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Fondaparinux In Acute Coronary Syndromes

Fondaparinux in Acute Coronary Syndromes

Authors: Dr Francis Joshi & Dr Denise Braganza


Correspondence: denise.braganza@papworth.nhs.uk
Agreed by Network Steering Group January 2012 reviewed November 2013
Review November 2016

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Fondaparinux In Acute Coronary Syndromes

Antiplatelet and antithrombotic therapy in Acute Coronary Syndromes

ST-Elevation
MI

PRIMARY
PCI
Aspirin
Clopidogrel
+/- GpIIb/IIIa
UFH if PCI

Non-ST-Elevation MI/ACS
Late presenting STEMI

Non-ST-Elevation MI/ACS
Late presenting STEMI

INVASIVE STRATEGY

CONSERVATIVE
STRATEGY

EARLY
ANGIOGRAPHY
within 2 hours

DEFERRED
ANGIOGRAPHY>
2 hours

Aspirin

Aspirin

Clopidogrel

Clopidogrel

+/- GpIIb/IIIa

FONDAPARINUX
2.5mg sc OD for up
to 8 days

UFH if PCI

CONSIDER:
Aspirin
Clopidogrel
FONDAPARINUX
2.5mg sc OD for
up to 8 days if
troponin +ve

+/- GpIIb/IIIa

CATH LAB
UFH if PCI

NOTES:
1. This is not a protocol. Clinical judgement should be applied to weigh individual benefit vs risk of bleeding
2. For renal impairment with eGFR<20ml/min OR Creatinine>265mol/litre give enoxaparin 1mg/Kg sc ONCE
daily and NOT fondaparinux
3. Fondaparinux does not need to be stopped prior to angiography but may be withheld at operators discretion
4. Unfractionated heparin (UFH) should be given at the time of PCI. A dose of 50-100U/kg is recommended
depending on concomitant use of a glycoprotein IIb/IIIa inhibitor (GpIIb/IIIa)
5. Closure devices (Angioseal or Terumo bands) allow immediate sheath withdrawal; alternatively sheath
removal needs to be delayed until 6 hours after the last dose of fondaparinux (and ACT < 150s if UFH given)
6. Enoxaparin remains the drug of choice for medical and surgical thromboprophylaxis, treatment of DVT/PE
2
and thromboprophylaxis in patients with AF

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Fondaparinux In Acute Coronary Syndromes

