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DESCRIPTION
TRANSCRIPT
DOI 10.1378/chest.11-2303 2012;141;e495S-e530SChest
L. Davidson, Sam Schulman and Mark CrowtherLori-Ann Linkins, Antonio L. Dans, Lisa K. Moores, Robert Bona, Bruce Practice GuidelinesChest Physicians Evidence-Based ClinicalThrombosis, 9th ed: American College of Antithrombotic Therapy and Prevention ofHeparin-Induced Thrombocytopenia : Treatment and Prevention of
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CHEST Supplement
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e495S
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES
Based Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.
2.1.1. For patients receiving heparin in whom clinicians consider the risk of HIT to be . 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14
Background: Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reac-tion that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke. Methods: The methods of this guideline follow the Methodology for the Development of Anti-thrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Pre-vention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. Results: Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be . 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs fi rst) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be , 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insuffi ciency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anti-coagulants or heparin plus antiplatelet agents (Grade 2C). Conclusions: Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed. CHEST 2012; 141(2)(Suppl):e495S–e530S
Abbreviations: ACT 5 activated clotting time; aPTT 5 activated partial thromboplastin time; CPB 5 cardiopulmonary bypass; CVA 5 cerebrovascular accident; DTI 5 direct thrombin inhibitor; ECT 5 ecarin clotting time; ELISA 5 enzyme-linked immunosorbent assay; FDA 5 US Food and Drug Administration; GP 5 glycoprotein; GTI 5 Genetics Testing Institute; HIPA 5 heparin-induced platelet activation; HIT 5 heparin-induced thrombocytopenia; HITT 5 heparin-induced thrombocytopenia with thrombosis; INR 5 international normalization ratio; LMWH 5 low-molecular-weight heparin; OD 5 optical density; PCI 5 percutaneous coronary intervention; PE 5 pulmonary embolism; PF4 5 platelet factor 4; RCT 5 randomized controlled trial; RR 5 relative risk; SC 5 subcutaneous; SRA 5 serotonin release assay; UFH 5 unfractionated heparin; VKA 5 vitamin K antagonist
Treatment and Prevention of Heparin-Induced Thrombocytopenia Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Lori-Ann Linkins , MD ; Antonio L. Dans , MD ; COL Lisa K. Moores , MC, USA , FCCP ; Robert Bona , MD ; Bruce L. Davidson , MD , MPH , FCCP ; Sam Schulman , MD , PhD ; and Mark Crowther , MD
Summary of Recommendations
Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommenda-tions sections to indicate recommendations that are newly added or have been changed since the publi-cation of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-
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e496S Treatment of HIT
of an invasive procedure with a high risk of bleeding (Grade 2C) .
3.4.1. In patients with strongly suspected or confi rmed HIT, we recommend against starting VKA until platelets have substantially recovered (ie, usually to at least 150 3 10 9 /L) over starting VKA at a lower platelet count and that the VKA be initially given in low doses (maximum, 5 mg of warfarin or 6 mg phenprocoumon) over using higher doses (Grade 1C) .
3.4.2. We further suggest that if a VKA has already been started when a patient is diag-nosed with HIT, vitamin K should be adminis-tered (Grade 2C) .
Remarks: We place a high value on the prevention of venous limb gangrene and a low value on the cost of the additional days of the parental nonheparin anticoagulant.
3.5. In patients with confi rmed HIT, we recom-mend that that the VKA be overlapped with a nonheparin anticoagulant for a minimum of 5 days and until the INR is within the target range over shorter periods of overlap and that the INR be rechecked after the anticoagulant effect of the nonheparin anticoagulant has resolved (Grade 1C) .
4.1. In patients with isolated HIT (HIT without thrombosis), we recommend the use of lepiru-din or argatroban or dana paroid over the further use of heparin or LMWH or initiation/continua-tion of a VKA (Grade 1C) .
4.2. In patients with isolated HIT (HIT without thrombosis) who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoag-ulants (Grade 2C) .
Remarks: Other factors such as drug availability, cost, and ability to monitor the anticoagulant effect may infl uence the choice of agent. The dosing consid-erations are the same as for patients with HITT (see section 3.2). For a recommendation on choice of nonheparin anticoagulants in the setting of renal insuffi ciency, see Recommendation 3.2.2.
5.1.1. In patients with acute HIT (thrombocyto-penic, HIT antibody positive) or subacute HIT (platelets recovered, but still HIT antibody pos-itive) who require urgent cardiac surgery, we suggest the use of bivalirudin over other non-heparin anticoagulants and over heparin plus antiplatelet agents (Grade 2C) .
(or until heparin is stopped, whichever occurs fi rst) (Grade 2C) .
2.1.2. For patients receiving heparin in whom clinicians consider the risk of HIT to be , 1%, we suggest that platelet counts not be moni-tored (Grade 2C).
3.1. In patients with HITT, we recommend the use of nonheparin anticoagulants, in partic-ular lepirudin, argatroban, and danaparoid, over the further use of heparin or LMWH or initiation/continuation of a vitamin K antagonist (VKA) (Grade 1C) .
3.2.1. In patients with HITT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonhepa-rin anticoagulants (Grade 2C) .
Remarks: Other factors not covered by our analysis, such as drug availability, cost, and ability to monitor the anticoagulant effect, may infl uence the choice of agent.
3.2.2. In patients with HITT and renal insuffi -ciency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C) .
3.3. In patients with HIT and severe thrombo-cytopenia, we suggest giving platelet transfu-sions only if bleeding or during the performance
Revision accepted August 31, 2011 . Affi liations: From the Department of Medicine (Drs Linkins, Schulman, and Crowther), McMaster University, Hamilton, ON, Canada; the College of Medicine (Dr Dans), University of the Philippines Manila, Manila, Philippines; The Uniformed Services (Dr Moores), University of Health Sciences, Bethesda, MD; School of Medicine (Dr Bona), Quinnipiac University, North Haven, CT; and the University of Washington School of Medicine (Dr Davidson), Seattle, WA . Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educa-tional grants was also provided by Bristol-Myers Squibb; Pfi zer, Inc; Canyon Pharmaceuticals; and sanofi -aventis US . Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S . Correspondence to: Lori-Ann Linkins, MD, Department of Medicine, McMaster University, Juravinski Hospital, Rm-M0118, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada ; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http://www.chestpubs.org/site/misc/reprints.xhtml ). DOI: 10.1378/chest.11-2303
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www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e497S
6.1.2. In patients with a history of HIT in whom heparin antibodies are still present who require cardiac surgery, we suggest the use of nonhepa-rin anticoagulants (see Recommendation 5.1.1) over heparin or LMWH (Grade 2C) .
6.2. In patients with a history of HIT in whom heparin antibodies have been shown to be absent who require cardiac catheterization or percutaneous coronary interventions, the rec-ommended treatment is the same as in Recom-mendation 5.2.
6.3. In patients with a past history of HIT who have acute thrombosis (not related to HIT) and normal renal function, we suggest the use of fondaparinux at full therapeutic doses until transition to a VKA can be achieved (Grade 2C) .
This article offers recommendations on diagnosis and management of heparin-induced thrombocy-
topenia (HIT). Table 1 describes the question defi ni-tion (ie, population, intervention, comparator, and outcome) addressed by the recommendations.
1.0 Methods and Overview of HIT
We adhered to the general approach to developing recommen-dations described in the methodology article of these guidelines. 1 We searched the PubMed English language literature from January 1976 to June 2010 using the following search terms: “heparin-induced thrombocytopenia,” “clinical trial,” “cohort,” “randomized clinical trial,” “argatroban,” “lepirudin,” “hirudin,” “bivalirudin,” “fondaparinux”, “diagnosis,” “laboratory assay,” “clinical prediction rule,” “platelet count monitoring,” “coronary artery bypass,” “cardiac surgery,” “cardiopulmonary bypass” (CPB), “angioplasty,” “transluminal percutaneous coronary,” “treatment,” “venous limb gangrene,” “platelet transfusion,” “renal replacement therapy,” “hemodialysis,” “hemofi ltration,” “pregnancy,” “re-exposure,” and “recurrence.”
The primary effi cacy outcome measures of interest were new thrombosis, limb amputation, major bleeding, and death (due to thrombosis or bleeding). In the cohort studies with historical con-trols, outcome events were counted if they occurred after treat-ment with the nonheparin anticoagulant was initiated, and from the date heparin was discontinued in the control group.
1.1 Value and Preferences
Based on the relevant literature and the value and preference rating exercise conducted by the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines panel, 2 we infer that from the patient’s perspective, a venous thromboem-bolic event (eg, pulmonary embolism [PE], proximal DVT) carries similar weight as a major bleeding event (eg, gastrointestinal bleeding event), and that a stroke carries 2.5 times the weight of a major bleeding event.
1.2 Overview of HIT
1.2.1 Pathogenesis of HIT: HIT is an adverse immune-mediated drug reaction that is associated with a high risk of venous
5.1.2. In patients with acute HIT who require nonurgent cardiac surgery, we recommend delaying the surgery (if possible) until HIT has resolved and HIT antibodies are negative (see section 6.1) (Grade 2C) .
Remarks: Other factors not covered by our analysis, such as drug availability, cost, and ability to monitor the anticoagulant effect may infl uence the choice of agent. For recommendations for patients with a past history of HIT (. 3 months previous) who require cardiac surgery, see section 6.1.
5.2. In patients with acute HIT or subacute HIT who require percutaneous coronary interventions, we suggest the use of bivalirudin (Grade 2B) or argatroban (Grade 2C) over other nonheparin anticoagulants.
Remarks: Other factors, such as drug availability, cost, and ability to monitor the anticoagulant effect, may infl uence the choice of agent.
5.3.1. In patients with acute or subacute HIT who require renal replacement therapy, we sug-gest the use of argatroban or dana paroid over other nonheparin anticoagulants (Grade 2C) .
Remarks: We acknowledge that the cost of argatroban may be prohibitive at some clinical centers. We fur-ther suggest that if the prothrombotic state of HIT appears to have resolved (as seen by normalization of the platelet count), saline fl ushes during dialysis would be a reasonable option. This suggestion is based on the presumed pathogenesis of thrombosis in this condition and not on the results of clinical trials.
5.3.2. In patients with a past history of HIT who require ongoing renal replacement therapy or catheter locking, we suggest the use of regional citrate over the use of heparin or LMWH (Grade 2C) .
5.4. In pregnant patients with acute or subacute HIT, we suggest danaparoid over other non-heparin anticoagulants (Grade 2C) . We suggest the use of lepirudin or fondaparinux only if danaparoid is not available (Grade 2C) .
Remarks: Other factors, such as drug availability, cost, and ability to monitor the anticoagulant effect, may infl uence the choice of agent.
6.1.1. In patients with a history of HIT in whom heparin antibodies have been shown to be absent who require cardiac surgery, we suggest the use of heparin (short-term use only) over nonheparin anticoagulants (Grade 2C) .
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
e498S Treatment of HIT
Tabl
e 1—
[Int
rodu
ctio
n] T
reat
men
t an
d P
reve
ntio
n of
HIT
: Qu
esti
on D
efi n
itio
ns
Sect
ion
PIC
O Q
uest
ion
Popu
latio
nIn
terv
entio
n(s)
Com
para
tor
Out
com
e(s)
Met
hodo
logy
2.0
Scre
enin
g fo
r H
IT2.
1Pa
tient
s re
ceiv
ing
hepa
rin
or L
MW
H fo
r � 5
dPl
atel
et c
ount
mon
itori
ng
com
bine
d w
ith th
e 4T
s Sc
ore
No
plat
elet
cou
nt m
onito
ring
Fal
se n
egat
ives
(inc
reas
ed r
isk
of th
rom
bosi
s if
not t
reat
ed w
ith n
onhe
pari
n an
ticoa
gula
nts)
Dec
isio
n an
alys
is
Fal
se p
ositi
ves
(incr
ease
d ri
sk o
f ble
edin
g if
trea
ted
with
non
hepa
rin
antic
oagu
lant
s)Tr
ue n
egat
ives
(do
not h
ave
HIT
)Tr
ue p
ositi
ves
(do
have
HIT
)3.
0 M
anag
emen
t of H
ITT
(HIT
with
thro
mbo
sis)
3.1
Patie
nts
with
str
ongl
y su
spec
ted
or c
onfi r
med
H
IT w
ith th
rom
bosi
s
Dis
cont
inue
hep
arin
with
or
with
out s
tart
ing
a V
KA
Trea
tmen
t with
non
hepa
rin
antic
oagu
lant
sD
eath
(thr
ombo
sis,
ble
edin
g)C
ohor
t stu
dies
with
hi
stor
ical
con
trol
sL
imb
ampu
tatio
n3.
2Tr
eatm
ent w
ith n
onhe
pari
n an
ticoa
gula
nts
Trea
tmen
t with
oth
er
nonh
epar
in a
ntic
oagu
lant
sN
ew th
rom
bosi
s (a
rter
ial,
veno
us)
RC
T, c
ohor
t stu
dies
Maj
or b
leed
ing
3.3
Plat
elet
tran
sfus
ions
No
plat
elet
tran
sfus
ions
Cas
e se
ries
3.4
Star
ting
VK
A b
efor
e pl
atel
et
reco
very
No
VK
A u
ntil
afte
r pl
atel
et
reco
very
Veno
us li
mb
gang
rene
Cas
e se
ries
Lim
b am
puta
tion
New
thro
mbo
sis
(art
eria
l, ve
nous
)3.
5D
isco
ntin
uing
thro
mbi
n in
hibi
tor
afte
r m
inim
um o
f 5
d of
ove
rlap
with
a V
KA
Dis
cont
inui
ng th
rom
bin
inhi
bito
r af
ter ,
5 d
of
over
lap
with
a V
KA
Seco
ndar
y an
alys
is
of c
ohor
t stu
dies
4.0
Man
agem
ent o
f iso
late
d H
IT (H
IT w
ithou
t thr
ombo
sis)
4.1
Patie
nts
with
str
ongl
y su
spec
ted
or c
onfi r
med
HIT
w
ithou
t thr
ombo
sis
Dis
cont
inue
hep
arin
with
or
with
out s
tart
ing
a V
KA
Trea
tmen
t with
non
hepa
rin
antic
oagu
lant
sD
eath
(thr
ombo
sis,
ble
edin
g)C
ohor
t stu
dies
with
hi
stor
ical
con
trol
sL
imb
ampu
tatio
n4.
2Tr
eatm
ent w
ith n
onhe
pari
n an
ticoa
gula
nts
Trea
tmen
t with
oth
er
nonh
epar
in a
ntic
oagu
lant
sN
ew th
rom
bosi
s (a
rter
ial,
veno
us)
Coh
ort s
tudi
esM
ajor
ble
edin
g5.
0 M
anag
emen
t of p
atie
nts
with
acu
te o
r su
bacu
te H
IT in
spe
cial
situ
atio
ns5.
1Pa
tient
s w
ho r
equi
re u
rgen
t ca
rdia
c su
rger
yTr
eatm
ent w
ith n
onhe
pari
n an
ticoa
gula
nts
Trea
tmen
t with
oth
er
nonh
epar
in a
ntic
oagu
lant
sD
eath
(thr
ombo
sis,
ble
edin
g)C
ohor
t stu
dies
Lim
b am
puta
tion
New
thro
mbo
sis
(art
eria
l, ve
nous
)5.
2Pa
tient
s w
ho r
equi
re u
rgen
t PC
IC
ohor
t stu
dies
5.3
Patie
nts
who
req
uire
ren
al
repl
acem
ent t
hera
pyM
ajor
ble
edin
gC
ase
seri
esPr
oced
ural
suc
cess
5.4
Preg
nant
pat
ient
sC
ase
seri
es (Con
tinu
ed)
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e499S
and arterial thrombosis. 3-6 Heparin exposure leads to the forma-tion of IgG antibodies that recognize multimolecular complexes of platelet factor 4 (PF4) and heparin that form on the surface of platelets. 7,8 These complexes bind to the Fc�IIa (IgG) receptors of platelets, 9,10 resulting in platelet activation and release of procoagulant, platelet-derived microparticles. 11,12 The end result is marked generation of thrombin and the formation of venous and arterial thromboses that are the clinical hallmark of HIT.
Risk factors for HIT include duration and type of heparin exposure, 13 patient population, 14-16 severity of trauma, 17 and gender. 18 Differences in the stoichiometry of heparin/PF4 complexes are believed to explain the 10-fold higher likelihood of HIT in patients who receive unfractionated heparin (UFH) compared with patients who receive low-molecular weight heparin (LMWH) or fondaparinux. 19,20 Patients who undergo cardiac or orthopedic surgery and receive UFH have a higher risk of HIT (1%-5%) than medical or obstetric patients (0.1%-1%). 13,14,21-24 Women have approximately twice the risk of developing HIT as men. 18 Table 2 25-35 presents the incidence of HIT in various patient populations.
1.2.2 Clinical Features: Thrombocytopenia (defi ned as a plate-let count , 150 3 10 9 /L) is the most common clinical manifesta-tion of HIT and occurs in 85% to 90% of patients. 4 If this defi nition is broadened to include a proportional fall in the platelet count (eg, 30%-50% fall even if the nadir remains . 150 3 10 9 /L), this increases to 90% to 95% of HIT cases. 4,5,27 The characteristic onset of the platelet count fall in HIT is 5 to 10 days after initiation of heparin (fi rst day of heparin 5 day 0), particularly when heparin is administered perioperatively (typical-onset HIT). 36 “Rapid-onset HIT” refers to an abrupt platelet count fall (within 24 h) that occurs in patients who already have circulating HIT antibodies because of recent exposure to heparin (usually within the past month, occasion-ally as long as 100 days earlier). 36,37 Occasionally, thrombocytopenia can occur as long as 3 weeks after cessation of heparin (delayed-onset HIT). 38 Although thrombocytopenia is the most common present-ing feature of HIT, in up to 25% of patients with HIT the develop-ment of thrombosis precedes the development of thrombocytopenia. 3,5
The pattern of thrombocytopenia following cardiac surgery using heparin is worthy of special mention. Although approximately 50% of patients who undergo cardiac surgery will develop HIT antibodies, only 1% to 2% will develop clinical HIT (thrombocy-topenia with or without thrombosis). 14 In general, the platelet count falls by approximately 38% immediately after CPB (and continues to decline for the fi rst 1-2 postoperative days before rising in a continuous fashion to a level above the preoperative
Sect
ion
PIC
O Q
uest
ion
Popu
latio
nIn
terv
entio
n(s)
Com
para
tor
Out
com
e(s)
Met
hodo
logy
6.0
Man
agem
ent o
f pat
ient
s w
ith a
pas
t his
tory
of H
IT6.
1Pa
tient
s w
ho r
equi
re c
ardi
ac
surg
ery
Hep
arin
or
LM
WH
Non
hepa
rin
antic
oagu
lant
sR
ecur
renc
e of
HIT
Cas
e se
ries
Ree
mer
genc
e of
HIT
ant
ibod
ies
6.2
Patie
nts
who
req
uire
PC
IC
ohor
t stu
dies
6.3
Patie
nts
who
req
uire
VT
E
prop
hyla
xis
or tr
eatm
ent
Cas
e re
port
s
HIT
5 h
epar
in-i
nduc
ed t
hrom
bocy
tope
nia;
HIT
T 5
hep
arin
-ind
uced
thr
ombo
cyto
peni
a w
ith
thro
mbo
sis;
LM
WH
5 lo
w-m
olec
ular
-wei
ght
hepa
rin;
PC
I 5 p
ercu
tane
ous
coro
nary
int
erve
ntio
n;
PIC
O 5
pop
ulat
ion,
inte
rven
tion,
com
para
tor,
and
outc
ome;
VK
A 5
vita
min
K a
ntag
onis
t.Tabl
e 1—
Con
tinu
ed
Table 2—[Overview of HIT] Incidence of HIT According to Patient Population and Type of Heparin Exposure
Patient Population (Minimum of 4-d Exposure)Incidence of HIT, %
Postoperative patients Heparin, prophylactic dose3,4,14,25 1-5 Heparin, therapeutic dose26 1-5 Heparin, fl ushesa 0.1-1 LMWH, prophylactic or therapeutic dose14,25 0.1-1 Cardiac surgery patients14,27,28,29 1-3Medical Patients with cancer24,30.31 1 Heparin, prophylactic or therapeutic dose24 0.1-1 LMWH, prophylactic or therapeutic dose26,30 0.6 Intensive care patients32 0.4 Heparin, fl ushes33 , 0.1 Obstetrics patients21,22,34,35 , 0.1
See Table 1 legend for expansion of abbreviations.aCase reports only.
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
e500S Treatment of HIT
bocytopenia (but with a nadir rarely , 20 3 10 9 /L), petechiae or other signs of bleeding are rarely seen. 3
HIT is recognized as a clinicopathologic syndrome because diag-nosis is based on the combination of a compatible clinical picture and the presence of platelet-activating anti-PF4 antibodies. 50 Clinical prediction rules to assist physicians with determining the probability that a patient has HIT have been developed, 51-55 the best studied of which is the 4Ts score ( Fig 1 ). 56-59 Evidence is emerging that patients with a low 4Ts score have a very low probability of HIT (0%-3%). 51,56 However, many patients (24%-61%) with a high 4Ts score prove not to have HIT. 51,56 Clinical assessment plays an essential role in the diagnosis of HIT for two reasons: (1) there is commonly a delay before the results of laboratory testing for HIT are available, and man-agement decisions must be made immediately (the rate of thrombosis prior to treatment is approximately 5% per day) 60 ; and (2) isolated HIT antibodies are both frequent and not diagnostic of HIT.
1.2.3 Laboratory Diagnosis of HIT: A large number of labora-tory assays are currently used to diagnose HIT. A recent survey of specialized coagulation laboratories in North America identifi ed eight different assays and wide discrepancies in practice between centers using the same assay. 61 The assays can be divided into
count). 39,40 The following two patterns of thrombocytopenia should alert clinicians to the possibility of HIT following cardiac surgery: a fall in platelet count that begins . 4 days postopera-tively (day of surgery 5 day 0), and thrombocytopenia that persists for . 4 days after surgery. 41
The most common complication of HIT is venous thrombosis; 17% to 55% of untreated patients who present with thrombocyto-penia develop DVT and/or PE. 6,14,42 Arterial thrombotic events, including limb artery thrombosis, thrombotic stroke, and myocar-dial infarction (MI), also occur, but less often (from 3%-10%). 6,43 After cardiac surgery, the majority of HIT-related thrombotic events are arterial. 44,45 Approximately 5% to 10% of patients with HIT die, usually as a result of thrombotic complications. 6,42
Less common manifestations of HIT include venous limb gan-grene (5%-10% of patients with HIT with DVT treated acutely with a vitamin K antagonist [VKA] [eg, warfarin]), 46 necrotizing skin lesions at heparin injection sites, 47,48 adrenal hemorrhagic necrosis (due to adrenal vein thrombosis), and acute systemic reac-tions within 30 min of an IV heparin bolus injection (eg, fever/chills, tachycardia, hypertension, dyspnea, cardiopulmonary arrest). 48 HIT can be complicated by disseminated intravascular coagulation severe enough to deplete fi brinogen. 38,49 Despite severe throm-
Figure 1. 4Ts score. *Timing of clinical sequelae, such as thrombocytopenia, thrombosis, or skin lesions. **Two points if necrotizing heparin-induced skin lesions even if thrombocytopenia not present. (Modifi ed with permission from Warkentin and Linkins.59)
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of the HIT antibodies (subacute HIT), particularly when using the ELISA for serologic testing. These patients are still at risk for developing rapid-onset HIT on heparin re-exposure (unless the washed platelet SRA or HIPA is negative and the ELISA is only weakly positive or strongly positive because of non-platelet-activating IgM or IgA antibodies).
