Expert Opinion on Drug Safety

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The safety of fondaparinux sodium for the

treatment of venous thromboembolism

Daniela Mastroiacovo, Girolamo Sala & Francesco Dentali

To cite this article: Daniela Mastroiacovo, Girolamo Sala & Francesco Dentali (2016) The safety
of fondaparinux sodium for the treatment of venous thromboembolism, Expert Opinion on
Drug Safety, 15:9, 1259-1265, DOI: 10.1080/14740338.2016.1221395

To link to this article: http://dx.doi.org/10.1080/14740338.2016.1221395

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EXPERT OPINION ON DRUG SAFETY, 2016
VOL. 15, NO. 9, 1259–1265
http://dx.doi.org/10.1080/14740338.2016.1221395

DRUG SAFETY EVALUATION

The safety of fondaparinux sodium for the treatment of venous thromboembolism

Daniela Mastroiacovoa, Girolamo Salab and Francesco Dentalib
a
Angiology Unit, Avezzano Hospital, Avezzano, Italy; bDepartment of Clinical Medicine, Insubria University, Varese, Italy

ABSTRACT ARTICLE HISTORY

Introduction: Venous thromboembolism (VTE) is a common and potentially fatal disease. Fondaparinux Received 7 March 2016
is a synthetic agent able to act on single factors involved in the coagulation network, which could be Accepted 3 August 2016
Published online
administered at fixed doses and with a more predictable response. 22 August 2016
Areas covered: This review will focus on the efficacy and safety of fondaparinux in the treatment of
major VTE (deep vein thrombosis and pulmonary embolism) and in the treatment of superficial vein KEYWORDS
thrombosis (SVT). Antithrombotic; bleeding;
Expert opinion: Results of high quality randomized controlled trials have clearly shown the efficacy and factor Xa inhibitors;
safety of fondaparinux in comparison to conventional treatment in patients with a major VTE. There are fondaparinux; venous
limited evidences on the safety and efficacy of different options in patients presenting with SVT. thromboembolism
Fondaparinux has been evaluated in a large population of patients presenting with a SVT. Results of
this high quality RCT provided the evidence on the efficacy and safety of fondaparinux 2.5 mg s.c./day
for 45 days in this setting. Thus, considering the evidence of the literature and thanks to its pharma-
cokinetic and pharmacodynamic characteristics, fondaparinux represent a valid treatment option for
both the acute management of patients with major VTE, and for the treatment of SVT.

1. Introduction [7,8]. Conventional antithrombotic drugs are nonselective as

they act on a broad range of coagulation factors. In addition,
Venous thromboembolism (VTE) is a common and potentially
heparins, derived from animal tissues, are heterogeneous mix-
fatal disease with an overall annual incidence of 100 per
tures of different molecules with fluctuating activities [9]. The
100,000 individuals in Western countries, which rises exponen-
disadvantages of these classes of drugs have, in recent dec-
tially to approximately 500 cases (0.5%) per 100,000 persons at
ades, stimulated an intense research aimed at developing new
age 80 [1]. Despite advances in all areas of its management,
synthetic agents able to act on single factors involved in the
VTE remains the third most frequent cardiovascular disease
coagulation network, which could be administered at fixed
after ischemic heart disease and stroke. The increase in life
doses and with a more predictable response. Since the
expectancy of the elderly population, the use of more com-
1970s, factor Xa inhibition has been considered an attractive
plex surgical procedures, the higher rate of survival in patients
option for the design of potent and safe antithrombotic
with diseases that predispose to thrombosis and, on the other
agents. Factor Xa is localized at the converging point of the
hand, the advances in imaging techniques, can help to explain
extrinsic and intrinsic pathways, and upstream of thrombin. As
the increased prevalence of VTE observed in recent decades
the amount of serine protease is amplified at each step of the
[2]. VTE may be fatal in the acute phase or lead to chronic
coagulation cascade, it has been hypothesized that anticoa-
disease and disability, but it is also often preventable [3,4]. In
gulants with targets located higher up the cascade, such as
addition, patients with symptomatic deep venous thrombosis
factor Xa, may be more effective [10]. Furthermore, by not
(DVT) and/or pulmonary embolism (PE), even when ade-
inhibiting thrombin activity directly, such compounds might
quately treated, have a high risk of recurrent VTE, with
allow traces of thrombin to escape neutralization, thereby
approximately one-quarter of patients experiencing a recur-
leading to a favorable safety profile with respect to bleeding
rent event within the subsequent 5 years [5,6]. Traditionally,
risk.
the standard treatment of noncritical patients with VTE has
included an initial anticoagulant therapy with adjusted doses
of unfractionated heparin (UFH) or, more recently, fixed doses 2. Fondaparinux sodium: mechanism of action and
of low-molecular-weight heparin (LMWH), followed by vitamin pharmacokinetics
K antagonists (VKAs) for variable periods. The main goal in
Fondaparinux sodium is the first agent of a class of anticoagu-
early treatment of VTE is a rapid therapeutic anticoagulation,
lants, that selectively and indirectly target factor Xa, to receive U.
which prevents clot propagation and early death. Indeed, fail-
S. Food and Drug Administration (FDA) approval for the preven-
ure to achieve therapeutic anticoagulation within the first few
tion and treatment of VTE. It is a synthetic pentasaccharide and
days is associated with high-risk recurrence rates of up to 20%
is the smallest heparine-based molecule (molecular weight of

CONTACT Francesco Dentali fdentali@libero.it U.O. Medicina Interna, Ospedale di Circolo, Viale Borri 57, Varese 21100, Italy
© 2016 Informa UK Limited, trading as Taylor & Francis Group
1260 D. MASTROIACOVO ET AL.

