Venog aphic compa ison o subcu aneous
low–molecula weigh hepa in wi h o al
an icoagulan he apy in he long- e m
ea men o deep enous h ombosis
Jose A. Gonzalez-Faja do, MD, Emilio A eba, MD, Ja ie Cas odeza, MD,
Jose L. Pe ez, MD, Leopold Fe nandez, MD, Ignacio Agundez, MD, An onio
M. Ma eo, MD, San iago Ca e a, MD, Vicen e Gu ié ez, MD, and Ca los
Vaque o, MD, Valladolid, Spain
Pu pose: The p ima y objec i e o his s udy was o e alua e wi h enog aphy he a e o
h ombus eg ession a e a ixed dose o low–molecula weigh hepa in (LMWH) pe
day o 3 mon hs compa ed wi h o al an icoagulan he apy o deep enous h ombo-
sis (DVT). Seconda y endpoin s we e he compa isons o he e icacy and sa e y o bo h
ea men s.
Me hods: This s udy was designed as an open andomized clinical s udy in a uni e si y hos-
pi al se ing. O he 165 pa ien s inally en olled in he s udy, 85 we e assigned LMWH
he apy and 80 we e assigned o al an icoagulan he apy. In he g oup andomized o o al
an icoagulan he apy, he pa ien s i s unde wen ea men in he hospi al wi h s an-
da d un ac iona ed hepa in and hen couma in o 3 mon hs. Doses we e adjus ed wi h
labo a o y moni o ing o main ain he in e na ional no malized a io be ween 2.0 and
3.0. Pa ien s in he LMWH g oup we e adminis e ed subcu aneous injec ions o ixed
doses o 40 mg enoxapa in (4000 an i-Xa uni s) e e y 12 hou s o 7 days, and a e dis-
cha ge om he hospi al, hey we e adminis e ed 40 mg enoxapa in once daily a ixed
doses o 3 mon hs wi hou a labo a o y con ol assay. A quan i a i e enog aphic sco e
(Ma de sco e) was used o assess he ex en o he enous h ombosis, wi h 0 poin s indi-
ca ing no DVT and 40 poin s indica ing o al occlusion o all deep eins. The a e o
h ombus educ ion was de ined as he di e ence in quan i a i e enog aphic sco es a e
e mina ion o LMWH o couma in he apy as compa ed wi h he sco es ob ained on he
ini ial enog aphic esul s. The e icacy was de ined as he abili y o p e en symp oma ic
ex ension o ecu ence o enous h omboembolism (documen ed wi h enog ams o
se ial lung scans). The sa e y was de ined as he occu ence o hemo hages.
Resul s: A e 3 mon hs o ea men , he mean Ma de sco e was signi ican ly dec eased
in bo h g oups in compa ison wi h he baseline sco e, al hough he e ec o he apy was
signi ican ly be e a e LMWH he apy (49.4% educ ion) han a e couma in he a-
py (24.5% educ ion; P< .001). LMWH he apy and male gende we e independen ly
associa ed wi h an enhanced esolu ion o he h ombus. A lowe equency o symp o-
ma ic ecu en enous h omboembolism was also shown in pa ien s who unde wen
ea men wi h LMWH he apy (9.5%) han wi h o al an icoagulan he apy (23.7%; P
< .05), al hough his di e ence was en i ely a esul o ecu ence o DVT. Bleeding
complica ions we e signi ican ly ewe in he LMWH g oup han in he couma in g oup
(1.1% s 10%; P< .05). This di e ence was caused by mino hemo hages. Couma in
he apy and cance we e independen ly associa ed wi h an enhanced isk o complica-
ions. Subcu aneous hepa in he apy was well ole a ed by all pa ien s.
Conclusion: The pa ien s who we e alloca ed o unde go enoxapa in he apy had a sig-
ni ican ly g ea e imp o emen in hei quan i a i e enog aphic sco e, a signi ican ly
283
F om he Di ision o Vascula Su ge y, Angio adiology (D
A eba), and Epidemiology Depa men (D Cas odeza),
Hospi al Clinico Uni e si a io.
Rep in eques s: Jose A. Gonzalez-Faja do, MD, Di ision o
Vascula Su ge y, Hospi al Clinico Uni e si a io, E-47011,
Valladolid, Spain.
Copy igh © 1999 by he Socie y o Vascula Su ge y and
In e na ional Socie y o Ca dio ascula Su ge y, No h
Ame ican Chap e .
