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

Learn about optimizing outcomes for ACS patients with Fondaparinux and Bivalirudin in the cath lab. Explore efficacy and bleeding insights from the 16th Interventional Cardiology Symposium in Montreal. Understand antithrombotics, coagulation cascade nuances, and clinical benefits comparing anticoagulants.

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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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