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342 Chapter 38/Congenital and Acquired Hypercoagulable Syndromes
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after giving a standardized methionine-loading test. In
patients who have been given the loading dose of methionine, hyperhomocysteinemia is present if the level of homocysteine is two standard deviations above the mean.
In patients with hyperhomocysteinemia, folate, B6 and/or
B12 can be given with normalization of homocysteine levels
after several weeks of therapy. Whether or not this treatment
has any affect on the prothombotic effects of hyperhomocysteinemia remains to be proven.
19
ACQUIRED HYPERCOAGULABLE
DISORDERS
There exist far more known causes of acquired hypercoagulable disorders than inherited disorders. Additionally,
several of the congenital hypercoagulable states may be seen
as acquired states due to a change in the production or consumption of various factors. Many of the common causes of
acquired hypercoagulable disorders will be discussed.
Heparin-induced Thrombocytopenia (HIT)
and Heparin-induced Thrombocytopenia and
Thrombosis Syndrome (HITTS)
Approximately 2 to 3% of patients who undergo heparin
therapy will develop HIT or HITTS. Patients with HIT will
have thrombocytopenia (characterized by a platelet count
less than 100,000/mm3 or a decrease in the baseline count
by more than 30%), will be resistant to anticoagulation with
heparin, and may develop arterial or venous thromboses.
Two types of HIT exist. The fi rst type is not associated
with an immune mediated response and typically is seen in
the fi rst few days after initiation of heparin therapy. Typically, platelet levels do not fall below 100,000/mm3. Type II
is immune-mediated with patients producing IgG antibodies
against complexes of heparin and platelet factor 4. Antibody
formation usually occurs between the fi fth and tenth day
after the fi rst heparin exposure. The formation of these
immune complexes creates a hypercoagulable state by activating platelets and the endothelium.
Antibodies may develop against any form of heparin and
the formation of antibodies is independent of the age or sex
of the patient, the route of administration of heparin, or the
amount of heparin administered. Clinically, a patient will
have a declining platelet count, may have an increasing
resistance to anticoagulation therapy with heparin, and may
develop a new thrombosis. Laboratory testing may be performed, which includes testing for antibodies to heparin.1
Functional assays to detect platelet aggregation or activation
in the presence of heparin-associated antibodies are well
established. Enzyme-linked immunosorbent assays (ELISA)
are readily available, but there is up to 40% discordance in
8,20
the results of these antigenic assays, when compared with
the functional platelet aggregation tests. The ELISA may
detect IgM and IgA varieties, whereas platelet aggregation
assays detect only the IgG antibodies.
The treatment of HIT includes the prompt discontinuation of heparin or low-molecular-weight heparin, and the
administration of alternative anticoagulants such as recombinant hirudin or argatroban (both direct thrombin inhibitors). Danaparoid (a low-molecular-weight heparinoid) has
been used in the past as an alternative anticoagulant in
patients with HIT. However, danaparoid production was discontinued in 2002 due to a shortage in the drug substance.
Fondaparinux (a pentasaccharide that inactivates factor Xa
via an antithrombin-dependent mechanism) has had recent
success as another alternative anticoagulant. As with hirudin
and argatroban, there are no reliable agents that can reverse
the anticoagulant effect of fondaparinux. Hirudin and
fondaparinux are metabolized primarily via renal excretion,
whereas argatroban is metabolized primarily by the liver.
Patients with heparin-induced thrombocytopenia are at
high risk for the development of subsequent thromboses,
and the discontinuation of heparin alone is usually not suffi cient. Warfarin may be used for prolonged anticoagulation
in patients with acute thromboses, but its initiation should
be delayed until the platelet count has substantially recovered. In addition, warfarin therapy should overlap with the
administration of a direct thrombin inhibitor until the platelet count normalizes.
Lupus Anticoagulant/Antiphospholipid
Antibody Syndrome
The term antiphospholipid syndrome was developed to
describe the clinical manifestations of a hypercoagulable
state associated with antiphospholipid antibodies. The
most commonly identifi ed antiphospholipid antibodies are
lupus anticoagulant, anti-cardiolipin antibody, and anti-β2glycoprotein I antibodies.
This syndrome is divided into primary and secondary
syndromes. The primary syndrome occurs in patients without
associated autoimmune disorders and the secondary syndromes occur in patients with systemic lupus erythematosus
and/or other autoimmune disorders. The procoagulant effects
of the antiphospholipid antibodies leading to thrombosis
include inhibition of the activated protein C pathway, inhibition of antithrombin activity, inhibition of anticoagulant
activity of β
-glycoprotein I, inhibition of fi brinolysis,
2
potentiation of platelet activation, and enhanced platelet
activation, among others.