0741-5214/99/$8.00 + 0 24/1/97709
Low–molecula weigh hepa in (LMWH) has
been shown o be a leas as e ec i e and sa e as in a-
enous adjus ed-dose hepa in in he ini ial ea men
o p oximal deep ein h ombosis (DVT).1-10
Howe e , common p ac ice is o ca y ou ea men
wi h o al an icoagulan s o a leas 3 mon hs as a o m
o seconda y p e en ion.11 O al an icoagulan he apy
is associa ed wi h a signi ican isk o bleeding compli-
ca ions, and pa ien s who unde go such he apy
equi e equen labo a o y moni o ing. Some o hese
pa ien s ha e ela i e o absolu e con aindica ions o
he use o o al an icoagulan s.12 Unde such ci cum-
s ances, an al e na i e o p e en delayed h omboem-
bolic ecu ence is adjus ed dose o subcu aneous
hepa in wice daily.11-13 Compa ed wi h un ac iona -
ed hepa in, LMWH has a longe hal li e, signi ican ly
ewe hemo hagic complica ions, and a g ea e
bioa ailabili y a low doses, which allows once-a-day
schedule and he e o e may be p e e able o s anda d
hepa in especially o long- e m adminis a ion.14
Some s udies ha e ecen ly e alua ed he ole o
LMWH as an al e na i e o o al an icoagula ion in he
p e en ion o ecu en h omboembolism.12,15,16
They sugges ha ixed doses o LMWH appea o be
qui e e ec i e and sa e, bu limi ed da a on he basis o
enog aphic obse a ions a e a ailable. P e ious in es-
iga ions ha compa ed LMWH wi h s anda d un ac-
ioned hepa in in he ini ial ea men o DVT e ealed
a phlebog aphic imp o emen in he pa ien s who
unde wen ea men wi h LMWH when he
enog ams we e pe o med app oxima ely 1 o 2
weeks la e ,14 bu no signi ican di e ences we e seen
a he 6 mon h ollow-up examina ion.17 F om he
exis ing e idence, i is likely ha a ma ked o o al
educ ion o h ombi will educe he incidence o pos -
h ombo ic synd ome.18 Because a longe du a ion o
he ea men wi h LMWH may inc ease he success
a e o ecanaliza ion o he occluded eins, i seems
legi ima e o use phlebog aphic endpoin s.19 Fo his
eason, he p ima y objec i e o he p esen s udy was
o e alua e wi h enog aphy he a e o h ombus
eg ession a e a single subcu aneous injec ion o
LMWH (enoxapa in, 40 mg) pe day o 3 mon hs as
compa ed wi h o al an icoagulan he apy o he
ea men o pa ien s wi h DVT. Seconda y endpoin s
we e o compa e he e icacy (p e en ion o symp o-
ma ic enous h omboembolism) and sa e y (occu -
ence o hemo hage) o bo h ea men s.
MATERIAL AND METHODS
S udy design. This was an open, andomized
s udy compa ing con en ional couma in he apy
wi h a 3-mon h cou se o enoxapa in (4000 an i-Xa
uni s; 40 mg) subcu aneously once daily in a ixed
dose. The p ima y endpoin was he abili y o
eopen h omboses eins, de ined as he di e ence
in quan i a i e enog aphic sco es a e e mina ion
o LMWH o couma in he apy compa ed wi h he
sco es ob ained on he ini ial enog aphy. The sec-
onda y endpoin s we e he de elopmen o symp o-
ma ic ecu en pulmona y embolism o symp o-
ma ic ecu en enous h ombosis (documen ed
wi h se ial pe usion lung scans o enog ams) and
bleeding episodes. Randomiza ion was achie ed by
means o a p esc ibed schedule. In o med w i en o
e bal consen was ob ained om all pa ien s in he
s udy. The s udy p o ocol was accep ed by he
Ins i u ional Re iew Boa d.
Pa ien s. Consecu i e eligible pa ien s wi h
clinically suspec ed DVT con i med wi h con as
enog aphy we e en olled in he s udy acco ding o
a compu e schedule. The easons o exclusion
we e: clinically suspec ed pulmona y embolism, cu -
en ly ac i e bleeding o coagula ion abno mali y o
diso de s con aindica ing an icoagulan he apy,
p egnancy, wo o mo e p e iously documen ed
episodes o DVT o pulmona y embolism, ongoing
an icoagulan ea men a he ime o e e al, his-
o y o hepa in-induced h ombocy openia, ca al il-
e inse ed, alle gic eac ion o con as ma e ial, a
coagula ion-inhibi o de iciency, a lupus an icoagu-
lan , o an iphospholipid an ibodies. In each pa ien ,
an icoagulan he apy was s a ed as soon as possible
a e DVT had been documen ed objec i ely wi h
ascending con as enog aphy. Whene e possible,
he pa ien s we e allowed o walk on he hi d day o
ea men , wea ing elas ic comp essi e s ockings.
Regimens. In he pa ien s andomized o o al
an icoagulan he apy, an in a enous bolus o 100
U/kg o un ac ioned hepa in was adminis e ed, ol-
lowed by a con inuous in a enous in usion o
hepa in. The ac i a ed pa ial h omboplas in ime
JOURNAL OF VASCULAR SURGERY
284 Gonzalez-Faja do e al Augus 1999
lowe ecu ence a e o symp oma ic enous h omboembolism, and a signi ican ly
lowe incidence o bleeding han pa ien s who unde wen ea men wi h couma in.
LMWH can be used on an ou pa ien basis as a sa e and mo e e ec i e al e na i e o
classical o al an icoagulan he apy o he seconda y p ophylaxis o selec ed pa ien s
wi h DVT. (J Vasc Su g 1999;30:283-92.)
was measu ed 4 hou s a e he beginning o in a-
enous hepa in ea men , and he es was epea ed
a in e als o 4 o 6 hou s un il he esul was wi h-
in he p esc ibed he apeu ic ange ( a io, 1.5 o
2.0) du ing he ini ial 24 hou s o he apy. O al
ea men wi h couma in (ini ial dose o 5 mg) was
s a ed in pa ien s on day 5 o hepa in ea men .
