European Heart Journal Supplements (2008) 10 (Supplement C), C14–C21

doi:10.1093/eurheartj/sun002

Clinical benefit and practical use of fondaparinux

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in the invasive management of patients
with acute coronary syndromes
Shamir R. Mehta*
Interventional Cardiology, Hamilton Health Sciences, General Division, 237 Barton Street East, Hamilton, Ontario,
Canada L6K 1B8

KEYWORDS In patients with high-risk non-ST-elevation acute coronary syndromes (NSTE-ACS), an

Acute coronary syndromes; invasive management strategy has been found to be superior to a conservative strat-
Anticoagulant; egy. In the real world, 50% of patients treated with an invasive strategy require a
Fondaparinux; percutaneous coronary intervention (PCI) procedure, whereas the remaining 40–50%
Low-molecular-weight
are treated medically and a small proportion (,10%) undergo coronary artery
heparins;
bypass graft surgery. Therefore, anti-thrombotic drugs need to be both safe and effec-
Percutaneous coronary
intervention;
tive when started early in a broad range of patients with ACS, regardless of ultimate
Unfractionated heparin revascularization status. Fondaparinux is the first selective inhibitor of factor Xa
approved for use across the whole spectrum of patients with ACS. In patients with
NSTE-ACS in the OASIS-5 study, upstream treatment with fondaparinux was found to
have superior net clinical benefit compared with enoxaparin in patients undergoing
PCI. Fondaparinux reduced death, myocardial infarction, stroke, or major bleeding
by 22% compared with enoxaparin (P ¼ 0.004). Even in those undergoing early PCI
(i.e. within the first 24 h), there was a 24% relative risk reduction in favour of fonda-
parinux (P ¼ 0.035). The main benefit was a large 54% reduction in major bleeding
(P , 0.001), which was achieved with near identical rates of ischaemic events (6.3
vs. 6.2%). Catheter thrombus occurred with very low incidence in both the fondapar-
inux and the enoxaparin groups and was virtually eliminated in both groups with
adjunctive unfractionated heparin (UFH) administered in the catheterization labora-
tory just prior to PCI. In the fondaparinux group, the mean dose of UFH was about
50 U/kg. On the basis of these data and the overall results of the OASIS-5 trial, the
experts of the American College of Cardiology/American Heart Association and of
the European Society of Cardiology gave fondaparinux a class I recommendation for
use in patients with NSTE-ACS undergoing invasive strategy. In practice, fondaparinux
is easy to use (fixed dose of 2.5 mg once daily for all patients) and is associated with
improved patient outcomes, including those patients managed with an invasive
strategy.

Introduction including those managed with an invasive strategy and

Anticoagulation is a standard of care for the management
of all patients with acute coronary syndromes (ACS),
* Corresponding author. Tel: þ1 905 521 2631; fax: þ1 905 527 4463.
E-mail address: smehta@mcmaster.ca
those managed with a conservative strategy.1,2 In
patients with high-risk non-ST-segment elevation ACS
(NSTE-ACS), an invasive management strategy has been
found to be superior to a conservative strategy.3,4 In
the real world, about half of all the patients with
NSTE-ACS managed with an invasive strategy will

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008.
For permissions please email: journals.permissions@oxfordjournals.org.
Clinical benefit and practical use of fondaparinux C15

receive a percutaneous coronary intervention (PCI)

procedure.5,6 When considering those also treated with
an initial conservative strategy (e.g. patients with
advanced age or co-morbidities, patient preference),
the true rate of PCI in the real world is closer to about
30%. Since it is not known at the time of patient first
contact whether a given patient referred for early angio-
graphy will receive a PCI or not, anti-thrombotic strat-
egies must be both safe and effective in a broad range
of patients.