Antiphospholipid antibodies are found in 1 to 5% of the
population and their prevalence increases with age. Among
patients with SLE, the prevalence of antiphospholipid antibodies is much higher, with 12 to 30% having anticardiolipin antibodies and 15 to 34% having lupus anticoagulant
21
8,21
Acquired Hypercoagulable Disorders 343
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TABLE 38.3 Criteria for the Classifi cation of the
Antiphospholipid Syndrome
International consensus statement on preliminary criteria for the
classifi cation of the antiphospholipid syndrome
Clinical Criteria:
Vascular thrombosis: 1 or more clinical episodes of arterial, venous, or
small vessel thrombosis, occurring within any tissue or organ.
Complications of Pregnancy:
1 or more unexplained deaths of morphologically normal fetuses at or
after the 10
1 or more premature births of morphologically normal neonates at or
before the 34th week of gestation; or
3 or more unexplained consecutive spontaneous abortions before the
10th week of gestation.
Laboratory Criteria:
Anticardiolipin antibodies
Anticardiolipin IgG or IgM antibodies present at moderate or high
levels in the blood on 2 or more occasions at least 6 weeks apart.
Lupus anticoagulant antibodies
Lupus anticoagulant antibodies detected in the blood on two or more
occasions at least six weeks apart.
th
week of gestation; or
22
antibodies. In patients with SLE and an antiphospholipid
antibody, 50 to 70% may develop the antiphospholipid syndrome.1 In order for the diagnosis of antiphospholipid syndrome to be made, the patient must meet the criteria of the
International Consensus Statement. A defi nitive diagnosis
may be made if the patient has at least one of the clinical
criteria and one of the laboratory criteria. The Consensus
Statement is defi ned in Table 38.3.
Clinically, the most common manifestation of the
antiphospholipid syndrome is deep venous thrombosis of the
legs. Arterial thrombosis also may be seen but less often than
venous thrombosis. Laboratory tests to detect the antiphospholipid antibodies include the activated partial thromboplastin time (aPTT), performed with and without exogenous
normal plasma to detect the presence of an inhibitor. Other
tests include the kaolin clotting time, and dilute Russell’s
viper venom time (dRVVT). ELISA tests are performed to
detect anticardiolipin antibodies and anti-β
antibodies.
21
-glycoprotein I
2
Aspirin and hydroxychloroquine have been used in
subsets of patients with the antiphospholipid syndrome for
prophylaxis against thrombotic events. The treatment of
established venous thromboembolism in these patients consists of acute heparinization and longer-term (possibly life
long) vitamin K antagonists. The optimal intensity of warfarin anticoagulation (INR 2.0–2.9 versus 3.0–3.9) has not
been determined.
21
Warfarin-induced Skin Necrosis
This disorder is the most severe nonhemorrhagic complication of oral anticoagulation. Although rare, it seems to
show a predilection for perimenopausal obese women who
are being anticoagulated. Venules and capillaries within the
subcutaneous fat and overlying skin thrombose, leading to
necrosis. This typically is seen in the subcutaneous fat of the
breasts, thighs, buttocks, and legs. Clinically, the patient
may initially have paresthesias, which are then followed by
painful, erythematous lesions. When hemorrhagic bullae are
present, this is indicative of full thickness skin necrosis.
The pathogenesis for this process is the depletion of
protein C prior to the other vitamin K-dependent coagulation
factors. As the half-life of protein C is only eight hours, its
rapid depletion causes a transient hypercoagulable state until
the rest of the vitamin K-dependent factors also are reduced
to levels that produce anticoagulation.
The primary treatment is prevention with heparin or lowmolecular-weight heparin anticoagulation for the fi rst 48 to
72 hours of anticoagulation with warfarin. If skin necrosis
develops, warfarin needs to be discontinued and anticoagulation may continue with heparin or a direct thrombin
inhibitor.
8
Surgery/Trauma
The risk of thrombosis is dependent on the type of surgery
and the presence of additional risk factors. This risk may
persist for up to several months after surgery. Patients who
are at particularly high risk include those who undergo hip
fracture surgery, hip or knee arthroplasty, neurosurgical procedures, and patients with major trauma. Injury to tissues
and vessels during the procedure may enhance thrombogen-
8,23
esis.
Operative dissection, thermal injuries, and soft tissue
trauma activate the coagulation cascade by inducing tissue
factor release, thereby increasing the thrombogenic risk.