The couma in dose was adjus ed daily o main ain
he in e na ional no malized a io (INR) be ween
2.0 and 3.0. Subsequen ly, hepa in ea men was
discon inued and he couma in dose was adjus ed
wi h labo a o y moni o ing o 3 mon hs. Al hough
du ing his s udy he classical app oach o he ea -
men o DVT was used, he esul s o wo andom-
ized clinical ials20,21 ha e shown ha o al an ico-
agulan he apy s a ing wi h hepa in a he ime o
diagnosis is as e ec i e and sa e as he con en ional
egimen. The in ensi y o an icoagula ion he apy in
he i s 3 mon hs was exp essed as he pe cen age o
ime du ing which a pa ien had a speci ic INR
(<2.0, 2.0 o 3.0, o >3.0), wi h his pe iod calcu-
la ed wi h linea in e pola ion. No pa ien s unde -
wen o al an icoagulan he apy a e 3 mon hs o
ea men , unless hey had symp oma ic ecu en
h omboembolism. Pa ien s in he LMWH g oup
we e adminis e ed subcu aneous injec ions e e y 12
hou s o ixed doses o 40 mg enoxapa in (co e-
sponding o 4000 in e na ional ac o Xa inhibi o y
uni s) o 7 days. A e discha ge om he hospi al,
he pa ien s unde wen ea men wi h 40 mg
enoxapa in subcu aneously once daily, which was
usually adminis e ed by he pa ien s hemsel es o
by ela i es and only occasionally by nu ses. LMWH
was adminis e ed a ixed doses, wi hou a labo a o-
y con ol assay o 3 mon hs.
Main ou come measu es. Venog aphy was pe -
o med wi h long-leg ilms and no ionic con as
ma e ial acco ding o he me hod o Rabino and
Paulin.22 The c i e ia o DVT we e an in aluminal
illing de ec con i med in a leas wo di e en p o-
jec ions and no illing o a enous de ec despi e
epea ed injec ions wi h con as ma e ial. A quan i-
a i e enog aphic sco e (Ma de sco e23) was used
o assess he ex en o he enous h ombosis, wi h
0 poin s indica ing no DVT and 40 poin s indica ing
o al occlusion o all deep eins (Table I). Con ol
phlebog aphies we e pe o med ou inely in all
pa ien s a e 3 mon hs o ea men . Each pa ien
was assigned o one o he ollowing g oups on he
basis o di e ences on he Ma de sco e be ween ini-
ial and pos - ea men phlebog aphy: inc eased
h ombosis (an inc ease in sco e poin s), unchanged
(unal e ed o al sco e o ≤10% dec ease in sco e
poin s), pa ly clea ed (>10% o ≤50% dec ease in
sco e poin s), subs an ially clea ed (>50% o 89%
dec ease in sco e poin s), and comple ely lysed
(≥90% dec ease in sco e poin s). Pe usion lung
scanning and ches adiog aphy we e pe o med o
all pa ien s a baseline. To exclude bias, he assess-
men o enog ams and lung scans we e sco ed by
wo obse e s who we e blind o ea men alloca-
ion and o he sequence in which he es s we e
done (be o e o a e ea men ). The e icacy o
ea men was de ined as he abili y o p e en symp-
oma ic ex ension o ecu ence o enous h om-
boembolism. The sa e y was de ined as he occu -
ence o hemo hages. Bleeding was de ined as
majo bleeding i i was in ac aneal o e ope i-
oneal o i i p oduced a dec ease in he hemoglo-
bin le el o a leas 2.0 g/dL, su icien o necessi-
a e discon inua ion o ea men o he ans usion
o 2 o mo e uni s o blood. Bleeding was de ined as
mino bleeding i i did no mee he c i e ia o
majo bleeding.
Su eillance and ollow-up. A e discha ge,
all he pa ien s we e seen in ou ascula clinic e e y
mon h du ing he i s imes e and hen e e y 3
mon hs du ing a o al o 1 yea o ollow-up. They
we e ins uc ed o come o he hospi al immedia e-
ly i symp oms o signs o ecu en DVT, pul-
mona y embolism, o bleeding de eloped. Those
pa ien s wi h suspec ed ecu en DVT unde wen
con as enog aphy. Recu en DVT was de ined as
a cons an in aluminal illing de ec no p esen he
i s day. Pa ien s wi h clinically suspec ed pul-
mona y embolism unde wen ano he pe usion
lung scan and ches adiog aphy. The diagnosis was
made on he basis o he p esence o a leas one seg-
men al de ec no seen on he p eceding scan and no
abno mali y on he ches adiog aph a ea. I he
esul s we e inconclusi e, pulmona y angiog aphy
JOURNAL OF VASCULAR SURGERY
Volume 30, Numbe 2 Gonzalez-Faja do e al 285
Table I. Venog aphic quan i a ion o h ombosis
(Ma de sco e)
Deep eins Sco e*
Iliac 6
Common emo al 4
Supe icial emo al 10
Popli eal 4
An e io ibial 4 (2 each)
Pos e io ibial 6 (3 each)
Pe oneal 6 (3 each)
*To al occlusion o non illing o a gi en ein was assigned he
maximum sco e; segmen al occlusion o illings de ec s we e
gi en lesse sco es in p opo ion o he deg ee o in ol emen .
was pe o med. Du ing he 3 mon hs o ea men ,
pla ele coun s we e ob ained each mon h in he
pa ien s unde going LMWH he apy o ule ou he
possibili y o hepa in-induced h ombocy openia.