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Unfractionated heparin (UFH) has been the traditional
anticoagulant of choice in patients with NSTE-ACS, but its
administration requires an intravenous infusion, it may
cause heparin-induced thrombocytopenia, and its anti-
coagulant effect shows a large intra- and inter-individual Figure 1 Comparison of percutaneous coronary interventions in OASIS-5
and EuroHeart Survey.5
variability, necessitating regular monitoring of the acti-
vated partial thromboplastin time (aPTT). Thus, although
it is useful in the catheterization laboratory because it
can be given as a single bolus, monitored easily using
the activated clotting time (ACT) and reversed if necess- Table 1 Baseline characteristics of patients undergoing
percutaneous coronary intervention in OASIS-515
ary using protamine sulphate, it is not an ideal agent for
upstream therapy. Enoxaparin was shown to be superior Parameter Fondaparinux Enoxaparin
to UFH in patients undergoing mainly a conservative (n ¼ 3134) (n ¼ 3104)
strategy,7,8 but in patients treated with an invasive strat-
egy, it was no better than UFH and resulted in higher Age (years), mean 64.6 64.5
rates of severe bleeding complications in the SYNERGY Female (%) 28.3 30.9
trial.9,10 Even in those patients who did not switch thera- Troponin/ 79.0 80.3
pies, in a recent meta-analysis by Petersen et al.,11 enox- CKMB.ULN (%)
aparin was still associated with higher bleeding rates ST depression 42.3 39.2
1 mm (%)
than UFH. Further, there was a significant hazard to
T wave inversion 21.3 22.0
using enoxaparin alone in those undergoing early PCI in 2 mm (%)
the SYNERGY trial, making this a sub-optimal agent in Prior heart failure (%) 7.2 7.4
this setting.12 Prior myocardial 22.6 20.0
Fondaparinux is the first selective inhibitor of factor Xa infarction (%)
approved for use across the whole spectrum of patients Diabetes (%) 23.5 23.1
with ACS.13 In the OASIS-5 trial, fondaparinux was found Prior CABG (%) 9.0 8.4
to be non-inferior to enoxaparin early, but reduced mor- Prior PCI (%) 16.9 16.1
tality and ischaemic events relative to enoxaparin at Lesion location (%)
30 days and 6 months.14 It was also substantially safer, Left main coronary 1.0 1.5
artery
with a reduction in major bleeding of about one-half.
Left anterior 41.5 42.0
The overwhelming majority of patients (.14 000) in the ascending coronary
OASIS-5 trial were treated with an invasive strategy and artery
about half of these underwent PCI. In this article, we Circumflex artery 26.4 25.9
review the data for fondaparinux in patients undergoing Right coronary 27.7 27.1
an invasive strategy15 and provide practical advice on artery
how to incorporate fondaparinux into routine clinical Saphenous vein graft 3.3 3.4
practice.
CABG, coronary arterial bypass graft surgery; PCI, percutaneous
coronary intervention; ULN, upper limit of normal.