A class of commercial antigen assays that are designed to have a faster turnaround time than the ELISA (approximately 15 min vs 3.5 h [or days, if batched]) have entered the market. One of these assays, the ID-PaGIA Heparin/PF4 antibody test (DiaMed), is a gel centrifugation assay that uses the binding of antibodies to antigen-coated (PF4/heparin) high-density, red polystyrene beads. 67 This method can be performed in any blood bank that utilizes a gel centrifugation system for red cell antibody screening. The oper-ating characteristics for this assay are reviewed in section 1.2.4.
1.2.4 Commercial Antigen Assays Compared With Reference Standard Assays for Diagnosis of HIT: To determine the accuracy of the commercially available antigen assays for HIT, we searched the literature for studies that: (1) compared the operating charac-teristics of these assays with at least one of the reference standard assays (ie, SRA or HIPA), and (2) used blood samples collected prospectively from consecutive patients with suspected HIT. The three studies that met our criteria evaluated two antigen assays: GTI-PF4 (Genetics Testing Institute [GTI]) and ID-PaGIA Hep-arin/PF4 antibody test (DiaMed AG) 56,68,69 ( Table 3 ). Both of these assays detect all classes of immunoglobulin. The sensitivity of the GTI-PF4 assay was 100% (if negative, HIT ruled out), whereas the specifi city (82%-85%) was lower. Thus, many patients with positive tests, particularly those with moderate or low pretest
two major categories according to the end point they measure: (1) antigen assays that detect the presence of HIT antibodies, and (2) functional assays that detect evidence of platelet activation (by HIT antibodies) in the presence of heparin. 62 Only a small proportion of patients who form HIT antibodies (seroconversion) will develop thrombocytopenia, and a smaller proportion will develop HIT-associated thrombosis. Antigen assays, the most com-monly used being enzyme-linked immunosorbent assays (ELISA) that test for antibodies that are reactive against PF4/heparin or PF4/polyvinyl sulfonate, are very sensitive for HIT because they detect seroconversion. 15,63 However, not all of the antibodies these assays detect are capable of causing clinical HIT; hence, the spec-ifi city of these assays is only moderate. In contrast, functional assays, such as the serotonin release assay (SRA) and heparin-induced platelet activation (HIPA), are sensitive and specifi c for HIT because they only detect antibodies that are capable of acti-vating platelets. 15
The washed platelet SRA and HIPA are generally accepted as the reference standard assays for HIT. However, they are only available at a few centers because they are technically diffi cult, require human platelets from known reactive donors, and, in the case of the SRA, require working with radiation. 64,65 Most clinical centers use commercially available ELISAs because they do not have these limitations. The primary drawback of the ELISAs is their potential to overdiagnose HIT by detecting antibodies that are not pathogenic. ELISAs that only detect IgG antibodies appear to have better specifi city for HIT (IgM and IgA antibodies are unlikely to cause HIT). 15,66
In patients recovering from HIT, there can be a lag time of several weeks between full platelet recovery and disappearance
Table 3—[Overview of HIT] Comparison of Commercial Antigen Assays With Reference Standard Assays
Study/Year Population Intervention Comparator Outcomes Comments, %
Bakchoul et al68/2009 500 consecutive surgical and medical patients with suspected HIT
GTI-PF4 polyanion ELISA (OD . 0.4 units)
PaGIA (DiaMed) (positive/negative)
HIPA GTI-PF4 ELISA GTI-PF4 ELISAClinical assessment: 4Ts
score (Greifswald modifi cation)
HIT positive 5 HIPA positive and high or intermediate 4Ts score
TP 35 of 35 PPV 5 28 TN 376 of 465 NPV 5 100 FP 89 of 124 Sens 5 100 FN 0 of 376 Spec 5 81PaGIA PaGIA TP 33 of 35 PPV 5 37 TN 408 of 465 NPV 5 99 FP 57 of 90 Sens 5 94 FN 2 of 410 Spec 5 88
Warkentin et al69/2008 417 consecutive patients with suspected HIT (excludes 18 patients with indeterminate SRA or insuffi cient sample for ELISA testing)
GTI-PF4 polyanion ELISA (OD . 0.4 units)
SRA (positive . 50% release)
GTI-PF4 ELISA GTI-PF4 ELISA TP 41 of 41 PPV 5 43
HIT positive 5 SRA pos
TN 309 of 364 NPV 5 100 FP 55 of 96 Sens 5 100 FN 0 of 309 Spec 5 85
Pouplard et al56/2007 213 consecutive patients with suspected HIT
GTI-PF4 polyanion ELISA (OD . 0.4 units)
SRA (positive . 20% release)
GTI-PF4 ELISA GTI-PF4 ELISA TP 22 of 22 PPV 5 39 TN 156 of 191 NPV 5 100
PaGIA (DiaMed) (positive/negative)
HIT positive 5 SRA pos
FP 35 of 57 Sens 5 100 FN 0 of 156 Spec 5 82
Clinical assessment: 4Ts score
PaGIA PaGIA TP 21 of 22 PPV 5 57 TN 175 of 191 NPV 5 99 FP 16 of 37 Sens 5 95 FN 1 of 176 Spec 5 92
ELISA 5 enzyme-linked immunosorbent assay; FN 5 false negative; FP 5 false positive; GTI 5 Genetics Testing Institute; HIPA 5 heparin-induced platelet activation; NPV 5 negative predictive value; PF4 5 platelet factor 4; PPV 5 positive predictive value; Sens 5 sensitivity; Spec 5 specifi city; SRA 5 serotonin release assay; TN 5 true negative; TP 5 true positive. See Table 1 legend for expansion of other abbreviation.
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e502S Treatment of HIT
HIT as the reference standard assay (SRA). However, this strategy requires validation in prospective studies.
For laboratories using the GTI-PF4 ELISA, we suggest report-ing the quantitative value of the test result, together with the threshold used to defi ne a positive result, over reporting the result only as positive or negative. For clinicians ordering the GTI-PF4 ELISA to determine whether a patient has HIT, we suggest taking into consideration both the pretest probability of HIT and the quantitative level of the GTI-PF4 ELISA result. A GTI-ELISA result between 0.40 and 1.0 OD in a patient with a low or mod-erate pretest probability for HIT should, if possible, be confi rmed with a functional assay.
2.0 Screening for HIT
2.1 Platelet Count Monitoring Combined With the 4Ts Score for Patients Receiving Heparin/LMWH
Platelet count monitoring is warranted when the benefi ts of early diagnosis and treatment of HIT exceed the potential harms of frequent platelet count monitoring, including cost, unnecessary anxiety and additional testing, unnecessary withdrawal of heparin, and the use of nonheparin anticoagulants with a higher bleeding risk. No studies have directly addressed the issue of whether advantages of platelet monitor-ing outweigh the disadvantages in patients receiving UFH/LMWH. Three retrospective studies showed a low rate of compliance with platelet count monitoring recommendations (4%-42%), a low rate of testing
Table 4—[Overview of HIT] Studies Comparing Different OD Threshold Levels for Commercial ELISAs
Study/Year Study Samples Participants Outcome ELISA OD
Warkentin et al69/2008 41 patients identifi ed as HIT positive by SRA
HITT (n 5 19)HIT (n 5 22)
Frequency SRA positive � 50% release (95% CI)
PF4/hep polyanion ELISA (GTI)
0% (0-1.2) OD , 0.4 3% (0.1-14.2) OD 0.4-1.0 18% (2.3-51.8) OD 1.0-1.4 50% (18.7-81.3) OD 1.4-2.0 89% (74.6-97) OD . 2.0
Lo et al72/2007 16 patients identifi ed as HIT positive according to different defi nitions (of laboratory and clinical criteria)
Classic HIT: SRA . 50% 1 , GTI-PF4 ELISA . 0.40 1 , IgG ELISA . 0.45 1 , 4Ts high or intermediate
Liberal HIT: (GTI-PF4 ELISA . 0.40)
Modifi ed conservative: GTI-PF4 ELISA . 1.20 1
4Ts high or intermediate
Clinical Events PF4/hep polyanion ELISA (GTI) 11 of 16 (69%) TECs
(2 TEC postdiagnosis)
12 of 32a (37%) TECs (2 TEC postdiagnosis)
Identifi ed same 16 patients as classic HIT defi nition
Median, 2.39 (IQR, 2.09-2.70)
Median, 0.89 (IQR, 0.54-1.13)
Median, 2.39 (IQR, 2.09-2.70)
Zwicker et al70/2004 63 patients identifi ed as HIT positive by PF4/hep polyanion ELISA (OD . 0.40) with clinical criteria determined by laboratoryb
Within 30 dc Clinical events PF4/hep polyanion ELISA (GTI)
Thrombosis (n 5 23) OD . 1: 59% TECs Mean, 1.41; SD, 0.87
Mean, 0.80; SD, 0.46No thrombosis (n 5 40)
OD , 1: 24% TECs (P 5 .01) OD . 1: 36% TECs OD , 1: 9% TECs (P 5 .07); OR, 5.7;
95% CI, 1.7-19.1IQR 5 interquartile range; OD 5 optical density; TEC 5 thromboembolic complication.aIncludes 16 patients identifi ed by the classic HIT defi nition and an additional 16 patients (one of the additional patients had a TEC).bRecent platelet count , 150 3 109/L, platelet count of � 50% in setting of heparin therapy or a prior history of HIT.cIncludes the 15 patients initially diagnosed with HITT and eight patients with HIT who developed thrombosis within 30 d of diagnosis with HIT.
probability, will not have HIT. The sensitivity of the PaGIA is lower than the GTI-PF4 (94%-95%), and the specifi city is higher (88%-92%) than the GTI-PF4.
In summary, both of these antigen assays can exclude a diagno-sis of HIT, but neither assay is ideal as a stand-alone test to con-fi rm the diagnosis of HIT. A negative ELISA or PaGIA in a patient with a low pretest probability of HIT excludes the diagnosis of HIT. A positive ELISA or PaGIA in a patient with a low pretest probability of HIT should not be interpreted as diagnostic for HIT and requires confi rmation with a functional assay.
1.2.5 Commercially Available ELISA Using Manufacturer’s Optical Density Threshold Compared With an Elevated Optical Density Threshold: There is a correlation between the strength of the reaction with an ELISA (measured using optical density units [OD]) and the likelihood of clinical HIT. 70,71 Three studies have addressed the question (retrospectively) of whether raising the OD threshold that is used to defi ne a positive result with an ELISA would improve the specifi city of the assay. 69.70,72 All three used the GTI-PF4 assay, which detects all classes of immunoglobulin (positive threshold set at 0.40 OD) ( Table 4 ). Two of the studies showed that raising the OD threshold to 1.0 increased the like-lihood of a positive SRA result (specifi city increased from 85% to 95%) 69 and increased the likelihood of new thromboembolic events (24% of patients at a threshold of 0.40 OD had a new thrombotic event compared with 59% at a threshold of 1.0 OD). 70 The third study showed that increasing the threshold of the GTI-PF4 to 1.20 OD and combining it with an intermediate or high 4Ts score identifi ed all of the same HIT-positive patients as the SRA alone. 72
In summary, it appears that the combination of a thresh-old . 1.0 OD with a high clinical suspicion for HIT (eg, interme-diate or high 4Ts score) may have a similar accuracy for diagnosing
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infl uence the benefi t-to-risk ratio of platelet count monitoring. Clinical centers that do not have access to the reference standard assays will have a higher number of false-positive results and consequently a higher pro-portion of major bleeding events (ie, when the ELISA is the only HIT assay available, two episodes of throm-bosis are prevented at the cost of 2.6-11.7 major bleeding events for every 1,000 patients screened).
Another factor that infl uences the feasibility of platelet monitoring with 4Ts screening is the cost. Although individual platelet counts are inexpensive, the cost of the HIT assays and nonheparin anti-coagulants can be substantial (eg, in a formal cost-effectiveness analysis the cost of treating one patient with HIT with argatroban for 5 days was estimated at $3,500-$4,500 in the United States 2004 prices). 77 The estimated cost in 2011, for the drug alone, for 5 days is $5,000 US.
The issues with respect to platelet count monitoring outlined above were discussed at the American Col-lege of Chest Physicians meeting in February 2011. Criticisms of the decision analysis included the use of bleeding estimates based on doses of argatroban that are no longer used, delay in obtaining prompt results even at centers that have the SRA or HIPA available, and the potential for harm in missing cases of HIT
for HIT antibodies in patients who became throm-bocytopenic (5%-19%), and a low rate of initiation of a nonheparin anticoagulant when the suspicion of HIT was high enough to warrant laboratory testing (0%-55%). 73-75
The fi ndings of the above studies suggest previous recommendations for platelet monitoring have not been widely implemented. 76 Furthermore, when plate-let count monitoring is done and platelets drop, hep-arin is not necessarily stopped nor is a nonheparin anticoagulant started. Possible reasons for these fi nd-ings include the burden of platelet count monitoring, the limited availability of laboratory assays for sero-logical confi rmation of HIT, expense associated with using nonheparin anticoagulants, and a lack of aware-ness of the guidelines.
We conducted a decision analysis to determine the reduction in HIT-related thrombotic events that could be achieved in an ideal setting if the recom-mendations for platelet count monitoring, laboratory testing for HIT, and initiation of a direct thrombin inhibitor (DTI) were all followed. To reduce the potential for expensive testing and inappropriate treatment of patients with a low clinical probability of HIT, we assumed that platelet count monitoring would be done as part of a clinical assessment of the patients’ probability of HIT using the 4Ts score (see Table 5 for key model assumptions; Table 6 for data sources and model inputs). Table 7 outlines the sum-mary of fi ndings for this decision analysis.
This decision analysis shows that, in an ideal set-ting, for every 1,000 patients screened with platelet count monitoring and application of the 4Ts Score, the best estimate suggests one episode of thrombosis will be prevented, at the cost of one major bleeding event (although CIs for both thrombosis and bleeding overlap no effect) ( Table 7 ). Both the baseline risk of thrombosis (ie, patient population and type of heparin) (see Table 2 ) and the availability of the HIT assays
Table 5—[Section 2.1.1] Key Model Assumptions for Platelet-Monitoring Decision Analysis
Platelet count monitoring is intended to identify patients with isolated HIT; therefore, patients who initially present with HIT-related thrombosis were excluded.
Patients with a moderate or high 4Ts score will have heparin discontinued, an ELISA ordered, and argatroban started, whereas patients with a low 4Ts score will be assumed not to have HIT and will continue to receive heparin.
Patients with a positive ELISA will have an SRA performed for confi rmation.
Patients with a positive SRA will continue to receive treatment with argatroban, and patients with a negative SRA will resume prophylaxis with heparin (assuming 100% sensitivity and specifi city of the SRA for HIT).
The results of the HIT assays are available within 24 h of being ordered.
See Table 1 and 3 legends for expansion of abbreviations.
Table 6—[Section 2.1.1] Data Sources and Model Inputs for Platelet Monitoring Decision Analysis
We selected a high-risk setting for HIT for this analysis: postoperative orthopedic surgery patients who are receiving UFH for thromboprophylaxis (incidence of HIT . 1%).14 The likelihood ratios for low, moderate, and high 4Ts scores were derived from the study by Lo et al.51 The sensitivity and specifi city of the ELISA were assumed to be 100% and 86%, respectively.15,52
The assumptions for rates of thrombosis are as follows: (A) Thrombosis rate in patients with HIT who received argatroban 5 argatroban arm of a pooled analysis of historical controlled studies (0.069).76 (B) Thrombosis rate in patients with HIT who did not receive argatroban 5 control group of a pooled analysis of historical controlled studies (0.224).76 (C) Thrombosis rate in patients without HIT who did not receive argatroban 5 1 of 37 of assumption (B) because HIT is reported to increase the risk of thrombosis by 37-fold (0.22/37 5 0.0059).3 (D) Thrombosis rate in patients without HIT who were treated with argatroban 5 one-third of Assumption (C) as derived from the hazard ratio in patients treated with argatroban (0.002).76
HIT was assumed not to infl uence the major bleeding rate independently of treatment with nonheparin anticoagulants. Consequently, the major bleeding rate in those treated with argatroban was the same as the major bleeding rate in patients with HITT treated with argatroban in the pooled argatroban studies (0.08), and the major bleeding rate in those who were untreated was the same as the major bleeding rate in the control arm of the pooled argatroban studies (0.022).76 Sensitivity analyses were performed using different sensitivities and specifi cities for the ELISA and SRA, and different assay availability (ie, only ELISA available, no HIT assays available).
UFH 5 unfractionated heparin. See Table 1 and 3 legends for expan-sion of other abbreviations.
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count prior to initiating anticoagulant therapy for a patient with VTE is considered standard medical practice; however, obtaining a platelet count 24 h later can be diffi cult because of the widespread use of outpatient LMWH therapy.
Statement 2.2 : For patients exposed to heparin within the past 100 days, we suggest that a baseline platelet count be obtained prior to starting heparin or LMWH therapy, and that a repeat platelet count should be drawn 24 h later, if feasible.
2.3 Platelet Count Monitoring in Patients With Acute Infl ammatory Reactions After IV Heparin Bolus
Rarely, a patient who is given an IV heparin bolus will develop an acute infl ammatory reaction (eg, fever, chills) and/or cardiorespiratory symptoms (eg, hyper-tension, tachycardia, dyspnea, chest pain, cardiore-spiratory arrest) within 30 min of drug administration. These acute systemic reactions are strongly sugges-tive of acute HIT. 48
Statement 2.3: For patients who present with acute systemic reactions within 30 min of an IV heparin bolus, we suggest performing a platelet count.
3.0 Management of HIT Complicated by Thrombosis
3.1 Discontinue Heparin or Initiate VKA vs Treatment With Nonheparin Anticoagulants
The fi rst step in the treatment of HIT complicated by thrombosis (HITT) is discontinuation of all forms of heparin and LMWH (including heparin fl ushes and heparin-coated catheters). Whether taking this step alone is enough to prevent further thrombotic
if platelet count monitoring is not performed. The attendees voted in favor, by a small margin, of provid-ing specifi c recommendations regarding platelet count monitoring despite the uncertainty of the benefi t-to-risk ratio of this practice. It should be noted that for each of the recommendations below, . 20% of the attendees voted in the opposite direction.
Recommendations
2.1.1. For patients receiving heparin in whom clinicians consider the risk of HIT to be . 1% ( Table 2 ), we suggest that platelet count moni-toring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, which-ever occurs fi rst) (Grade 2C) .
2.1.2. For patients receiving heparin in whom clinicians consider the risk of HIT to be , 1% ( Table 2 ), we suggest that platelet counts not be monitored (Grade 2C) .
2.2 Platelet Count Monitoring in Patients Recently Treated With Heparin/LMWH
Platelet count monitoring for HIT in patients who have recently been exposed to heparin or LMWH differs from that described above because the timing of onset of HIT in these patients differs. If a patient still has circulating HIT antibodies from a previous exposure to heparin (typically within the past 30-100 days), re-exposure can lead to a large platelet count fall within 24 h. 36 As with typical-onset HIT, there are no studies evaluating the benefi t-to-risk ratio of this approach. Obtaining a baseline platelet
Table 7—[Section 2.1.1] Summary of Findings for Platelet Count Monitoring Decision Analysis: Should Platelet Count Monitoring Be Performed in Patients Who Receive Heparin or LMWH for � 5 d?
OutcomesNo. of Participants (Studies) Follow-up
Quality of the Evidence (GRADE) Relative Effect
Anticipated Absolute Effects, Time Frame for All Outcomes 30 d
Risk Without Monitoring Risk Difference With Monitoring
New thrombosis
No studies available Very low due to uncertainty of model assumptions
RR, 0.82-0.84 SRA and ELISA both available8.2 thrombotic events
per 1,0001.3-1.4 fewer thrombotic
events per 1,000RR, 0.73-0.80 Only ELISA available
8.2 thrombotic events per 1,000
1.6-2.2 fewer thrombotic events per 1,000
Major bleeding
No studies available Very low due to uncertainty of model assumptions
RR, 1.02-1.05 SRA and ELISA both available22 bleeding events
per 1,0000.5-1 more bleeding events
per 1,000RR, 1.12-1.53 Only ELISA available
22 bleeding events per 1,000
2.6-11.7 more bleeds per 1,000
The basis for the risks are provided in Tables 5 and 6. The anticipated absolute effect is expressed as risk difference, and is based on the baseline risk in the comparison group and the relative effect of the intervention. High quality: Further research is very unlikely to change our confi dence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. GRADE 5 Grades of Recommendations, Assessment, Development, and Evaluation; RR 5 risk ratio.
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care consisted of discontinuation of heparin alone or substitution of heparin with a VKA. An overview of the methodology of these studies is available in Table S1 (tables that contain an “S” before the number denote supplementary tables not contained in the body of the article and available instead in an online data
complications secondary to HITT has been evaluated in pooled analyses of prospective cohort studies with historical controls. 76,78 DTIs lepirudin and argatroban have each been compared with historical controls who received the best available care at the time. 79-83 ( Tables 8, 9 ). In the majority of cases, best available
Table 8—[Section 3.1] Summary of Findings for Argatroban for Treatment of HITT: Should Patients With HITT Receive Argatroban Over Discontinuing Heparin and/or Starting a VKA?