1728 Da) designed specifically to potentiate its affinity and bind Table 1. Mechanism of action and pharmacokinetics of fondaparinux.
exclusively to its sole target in the plasma, antithrombin (AT). In Mechanism of action Binding to antithrombin with high affinity
fact, after a rapid, noncovalent, and reversible-binding, fonda- Bioavailability 100%, 2 h after s.c. application
parinux induces a critical conformational change in AT that Elimination half-life 17–21 h (young healthy volunteers – elderly)
Elimination Excreted unmetabolized in urine (80%)
improve the affinity of AT for factor Xa, increasing the natural Metabolism Not demonstrated
inhibitory effect of AT against factor Xa by a factor of about 300 Within-subject variability Low (4.4–5.5%)
[11]. Once AT forms a covalent complex with factor Xa, fonda- Inter-subject variability Low (11.6–17.5%)
Interaction with digoxin None
parinux is released unchanged and it can bind to other mole- Interaction with aspirin None
cules of AT, whereas the complex is removed from circulation. Batch-to-batch variability None
Contrary to other heparins, fondaparinux is too short to provide
linking between AT and thrombin necessary to promote AT-
mediated inhibition of thrombin. Despite that, plasma inhibition
factor 4 (PF4). Data on pharmacokinetics are summarized in
of free factor Xa has been shown to correlate to a linear dose
Table 1.
dependent inhibition of thrombin generation, whether acti-
vated by the extrinsic or intrinsic pathway, and in platelet rich
or poor plasma. Conversely, fondaparinux is unable to inhibit 3. The treatment trials
factor Xa within the assembled prothrombinase complex [12].
Fondaparinux has a linear, dose-dependent pharmacoki- An overview of characteristics and results of principal studies
netic profile, which provides a highly predictable response. It on the use of fondaparinux in patients with major VTE and
is 100% bioavailable, has a rapid onset of action, with a half- with a superficial vein thrombosis (SVT) is given in Table 2.
life of 17 h in young subjects and 21 h in elderly volunteers
independently from the initial dose. These characteristics
3.1. Efficacy outcomes in the treatment of VTE
allow a once daily subcutaneous administration in fixed
doses without coagulation monitoring. Fondaparinux is not The Rembrandt study is a phase II randomized dose finding
metabolized and is almost entirely excreted by the kidneys trial evaluating the efficacy and safety of fondaparinux (5, 7.5,
as the unchanged compound, so patients with impaired renal or 10 mg once daily) compared to LMWH (dalteparin, 100 IU/
function require dose adjustment. It does not inhibit the kg twice daily) in symptomatic proximal DVT. A positive out-
oxidative metabolism of various cytochrome P450 substrates come (defined as improvement of the ultrasound and/or per-
commonly involved in the metabolism of the drugs [13]. fusion scan result without deterioration of either test) was
Unlike heparins, fondaparinux does not inhibit the mitochon- observed in 46%, 48%, 42%, and 49% of the subjects treated
drial activity or protein synthesis of human osteoblast, sug- respectively with 5, 7.5, or 10 mg of fondaparinux or dalte-
gesting that its use will not result in osteoporosis [14]. parin. There were 2.4% recurrent thromboembolic complica-
Furthermore, the drug does not bind to platelets or platelet tions in the group treated with fondaparinux and 5.0% in the

Table 2. Phase III trial results of fondaparinux in VTE and SVT treatment.
Trial Study design Safety outcomes Results Conclusion
Matisse Study design: randomized, double- Major bleeding during initial Major bleeding Once daily subcutaneous fondaparinux was
−DVT, 2004 blind study treatment period – Fondaparinux: at least as safe as twice daily, body
Aim of the study: Death during the 3-month study 1.1% weight-adjusted enoxaparin in the initial
fondaparinux (7.5 mg OD) vs. period – Enoxaparin: 1.2% treatment of patients with symptomatic
enoxaparin (100 UI prokg) for initial Mortality rates DVT
treatment for DVT (popliteal, – Fondaparinux:
femoral, or iliac veins or the 3.8%
trifurcation of the calf veins) – Enoxaparin: 3.0%

Matisse−PE, Study design: Major Bleeding during initial Major bleeding Once daily, subcutaneous administration of
2003 randomized, open-label study treatment period – Fondaparinux: fondaparinux without monitoring is at
Aim of the study: fondaparinux Death during the 3-month study 1.3% least as safe as UFH in the initial
(7.5 mg OD) vs. UFH (adjusted- period – UFH: 1.1% treatment of hemodynamically stable
dose) for the initial treatment of Mortality rates patients with PE
symptomatic PE – Similar in the two
groups