Results in patients undergoing percutaneous

coronary intervention: superior net benefit
of fondaparinux
Out of 20 078 patients enrolled in OASIS-5, 14 206
patients underwent heart catheterization and 12 715
during the study drug administration period; this pro-
cedure was performed in 8919 patients within the first
72 h after randomization, respectively. A total of 6238
patients underwent PCI during the study drug adminis-
tration period; the procedure was performed within
24 h after randomization in 2834 patients. These data
closely reflect current European practice5 (Figure 1).
The baseline characteristics were well matched
between the two randomized treatment groups
(Table 1). Overall, these patients represented an inter-
mediate to a high-risk population; they exhibited high-
risk features indicating the need for an early invasive
strategy according to the European Society of Cardiology
(ESC) guidelines1 (Figure 2).
C16
Figure 2 Criteria for early invasive management according to the European Society of Cardiology Guidelines in patients enrolled in OASIS-5. Asterisk
indicates that data were not available to assess two of the criteria: reduced left ventricular function (ejection fraction ,35%) and early post-infarction
angina. CABG, coronary arterial bypass graft surgery; ESC, European Society of Cardiology; PCI, percutaneous coronary intervention.
Table 2 Concomitant medications in patients undergoing
percutaneous coronary intervention in OASIS-515
Medication Fondaparinux Enoxaparin
(n ¼ 3134) (n ¼ 3104)
Aspirin (%) 98.6 98.9
Thienopyridine (%) 91.1 92.3
GP IIb/IIIa 40.4 38.8
antagonist (%)
b-blocker (%) 88.1 89.5
ACE/ARB (%) 73.7 73.8
Statin (%) 83.7 83.6
ACE, angiotensin-converting enzyme-inhibitor; ARB, angiotensin
receptor blocker.
Subcutaneous fondaparinux and enoxaparin were given
for a mean (+SD) of 2.4 (1.8) days and 2.6 (1.8) prior to
PCI, respectively. The median duration of therapy in
patients undergoing PCI was 2.5 days. The study drug
was stopped either because of clinical stabilization, a
revascularization procedure or discharge from hospital.
Overall, 99% of patients received aspirin and 92% a
thienopyridine (Table 2).
At Day 9, death, myocardial infarction, or stroke in
patients undergoing PCI occurred with a similar fre-
quency in the fondaparinux and the enoxaparin group
(Table 3). Taken individually, the rate of each of these
outcomes was also similar in the two groups. In contrast,
major bleeding was reduced by 54% (P , 0.001) in
fondaparinux-treated patients. There was a similarly
large reduction in the rate of minor and total bleeding
with fondaparinux. Overall, the net clinical composite
of death, myocardial infarction, stroke, or major bleed-
ing was significantly (P ¼ 0.004) lower in the fondapari-
nux group than in the enoxaparin group.
Whereas the restarting of the study drug after PCI did
not increase the rate of major bleeding, fondaparinux
was superior to enoxaparin in reducing major bleeding
irrespective of whether the study drug was restarted
[1.9 vs. 4.4%; hazard ratio (95% confidence interval):
0.42 (0.29–0.60); P , 0.001] or not restarted [3.7 vs.
S.R. Mehta
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6.6%; hazard ratio (95% confidence interval): 0.55
(0.35–0.84); P , 0.001] after the procedure.
The bleeding reduction observed in patients treated
with fondaparinux was consistent irrespective of age:
the hazard ratio (95% confidence interval) was 0.49
(0.37–0.66) (P , 0.001) and 0.58 (0.34–0.99) (P ¼
0.047) in favour of fondaparinux in patients 65 years
and ,65 years, respectively. Fondaparinux also reduced
major bleeding compared with enoxaparin irrespective
of GPIIb/IIIa inhibitors or thienopyridine use. The trans-
radial approach was associated with fewer major bleed-
ing complications than the trans-femoral approach
(1.6 vs. 3.5%, P , 0.003), but fondaparinux markedly
reduced major bleeding when compared with enoxaparin
regardless of the arterial vascular access (Figure 3).16
Furthermore, the net clinical benefit in favour of fon-
daparinux was maintained at Days 30 and 180, highlight-
ing the clinical superiority of fondaparinux over
enoxaparin in PCI patients over the long term.
Fondaparinux in very early percutaneous
coronary intervention
Consistent results were obtained in the subgroup of
patients in whom PCI was performed within 24 h after
randomization (Table 3). At Day 9, death, myocardial
infarction or stroke occurred with a similar frequency in
the fondaparinux and the enoxaparin group. However,
there was a substantial reduction (52%, P , 0.001) in
major bleeding in fondaparinux-treated patients. Overall,
the net clinical composite of death, myocardial
infarction, stroke, or major bleeding was significantly
(P ¼ 0.035) lower in the fondaparinux group than in the
enoxaparin group.
Rapid emergence of bleeding benefit
with fondaparinux
The safety benefit of fondaparinux in terms of bleeding
risk appeared as early as the day of randomization (i.e.
within hours of the administration of the first dose of
study drug), indicating that, even with very short
Clinical benefit and practical use of fondaparinux
Table 3 Clinical outcomes at Day 9 in patients undergoing percutaneous coronary intervention in OASIS-515
All PCI patients Fondaparinux
(n ¼ 3105)
Death, myocardial infarction, stroke, major 8.2%
bleeding
Death, myocardial infarction, stroke 6.3%
Major bleeding 2.4%
Early PCI (i.e. within 24 h of randomization) Fondaparinux
(n ¼ 1414)
Death, myocardial infarction, stroke, major 7.3%
bleeding
Death, myocardial infarction, stroke 5.3%
Major bleeding 2.3%
CI, confidence interval; PCI, percutaneous coronary intervention.
Figure 3 Major bleeding at Day 9 in patients undergoing percutaneous
coronary intervention according to arterial access site.16
durations of therapy, fondaparinux was safer in terms of
bleeding risk than enoxaparin (Table 4). On subsequent
days, the occurrence of major bleeding remained sub-
stantially lower with fondaparinux compared with enoxa-
parin. These results support the administration of
fondaparinux in patients with NSTE-ACS who are dis-
charged early from hospital.
Minimization of catheter thrombus risk with
unfractionated heparin as adjunct
In the initial protocol, patients randomized to fondapar-
inux underwent PCI without adjunct UFH. In contrast, in
patients randomized to enoxaparin, no additional study
drug was given if PCI was performed within 6 h of the
last study drug injection. When the interval was more
than 6 h, UFH was used in the enoxaparin arm. This strat-
egy was used since enoxaparin is not approved for use in
PCI.17 Moreover, neither the ESC nor the American
College of Cardiology/American Heart Association (ACC/
AHA) guidelines recommend its use in PCI.1,2 So far, no