OutcomesNo. of Participants (Studies) Follow-up
Quality of the Evidence (GRADE)
Relative Effect (95% CI)
Anticipated Absolute Effects, Time Frame 37 d for All Outcomes
Risk With Discontinue Heparin/Start VKA
Risk Difference With Argatroban (95% CI)
Death due to thrombosisa
419 (2 cohorts) 37 db Very low due to risk of bias and imprecision
RR, 0.12 (0.05-0.34) 152 deaths per 1,000 134 fewer deaths per 1,000 (from 100 fewer to 145 fewer)
Limb amputation
419 (2 cohorts) 37 db Very low due to risk of bias and imprecision
RR, 1.26 (0.53-2.99) 109 amputations per 1,000
28 more amputations per 1,000 (from 51 fewer to 216 more)
New thrombosis
419 (2 cohorts) 37 db Moderate due to risk of bias, but with large effect
RR, 0.45 (0.28-0.71) 348 thrombotic events per 1,000
191 fewer thrombotic events per 1,000 (from 101 fewer to 250 fewer)
Major bleedingc
419 (2 cohorts) 37 db Very low due to risk of bias and imprecision
RR, 3.70 (0.52-26.5) 22 major bleeding events per 1,000
59 more major bleeding events per 1,000d (from 10 fewer to 554 more)
The anticipated absolute effect is expressed as risk difference (and its 95% CI) and is based on the baseline risk in the comparison group and the relative effect of the intervention (and its 95% CI). For evidence profi le, see Table S3. High quality: Further research is very unlikely to change our confi dence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. PRBC 5 packed RBCs. See Table 1 and 7 legends for expansion of other abbreviations.aAs judged by the investigatorsbFollow-up was 30 d past cessation of treatment in patients receiving argatroban and 37 d from baseline in control patients.cDefi ned as a hemoglobin drop of at least 20 g/L or requirement for 2 units of PRBC or an intracranial hemorrhage or a bleed into a joint.dThere were three fatal bleeding events in patients who received argatroban (HIT and HITT combined).
Table 9—[Section 3.1] Summary of Findings for Lepirudin for Treatment of HITT: Should Patients With HITT Receive Lepirudin Over Discontinuing Heparin and/or Starting a VKA?
OutcomesNo. of Participants (Studies) Follow-up
Quality of the Evidence (GRADE)
Relative Effect (95% CI)
Anticipated Absolute Effects, Time Frame 35 d for All Outcomes
Risk With Discontinue Heparin/Start VKA
Risk Difference With Lepirudin (95% CI)
Limb amputation
289 (3 cohorts) 35 d Very low due to risk of bias and imprecision
RR, 0.70 (0.27-1.8) 80 amputations per 1,000 24 fewer amputations per 1,000 (from 58
fewer to 64 more)New
thrombosis289 (3 cohorts) 35 d Moderate due to risk
of bias, but with large effect
RR, 0.28 (0.15-0.52) 253 thrombotic events per 1,000
182 fewer thrombotic events per 100a (from
122 fewer to 215 fewer)Major
bleedingb
289 (3 cohorts) 35 d Very low due to risk of bias and imprecision
RR, 2.31 (0.94-5.71) 67 major bleeding events per 1,000
87 more major bleeding events per 1,000c (from
4 fewer to 314 more)
The anticipated absolute effect is expressed as risk difference (and its 95% CI) and is based on the baseline risk in the comparison group and the relative effect of the intervention (and its 95% CI). For evidence profi le, see Table S4. High quality: Further research is very unlikely to change our con fi dence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. See Tables 1, 7, and 8 for expansion of abbreviations.aThere were three deaths due to thrombosis in patients who received lepirudin (HITT and HIT combined).bDefi ned as a fatal bleeding event or an intracranial hemorrhage or a bleeding event that led to permanent disability or requirement for 2 units of PRBC.cThere were fi ve fatal bleeding events in patients who received lepirudin (HITT and HIT combined).
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we have included danaparoid in the recommendation for this section.
Recommendation
3.1. In patients with HITT, we recommend the use of nonheparin anticoagulants, in particular lepirudin, argatroban, and danaparoid, over the further use of heparin or LMWH or initiation/continuation of VKA (Grade 1C) .
3.2 Choice of Nonheparin Anticoagulants in Patients With HITT
Inhibition of thrombin generated by HITT can be achieved with DTIs, such as lepirudin (recombinant hirudin), desirudin (recombinant hirudin), argatroban, or bivalirudin, or indirect factor Xa inhibitors, such as danaparoid or fondaparinux. All of these agents have been used to treat patients with HITT, but there are no high-quality prospective head-to-head trials com-paring one agent with another. Table 10 presents a comparison of the properties of these fi ve agents.
3.2.1 Normal Renal Function: Argatroban and Lep-irudin: The highest level of evidence for argatroban and lepirudin comes from pooled analyses of their respective historical controlled trials as reviewed in section 3.1 ( Tables 8, 9 ). We did not compare the effi cacy and safety of argatroban with lepirudin in an evidence profi le (using the data from these trials) for the following reasons: (1) because the lepirudin trials required laboratory confi rmation of HIT, whereas the argatroban trials did not, results may overestimate the
supplement; see the “Acknowledgments” for more information).
From these pooled analyses, we conclude that both agents may be more effective at preventing new thrombosis than discontinuing heparin alone or sub-stituting heparin with a VKA (lepirudin: relative risk [RR], 0.28; argatroban: RR, 0.45). Although the total number of thrombotic events is small, the well-established need for a thrombin inhibitor in patients with acute thrombosis (see Kearon et al 84 in this supplement) and the effectiveness of these agents as anti coagulants in other settings 85-88 was the basis for rating the evidence for this outcome as moderate. Major bleeding may be more likely with lepirudin and argatroban than substituting heparin with a VKA (lepirudin 15.4%, argatroban 8%), and it is unlikely that either agent reduces the risk of limb amputation. Death due to thrombosis (as determined by the in-vestigators) was signifi cantly reduced by argatroban (RR, 0.12), but we are unable to comment on the impact of lepirudin on this outcome because it was not reported separately for patients with HITT (there were a total of three deaths due to thrombosis in the lepirudin trials). Fatal bleeding events were not reported separately for patients with HITT for either nonheparin anticoagulant (fi ve fatal bleeding events out of 403 patients [1.2%] who received lepirudin, and three fatal bleeding events out of 722 patients [0.4%] who received argatroban).
There are no studies comparing danaparoid with discontinuation of heparin alone or substituting heparin with a VKA. However, given the effi cacy of danaparoid in treating HITT (reviewed in section 3.2),
Table 10—[Sections 3.2 and 4.2]: Characteristics of Anticoagulants Used to Treat Patients with HIT
Characteristic Lepirudin Argatroban Danaparoid Bivalirudin Fondaparinux
Target Thrombin Thrombin Factor Xa (predominantly) Thrombin Factor XaHalf-life 80 min 40-50 min 24 h 25 min 17-20 hElimination Renal Hepatobiliary Renal Enzymatic (80%) Renal
Renal (20%)Approved for patients
with HITa
Treatment Treatment/PCI Treatment PCI/cardiac surgery No
Method of administration IV, SC IV IV, SC IV SCMonitoring aPTT aPTT Anti-Xa level aPTT Anti-Xa level
ECT (high doses) ACT ACT or ECT (high doses)Effect on INR 1 1 1 1 0 1 1 0Immunologic features 40%-60% lepirudin Abb None 5% cross-reactivity with
HIT Abc
Potentially cross-reactive with anti-lepirudin Ab
May cause HITd
Antidote available No No No No NoCrosses placenta Uncleare Uncleare Noe Uncleare Yese
Dialyzable High-fl ux dialyzers 20% Yes 25% 20%
Ab 5 antibodies; ACT 5 activated clotting time; aPTT 5 activated partial thromboplastin time; ECT 5 ecarin clotting time; FDA 5 US Food and Drug Administration; INR 5 international normalized ratio.aIn some countries (check with local health regulatory authorities).bFatal anaphylaxis has been reported; therefore, patients should only be treated once with this agent.cClinical signifi cance is uncertain and routine testing for cross-reactivity is not recommended.dCase reports only.eFDA pregnancy category B.
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e507S
ilar (lepirudin 7.9%, danaparoid 9.4%; P 5 .74), and bleeding requiring two or more units of packed RBC occurred more frequently with lepirudin (8.1%) than danaparoid (2.3%); however, lepirudin was more fre-quently given at a therapeutic dose.
Lubenow et al 95 reported that patients with HIT who received therapeutic doses of danaparoid (with or without a VKA) in comparison with historical con-trols who received the defi brinogenating snake venom ancrod (with or without VKA) signifi cantly reduced both the risk of new thrombosis (RR, 0.41) and major bleeding (RR, 0.38) ( Table 12 , Table S1). 96,97
Desirudin: The highest quality of evidence sup-porting desirudin for treatment of HITT comes from an open-label randomized trial comparing fi xed doses of this agent (30 mg bid ) with argatroban. 98 This study was terminated after eight patients were enrolled in each arm due to poor accrual. None of the fi ve patients with laboratory-confi rmed HITT (or HIT) in the desirudin arm experienced recurrent VTE or major bleeding.
Bivalirudin: The highest level of direct evidence supporting bivalirudin for treatment of HITT comes from case series (with the largest published only as an abstract). 99-101
Fondaparinux: The highest quality of evidence supporting fondaparinux for treatment of HITT comes from one small prospective cohort with his-torical controls 97 and one retrospective cohort with historical controls 96 ( Table 12 , Recommendation 3.2.1; Table S1, Recommendations 3.1, 3.2.1, 4.1, and 4.2). Lobo et al 97 reported that neither six patients with HITT who were treated with a weight-based dose of fondaparinux nor eight patients treated with DTIs (lepirudin or argatroban) experienced recur-rent VTE or major bleeding. Grouzi et al 96 reported that neither 24 patients with HITT who were treated with a weight-based dose of fondaparinux nor a his-torical control group of 20 patients treated with lepirudin experienced recurrent VTE or major bleeding.
The literature includes three case reports of possi-ble fondaparinux-induced HIT, 102-104 one case in which fondaparinux appeared to exacerbate HIT caused by heparin, 105 and a fi fth case in which prophylactic fondaparinux failed to prevent the development of delayed HIT. 106 Although the quality of the evidence for fondaparinux-induced HIT is of low quality and experts dispute its existence, the quality of the evi-dence in favor of fondaparinux as a treatment of HIT is also very low quality. The use of argatroban, lepiru-din, and danaparoid to treat patients with HITT is supported by studies with less risk of bias. There is no published evidence to support the use of novel anti-coagulants (such as rivaroxaban or dabigatran) for the treatment of HITT.
effi cacy of argatroban as patients who do not have HIT are less prone to thrombosis than patients who have HIT; (2) because lepirudin was given for a mean of 15.8 days, whereas argatroban was given for a mean of 6.6 days, results may overestimate the rate of bleeding with lepirudin; and (3) because the propor-tion of patients who were transitioned to a VKA was lower in the argatroban trials (62%) than in the lepiru-din trials (83%), results may overestimate the effi cacy of lepirudin because patients who are safely transitioned to VKA are less likely to have thrombotic events. 76,89 An overview of the methodology of these studies is available in the online data supplement (Table S1).
Argatroban and lepirudin have been directly com-pared in small retrospective cohort studies. 90-92 How-ever, comparison across these studies is problematic because the primary outcome measure differed, and the outcomes we have identifi ed as important were not consistently reported. However, two of these studies contribute to our understanding of the bleed-ing risk of these two agents. Kiser et al 90 reported that important bleeding occurred in 6% of patients taking argatroban and 5% of patients taking lepirudin, and Smythe et al 91 observed important bleeding in 11.5% of patients taking lepirudin and 10.3% of patients tak ing argatroban. The doses of argatroban and lep-irudin given in these retrospective cohorts were lower than the doses given in the historical controlled trials.
Danaparoid: (Please note: danaparoid was with-drawn from the US market by the manufacturer in 2002; it remains available in other markets.) The highest level of evidence supporting the use of dan-aparoid for treat ment of HITT comes from one ran-domized controlled trial (RCT), 93 ( Table 11 , Table S2) and two retrospective cohort studies with historical control subjects. 94,95 In the RCT, dana paroid (plus warfarin) as compared with dextran 70 (plus warfarin) in 42 patients was associated with a trend toward reduced recurrent thrombosis (RR, 0.30; P 5 .063) without increasing the risk of major bleeding. 93 Dex-tran 70 is a weak antithrombotic agent that has been used for thromboprophylaxis following surgery, and it was the only rapidly acting nonheparin antithrom-botic available in Australia at the time of the study. Major limitations of this RCT include a subjective pri-mary effi cacy outcome measure and open-label design.
Farner et al 94 reported on 124 patients with HITT enrolled in the fi rst two lepirudin historical controlled trials 79,80 and 91 patients with HITT who received nonprotocolized danaparoid. 94 Comparison of the individual outcomes of interest in patients with HITT in this study is problematic because not all patients with HITT received therapeutic doses of a nonheparin anticoagulant (lepirudin 84.7%, dana-paroid 52.8%) and not all outcomes of interest were reported. Rates of recurrent thrombosis were sim-
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
e508S Treatment of HIT
Tabl
e 11
—[S
ecti
on 3
.2.1
] D
escr
ipti
on o
f R
ando
miz
ed C
ontr
olle
d T
rial
s C
ompa
ring
Non
hepa
rin
Ant
icoa
gula
nts
for
Tre
atm
ent
of H
ITT
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Cho
ng e
t al93
/200
1;
War
kent
in
et a
l76/2
008
RC
T, m
ultic
ente
r, op
en-la
bel
42 p
atie
nts
with
clin
ical
di
agno
sis
of H
ITa
(pla
tele
ts �
100
3 1
09 /L
and
TE
C)
Stra
tifi e
d ac
cord
ing
to m
ild o
r se
vere
th
rom
bosi
s
Dan
apar
oid
2,40
0 an
ti-X
a un
its I
V
(bol
us) t
hen
400
units
/h 3
2 h
th
en 3
00 u
nits
/h 3
2 h
then
20
0 un
its/h
for
5 d;
b War
fari
n 10
mg
daily
3 2
then
5 m
g (n
5 2
4)c O
RD
extr
an 1
,000
mL
IV
on
day
1 th
en 5
00 m
L d
aily
for
4 d;
War
fari
n 10
mg
daily
3 2
then
5
mg
(n 5
17)
Prop
ortio
n of
initi
al T
EC
w
ith c
ompl
ete
clin
ical
re
solu
tiond ;
Fro
m s
tart
of t
reat
men
t un
til d
isch
arge
from
ho
spita
l or
deat
h
Am
puta
tion:
D
anap
aroi
d 1
of 2
4 (4
.2%
)
Dex
tran
3 o
f 17
(17.
6%)
Num
ber
of d
ays
for
plat
elet
cou
nts
to
retu
rn to
nor
mal
;O
vera
ll cl
inic
al r
espo
nse
to tr
eatm
entd
R
R: 0
.24
(0.0
3-2.
08);
P 5
.29
New
thro
mbo
sis:
D
anap
aroi
d 3
of 2
4 (1
2.5%
)
Dex
tran
7 o
f 17
(41.
2%)
R
R: 0
.30
(0.0
9-1.
01);
P 5
.063
Maj
or b
leed
ing:
non
eD
eath
(all-
caus
e):
D
anap
aroi
d 3
of 2
4 (1
2.5%
)
Dex
tran
4 o
f 17
(23.
5%)
R
R: 0
.53
(0.1
4-2.
07);
P 5
.61
Dea
th (t
hrom
bosi
sd ):
D
anap
aroi
d 1
of 2
4 (4
.2%
)
Dex
tran
3 o
f 17
(17.
6%)
R
R: 0
.24
(0.0
3-2.
08);
P 5
.37
See
Tabl
e 1,
4, a
nd 7
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a HIT
con
fi rm
ed b
y la
bora
tory
test
ing
in 7
6% o
f pat
ient
s gi
ven
dana
paro
id a
nd 8
8% o
f pat
ient
s gi
ven
dext
ran.
b No
antic
oagu
lant
mon
itori
ng w
as p
erfo
rmed
.c E
xclu
ded
one
patie
nt in
dan
apar
oid
grou
p w
ho d
id n
ot m
eet i
nclu
sion
cri
teri
a.d S
ubje
ctiv
e as
sess
men
t by
inve
stig
ator
s.
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e509S
Tabl
e 12
—[S
ecti
on 3
.2.1
] D
escr
ipti
on o
f C
ohor
t St
udi
es C
ompa
ring
Non
hepa
rin
Ant
icoa
gula
nts
for
Tre
atm
ent
of H
ITT
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Gro
uzi e
t al96
/201
0C
ohor
t, hi
stor
ical
co
ntro
ls,
retr
ospe
ctiv
e
Patie
nts
diag
nose
d w
ith
HIT
(all
confi
rm
ed w
ith
PF4/
H E
LIS
A (S
tago
) an
d Pa
GIA
(Dia
Med
); al
l had
thro
mbo
sis)
Fon
dapa
rinu
x 5
mg
SC o
d (,
50
kg),
7.5
mg
SC o
d (5
0-10
0 kg
), 10
mg
SC o
d (.
100
kg)
Lep
irud
in 0
.15
mg/
kg/h
Com
plic
atio
ns: d
eath
, lim
b am
puta
tion,
new
TE
C,
veno
us g
angr
ene
Maj
or b
leed
ing
defi n
ed
as o
vert
and
ass
ocia
ted
with
Hb
drop
� 2
g/d
L,
tran
sfus
ion
� 2
uni
ts,
RPH
, IC
H, o
r cr
itica
l or
gan
or fa
tal
Plat
elet
cou
nt r
ecov
ery
Succ
essf
ul b
ridg
ing
to V
KA
2 y
Am
puta
tions
:
Fon
dapa
rinu
x 0
of 2
4a
L
epir
udin
0 o
f 20
New
thro
mbo
sis:
F
onda
pari
nux
0 of
24
L
epir
udin
0 o
f 20
Maj
or b
leed
ing:
F
onda
pari
nux
0 of
24
L
epir
udin
0 o
f 20
Dea
th (a
ll-ca
use)
:b
F
onda
pari
nux
1 of
24
(4.2
%)
L
epir
udin
2 o
f 20
(10%
)D
eath
(thr
ombo
sis)
:
Fon
dapa
rinu
x 0
of 2
4
Lep
irud
in 0
of 2
0A
ll ha
d pl
atel
et r
ecov
ery
and
succ
essf
ul b
ridg
ing
to V
KA
Lub
enow
et a
l95/2
006;
W
arke
ntin
et
al76
/200
8
Coh
ort,
hist
oric
al
cont
rols
, m
ultic
ente
r, re
tros
pect
ive
62 p
atie
nts
with
HIT
c and
an
indi
catio
n fo
r on
goin
g th
erap
eutic
ant
icoa
gula
nt
ther
apyd w
ho r
ecei
ved
dana
paro
id w
ith o
r w
ithou
t a
VK
A (1
993-
1999
)56
pat
ient
s w
ith H
ITc a
nd
an in
dica
tion
for
ongo
ing
ther
apeu
tic a
ntic
oagu
lant
th
erap
yd who
rec
eive
d an
crod
with
or
with
out a
V
KA
(198
6-19
93)
Dan
apar
oid
at le
ast 3
,000
an
ti-X
a un
its I
V o
r SC
in
fi rs
t 24
he (53
pat
ient
s al
so r
ecei
ved
VK
A) O
RC
ontr
ols
Anc
rod
IV o
r SC
to
redu
ce fi
brin
ogen
to ,
0.5
g/L
or
at l
east
70
units
per
24
h (1
8 re
ceiv
ed V
KA
al
one
and
31 r
ecei
ved
ancr
od 1
VK
Ag )
Com
posi
te o
f new
or
prog
ress
ive
TE
C, a
nd/o
r am
puta
tion,
and
/or
thro
mbo
tic d
eath
Maj
or b
leed
ingf
Fro
m s
tart
of t
reat
men
t un
til d
ay 7
of t
reat
men
t of
pri
mar
y ef
fi cac
y an
d m
ajor
ble
edin
gSe
cond
ary:
sam
e ou
tcom
e m
easu
res
at d
ay 3
5
At d
ay 3
5:
Am
puta
tion
Dan
apar
oid
3 of
62
(4.8
%)
Con
trol
s 4
of 5
6 (7
.1%
)
R
R: 0
.68
(0.1
6-2.
90);
P 5
.71
N
ew th
rom
bosi
s
D
anap
aroi
d 11
of 6
2 (1
7.7%
)
C
ontr
ols
24 o
f 56
(42.
9%)
RR
: 0.4
1 (0
.22-
0.77
); P
5 .0
04
Maj
or b
leed
ing
Dan
apar
oid
8 of
62
(12.
9%)
Con
trol
s 19
of 5
6 (3
3.9%
)
R
R: 0
.38
(0.1
8-0.
80);
P 5
.008
D
eath
(all-
caus
e):h
Dan
apar
oid
6 of
62
(9.7
%)
Con
trol
s 8
of 5
6 (1
4.3%
)
R
R: 0
.68
(0.2
5-1.
83);
P 5
.63
D
eath
(thr
ombo
sis)
:
D
anap
aroi
d 2
of 6
2 (3
.2%
)
C
ontr
ols
3 of
56
(5.3
%)
RR
: 0.6
0 (0
.10-
3.47
); P
5 .9
1
(Con
tinu
ed)
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
e510S Treatment of HIT
Tabl
e 12
—C
onti
nued
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Lob
o et
al97
/200
8C
ohor
t, hi
stor
ical
co
ntro
ls,
pros
pect
ive
Patie
nts
with
a d
iagn
osis
of
HIT
(14
had
HIT
T;
3 ha
d H
IT) (
all h
ad H
IT
confi
rm
ed w
ith h
epar
in
PF4
antib
ody
test
)
Fon
dapa
rinu
x 5
mg
SC o
d (,
50
kg),
7.5
mg
SC o
d (5
0-10
0 kg
), 10
mg
SC o
d (.
