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16th Interventional Cardiology Symposium Montreal, Quebec / June 14-16, 2007

16th Interventional Cardiology Symposium Montreal, Quebec / June 14-16, 2007. Adapted from a presentation by: Shamir R. Mehta, MD, MSc, FRCPC, FACC “Transitioning ACS Patients to the Cath Lab: Optimizing Outcomes with Upstream Fondaparinux and Bivalirudin/UFH” Friday, June 15, 2007.

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16th Interventional Cardiology Symposium Montreal, Quebec / June 14-16, 2007

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  1. 16th Interventional Cardiology SymposiumMontreal, Quebec / June 14-16, 2007 Adapted from a presentation by: Shamir R. Mehta, MD, MSc, FRCPC, FACC “Transitioning ACS Patients to the Cath Lab: Optimizing Outcomes with Upstream Fondaparinux and Bivalirudin/UFH” Friday, June 15, 2007

  2. Transitioning ACS Patients to the Cath Lab: Optimizing Outcomes with Upstream Fondaparinux and Bivalirudin/UFH Shamir R. Mehta, MD, MSc, FRCPC, FACC Director, Interventional Cardiology Hamilton Health Sciences Associate Professor of Medicine McMaster University Hamilton, Ontario, Canada

  3. Antithrombotics in UA/NSTEMI Patients in the Last Decade: Increased Efficacy at the Price of Increased Bleeding Bleeding 2003 ASA+ LMWH + Clopidogrel + PCI 1998 ASA+ UFH+GPIIb/IIIa Inhib 1988 ASA 1992 ASA+ UFH 16-20% 12-15% 8-12% Death / MI 6-10% 4-8%

  4. Coagulation Cascade and New Anticoagulants Extrinsic pathway Intrinsic pathway IXa 1 Fondaparinux VIIIa Ca2+ X Xa PL Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin Xa Va 50 Ca2+ IIa II PL Fibrinogen Fibrin Bivalirudin Clot Rosenberg & Aird. N Engl J Med. 1999;340:1555–64. Wessler & Yin. Thromb Diath Haemorrh. 1974;32:71–8.

  5. OASIS-5: A Randomized, Double-Blind, Double-Dummy Trial 20,078 patients with UA/NSTEMI Aspirin, Clopidogrel, anti-GPIIb/IIIa, planned Cath/PCI as per local practice Randomization Enoxaparin 1 mg/kg s.c. bid for 2-8 days 1 mg/kg s.c. od if ClCr<30mL/min Fondaparinux 2.5 mg s.c. od up to 8 days Michelangelo OASIS-5 Steering Committee. Am Heart J. 2005;150:1107.e1-.e10. OASIS 5 Investigators. I. 1464-76.

  6. Majority of Patients Undergoing Catheterizationin OASIS-5 Went Early N = 14,206 50 44.2% 45 38.4% 40 35 30 25 Patients (%) 17.4% 20 15 10 5 0 <24 hrs 24-48 hrs >48 hrs Mehta et al. JACC 2006; abstract 821-5

  7. Fondaparinux and Enoxaparin Non-inferiorfor Efficacy at 9 Days Non-inferiority Margin = 1.185 P=0.002 Enoxaparin Fondaparinux Death/MI/RI 5.7% 5.8% Death/MI 4.1% 4.1% Death 1.9% 1.8% MI 2.7% 2.6% Refractory Ischemia 1.9% 1.9% Hazard Ratio 0.8 1.0 1.2 Fondaparinux better Enoxaparin better OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

  8. Fondaparinux Substantially Reduces Major BleedingCompared with Enoxaparin 0.04 HR 0.52 95% CI 0.44-0.61 P<<0.00001 Enoxaparin 0.03 Cumulative Hazard 0.02 Fondaparinux 0.01 0.0 0 1 2 3 4 5 6 7 8 9 Days

  9. Fondaparinux Reduces 30-Day all-cause Mortality Compared with Enoxaparin Enoxaparin 0.03 Fondaparinux 0.02 Cumulative Hazard HR 0.83 95% CI 0.71-0.97 P=0.02 0.01 0.0 0 3 6 9 12 15 18 21 24 27 30 Days

  10. Fondaparinux Superior to Enoxaparin for Efficacy at 6 Months Enoxaparin Fondaparinux Hazard Ratio P value Death/MI/RI 13.2% 12.3% 0.06 Death/MI 11.4% 10.5% 0.05 Death 6.5% 5.8% 0.05 MI 6.6% 6.3% Stroke 1.7% 1.3% 0.04 Death/MI/Stroke 12.5% 11.3% 0.007 0.8 1 1.2 Hazard Ratio Fondaparinux better Enoxaparin better OASIS 5 Investigators. N Engl J Med. 2006;354:1464-76.

  11. Net Clinical Benefit FavoursFondaparinux in Patients Undergoing PCI and Early PCI Early PCI<24 hours Mehta et al. JACC. 2006;abstract 821-5.

  12. Catheter Thrombus Virtually Eliminated After Protocol Amendment Allowing UFH to be Used for PCI Final 1758 patients randomized *represents 1 patient with low dose of UFH 5 IU/kg vs mean dose of 47 IU/kg Mehta et al. JACC. 2006;abstract 821-5

  13. Adding UFH to Fondaparinux for PCI is Safe and Preserves the Lower Bleeding with FondaparinuxvsEnoxaparin Mean Dose of UFH for PCI Used in OASIS 5: 47 IU/Kg Yusuf S. et al. N Engl J Med. 2006; 354:2829.