anticoagulant has been demonstrated to be more effec-
tive than UFH for anticoagulation during PCI. Thus, in
enoxaparin patients recruited in OASIS-5, the additional
C17
Enoxaparin Hazard ratio (95% CI) P-value
(n ¼ 3072)
10.4% 0.78 (0.67–0.93) 0.004
6.2% 1.03 (0.84–1.25) 0.79
5.1% 0.46 (0.35–0.61) ,0.001
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Enoxaparin
(n ¼ 1420)
9.5% 0.76 (0.59–0.98) 0.035
5.4% 0.98 (0.71–1.34) 0.89
4.9% 0.48 (0.31–0.72) ,0.001
dose of UFH was 100 U/kg when no GPIIb/IIIa inhibitor
was used and 65 U/kg when a GPIIb/IIIa inhibitor was
administered. Of note, the addition of UFH to the enox-
aparin group 6 h after the last subcutaneous enoxaparin
administration lowered the rate of abrupt/threatened
vessel closure compared with those undergoing PCI with
enoxaparin alone (4.3% with UFHþenoxaparin vs. 6.2%
with enoxaparin alone, P ¼ 0.026). Importantly, the use
of UFH at least 6 h after the last subcutaneous enoxa-
parin injection did not increase the risk of major bleeding
in the enoxaparin group (Figure 4).
During the trial, catheter thrombosis was reported to
occur in a small number of patients. To reduce this
event, the Operations Committee (without any knowl-
edge of the number of catheter thromboses by random-
ized group) reminded the centres that they were
allowed to give open-label UFH prior to PCI in addition
to protocol-mandated study drug. Moreover, to record
this issue in a more systematic way, the case report
forms were amended to capture all cases of catheter
thrombus and whether open-label UFH was given in the
catheterization laboratory prior to PCI. These data
were routinely collected in the final 1758 patients under-
going PCI. For the first time, information on the occur-
rence of catheter thrombosis was systematically
collected in a randomized trial.
Overall, catheter thrombosis occurred very rarely in
both groups (but significantly more with fondaparinux)
before the implementation of the amendment recom-
mending the open-label use of UFH (Table 5). Of note,
previous studies also showed that catheter thromboses
may occur in enoxaparin-treated patients.18–20 In the
fondaparinux group, the occurrence of this event was vir-
tually eliminated after the amendment with the use of
open-label UFH at an average dose of 47 U/kg. Catheter
thrombus occurred in 10 fondaparinux-treated patients
following the protocol amendment; nine events occurred
when no UFH was given prior to PCI and the remaining
case occurred in a patient who received a very low
dose of open-label UFH (570 U or 5.0 U/kg). Importantly,
the addition of open-label UFH did not increase the
C18
Table 4 Incidence of major bleeding events according to the day after randomization in patients undergoing percutaneous coronary
intervention in OASIS-515
Days after randomization Fondaparinux (n ¼ 3105)
Same day 0.2%
1 0.7%
2 1.1%
3 1.4%
4 1.7%
5 1.8%
6 2.0%
7 2.2%
8 2.4%
Figure 4 Major bleeding 48 h after percutaneous coronary intervention
according to the use of protocol-specified unfractionated heparin in the
enoxaparin group.15 If percutaneous coronary intervention was performed
within 6 h of the last subcutaneous enoxaparin dose, no additional UFH
was given. If percutaneous coronary intervention was performed 6 h
after the last subcutaneous enoxaparin dose, UFH was administered for
the procedure. PCI, percutaneous coronary intervention; UFH, unfractio-
nated heparin.
bleeding rate in the fondaparinux group (1.3% with open-
label UFH vs. 3.3% with no open-label UFH) and did not
influence the safety benefit of fondaparinux over
enoxaparin.
Other data showed that whether examining the inci-
dence of local PCI complications þ major adverse
cardiac events (MACE), or of local PCI complications þ
major bleeding, there was a consistent net clinical
benefit in favour of fondaparinux compared with enoxa-
parin in PCI patients.
The data of OASIS-6 trial in patients with ST-elevation
acute myocardial infarction (STEMI) confirmed the fact
that adding UFH to fondaparinux patients undergoing
PCI is effective for preventing catheter thrombosis and
safe in terms of bleeding risk.21 A total of 250 fondapar-
inux patients (corresponding to targeted patients in the
current European labelling of fondaparinux) and 239
control patients (receiving UFH or placebo upstream
PCI) underwent a PCI other than primary PCI (including
rescue PCI, routine PCI and PCI for recurrent ischaemia);
all of them received UFH as recommended prior to the
procedure and no catheter thrombosis was reported in
either group. The respective rates of death/myocardial
S.R. Mehta
Enoxaparin (n ¼ 3072) Relative risk P-value
0.5% 0.35 0.037
1.7% 0.40 ,0.001
2.8% 0.40 ,0.001
3.6% 0.40 ,0.001
4.0% 0.42 ,0.001
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4.3% 0.42 ,0.001
4.7% 0.42 ,0.001
5.0% 0.43 ,0.001
5.0% 0.45 ,0.001
infarction/stroke were 14.3 and 16.0%, whereas the
rates of major bleeding were 2.4 and 3.3%. These
results are therefore very consistent with the OASIS-5
data in PCI patients and corroborate the statement that
it is reasonable to recommend the intravenous use of
UFH during PCI at a dose between 50 and 100 U/kg in fon-
daparinux patients in order to minimize the risk of cath-
eter thrombus without impairing the clinical benefit of
the drug.
Integrating fondaparinux into daily practice
in patients managed with an invasive
strategy
In the latest guidelines established by the ACC/AHA and
the ESC, fondaparinux was recommended with a class I
recommendation in patients undergoing invasive
strategy.1,2
Figures 5 and 6 show a flow diagram on the rec-
ommended use of fondaparinux in patients with
NSTE-ACS, with invasive strategy in higher-risk patients
and conservative strategy in low-risk patients.
In patients requiring primary PCI for STEMI or urgent
PCI within minutes to hours (e.g. shock), UFH is
recommended for initial treatment. All other NSTE-ACS
patients, for whom the decision to undergo conservative
or invasive management is pending, should receive initial
treatment by fondaparinux 2.5 mg subcutaneously.1,2
Percutaneous coronary intervention procedures
If a patient treated with fondaparinux is scheduled to
undergo PCI, the transition to the catheterization labora-
tory is simple in practice. In situations where a patient
has on-going chest pain and haemodynamic instability,
there is no need to delay the procedure—in this scenario
of early PCI, patients should proceed to the catheteriza-
tion laboratory and UFH should be administered intrave-
nously in the catheterization laboratory at a standard
dose (50–100 U/kg). If patients have stabilized initially,
catheterization can be delayed and if PCI is needed, stan-
dard UFH should be administered as a bolus prior to the
Clinical benefit and practical use of fondaparinux C19