Adhe ence o he s udy egimens was moni o ed by
e iews o he pa ien s’ cha s. A each isi , pa ien s
we e ques ioned abou he appea ance o new symp-
oms, bleeding, swelling, hea iness o leg, leg i ed-
ness, o pain. The clinical s a us a e 3 mon hs o
ea men was g aded subjec i ely by each pa ien as
imp o ed, unchanged, o wo se in ela ion o he
p e ea men s a us.
S a is ical analysis. On he basis o esul s om
p e ious ials,24 he p opo ion o pa ien s wi h an
unchanged o imp o ed Ma de sco e a e LMWH
ea men was assumed o be 90%. By sample size,
we de e mined a 15% absolu e di e ence in he
p opo ions o pa ien s whose condi ions we e
unchanged and imp o ed ha we e needed o show
a s a is ically signi ican di e ence be ween he wo
ea men s. A an 80% powe o showing his di -
e ence a he 5% signi icance le el, wi h a one-sided
es , a o al o 78 pa ien s would be necessa y a leas
in each ea men g oup. The numbe o pa ien s
planned o inclusion in o each g oup was he e o e
92, o accoun o an an icipa ed d op-ou a e o
15%. Quan i a i e da a we e exp essed as mean ±
s anda d e o . Con idence in e als (CI) o 95% o
he di e ence be ween he wo ea men g oups
we e calcula ed wi h he no mal app oxima ion o
he binomial dis ibu ion. The a es o asymp oma ic
pulmona y embolism, ecu en h omboembolism,
bleeding, dea h, deg ee o h ombus eg ession, and
clinical s a us in he wo g oups we e compa ed by
means o Fishe exac es o χ2 es as app op ia e.
The changes in enog aphic sco e we e analyzed
wi hin and be ween g oups wi h wo-sample and
ma ched-pai and unpai ed es s. Uni a ia e analy-
sis was pe o med o iden i y ac o s ha a ec ed he
di e ences on he Ma de sco e be ween ini ial and
pos - ea men phlebog aphy. A mul i a ia e s ep-
wise eg ession model was used o iden i y indepen-
den a iables ha could in luence he pe cen age o
change in Ma de sco e and complica ions o bo h
g oups. Two-sided P alues o less han .05 we e
conside ed signi ican . So wa e JMP 3.1 om he
S.A.S. Ins i u e Inc (Ca y, NC) was used.
RESULTS
Pa ien s. F om June 1994 o June 1997, 257
consecu i e pa ien s wi h clinically suspec ed DVT
unde wen ea men in ou hospi al. Eligible
JOURNAL OF VASCULAR SURGERY
286 Gonzalez-Faja do e al Augus 1999
Fig 1. Venog aphic changes wi h 40 mg enoxapa in (4000 an i-Xa uni s). A, To al occlusion
o popli eal and emo al eins in pa ien wi h deep enous h ombosis. B, Comple e ecana-
liza ion a e ixed dose pe day o 3 mon hs o ea men .
AB
pa ien s (n = 185) had DVT con i med wi h con as
enog aphy, pe usion lung scanning wi hin 48
hou s o s udy en y, and ches adiog aphy. O
hese, 93 we e assigned o unde go LMWH he apy
and 92 o unde go ea men wi h couma in.
Twen y pa ien s we e excluded om he analysis
(eigh in he LMWH g oup, and 12 in he couma in
g oup) because he second enog am was no
ob ained (n = 12), he egimen o ea men was no
pe o med co ec ly by he pa ien (n = 5), o he
pa ien s we e los du ing he ollow-up pe iod (n =
3). Fo he 165 pa ien s inally en olled in o he
s udy, he baseline clinical cha ac e is ics a e shown
in he Table II. The ea men g oups we e compa-
able a en y excep o age (younge in he
couma in g oup) and incidence o silen pulmona y
embolism (highe in he couma in g oup). To assess
he possible e ec o his po en ial age and asymp o-
ma ic pulmona y embolism imbalance, mul iple
logis ic eg ession was used. No signi ican e ec
was ound.
Deg ee o h ombus eg ession. The in ensi y
o o al an icoagulan he apy in he couma in g oup
was 15% wi h INR less han 2.0, 64% wi h INR om
2.0 o 3.0, and 21% wi h INR mo e han 3.0. A sec-
ond enog am was pe o med in all pa ien s. The
changes in he ex en o enous h ombosis on enog-
aphy a e summa ized in Table III. No signi ican di -
e ence in Ma de sco e was obse ed be ween he
wo ea men g oups a inclusion. A e 3 mon hs o
ea men , he mean Ma de sco e was signi ican ly
dec eased in bo h g oups in compa ison wi h he
baseline sco e, al hough he e ec o he apy was sig-
ni ican ly be e a e LMWH he apy (49.4% educ-
ion o he Ma de sco e) han a e couma in he apy
(24.5% educ ion o he Ma de sco e; P< .001; Fig
1). The esul s o he s a i ied analysis o he e olu-
ion o he h ombus (Table III), on he basis o he
pe cen age o he di e ences o sco e be ween he ini-
ial and pos - ea men phlebog aphy, also showed a
s a is ically signi ican supe io i y o LMWH he apy
o e couma in he apy (P< .001).