With a major traumatic injury, risk for venous thrombosis
is highest in patients with spinal injuries, pelvic fractures,
and lower extremity fractures. The risk of thrombosis also
increases with greater injury severity. In part, this may be
due to the accompanying systemic infl ammatory response
(another prothrombotic state, covered later).
Pregnancy
During pregnancy, there is an associated hypercoagulable
state due to the increase in factors I, VII, VIII, IX, X, XI,
and XII. Additionally, platelet counts increase and concentrations of protein S and antithrombin decrease. The fi brinolytic system also may be inhibited secondary to the increased
production of plasminogen-activated inhibitors 1 and 2 by
the placenta. Compounding this risk is the degree of stasis
that occurs as a result of compression of the lower extremity
veins by the gravid uterus. In the postpartum period, the risk
for thrombosis is up to fi ve times greater than during pregnancy. Approximately two months after delivery, the coagulation and fi brinolytic systems will return to normal.
1
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The risk of thrombosis is increased further in pregnant
women who have a genetic risk for thrombosis. Depending
on the inherited thrombophilia, a woman with a thrombophilia who becomes pregnant may have a risk of venous
thrombosis up to eight times higher than those without a
thrombophilia.4 In addition, women with a genetic risk for
thrombosis are also at an increased risk for fetal loss and
pre-eclampsia. Many women with a history of thrombophilia or thromboembolism are treated with heparin, lowmolecular-weight heparin, and/or aspirin while pregnant.
24
Oral Contraceptive-related Thrombosis
Oral contraceptives are one of the most frequently used
drugs by women. The use of oral contraceptives initially was
associated with a three-fold increased risk of venous thrombosis. With the decrease in the amount of estrogen placed
in the pill, a subsequent decrease in the incidence of
venous thrombosis was seen. With lower levels of estrogen,
the risk of thrombosis is 1.5 to 2 times that over control
patients. Additionally, newer oral contraceptives using
newer progesterones have shown an increased risk of
thromboembolism.
The risk for venous thrombosis is highest during the fi rst
year of use of the oral contraceptive and the risk is not
cumulative with prolonged use. Once the pill is discontinued, the risk returns to baseline for that patient.
Oral contraceptives infl uence the plasma levels of nearly
every protein involved in coagulation. Factors VII, VIII, IX,
X, and XI increase, and the natural anticoagulants antithrombin and protein S decrease. However, oral contraceptive administration is associated with elevated protein C,
α1-antitrypsin, and fi brinolytic proteins, producing an anti-
thrombotic effect. Additionally, the pill has been associated
with an acquired activated protein C resistance occurring
within three days of initiation of the pill and reversing with
discontinuation. This resistance has been shown to have
a more pronounced increase in those women using
third-generation oral contraceptives. The combination of
activated protein C resistance, increased prothrombin
levels, and decreased protein S levels produces a net prothrombotic affect and confers the prothrombotic risk of oral
contraceptives.
In women with inherited thrombophilias who also take
oral contraceptives, the risk for thrombosis increases 30- to
50-fold. For example, women who take oral contraceptives
and are heterozygous for the Factor V Leiden mutation have
been shown to have an increased risk of venous thrombosis
by a factor of approximately 35. This increased relative risk
for venous thrombosis is in the same order of magnitude as
patients who are homozygous for the Factor V Leiden mutation (almost 50-fold increased risk). The women who have
other inherited thrombophilias also appear to have a remarkably increased risk.
25
25,26
27,28
4,25
Hormone Replacement
Therapy–related Thrombosis
Historically, hormone replacement therapy (HRT) has
been used to reduce the progression of osteoporosis, relieve
the symptoms of menopause, and reduce the cardiovascular
risk profi le. Several studies including the Heart Estrogen/
Progestin Replacement Study (HERS) and the Women’s
Health Initiative (WHI) have shown an increased risk of
venous thromboembolism with the use of HRT. A two- to
four-fold increased risk, compared to nonusers, has been
26,29
shown.
Similar to oral contraceptives, the risk of venous thromboembolism is highest during the fi rst year of HRT. Once
HRT is discontinued, the risk of thrombosis returns to baseline. Additionally, increasing age has been associated with
an increased risk of venous thrombosis. Several studies also
have shown an increased risk in patients using HRT who had
lower extremity fractures, recent surgery, previous venous
29
thromboembolism, cancer, and obesity.
Also similar to oral
contraceptive pills, patients on HRT with thrombophilias
have a signifi cantly increased risk of venous thromboembolism.4 The coagulation factor changes, which occurs as a
result of hormone replacement therapy, and is similar to
those changes that occur with oral contraceptive pills, but to
a lesser degree.