CALISTO−SVT, Study design: Major bleeding Major bleeding Fondaparinux at a dose of 2.5 mg once a
2010 randomized, double-blind, placebo- – one patient in day for 45 days was safe in the treatment
controlled study each group of patients with acute, symptomatic SVT
Aim of the study: Serious adverse of the legs
fondaparinux (2.5 mg OD) in events
patients with acute, isolated SVT – Fondaparinux
of the legs 0.7%
– Placebo: 1.1%

DVT: deep venous thrombosis; PE: pulmonary embolism; SVT: superficial vein thrombosis; UFH: unfractionated heparin; CALISTO: Comparison of Arixtra in Lower
Limb Superficial Vein Thrombosis with Placebo.

dalteparin group. Overall, the incidence of bleeding was low
and was similar among the groups [15].
Subsequently the Matisse investigators evaluated in two
phase III large randomized noninferiority trials the clinical
benefit of the selected doses of fondaparinux (7.5 mg once
daily, or 5 mg for body weight <50 kg and 10 mg for body
weight >100 kg) for the treatment of VTE. The treatment drugs
were given for at least 5 days until an international normalized
ratio >2 was achieved. The primary efficacy outcome of these
trials was a composite of recurrent fatal or nonfatal VTE during
the 3-month follow-up period. The researchers selected a fixed
noninferiority margin of 3.5% for the absolute difference of
the VTE rates between the two treatment group (fondaparinux
vs. UFH/enoxaparin) . From these assumption, they calculated
that a study with a 1100 patients per treatment group would
provide 95% power, with a one-side, type I error of 0.025 for
rejecting the hypothesis that the rate of recurrence with fon-
daparinux would be 3.5% higher than with UFH or enoxaparin)
[16,17]. In the Matisse−PE, an open label study, the benefit-to-
risk ratio of fondaparinux was compared with that of adjusted-
dose continuous intravenous UFH in the initial treatment of
2213 patients with acute symptomatic hemodynamically
stable PE with or without DVT. At 3 months, recurrent VTE
occurred in 3.8% of fondaparinux treated patients versus 5%
of UFH patients, for a relative risk reduction of 25% and an
absolute difference of −1.2% (95% confidence interval [CI]:
−3% to 0.5%) in favor of fondaparinux [16]. In the Matisse
−DVT double blind study, the researchers randomly assigned
2205 patients with proximal symptomatic DVT to receive
either fondaparinux once daily or enoxaparin (1 mg/kg)
twice daily. At 3 months, symptomatic recurrent thromboem-
bolic events occurred in 3.9% of fondaparinux-treated patients
and in 4.1% of enoxaparin treated patients (absolute differ-
ence = 0.15% in favor of fondaparinux; 95% CI: −1.8% to
1.5%) [17].
3.2. Efficacy outcomes in the treatment of SVT
Superficial vein thrombosis of the leg is a frequent condition
with an incidence estimated to be higher than that of DVT
[18,19]. Traditionally, SVT has been considered as a benign,
self-limiting disease, expected to resolve promptly and
needing only symptomatic treatments. However, the per-
ception of this disease is nowadays changing since the
recent data has underlined its potential severity and
attested indubitably that it is closely linked to DVT or PE.
In fact, 20–30% of patients with SVT have a concomitant
major VTE at presentation, and a non-negligible rate of
patients with isolated SVT can develop this complication in
the subsequent 3 months [20–22]. Historical treatment of
uncomplicated SVT had consisted of compression with ban-
dages or stockings and local or systemic anti-inflammatory
agents. The best therapeutic strategy of this disease remains
today poorly defined and heterogeneous, still ranging from
antithrombotic drugs and surgery [23]. In two randomized
studies, high-prophylactic doses of LMWH turned out to be
equally effective when compared with anti-inflammatory
agents and full-therapeutic dose of LMWH [24,25]. In
EXPERT OPINION ON DRUG SAFETY 1261
addition, the results of these trials suggest that the optimal
duration of antithrombotic therapy should be greater than
12 and 30 days, respectively, the most thromboembolic
complications occurring after treatment discontinuation.
On the other hand, prophylactic saphenous vein ligation
alone resulted less effective than conservative therapy [26–
28]. In this context, the Comparison of Arixtra in Lower Limb
Superficial Vein Thrombosis with Placebo (CALISTO) study
has proved the first effective medical therapy for patients
with isolated SVT of the legs. Indeed, when compared with
placebo, a 45-day subcutaneous once-daily dose of fonda-
parinux 2.5 mg was associated with an 85% reduction (95%
CI: 74–92; P < 0.001) in the composite end point of all-cause
death, symptomatic DVT or PE, and symptomatic recurrence
of SVT or extension of SVT to the saphenous–femoral junc-
tion [29].
3.3. Safety outcomes in the treatment of VTE
The primary safety outcomes of Matisse−DVT and Matisse−PE
were major bleeding during the initial treatment and 3-month
mortality. Bleeding episodes that were clinically relevant but
not major were an additional safety outcome. Bleeding during
initial treatment was defined as occurring during initial treat-
ment plus 3, 4, or 9 days in patients with a creatinine clearance
more than 0.84 ml/s, between 0.5 and 0.84 ml/s, or below
0.5 ml/s, respectively. Safety analyses were based on data from
all the patients who actually received treatment. A central
adjudication committee whose members were unaware of
treatment assignment reviewed and classified all suspected
outcome events [16,17]. In the Matisse−PE, major bleeding
during initial treatment occurred in 1.3% of patients in fonda-
parinux group and in 1.1% of those in UFH group (absolute
difference = 0.2%; 95% CI: −0.7 to 1.1). Bleeding contributed to
death in one patient in each treatment group. Major or clini-
cally relevant nonmajor bleeding during initial treatment
occurred in 4.5% of patients treated with fondaparinux and
in 6.3% of patients treated with UFH (absolute difference =
−1.8%; 95% CI: −3.7 to 0.1). The incidence of bleeding during
treatment with VKA was low and was comparable in the two
groups. With regard to mortality, during the 3-month study
period, 5.2% of patients in fondaparinux group died, as com-
pared with 4.4% of those in UFH group (absolute difference =
0.8%; 95% CI: −1.0 to 2.6). Of the 158 patients who received
fondaparinux on an outpatient basis (14.3%), none had major
bleeding or died during the initial treatment [16]. In the
Matisse−DVT major bleeding during initial treatment occurred
in 1.1% of fondaparinux patients and in 1.2% of enoxaparin
patients. Bleeding contributed to death in two patients in the
fondaparinux group, but these patients were concomitantly
treated with VKAs and had a supratherapeutic international
normalized ratio. Major or clinically relevant nonmajor bleed-
ing during initial treatment occurred in 3.7% of patients