JOURNAL OF VASCULAR SURGERY
Volume 30, Numbe 2 Gonzalez-Faja do e al 287
Table II. Clinical cha ac e is ics o pa ien s wi h deep enous h ombosis ea ed wi h enoxapa in o
couma in
Enoxapa in (n = 85) Couma in (n = 80) P alue
Mean age (yea s) 62.7 ( , 19 o 83) 58.3 ( , 20 o 82) <.05
Sex (male: emale) 41:44 46:34
Days since onse o symp oms 4.9 ( , 1 o 30) 4.1 ( , 1 o 20)
Asymp oma ic pulmona y embolism 21 (24.7%) 45 (56.2%) <.001
Risk ac o s o DVT
Recen auma, su ge y, o immobiliza ion 34 (40%) 23 (28.77%)
Cance 10 (11.7%) 8 (10%)
Unknown 41 (48.2%) 49 (61.2%)
Loca ion o h ombus
Cal wi h popli eal ein 6 (7.05%) 7 (8.7%)
Popli eal and emo al ein 43 (50.5%) 35 (43.7%)
Popli eal, emo al, and iliac ein 26 (30.5%) 30 (37.5%)
Iliac ein 10 (11.7%) 8 (10%)
DVT, Deep enous h ombosis.
Table III. Venog aphic e alua ion
Enoxapa in (n = 84)* Couma in (n = 80) P alue
Ma de sco e
Be o e ea men 24.7 ± 1.1 26.06 ± 1.1
A e ea men 12.5 ± 1.05 19.7 ± 1.1 <.001
Di e ence (∆) –12.2 ± 0.9 –6.4 ± 0.8 <.001
Fa e o he h ombus <.001
Inc ease in size 2 (2.3%) 8 (10%)
No change 3 (3.5%) 13 (16.2%)
Pa ial clea ance 39 (46.4%) 45 (56.2%)
Subs an ial clea ance 24 (28.5%) 13 (16.2%)
Comple e lysis 16 (19.04%) 1 (1.2%)
*One pa ien died o massi e pulmona y embolism.

Uni a ia e analysis shows ha no signi ican di -
e ences we e obse ed in he dis ibu ion o
changes in enog aphic sco e be ween bo h g oups
when he cause o DVT was cance o he h ombus
was placed only a genicula e o iliac le el (Table
IV). In con as , a highe eopening a e o h om-
bosed eins was shown in he pa ien s assigned o
unde go LMWH he apy as compa ed wi h he
pa ien s assigned o unde go ea men wi h
couma in when he cause o DVT was ecen au-
ma, su ge y, o immobiliza ion (P= .0037), when
he DVT was idiopa hic (P= .0009), o when he
h ombus was placed in popli eal and emo al eins
(P= .0011) o a ec ed comple ely all o he limb (P
= .01005). In a s ep-wise linea eg ession model,
LMWH he apy (P< .0001) and male gende (P=
.0199) we e independen ly associa ed wi h an
enhanced esolu ion o he h ombus (Table V). The
2 alue was 0.11435.
Recu en h omboembolism. Symp oma ic
ex ension o ecu en enous h omboembolism
con i med wi h objec i e es s de eloped in eigh
pa ien s (9.5%) o he LMWH g oup and in 19
pa ien s (23.7%) assigned o unde go couma in
he apy (P= .0196; Table V). O he 19 e en s in
he couma in g oup, 15 in ol ed ecu en h om-
bosis (13 ecu ences we e in he same limb, wo
we e con ala e al) and ou in ol ed pulmona y
embolism ( om which all pa ien s equi ed ca a il-
e placemen ). O he eigh e en s in he LMWH
g oup, i e in ol ed ecu en h ombosis (all in he
same limb) and h ee in ol ed pulmona y embolism
( om which one pa ien died on he i h day a e
andomiza ion). The absolu e di e ence in he e-
quency o pulmona y embolism did no each s a is-
ical signi icance (P= .7149). Howe e , signi ican
di e ences we e obse ed in he equency o ecu -
en h ombosis (P= .0161). Du ing he 12-mon h
su eillance pe iod, wo pa ien s in he couma in
g oup had a ecu ence o symp oma ic DVT docu-
men ed wi h enog aphy a e discon inua ion o
he an icoagulan ea men (one in he 20 h week,
and he o he in he 24 h week). In he LMWH
g oup, h ee pa ien s had symp oma ic ecu en
DVT documen ed wi h enog aphy (one in he 20 h
week, ano he in he 24 h week, and ano he in he
32nd week). Only one pa ien o he couma in
g oup was eadmi ed o he hospi al in he 21s
week because o symp oma ic ecu en pulmona y
embolism con i med wi h pe usion lung scanning
and ches adiog aphy. No symp oma ic pulmona y
embolisms we e obse ed in he LMWH g oup.
Recu en h omboembolism was associa ed wi h
ecen su ge y o auma in h ee pa ien s ( h ee
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288 Gonzalez-Faja do e al Augus 1999
Table IV. Uni a ia e analysis o isk ac o s and loca ion o h ombus associa ed wi h di e ences on he
Ma de sco e be ween ini ial and pos - ea men phlebog aphy
Enoxapa in ∆Ma de sco e Couma in ∆Ma de sco e P alue
Risk ac o s o DVT
Recen auma, su ge y, o immobiliza ion 11.4 ± 1.3 6.2 ± 1.04 <.01
Cance 8.1 ± 2.1 3.5 ± 1.5
Unknown 13.7 ± 1.5 7 ± 1.2 <.001
Loca ion o h ombus
Cal wi h popli eal ein 7 ± 2.3 5.1 ± 2.2
Popli eal and emo al ein 11.8 ± 1.3 6.1 ± 1.06 <.01
Popli eal, emo al, and iliac ein 15.2 ± 2.07 8.7 ± 1.2 <.05
Iliac ein 8.3 ± 1.8 0.25 ± 4.1
∆
Ma de sco e, Ma de sco e be o e ea men – Ma de sco e a e ea men ; DVT, deep enous h ombosis.