Systemic Infl ammatory Response (SIR)
and Sepsis
With the systemic infl ammatory response, cytokines and
other infl ammatory mediators are released causing a prothrombotic state. Specifi cally, tumor necrosis factor α and
interleukin-1α are increased. These factors activate the
coagulation cascade, cause an increase in tissue factor
expression, and decrease levels of protein C and S. Fibrinogen synthesis also will increase as part of the infl ammatory
response. Additionally, the infl ammatory response is
enhanced by thrombin, which augments leukocyte adhesion
and activates platelets. Platelet activation in turn, further
promotes tissue factor expression and increases cytokine
release. All these factors contribute to the hypercoagulable
state seen with SIRS and sepsis and predispose the patient
to thrombosis.
30
Malignancy
Venous thromboembolism (VTE) is a common complication of cancer. In 10% of patients who present with an idiopathic VTE, malignancy will be discovered. The majority of
thrombotic episodes occur spontaneously, although patients
with cancer often have other concurrent risk factors (inherited thrombophilias, immobilization, major surgical proce-
Conclusion 345
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dures, chemotherapy, and central venous catheters) that
place them at high risk for venous thromboembolism.
Tissue factor and cancer procoagulant are produced by
tumor cells. The cancer procoagulant directly activates
factor X independently of factor VII. Additionally, tumor
cells produce proteins that may regulate the fi brinolytic
system. These proteins impair fi brinolytic activity leading to
a prothrombotic state.31 Tumor cells also produce various
cytokines and affect the coagulation cascade and induce a
thrombogenic state in a similar manner as SIRS. TNF-α and
interleukin 1β are released by cancer cells and induce tissue
factor expression and down-regulate thrombomodulin. Furthermore, tumor cells activate other cytokines and several
different types of leukocytes, which also increase tissue
factor expression and activate platelets. The interaction of
all these processes lead to a prothombotic condition.
31
Testing for Inherited
Thrombophilic Conditions
We perform testing for inherited thrombophilic conditions in the following clinical circumstances: idiopathic
DVT, recurrent DVT, DVT with young age at onset, and
venous thromboses in unusual locations (mesenteric or
portal venous thrombosis, cerebral vein thrombosis). Many
hospitals provide testing with a “hypercoagulable panel.”
However, the clinician should ascertain that the following
tests are being performed: antithrombin activity, protein C
activity, protein S activity, testing for either activated protein
C resistance or factor V Leiden, prothrombin gene mutation,
homocysteine levels, anticardiolipin antibody and lupus
anticoagulant testing, factor VIII activity. Antithrombin,
protein C, and protein S levels may be depressed by the
presence of acute thrombosis. Protein C and S may be similarly affected by warfarin administration. Therefore, an
abnormal test result drawn during these time periods does
not necessarily signify the presence of an inherited thrombophilic condition. Repeat testing is required.
Other Acquired Hypercoagulable Conditions
and Treatment Stratifi cation
TABLE 38.4 American College of Chest Physicians
Recommendations for Duration of Anticoagulation for
Venous Thromboembolism
Clinical subgroup Treatment duration
First episode DVT/transient risk UH/LMWH followed by 3 mos
VKA
First episode DVT/concurrent 3–6 mos LMWH
cancer Indefi nite anticoagulation until
cancer resolves
First episode idiopathic DVT UH/LMWH followed by 6–12 mos
VKA (suggest indefi nite)
First episode DVT/thrombophilia UH or LMWH followed by
antithrombin defi ciency 6–12 mos VKA (suggest
protein C and S defi ciency indefi nite if idiopathic)
factor V leiden
prothrombin 20210
homocysteinemia
factor VIII elevation (>90th %)
First episode DVT/thrombophilia UH or LMWH followed by 12 mos
Antiphospholipid antibodies VKA (suggest indefi nite)
2 or more thrombophilias
Recurrent DVT UH or LMWH followed by
indefi nite VKA
UH = unfractionated heparin, LMWH = low-molecular-weight heparin,
VKA = vitamin K antagonist.
32
thrombus, anticoagulation potentially has a role in achieving
all of these objectives. Initial anticoagulation with unfractionated heparin or low-molecular-weight heparin, followed
by six weeks to six months of oral vitamin K antagonists
has been the mainstay of therapy. More recently, the American College of Chest Physicians Consensus Statement has
stratifi ed the type and duration of anticoagulation, based in
part on the whether the patient has a concurrent thrombophilic condition (see Table 38.4).32 In general, the overall
trend is to extend the duration of anticoagulation, especially
in patients with recurrent DVT, antiphospholipid syndrome,
and patients with multiple thrombophilic conditions. In
patients with malignancy and venous thromboembolism, the
recommended duration of low-molecular-weight heparin
therapy has been extended to three to six months, followed
by long-term vitamin K antagonists.