receiving fondaparinux and in 4.2% of patients treated with
enoxaparin (absolute difference = −0.5%; 95% CI: −2.1% to
1.1%). Bleeding events during VKA treatment were low and
similar in the two groups. Mortality rates at 3 months were
comparable in the two groups (3.8% vs. 3.0%, absolute
1262 D. MASTROIACOVO ET AL.
difference = −0.8%; 95% CI: −0.8% to 2.3%). Nearly a third of
patients were treated partially or entirely on an outpatient
basis. Among these, major bleeding during initial treatment
occurred in 1.5% and 0.8% of the patients receiving fondapar-
inux or enoxaparin, respectively [17]. Moreover, in both
Matisse studies, thrombocytopenia was rare and was never
associated with heparin-related antibodies.
3.4. Safety outcomes in the treatment of SVT
Interestingly, in addition to great efficacy, in the CALISTO
study fondaparinux 2.5 mg showed to be as safe as placebo.
The 3002 patients randomized were followed until day 77. By
day 47, major bleeding had occurred in one patient (0.1%) in
each group. Safety outcomes, including major bleeding, clini-
cally relevant nonmajor, minor and total bleeding, and arterial
thromboembolic events, did not differ significantly between
the two groups and were similar in on-treatment analysis and
in analysis at day 77. Moreover, there were no differences in
the incidence of any other adverse events between fondapar-
inux and placebo group. No manifestations of thrombocyto-
penia were reported in the fondaparinux group [29].
4. Special populations
The results of the Matisse Investigators’ studies suggest that
fondaparinux could be a simplified option of either DVT or PE
also in home treatment of VTE. In these studies, patients with
a CrCl <0.5 ml/s had an increased risk of bleeding regardless of
which treatment they received.
A post hoc analysis of Matisse trials was performed in
order to compare primary outcomes in obese patients. Four
hundred ninety-six patients (11%) weighed >100 kg and
1216 (55%) with a BMI ≥30 were included. The incidences
of recurrence and major bleeding were not significantly
different between fondaparinux and heparin treatment
groups in any of the weight or BMI subgroups. So, once-
daily subcutaneous 10-mg fondaparinux dosing for obese
patients appeared to be as safe and as effective as compara-
tor therapy, and also as safe and effective as it was in study
patients weighing ≤100 kg or having BMI <30 [30]. The
Matisse Investigators also performed two post hoc analyses
in order to assess the efficacy and safety of fondaparinux
with either LMWH or UFH in patients with cancer. A total of
477 cancer patients were included in both Matisse studies.
In DVT patients, a recurrence was observed in 5.4% of
patients treated with enoxaparin and in 12.7% of those
treated with fondaparinux (absolute difference = 7.3%; 95%
CI: 0.1–14.5; P = 0.046). However, in patients with advanced
malignancy there was no significant difference in VTE recur-
rence between fondaparinux and enoxaparin: 11.5% versus
3.7%, for an absolute difference of 7.8% (95% CI: 6.4–22.0;
P = 0.28). Conversely, in PE patients a recurrence was
observed in 17.2% of patients receiving UFH and in 8.9%
of fondaparinux recipients (absolute difference = −8.3; 95%
CI: −16.7 to 0.1). The opposite efficacy outcomes observed
might be in some measure due to the moderate number of
patients with cancer, not randomized separately, studied in
these retrospective underpowered analyses. Regarding over-
all survival and bleeding, fondaparinux appeared equally as
safe as enoxaparin and UFH in the initial treatment of VTE in
cancer patients [31]. In addition, a recent review of Cochrane
collaboration did not show any significant difference con-
cerning efficacy and safety compared to LMWH/UFH [32].
Only a few studies evaluated the efficacy and safety of
long-term treatment with fondaparinux in patients with
cancer-associated thrombosis (CAT). In a recent analysis of
the RIETE study, use of fondaparinux for at least 3 months
for the treatment of VTE (n = 263 patients) resulted asso-
ciated with a similar rate of VTE recurrence and of major
bleeding in cancer patients, and with a similar rate of VTE
recurrence and with an increased risk of major bleeding in
noncancer patients in comparison to patients treated with
long-term LMWH (n = 3928) and with VKA (n = 31,386)
respectively [33]. Another prospective observational study
reported on good efficacy and safety of fondaparinux in a
cohort of 231 patients in a real life setting, including 23 with
active malignancy [34]. Additional studies directly comparing
long-term fondaparinux and LMWH in oncology patients are
lacking. In a small RCT involving 64 patients with CAT and
comparing fondaparinux alone for 90 days with fondapari-
nux and vena cava filter placement, no difference in terms
of safety, recurrent thrombosis, recurrent pulmonary embo-
lism, or survival was found [35]. Although the number of
patients included in these reports was small and data con-
cerning treatment are generally more limited [34] than data
regarding VTE prophylaxis, ASCO guidelines consider fonda-
parinux as a possible option both in prevention and in
treatment of CAT [36].
Another intriguing issue is the potential role of fondapar-
inux in the management of immune-mediated heparin-
induced thrombocytopenia (HIT), well recognized as an
uncommon but severe complication of heparin therapy that
leads to a paradoxical prothrombotic state [37]. In this regard,
even patients treated with fondaparinux have been reported
to develop anti-heparin/PF4 antibodies. However this drug,
contrary to UFH/LMWH, does not usually bind to platelets or
PF4 due to absent or weak ‘cross-reactivity’ with this epitope
[38]. Despite fondaparinux not being approved by FDA in this
setting, its off-label use in clinical practice is frequent in
patients with acute, suspected, and antecedent HIT. Findings
from a recent retrospective cohort study, assessing 239
patients treated with a nonheparin anticoagulant for sus-
pected or confirmed HIT, suggest that fondaparinux is as
effective as danaparoid or argatroban in preventing thrombo-
tic events, with a similar safety profile [39]. Reports from an
American registry indicate that HIT might be the most fre-
quent indication for its prescription in the United States,
where more than 94% of prophylactic dose prescriptions
were HIT associated [40]. Similarly, real life data from a retro-
spective German registry show that fondaparinux is used off-
label in up to 50.3% of patients, even in patients with a high
clinical pretest probability for underlying HIT [41]. Moreover,
several case reports and case series describe a successful
management of HIT with fondaparinux [42]. In contrast to
these findings, there are few case reports referring to a possi-
ble association of fondaparinux with HIT or to a failure in