100
kg)
for
HIT
T; 2
.5
mg
SC o
d fo
r H
IT (n
5 1
) fo
r at
leas
t 7 d
or
until
IN
R th
erap
eutic
for
2 co
nsec
utiv
e da
ysi
Plat
elet
rec
over
y w
ith
defi n
ition
dep
ende
nt
on p
rese
nce
or a
bsen
ce
of th
rom
bocy
tope
nia
1 da
y pr
ior
to tr
eatm
ent
4 w
k af
ter
disc
ontin
uatio
n of
fond
apar
inux
Am
puta
tions
:
Fon
dapa
rinu
x 1
of 7
(14%
)
DT
I 1
of 1
0 (1
0%)
New
thro
mbo
sis:
F
onda
pari
nux
0 of
7
DT
I 0
of 1
0M
ajor
ble
edin
g:
Fon
dapa
rinu
x 0
of 7
D
TI
0 of
10
Dea
th (a
ll-ca
use)
:
Fon
dapa
rinu
x 0
of 7
D
TI
2 of
10
(20%
)Pl
atel
et r
ecov
ery:
F
onda
pari
nux
7 of
7 (1
00%
)
DT
I 8
of 1
0 (8
0%)
Succ
essf
ul b
ridg
ing
to V
KA
:
Fon
dapa
rinu
x 2
of 6
(33%
)
DT
I 0
of 1
0 (0
%)
Com
plic
atio
ns: d
eath
, lim
b am
puta
tion,
new
TE
C,
veno
us g
angr
ene
His
tori
cal c
ontr
ols
DT
I:
lepi
rudi
n (n
5 6
) or
arga
trob
an (n
5 4
) ac
cord
ing
to
FD
A-a
ppro
ved
mon
ogra
ph
Maj
or b
leed
ing
defi n
ed
as o
vert
and
ass
ocia
ted
with
Hb
drop
� 2
g/dL
, tr
ansf
usio
n �
2 u
nits
, or
fata
lSu
cces
sful
bri
dgin
g to
V
KA
: IN
R 2
-3 fo
r tw
o co
nsec
utiv
e da
ys w
hile
no
t rec
eivi
ng a
DT
I
DT
I 5 d
irec
t thr
ombi
n in
hibi
tor;
Hb
5 h
emog
lobi
n; I
CH
5 in
trac
rani
al h
emor
rhag
e; o
d 5
onc
e da
ily; R
PH 5
retr
oper
itone
al h
emor
rhag
e. S
ee T
able
1, 3
, 4, 7
, and
10
for
expa
nsio
n of
oth
er a
bbre
viat
ions
.a O
ne p
atie
nt in
the
fond
apar
inux
arm
and
two
patie
nts
in th
e le
piru
din
arm
dev
elop
ed v
enou
s ga
ngre
ne b
efor
e th
e st
udy
drug
was
sta
rted
.b N
one
was
cla
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© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
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Danaparoid—We suggest an initial bolus IV (weight , 60 kg: 1,500 units; 60-75 kg: 2,250 units; 75-90 kg: 3,000 units; . 90 kg: 3,750 units) followed by infusion 400 units/h 3 4 h then 300 units/h 3 4 h then 200 units/h IV, adjusted subsequently according to anti-Xa levels (target, 0.5-0.8 anti-Xa U/mL).
Bivalirudin—We suggest no initial bolus and a starting infusion rate of 0.15-0.20 mg/kg/h IV (target, 1.5-2.5 times patient’s baseline aPTT [or mean of laboratory normal range]).
Fondaparinux—We suggest for patients who weigh , 50 kg: 5.0 mg SC daily; for those who weigh 50-100 kg: 7.5 mg subcutaneously (SC) daily; for those who weigh . 100 kg: 10 mg SC daily.
3.3 Platelet Transfusions
Spontaneous bleeding is uncommon with HIT despite sometimes profound thrombocytopenia. How-ever, patients with HIT may require invasive pro-cedures for which a prophylactic platelet trans fusion would normally be given to reduce the risk of bleeding. It has been widely reported that giving a platelet transfusion to a patient with HIT “adds fuel to the fi re” and increases the risk of thrombosis.
Two case series reported in the mid to late 1970s suggest that platelet transfusions may exacerbate HIT. 110,111 In the fi rst report, two out of fi ve patients with suspected HIT received a single platelet transfu-sion, one of whom developed arterial thromboembo-lism post transfusion (while still receiving heparin). 110 In the second report, one out of 11 patients with sus-pected HIT received a platelet transfusion and had an inadequate increase in platelet count (but no thrombotic events). 111
More recently, a case series reported 37 patients with PF4-ELISA-confi rmed HIT who received one or more platelet transfusions during a 1-year period at a single center. 112 No thrombotic complications developed in any of the patients following platelet transfusion, and three deaths within a few days of transfusion were deemed unrelated to transfusion. Of the 37 patients, 23 patients had a high 4Ts score, and ELISA results suggesting that at least this many patients actually had HIT. HIT-related thrombosis was documented in eight patients prior to platelet trans-fusion; six received a platelet transfusion during thrombectomy and none experienced any further thrombotic complications (all six patients received argatroban).
In summary, there is no direct evidence supporting an increased risk of thrombosis in patients with HIT who are given platelet transfusions. However, the evidence is also too limited to support the safety of platelet transfusions.
Recommendation
3.2.1. In patients with HITT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C) .
Remarks: Other factors not covered by our analysis, such as drug availability, cost, and ability to monitor the anticoagulant effect, may infl uence the choice of agent.
3.2.2 Renal Insuffi ciency: Both lepirudin and danaparoid are renally cleared, but argatroban is not. Furthermore, there are retrospective, observational data to suggest that the use of lepirudin in renal fail-ure is associated with an increased risk of major bleeding, 60,107 whereas a secondary analysis of the argatroban historical controlled trials did not show such a relationship. 108
Recommendation
3.2.2. In patients with HITT and renal insuffi -ciency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C) .
Dosing Considerations (modifi ed from Warkentin et al 76 ) Lepirudin—We suggest that the initial bolus either be omitted or, in the case of perceived life- or limb-threatening thrombosis, be given at a reduced dose (0.2 mg/kg). The initial infusion rate should be � 0.10 mg/kg/h (in patients with serum creati-nine , 90 m mol/L), with lower infusion rates for patients with higher serum creatinine levels (serum creatinine 90-140 m mol/L: starting infusion rate, 0.05 mg/kg/h; 140-400 m mol/L: starting infusion rate, 0.01 mg/kg/h; . 400 m mol/L: starting infusion rate, 0.005 mg/kg/h). Activated partial thrombo-plastin time (aPTT) monitoring should be performed at 4-h intervals until it is apparent that steady state within the therapeutic range (1.5-2.0 times patient baseline [or mean laboratory] aPTT) is achieved. (These dosing guidelines refl ect modifi cations of the US Food and Drug Administration [FDA] labeling dosing guidelines due to concern about an increased risk of bleeding. 60,107 )
Argatroban—We suggest an initial bolus be omitted, and that the initial infusion rate be � 2 m g/kg/min IV. For patients who have heart failure, multiple organ system failure, or severe anasarca, or who are post cardiac surgery, we suggest beginning the initial infu-sion at a rate between 0.5 and 1.2 m g/kg/min, with subsequent q2h adjustments using the aPTT (target aPTT 1.5-3 times patient baseline). (These dosing guidelines refl ect modifi cations of the FDA labeling dosing guidelines due to concern about an increased risk of bleeding. 109 )
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e512S Treatment of HIT
3.4.2. We further suggest that if a VKA has already been started when a patient is diagnosed with HIT, vitamin K should be administered (Grade 2C) .
Remarks: We place a high value on the prevention of venous limb gangrene and a low value on the cost of the additional days of the parental nonheparin anticoagulant.
3.5 Discontinuing Thrombin Inhibitor After a Minimum of 5 Days of Overlap With a VKA
There is no direct evidence addressing the optimal duration of treatment with thrombin or factor Xa inhibitors while overlapping with VKAs in patients with HITT. There are, however, data suggesting that premature discontinuation of the thrombin or factor Xa inhibitor may result in an increased risk of recur-rent thrombosis. Hursting et al 115 found that seven out of 16 new episodes of thrombosis occurred on the day after argatroban was discontinued in a sub-group of patients who received argatroban and warfa-rin. Of the patients who had an adverse event during the transition to warfarin, 70% had received , 5 days of treatment with argatroban (5 days is the accepted minimum length of time necessary for warfarin to reduce prothrombin levels to those commonly associ-ated with effective anticoagulation).
The primary reason argatroban was discontinued prematurely was likely misinterpretation of a high INR (secondary to the infl uence of argatroban) as indicative of therapeutic anticoagulation with warfa-rin. This is supported by the fi nding that 21% of patients with an INR . 3.0 while receiving arga-troban and warfarin cotherapy had a subtherapeutic INR 4 h after discontinuation of argatroban. 116 The INR should not be interpreted as an indicator of the effect of warfarin alone when administered with argatroban.
Among the advantages of using danaparoid over the DTIs to treat HITT is the lack of infl uence of this agent on the INR and aPTT. Infl uence on the INR complicates transition from the DTIs to war-farin, whereas infl uence on the aPTT complicates drug monitoring, particularly in patients with coag-ulopathy due to HIT-induced DIC. Fondaparinux shares the same potential advantage, but without the same level of evidence supporting its use as a treatment option for HITT (section 3.2). Some experts have suggested switching from a DTI (eg, arga-troban or lepirudin) to fondaparinux once the patient’s platelets have recovered ( . 150 3 10 9 /L) and transition to warfarin is about to begin. 117 Suc-cess with this approach has been published in case reports. 118,119
Recommendation
3.3. In patients with HIT and severe thrombo-cytopenia, we suggest giving platelet transfusions only if bleeding or during the performance of an invasive procedure with a high risk of bleeding (Grade 2C) .
3.4 Starting a VKA Before Platelet Recovery
Following treatment with a parenteral thrombin or factor Xa inhibitor, transition to a VKA (eg, warfarin) is required for longer-term anticoagulation (HIT-related thrombosis is considered provoked by a tran-sient risk factor and should be treated for a minimum of 3 months; see Kearon et al 84 ). The rapid initiation of warfarin in patients with HIT may produce a pro-thrombotic state because the level of the natural anticoagulant, protein C, falls faster than prothrombin levels. This can lead to serious adverse events, such as warfarin-induced skin necrosis and venous limb gangrene (distal ischemic limb necrosis in the absence of arterial occlusion).
Patients who develop venous limb gangrene typi-cally have the following characteristics: (1) recent dis-continuation of a parenteral anticoagulant that was being used to treat a DVT in the affected leg; (2) a supratherapeutic INR (due to a decrease factor VII, which parallels a drop in protein C), and (3) a platelet count , 150 3 10 9 /L (refl ecting an ongoing prothrom-botic state due to HIT). 46 There are no prospective studies comparing the incidence of adverse events, such as venous limb gangrene, when warfarin is started at different platelet thresholds in patients with HIT. The reports that are available suggest the possibility that higher INRs when receiving warfarin are associ-ated with venous limb gangrene, 46,113 although even this fi nding is not consistent 114 (Table S5).
In summary, there is no direct evidence supporting initiation of VKA at a particular platelet threshold in patients with HIT. However, there is low-quality evi-dence suggesting a potential for substantial harm if a supratherapeutic INR is reached while a patient with HIT still has a low platelet count and is receiving war-farin without concurrent treatment with a thrombin or factor Xa inhibitor.
Recommendations
3.4.1. In patients with strongly suspected or con-fi rmed HIT, we recommend against starting VKA until platelets have substantially recovered (ie, usually to at least 150 3 10 9 /L) over starting VKA at a lower platelet count and that the VKA be initially given in low doses (maximum, 5 mg of warfarin or 6 mg phenprocoumon) over using higher doses (Grade 1C) .
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tinued for 3 months. For patients with HIT, we sug-gest VKA therapy or an alternative anticoagulant be continued for 4 weeks.
4.0 Management of Isolated HIT (HIT Without Thrombosis)
4.1 Discontinue Heparin or Initiate VKA vs Treatment With Nonheparin Anticoagulants
The fi rst step in the treatment of HIT is discontin-uation of all forms of heparin and LMWH (including heparin fl ushes and heparin-coated catheters). Whether taking this step alone is enough to prevent the devel-opment of thrombotic complications in patients who have isolated HIT has been evaluated in pooled analyses of prospective cohort studies with historical controls 76,78 and in three retrospective case series. 6,42,70 The prospective studies compared DTIs lepirudin and argatroban with historical controls in whom hep-arin was discontinued with or without the addition of warfarin 79-83 ( Tables 13,14 ). An overview of the meth-odology of these studies is available in the online data supplement (Table S1).
From these pooled analyses, we conclude that both agents may be more effective at preventing new thrombosis than discontinuing heparin alone or sub-stituting heparin with a VKA (lepirudin: RR, 0.30; argatroban: RR, 0.29) and may or may not increase
Recommendation
3.5. In patients with confi rmed HIT, we rec-ommend that that the VKA be overlapped with a nonheparin anticoagulant for a minimum of 5 days and until the INR is within the target range over shorter periods of overlap and that the INR be rechecked after the anticoagulant effect of the nonheparin anticoagulant has resolved (Grade 1C) .
3.6 Duration of VKA Therapy in Patients With HITT or HIT
There are no studies evaluating the duration of VKA therapy in patients with HITT or HIT. Given that HIT is generally considered a reversible pro-voking risk factor for VTE, 3 months of anticoagu-lant therapy in patients with thrombosis secondary to HIT is consistent with the recommended duration of treatment of VTE in the context of other revers-ible provoking risk factors (see Kearon et al 84 ). HIT investigators have suggested that due to the high risk of thrombosis that extends for 2 to 4 weeks after treatment of HIT is initiated, consideration should be given to continuing anticoagulant therapy with an alternative agent or warfarin for up to 4 weeks in patients with isolated HIT. 120
Statement 3.6: For patients with HITT, we suggest VKA therapy or an alternative anticoagulant be con-
Table 13—[Section 4.1] Summary of Findings for Argatroban for Treatment of Isolated HIT: Should Patients With Isolated HIT Receive Argatroban Over Discontinuing Heparin and/or Starting a VKA?
OutcomesNo. of Participants (Studies) Follow-up
Quality of the Evidence (GRADE)
Relative Effect (95% CI)
Anticipated Absolute Effects, Time Frame 37 d for All Outcomes
Risk With Discontinue Heparin/Start VKA
Risk Difference With Argatroban (95% CI)
Death due to thrombosisa
488 (2 cohorts) 37 db Very low due to risk of bias and imprecision
RR, 0.07 (0.01-0.55) 43 deaths per 1,000 40 fewer deaths per 1,000 (from 19 fewer to 43 fewer)
Limb amputation 488 (2 cohorts) 37 db Very low due to risk of bias and imprecision
RR, 1.10 (0.35-3.38) 29 amputations per 1,000
3 more amputations per 1,000 (from 19 fewer to 68 more)
New thrombosis 488 (2 cohorts) 37 db Moderate due to risk of bias, but with large effect
RR, 0.29 (0.18-0.47) 237 thrombotic events per 1,000
169 fewer thrombotic events per 1,000 (from 126 fewer to 195 fewer)
Major bleedingc 488 (2 cohorts) 37 db Very low due to risk of bias and imprecision
RR, 0.50 (0.24-1.04) 86 major bleeding events per 1,000
43 fewer major bleeding events per 1,000d (from 66 fewer to 3 more)
The anticipated absolute effect is expressed as risk difference (and its 95% CI) and is based on the baseline risk in the comparison group and the relative effect of the intervention (and its 95% CI). For evidence profi le see Table S6. High quality: Further research is very unlikely to change our con fi dence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. See Table 1 and 7 legends for expansion of abbreviations.aAs judged by the investigators.bFollow-up was 30 d past cessation of treatment in patients receiving argatroban and 37 d from baseline in control patients.cDefi ned as a hemoglobin drop of at least 20 g/L or requirement for 2 units of PRBC or an intracranial hemorrhage or bleeding into a joint.dThere were three fatal bleeding events in patients who received argatroban (HIT and HITT combined).
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e514S Treatment of HIT
rospective case series ( Table 15 ). 6,42,70 Warkentin et al 6 reported that 55.5% of 62 patients with HIT who just had heparin discontinued, and 47.6% of patients who had heparin substituted by a VKA developed thrombosis. Wallis et al 42 reported new thrombosis in
the risk of major bleeding (lepirudin 14%, arga-troban 4%) and that neither agent is likely to reduce the risk of limb amputation.
The high risk of a thrombotic event in patients with isolated HIT is also supported by data from three ret-
Table 14—[Section 4.1] Summary of Findings for Lepirudin for Treatment of Isolated HIT: Should Patients With Isolated HIT Receive Lepirudin Over Discontinuing Heparin and/or Starting a VKA?
OutcomesNo. of Participants (studies) Follow-up
Quality of the Evidence (GRADE)
Relative Effect (95% CI)
Anticipated Absolute Effects, Time Frame 35 d for All Outcomes
Risk With Discontinue Heparin/Start VKA
Risk Difference With Lepirudin (95% CI)
Limb amputation 138 (2 cohorts) 35 d Very low due to risk of bias and imprecision
RR, 3.65 (0.19-69.27) 0 amputations per 1,000
0 more amputations per 1,000 (from 58 fewer to 64 more)
New thrombosis 138 (2 cohorts) 35 d Low due to risk of bias
RR, 0.30 (0.09-0.96) 149 thrombotic events per 1,000
104 fewer thrombotic events per 1,000a (from 6 fewer to 136 fewer)
Major bleedingb 138 (2 cohorts) 35 d Very low due to risk of bias and imprecision
RR, 1.68 (0.58-4.86) 85 major bleeding events per 1,000
58 more major bleeding events per 1,000c (from 36 fewer to 329 more)
The anticipated absolute effect is expressed as risk difference (and its 95% CI) and is based on the baseline risk in the comparison group and the relative effect of the intervention (and its 95% CI). For evidence profi le see Table S7. High quality: Further research is very unlikely to change our confi dence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. See Table 1, 7, and 8 legends for expansion of abbreviations.aThere were three deaths due to thrombosis in patients who received lepirudin (HITT and HIT combined).bDefi ned as a fatal bleeding event or an intracranial hemorrhage or bleeding that led to permanent disability or requirement for 2 units of PRBC.cThere were fi ve fatal bleeding events in patients who received lepirudin (HITT and HIT combined).
Table 15—[Section 4.1] Studies Evaluating Discontinuation of Heparin for Treatment of Isolated HIT
Study/Year Type of Study Participants Intervention Outcomes Follow-up Results
Warkentin et al6/1996
Case series, retrospective, multicenter
62 consecutive patients with SRA-confi rmed HIT over 14-y period
Heparin discontinued (n 5 36)
Warfarin (n 5 21)
Not specifi ed (n 5 5)
New thrombosis
30 d New thrombosis: Heparin discontinued 20 of
36 (55.5%) Warfarin 10 of 21 (47.6%) Not specifi ed 2 of 5 (40%)Death due to thrombosis: 3 of
62a (4.8%)Death (all-cause): 13 of 62 (21%)
Wallis et al42/1999
Case series, retrospective, single center
113 consecutive patients with PAT-confi rmed HIT
Heparin discontinuedb
New thrombosis
Not specifi ed
New thrombosis: 43 of 113 (38%)c
In-hospital death
New thrombosis . 24 h after heparin discontinued:d 21 (18.6%)
Death due to thrombosis: 12 of 113 (10.6%)
Death (all cause): 31 of 113 (27.4%)Zwicker
et al70/2004Case series,
retrospective, single center
48 patients with ELISA-confi rmed HIT
Heparin discontinuede
New thrombosis
30 d New thrombosis: 8 of 48 (17%)f 2 patients were receiving
warfarin
PAT 5 platelet aggregation test; PE 5 pulmonary embolism. See Table 1 and 3 legends for expansion of abbreviations.aTwo patients had a fatal PE confi rmed at post mortem, one was a sudden death with no post mortem.b21 patients received alternate therapy after heparin discontinued (thrombolytics [4], plasmapheresis [3], dextran [17], g globulin [1], LMWH [1], danaparoid [1], hirudin [1], bivalirudin [1]). Outcomes were not stratifi ed by treatment.c11 patients had more than one thrombotic event.dThrombotic events within the fi rst 24 h may have been due to the presence of residual heparin.eOne patient received a direct thrombin inhibitor; six patients were treated with heparin.fThe development of thrombotic complications was correlated with increasing OD of ELISA for HIT antibodies.
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Danaparoid: (Please note: danaparoid was with-drawn from the US market in 2002 but remains avail-able in other markets.): The highest level of evidence supporting the use of danaparoid for treatment of isolated HIT comes from a small prospective cohort study without internal controls 121 and a small retrospec-tive study with historical controls. 94 Schenk et al 121 reported that none of 24 patients with isolated HIT (15 with laboratory confi rmation) who received danaparoid bid (10 International Units/kg) for a mean of 16 days (mean anti-Xa level 0.2 units/mL) developed thrombotic events or major bleeding.
Farner et al 94 reported on 51 patients with isolated HIT enrolled in the fi rst two lepirudin historical con-trolled trials 79.80 and 35 patients with isolated HIT who received nonprotocolized danaparoid. 94 Rates of recurrent thrombosis were higher for danaparoid com-pared with lepirudin (20%; 95% CI, 8.4%-36.9% and 6.3%; 95% CI, 1.3%-17.2%, respectively). The inves-tigators attributed this fi nding to the more frequent use of prophylactic doses of danaparoid in patients with HIT. In contrast, patients with HITT who were treated with danaparoid (and were more likely to have received a therapeutic dose) had a similar risk of new thrombosis compared with patients treated with lepirudin. Other retrospective reports have also suggested that low doses of danaparoid (750 units SC bid or tid, or 1,250 units SC bid) are associated with a higher risk of thrombosis. 122,123
Desirudin: The highest quality of evidence sup-porting desirudin for treatment of HIT comes from an open-label randomized trial comparing fi xed doses of this agent (15 mg bid) with argatroban. 98 This study was terminated after eight patients were enrolled in each arm due to poor accrual. None of the fi ve patients with laboratory-confi rmed HITT (or HIT) in the desiru-din arm experienced recurrent VTE or major bleeding.
Bivalirudin: The highest level of evidence support-ing bivalirudin for treatment of isolated HIT is limited to case series.
Fondaparinux: The highest level of evidence sup-porting fondaparinux for treatment of isolated HIT is limited to case series.
Recommendation
4.2. In patients with isolated HIT (HIT without thrombosis) who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagu-lants (Grade 2C) .
Remarks: Other factors such as drug availability, cost, and ability to monitor the anticoagulant effect may
18.6% of 113 consecutive patients with laboratory-confi rmed HIT who just had heparin discontinued; 12 of these patients subsequently died. Zwicker et al 70 found that 17% of 48 patients with ELISA-confi rmed isolated HIT went on to develop thrombosis. Overall, the risk of thrombosis in patients with isolated HIT who are not treated with a nonheparin anticoagulant is substantial (ranges from 17%-55%).
Based on the data above, the risk of thrombosis in patients with isolated HIT who have heparin discontinued or substituted by a VKA is approxi-mately fi vefold higher than patients with isolated HIT who receive lepirudin or argatroban. For this reason, we rated the evidence for this outcome as moderate.
There are no studies comparing danaparoid with discontinuation of heparin alone or substituting hep-arin with a VKA. However, given the effi cacy of danaparoid in treating HIT (reviewed in section 4.2), we have included danaparoid in the recommendation for this section.
Recommendation
4.1. In patients with isolated HIT (HIT without thrombosis), we recommend the use of lepiru-din or argatroban or danaparoid over the further use of heparin or LMWH or initiation/continua-tion of a VKA (Grade 1C) .
4.2 Choice of Nonheparin Anticoagulants in Patients With Isolated HIT
Lepirudin, desirudin, argatroban, bivalirudin, dana-paroid, and fondaparinux have all been used to treat patients with isolated HIT, but there are no prospec-tive head-to-head trials comparing one agent with another. Table 10 presents a comparison of the prop-erties of these fi ve agents.