Table 5 Clinical outcomes at Day 30 according to the use of open label unfractionated heparin given in the catheterization
laboratory prior to percutaneous coronary intervention in OASIS-515

Outcome No open-label UFH prior to PCI Open-label UFH prior to PCI

Fondaparinux Enoxaparin Hazard ratio Fondaparinux Enoxaparin Hazard ratio

(n ¼ 793) (n ¼ 810) (95% CI) (n ¼ 75) (n ¼ 80) (95% CI)

Catheter thrombus, 9 (1.1) 4 (0.5) 2.30 (0.71–7.4) 1 (1.3)a 0 –

n (%)

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Death, myocardial 57 (7.2) 60 (7.4) 0.97 (0.68–1.40) 3 (4.0) 5 (6.3) 0.62 (0.15–2.61)
infarction, stroke,
n (%)
Major bleeding, n (%) 26 (3.3) 35 (4.3) 0.75 (0.45–1.25) 1 (1.3) 5 (6.2) 0.21 (0.02–1.79)
Death, myocardial 80 (10.1) 90 (11.1) 0.90 (0.67–1.22) 4 (5.3) 9 (11.2) 0.45 (0.14–1.47)
infarction, stroke,
major bleeding,
n (%)

CI, confidence interval; PCI, percutaneous coronary intervention; UFH, unfractionated heparin.
a
This event occurred in a patient who received 5 U/kg of UFH vs. a mean dose of 47 U/kg in the total PCI group.