Table V. Independen de e minan s o he pe cen age o change in Ma de sco e as selec ed wi h mul i-
a ia e s ep-wise linea eg ession model
Signi ican independen
95% CI
a iables Lowe Uppe F alue P alue
T ea men (enoxapa in) –28.329 –9.889 16.5 .0001
Sex (male) –20.348 –1.851 5.53 .0199
F, Fishe -Snedeco .
R2= 0.11435.
cases in he LMWH g oup, and none in he
couma in g oup), cance in 10 pa ien s ( i e cases in
he LMWH g oup, and i e in he couma in g oup),
and idiopa hic disease in 20 pa ien s ( h ee cases in
he LMWH g oup, and 17 in he couma in g oup).
Bleeding complica ions. Bleeding complica-
ions we e signi ican ly ewe in he LMWH g oup
(1.1% s 10%; P= .0160; Table VI). Majo bleeding
occu ed du ing o immedia ely a e he ini ial he -
apy in one pa ien unde going LMWH he apy
(1.1%) and in 2 pa ien s unde going ea men wi h
couma in (2.5%; P= .6136). The hemo hage in he
LMWH g oup consis ed o uppe gas oin es inal
bleeding, and in he couma in g oup, he e we e
one uppe gas oin es inal bleeding and one
e ope i oneal bleeding wi h hema u ia. Mino
hemo hagic complica ions occu ed in none o he
pa ien s who unde wen LMWH he apy and in six
pa ien s who unde wen ea men wi h couma in
(7.5%; P= .0121). The mino bleedings in he
couma in g oup consis ed o wo hema u iax, h ee
epis axis, and one hemop ysis. Small hema omas in
he abdominal wall we e seen in pa ien s assigned o
unde go LMWH he apy. In a s ep-wise logis ic
eg ession model (Table VII), couma in he apy
(odds a io, 2.82; CI, 1.719 o 4.623; P< .0001)
and cance (odds a io, 2.15; CI, 1.101 o 4.233; P
= .025) we e independen ly associa ed wi h an
enhanced isk o complica ions (symp oma ic ecu -
en h omboembolism and bleeding). These con-
clusions emained unchanged when he ew pa ien s
wi h documen ed DVT who we e wi hd awn a e
andomiza ion because o p o ocol iola ion we e
included in an in en ion- o- ea analysis.
Dea hs. One pa ien om he LMWH g oup
died o massi e pulmona y embolism, con i med
wi h angiog aphy, on he i h day a e he ini ial
ea men . Du ing he 12-mon h s udy pe iod, ou
pa ien s who we e assigned o he LMWH g oup
died, as compa ed wi h h ee pa ien s assigned o he
couma in g oup. The causes o dea h included can-
ce ( i e pa ien s) and ca dio ascula disease ( wo
pa ien s).
Compliance. Only one case o h ombocy ope-
nia (<100.000/mm3) was obse ed immedia ely
a e he ini ial he apy wi h un ac ioned hepa in.
This diso de dissapea ed wi h o al an icoagulan
he apy. Subcu aneous hepa in he apy was well ol-
e a ed by all pa ien s. No pa ien s showed hepa in-
induced h ombocy openia in he 3-mon h g oup
wi h LMWH. The clinical s a us g aded subjec i ely
by each pa ien was signi ican ly be e a e LMWH
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Table VI. Th omboembolic and bleeding complica ions du ing ini ial ea men and ollow-up examina ion
Enoxapa in (n = 85) Couma in (n = 80) P alue
T ea men pe iod (3 mon hs)
Majo bleeding 1 2
Mino bleeding 0 6 .0121
To al e en s 1 8 .0160
Recu ence o DVT 5 15 .0161
Pulmona y embolism 3* 4
To al e en s 8 19 .0196
Su eillance pe iod (9 mon hs)
Recu ence o DVT 3 2
Pulmona y embolism 0 1
To al e en s 3 3
DVT, Deep enous h ombosis.
*One a al pulmona y embolism.
Table VII. Independen de e minan s o complica ions ( enous h omboembolism and bleeding) as
selec ed wi h mul i a ia e s ep-wise logis ic eg ession model
Signi ican independen
95% CI
a iables Lowe Uppe Odds a io P alue
T ea men (couma in) 1.719 4.623 2.82 .0001
Risk ac o (cance ) 1.101 4.233 2.15 .0250
CI, Con idence in e al.
he apy han a e couma in he apy (P< .001).
The e was an imp o emen a e 3 mon hs o ea -
men in ela ion o he p e ea men s a us in 68 o
84 pa ien s (80.9%) in he LMWH g oup and in 40
o 80 (50%) in he couma in g oup. The e we e no
changes in 15 o 84 pa ien s (17.8%) in he LMWH
g oup and in 35 o 80 (43.7%) in he couma in
g oup. Finally, he e was wo sening in one o 84
pa ien s (1.1%) and i e o 80 (6.2%), espec i ely.