Patients are predisposed to thrombosis via many other
clinical conditions. These conditions may affect the coagulation cascade, the fi brinolytic system, and/or platelet function, thereby increasing the risk of thrombosis. With two or
more conditions that predispose to thrombosis, the patient is
at a higher risk for suffering a thrombosis.
The objectives for treating acute venous thromboembolism include the prevention of death from pulmonary embolism, reduction of lower extremity symptoms, prevention of
the post-phlebitic syndrome, and prevention of recurrent
venous thromboembolism. By limiting the propagation of
CONCLUSION
A clear understanding of the various conditions and situations in which a patient may have a hypercoagulable state
is important for the ability to manage and appropriately treat
patients in whom the risk of thrombosis exists. Once that
risk is recognized, appropriate observation, prophylaxis, and
treatment may ensue. It must be recognized that the number
of acquired disease processes that predispose patients to
thrombosis far outweighs the number of patients with congenital thrombophilias. Although a large portion of the
346 Chapter 38/Congenital and Acquired Hypercoagulable Syndromes
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population may have a thrombosis, few thromboses are
caused by an inherited thrombophilia alone.
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18. Hertzberg MS. Genetic testing for thrombophilia mutations, Semin
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19. Coppola A, Davi G, De Stefano V et al. Homocysteine, coagulation,
platelet function and thrombosis, Semin Thromb Hemost. 2000. 26:
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20. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia, N Engl J Med. 2001. 344: 1286–1292.
21. Levine JS, Branch DW, Ruach J. The antiphospholipid syndrome, N
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22. Wilson WA, Ghavari AE, Koike T et al. International consensus statement on preliminary classifi cation criteria for defi nite antiphospholipid
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CHAPTER
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39
New Ways to Prevent Venous
Thromboembolism: The Factor Xa Inhibitor
Fondaparinux and the Thrombin Inhibitor
Ximelagatran
DAVID BERGQVIST
ABSTRACT
During the last decade low molecular weight heparins
have been the dominant methodology to prevent postoperative venous thromboembolism. They are effective and safe
but in high risk surgery (major orthopedic and abdominal/
pelvic cancer) there is still a signifi cant thromboembolic
risk. Recently two new thromboprophylactic agents have
been developed—one, a factot Xa inhibitor in the form of
the pentasaccharide fondaparinux and the other a direct
thrombin inhibitor in the form of melagatran with an orally
absorbable prodrug—ximelagatran. Both have been evaluated in extensive research programs and both have
been approved for use in major orthopedic surgery by the
European health care authorities.
INTRODUCTION
In prevention of postoperative venous thromboembolism,
one or another of the low molecular weight heparins has
dominated the market for about 15 years. There is, however,
still room for improvement, especially in patients undergoing high risk surgery such as major orthopedic surgery and
surgery for abdominal/pelvic malignancies. For the clinician
and for the patient new methods either should be more effective or safer than low molecular weight heparins, costeffective or easier to administer (i.e., available for oral
administration). The latter is especially true as long-term
prophylaxis will undoubtedly increase.
The various low molecular weight heparins have a rather
complex mechanism of action, inhibiting activated factor X
to a greater degree than inhibiting thrombin. This has been
considered necessary for a good prophylactic effect.
Recently, there have been two important developments
within the fi eld of antithrombotic agents. One development
was to use the heterogenous heparin molecule as a basis, and
working with the relation between structure and function
Lindahl et al.
pentasaccharide sequence. The research group of Choay in
Paris was able synthesize thus as fondaparinux—a selective Xa inhibitor.
small direct thrombin inhibitors, knowing the pivotal role
thrombin plays within the hemostatic system and knowing
that the thrombin inhibitor hirudin (originally from the saliva
of medicinal leeches) had a good thromboprophylactic
effect.5 Many attempts have been made to synthesize such
small selective thrombin inhibitors and so far most clinical
documentation is available on ximelagatran/melagatran.
Those two new principal ways of preventing venous
thromboembolism with molecules that are more selective and
structurally more homogenous now have been investigated in
large clinical trial programs and both have European approval,
fondaparinux in major orthopedic surgery and ximelagatran/
melagatran in elective major orthopedic surgery.