Figure 5 Evidence-based risk stratification to target therapies in patients with non-ST elevation acute coronary syndromes. Asterisk indicates class I
recommendations in the guidelines established by the ACC/AHA (Level of evidence B) and ESC. CHF, congestive heart failure; PCI, percutaneous coronary
intervention; TRS, TIMI risk score; UFH, unfractionated heparin.

Figure 6 Fondaparinux in practice in patients with non-ST-elevation acute coronary syndromes undergoing percutaneous coronary intervention. UA,
unstable angina; NSTEMI, non-ST-elevation myocardial infarction.
C20
procedure at a dose of 50–100 U/kg. The dose of 50 U/kg
of UFH may be preferred in fondaparinux patients who
were co-administered GPIIb/IIIa antagonists. However,
it must be underlined that no change to current practice
is needed concerning the use and dose of GPIIb/IIIa
inhibitors. Thus, for interventional cardiologists accus-
tomed to using UFH for the PCI procedure, adding UFH
on top of fondaparinux for the PCI procedure does not
represent a significant change from their routine prac-
tice. Bivalirudin may be an option instead of UFH and a
GPIIb/IIIa antagonist in patients treated upstream with
fondaparinux based on the low bleeding risk with both
agents, but no data have been published using this
novel combination (trials are on-going).
Sheath removal procedures
If a closure device is used, or in the case of radial access,
sheath removal should be immediate; if no closure device
is used, sheath removal should be performed at least 6 h
after last fondaparinux subcutaneous dose. As with other
anticoagulants, the administration of fondaparinux may
be stopped within 24 h of the invasive procedure, but
this may be left to the physician’s discretion. If restarted
after the PCI, the next fondaparinux injection should be
performed 2 h after sheath removal, while leaving 24 h
between two fondaparinux injections. If coronary artery
bypass graft surgery was selected after diagnostic angio-
graphy, discontinuation of fondaparinux 24 h before the
procedure is recommended.
Conclusion
Fondaparinux is the first selective inhibitor of factor Xa
approved for use in patients with NSTE-ACS (excluding
patients requiring PCI within two hours after symptom
onset) or STEMI (treated with thrombolytics or no reper-
fusion) at a dose of 2.5 mg once daily. The clinical benefit
of fondaparinux was demonstrated in patients with
NSTE-ACS undergoing early PCI and in patients with
STEMI undergoing non primary PCI. In a combined analysis
of patients undergoing PCI in the OASIS-5 and OASIS-6
studies, fondaparinux was similar to UFH or enoxaparin
in reducing death, myocardial infarction, or stroke (8.0
vs. 8.0%), but reduced major bleeding (2.9 vs. 5.5%;
hazard ratio: 0.52; P , 0.0001), resulting in a superior
net clinical benefit as assessed by death, myocardial
infarction, stroke, or major bleeding (9.0 vs. 11.8%;
hazard ratio: 0.75; P ¼ 0.01).22 If a PCI is performed in
patients treated upstream with fondaparinux, it is rec-
ommended that adjunctive intravenous UFH be given at
a dose of 50–100 U/kg to minimize the risk of catheter
thrombus.
In practice, fondaparinux is easy to use (2.5 mg once
daily for all patients) and is a simplification vs. UFH or
enoxaparin treatments as no dose adjustments are
necessary. Because dose adjustments are not needed, it
may limit dosing errors that have been reported with
other anti-thrombotic drugs which may increase bleeding
or death.23 Fondaparinux is a new standard of
S.R. Mehta
anticoagulation that should bring significant reductions
in bleeding and improve the overall prognosis of patients
with ACS who are managed both with an invasive and a
non-invasive approach.
Conflict of interest: Consultant and/or research grants and/or
honoraria from GlaxoSmithKline, Sanofi-Aventis, Boston Scienti-
fic, Abbott Vascular, Bristol Myers Squibb, Eli Lilly, Oryx,
Astrazeneca.
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