managing HIT appropriately, which raised a scientific debate
about this off-label indication [43,44]. ACCP guidelines and a
recent Anticoagulation Forum consensus expert opinion,
although highlighting the requirement of further randomized
trials evaluating efficacy and safety of fondaparinux in this
area, consider this drug as an option for treatment of patients
with HIT without thrombosis as well as for patients with a past
history of HIT and an acute thrombosis [45,46].
5. Expert opinion
Fondaparinux is currently registered for the treatment of
major VTE (DVT and PE) and for the treatment of SVT
(Box 1).
In two large phase III studies on patients with acute DVT or PE
recurrent VTE, bleeding complications and mortality rates in
patients treated in the acute phase with fondaparinux were similar
to the comparator (LMWH or UFH/VKA). The 9th edition of ACCP
guidelines considers therapeutic doses of fondaparinux (7.5 mg,
respectively, 10 mg in case of body weight >100 kg and 5 mg if
<50 kg) equivalent and comparably safe to therapeutic doses of
UFH/LMWH for the initial treatment of DVT [47]. In addition, ESC
and ACCP guidelines recommend LMWH or fondaparinux over
subcutaneous or intravenous UFH for most cases of acute PE
without hemodynamic compromise except for cases of severe
renal dysfunction [3,47]. The current edition of ACCP guidelines,
focused particularly on direct oral anticoagulants (DOACs), has not
updated recommendations regarding fondaparinux [48]. If the
introduction of DOACs has undoubtedly opened up new pro-
spects in managing thromboembolic disease, it should be remem-
bered that both dabigatran and edoxaban require a ‘dual-drug’
approach and fondaparinux is one of the available options for the
acute phase of VTE [49]. Use of fondaparinux for the long-term
treatment of major VTE is more debatable. Once daily administra-
tion in fixed doses without coagulation monitoring is potentially
Box 1. Drug summary.
Drug name (generic) Fondaparinux sodium
Phase (for indication under IV
discussion)
Indication (specific to Treatment of acute deep venous
discussion) thrombosis (DVT) and pulmonary
embolism
Treatment of acute symptomatic
spontaneous superficial-vein thrombosis
of the lower limbs without concomitant
DVT
Pharmacology description/ The antithrombotic activity is the result of
mechanism of action ATIII-mediated selective inhibition of
factor Xa. By binding selectively to ATIII,
fondaparinux potentiates (about 300
times) the innate neutralization of factor
Xa by ATIII. Neutralization of factor Xa
interrupts the blood coagulation
cascade and inhibits both thrombin
formation and thrombus development
Route of administration Subcutaneous injection
Chemical structure Synthetic pentasaccharide (molecular
weight: 1728 Da)
Pivotal trial(s) Matisse−DVT [17]; Matisse−PE [16];
CALISTO [29]
EXPERT OPINION ON DRUG SAFETY 1263
attractive in patients not eligible or not keen on a treatment with
VKA or with DOACs. On the other hand, the scarcity of evidences in
this setting deserves caution in the use of fondaparinux for this
indication.
There are limited evidences on the safety and efficacy of
different options in patients presenting with SVT. Existing litera-
ture is generally limited by the small number of different studies.
Furthermore, in these studies, patients were generally treated for
a relatively short period of time and follow up is frequently
insufficient to draw definitive conclusions on the safety and
efficacy of different treatment options. In the CALISTO study,
fondaparinux has been evaluated in a large population of
patients presenting with a SVT. Results of this high-quality RCT
for the first time provided firm evidence on the efficacy and
safety of a treatment (namely fondaparinux 2.5 mg s.c./day for
45 days) in this setting. Thus, American and European guidelines
suggest the use of a prophylactic dose of fondaparinux even
over a prophylactic dose of LMWH in patients with SVT of the
lower limb of at least 5 cm in length [47,50].
Treatment with fondaparinux is associated with a negligible
risk of HIT and it is frequently used with good results even for
the management of patients with suspected HIT [51]. Thus,
fondaparinux may contribute to reduce or even avoid HIT.
In conclusion, thanks to its pharmacokinetic and pharma-
codynamic characteristics, fondaparinux represent a valid
treatment option for both the acute management of patients
with DVT and PE, and for the treatment of SVT.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Heit JA, Spencer FA, White RH. The epidemiology of venous throm-