  14. OASIS 5: Using UFH for PCI Reduces Angiographic Complications with Enoxaparin without Increasing Bleeding Abrupt/threatened abrupt closure Major Bleeding 48 hours after PCI RR 0.70 95% CI 0.51-0.96 P=0.026 RR 0.94 95% CI 0.63-1.33 P=0.62 7 6.2 6 5.9 6 5 4.3 3.8 % Events 4 3.4 N = 1648 3 N = 1277 Enox alone Fonda UFH + Enox Fonda N = 1277 N = 1648 N = 1633 N = 1275 1.6 N= 1633 2 N = 1275 1.3 N = 1275 N = 1633 N = 1648 N = 1277 Enox alone UFH + Enox 1 Fonda Fonda 0 RR 0.42 95% CI 0.26-0.65 P <0.0001 RR 0.39 95% CI 0.22-0.67 P <0.0001 RR 0.96 95% CI 0.73-1.26 P = 0.78 RR 1.40 95% CI 1.00-1.97 P = 0.048 Mehta et al. Presented at WCC/ESC Hotline Session, Barcelona, 2006

  15. OASIS 5: Fondaparinux Reduces Major Bleeding with or without Concomittant Use of IV GP IIb/IIIa Inhibitors HR 0.60 P = 0.0001 HR 0.63 P<0.0001 N = 3630 N = 16448

  16. Fondaparinux Superior to Enoxaparin Even with Very Short Durations of Treatment HR 0.69 P = 0.001 HR 0.55 P <0.0001 HR 0.67 P = 0.018 N = 8712 N = 5785 N = 5581

  17. How to Transition Patients Initiated on Fonda to the Cath Lab • Treat with ASA, Clopidogrel, Statin and Fondaparinux +/- IV nitro in the ER • Proceed to Cath Lab as usual* • If PCI needed, give bivalirudin or UFH (dose 50 IU/kg) +/- IIb/IIIa • Post procedure, follow usual practice for sheath removal. Immediate removal if closure device or radial and 6 hours after last fonda sc dose if no closure device used *May perform cath>6 hours after last sc dose if this was center’s usual practice with using LMWH

  18. ACUITY Study Design – Patient Flow Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy UFH/Enox + GP IIb/IIIa (N = 4,603) GPI upstream (N = 2294) GPI CCL for PCI (N = 2309) Moderate- high risk ACS Bivalirudin + GP IIb/IIIa (N = 4,604) GPI upstream (N = 2311) R* GPI CCL for PCI (N = 2293) Aspirin in all Clopidogrel dosing and timing per local practice Bivalirudin Alone (N = 4,612) * Stratified by pre-angiography thienopyridine use or administration Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.

  19. ACUITY Primary Endpoint: Lower Bleeding with BIV vsHep+IIb/IIIa PSup = 0.015 PSup = 0.32 PSup <0.0001 Stone GW, et al. N Engl J Med. 2006;355:2203-16.

  20. ACUITY PCI: Influence of Thienopyridine Exposure – PCI pts RR [95%CI] 0.81 (0.68-0.96) RR [95%CI] 0.96 (0.77-1.20) RR [95%CI] 0.50 (0.37-0.67) RR [95%CI] 1.07 (0.83-1.39) RR [95%CI] 1.37 (1.00-1.88) RR [95%CI] 0.61 (0.39-0.97) Thienopyridine Exposed* Not Thienopyridine Exposed *Thienopyridine at any time, any dose, up to time of PCI Interaction P values = 0.17, 0.19 and 0.65 respectively

  21. ACUITY PCI: “ISAR-REACT-2 Like” Patients Troponin+ PCI pts, Thienopyridine use prior to PCIGPI started after angiography but before PCI (N=1358) RR [95%CI] 0.84 [0.62-0.1.13] RR [95%CI] 1.00 [0.67-1.49] RR [95%CI] 0.53 [0.34-0.83]

  22. Anticoagulation is recommended for all patients in addition to antiplatelet therapy (I-A) • Anticoagulation should be selected according to the risk of both ischaemic and bleeding events (I-B) • Several anticoagulants are available, namely UFH

  23. Evidence-Based Risk Stratification to Target Therapies in UA/NSTEMI Aspirin, Clopidogrel, Fondaparinux (Class 1A) β-blocker, Nitrates Higher Risk +Troponin, ST s, TRS 3, Recurrent Ischemia, CHF, Prior Revascularization Lower Risk – ECG, – Markers, TRS 0-2 Conservative Strategy Invasive Strategy Recurrent Ischemia or high risk stress test PCI Bivalirudin or UFH (+IV GP IIb/IIIa) UFH dose 50 IU/kg No PCI Medical Rx or CABG (hold fonda and clopidogrel)

  24. Summary • Fondaparinux reduces bleeding and mortality in patients with NSTEACS compared with enoxaparin including those undergoing early intervention (<24 hours) • Bivalirudin with a thienopyridine reduces bleeding compared with UFH/enox + GPI • Fondaparinux and bivalirudin are likely to be complementary—fondaparinux for initial upstream therapy of ACS and bivalirudin in place of UFH+GP IIb/IIIa in those undergoing PCI • This strategy has the potential to lead to the lowest rates of bleeding (and enhanced efficacy) we have ever seen in ACS

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