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

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

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

Coagulation Cascade and New Anticoagulants Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin Intrinsic pathway Extrinsic pathway 1 50 X II Fibrin Fibrinogen Clot Xa Va PL Ca 2+ VIIIa Ca 2+ PL IXa Bivalirudin Fondaparinux Xa IIa Rosenberg & Aird. N Engl J Med. 1999;340:1555–64. Wessler & Yin. Thromb Diath Haemorrh. 1974;32:71–8.

OASIS-5: A Randomized, Double-Blind, Double-Dummy Trial 20,078 patients with UA/NSTEMI Fondaparinux 2.5 mg s.c. od up to 8 days 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 Michelangelo OASIS-5 Steering Committee. Am Heart J. 2005;150:1107.e1-.e10. OASIS 5 Investigators. I

Majority of Patients Undergoing Catheterization in OASIS-5 Went Early Mehta et al. JACC 2006; abstract % 17.4% 38.4% <24 hrs24-48 hrs>48 hrs Patients (%) N = 14,206

Fondaparinux and Enoxaparin Non-inferior for Efficacy at 9 Days OASIS-5 Investigators. N Engl J Med. 2006;354: %5.7%Death/MI/RI 1.9% Refractory Ischemia 2.6%2.7%MI 1.8%1.9%Death 4.1% Death/MI FondaparinuxEnoxaparin Non-inferiority Margin = P=0.002 Hazard Ratio Fondaparinux better Enoxaparin better

Fondaparinux Substantially Reduces Major Bleeding Compared with Enoxaparin Days Cumulative Hazard HR % CI P<< Enoxaparin Fondaparinux

Fondaparinux Reduces 30-Day all-cause Mortality Compared with Enoxaparin Days Cumulative Hazard HR % CI P=0.02 Enoxaparin Fondaparinux

Fondaparinux Superior to Enoxaparin for Efficacy at 6 Months OASIS 5 Investigators. N Engl J Med. 2006;354: %12.5% Death/MI/Stroke 12.3%13.2%Death/MI/RI 1.3%1.7%Stroke 6.3%6.6%MI 5.8%6.5%Death 10.5%11.4%Death/MI P value Fondaparinux betterEnoxaparin better Enoxaparin FondaparinuxHazard Ratio 1

Net Clinical Benefit Favours Fondaparinux in Patients Undergoing PCI and Early PCI Outcome Day 9 Enox N = 3072 Fonda N = 3105 HR (95% CI)P value Death, MI or Stroke Major Bleeding < Death, MI, stroke, major bleeding Mehta et al. JACC. 2006;abstract Death, MI or Stroke Major Bleeding Death, MI, stroke, major bleeding Early PCI<24 hours

Catheter Thrombus Virtually Eliminated After Protocol Amendment Allowing UFH to be Used for PCI No UFH Prior to PCIUFH Prior to PCI Enox (%) Fonda (%) HR (95% CI) Enox (%) Fonda (%) HR (95% CI) No. randomized Death/MI/Stroke60 (7.4)57 (7.2) 0.97 ( ) 5 (6.3)3 (4.0) 0.62 ( ) Major Bleed35 (4.3)26 (3.3) 0.75 ( ) 5 (6.2)1 (1.3) 0.21 ( ) Catheter Thrombus4 (0.5)9 (1.1) 2.30 ( ) 01 (1.3)*-- 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

Adding UFH to Fondaparinux for PCI is Safe and Preserves the Lower Bleeding with Fondaparinux vs Enoxaparin EnoxFondaHRCI No UFH post- Randomization 1.2 (n = 1277) 0.5 (n = 1313) UFH or equivalent placebo mandated by protocol during PCI 1.1 (n = 1229) 0.4 n = 1279) Open Label UFH2.7 (n = 598) 1.3 (n = 543) Overall1.5 (n = 3104) 0.6 (n = 3135) Yusuf S. et al. N Engl J Med. 2006; 354:2829. Mean Dose of UFH for PCI Used in OASIS 5: 47 IU/Kg

OASIS 5: Using UFH for PCI Reduces Angiographic Complications with Enoxaparin without Increasing Bleeding Mehta et al. Presented at WCC/ESC Hotline Session, Barcelona, 2006 RR % CI P < RR % CI P = 0.78 RR % CI P < RR % CI P = Major Bleeding 48 hours after PCI Abrupt/threatened abrupt closure N = 1277 N = 1275 N = 1633 N = 1648 N = 1275 RR % CI P=0.62 RR % CI P= % Events Fonda Enox alone UFH + Enox Fonda Enox alone UFH + Enox 1 N= 1633 N = N = 1277 N = 1633 N = 1648 N = 1277 N = 1275

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

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

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

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

ACUITY Primary Endpoint: Lower Bleeding with BIV vs Hep+IIb/IIIa P Sup = 0.015P Sup = 0.32P Sup < Stone GW, et al. N Engl J Med. 2006;355:

Thienopyridine Exposed* Not Thienopyridine Exposed ACUITY PCI: Influence of Thienopyridine Exposure – PCI pts RR [95%CI] 0.81 ( ) RR [95%CI] 0.96 ( ) RR [95%CI] 0.50 ( ) RR [95%CI] 1.07 ( ) RR [95%CI] 1.37 ( ) RR [95%CI] 0.61 ( ) Interaction P values = 0.17, 0.19 and 0.65 respectively *Thienopyridine at any time, any dose, up to time of PCI

RR [95%CI] 1.00 [ ] RR [95%CI] 0.53 [ ] RR [95%CI] 0.84 [ ] Troponin+ PCI pts, Thienopyridine use prior to PCI GPI started after angiography but before PCI (N=1358) ACUITY PCI: “ISAR-REACT-2 Like” Patients

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

Evidence-Based Risk Stratification to Target Therapies in UA/NSTEMI Recurrent Ischemia or high risk stress test 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 Invasive Strategy Conservative Strategy PCI Bivalirudin or UFH (+IV GP IIb/IIIa) UFH dose 50 IU/kg No PCI Medical Rx or CABG (hold fonda and clopidogrel)

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