When evaluating new thromboprophylactic substances
and principles in the clinical setting, ideally there should be
a three-step research program:
1. Studies on mechanism of action, pharmacokinetics, and
pharmacodynamics.
2. Proof of principle with phlebographic evaluation of the
antithrombotic effect in high risk
a. major orthopedic surgery
b. major abdominal/pelvic surgery (especially cancer)
3. Proof of clinical importance in
a. large studies with a simple protocol on clinical
venous thromboembolism (VTE)
b. meta-analyses
1,2
to defi ne the specifi c antithrombin-binding
3,4
The other development was to synthesize
6–8
The Vein Book
347
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348 Chapter 39/New Ways to Prevent Venous Thromboembolism
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Regarding step 2, although elective hip surgery is a wellestablished clinical model, it is important also to evaluate
other high-risk surgical procedures. This is to make conclusions and clinical use more generalizible. From a practical
point of view it is not ideal to have different prophylactic
programs for various surgical procedures in a hospital or a
surgical department. Prophylaxis must be simple to obtain
widespread and well-accepted use. The manufacturers of the
two new substances discussed in this chapter fi rst have
focused on major orthopedic surgery and also got European
approval in major orthopedic surgery.
FONDAPARINUX
Fondaparinux is a synthetized analogue of the natural
pentasaccharide sequence of the heparin molecule, that
mediates its interaction with antithrombin.4 The molecular
weight is 1728 Dalton and with a very high batch-to-batch
consistency. The reversible binding, to a specifi c site on
antithrombin, results in a 300-fold increase in the rate of
factor Xa inhibition by antithrombin. After subcutaneous
administration with a 100% bioavailability the peak plasma
level is obtained in about 2 h with an elimination half life of
about 17 to 21 h, longer in elderly, which allows once-daily
administration.
through the renal route. The drug is contraindicated in
patients with renal failure as defi ned by a creatinine clearance of less than 30 ml/min. If used there is a potential for
bleeding complications. A peak steady state plasma level is
reached after three to four days (dose 2.5 mg daily). There
is no specifi c antidote to fondaparinux but in case of an
emergency recombinant factor VIIa may be used.11 This
would be the case in accidental overdosing with clinical
hemorrhage.
A large phase III clinical program has been performed to
evaluate the effect of fondaparinux in major orthopedic
surgery of the lower limbs. The studies have used various
acronyms: EPHESUS (European Pentasaccharide Hip Elective SUrgery Study with 2309 patients
(PENTAsaccharide in Total Hip Replacement Surgery with
2275 patients13), PENTAMAKS (PENTAsaccharide in
MAjor Knee Surgery with 1049 patients14), and PENTHIFRA (PENTAsaccharide in HIp FRActure surgery with 1711
patients15). The studies have been consistently performed
using 2.5 mg fondaparinux daily starting postoperatively.
The comparator has been enoxaparin: in EPHESUS and
PENTHIFRA with 40 mg once daily with a preoperative
start as used in Europe and in PENTATHLON and PENTAMAKS with 30 mg twice daily with a postoperative start as
used in North America. Phlebography was used for endpoint
assessment and the studies have been evaluated in a metaanalysis.
Table 39.1, the common odds reduction being 55% in favor
9,10
The elimination is mainly unchanged
12
), PENTATHLON
16
The primary effi cacy outcome is summarized in
TABLE 39.1 Frequency of Venous Thromboembolism (VTE)
Up to Day 11
Fondaparinux Enoxaparin
(n = 2682) (n = 2703)
VTE 182 (6.8) 371 (13.7)
Any DVT 174 (6.5) 363 (13.5)
Any proximal DVT 35 (1.3) 81 (2.9)
TABLE 39.2 Fondaparinux in High Risk Abdominal Surgery
(PEGASUS)
Fondaparinux Dalteparin
Primary effi cacy analyses 47/1027 (4.6%) 62/1021 (6.1%)
Patients with cancer 37/696 (4.7%) 55/712 (7.7%)
16
(Percent within brackets)
19
(venographic DVT)
of fondaparinux (p < 0.001). The incidence of symptomatic
VTE was low without a difference between the groups
(0.6% in the fondaparinux group and 0.4 in the enoxaparin
group; p > 0.25). Fatal pulmonary embolism was diagnosed
in two and three patients, respectively. The benefi cial effect
of fondaparinux was consistent regarding sex, age, body
mass index, type of anesthesia, use of cement for fi xation of
prosthesis, and duration of the surgical procedure.
There were 2.7% adjudicated major bleedings in the
fondaparinux group versus 1.7 in the enoxaparin group (p =
0.008). This difference was due mainly to a difference in
bleeding index whereas fatal bleeding, bleeding in critical
organs, and bleeding leading to reoperation did not differ.