Fondaparinux in Acute Coronary Syndromes


Use of antithrombotic heparins has been commonplace in ACS. Unfractionated heparins (UFH) were
used initially. Limitations include poor bioavailability at low doses and short half-lives requiring
intravenous infusions for prolonged use, with monitoring of therapeutic effect.
Low molecular weight heparins (LMWH), including enoxaparin, have a more predictable dose-effect
relationship and can be administered subcutaneously without need for monitoring of coagulation.
Maximum plasma levels are achieved 3 to 5 hours after administration subcutaneously. Use of
LMWH has been shown to have a lower risk of inducing thrombocytopenia than UFH 1. In ACS, LMWH
have been shown superior to UFH2,3, though the SYNERGY study suggested increased bleeding with
crossover from enoxaparin to receiving additional UFH 4.
Bleeding complications remain an important issue in patients presenting with ACS. Patient-related
risk factors include increasing age, female sex, a history of bleeding and chronic renal impairment 5.
Procedural factors include choice of arterial access for invasive management, and use of antiplatelet
and antithrombotic therapy. Major bleeding after both conservative and invasive treatment of ACS is
associated with worse outcomes over the short and medium term 6.
The indirect Factor Xa inhibitor fondaparinux has been trialled extensively in ACS. It binds selectively
to antithrombin and neutralises Factor Xa at the convergence of the intrinsic and extrinsic
coagulation cascade. Generation of thrombin is attenuated, with reduced thrombus formation.
Dose-effect relationship is predictable, with a peak plasma concentration less than 2 hours after sc
administration, and a plasma half-life of 15 to 17 hours 7. No monitoring of effect is required. A oncedaily dose of 2.5mg s.c. is effective for all patients 8. It is excreted unchanged via the kidneys and is
contraindicated in those with a CrCl <30ml/min. It does not appear to cross-react with sera from
patients with heparin-induced thrombocytopenia, and this complication is thought very unlikely.
Protamine does not reverse its effect, though the use of recombinant Factor VIIa may do so 9.
In the multi-centre OASIS-5 study10, over 20,000 patients presenting with NSTEACS were randomised
to receive upstream either enoxaparin (1mg/Kg) bd or fondaparinux 2.5mg sc od, in addition to
standard antiplatelet therapy. Exclusion criteria were serum creatinine >265mol/litre, recent
haemorrhagic stroke, contraindications to LWMH and indications for anticoagulation other than ACS.
Over 12,000 patients went on to have angiography within the study drug period. The study drug was
given for up to 8 days, to the point of discharge, or until PCI was performed. It could be restarted
after intervention at the discretion of the operator. Consistent with European data, about half of
these patients underwent PCI, and represented an intermediate-to-high risk group. Overall, at 9
days, fondaparinux was non-inferior to enoxaparin on the primary efficacy outcome measure of
Death/MI/Refractory Ischaemia (5.8% vs 5.7%; HR 1.01, 95% CI 0.90-1.13). The rates of the main
secondary outcome of Death or MI at 9 days were similar. (4.1% vs 4.1%) Major bleeding at 9 days,
defined by Thrombolysis In Myocardial Infarction criteria, was reduced significantly. (2.2% vs 4.1%;
HR 0.52, p<0.001) Largely driven by this reduction in bleeding, there were significant differences
noted at 30 days in rates of Death (2.9% vs 3.5%; HR 0.83, p 0.02) and composite
Death/MI/Refractory Ischaemia/Major Bleeding (10.2% vs 12.4%; HR 0.82, P=0.001) that persisted
out to 180 days. A reduction in bleeding was seen regardless of age, sex, use of additional UFH, the
presence of cath lab facilities on-site, or time to revascularisation.

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Fondaparinux In Acute Coronary Syndromes

In patients undergoing PCI11, use of fondaparinux was associated at Day 9 with a similar reduction in
major bleeding (2.4% vs 5.1%; HR 0.46, p=0.001) and the composite endpoint of
Death/MI/Stroke/Major Bleeding (8.2% vs 10.4%; HR 0.78, p=0.004). This effect again persisted to 30
and 180 days, as for the study population as a whole. Vascular access site complications including
pseudoaneurysm and large haematoma were reduced (3.3% vs 8.1%, p<0.001)

Subgroup analysis demonstrated reductions in bleeding in all subgroups including those with
transradial access, chronic renal impairment, patients undergoing PCI within 24 hours, and the use
of clopidogrel and/or glycoprotein inhibtors 12.

Patients presenting with ST-elevation MI were studied in the OASIS-6 trial. Relevant to local practice
with Primary PCI, no benefit in terms of a reduction in bleeding or the composite endpoint of
Death/Re-infarction with the use of fondaparinux over UFH 13.

The OASIS-8/FUTURA study14 looked specifically at dosing of UFH at the time of PCI in fondaparinuxtreated patients who had presented with unstable angina or NSTEMI, with a focus on bleeding
complications. 2026 patients were randomised to receive either an adjunctive standard dose of
85U/Kg of UFH (60U/Kg if on glycoprotein inhibitors) with further boluses to achieve a target ACT or
a low-dose regimen of 50U/Kg irrespective of glycoprotein inhibitor use. Three quarters of patients
had presented with NSTEMI. Glycoprotein inhibitors were used in just one quarter of patients,
predominantly upfront rather than for bail-out indications. The primary outcome measure was a
composite of peri-PCI (within 48 hours) major bleeding, minor bleeding and major access site
complications. The main secondary outcome measure was a composite of major bleeding peri-PCI,
death, myocardial infarction and target vessel revascularization (TVR). The trial was underpowered
for analysis of ischaemic outcomes alone. The incidence of bleeding complications was consistent
with those seen in OASIS-5. No differences were noted between the two groups with regard to the
primary outcome measure. A benefit in favour of the standard UFH regime just reached a level of
significance for the main secondary endpoint (3.9%vs 5.8%, p=0.05), though pre-specified analysis of
the components of this showed no significant differences between the two arms. A reduction in
minor bleeding was noted in the low-dose UFH group.