Argatroban and Lepirudin: The highest level of evi-dence for argatroban and lepirudin comes from pooled analyses of their respective historical controlled trials as reviewed in section 3.1 We did not formally com-pare the effi cacy and safety of argatroban with lepiru-din in the treatment of isolated HIT in an evidence profi le (using the data from their respective historical controlled trials) for the reasons outlined in section 3.2.1. Patients with isolated HIT treated with lepiru-din in these trials did not receive an initial bolus, and the infusion rate was 33% lower than in patients with HITT. Dose adjustments following initiation of lep-irudin were, however, based on aPTT, and therapeutic levels were therefore generally achieved within 24 h. In the argatroban trials, there was no difference in the dosing regimen used for patients with isolated HIT and patients with HITT.
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e516S Treatment of HIT
Lepirudin: The highest level of evidence for use of lepirudin during cardiac surgery in patients with HIT comes from a retrospective case series (n 5 57) 129 ( Table 16 , Recommendation 5.1.1) and, indirectly, from a small RCT (n 5 20) in patients without HIT 131 (Table S8). Although thromboembolic complications were rare, reoperation for bleeding was required in four patients (7%) in the case series, all in patients with postoperative renal insuffi ciency. 129 An increased risk of bleeding was also noted in another small retro-spective case series of patients with HIT who under-went cardiac surgery. 132 The limitations associated with lepirudin during cardiac surgery include diffi -culty with monitoring (the ACT is not accurate with high doses of lepirudin, and the best alternative, the ECT, is not widely available), long plasma half-life, and the reported increased risk of bleeding, particu-larly in patients with renal insuffi ciency. Special con-siderations with respect to intraoperative surgical, anesthesiologic and perfusion techniques are required when lepirudin is used during cardiac surgery (for a detailed review of dosing and precautions see Warkentin and Greinacher 130 ).
Danaparoid: The highest level of data supporting the use of danaparoid in patients with HIT who require urgent cardiac surgery come from a small RCT in patients without HIT. 133 The RCT (n 5 71) was terminated early due to concern about higher mediastinal blood loss and transfusion requirements in patients who received danaparoid compared with patients who received heparin (Table S8). The limita-tions that applied to the use of lepirudin with respect to need for monitoring, long half-life, and increased risk of bleeding in patients with renal failure also apply to danaparoid.
Epoprostenol, Iloprost, and Tirofi ban: The data sup-porting use of these agents are limited to case series in patients with HIT. 134-137
In summary, there is no direct evidence supporting the use of one alternative nonheparin anticoagulant over another in patients with acute HIT or subacute HIT who undergo cardiac surgery. Of the alternative anticoagulants that have been used for this indica-tion, bivalirudin is the only one that is supported by prospective, multicentre cohort studies (without inter-nal controls) in patients with HIT and indirectly by small randomized heparin-controlled trials in patients without HIT.
Recommendations
5.1.1. In patients with acute HIT (thrombocyto-penic, HIT antibody positive) or subacute HIT (platelets recovered, but still HIT antibody pos-itive) who require urgent cardiac surgery, we
infl uence the choice of agent. The dosing consider-ations are the same as for patients with HITT (see section 3.2). For a recommendation on choice of nonheparin anticoagulants in the setting of renal insuffi ciency, see Recommendation 3.2.2.
5.0 Management of Patients With Acute HIT or Subacute HIT in Special Situations
5.1 Patients Who Require Urgent Cardiac Surgery
During cardiac surgery, heparin is commonly used to maintain patency in the CPB apparatus and to pre-vent coagulation in the tissue factor-rich operative fi eld. Heparin is ideally suited for this role because it has a rapid onset of action, has a short half-life, is revers-ible with protamine sulfate, and has a point-of-care assay (activated clotting time [ACT]). Substituting a nonheparin anticoagulant, such as bivalirudin, lepiru-din, or argatroban, for heparin is one strategy that has been used in patients with HIT during cardiac surgery. Another strategy has been combining hep-arin with a short-acting antiplatelet agent, such as a prostacyclin analog (eg, epoprostenol, iloprost) or a glycoprotein (GP) IIb/IIIa inhibitor (eg, tirofi ban) to attenuate platelet activation. There are no prospective head-to-head trials comparing one agent (or strategy) with another in patients with HIT.
Bivalirudin: The highest level of evidence for bivalirudin comes from prospective, cohort studies without internal controls in patients with HIT who underwent cardiac surgery 124,125 and indirectly by small randomized trials in patients without HIT. 126-128 The rate of procedural success (defi ned as absence of death, Q-wave MI, repeat operation for coronary revascularization, or stroke) was 94% and 92% in patients with HIT who received bivalirudin for either on-pump or off-pump surgery, respectively ( Table 16 ). 129 The incidence of complications, such as MI, cerebrovascular accident (CVA), or major bleeding, were similar to patients without HIT who received either bivalirudin or heparin in the RCTs (Table S8).
Special considerations with respect to intraopera-tive surgical, anesthesiology, and perfusion tech-niques are required when bivalirudin is used during cardiac surgery. For example, stasis in the CPB cir-cuit must be minimized to reduce the potential for cleavage of bivalirudin by thrombin in stagnant blood (for a detailed review of dosing and precautions see Warkentin and Greinacher 130 ). The ACT has been successfully used to monitor the anticoagulant effect of bivalirudin during cardiac surgery. However, the ecarin clotting time (ECT) is the preferred assay, if available.
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e517S
Tabl
e 16
—[5
.1.1
] St
udi
es E
valu
atin
g N
onhe
pari
n A
ntic
oagu
lant
s in
Pat
ient
s W
ith
HIT
Who
Req
uir
e U
rgen
t C
ardi
ac S
urg
ery
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Kos
ter
et a
l124 /2
007
Coh
ort w
ithou
t in
tern
al c
ontr
ols,
pr
ospe
ctiv
e,
mul
ticen
ter
49 p
atie
nts
with
HIT
or
sus
pect
ed H
IT
unde
rgoi
ng C
PB,
(42
patie
nts
HIT
A
b-po
sitiv
e at
tim
e of
pro
cedu
re)
Biv
alir
udin
1 m
g/kg
bol
us
then
2.5
mg/
kg/h
Proc
edur
al s
ucce
ssa
Maj
or b
leed
ingb
Day
7 o
r da
y of
dis
char
ge,
whi
chev
er c
ame
fi rst
for
proc
edur
al s
ucce
ss a
nd
maj
or b
leed
ing;
pro
cedu
ral
succ
ess
at d
ay 3
0 an
d 12
wk
At d
ay 7
Pr
oced
ural
suc
cess
: 46
of 4
9 (9
4%)
AC
T .
2.5
-fol
d in
crea
se
over
bas
elin
e
MI:
0 o
f 49
C
VA: 1
of 4
9 (2
%)
M
ajor
ble
edin
g: 0
of 4
9
Dea
th: 1
of 4
9 (2
%)
Dyk
e et
al12
5 /200
7C
ohor
t with
out
inte
rnal
con
trol
s,
pros
pect
ive,
m
ultic
ente
r
51 p
atie
nts
with
HIT
or
sus
pect
ed H
IT
unde
rgoi
ng O
PCA
B,
(35
patie
nts
HIT
A
b-po
sitiv
e at
tim
e of
pro
cedu
re)
Biv
alir
udin
0.7
5 m
g/kg
bo
lus
then
1.7
5 m
g/kg
/hPr
oced
ural
suc
cess
a D
ay 7
or
day
of d
isch
arge
, w
hich
ever
cam
e fi r
st
for
proc
edur
al s
ucce
ss
and
maj
or b
leed
ing;
pr
oced
ural
suc
cess
at
day
30 a
nd 1
2 w
k
At d
ay 7
Maj
or b
leed
ingb
Pr
oced
ural
suc
cess
: 47
of 5
1 (9
2%)
AC
T .
300
s
MI:
3 o
f 51
(6%
)
CVA
: 1 o
f 51
(2%
)
Maj
or b
leed
ing:
0 o
f 51
D
eath
: 0 o
f 49
Kos
ter
et a
l129 /2
000
Cas
e se
ries
, re
tros
pect
ive,
si
ngle
cen
ter
57 p
atie
nts
with
con
fi rm
ed
HIT
und
ergo
ing
CPB
(5
2 pa
tient
s H
IT
Ab-
posi
tive
at ti
me
of p
roce
dure
)
r-hi
rudi
n 0.
25 m
g/kg
bol
us
then
0.5
mg/
min
(E
CT
350
-400
s)
Not
pre
spec
ifi ed
6 m
oR
eope
ratio
n fo
r bl
eedi
ng: 4
of 5
7
(7%
); al
l 4 h
ad p
osto
pera
tive
rena
l fai
lure
Dea
th: 3
of 5
7 (5
%)c
CPB
5 ca
rdio
pulm
onar
y by
pass
; C
VA 5
cere
brov
ascu
lar
acci
dent
; M
I 5 m
yoca
rdia
l in
farc
tion;
OPC
AB
5 o
ff-p
ump
coro
nary
art
ery
bypa
ss.
See
Tabl
e 1
and
10 l
egen
ds f
or e
xpan
sion
of
othe
r ab
brev
iatio
ns.
a Defi
ned
as
abse
nce
of d
eath
, Q-w
ave
MI,
rep
eat o
pera
tion
for
coro
nary
rev
ascu
lari
zatio
n, o
r st
roke
.b D
efi n
ed a
s in
trac
rani
al h
emor
rhag
e, r
etro
peri
tone
al o
r G
I bl
eedi
ng, o
r pe
rsis
tent
pos
tope
rativ
e he
mor
rhag
e re
quir
ing
surg
ical
re-
expl
orat
ion.
c Dee
med
unr
elat
ed to
per
iope
rativ
e an
ticoa
gula
tion
by in
vest
igat
ors.
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
e518S Treatment of HIT
nist 140 ( Table 17 ). Clinical success was achieved in 92% of patients but with an 8% incidence of major bleeding (including one fatal bleeding event).
Argatroban: Data regarding the effi cacy and safety of argatroban during PCI in patients with HIT come from a secondary analysis of the argatroban prospec-tive, historical controlled trials. 141 In these trials, 91 patients underwent PCI with a clinical success rate of 98% and an incidence of major bleeding of 1% 141 ( Table 17 ). Laboratory confi rmation of HIT was not required for these trials, so the proportion of patients who truly had HIT at the time of the proce-dure is uncertain. In patients without HIT (n 5 152), argatroban alone or in combination with GP IIb/IIIa inhibitors during PCI was evaluated in a prospective cohort study without internal controls. 145 The inci-dence of the composite effi cacy outcome (death, Q-wave MI, and urgent revascularization) and major bleeding was acceptably low in both groups (0%-3%) 145 (Table S9).
Danaparoid and Fondaparinux: The evidence sup-porting the use of danaparoid is limited to case series in patients with HIT undergoing PCI; fonda-parinux has not been evaluated for this indication. The increased rate of catheter-related thrombosis seen in patients who underwent PCI after receiving fonda-parinux in the Organization for the Assessment of Strategies for Ischemic Syndromes (OASIS)-6 trial raises concern about the effi cacy of this agent in interventional settings. 146
In summary, although the level of evidence sup-porting the use of bivalirudin during PCI in patients with HIT is limited to a small prospective cohort, the data in patients without HIT is high quality (RCTs summarized in meta-analyses). The use of lepirudin is supported by data from studies with patients with-out HIT; however, there is concern about an associ-ated increased risk of bleeding with this agent. The highest level of evidence supporting argatroban for PCI in patients with HIT comes from a subgroup analysis of the prospective, historical controlled HIT treatment trials. There is no evidence to support the use of fondaparinux in this setting.
Recommendation
5.2. In patients with acute HIT or subacute HIT who require PCI, we suggest the use of bivalirudin (Grade 2B) or argatroban (Grade 2C) over other nonheparin anticoagulants .
Remarks: Other factors, such as drug availability, cost, and ability to monitor the anticoagulant effect, may infl uence the choice of agent.
suggest the use of bivalirudin over other non-heparin anticoagulants and over heparin plus antiplatelet agents (Grade 2C) .
5.1.2. In patients with acute HIT who require nonurgent cardiac surgery, we recommend delay-ing the surgery (if possible) until HIT has resolved and HIT antibodies are negative (see section 6.1) (Grade 2C) .
Remarks: Other factors not covered by our analysis, such as drug availability, cost, and ability to monitor the anticoagulant effect may infl uence the choice of agent.
For recommendations for patients with a past his-tory of HIT ( . 3 months previous) who require car-diac surgery, see section 6.1.
5.2 Patients Who Require Urgent Percutaneous Coronary Interventions
Anticoagulants are used to prevent ischemic complications secondary to plaque disruption and endothelial injury during percutaneous coronary interventions (PCI), such as angioplasty and stent placement. Bivalirudin, lepirudin, argatroban, and danaparoid have all been evaluated for use during PCI in patients with acute or subacute HIT. There are no head-to-head trials comparing these anticoag-ulants in patients with HIT.
Bivalirudin: The highest level of evidence support-ing the use of bivalirudin during PCI comes from a pooled analysis of fi ve large RCTs comparing bivali-rudin with heparin plus GP IIb/IIIa inhibitors in patients without HIT 138 (Table S9). This analysis of . 19,000 patients showed that bivalirudin had a similar risk of ischemic adverse events as the control group (OR, 1.07; 95% CI, 0.96-1.19) but a lower risk of major bleeding (OR, 0.55; 95% CI, 0.44-0.69). Bivalirudin also showed a high procedural success rate (98%) with a low risk of major bleeding (2%) in patients with HIT who underwent PCI in a prospec-tive cohort study of 52 patients 139-141 ( Table 17 ).
Lepirudin (Recombinant Hirudin): In patients with-out HIT, randomized controlled trials of patients with acute coronary syndromes have shown that hirudin is more effective than heparin at reducing the risk of reinfarction in patients undergoing PCI, but at the cost of an increased risk of major bleeding. 142-144 Experience with patients with HIT is limited to a small prospective cohort study in which 21 patients undergoing PCI (or peripheral vascular interven-tions) received lepirudin plus a GP IIb/IIIa antago-
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www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e519S
Tabl
e 17
—[S
ecti
on 5
.2]
Stu
dies
Eva
luat
ing
Non
hepa
rin
Ant
icoa
gula
nts
Du
ring
PC
I in
Pat
ient
s W
ith
HIT
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Mah
affe
y et
al13
9 /200
3C
ohor
t with
out
inte
rnal
con
trol
s,
pros
pect
ive,
m
ultic
ente
r
52 p
atie
nts
with
HIT
or
sus
pect
ed H
IT
unde
rgoi
ng P
CI,
(t
estin
g fo
r H
IT
Ab
was
not
req
uire
d)
Biv
alir
udin
1 m
g/kg
bol
us
then
2.5
mg/
kg/h
fo
r 4
h; a
fter
yea
r 20
02
chan
ged
to 0
.75
mg/
kg
bolu
s fo
llow
ed b
y 1.
75 m
g/kg
/h fo
r up
to 4
h
Proc
edur
al s
ucce
ss: T
IMI
grad
e 3
fl ow
and
fi na
l le
sion
ste
nosi
s , 5
0%
48 h
aft
er d
rug
adm
inis
trat
ion
or h
ospi
tal d
isch
arge
(w
hich
ever
cam
e fi r
st)
Proc
edur
al s
ucce
ss:
49 o
f 50
(98%
)
Clin
ical
suc
cess
: abs
ence
of
deat
h, r
equi
rem
ent f
or
emer
gent
byp
ass
or Q
-wav
e M
I
Clin
ical
suc
cess
: 48
of 5
0 (9
6%)
Maj
or b
leed
ing:
IC
H, R
PH,
hem
odyn
amic
com
prom
ise,
bl
eedi
ng w
ith �
3 U
PR
BC
tr
ansf
usio
n or
Hb
, 3
g/d
L
or H
ct �
9%
)
MI:
0C
VA: 0
Maj
or b
leed
ing
even
t: 1
of 5
0 (2
%)
Dea
th: 1
of 5
0 (2
%)a
Coc
hran
et a
l140 /2
003
Coh
ort w
ithou
t in
tern
al c
ontr
ols,
pr
ospe
ctiv
e,
sing
le c
ente
r
25 p
atie
nts
with
sus
pect
ed
or c
onfi r
med
HIT
who
un
derw
ent P
CI
or
peri
pher
al in
terv
entio
ns
(20
patie
nts
HIT
A
b-po
sitiv
e at
tim
e of
pro
cedu
re;
11 p
atie
nts
had
HIT
T)
Lep
irud
in 0
.1-0
.8 m
g/kg
al
one
(AC
T .
300
s)
(n 5
4) O
R
Ang
iogr
aphi
c su
cces
s: p
ost
angi
opla
sty
sten
osis
, 5
0%;
post
ste
nt s
teno
sis ,
20%
Hos
pita
l dis
char
geA
ngio
grap
hic
succ
ess:
10
0%
Lep
irud
in A
ND
ept
ifi ba
tide
180
m g/
kg b
olus
3 2
then
2
m g/
kg/m
in O
R T
irofi
ban
10
m g/
kg b
olus
then
0.
15 m
g/kg
/min
(A
CT
. 2
50 s
) (n
5 2
1)
Clin
ical
suc
cess
: ang
iogr
aphi
c su
cces
s an
d fr
eedo
m
from
MA
CE
Clin
ical
suc
cess
: 23
of 2
5 (9
2%)
Maj
or b
leed
ingb
MI:
0C
VA: 0
Maj
or b
leed
ing
even
ts:
2 of
25
(8%
) bot
h re
ceiv
ed le
piru
din
1 G
PD
eath
: 2 o
f 25
(8%
)c
Lew
is e
t al14
1 /200
2Po
st h
oc s
ubgr
oup
anal
ysis
of
AR
G-2
16,
AR
G-3
10,
AR
G-3
11
91 p
atie
nts
with
HIT
or
susp
ecte
d H
IT o
r pa
st
hist
ory
of H
IT w
ho
unde
rwen
t PC
I (t
his
tabl
e in
clud
es d
ata
on in
itial
PC
I on
ly
for
21 p
atie
nts
who
un
derw
ent .
1 P
CI)
Arg
atro
ban
350
m g/
kg
bolu
s th
en 2
5 m
g/kg
/min
(3
0 m
g/kg
/min
in A
RG
-216
) an
d ad
just
ed to
mai
ntai
n A
CT
300
-450
s
Ang
iogr
aphi
c su
cces
s: fi
nal
sten
osis
, 5
0% in
� 1
le
sion
att
empt
ed
For
24
h af
ter
drug
ce
ssat
ion
or u
ntil
hosp
ital d
isch
arge
(w
hich
ever
cam
e fi r
st)
Ang
iogr
aphi
c su
cces
s:
86 o
f 88
(98%
)
Clin
ical
suc
cess
: abs
ence
of
deat
h, e
mer
gent
byp
ass,
Q
-wav
e in
farc
tion
Clin
ical
suc
cess
: 86
of 8
8 (9
8%)
Maj
or b
leed
ing:
ove
rt a
nd
asso
ciat
ed w
ith d
rop
in H
b .
5 g
/dL
and
tr
ansf
usio
n �
2 u
nits
PR
BC
or
ICH
, RPH
, or
into
a p
rost
hetic
join
t
MI:
4 o
f 91
(4%
)E
mer
gent
byp
ass:
2
of 9
1 (2
%)
Maj
or b
leed
ing:
1
of 9
1 (1
%)
Dea
th: 0
of 9
1
AC
S 5
acut
e co
rona
ry s
yndr
ome;
GP
5 g
lyco
prot
ein
Iib/
IIIa
inhi
bito
r; H
ct 5
hem
atoc
rit;
MA
CE
5 co
mpo
site
of d
eath
, non
fata
l MI,
str
oke
and
targ
et v
esse
l rev
ascu
lari
zatio
n.a A
syst
olic
arr
est.
b Defi
ned
as
requ
irin
g tr
ansf
usio
n .
2 u
nits
PR
BC
or
ICH
or
RPH
.c O
ne d
eath
was
det
erm
ined
to b
e re
late
d to
the
proc
edur
e (r
etro
peri
tone
al h
emor
rhag
e).
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
e520S Treatment of HIT
tent hemodialysis (n 5 122). 153 In the review, throm-bosis of either the patient or the hemodialysis circuit occurred in 7% of the 97 patients with HIT, and major bleeding occurred in 6%. 153 Only one-third of the patients in this study had the diagnosis of HIT confi rmed with a functional assay. Small RCTs that compared danaparoid with heparin or LMWH during hemodialysis in patients without HIT have also shown it to be effective and safe. 154,155
Lepirudin and Fondaparinux: Lepirudin is depen-dent on renal clearance and antihirudin antibodies may develop that further reduce renal clearance. 156,157 Because of the prolonged half-life of this agent in renal failure, intermittent doses of lepirudin prior to dialysis may continue to exert an anticoagulant effect between dialysis sessions. Small studies evaluating hirudin during continuous venovenous hemofi ltra-tion, predominantly in patients without HIT, have reported an increased risk of hemorrhagic compli-cations. 158-160 The evidence regarding the use of fonda-parinux is limited to case reports. 161,162
In summary, there is no direct evidence supporting the use of one alternative nonheparin anticoagulant over another in patients with acute HIT who require renal replacement therapy. There has been more experience with danaparoid than argatroban for this indication; however, although the highest level of evidence supporting the use of danaparoid comes from comparative studies in patients without HIT, the use of argatroban is supported by prospective data (albeit limited) and pharmacokinetics (ie, lack of renal clearance). Although successful use of lep-irudin has been reported, an increased risk of bleeding has been raised as a concern.
Recommendation
5.3.1. In patients with acute or subacute HIT who require renal replacement therapy, we suggest the use of argatroban or danaparoid over other nonheparin anticoagulants (Grade 2C) .
Remarks: We acknowledge that the cost of argatroban may be prohibitive at some clinical centers. We fur-ther suggest that if the prothrombotic state of HIT appears to have resolved (as seen by normalization of the platelet count), saline fl ushes during dialysis would be a reasonable option. This suggestion is based on the presumed pathogenesis of thrombosis in this con-dition and not on the results of clinical trials.
