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Fondaparinux in ACS
James Huffman, PGY-3
Emergency Medicine Grand Rounds
March 5, 2009
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Background
Early 2009, I received an e-mail with the following information:
1. Fonadaparinux and bivalirudin have been added to our hospital formulary.
2. Fondaprinux will be our anti-coagulant of choice for ACS/NSTEMI based on the OASIS- 5 trial…
Signed by Dr. Todd Anderson, Chief, Division of Cardiology
January 25, 2009
E-mail sent to ED group quoting:
“decreased bleeding risk, decreased mortality, once daily dosing, not weight dependant and decreased cost”
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Objectives
Review Anticoagulation
What is Fondaparinux?Brief pharmacology overview
What is the evidence behind its use in ACS?Role in the ED
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Unfractionated Heparin
Image Source: www.aafp.org
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LMWH
Image Source: www.aafp.org
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Fondaparinux
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Fondaparinux: pharmacology
Synthetic polysaccharide
Indirect, selective factor Xa inhibitor
Binds to antithrombin III
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Fondaparinux: pharmacology
More pharmacologic benefits:
Binds specifically to antithrombin III and not to irrelevant plasma proteins
Paolucci, et al. 2002.
Exhibits no inhibitory effect on platelet aggregation
Messmore, et al. 1989.
Favorable pharmacokinetic profile after SC administration
100% absorption into plasma
Maximal concentration in 2h
Relatively long half-life (17h)
Predictable dose response, independent of age or sex
Donat, et al. 2002.
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Fondaparinux: pharmacology
Metabolism:100% renal clearance (same as LMWH)
No studies on renal dose-adjustment
Thus, GFR < 30mL/min (≈ Cr > 265mmol/L) is a contraindication
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Pharmacologic comparisonPharmacotherapy 23(6):772-787, 2003
Property UFH LMWH Fondaparinux
Source animal animal synthetic
T1/2 ~3h ~4h (variable) 17-21h
Bioavailability (SC)
30% >90% 100%
EliminationReticuloendothelial
and renalrenal renal
Induced HIT* 2-5% 1-2% Not observed
Inter or intra-patient
variability +++ ++ +
MonitoringaPTT
Plt countPlt count nil
Reversal Protamine Protamine FFP
* Discussed later
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Evidence
“Fondaparinux will be our anti-coagulant of choice for ACS/NSTEMI
based on the OASIS-5 trial”
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OASIS-5: Fondaparinux in UA/NSTEMI N Engl J Med 2006;354:1464-76
Double-blind, double-dummy, industry sponsored trial comparing fondaparinux to enoxaparin in pts with UA or NSTEMI
N = 20 078, 576 centers, 41 countries
Inclusion criteria: (need 2/3 of)
Age ≥ 60
Elevated level of troponin or CKMB
ECG changes indicative of ischemia
Exclusion criteria:
Contraindications to LMWH
Recent hemorrhagic stroke
Need to be anti-coagulated for other reasons
Cr > 265mmol/L
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OASIS-5: Fondaparinux in UA/NSTEMI N Engl J Med 2006;354:1464-76
Primary Outcome (efficacy):
Death, MI or refractory ischemia at 9 days
H0: non-inferiority of fondaparinux vs. enoxaparin
Primary Outcome (safety):
Major bleeding at 9 days
Secondary Outcome:
Primary outcome beyond 9 days
Major bleeding beyond 9 days
Composite end point
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OASIS-5: Fondaparinux in UA/NSTEMI N Engl J Med 2006;354:1464-76
• Other standard treatments as per investigator’s discretion
•Fondaparinux could be given up to hospital d/c or 8d
•Enoxaparin was continued 2-8d (until patient was deemed stable)
* Enoxaparin dosing was q24h if GFR was less than 30 mL/min
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OASIS-5: Fondaparinux in UA/NSTEMI N Engl J Med 2006;354:1464-76
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OASIS-5: Fondaparinux in UA/NSTEMI N Engl J Med 2006;354:1464-76
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OASIS-5: Fondaparinux in UA/NSTEMI N Engl J Med 2006;354:1464-76
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Fondaparinux in PCIJ Am Coll Cardiol 2007;50:1742–51
Prospective, planned analysis of OASIS-5 data for pts undergoing PCI
N = 12 715
Inclusion/Exclusion: same as OASIS-5
Results:
Efficacy at 9d: no difference (i.e. non-inferiority for death, MI or stroke)
Safety at 9d: major, minor and total bleeding significantly reduced with fondaparinux
Catheter Thrombus: overall, <1%,
Fondaparinux group (0.9%)
Enoxaparin alone (0.4%)
Enoxaparin with UFH (0.2%)
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Fondaparinux in PCIJ Am Coll Cardiol 2007;50:1742–51
Why more catheter thrombosis in fondaparinux group?