boembolism. J Thromb Thrombolysis. 2016 Jan;41(1):3–14.
2. Deitelzweig SB, Johnson BH, Lin J, et al. Prevalence of clinical
venous thromboembolism in the USA: current trends and future
projections. Am J Hematol. 2011 Feb;86(2):217–220.
3. Task Force for the Diagnosis and Management of Acute Pulmonary
Embolism of the European Society of Cardiology (ESC). 2014 ESC
guidelines on the diagnosis and management of acute pulmonary
embolism. Eur Heart J. 2014 Nov 14;35(43):3033–3069, 3069a–3069k.
4. Raskob GE, Angchaisuksiri P, Blanco AN, et al.; ISTH Steering
Committee for World Thrombosis Day. Thrombosis: a major con-
tributor to global disease burden. Arterioscler Thromb Vasc Biol.
2014 Nov;34(11):2363–2371.
5. Palareti G. Recurrent venous thromboembolism: what is the risk
and how to prevent it. Scientifica (Cairo). 2012;2012:391734.
6. Zhu T, Martinez I, Emmerich J. Venous thromboembolism: risk factors
for recurrence. Arterioscler Thromb Vasc Biol. 2009 Mar;29(3):298–310.
1264 D. MASTROIACOVO ET AL.
7. Brandjes DP, Heijboer H, Büller HR, et al. Acenocoumarol and
heparin compared with acenocoumarol alone in the initial treat-
ment of proximal-vein thrombosis. N Engl J Med. 1992 Nov 19;327
(21):1485–1489.
8. Hull RD, Raskob GE, Brant RF, et al. The importance of initial
heparin treatment on long-term clinical outcomes of antithrombo-
tic therapy. The emerging theme of delayed recurrence. Arch
Intern Med. 1997 Nov 10;157(20):2317–2321.
9. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-
molecular-weight heparin: mechanisms of action, pharmacoki-
netics, dosing, monitoring, efficacy, and safety. Chest. 2001
Jan;119(1 Suppl):64S–94S.
10. Esmon CT, Jackson CM. The conversion of prothrombin to throm-
bin. III. The factor Xa-catalyzed activation of prothrombin. J Biol
Chem. 1974 Dec 25;249(24):7782–7790.
11. Bauer KA. New anticoagulants. Hematology Am Soc Hematol Educ
Program. 2006;2006(1):450–456.
12. Bauer KA. New anticoagulants: anti IIa vs anti Xa–is one better? J
Thromb Thrombolysis. 2006 Feb;21(1):67–72.
13. O’Shaughnessy DF. Current perspectives on the treatment of
venous thromboembolism: need for effective, safe and convenient
new antithrombotic drugs. Int J Clin Pract. 2004 Mar;58(3):277–284.
14. Matziolis G, Perka C, Disch A, et al. Effects of fondaparinux com-
pared with dalteparin, enoxaparin and unfractionated heparin on
human osteoblasts. Calcif Tissue Int. 2003 Oct;73(4):370–379.
• An in vitro study suggesting no inhibitory effects of fondapar-
inux on human osteoblasts.
15. The Rembrandt Investigators. Treatment of proximal deep vein
thrombosis with a novel synthetic compound (SR90107A/
ORG31540) with pure anti-factor Xa activity: A phase II evaluation.
Circulation. 2000 Nov 28;102(22):2726–2731.
16. Büller HR, Davidson BL, Decousus H, et al.; Matisse Investigators.
Subcutaneous fondaparinux versus intravenous unfractionated
heparin in the initial treatment of pulmonary embolism. N Engl J
Med. 2003 Oct 30;349(18):1695–1702.
•• Results of a phase III randomized trial of fondaparinux in the
treatment of pulmonary embolism.
17. Büller HR, Davidson BL, Decousus H, et al.; Matisse Investigators.
Fondaparinux or enoxaparin for the initial treatment of sympto-
matic deep venous thrombosis: a randomized trial. Ann Intern Med.
2004 Jun 1;140(11):867–873.
•• Results of a phase III randomized trial of fondaparinux in the
treatment of deep vein thrombosis.
18. Di Minno G, Mannucci PM, Tufano A, et al.; First Ambulatory
Screening On Thromboembolism (FAST) Study Group. The first
ambulatory screening on thromboembolism: a multicentre, cross-
sectional, observational study on risk factors for venous throm-
boembolism. J Thromb Haemost. 2005 Jul;3(7):1459–1466.
19. Frappé P, Buchmuller-Cordier A, Bertoletti L, et al.; STEPH Study
Group. Annual diagnosis rate of superficial vein thrombosis of the
lower limbs: the STEPH community-based study. J Thromb
Haemost. 2014 Jun;12(6):831–838.
20. Decousus H, Quéré I, Presles E, et al.; POST (Prospective
Observational Superficial Thrombophlebitis) Study Group.
Superficial venous thrombosis and venous thromboembolism: a
large, prospective epidemiologic study. Ann Intern Med. 2010 Feb
16;152(4):218–224.
21. Galanaud J-P, Genty C, Sevestre M-A, et al.; OPTIMEV SFMV inves-
tigators. Predictive factors for concurrent deep-vein thrombosis
and symptomatic venous thromboembolic recurrence in case of
superficial venous thrombosis. The OPTIMEV study. Thromb
Haemost. 2011 Jan;105(1):31–39.
22. Pomero F, Di Minno MN, Tamburini Premunian E, et al. A clinical