5.3.2 Patients With a Past History of HIT: Citrate has been evaluated as a substitute for heparin during renal replacement therapy in patients who are unable to receive heparin because of a high risk of bleed-ing. 163-165 Citrate acts as a regional anticoagulant by
5.3 Patients Who Require Renal Replacement Therapy
5.3.1 Patients With Acute HIT: Renal replacement therapy is a term that encompasses a large number of different procedures in patients with renal failure (eg, intermittent hemodialysis, continuous venovenous hemofi ltration, continuous venovenous hemodialysis, continuous arteriovenous hemodialysis). Heparin is the anticoagulant most commonly used to maintain patency of the fi lter and extracorporeal circuit during these procedures. Although hemodialysis can be performed without anticoagulant therapy, 147 we do not recommend this approach for patients with acute or subacute HIT because of the prothrombotic nature of HIT (high risk of thrombosis within the renal replacement circuit and the patient). 148
There are no head-to-head studies comparing the effi cacy and safety of nonheparin anticoagulants dur-ing renal replacement therapy in patients with HIT. Caution must be exercised when comparing the results of different studies using nonheparin antico-agulants because of the large variety of procedures and signifi cant interstudy differences with respect to type of hemofi lter membrane, blood fl ow rates, dialysate fl ow rates, and other specifi c aspects of renal replacement therapy. For a more comprehensive review, including dosing information, see Davenport and Davenport 148 ).
Argatroban: Argatroban has two properties that make it ideal for renal replacement therapy: (1) it is not renally cleared, and (2) dialytic clearance by high-fl ux membranes is considered clinically insignif-icant. 149 The evidence for the use of argatroban dur-ing renal replacement therapy in patients with HIT comes from one small prospective, dose-fi nding study in patients undergoing continuous renal replacement therapy (n 5 30) 150 and a secondary analysis of the prospective, historical controlled treatment studies (47 patients who received seven different methods of renal replacement therapy). 151 The incidence of new thrombosis (0%-4%) and major bleeding (0%-6%) while on argatroban in these studies was low. An RCT evaluating three different doses of argatroban during intermittent hemodialysis in patients without HIT (n 5 13) showed similar results. 149
Danaparoid: Danaparoid has been successfully used during renal replacement therapy despite its dependence on renal clearance. The highest level of evidence supporting the use of danaparoid during renal replacement therapy in patients with HIT comes from one small pilot study (fi ve patients with contin-uous venovenous hemofi ltration) 152 and a retrospec-tive review of cases and comparative studies of HIT and patients without HIT who underwent intermit-
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proposed strategy for reducing the duration of expo-sure to lepirudin in a patient diagnosed with HIT during the fi rst trimester of pregnancy is to use SC lepirudin during the fi rst two trimesters and then switch to warfarin in the last trimester when the risk of teratogenicity secondary to warfarin is lower (assuming the patient’s platelet count has fully recov-ered). Investigators recommend that lepirudin be started intravenously with a switch to SC administra-tion once platelet counts have recovered (overlap-ping with IV lepirudin by 1 hour). 170,176
Argatroban cannot be given SC and has only been evaluated in pregnancy in case reports. Fondaparinux can be given SC, but unlike lepirudin, the effective-ness of fondaparinux for treating HIT is still uncer-tain (see section 3.2). Indirect support for the safety of fondaparinux during pregnancy in patients without HIT is derived from one small prospective cohort study without internal controls in which women who developed hypersensitivity skin reactions while receiving LMWH for a history of VTE or recurrent fetal loss were treated with fondaparinux. 177 In this study, 10 patients (during 12 pregnancies) received fondaparinux 2.5 mg bid until the start of sponta-neous labor. None of the 13 infants had any congen-ital abnormalities and no major bleeding occurred during the pregnancies (three patients had . 1,000 mL blood loss at delivery). A retrospective case series of 29 pregnant women who received fondaparinux 2.5 mg daily (staring in the fi rst trimester) for infer-tility and unexplained recurrent fetal loss reported similar results. 178 However, fondaparinux crosses the human placenta, as shown in a case report of four patients who had elevated anti-Xa activity in umbil-ical cord blood (approximately one-tenth the concen-tration in the maternal plasma). 179 Further studies on the safety and effi cacy of this drug in context of preg-nancy are needed.
Despite the low quality of evidence supporting the use of danaparoid for treatment of HIT during preg-nancy, the number of patients who have been exposed to this agent compared with the alternatives and the lack of placental transfer make it the current best choice.
Recommendation
5.4. In pregnant patients with acute or subacute HIT, we suggest danaparoid over other non-heparin anticoagulants (Grade 2C) . We suggest the use of lepirudin or fondaparinux only if danaparoid is not available (Grade 2C) .
Remarks: Other factors, such as drug availability, cost, and ability to monitor the anticoagulant effect, may infl uence the choice of agent.
chelating ionized calcium. However, it requires spe-cial dialysates and careful monitoring for metabolic derangements. Citrate has also been used for cath-eter locking, although the evidence to support its effi cacy is not as high quality as for heparin. 166 Although it has not been evaluated in patients with acute HIT, citrate for renal replacement and catheter locking appears to be a reasonable alternative for patients with a past history of HIT.
Recommendation
5.3.2. In patients with a past history of HIT who require ongoing renal replacement therapy or catheter locking, we suggest the use of regional citrate over the use of heparin or LMWH (Grade 2C) .
5.4 Pregnant Patients
The incidence of HIT during pregnancy is lower than in the nonpregnant population, especially when LMWH is used (at either prophylactic or thera-peutic doses [one in 1,167 pregnancies 21,22,34 and zero in 2,777 pregnancies 35 ]). When it does occur, how-ever, heparin should be discontinued and treatment with a nonheparin anticoagulant initiated. The qual-ity of evidence on the effi cacy and safety of non-heparin anticoagulants in this patient population is very low.
Danaparoid: The highest level of evidence for danaparoid comes from a retrospective case series 167 in which 30 women with acute HIT (28 with VTE) received danaparoid (at various doses) during preg-nancy. Five of the patients (17%) developed recur-rent VTE and three (10%) developed major bleeding during treatment. There was no evidence of anti-Xa activity due to danaparoid in the umbilical cord blood of the six infants who were checked after delivery.
Lepirudin, Argatroban, and Fondaparinux: Data supporting the use of lepirudin, 168-170 argatroban, 171,172 and fondaparinux 173-175 to treat HIT during pregnancy are limited to case reports. The advantage of lepiru-din is that it can be administered SC (it has been given in doses ranging from 25 mg bid to 125 mg bid; monitored by aPTT 2 h post injection). 170,176 However, long-term administration has been associated with the development of antilepirudin antibodies that pro-long the drug’s effective half-life. Consequently, a patient who develops HIT in the fi rst trimester and is treated with lepirudin will be at higher risk for devel-oping antilepirudin antibodies than a patient who is diagnosed with HIT in the third trimester. 176 One
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
e522S Treatment of HIT
(n 5 45), but the proportion of patients who were re-exposed . 3 months after their episode of acute HIT is not available, nor was the incidence of re-emergence of HIT antibodies; however, 91% of the re-exposed patients developed thrombocyto-penia by day 15 of re-exposure.
6.1 Patients With a History of HIT Who Require Cardiac Surgery
Although the evidence is very limited, the combi-nation of the unique properties of HIT antibodies as previously described, and the serious diffi culties that may be encountered using nonheparin antico-agulants during procedures such as CPB, lead us to conclude that the risk of short-term re-exposure may be justifi ed in specifi c circumstances. 76 In these cases, the use of heparin should be restricted to the time of surgery, and other heparin exposure before and after the procedure should be scrupu-lously avoided. Patients with recent HIT whose platelet count has recovered but who still have detectable HIT antibodies are at risk for developing rapid-onset HIT with heparin re-exposure unless a washed platelet activation assay (eg, SRA or HIPA) is negative and the ELISA is negative or only weakly positive. 76
Recommendations
6.1.1. In patients with a history of HIT in whom heparin antibodies have been shown to be absent who require cardiac surgery, we sug-gest the use of heparin (short-term use only) over nonheparin anticoagulants (Grade 2C) .
6.1.2. In patients with a history of HIT in whom heparin antibodies are still present who require cardiac surgery, we suggest the use of nonhepa-rin anticoagulants (see Recommendation 5.1.1) over heparin or LMWH (Grade 2C) .
6.2 Patients Who Require PCI
In theory, the same approach described for re-exposure to heparin for patients with a past his-tory of HIT who require cardiac surgery could be used for patients who require PCI. However, there are two reasons we would favor the use of nonheparin anticoagulants over re-exposure to heparin for PCI: (1) the risk for recurrent immunization that could present as acute HIT if heparin is then used for car-diac surgery in the same patient, and (2) the favor-able experience with bivalirudin during PCI (as compared with the diffi culties of using bivalirudin and other nonheparin anticoagulants during car-diac surgery). 76
6.0 Management of Patients With a Past History of HIT
With certain procedures (eg, surgery requiring CPB, hemodialysis), the properties of heparin make it preferable to alternative nonheparin anticoagu-lants (eg, short half-life, reversibility, readily available assays for monitoring the anticoagulant effect, low cost). The risk of giving heparin to patients with acute or subacute HIT is too high (ie, risk of fatal thrombo-sis); hence, our recommendations for management of patients who require these procedures are given in section 5.0. This section will address patients who have a past history of HIT ( . 3 months previous) for whom re-exposure to heparin (or LMWH) is being considered.
Patients with a past history of HIT can theoreti-cally be re-exposed to heparin, in specifi c circum-stances, because of several unique properties of HIT antibodies. First, the HIT antibody is known to be transient, with a median time to disappearance of 50 to 80 days (depending on the assay performed). 36 Second, there is no evidence to suggest that patients with a prior history of HIT (who are currently HIT antibody negative) will have an amnestic immune response on re-exposure to heparin (ie, sensitization does not occur with , 4 days of exposure to heparin and the level of response is not stronger than with the initial episode of HIT). 36 Patients who have devel-oped rapid-onset HIT (within 24 h of heparin expo-sure) have been found to have residual HIT antibodies in their blood from their initial heparin exposure (typically within the past 100 days). 36,37 These obser-vations suggest that it may be possible to re-expose a patient with a previous history of HIT to heparin for , 4 days without precipitating a second episode of acute HIT. Because there are no clinical trials evalu-ating the safety of this premise, our recommenda-tions are based on the incidence of recurrent HIT or re-emergence of HIT antibodies following intentional (or accidental) re-exposure to heparin or LMWH in observational studies.
Five studies have reported outcomes in patients who were re-exposed to heparin or LMWH in the context of a past history of HIT 6,37,132,180,181 ( Table 18 ). Three studies including a total of 20 patients who were re-exposed to heparin during cardiac or vascu-lar surgery reported no episodes of recurrent HIT and only one episode of re-emergence of HIT anti-bodies. 6,132,180 Similar results were seen in the case series by Wanaka et al, 181 in which fi ve patients were re-exposed to heparin during multiple episodes of intermittent hemodialysis (see section 5.3 for patients with a past history of HIT who require hemodialysis). The registry by Lubenow et al 37 included the largest number of patients who were re-exposed to heparin
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Tabl
e 18
—[S
ecti
on 6
.0]
Stu
dies
of
Pat
ient
s W
ith
a P
ast
His
tory
of
HIT
Who
Wer
e R
e-ex
pose
d to
Hep
arin
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Wan
aka
et a
l181 /2
010
Cas
e se
ries
, re
tros
pect
ive,
sing
le c
ente
r (le
tter
)
5 pa
tient
s w
ith la
bora
tory
-co
nfi r
med
HIT
(P
AT-p
ositi
ve E
LIS
A)
who
req
uire
d he
mod
ialy
sis
Re-
expo
sure
to
hepa
rin
(aft
er
initi
al tr
eatm
ent
with
arg
atro
ban
and
confi
rm
ed H
IT
Ab-
neg
ativ
e . 10
0 d
late
r)
Thr
ombo
cyto
peni
a1-
6 yr
Thr
ombo
cyto
peni
a: 0
HIT
ant
ibod
ies
HIT
ant
ibod
ies:
0C
lott
ing
of d
ialy
zer
Clo
ttin
g in
dia
lyze
r: 2
of 5
(bot
h re
solv
ed w
ith a
spir
in)
Nut
tall
et a
l132 /2
003
Coh
ort w
ith
conc
urre
nt
cont
rols
, pr
ospe
ctiv
e,
sing
le c
ente
r
12 c
ardi
ac s
urge
ry p
atie
nts
with
a p
revi
ous
clin
ical
di
agno
sis
of H
ITa w
ho
requ
ired
CPB
Hep
arin
dur
ing
CPB
onl
y (H
IT
Ab-
nega
tive)
b
Volu
me
of a
lloge
nic
bloo
d pr
oduc
tsN
ot p
resp
ecifi
edR
ecur
renc
e of
thro
mbo
cyto
peni
a o
r H
IT a
ntib
odie
s no
t rep
orte
dB
lood
loss
Volu
me
of a
lloge
nic
bloo
d pr
oduc
ts a
nd
bl
ood
loss
: hig
her
in r-
hiru
din
grou
pr-
hiru
din
0.25
mg/
kg
bolu
s, 0
.20
mg/
kg
in C
PB p
ump
prim
e, 0
.5 m
g/m
in
infu
sion
(EC
T)
(HIT
Ab-
posi
tive)
Nee
d fo
r re
oper
atio
nN
eed
for
reop
erat
ion:
Thr
ombo
tic e
vent
s
Hep
arin
1 o
f 6 (1
7%)
Dea
th
r-H
irud
in 3
of 6
(50%
)T
hrom
botic
eve
nts:
0D
eath
: 0
Lub
enow
et a
l37/2
002
Reg
istr
y,
retr
ospe
ctiv
e,
mul
ticen
tre
45 p
atie
nts
with
la
bora
tory
-con
fi rm
ed
HIT
(HIP
A)
Re-
expo
sure
to
hepa
rin
Rel
atio
n of
the
time
inte
rval
to p
revi
ous
hepa
rin
expo
sure
an
d on
set o
f pl
atel
ets ,
100
x 1
09 /L
Unt
il de
velo
pmen
t of
thro
mbo
cyto
peni
a (p
late
let
coun
t , 1
00 3
109 /L
)
Inte
rval
bet
wee
n he
pari
n ex
posu
res:
1 d
to 2
1 y
Ons
et o
f thr
ombo
cyto
peni
a if
re-e
xpos
ure
with
in 3
mo:
Day
4.9
� 4
.4 (m
ean
� S
D)
Ons
et o
f thr
ombo
cyto
peni
a if
re-e
xpos
ure
af
ter
3 m
o:c d
ay 1
1.5
� 5
.5 (m
ean
� S
D)
Lik
elih
ood
of th
rom
bocy
tope
nia
(n 5
45)
D
ay 5
(45%
)
Day
8 (5
4%)
D
ay 1
5 (9
1%)
Potz
sch
et a
l180 /2
000
Cas
e se
ries
, re
tros
pect
ive,
si
ngle
cen
ter
(lett
er)
10 p
atie
nts
with
his
tory
of
con
fi rm
ed H
IT
(HIP
A-p
ositi
ve) w
ho
requ
ired
CPB
sur
gery
d
Re-
expo
sure
to
hepa
rin
Prol
onge
d th
rom
bocy
tope
niae
10 d
aft
er s
urge
ryN
o pr
olon
ged
thro
mbo
cyto
peni
a or
incr
ease
in H
IT a
ntib
odie
sH
IT a
ntib
odie
s
(Con
tinu
ed)
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
e524S Treatment of HIT
Recommendation
6.2. In patients with a history of HIT who require cardiac catheterization or PCI, the recommended treatment is the same as in Recommendation 5.2.
6.3 Patients Who Require Prophylaxis or Treatment of Thrombosis
In contrast to the situation with cardiac surgery or PCI, re-exposure to heparin or LMWH in patients with a past history of HIT who require anticoagulant therapy for prophylaxis or treatment of venous or arterial thrombosis is unlikely to be limited to , 4 days. The limited available evidence suggests that the longer the re-exposure to heparin, the higher the likelihood of re-emergence of HIT antibodies and, potentially, acute HIT. 37 Furthermore, 25% of patients with HIT will present with thrombosis before their platelet count drops. Therefore, relying on platelet count monitoring alone to watch for sensitization may not be safe. 3,5 Given the established effi cacy and safety of alternative anticoagulants, such as warfarin, danapa-roid, fondaparinux, and the new oral anticoagulants, dabigatran and rivaroxaban, for thromboprophylaxis, re-exposure to heparin/LMWH should be avoidable in most cases.
The options for treatment of acute thrombosis are more limited. Warfarin will not inhibit active throm-bin and should not be used alone to treat acute thrombosis. A recent secondary analysis of two large RCTs comparing heparin or LMWH with fonda-parinux for treatment of VTE showed that fonda-parinux was less likely to exacerbate HIT in patients who had preexisting platelet-activating antibodies than patients who received heparin or LMWH (zero out of 10 patients who received fondaparinux went on to develop clinical HIT compared with four out of four patients who received heparin or LMWH). 182 This suggests that fondaparinux may be safe to use in patients with a previous history of HIT.
Recommendation
6.3. In patients with a past history of HIT who have acute thrombosis (not related to HIT) and normal renal function, we suggest the use of fondaparinux at full therapeutic doses until transition to VKA can be achieved (Grade 2C) .
Conclusions
The diagnosis and treatment of HIT is an ongoing challenge. Studies evaluating the effi cacy and safety of fondaparinux and new anticoagulants in the treat-ment of HIT would be of tremendous value to the medical community. St
udy/
Year
Type
of S
tudy
Part
icip
ants
Inte
rven
tion
Out
com
esF
ollo
w-u
pR
esul
ts
War
kent
in e
t al6 /1
996
Cas
e se
ries
, re
tros
pect
ive,
m
ultic
ente
r
7 pa
tient
s w
ith la
bora
tory
-co
nfi r
med
HIT
(SR
A)
over
14-
y pe
riod
Re-
expo
sure
to
hepa
rin
New
thro
mbo
sis
Unt
il en
d of
trea
tmen
t in
pts
re-
expo
sed
to fu
ll he
pari
n tr
eatm
ent (
n 5
3)f
No
decr
ease
in p
late
let c
ount
or
new
thro
mbo
sis
in a
ny o
f the
pat
ient
sH
IT a
ntib
odie
s po
sitiv
e in
1 p
atie
nt w
ith
sh
ort-
term
exp
osur
e an
d te
stin
g no
t do
ne in
1 p
atie
nt w
ith lo
nger
exp
osur
eD
ecre
ase
in p
late
let
coun
tU
ntil
disc
harg
e in
pat
ient
s re
-exp
osed
to h
epar
in
duri
ng c
ardi
ac o
r va
scul
ar
surg
ery
only
(n 5
4)
See
Tabl
e 1,
2, 8
, 10,
12,
15,
and
16
for
expa
nsio
n of
abb
revi
atio
ns.
a Six
wer
e PF
4-E
LIS
A p
ositi
ve im
med
iate
ly p
rior
to s
urge
ry.
b Onl
y on
e pa
tient
who
was
PF
4-E
LIS
A n
egat
ive
prio
r to
stu
dy h
ad a
pos
itive
PF
4-E
LIS
A w
ith H
IT in
pas
t; th
eref
ore,
fi ve
pat
ient
s m
ay n
ever
hav
e ha
d H
IT.
c Pro
port
ion
of p
atie
nts
in th
is c
ateg
ory
was
not
pro
vide
d (a
utho
r w
as c
onta
cted
and
no
furt
her
deta
ils a
vaila
ble)
.d N
egat
ive
for
HIT
ant
ibod
ies
at ti
me
of s
urge
ry.
e Not
defi
ned
.f D
urat
ion
of fo
llow
-up
was
8 d
, 11
d, a
nd 1
9 d
in th
e pt
s w
ho r
ecei
ved
mor
e th
an a
sho
rt te
rm r
e-ex
posu
re to
hep
arin
.
Tabl
e 18
—C
onti
nued
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e525S
3 . Warkentin TE , Levine MN , Hirsh J , et al . Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin . N Engl J Med . 1995 ; 332 ( 20 ): 1330 - 1335 .
4 . Warkentin TE , Roberts RS , Hirsh J , Kelton JG . An improved defi nition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients . Arch Intern Med . 2003 ; 163 ( 20 ): 2518 - 2524 .
5 . Greinacher A , Farner B , Kroll H , Kohlmann T , Warkentin TE , Eichler P . Clinical features of heparin-induced thrombo-cytopenia including risk factors for thrombosis. A retro-spective analysis of 408 patients . Thromb Haemost . 2005 ; 94 ( 1 ): 132 - 135 .
6 . Warkentin TE , Kelton JG . A 14-year study of heparin-induced thrombocytopenia . Am J Med . 1996 ; 101 ( 5 ): 502 - 507 .
7 . Greinacher A , Pötzsch B , Amiral J , Dummel V , Eichner A , Mueller-Eckhardt C . Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimo-lecular PF4-heparin complex as the major antigen . Thromb Haemost . 1994 ; 71 ( 2 ): 247 - 251 .
8 . Amiral J , Bridey F , Dreyfus M , et al . Platelet factor 4 com-plexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia . Thromb Haemost . 1992 ; 68 ( 1 ): 95 - 96 .
9 . Kelton JG , Smith JW , Warkentin TE , Hayward CP , Denomme GA , Horsewood P . Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4 . Blood . 1994 ; 83 ( 11 ): 3232 - 3239 .
10 . Chong BH , Fawaz I , Chesterman CN , Berndt MC . Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets . Br J Haematol . 1989 ; 73 ( 2 ): 235 - 240 .
11 . Warkentin TE , Hayward CP , Boshkov LK , et al . Sera from patients with heparin-induced thrombocytopenia gen-erate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia . Blood . 1994 ; 84 ( 11 ): 3691 - 3699 .
12 . Warkentin TE , Sheppard JI . Generation of platelet-derived microparticles and procoagulant activity by heparin-induced thrombocytopenia IgG/serum and other IgG platelet ago-nists: a comparison with standard platelet agonists . Platelets . 1999 ; 10 ( 5 ): 319 - 326 .
13 . Martel N , Lee J , Wells PS . Risk for heparin-induced throm-bocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis . Blood . 2005 ; 106 ( 8 ): 2710 - 2715 .
14 . Warkentin TE , Sheppard JA , Horsewood P , Simpson PJ , Moore JC , Kelton JG . Impact of the patient population on the risk for heparin-induced thrombocytopenia . Blood . 2000 ; 96 ( 5 ): 1703 - 1708 .
15 . Warkentin TE , Sheppard JA , Moore JC , Moore KM , Sigouin CS , Kelton JG . Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need? J Lab Clin Med . 2005 ; 146 ( 6 ): 341 - 346 .
16 . Lindhoff-Last E , Nakov R , Misselwitz F , Breddin HK , Bauersachs R . Incidence and clinical relevance of heparin-induced antibodies in patients with deep vein thrombosis treated with unfractionated or low-molecular-weight hep-arin . Br J Haematol . 2002 ; 118 ( 4 ): 1137 - 1142 .
17 . Lubenow N , Hinz P , Thomaschewski S , et al . The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia . Blood . 2010 ; 115 ( 9 ): 1797 - 1803 .
