fondaparinux in acs james huffman, pgy-3 emergency medicine grand rounds march 5, 2009

Fondaparinux in ACS

James Huffman, PGY-3

Emergency Medicine Grand Rounds

March 5, 2009

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”

Objectives

Review Anticoagulation

What is Fondaparinux?Brief pharmacology overview

What is the evidence behind its use in ACS?Role in the ED

Unfractionated Heparin

Image Source: www.aafp.org

LMWH

Image Source: www.aafp.org

Fondaparinux

Fondaparinux: pharmacology

Synthetic polysaccharide

Indirect, selective factor Xa inhibitor

Binds to antithrombin III


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.


Metabolism:100% renal clearance (same as LMWH)

No studies on renal dose-adjustment

Thus, GFR < 30mL/min (≈ Cr > 265mmol/L) is a contraindication

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

Evidence

“Fondaparinux will be our anti-coagulant of choice for ACS/NSTEMI

based on the OASIS-5 trial”

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


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


• 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

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%)

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

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

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

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)

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

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

OASIS-6JAMA. 2006;295:1519-1530

Primary End point: death/reinfarction at 30d

Fondaparinux vs UFH, death/reinfarction in patients undergoing primary PCI

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

Drug Life-cycle

Cures Nothing

Balance

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

fondaparinux in acs james huffman, pgy-3 emergency medicine grand rounds march 5, 2009

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