score to rule out the concomitant presence of deep vein throm-
bosis in patients presenting with superficial vein thrombosis: the
ICARO study. Thromb Res. 2015 Nov;136(5):938–942.
23. Blättler W, Schwarzenbach B, Largiadèr J. Superficial vein throm-
bophlebitis–serious concern or much ado about little? Vasa. 2008
Feb;37(1):31–38.
24. Prandoni P, Tormene D, Pesavento R; Vesalio Investigators Group.
High vs. low doses of low-molecular-weight heparin for the treat-
ment of superficial vein thrombosis of the legs: a double-blind,
randomized trial. J Thromb Haemost. 2005 Jun; 3(6):1152–1157.
25. Superficial Thrombophlebitis Treated By Enoxaparin Study Group.
A pilot randomized double-blind comparison of a low-molecular-
weight heparin, a nonsteroidal anti-inflammatory agent, and pla-
cebo in the treatment of superficial vein thrombosis. Arch Intern
Med. 2003 Jul 28;163(14):1657–1663.
26. Di Nisio M, Wichers IM, Middeldorp S. Treatment for superficial
thrombophlebitis of the leg. Cochrane Database Syst Rev. 2013
Apr 30;4:CD004982.
27. Belcaro G, Nicolaides AN, Errichi BM, et al. Superficial thromboph-
lebitis of the legs: a randomized, controlled, follow-up study.
Angiology. 1999 Jul;50(7):523–529.
28. Lozano FS, Almazan A. Low-molecular-weight heparin versus
saphenofemoral disconnection for the treatment of above-knee
greater saphenous thrombophlebitis: a prospective study. Vasc
Endovascular Surg. 2003 Nov-Dec;37(6):415–420.
29. Decousus H, Prandoni P, Mismetti P, et al.; CALISTO Study Group.
Fondaparinux for the treatment of superficial-vein thrombosis in
the legs. N Engl J Med. 2010 Sep 23; 363(13): 1222–1232.
•• Results of a phase III randomized trial of fondaparinux in the
treatment of superficial vein thrombosis.
30. Davidson BL, Büller HR, Decousus H, et al.; Matisse Investigators.
Effect of obesity on outcomes after fondaparinux, enoxaparin, or
heparin treatment for acute venous thromboembolism in the
Matisse trials. J Thromb Haemost. 2007 Jun;5(6):1191–1194.
• A post hoc analysis of Matisse trials in obese patients.
31. van Doormaal FF, Raskob GE, Davidson BL, et al. Treatment of venous
thromboembolism in patients with cancer: subgroup analysis of the
Matisse clinical trials. Thromb Haemost. 2009 Apr;101(4):762–769.
• Post hoc analyses of Matisse trials in cancer patients..
32. Akl EA, Kahale L, Neumann I, et al. Anticoagulation for the initial
treatment of venous thromboembolism in patients with cancer.
Cochrane Database Syst Rev. 2014 ;(6). Article No. CD006649.
33. Pesavento R, Amitrano M, Trujillo-Santos J, et al.; RIETE Investigators.
Fondaparinux in the initial and long-term treatment of venous
thromboembolism. Thromb Res. 2015 Feb;135(2):311–317.
• Real life data on fondaparinux in VTE treatment.
34. Schindewolf M, Scheuermann J, Kroll H. Application, tolerance and
safety of fondaparinux therapy in a German hospital: a prospective
single-centre experience. Thromb Res. 2012 Jan;129(1):17–21.
35. Barginear MF, Gralla RJ, Bradley TP, et al. Investigating the benefit
of adding a vena cava filter to anticoagulation with fondaparinux
sodium in patients with cancer and venous thromboembolism in a
prospective randomized clinical trial. Support Care Cancer. 2012
Nov;20(11):2865–2872.
36. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembo-
lism prophylaxis and treatment in patients with cancer: American
Society of Clinical Oncology clinical practice guideline update. J
Clin Oncol. 2013 Jun 10;31(17):2189–2204.
37. Greinacher A. Clinical practice. Heparin-induced thrombocytopenia.
N Engl J Med. 2015 Jul 16;373(3):252–261.
38. Warkentin TE, Cook RJ, Marder VJ, et al. Anti-platelet factor 4/
heparin antibodies in orthopedic surgery patients receiving antith-
rombotic prophylaxis with fondaparinux or enoxaparin. Blood.
2005 Dec 1;106(12):3791–3796.
39. Kang M, Alahmadi M, Sawh S, et al. Fondaparinux for the treatment
of suspected heparin-induced thrombocytopenia: a propensity
score-matched study. Blood. 2015 Feb 5;125(6):924–929.
•• A retrospective cohort study suggesting the safety of fonda-
parinux in patients with heparin-induced thrombocytopenia.
40. Baroletti S, Labreche M, Niles M, et al. Prescription of fondaparinux
in hospitalised patients. Thromb Haemost. 2009 Jun;101(6):1091–
1094.
41. Schindewolf M, Steindl J, Beyer-Westendorf J, et al. Frequent off-
label use of fondaparinux in patients with suspected acute heparin-
induced thrombocytopenia (HIT)–findings from the GerHIT multi-
centre registry study. Thromb Res. 2014 Jul;134(1):29–35.