18 . Warkentin TE , Sheppard JA , Sigouin CS , Kohlmann T , Eichler P , Greinacher A . Gender imbalance and risk factor
Acknowledgments Author Contributions: As Topic Editor, Dr Linkins oversaw the development of this article, including the data analysis and subse-quent development of the recommendations contained herein. Dr Linkins: contributed as Topic Editor . Dr Dans: contributed as panelist. COL Moores: contributed as panelist. Dr Bona: contributed as frontline clinician. Dr Davidson: contributed as panelist. Dr Schulman: contributed as panelist. Dr Crowther: contributed as panelist. Financial/nonfi nancial disclosures: The authors of this guide-line provided detailed confl ict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e495S/suppl/DC1. In summary, the authors have reported to CHEST the following confl icts of interest: Dr Linkins has two potential indirect fi nancial confl ict of interests based on a peer-reviewed grant received from the Heart and Stroke Foundation of Canada to conduct a research study evaluating a diagnostic assay (PaGIA) for HIT and a single lecture (paid an honorarium by Pfi zer) that included a brief discus-sion about HIT. Dr Linkins also discloses primary intellectual confl ict of interest for diagnosis of HIT (holds a peer-reviewed research grant from the Heart and Stroke Foundation) and sec-ondary intellectual confl ict of interest (published reviews on HIT). Dr Dans received funding from GlaxoSmithKline for research in an area unrelated to HIT. Dr Davidson received consulting fees from Bayer and Daiichi Sankyo, makers of synthetic oral anti-coagulants currently in clinical trials, and expenses for travel to a Steering Committee meeting. Dr Crowther has served on vari-ous advisory boards, has assisted in the preparation of educational materials, has sat on data safety management boards, and his insti-tution has received research funds from the following companies: Leo Pharma A/S, Pfi zer Inc, Boehringer Ingelheim GmbH, Bayer Healthcare Pharmaceuticals, Octapharm AG, CSL Behring, and Artisan Pharma. Personal total compensation for these activities over the past 3 years totals less than US $10,000. COL Moores and Drs Bona and Schulman have reported that no potential con-fl icts of interest exist with any companies/organizations whose prod-ucts or services may be discussed in this article . Role of sponsors: The sponsors played no role in the develop-ment of these guidelines. Sponsoring organizations cannot recom-mend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Sci-ence Policy Committee are blinded to the funding sources. Fur-ther details on the Confl ict of Interest Policy are available online at http://chestnet.org. Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clin-ical Pharmacy, the American Society of Health-System Pharma-cists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis. Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content /141/2_suppl/e495S/suppl/DC1.
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© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
CHEST
1 © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http :// www . chestpubs . org / site / misc / reprints . xhtml ). DOI: 10.1378/chest.11-2303
Online Data Supplement
Treatment and Prevention of Heparin-Induced Thrombocytopenia
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Lori-Ann Linkins , MD ; Antonio L. Dans , MD ; COL Lisa K. Moores , MC, USA, FCCP ; Robert Bona , MD ; Bruce L. Davidson , MD, MPH, FCCP ; Sam Schulman , MD, PhD ; and Mark Crowther , MD
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
2© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2303
Tabl
e S1
—[S
ecti
ons
3.1,
3.2
.1, 4
.1, a
nd 4
.2]:
Met
hodo
logi
c Q
ual
ity
of C
ohor
t St
udi
es f
or T
reat
men
t of
HIT
Stud
y/Ye
arIn
terv
entio
n/C
ontr
olSt
udy
Des
ign
Inte
rven
tion/
Con
trol
Se
ttin
g Si
mila
rIn
terv
entio
n/C
ontr
ol
Tim
e F
ram
e Si
mila
rA
djus
tmen
tE
ffec
tivel
y B
linde
d A
sses
smen
t of O
utco
mes
Los
s to
F
ollo
w-u
pC
omm
ents
Gro
uzi e
t al 1 /2
010
Fon
da: 7
.5 m
g a C
ohor
t (hi
stor
ical
co
ntro
ls)
Iden
tical
Iden
tical
Non
ePN
Non
eA
ll pa
tient
s re
quir
ed
posi
tive
test
ing
for
HIT
ant
ibod
ies
L
ep: 0
.15
mg/
kg/h
Lob
o et
al 2 /2
008
Fon
da: 7
.5 m
g a C
ohor
t (hi
stor
ical
co
ntro
ls)
Clo
seSo
mew
hat
Non
ePN
Non
eA
ll pa
tient
s re
quir
ed
posi
tive
test
ing
for
HIT
ant
ibod
ies
L
ep o
r A
rg a
ccor
ding
to
FD
A la
belin
g
Lub
enow
et a
l 3 /200
6D
an: v
arie
d 1
VK
AC
ohor
t (hi
stor
ical
co
ntro
ls)
Very
Not
clo
seN
one
No
Non
eA
ll pa
tient
s re
quir
ed
posi
tive
test
ing
for
HIT
ant
ibod
ies
C
on: a
ncro
d 1
VK
A
Lub
enow
et a
l 4 /200
5L
ep: b
olus
0.4
mg/
kg b ;
0.15
mg/
kg C
on:
vari
ed (D
an, n
5 2
4;
phen
proc
oum
on,
n 5
21;
oth
er, n
5 3
0)
Coh
ort (
hist
oric
al
cont
rols
)Ve
ryN
ot c
lose
Non
eN
oN
one
All
patie
nts
requ
ired
po
sitiv
e te
stin
g fo
r H
IT a
ntib
odie
s
Lew
is e
t al 5 /2
003
Arg
: 2 m
g/kg
/min
c (n
o bo
lus)
Coh
ort (
hist
oric
al
cont
rols
)So
mew
hat
Not
clo
seN
one
No
Non
eH
IT a
ntib
ody
data
for
case
s no
t pro
vide
d
C
on: v
arie
d (t
ypic
ally
he
pari
n di
scon
tinua
tion
and
oral
ant
icoa
gula
tion)
Lew
is e
t al 6 /2
001
Arg
: 2 m
g/kg
/min
b (no
bol
us)
Coh
ort (
hist
oric
al
cont
rols
)Ve
ryN
ot c
lose
Non
eN
oN
one
65%
of c
ases
and
con
trol
s te
sted
pos
itive
for
HIT
an
tibod
ies
(rem
aind
er
nega
tive
or n
ot te
sted
)
C
on: v
arie
d (t
ypic
ally
di
scon
tinua
tion
of
hepa
rin
and
oral
an
ticoa
gula
tion)
aPT
T 5
activ
ated
par
tial t
hrom
bopl
astin
tim
e; A
rg 5
arga
trob
an; C
on 5
cont
rol;
Dan
5 d
anap
aroi
d; F
onda
5 fo
ndap
arin
ux; H
IT 5
hep
arin
-indu
ced
thro
mbo
cyto
peni
a; L
ep 5
lepi
rudi
n; P
N 5
pro
babl
y no
t; V
KA
5 vi
tam
in K
ant
agon
ist.
a Adj
uste
d ac
cord
ing
to w
eigh
t. b a
PTT
adj
uste
d to
1.5
-2.5
tim
es b
asel
ine
aPT
T (o
r th
e m
ean
labo
rato
ry n
orm
al r
ange
if th
e ba
selin
e aP
TT
una
vaila
ble)
. c a
PTT
adj
uste
d to
1.5
-3.0
tim
es b
asel
ine
aPT
T.
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Table S2 — [Section 3.2.1]: Methodologic Quality of Randomized Trials for Treatment of HITT
Study/Year Intervention/ControlRandomize Concealed Blinding
Unavailable for Follow-up, No of Total Analysis Comments
Chong et al 7 /2001 Danaparoid: bolus 2,400 units 1 200 units/h for 5 d
Certainly yes Patients: certainly no
Danaparoid: 0 of 24 Intention to treat
A 1:1 randomization was prestratifi ed for city and presence of mild or serious thrombosis; differences in number of patients allocated to the two groups occurred by chance
Caregivers: certainly no
Adjudicators: probably no
Data analysts: probably no
Dextran 70: 1-L infusion day 1, then 500 mL for 4 d
Dextran: 0 of 17
HITT 5 heparin-induced thrombocytopenia with thrombosis.
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S3
—[S
ecti
on 3
.1]:
Evi
denc
e P
rofi l
e fo
r A
rgat
rob
an f
or T
reat
men
t of
HIT
T: S
hou
ld P
atie
nts
Wit
h H
ITT
Rec
eive
Arg
atro
ban
Ove
r D
isco
ntin
uin
g H
epar
in
and/
or S
tart
ing
a V
KA
?
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
t, Ti
me
Fra
me
37 d
for
All
Out
com
es
No.
of
Part
icip
ants
(S
tudi
es)
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
e
With
D
isco
ntin
ue
Hep
arin
/ St
art V
KA
With
A
rgat
roba
n
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
Dis
cont
inue
H
epar
in/S
tart
V
KA
Ris
k D
iffer
ence
W
ith
Arg
atro
ban
(95%
CI)
Dea
th d
ue to
thro
mbo
sis
(cri
tical
out
com
e): a
s ju
dged
by
the
inve
stig
ator
s
419
(2 c
ohor
ts)
37 d
a Se
riou
s ri
sk
of b
ias
His
tori
cal
cont
rols
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
nSm
all n
umbe
r of
eve
nts
Und
etec
ted
Very
low
due
to
ris
k of
bi
as a
nd
impr
ecis
ion
7 of
46
(15.
2)7
of 3
73 (1
.9)
RR
, 0.1
2 (0
.05-
0.34
)15
2 de
aths
pe
r 1,
000
134
few
er
deat
hs p
er
1,00
0 (f
rom
10
0 fe
wer
to
145
few
er)
Lim
b am
puta
tion
(cri
tical
out
com
e)
419
(2 c
ohor
ts)
37 d
a Se
riou
s ri
sk
of b
ias
His
tori
cal
cont
rols
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssVe
ry s
erio
us
impr
ecis
ion
CI
incl
udes
im
port
ant
bene
fi t
and
harm
Und
etec
ted
Very
low
due
to
ris
k of
bi
as a
nd
impr
ecis
ion
5 of
46
(10.
9)51
of 3
73 (1
3.7)
RR
, 1.2
6 (0
.53-
2.99
)10
9 ampu
tatio
ns
per
1,00
0
28 m
ore
ampu
tatio
ns
per
1,00
0 (f
rom
51
few
er to
21
6 m
ore)
New
thro
mbo
sis
(cri
tical
out
com
e)
419
(2 c
ohor
ts)
37 d
a
Seri
ous
risk
of
bia
sH
isto
rica
l co
ntro
ls
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dM
oder
ate
due
to r
isk
of
bias
, but
w
ith la
rge
effe
ct
16 o
f 46
(34.
8)58
of 3
73 (1
5.5)
RR
, 0.4
5 (0
.28-
0.71
)34
8 th
rom
botic
ev
ents
per
1,
000
191
few
er
thro
mbo
tic
even
ts p
er
1,00
0 (f
rom
10
1 fe
wer
to
250
few
er)
(Con
tinu
ed)
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
5© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2303
Tabl
e S3
—C
onti
nued
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
t, Ti
me
Fra
me
37 d
for
All
Out
com
es
No.
of
Part
icip
ants
(S
tudi
es)
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
e
With
D
isco
ntin
ue
Hep
arin
/ St
art V
KA
With
A
rgat
roba
n
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
Dis
cont
inue
H
epar
in/S
tart
V
KA
Ris
k D
iffer
ence
W
ith
Arg
atro
ban
(95%
CI)
Maj
or b
leed
ing
(cri
tical
out
com
e): h
emog
lobi
n dr
op o
f � 2
0 g/
L o
r re
quir
emen
t for
� 2
uni
ts o
f PR
BC
or
ICH
or
blee
ding
into
a jo
int
419
(2 c
ohor
ts)
37 d
a
Seri
ous
risk
of
bia
sH
isto
rica
l co
ntro
ls
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssVe
ry s
erio
us
impr
ecis
ion
CI
incl
udes
im
port
ant
bene
fi t a
nd
harm
Und
etec
ted
Very
low
due
to
ris
k of
bi
as a
nd
impr
ecis
ion
1 of
46
(2.2
)30
of 3
73 (8
)R
R, 3
.70
(0.5
2-26
.5)
22 m
ajor
bl
eedi
ng
even
ts p
er
1,00
0
59 m
ore
maj
or
blee
ding
ev
ents
per
1,
000b (
from
10
few
er to
55
4 m
ore)
Bib
liogr
aphy
: War
kent
in T
E, G
rein
ache
r A
, Kos
ter
A, L
inco
ff A
M; A
mer
ican
Col
lege
of
Che
st P
hysi
cian
s. T
reat
men
t an
d pr
even
tion
of h
epar
in-in
duce
d th
rom
bocy
tope
nia:
Am
eric
an C
olle
ge o
f C
hest
Ph
ysic
ians
evi
denc
e-ba
sed
clin
ical
pra
ctic
e gu
idel
ines
(8th
Edi
tion)
. Che
st . 2
008;
133(
supp
l 6):3
40S-
380S
. IC
H 5
intr
acra
nial
hem
orrh
age;
PR
BC
5 p
acke
d R
BC
. See
Tab
le S
1 an
d S2
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a F
ollo
w-u
p w
as 3
0 d
past
ces
satio
n of
trea
tmen
t in
arga
trob
an p
atie
nts
and
37 d
from
bas
elin
e in
con
trol
pat
ient
s.
b The
re w
ere
thre
e fa
tal b
leed
ing
even
ts in
pat
ient
s w
ho r
ecei
ved
arga
trob
an (H
IT a
nd H
ITT
com
bine
d).
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
6© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2303
Tabl
e S4
—[S
ecti
on 3
.1]:
Evi
denc
e P
rofi l
e fo
r L
epir
udi
n fo
r T
reat
men
t of
HIT
T: S
hou
ld P
atie
nts
Wit
h H
ITT
Rec
eive
Lep
iru
din
Ove
r D
isco
ntin
uin
g H
epar
in
and/
or S
tart
ing
a V
KA
?
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
t, Ti
me
Fra
me
35 d
for
All
Out
com
es
No.
of
Part
icip
ants
(S
tudi
es)
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
e
With
D
isco
ntin
ue
Hep
arin
/Sta
rt
VK
AW
ith
Lep
irud
in
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k w
ith
Dis
cont
inue
H
epar
in/
Star
t VK
A
Ris
k D
iffer
ence
W
ith L
epir
udin
(9
5% C
I)
Lim
b am
puta
tion
(cri
tical
out
com
e)
289
(2 c
ohor
ts)
35 d
Seri
ous
risk
of
bia
sH
isto
rica
l co
ntro
ls
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssVe
ry s
erio
us
impr
ecis
ion
CI
incl
udes
im
port
ant
bene
fi t a
nd h
arm
Und
etec
ted
Very
low
due
to
ris
k of
bi
as a
nd
impr
ecis
ion
6 of
75
(8)
12 o
f 21
4 (5
.6)
RR
, 0.7
0 (0
.27-
1.8)
80 a
mpu
tatio
ns
per
1,00
024
few
er
ampu
tatio
ns
per
1,00
0 (f
rom
58
few
er to
64
mor
e)
New
thro
mbo
sis
(cri
tical
out
com
e)
289
(2 c
ohor
ts)
35 d
Seri
ous
risk
of
bia
sH
isto
rica
l co
ntro
ls
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dM
oder
ate
due
to r
isk
of b
ias,
but
w
ith la
rge
effe
ct
19 o
f 75
(25.
3)15
of
214
(7)
RR
, 0.2
8 (0
.15-
0.52
)25
3 th
rom
botic
ev
ents
pe
r 1,
000
182
few
er
thro
mbo
tic
even
ts p
er
1,00
0 a (fr
om
122
few
er to
21
5 fe
wer
)
Maj
or b
leed
ing
(cri
tical
out
com
e): f
atal
or
ICH
or
perm
anen
t dis
abili
ty o
r re
quir
emen
t for
� 2
uni
ts o
f PR
BC
289
(2 c
ohor
ts)
35 d
Seri
ous
risk
of
bia
sH
isto
rica
l co
ntro
ls
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssVe
ry s
erio
us
impr
ecis
ion
CI
incl
udes
ne
glig
ible
be
nefi t
and
im
port
ant h
arm
Und
etec
ted
Very
low
due
to
ris
k of
bi
as a
nd
impr
ecis
ion
5 of
75
(6.7
)33
of
214
(15.
4)R
R, 2
.31
(0.9
4-5.
71)
67 m
ajor
bl
eedi
ng
even
ts
per
1,00
0
87 m
ore
maj
or
blee
ding
eve
nts
per
1,00
0 b (f
rom
4 fe
wer
to
314
mor
e)
B
iblio
grap
hy: W
arke
ntin
TE
, Gre
inac
her
A, K
oste
r A
, Lin
coff
AM
; Am
eric
an C
olle
ge o
f C
hest
Phy
sici
ans.
Tre
atm
ent
and
prev
entio
n of
hep
arin
-indu
ced
thro
mbo
cyto
peni
a: A
mer
ican
Col
lege
of
Che
st
Phys
icia
ns E
vide
nce-
Bas
ed C
linic
al P
ract
ice
Gui
delin
es (8
th E
ditio
n). C
hest
. 200
8;13
3(6
supp
l):34
0S-3
80S.
See
Tab
le S
1, S
2, a
nd S
3 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a T
here
wer
e th
ree
deat
hs d
ue to
thro
mbo
sis
in p
atie
nts
who
rec
eive
d le
piru
din
(HIT
T a
nd H
IT c
ombi
ned)
. b T
here
wer
e fi v
e fa
tal b
leed
ing
even
ts in
pat
ient
s w
ho r
ecei
ved
lepi
rudi
n (H
IT a
nd H
ITT
com
bine
d).
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
7© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2303
Tabl
e S5
—[S
ecti
on 3
.4.1
]: S
tudi
es E
valu
atin
g In
itia
tion
of
VK
A i
n P
atie
nts
Wit
h H
IT
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Hur
stin
g et
al 8 /2
005
Seco
ndar
y an
alys
is
of p
rosp
ectiv
e hi
stor
ical
con
trol
led
tria
ls (A
rg 9
11 o
f 915
)
165
patie
nts
with
clin
ical
di
agno
sis
of H
IT a w
ho
rece
ived
arg
atro
ban
and
war
fari
n an
d co
mpl
eted
th
e st
udy
Arg
atro
ban
2 m
g/kg
/min
an
d w
arfa
rin
New
thro
mbo
sis
Am
puta
tion
Maj
or b
leed
ing b
Dea
th (a
ll-ca
use)
Dea
th d
ue to
thro
mbo
sis
Tim
e to
ther
apeu
tic
INR
with
war
fari
n m
onot
hera
pyR
equi
rem
ent f
or v
itam
in K
or
fres
h fr
ozen
pla
sma
to r
ever
se w
arfa
rin
The
rape
utic
IN
R 4
-24
h af
ter
arga
trob
an w
as
disc
ontin
ued
Dur
ing
the
peri
od
of c
othe
rapy
with
ar
gatr
oban
and
w
arfa
rin
until
the
cale
ndar
day
aft
er
disc
ontin
uatio
n of
ar
gatr
oban
New
thro
mbo
sis:
16 o
f 165
(10%
) c A
mpu
tatio
n: 2
of 1
65 (1
%)
Maj
or b
leed
ing:
0
Dea
th: 1
D
eath
due
to th
rom
bosi
s: 0
Pl
atel
et c
ount
at t
ime
of
w
arfa
rin
initi
atio
n:
132
(31-
339)
3 1
0 9 /L
War
fari
n, in
itial
dos
e, m
g:
5
(1-1
0)
Max
imum
IN
R:
5.
3 (2
.4-1
6)
Veno
us g
angr
ene:
not
repo
rted
Wal
lis e
t al 9 /1
999
Cas
e se
ries
, re
tros
pect
ive,
co
nsec
utiv
e,
sing
le c
ente
r
114
patie
nts
with
HIT
co
nfi r
med
with
PAT
War
fari
n (s
tart
ed p
rior
to
or
afte
r H
IT
diag
nosi
s) �
alte
rnat
ive
agen
ts d
No
war
fari
n (s
tart
ed p
rior
to
or
afte
r H
IT
diag
nosi
s) �
alte
rnat
ive
agen
ts d
Thr
ombo
sis
Veno
us g
angr
ene
Unt
il di
scha
rge
or d
eath
New
thro
mbo
sis:
War
fari
n 23
of
51
e (45
%)
N
o w
arfa
rin
20 o
f 63
(3
2%)
R
R: 1
.42
(0.8
9-2.
28),
P
5 .2
1 Ve
nous
gan
gren
e:
W
arfa
rin
0 of
51
N
o w
arfa
rin
0 of
63
Dea
th:
W
arfa
rin
4 of
51
(8%
)
No
war
fari
n 27
of
63
(43%
) Pl
atel
et c
ount
at t
ime
of
war
fari
n in
itiat
ion:
97
� 1
3 m
L
Max
imum
IN
R: 7
.5 �
1.4
M
ean
daily
dos
e of
war
fari
n,
m
g: 3
.5 �
0.5
Plat
elet
nad
ir a
nd
reco
very
War
fari
n tim
ing
and
dosi
ngD
eath
(Con
tinu
ed)
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
8© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2303
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
War
kent
in e
t al 10
/199
7
Cas
e se
ries
re
tros
pect
ive,
co
nsec
utiv
e,
mul
ticen
tre
158
patie
nts
with
SR
A-c
onfi r
med
HIT
: 8
patie
nts
with
HIT
and
D
VT
and
ven
ous
gang
rene
58 p
atie
nts
with
HIT
and
DV
T
with
out v
enou
s ga
ngre
ne
War
fari
nPl
atel
et c
ount
nad
irM
axim
um I
NR
dur
ing
isch
emia
War
fari
n do
se in
fi r
st 5
dD
eath
Not
spe
cifi e
dA
mpu
tatio
n: C
ases
: 2 li
mb,
2 di
stal
por
tions
of f
eet
(50%
) D
eath
: Cas
es: 2
of 8
(25%
) Pl
atel
et c
ount
nad
ir
( 3 1
0 9 /L):
C
ases
: 35.
5 (1
5-69
)
Con
trol
s: 5
7.5
(13-
146)
M
axim
um I
NR
:
Cas
es: 5
.8 (3
.8-9
.4)
C
ontr
ols:
3.1
(1.4
-6.4
) W
arfa
rin
dose
(mg)
in
fi r
st 5
d:
C
ases
: 33.
8 (1
5-55
)
Con
trol
s: 2
7.5
(10-
62)
INR
5 in
tern
atio
nal n
orm
aliz
ed r
atio
; PAT
5 p
late
let a
ggre
gom
etry
test
; SR
A 5
sero
toni
n re
leas
e as
say.