There was a signifi cant relation between the incidence of
major bleeding and the timing of the fi rst injection of
fondaparinux (between 3 and 9 hours postoperatively,
p < 0.008), whereas the thromboprophylactic effect was not
infl uenced by timing (p > 0.67). Thrombocytopenia has not
been reported (there is no binding to platelet factor 4).
17
In PENTHIFRA Plus,18 the effect of prolonged prophylaxis with fondaparinux has been evaluated in patients
undergoing hip fracture surgery. All 656 patients received
fondaparinux for six to eight days, thereafter they were randomized to placebo or fondaparinux for another 19 to 23
days. Venous thromboembolism (bilateral phlebography or
symptomatic VTE) differed signifi cantly, being 35% in the
placebo group and 1.4% in the fondaparinux group, a reduction that is highly remarkable. The effect was also signifi cant
when symptomatic VTE was used as endpoint (2.7% vs
0.3%; p < 0.02).
In a recent multicenter, double-blind study (PEGASUS
trial) on 2048 patients undergoing high risk abdominal
surgery, fondaparinux was shown to be noninferior to dalteparin (Agnelli et al.
19
). In the subgroup operated on for
malignant disorders the difference was signifi cant in favor
of fondaparinux (see Table 39.2).
Concluding Remarks 349
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TABLE 39.3 Design of Orthopedic Studies on
Ximelagatran/Melagatran
METHRO II Dose fi nding study. Four groups with melagatran
1–3 mg × 2 and then ximelagatran 8–24 mg × 2.
Preop start.
METHRO III Melagatran 3 mg and then ximelagatran 24 mg × 2.
Postop start.
EXPRESS Melagatran 2 mg preoperatively, 3 mg postoperatively,
and then ximelagatran 24 mg × 2.
EXULT A Ximelagatran 24 and 36 mg × 2. Late postop start.
EXULT B Ximelagatran 36 mg × 2. Late postop start.
Idraparinux is a fondaparinux analogue with modifi ed
pharmacokinetics making once weekly administration possible, clinical studies being on the way.
20–22
XIMELAGATRAN/MELAGATRAN
Ximelagatran is a novel oral direct thrombin inhibitor,
which is a prodrug rapidly absorbed in the small intestine and
bioconverted to the dipeptide melagatran (429 Da), which is
the active form.23 Melagatran is a selective, competitive
small–molecular direct inhibitor of free and clot-bound
thrombin with a complete bio-availability on subcutaneous
injection. Melagatran is mainly excreted via the kidneys
(around 80%).24 After single and repeated oral dosing of
ximelagatran the bioavailability of melagatran is around
20%.25 Maximum melagatran concentrations are reached in
approximately two hours. A similar absorption is also seen
three days after abdominal surgery.26 The main absorption
site is the duodenum. Ximelagatran/melagatran has no known
food interaction and no clinically relevant drug interactions
involving cytochrome P450 enzymes. Ximelagatran is the
fi rst oral direct thrombin inhibitor on the market.
In an extensive phase III clinical program ximelagatran
has been evaluated in major orthopedic surgery. Again
various investigation acronyms have been used: METHRO
II (MElagatran for THRombin inhibition in Orthopaedic
surgery; hip and knee replacement, 1876 patients, dose
fi nding study, comparator dalteparin with preoperative
27
start
), METHRO III (hip and knee replacement, 2788
patients, comparator enoxaparin with preoperative start28),
EXPRESS (EXpanded PRophylaxis Evaluation Surgery
Study, hip and knee replacement, 2835 patients, comparator
enoxaparin with preoperative start
A (EXanta Used to Lessen Thrombosis, knee replacement,
2285 patients, comparator warfarin30), and EXULT B (knee
replacement, 2299 patients, comparator warfarin31) in North
America. The design of the various studies is summarized
in Table 39.3. In METHRO II the effi cacy of melagatran/
ximelagatran was dose dependent and the highest dose was
superior to dalteparin both for total VTE (15.1 vs 28.2%,
respectively, p < 0.0001) and major VTE (2.5 vs 6.5%, p <
29
) in Europe and EXULT
0.05). In METHRO III with postoperative start melagatran/
ximelagatran was at least as effective as enoxaparin (overall
VTE 31 vs 27%), but in hip replacement there was signifi cant difference in favor of enoxaparin for total VTE (25 vs
19%, p < 0.004). Initiation of prophylaxis closer (4–8 h) to
surgery was signifi cantly more effective than later institution
(8–12 h) in prevention of total VTE.28 In EXPRESS with
preoperative start again there was signifi cant advantage for
melagatran/ximelagatran in total VTE (20 vs 27%, p <
0.001) and major VTE (2.3 vs 6.3%, p < 0.0001). In the
EXULT A with start the day after surgery the higher dose
ximelagatran (36 mg × 2) was more effective than warfarin
to prevent total VTE (20 vs 28%, p < 0.01), a result that was
further verifi ed in EXULT B (23 vs 32%, p < 0.001). Regarding major VTE there were no signifi cant differences in the
EXULT studies.