The use of fondaparinux has been reviewed and incorporated into the most recent guidelines
regarding NSTEACS. The 2007 ESC guidelines 15 have given it a Class 1 Recommendation (Level of
Evidence A) for anticoagulation in a non-urgent setting, though suggested UFH, bivalirudin or
enoxaparin as antithrombotics when emergent invasive treatment is required on presentation. NICE
Clinical Guideline 9416 recommended its use for cases where angiography was planned to take place
more than 24 hours after admission, with UFH as an alternative for more emergent cases.
Fondaparinux was thought cost-effective as compared to UFH, easier to administer and superior in
clinical outcomes to enoxaparin.

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Fondaparinux In Acute Coronary Syndromes

Specific issues
Chronic renal impairment
Patients with renal dysfunction pose a particular problem, with higher risks associated with
presentations with ACS and also an increased bleeding risk with current therapy. A subsequent
analysis of OASIS-5 indicated that the benefit in reducing bleeding risk of fondaparinux over
enoxaparin was actually greatest in those with the most renal impairment (GFR<58ml/min/1.73m 2)15
The definiton of renal impairment precluding use of fondaparinux has varied between trials. In
OASIS-5 and OASIS-6, fondaparinux was not given to patients with a serum creatinine of
>265mol/litre. The manufacturers website reports that it is contraindicated in those with a
creatinine clearance less than 30ml/minute 17, while a creatinine clearance of less than 20ml/min was
the cut-off used in OASIS-8. It should be remembered that creatinine clearance will over estimate
GFR in severe renal impairment because of tubular secretion and that this measure is not used
routinely in clinical practice. Using a more practical measure, the British National Formulary 18 states
that fondaparinux should not be given for treatment of acute coronary syndromes when the
estimated GFR is less than 20ml/min/1.73m 2.
Based on the above analysis, NICE guidance recommend unfractionated heparin as an alternative for
those with renal dysfunction outside either of these parameters, rather than once-daily enoxaparin
(1mg/Kg) given currently. Whilst apparently logical, real-world experience of monitoring of
intravenous heparin infusions is now minimal and evidence suggests that supratherapeutic dosing is
frequent and commonplace19. It is probable, though not evidence-based, that continuing to use
once-daily enoxaparin will remain the most practical antithrombotic to use in patients with a serum
creatinine >265mol/litre or GFR<20ml/min/1.73m2.

Low Body Weight


Fondaparinux should be used with caution in patients with a body weight < 50kg as elimination is
reduced.

Conservatively managed patients


Such patients are currently treated as inpatients for 5 days. OASIS-5 allowed for treatment with
fondaparinux for up to 8 days, though the mean duration of therapy was 5.4 days. Current European
guidelines suggest continuing therapy until discharge, for a maximum of 8 days.

Late presentation/non-reperfused ST-elevation MI


Around a quarter of patients will present either late or with other reasons precluding reperfusion for
STEMI. Equivalent efficacy in terms of Death and Re-infarction has previously been shown for LMWH
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Fondaparinux In Acute Coronary Syndromes

as compared to UFH20. Analysis of the OASIS-6 study population presenting with STEMI but not
reperfused demonstrated a modest reduction in a composite of Death/Re-infarction at 30 days with
fondaparinux over placebo or UFH infusion (12.2%vs 15.1%; HR 0.80; 95% CI 0.650.98). There was
no difference in severe bleeding between the groups 21. This subgroup were older than the OASIS-6
population as a whole, and presented later. Use of dual anti-platelet therapy and statins was limited.
Its value in terms of local practice is likely limited, but use of fondaparinux as for NSTEACS appears
safe.