See
Tab
le S
1 an
d S3
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a G
reat
er th
an 5
0% d
ecre
ase
in p
late
lets
or
� 1
00 3
10 9 /L
and
thro
mbo
embo
lic c
ompl
icat
ions
; lab
orat
ory
confi
rm
atio
n of
HIT
was
not
req
uire
d.
b Defi
ned
as
over
t with
tran
sfus
ion
of �
2 u
nits
PR
BC
, IC
H, r
etro
peri
tone
al b
leed
ing,
or
blee
ding
into
a p
rost
hetic
join
t. c S
even
new
thro
mbo
tic e
vent
s oc
curr
ed o
n th
e da
y af
ter
arga
trob
an d
isco
ntin
uatio
n.
d 28%
of p
atie
nts
rece
ived
add
ition
al tr
eatm
ent i
n th
e w
arfa
rin
grou
p an
d 13
% r
ecei
ved
addi
tiona
l tre
atm
ent i
n th
e no
war
fari
n gr
oup
(pla
smap
here
sis,
dex
tran
, g -g
lobu
lin, l
ow m
olec
ular
wei
ght h
epar
in,
hiru
din,
Hir
ulog
, dan
apar
oid)
. e S
ixte
en p
atie
nts
wer
e re
ceiv
ing
war
fari
n fo
r he
pari
n-re
late
d th
rom
botic
eve
nts.
Tabl
e S5
—C
onti
nued
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
9© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2303
Tabl
e S6
—[S
ecti
on 4
.1]:
Evi
denc
e P
rofi l
e fo
r A
rgat
rob
an f
or T
reat
men
t of
Iso
late
d H
IT: S
hou
ld P
atie
nts
Wit
h Is
olat
ed H
IT R
ecei
ve A
rgat
rob
an O
ver
Dis
cont
inu
ing
Hep
arin
and
/or
Star
ting
a V
KA
?
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
t, Ti
me
Fra
me
37 d
for
All
Out
com
es
No.
of
Part
icip
ants
(S
tudi
es)
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
e
With
D
isco
ntin
ue
Hep
arin
/ St
art V
KA
With
A
rgat
roba
n
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
Dis
cont
inue
H
epar
in/
Star
t VK
A
Ris
k D
iffer
ence
W
ith A
rgat
roba
n (9
5% C
I)
Dea
th d
ue to
thro
mbo
sis
(cri
tical
out
com
e): a
s ju
dged
by
the
inve
stig
ator
s
488
(2 c
ohor
ts)
37 d
a Se
riou
s ri
sk
of b
ias
His
tori
cal
cont
rols
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
nSm
all
num
ber
of e
vent
s
Und
etec
ted
Very
low
due
to
ris
k of
bi
as a
nd
impr
ecis
ion
6 of
139
b (4.
3)1
of 3
49 (0
.3)
RR
, 0.0
7 (0
.01-
0.55
)43
dea
ths
per
1,00
040
few
er d
eath
s pe
r 1,
000
(fro
m 1
9 fe
wer
to
43 fe
wer
)
Lim
b am
puta
tion
(cri
tical
out
com
e)
488
(2 c
ohor
ts)
37 d
a Se
riou
s ri
sk
of b
ias
His
tori
cal
cont
rols
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssVe
ry s
erio
us
impr
ecis
ion
CI
incl
udes
im
port
ant
bene
fi t
and
harm
Und
etec
ted
Very
low
due
to
ris
k of
bi
as a
nd
impr
ecis
ion
4 of
139
b (2.
9)11
of 3
49 (3
.2)
RR
, 1.1
0 (0
.35-
3.38
)29
am
puta
tions
pe
r 1,
000
3 m
ore
ampu
tatio
ns
per
1,00
0 (f
rom
19
few
er to
68
mor
e)
New
thro
mbo
sis
(cri
tical
out
com
e)
488
(2 c
ohor
ts)
37 d
a Se
riou
s ri
sk
of b
ias
His
tori
cal
cont
rols
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dM
oder
ate
due
to
risk
of b
ias,
bu
t with
la
rge
effe
ct
33 o
f 139
b (2
3.7)
24 o
f 349
(6.9
)R
R, 0
.29
(0.1
8-0.
47)
237
thro
mbo
tic
even
ts
per
1,00
0
169
few
er
thro
mbo
tic
even
ts p
er
1,00
0 (f
rom
12
6 fe
wer
to
195
few
er)
(Con
tinu
ed)
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
10© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2303
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
t, Ti
me
Fra
me
37 d
for
All
Out
com
es
No.
of
Part
icip
ants
(S
tudi
es)
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
e
With
D
isco
ntin
ue
Hep
arin
/ St
art V
KA
With
A
rgat
roba
n
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
Dis
cont
inue
H
epar
in/
Star
t VK
A
Ris
k D
iffer
ence
W
ith A
rgat
roba
n (9
5% C
I)
Maj
or b
leed
ing
(cri
tical
out
com
e): h
emog
lobi
n dr
op o
f � 2
0 g/
L o
r re
quir
emen
t for
� 2
uni
ts o
f PR
BC
or
ICH
or
blee
ding
into
a jo
int
488
(2 c
ohor
ts)
37 d
a Se
riou
s ri
sk
of b
ias
His
tori
cal
cont
rols
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssVe
ry s
erio
us
impr
ecis
ion
CI
incl
udes
im
port
ant
bene
fi t a
nd
harm
Und
etec
ted
Very
low
due
to
ris
k of
bi
as a
nd
impr
ecis
ion
12 o
f 139
b (8.
6)15
of 3
49 (4
.3)
RR
, 0.5
0 (0
.24-
1.04
)86
maj
or
blee
ding
ev
ents
pe
r 1,
000
43 fe
wer
maj
or
blee
ding
ev
ents
per
1,
000 c (
from
66
few
er to
3
mor
e)
Bib
liogr
aphy
: War
kent
in T
E, G
rein
ache
r A
, Kos
ter
A, L
inco
ff A
M; A
mer
ican
Col
lege
of
Che
st P
hysi
cian
s. T
reat
men
t an
d pr
even
tion
of h
epar
in-in
duce
d th
rom
bocy
tope
nia:
Am
eric
an C
olle
ge o
f C
hest
Ph
ysic
ians
Evi
denc
e-B
ased
Clin
ical
Pra
ctic
e G
uide
lines
(8th
Edi
tion)
. Che
st . 2
008;
133(
6 su
ppl):
340S
-380
S. S
ee T
able
S1
and
S3 fo
r ex
pans
ion
of a
bbre
viat
ions
. a F
ollo
w-u
p w
as 3
0 d
past
ces
satio
n of
trea
tmen
t in
arga
trob
an p
atie
nts
and
37 d
from
bas
elin
e in
con
trol
pat
ient
s.
b Diff
ers
from
AC
CP
2008
gui
delin
es in
that
eig
ht p
atie
nts
who
had
a h
isto
ry o
f HIT
onl
y w
ere
excl
uded
. c T
here
wer
e th
ree
fata
l ble
edin
g ev
ents
in p
atie
nts
who
rec
eive
d ar
gatr
oban
(HIT
and
HIT
T c
ombi
ned)
.
Tabl
e S6
—C
onti
nued
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
11© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2303
Tabl
e S7
—[S
ecti
on 4
.1]:
Evi
denc
e P
rofi l
e fo
r L
epir
udi
n fo
r T
reat
men
t of
Iso
late
d H
IT: S
hou
ld P
atie
nts
Wit
h Is
olat
ed H
IT R
ecei
ve L
epir
udi
n O
ver
Dis
cont
inu
ing
Hep
arin
and
/or
Star
ting
a V
KA
?
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
t, Ti
me
Fra
me
35 d
for
All
Out
com
es
No.
of
Part
icip
ants
(S
tudi
es)
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
e
With
D
isco
ntin
ue
Hep
arin
/ St
art V
KA
With
L
epir
udin
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
Dis
cont
inue
H
epar
in/
Star
t VK
A
Ris
k D
iffer
ence
W
ith L
epir
udin
(9
5% C
I)
Lim
b am
puta
tion
(cri
tical
out
com
e)
138
(2 c
ohor
ts)
35 d
Seri
ous
risk
of
bia
sH
isto
rica
l co
ntro
ls
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssVe
ry s
erio
us
impr
ecis
ion
CI
incl
udes
ne
glig
ible
be
nefi t
and
im
port
ant
harm
Und
etec
ted
Very
low
due
to
ris
k of
bi
as a
nd
impr
ecis
ion
0 of
47
(0)
3 of
91
(3.3
)R
R, 3
.65
(0.1
9-69
.27)
0 am
puta
tions
pe
r 1,
000
0 m
ore
ampu
tatio
ns
per
1,00
0 (f
rom
58
few
er to
64
mor
e)
New
thro
mbo
sis
(cri
tical
out
com
e)
138
(2 c
ohor
ts)
35 d
Seri
ous
risk
of
bia
sH
isto
rica
l co
ntro
ls
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
nSm
all n
umbe
r of
eve
nts
Und
etec
ted
Low
due
to
risk
of b
ias
7 of
47
(14.
9)4
of 9
1 (4
.4)
RR
, 0.3
0 (0
.09-
0.96
)14
9 th
rom
botic
ev
ents
pe
r 1,
000
104
few
er
thro
mbo
tic
even
ts p
er 1
,000
a (f
rom
6 fe
wer
to
136
few
er)
Maj
or b
leed
ing
(cri
tical
out
com
e): f
atal
or
ICH
or
perm
anen
t dis
abili
ty o
r re
quir
emen
t for
� 2
uni
ts o
f PR
BC
138
(2 c
ohor
ts)
35 d
Seri
ous
risk
of
bia
sH
isto
rica
l co
ntro
ls
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssVe
ry s
erio
us
impr
ecis
ion
CI
incl
udes
im
port
ant
bene
fi t a
nd
harm
Und
etec
ted
Very
low
due
to
ris
k of
bi
as a
nd
impr
ecis
ion
4 of
47
(8.5
)13
of 9
1 (1
4.3)
RR
, 1.6
8 (0
.58-
4.86
)85
maj
or
blee
ding
ev
ents
pe
r 1,
000
58 m
ore
maj
or
blee
ding
eve
nts
per
1,00
0 b (fr
om
36 fe
wer
to
329
mor
e)
Bib
liogr
aphy
: War
kent
in T
E, G
rein
ache
r A
, Kos
ter
A, L
inco
ff A
M; A
mer
ican
Col
lege
of
Che
st P
hysi
cian
s. T
reat
men
t an
d pr
even
tion
of h
epar
in-in
duce
d th
rom
bocy
tope
nia:
Am
eric
an C
olle
ge o
f C
hest
Ph
ysic
ians
evi
denc
e-ba
sed
clin
ical
pra
ctic
e gu
idel
ines
(8th
Edi
tion)
. Che
st . 2
008;
133(
supp
l 6):3
40S-
380S
. See
Tab
le S
1 an
d S3
for
expa
nsio
n of
abb
revi
atio
ns.
a The
re w
ere
thre
e de
aths
due
to th
rom
bosi
s in
pat
ient
s w
ho r
ecei
ved
lepi
rudi
n (H
ITT
and
HIT
com
bine
d).
b The
re w
ere
fi ve
fata
l ble
edin
g ev
ents
in p
atie
nts
who
rec
eive
d le
piru
din
(HIT
and
HIT
T c
ombi
ned)
.
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
12© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2303
Tabl
e S8
—[S
ecti
on 5
.1.1
]: S
tudi
es E
valu
atin
g N
onhe
pari
n A
ntic
oagu
lant
s in
Pat
ient
s W
itho
ut
HIT
Who
Req
uir
e U
rgen
t C
ardi
ac S
urg
ery
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Dyk
e et
al 11
/200
6
RC
T, m
ultic
ente
r, op
en-la
bel
150
patie
nts
unde
rgoi
ng
CPB
Biv
alir
udin
1 m
g/kg
bo
lus
then
2.
5 m
g/kg
/hA
CT
2.5
tim
es
base
line
orH
epar
in w
ith
prot
amin
e re
vers
al
as p
er in
stitu
tion
prac
tice
Proc
edur
al s
ucce
ss a
Maj
or b
leed
ing:
IC
H,
retr
oper
itone
al, o
r G
I bl
eedi
ng, o
r pe
rsis
tent
po
stop
erat
ive
hem
orrh
age
requ
irin
g su
rgic
al r
e-ex
plor
atio
n
Day
7 o
r da
y of
dis
char
ge,
whi
chev
er c
ame
fi rst
, fo
r pr
oced
ural
suc
cess
an
d m
ajor
ble
edin
g;
proc
edur
al s
ucce
ss a
t da
y 30
and
12
wk
At d
ay 7
Pr
oced
ural
suc
cess
: bi
valir
udin
93
of 9
8 (9
5%);
hepa
rin
50
of 5
2 (9
6%)
MI:
biv
alir
udin
6 o
f 98
(6.1
%);
hepa
rin
6 of
52
(11.
5%)
Maj
or b
leed
ing:
biv
alir
udin
6
of 9
8 (6
%);
hepa
rin
1 of
52
(2%
) A
t day
30
CVA
: biv
alir
udin
1 o
f 98
(1%
); he
pari
n 1
of
52 (2
%)
Dea
th: b
ival
irud
in 3
of
98 (3
%);
hepa
rin
1 of
52
(2%
)
Smed
ira
et a
l 12 /2
006
RC
T, m
ultic
ente
r, op
en-la
bel
157
patie
nts
unde
rgoi
ng
OPC
AB
Biv
alir
udin
0.7
5 m
g/kg
bo
lus
then
1.
75 m
g/kg
/h o
rH
epar
in w
eigh
t-ad
just
ed
to r
each
AC
T .
300
s
with
pro
tam
ine
reve
rsal
Proc
edur
al s
ucce
ss a
Maj
or b
leed
ing:
IC
H,
intr
aocu
lar,
retr
oper
itone
al
or G
I bl
eedi
ng;
bloo
d lo
ss; t
rans
fusi
ons
Day
7 o
r da
y of
dis
char
ge,
whi
chev
er c
ame
fi rst
, fo
r pr
oced
ural
suc
cess
an
d m
ajor
ble
edin
g;
proc
edur
al s
ucce
ss a
t da
y 30
and
12
wk
At d
ay 7
Pr
oced
ural
suc
cess
: bi
valir
udin
97
of 1
01
(96%
); he
pari
n 53
of
56
(95%
) M
I: b
ival
irud
in 2
of 1
01
(2%
); he
pari
n 0
of 5
6 C
VA: b
ival
irud
in 0
of 1
01;
hepa
rin
2 of
56
(4%
) M
ajor
ble
edin
g: b
ival
irud
in
8 of
101
(8%
); he
pari
n 3
of 5
6 (5
%)
Dea
th: b
ival
irud
in 1
of
101
(1%
); he
pari
n 1
of 5
6 (2
5%)
(Con
tinu
ed)
© 2012 American College of Chest Physicians at McGill University Libraries on February 27, 2012chestjournal.chestpubs.orgDownloaded from
13© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2303
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Rie
ss e
t al 13
/200
7R
CT,
mul
ticen
ter,
open
-labe
l20
pat
ient
s un
derg
oing
C
PB
r-H
irud
in 0
.25
mg/
kg b
olus
th
en a
dditi
onal
5-m
g bo
luse
s as
nee
ded
to k
eep
plas
ma
leve
ls .
4 m
g/m
L
usin
g E
CT
mon
itori
ng o
r
Thr
ombu
s fo
rmat
ion
in
hear
t-lu
ng m
achi
ne;
peri
oper
ativ
e bl
ood
loss
; maj
or b
leed
ing
(not
defi
ned
); an
y ad
vers
e ev
ent
3 d
afte
r en
d of
stu
dy
med
icat
ion
Thr
ombo
embo
lic e
vent
s:
r-hi
rudi
n 1
PE o
f 10
(1%
); H
epar
in 0
of 1
0
H
epar
in 4
00 I
nter
natio
nal
Uni
ts/k
g bo
lus
then
add
ition
al
5,00
0-In
tern
atio
nal U
nits
bo
luse
s as
nee
ded
to k
eep
AC
T .
400
s; p
rota
min
e re
vers
al
Dea
ths:
0
Car
rier
et a
l 14 /2
003
RC
T, s
ingl
e ce
nter
, do
uble
-blin
d71
pat
ient
s un
derg
oing
O
PCA
B
Dan
apar
oid
40 u
nit/k
g bo
lus
Post
oper
ativ
e bl
ood
loss
; tr
ansf
usio
ns; a
nti-X
a le
vel;
trop
onin
T le
vel
Not
spe
cifi e
dM
I: d
anap
aroi
d 1
of
34 (3
%);
hepa
rin
1 of
37
(3%
)
H
epar
in 1
mg/
kg b
olus
; pr
otam
ine
reve
rsal
Reo
pera
tion
for
blee
ding
: da
napa
roid
1 o
f 34
(3%
); he
pari
n 0
D
eath
s: 0
AC
T 5
activ
ated
clo
ttin
g tim
e; C
PB 5
card
iopu
lmon
ary
bypa
ss;
CVA
5 ce
rebr
ovas
cula
r ac
cide
nt;
EC
T 5
eca
rin
clot
ting
time;
MI 5
Q-w
ave
myo
card
ial
infa
rctio
n; O
PCA
B 5
off
-pum
p co
rona
ry a
rter
y by
pass
; PE
5 p
ulm
onar
y em
bolis
m; R
CT
5 ra
ndom
ized
con
trol
led
tria
l. Se
e Ta
ble
S1 le
gend
for
expa
nsio
n of
oth
er a
bbre
viat
ion.
a D
efi n
ed a
s ab
senc
e of
dea
th, M
I, r
epea
t ope
ratio
n fo
r co
rona
ry r
evas
cula
riza
tion,
or
stro
ke.
Tabl
e S8
—C
onti
nued
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Tabl
e S9
—[S
ecti
on 5
.2]:
Stu
dies
Eva
luat
ing
Non
hepa
rin
Ant
icoa
gula
nts
Du
ring
PC
I in
Pat
ient
s W
itho
ut
HIT
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Lee
et a
l 15 /2
010
Met
a-an
alys
is o
f pat
ient
s w
ho
unde
rwen
t PC
I in
AC
UIT
Y,
HO
RIZ
ON
S-A
MI,
CA
CH
ET,
PR
OT
EC
T-T
IMI
30,
RE
PLA
CE
-2 r
ando
miz
ed
cont
rolle
d tr
ials
19,7
72 p
atie
nts
who
un
derw
ent P
CI
Diff
eren
t pro
toco
ls
acro
ss tr
ials
:B
ival
irud
in 1
pro
visi
onal
GP
or Hep
arin
/eno
xapa
rin
alon
eH
epar
in/e
noxa
pari
n 1
GP
Effi
cacy
out
com
e: c
ompo
site
of
dea
th, M
I, a
nd u
rgen
t re
vasc
ular
izat
ion
Vari
ed a
ccor
ding
to
indi
vidu
al tr
ials
fr
om 7
d-3
0 d
Effi
cacy
out
com
e:
bi
valir
udin
vs
Hep
1 G
P
OR
, 1.0
7 (0
.96-
1.19
)
MI:
biv
alir
udin
1.2
% H
ep 1
GP
1.3%
OR
, 0.9
3 (0
.72-
1.21
) M
ajor
ble
edin
g: b
ival
irud
in
vs
Hep
1 G
P
OR
, 0.5
5 (0
.44-
0.69
)
M
ajor
ble
edin
g: b
leed
ing
asso
ciat
ed w
ith H
b dr
op .
5 g
/dL
or .
15%
de
crea
se in
hem
atoc
rit,
ICH
, or
card
iac
tam
pona
de
Jang
et a
l 16 /2
004
Coh
ort w
ith c
oncu
rren
t co
ntro
ls, m
ultic
ente
r, pr
ospe
ctiv
e
152
patie
nts
unde
rgoi
ng P
CI
Part
1: a
rgat
roba
n 25
0 m
g/kg
bo
lus
follo
wed
by
15 m
g/kg
/min
(A
CT
275
-325
s)
or
Effi
cacy
out
com
e: c
ompo
site
of
dea
th, Q
-wav
e M
I, a
nd
urge
nt r
evas
cula
riza
tion
Effi
cacy
out
com
e:
30 d
Effi
cacy
out
com
e: p
art 1
,
3 of
101
(3%
); pa
rt 2
, 1
of 5
1 (2
%)
Part
2: a
rgat
roba
n 30
0 m
g/kg
bo
lus
follo
wed
by
15 m
g/kg
/min
(A
CT
275
-325
s)
Ang
iogr
aphi
c su
cces
s:
resi
dual
ste
nosi
s , 5
0%
Proc
edur
al s
ucce
ss:
angi
ogra
phic
suc
cess
w
ithou
t dea
th, M
I, o
r ur
gent
rev
ascu
lari
zatio
n
Maj
or b
leed
ing:
7 d
or
at d
isch
arge
, w
hich
ever
occ
urre
d fi r
st
Ang
iogr
aphi
c su
cces
s: 1
00%
of p
atie
nts
Proc
edur
al s
ucce
ss: p
art 1
,
98 o
f 101
(97%
); pa
rt 2
, 50
of 5
1 (9
8%)
an
dM
ajor
ble
edin
g: I
CH
or
Hb
drop
. 5
g/d
LM
I: p
art 1
, 3 o
f 101
(3%
);
part
2, 1
of 5
1 (2
%)
A
bcix
imab
(n 5
150
) 0.2
5 m
g/kg
bo
lus
then
0.1
25 m
g/kg
/min
3 1
2 h
or
Maj
or b
leed
ing:
par
t 1, 2
of
10
1 (2
%);
part
2, 0
of 5
1 (0
)
Ept
ifi ba
tide
(n 5
2) d
oubl
e-bo
lus
Dea
th: 0
18
0 m
g/kg
/min
then
1.
5 m
g/kg
/min
3 1
2 h
L
ost t
o fo
llow
-up:
3 a
t 30
d
GP
5 g
lyco
prot
ein
IIb/
IIIa
inhi
bito
rs; H
b 5
hem
oglo
bin;
PC
I 5 p
ercu
tane
ous
coro
nary
inte
rven
tions
. See
Tab
le S
1 an
d S8
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
.
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DOI 10.1378/chest.11-2303 2012;141; e495S-e530SChest
Davidson, Sam Schulman and Mark CrowtherLori-Ann Linkins, Antonio L. Dans, Lisa K. Moores, Robert Bona, Bruce L.
Practice GuidelinesAmerican College of Chest Physicians Evidence-Based ClinicalAntithrombotic Therapy and Prevention of Thrombosis, 9th ed:
Treatment and Prevention of Heparin-Induced Thrombocytopenia :
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