c i ically e ised he manusc ip ;
and ga e inal app o al o he submi ed manusc ip . FR con-
ibu ed o he da a analysis and in e p e a ion; con ibu ed
o he i s d a ; c i ically e ised he manusc ip ; and ga e
inal app o al o he submi ed manusc ip . JC con ibu ed o
he concep and design, and in e p e a ion o he da a; c i i-
cally e ised he manusc ip ; and ga e inal app o al o he
submi ed manusc ip . FJP and JJF con ibu ed o he in e -
p e a ion o da a, c i ically e ised he manusc ip , and ga e
inal app o al o he submi ed manusc ip . DC and JC a e
he gua an o s.
Re eRenCes
1. Gee s WH, Be gq is D, Pineo GF, e al. P e en ion o enous h omboembo-
lism: Ame ican College o Ches Physicians E idence-Based Clinical P ac ice
Guidelines (8 h Edi ion). Ches . 2008;133:381S–453S.
2. Falck-Y e Y, F ancis CW, Johanson NA, e al. P e en ion o VTE in o hope-
dic su ge y pa ien s: an i h ombo ic he apy and p e en ion o h ombosis, 9 h
ed: Ame ican College o Ches Physicians E idence-Based Clinical P ac ice
Guidelines. Ches . 2012;141:e278S–e325S.
3. Caldei a D, Cos a J, Fe ei a JJ, Pin o FJ. Ne clinical bene i ou come should be
s anda dized in ials e alua ing an i h ombo ic d ugs: he example o NOACs
in a ial ib illa ion. In J Ca diol. 2014;174:405–406.
4. Libe a i A, Al man DG, Te zla J, e al. The PRISMA s a emen o epo ing
sys ema ic e iews and me a-analyses o s udies ha e alua e heal hca e in e -
en ions: explana ion and elabo a ion. BMJ. 2009;339:b2700.
5. Lang TA, Al man DG. Basic s a is ical epo ing o a icles published in
Biomedical Jou nals: he “S a is ical Analyses and Me hods in he Published
Li e a u e” o The SAMPL Guidelines.” In: Science Edi o s’ Handbook. Eu opean
Associa ion o Science Edi o s; 2013. h p://www.equa o -ne wo k.o g/wp-
con en /uploads/2013/07/SAMPL-Guidelines-6-27-13.pd .
6. Caldei a D, Ba a M, San os AT, e al. Risk o d ug-induced li e inju y wi h he
new o al an icoagulan s: sys ema ic e iew and me a-analysis. Hea . 2014;100:
550–556.
7. Caldei a D, Ba a M, Pin o FJ, Fe ei a JJ, Cos a J. In ac anial hemo hage isk
wi h he new o al an icoagulan s: a sys ema ic e iew and me a-analysis. J
Neu ol. 2015;262:516–522.
8. Caldei a D, Ba a M, Da id C, Cos a J, Fe ei a JJ, Pin o FJ. The p e alence o o al
an icoagula ion in pa ien s wi h a ial ib illa ion in Po ugal: sys ema ic e iew
and me a-analysis o obse a ional s udies. Re Po Ca diol. 2014;33:555–560.
9. Schulman S, Kea on C. De ini ion o majo bleeding in clinical in es iga ions o
an ihemos a ic medicinal p oduc s in non-su gical pa ien s. J Th omb Haemos .
2005;3:692–694.
10. Higgins JPT, G een S. Coch ane Handbook o Sys ema ic Re iews o In e en ions.
5.1.0 ed. Hoboken, NJ: John Wiley & Sons; 2011.
11. Deeks JJ. Issues in he selec ion o a summa y s a is ic o me a-analysis o clini-
cal ials wi h bina y ou comes. S a Med. 2002;21:1575–1600.
12. Higgins JP, Thompson SG. Quan i ying he e ogenei y in a me a-analysis. S a
Med. 2002;21:1539–1558.
13. B ok J, Tho lund K, Gluud C, We e sle J. T ial sequen ial analysis e eals insu -
icien in o ma ion size and po en ially alse posi i e esul s in many
me a-analyses. J Clin Epidemiol. 2008;61:763–769.
14. Caldei a D, Rod igues FB, Ba a M, e al. Non- i amin K an agonis o al an i-
coagulan s and majo bleeding- ela ed a ali y in pa ien s wi h a ial ib illa ion
and enous h omboembolism: a sys ema ic e iew and me a-analysis. Hea .
2015;101:1204–1211.
15. Alonso-Coello P, Oxman AD, Mobe g J, e al. GRADE E idence o Decision
(E D) amewo ks: a sys ema ic and anspa en app oach o making well in-
o med heal hca e choices. 2: clinical p ac ice guidelines. BMJ. 2016;353:i2089.
16. Alonso-Coello P, Schunemann HJ, Mobe g J, e al. GRADE E idence o
Decision (E D) amewo ks: a sys ema ic and anspa en app oach o making
well in o med heal hca e choices. 1: in oduc ion. BMJ. 2016;353:i2016.
17. Balshem H, Hel and M, Schunemann HJ, e al. GRADE guidelines: 3. Ra ing
he quali y o e idence. J Clin Epidemiol. 2011;64:401–406.
18. Lassen MR, Da idson BL, Gallus A, Pineo G, Ansell J, Dei chman D. The e i-
cacy and sa e y o apixaban, an o al, di ec ac o Xa inhibi o , as
h ombop ophylaxis in pa ien s ollowing o al knee eplacemen . J Th omb
Haemos . 2007;5:2368–2375. h p://onlinelib a y.wiley.com/o/coch ane/clcen-
al/a icles/373/CN-00619373/ ame.h ml.
19. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Po man RJ. Apixaban o
enoxapa in o h ombop ophylaxis a e knee eplacemen . N Engl J Med.
2009;361:594–604. h p://onlinelib a y.wiley.com/o/coch ane/clcen al/a i-
cles/569/CN-00700569/ ame.h ml.
20. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Ho nick P; ADVANCE-2
In es iga o s. Apixaban e sus enoxapa in o h ombop ophylaxis a e knee
eplacemen (ADVANCE-2): a andomised double-blind ial. Lance . 2010;
375:807–815.
21. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D Rami ez LM;
ADVANCE-3 In es iga o s. Apixaban e sus enoxapa in o h ombop ophy-
laxis a e hip eplacemen . N Engl J Med. 2010;363:2487–2498.
22. Li XM, Sun SG, Zhang WD. Apixaban e sus enoxapa in o h ombop ophy-
laxis a e o al hip o knee a h oplas y: a me a-analysis o andomized
con olled ials. Chin Med J (Engl). 2012;125:2339–2345.
23. Gómez-Ou es A, Te lei a-Fe nandez AI, Sua ez-Gea ML, Va gas-Cas illon
E. Dabiga an, i a oxaban, o apixaban e sus enoxapa in o h ombop ophy-
laxis a e o al hip o knee eplacemen : sys ema ic e iew, me a-analysis, and
indi ec ea men compa isons. BMJ. 2012;344:e.3675.