DISCUSSION
This s udy showed ha enoxapa in, a LMWH, no
only can be used sa ely and e ec i ely o ea DVT a
home o long e m bu also ha i s abili y o eopen
h omboses eins is be e han couma in, an an i– i -
amin K o al an icoagulan . Al hough he mean Ma de
sco e was signi ican ly imp o ed in bo h g oups a he
3-mon h ollow-up examina ion, a highe deg ee o
ecanaliza ion was shown wi h enog aphy in he
pa ien s assigned o unde go LMWH he apy (49.4%)
as compa ed wi h he pa ien s assigned o unde go
ea men wi h couma in (24.4%). Mo eo e , in a
mul i a ia e analysis, he male pa ien s we e indepen-
den ly associa ed wi h an enhanced esolu ion o he
h ombus. A h ombus educ ion o a leas 30% o
mo e is a p esen used in se e al ials as a sign o clin-
ical bene i o he indi idual pa ien ,19 wi h he
expec ancy ha a majo ecanaliza ion may also esul
in a educed incidence o pos - h ombo ic syn-
d ome.18,19 Because o his, e idence on he basis o
enog aphic indings sugges s ha a LMWH may
educe he isk o he la e sequelae o DVT, al hough
i will open o discussion o wha ex en he educ ion
o h ombus size eally is accomplished by long- e m
bene i s. The 12-mon h ollow-up pe iod used in his
s udy is oo sho o e lec he ue de elopmen o
clinical pos - h ombo ic synd ome. Howe e , LMWH
was subjec i ely associa ed by each pa ien wi h be e
clinical s a us han couma in he apy a e 3 mon hs o
ea men .
Long- e m enog aphic ollow-up da a in
pa ien s wi h DVT a e limi ed.17 Ou s udy is he
i s o analyse a longe du a ion o ea men wi h
LMWH and he endency o h ombus eg ession in
compa ison wi h pa ien s unde going o al an icoag-
ulan he apy as a o m o seconda y p e en ion. The
mechanism by which LMWH acili a es h ombus
eg ession is no unde s ood. P obably he inhibi-
ion o h ombin o ma ion, he lesse isk o pla ele
agg ega ion, and local e ec s a he endo helial le el
play a c i ical ole.25,26 Indeed, endo helial cells a e
he p incipal physiologic sou ce o issue- ype plas-
minogen ac i a o , and he subcu aneous adminis-
a ion o LMWH causes an inc ease in plasma o is-
sue- ype plasminogen ac i a o wi h peak a 3 hou s
a e injec ion.27,28
The ecanaliza ion o h ombosed eins was qui e
di e en in hese wo pa ien g oups acco ding o he
cause o DVT and he localiza ion o he enous
occlusion. Pa icula ly, he e was a signi ican end
in a o o LMWH when he cause o DVT was
ecen auma, su ge y, o immobiliza ion, when he
DVT was idiopa hic, o when he h ombus was
placed in popli eal and emo al eins o a ec ed com-
ple ely all o he limb. By con as , i he cause o
DVT was cance o he in aluminal illing de ec was
exclusi ely placed a genicula e o iliac le el, no sig-
ni ican di e ences we e obse ed be ween pa ien s
assigned o unde go LMWH he apy and pa ien s
assigned o unde go ea men wi h couma in.
Ne e heless, because o he la ge s anda d e o and
he ela i ely small numbe o pa ien s among hese
subg oups, his s udy does no ha e su icien s a is-
ical powe o de ec signi ican di e ences. Fu he
s udies a e necessa y be o e de ini i e conclusions
can be eached.
LMWH ha e unde gone limi ed in es iga ions
o he seconda y p e en ion o enous h omboem-
bolism.9In hese s udies, pa ien s i s unde wen
ea men in he hospi al wi h s anda d hepa in, and
hen he apy wi h LMWH was compa ed wi h he a-
py wi h wa a in15,16 o subcu aneous s anda d
hepa in12 o 3 o 6 mon hs. Mon eal e al12 showed,
in a consecu i e se ies o pa ien s wi h con aindica-
ion o couma in he apy, ha pa ien s who unde -
wen ea men wi h LMWH had a lowe equency
o ei he ecu en pulmona y embolism o mino
bleeding in compa ison wi h un ac ioned hepa in,
al hough none o hese di e ences we e s a is ically
signi ican pe haps because o he small numbe o
pa ien s (be a e o ). Pini e al15 con i med hese
indings in a su icien ly la ge andomized s udy o
pa ien s wi h DVT, al hough he diagnosis o ecu -
en DVT was o en made on he basis o nonin asi e
es ing and diagnosis o pulmona y embolism could
be ques ioned because baseline lung scans we e no
pe o med. Despi e hese ac s, hey showed essen-
ially no di e ence in he incidence o ecu en
h ombosis be ween pa ien s who unde wen ea -
men wi h LMWH (enoxapa in 40 mg) and pa ien s
who unde wen ea men wi h wa a in, bu pa ien s
alloca ed o unde go LMWH he apy had a signi i-
can ly lowe incidence o bleeding. In he hi d ial,
which has been epo ed in abs ac o m, Kakka 16
co obo a ed hese indings wi h dal epa in.