42. Blackmer AB, Oertel MD, Valgus JM. Fondaparinux and
the management of heparin-induced thrombocytopenia: the
journey continues. Ann Pharmacother. 2009 Oct;43(10):1636–
1646.
43. Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocyto-
penia associated with fondaparinux. N Engl J Med. 2007 Jun 21;356
(25):2653–2655; discussion 2653–2655.
44. Salem M, Elrefai S, Shrit MA, et al. Fondaparinux thromboprophy-
laxis-associated heparin-induced thrombocytopenia syndrome
complicated by arterial thrombotic stroke. Thromb Haemost. 2010
Nov;104(5):1071–1072.
45. Smythe MA, Priziola J, Dobesh PP, et al. Guidance for the practical
management of the heparin anticoagulants in the treatment of
venous thromboembolism. J Thromb Thrombolysis. 2016 Jan;41
(1):165–186.
46. Linkins L-A, Dans AL, Moores LK, et al. Treatment and prevention of
heparin-induced thrombocytopenia: antithrombotic Therapy and
Prevention of Thrombosis, 9th ed: American College of Chest
EXPERT OPINION ON DRUG SAFETY 1265
Physicians Evidence-Based Clinical Practice Guidelines. Chest.
2012 Feb;141(2 Suppl):e495S–e530S.
47. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE
disease: antithrombotic Therapy and Prevention of Thrombosis, 9th
ed: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e419S–e494S.
48. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE
disease: CHEST guideline and expert panel report. Chest. 2016
Feb;149(2):315–352.
49. Streiff MB, Agnelli G, Connors JM, et al. Guidance for the treatment
of deep vein thrombosis and pulmonary embolism. J Thromb
Thrombolysis. 2016 Jan;41(1):32–67.
50. Nicolaides AN, Fareed J, Kakkar AK, et al. Prevention and treatment
of venous thromboembolism–international consensus statement.
Int Angiol. 2013 Apr;32(2):111–260.
51. Warkentin TE, Davidson BL, Büller HR, et al. Prevalence and risk
of preexisting heparin-induced thrombocytopenia antibodies in
patients with acute VTE. Chest. 2011 Aug;140(2):366–373.