Fondaparinux Dosing prior to Angiography


Fondaparinux does not need to be stopped prior to angiography. This is supported by the OASIS-8
protocol which aimed for angiography to be undertaken within 18 hours of the previous
fondaparinux dose. In the published results, the median time from last dose of fondaparinux to
index PCI was 4 hours.

Dosing of UFH at the time of PCI


The results of OASIS-8 suggest that there is no evidence to support a routine use of low-dose UFH in
all fondaparinux-treated patients. The adjunctive standard regime used in the trial protocol
mandated an initial bolus of 85U/Kg, with further doses up to a maximum of 10000 Units. Further
dosing was guided by measurement of ACT at 5 minutes, aiming for an ACT of 250-300 seconds on a
Hemotech device (300 to 350 seconds on a Hemochron).
It is recommended by both the authors of OASIS -5 11,21 (and NICE) that patients undergoing PCI are
given UFH at a dose of 50-100U/Kg as per standard treatment in the cath lab, and not additional
intravenous doses of fondaparinux. Current European guidelines follow the OASIS-8 protocol more
closely, recommending an initial bolus of 85U/Kg and ACT-guided further doses as described above.

Glycoprotein IIb/IIIa inhibitors (GpIIb/IIIa)


In OASIS-5, around 40% of those undergoing an invasive strategy were on glycoprotein inhibitors.
Post-hoc analysis12 demonstrated a statistically significant 40% reduction in Major Bleeding and
composite clinical outcomes consistent with the study results as a whole.
As per OASIS-8 and current European guidelines 15, an UFH dose of 60U/Kg should be given in those
undergoing PCI who are treated with GpIIb/IIIa inhibitors, aiming for a target ACT of 200 seconds.

Guide catheter thrombosis


In OASIS-5, this was reported in both study arms, though with an excess in those given fondaparinux
(0.3% vs 1.2%). This did not appear to impact on the rate of PCI-related coronary complications (8.6
vs. 9.5%, RR 1.11 95% CI 0.941.29, p=0.21) for enoxaparin vs. fondaparinux. Interventional
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Fondaparinux In Acute Coronary Syndromes

operators were reminded that the protocol allowed for the unblinded use of UFH at their discretion.
The final 1758 cases were analysed specifically for this. Use of UFH at a mean dose of 47U/Kg
appeared to reduce this complication. In those fondaparinux-treated patients documented as having
developed catheter thrombosis after 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 low dose of
open-label UFH of 5 U/Kg11.
In support of the use of additional UFH at the time of PCI, patients undergoing non-Primary PCI after
STEMI in the OASIS-6 trial17 (250 on fondaparinux and 239 controls) were mandated to receive UFH
prior to PCI. No catheter thrombosis was noted in either group. In the much larger OASIS-8
population, guide catheter thrombosis was rare in both groups and very rare (0.1%) in the group
receiving standard doses of UFH14.
Management of vascular access after angiography/PCI
No change is required in the use of femoral artery closure devices or the removal of radial artery
sheaths. If a femoral puncture is not suitable for closure device, or the sheath left in at the discretion
of the operator, then the sheath should remain until at least 6 hours 21 after the last dose of
fondaparinux, and manual compression/Femstop applied in the usual way. If felt clinically
appropriate, fondaparinux can be continued 2 hrs after sheath removal, providing there has been a
delay of at least 18 hours after the last dose 14.

Management of bleeding complications whilst on fondaparinux


The effect of fondaparinux is non reversible and unless there is a life threatening bleed or a bleed
into a critical site like the CNS management is supportive only. Anti-Xa levels will allow an
assessment of the residual activity of Fondaparinux in the patient
Recombinant Factor VIIa (rVIIa) is a therapeutic option should only be used with extreme caution
due to the increased risk of thromboembolic complications and high cost and is only available from
blood bank after discussion with the duty Haematologist.
Protamine is not effective in reversal of Fondaparinux.

Agreed by Network Steering Group January 2012 reviewed November 2013


Review November 2016

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Fondaparinux In Acute Coronary Syndromes

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Agreed by Network Steering Group January 2012 reviewed November 2013
Review November 2016
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