In ou s udy, a es o symp oma ic ecu en
JOURNAL OF VASCULAR SURGERY
290 Gonzalez-Faja do e al Augus 1999
h omboembolism and bleeding also ended o occu
less in he pa ien s unde going enoxapa in he apy
han in hose pa ien s unde going couma in he apy
(odds a io, 2.82; CI, 1.719 o 4.623). As expec ed,
a low bleeding a e was obse ed in he LMWH
g oup. The egimen o 40 mg enoxapa in, a a ixed
dose once daily subcu aneously, esul ed in 1.1% e -
sus 10% o hemo hagic complica ions compa ed wi h
he couma in ea men (P< .05). This di e ence was
a esul o mino hemo hages. Concomi an ly, a
lowe equency o symp oma ic ecu en enous
h omboembolism was shown in pa ien s who unde -
wen ea men wi h LMWH (9.5%) han wi h o al
an icoagulan s (23.7%; P< .05), al hough his di e -
ence was en i ely a esul o ecu ence o DVT. Thus,
we ind a s a is ically signi ican supe io i y o LMWH
o e couma in ega ding bo h e icay and sa e y.
Al hough he doses ha we used in he p esen s udy
we e ac ually p ophylac ic doses a he han ea men
doses, especially o he i s 7 days o ea men , i is
impo an o conside whe he ou esul s we e
caused by a ue p ope y o enoxapa in because ade-
qua e dosage inding s udies a e no a ailable.29,30
The ac ha a pa ien died in he LMWH g oup o a
ecu en pulmona y embolism on he i h day o
andomiza ion sugges s ha he dosage used may be
insu icien and ha highe le els should be p e e able
in hese pa ien s. Pa icula ly, we belie e ha an
adjus ed dose pe kilog am o body weigh would be
ecommendable o he managemen o DVT,
al hough u he dose- ela ed s udies a e necessa y o
de ine minimal and maximal doses.
Because he wo egimens we e gi en by di e en
ou e and because dose adjus men s we e necessa y
in he couma in g oup, we could no use a double-
blind design. To minimize bias in he assessmen o
symp oma ic ecu en enous h omboembolism, all
suspec ed ecu ences we e e alua ed wi h objec i e
es s and he da a we e analyzed by wo blinded
obse e s. Gi en ha we did ou inely sc een all
pa ien s wi h enog aphy a 3 mon hs, silen enous
ecu ences may no ha e gone unde ec ed, bu silen
pulmona y embolism may ha e occu ed, because
lung scans we e only aken o assis diagnosis o
symp oma ic pulmona y embolism. Some conce n
may a ise om he inding ha he e was a highe
equency o silen pulmona y embolism in pa ien s
alloca ed o he couma in g oup han in pa ien s allo-
ca ed o he LMWH g oup, which could ha e po en-
ially skewed he esul s. Howe e , a mul iple logis ic
eg ession showed ha his a iable was no inde-
penden ly associa ed wi h he ecu ence o enous
h omboembolism and bleeding. In addi ion, bo h
g oups we e compa able acco ding o loca ion o
h ombus, p edisposing ac o s, and ex ension o he
enous h ombosis. The highe equency o silen
pulmona y embolism con i ms p e ious s udies
ha show ha , by he ime he DVT has been diag-
nosed, many pa ien s ha e al eady had a pulmona y
embolism.31
The numbe o dea hs and, in pa icula , he p o-
po ion o dea hs in pa ien s wi h cance ( h ee o
i e in he LMWH g oup, and wo o h ee in he
couma in g oup) we e compa able in bo h ea -
men g oups. Ou da a he e o e do no subs an ia e
he hypo hesis ha LMWH adminis a ion could
exe a a o able e ec on cance p og ession.1,6
Howe e , he pa ien s wi h cance we e indepen-
den ly associa ed wi h mo e complica ions (odds
a io, 2.15; CI, 1.101 o 4.233).
Rega ding he compliance o he pa ien s wi h
LMWH he apy, his was well ole a ed and allowed
he pa ien s o be ully ambulan . None o he
pa ien s had nega i e eac ions o unde going ea -
men a home wi h a subcu aneous injec ion daily
o 3 mon hs, and no pa ien s showed hepa in-
induced h ombocy openia in he 3-mon h g oup
wi h LMWH he apy. Howe e , mos pa ien s had
small hema omas in he injec ion si es. Al hough
os eopo osis is a well-known side-e ec o hepa in
he apy, pa icula ly in long- e m he apy, we ha e
no pe o med any bone densi y measu emen s, x-
ays, o o he s udies o look o his po en ial com-
plica ion. Acco ding o he only s udy ha has ana-
lyzed his ac , LMWH he apy was associa ed wi h
a lesse isk o bone ac u e han un ac iona ed
hepa in he apy.12 This means ha LMWH seems o
be a good al e na i e o s anda d hepa in o pa ien s
in whom o al an icoagulan he apy is con aindica -
ed, especially elde ly pa ien s, in whom spine ac-
u es a e qui e common.
In conclusion, he pa ien s alloca ed o unde go
ea men wi h enoxapa in had a signi ican ly g ea e
imp o emen in hei clinical s a us and quan i a i e
enog aphic sco e, a signi ican ly lowe ecu ence
a e o symp oma ic enous h omboembolism, and a
signi ican ly lowe incidence o bleeding han pa ien s
who unde wen ea men wi h couma in. These
p omising esul s ob ained wi h LMWH he apy
adminis e ed by subcu aneous injec ion, wi hou lab-
o a o y moni o ing, aise he possibilli y ha hese
agen s can be used on an ou pa ien basis as a sa e
and mo e e ec i e al e na i e o classic o al an icoag-
ulan he apy o he seconda y p ophylaxis o selec -
ed pa ien s wi h es ablished DVT. Pa icula ly good
candida es would be p egnan women, pa ien s wi h a
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