Potentially secondary to lack of any anti-thrombin activity
Prior to protocol amendment, none of these pts had additional heparin
Despite higher rate of thrombosis in fondaparinux group, initially similar rates of death, MI and stroke.
Probably off-set by decreased rates of bleeding
Addition of UFH to fondaparinux did not increase major bleeding
1.3% with open-label UFH vs 3.3% prior to UFH
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Heparin-Induced Thrombocytopenia
4 in-vitro studies showed no platelet activation and no cross-reactivity of fondaparinux to HIT antibodies
Elalamy I. Thromb Haemost 1995;74(5):1384–5.
Amiral J, et al. Blood Coagul Fibrinolysis 1997;8:114–17.
Ahmad S, et al. Clin Appl Thromb Hemost 1999;5(4):259–66.
Savi P, et al. Blood 2005;105(1):139–44.
OASIS-5:
Not reported
OASIS-6:
Not reported
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2007 ACC/AHA GuidelinesCirculation 2007;116;e148-e304
In patients for whom the diagnosis of UA/NSTEMI is likely or definite:
Invasive & Conservative management strategies:
Anti-coagulant therapy receives a class 1 recommendation
Level of evidence for Fondaparinux: B
Note: Enoxaparin & UFH have level of evidence: A
Conservative strategy and increased bleeding risk:
Fondaparinux is preferable. LOE: B
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2007 ACC/AHA GuidelinesCirculation 2007;116;e148-e304
Concerns with OASIS-5:
1. Dose of UFH needed to prevent catheter thrombosis not defined
2. The suggestion that fondaparinux may be preferable in pts with higher bleeding risk has face validity, but has not been studied a priori
3. and some question the enoxaparin dosing in OASIS-5 for higher risk patients (renal failure)
4. Safety of open-label UFH (appeared safe, but discordant with SYNERGY)
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UA/NSTEMI: Bottom Line
Evidence is generally robust for use in UA/NSTEMI
In this setting, fondaparinux appears to be at least as effective as enoxaparin, is cheaper, and maybe more safe
Endorsed by ACC/AHA, SAEM and our local cardiologists
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OASIS-6JAMA. 2006;295:1519-1530
Randomized, double-blinded, controlled trial comparing fondaparinux (2.5mg sc daily) to usual care (either placebo, or UFH)
N = 12 092
Inclusion:
STEMI within 24h* onset of symptoms (shortened to 12h after 4300 pts)
Exclusion:
Contraindications to anticoagulation (including high bleeding risk)
Renal failure
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OASIS-6JAMA. 2006;295:1519-1530
Primary End point: death/reinfarction at 30d
Fondaparinux vs UFH, death/reinfarction in patients undergoing primary PCI
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AHS Current Recommendations
Don’t give fondaparinux to:
1. STEMI patients going directly to PCI
2. Patients with Renal failure (GFR <30 mL/min or Cr <265mmol/L)
3. Patients going directly to the cath lab
Fondaparinux can generally be used for all other cases of ACS/NSTEMI as 2.5mg SC daily
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Drug Life-cycle
Cures Nothing
Balance
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Take Home:
1. Renal failure is a contraindiation (Cr > 265mmol/L or GFR <30)
2. HIT does not appear to be an issue (don’t need to monitor)
3. Reversal is discontinuation and FFP
4. In setting of UA/NSTEMI, fondaparinux is as effective as enoxaparin and maybe safer (bleeding)
5. Likely no benefit if going directly to cath lab