1. Fondaparinux in ACS James Huffman, PGY-3 Emergency Medicine Grand Rounds March 5, 2009

3. 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”

4. Objectives  Review Anticoagulation  What is Fondaparinux?  Brief pharmacology overview  What is the evidence behind its use in ACS?  Role in the ED

5. Unfractionated Heparin Image Source: www.aafp.org

6. LMWH Image Source: www.aafp.org

7. Fondaparinux

8. Fondaparinux: pharmacology  Synthetic polysaccharide  Indirect, selective factor Xa inhibitor  Binds to antithrombin III

9. 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.

10. Fondaparinux: pharmacology  Metabolism:  100% renal clearance (same as LMWH)  No studies on renal dose-adjustment  Thus, GFR 265mmol/L) is a contraindication

11. Pharmacologic comparison Pharmacotherapy 23(6):772-787, 2003 Property UFHLMWHFondaparinux Source animal synthetic T 1/2 ~3h~4h (variable)17-21h Bioavailability (SC) 30%>90%100% Elimination Reticuloendothelial and renal renal Induced HIT* 2-5%1-2%Not observed Inter or intra- patient variability ++++++ Monitoring aPTT Plt count nil Reversal Protamine FFP * Discussed later

12. Evidence “Fondaparinux will be our anti- coagulant of choice for ACS/NSTEMI based on the OASIS-5 trial”

13. 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

14. 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  H 0 : 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

15. OASIS-5: Fondaparinux in UA/NSTEMI N Engl J Med 2006;354:1464-76 Fondaparinux Group 2.5mg SC q24h Enoxaparin Placebo q12h Enoxaparin Group 1mg/kg SC q12h* Fondaparinux placebo q24h 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

16. OASIS-5: Fondaparinux in UA/NSTEMI N Engl J Med 2006;354:1464-76

19. Fondaparinux in PCI J 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%)

20. Fondaparinux in PCI J 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

21. 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

22. 2007 ACC/AHA Guidelines Circulation 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

23. 2007 ACC/AHA Guidelines Circulation 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)

24. 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

25. OASIS-6 JAMA. 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

26. OASIS-6 JAMA. 2006;295:1519-1530 Primary End point: death/reinfarction at 30d Fondaparinux vs UFH, death/reinfarction in patients undergoing primary PCI

27. 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

28. Drug Life-cycle Cures Nothing Balance

29. 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