Bleeding events and measured blood loss did not differ
between ximelagatran/melagatran and the various comparators. In METHRO II there was a signifi cant dose-dependent
(from 8 mg to 24 mg) increase in the proportion of patients
on ximelagtran/melagatran with severe bleeding. In Table
39.4 the bleeding events in the various studies are
summarized.
There is no specifi c antidote and the effect is limited by
the rapid renal clearance. Intravenous activated prothrombin
complex or recombinant activated factor VII rapidly attenuates the melagatran effect.
32
An increase in liver enzymes (ALT, alanine aminotransferase) has been reported in patients receiving long-term
(mostly > 35 days) melagatran/ximelagatran.33 However, in
the prophylactic trials with short-term administration (≤11
days) this incidence has been of the same order of magnitude
as in the low molecular weight heparin groups. The effect
has been reversible. The mechanism responsible for the liver
enzyme changes is not yet established.
Trials in nonorthopedic surgery basically are lacking.
There is one study primarly focused on pharmacodynamics
in patients undergoing major abdominal surgery.26 In the
study on 90 patients venographic DVT was evaluated on the
fi nal day of treatment and the results are given in Table 39.5.
Although a small study, the DVT frequencies are of the same
order of magnitude as in similar studies on low molecular
weight heparins. The data are of interest when discussing
the possibility of prolonged prophylaxis, which may be of
value in patients operated on for abdominal/pelvic cancer.
34
The advantage of an oral drug in this situation seems
obvious.
CONCLUDING REMARKS
Today, there are two synthetic substances inhibiting very
well-defi ned steps or specifi c factors in the hemostatic
system, both showing a clear effect in prevention of
350 Chapter 39/New Ways to Prevent Venous Thromboembolism
https://t.me/med1917
TABLE 39.4 Bleeding Complications in Orthopedic Trials with Melagatran/Ximelagatran
Number of patients Total bleeding (%)
European trials in population Severe bleeding (%) (severe and minor)
METHRO II (ITT):
Ximelagatran 8 mg 364 1.1 NA
Ximelagatran 12 mg 377 2.1 NA
Ximelagatran 18 mg 375 2.9 NA
Ximelagatran 24 mg 379 5.0 NA
Dalteparin 381 2.4 NA
METHRO III (ITT):
Ximelagatran 1399 1.4 NA
Enoxaparin 1389 1.7 NA
EXPRESS (ITT):
Ximelagatran 1410 3.3 12.5
Enoxaparin 1425 1.2 8.2
Number of patients Total bleeding (%)
North American trials in population Major bleeding (%) (major and minor)
Francis et al. (ITT) (22):
Ximelagatran 24 mg 348 1.7 9.5
Warfarin 332 0.9 7.3
EXULT A (ITT):
Ximelagatran 24 mg 775 0.8 5.3
Ximelagatran 36 mg 762 0.8 4.8
Warfarin 764 0.7 4.5
EXULT B (OT):
Ximelagatran 36 mg 1151
Warfarin 1148§ 0.4 3.8
§
1.0 5.0
35
TABLE 39.5 Frequency of DVT According to Phlebography
(%) in High-Risk Abdominal Surgery
Melagatran/
Ximelagatran
8 days 35 days Dalteparin
Intention-to-treat population 13.6 12.0 8.7
Per protocol population 12.5 5.0 10.0
26
postoperative venous thromboembolism in major orthopedic
surgery. Apart from being of practical importance the principal mechanisms of action are of great theoretical
interest.
The Xa inhibitor fondaparinux and the direct thrombin
inhibitor ximelagatran/melagatran have been evaluated
extensively in clinical studies of high quality with
large sample sizes. Both substances are at least as effective
or more effective than today’s dominating prophylactic
methods (low molecular weight heparins and warfarin). Still
data largely are lacking on prophylaxis in nonorthopedic
surgery but the few results seem promising. A second and
direct thrombin inhibitor, dabigatran, is in phase II trials in
2005.
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