1. Shamir Mehta, MD, MSc, FRCPC Director Interventional Cardiology Associate Professor of Medicine McMaster University Hamilton, Ontario, Canada The Balancing Act in ACS Continues – But with Better Outcomes? A Critical Appraisal of Recent Clinical Data

2. 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 / MIBleeding 1988 ASA 1992 ASA+ Heparin 1998 ASA+ Heparin+ Anti- GPIIB/IIIA 2003 ASA+ LMWH + Clopidogrel + Intervention

3. Bleeding is Associated with an Increased 30-Day Mortality in NSTEMI Patients Rao et al. Am J Cardiol 2005;96:1200-1206 N = 26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A&B Log-rank p values are 0.0001 for all 4 categories, 0.20 for no bleeding vs. mild bleeding, 0.0001 for mild vs. moderate bleeding, and 0.001 for moderate vs. severe bleeding. Adjusted HR (95% CI) % Death 2.9%1.0 3.5%1.6 (1.3-1.9) 5.9%2.7 (2.3-3.4) 25.7%10.6 (8.3-13.6) GUSTO bleedingNoneMildModerateSevere 051015202530 0.70 0.75 0.80 0.85 0.90 0.95 1.00 Days to Death Cumulative survival

4. Procedure-Related and Non-Procedure-Related Bleeds are Associated with an Increased 30-Day Mortality in NSTEMI Patients Rao et al. Am J Cardiol 2005;96:1200-1206 Procedure-related GUSTO bleeds Non-procedure-related GUSTO bleeds Risk of death (Hazard Ratio) None 1.0 Mild 1.3 Severe 16.5 0 5 20 10 15 None 1.0 Mild 2.1 Moderate 2.5 Severe 10.9 Moderate 3.7 N = 26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A & B

5. OASIS Registry, OASIS-2, CURE Strong, Independent Association Outcome Major Bleed No Major Bleed Hazard (Adjusted) P- Value Death 60/470 (12.8%) 833/33676 (2.5%) 5.37 (3.97-7.26) <0.0001 MI 46/436 (10.6%) 1375/33710 (4.1%) 4.44 (3.16-6.24) <0.0001 Stroke 12/469 (2.6%) 187/33677 (0.6%) 6.46 (3.54-11.79) <0.0001 Eikelboom JW et al. Circulation. 2006;114(8):774-82. N = 34,126

6. Increased Mortality at Days 30/180 in Patients with Major Bleeds by Day 9 (All Patients) Budaj et al. JACC. 2006;abstract 972-224 Adjusted HR (95% CI) at day 30: 5.06 (4.59-5.62); at day 180: 3.16 (2.92-3.44) 0.00 0.05 0.10 0.15 0.20 030 6090120150 180 Major Bleed 9 days No Major Bleed 9 days Cumulative Hazard Days

7. Increased Risk of MI at Days 30/180 in Patients with Major Bleeds by Day 9 (All Patients) Adjusted HR (95% CI) at day 30: 5.01 (4.56-5.57); at day 180: 2.99 (2.75-3.28) Budaj et al. JACC. 2006;abstract 972-224 030 6090120150180 Days 0.00 Cumulative Hazard 0.05 0.10 0.15 Major Bleed 9 days No Major Bleed 9 days

8. Increased Risk of Stroke at Days 30/180 in Patients with Major Bleeds by Day 9 (All Patients) Adjusted HR (95% CI) at day 30: 4.77 (3.95-6.00); at day 180: 3.30 (2.82-3.97) Budaj et al. JACC. 2006;abstract 972-224. 030 6090120150180 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Hazard Days Major Bleed 9 days No Major Bleed 9 days

9. Potential Mechanisms for the Higher Morbidity/Mortality Associated with Bleeding 1.Activation of clotting cascade as a response to bleeding--may lead to recurrent events in at the site of plaque rupture 2.Cessation of antithrombotic therapies (eg. ASA, clopidogrel, heparin) after a bleeding event 3.Adverse effects of hypotension due to the bleed 4.Adverse effects of transfusion 5.Common risk factors for bleeding and adverse outcome

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

11. Herbert JM et al. Cardiovasc Drug Rev. 1997;15:1. van Boeckel CAA et al. Angew Chem, Int Ed Engl. 1993;32:1671.  Once daily administration  Rapid onset (C max /2=25 min)  Effects reversible with administration of activated Factor VII (Novoseven®)  No liver metabolism  No protein binding (other than AT)  No risk of pathogen contamination  No reported cases of HIT  No dose adjustment necessary in elderly Fondaparinux: A Synthetic Inhibitor of Factor Xa

12. IIaII Fibrinogen Fibrin clot Extrinsic pathway Intrinsicpathway AT Xa Fondaparinux Xa Antithrombin Fondaparinux Mechanism of Action Olson et al. J Biol Chem. 1992;267:12528-38. Turpie et al. N Engl J Med. 2001;344:619-25. THROMBIN Recycled

13. Ephesus N = 1817 Pentathlon 2000 N = 1584 Penthifra N = 1250 Pentamaks N = 724 Overall Odds Reduction % odds reduction Fondaparinux better Enoxaparin better -100 -80-60-40-2020 0 406080 100 58.5% 28.1% 61.6% 63.1% 55.3% P = 0.000000000000000001 Overall odds reduction for proximal DVT = 57.4% [CI: 72.3 - 35.6]; p = 10 -6 Overall Efficacy of Fondaparinux vs Enoxaparin in VTE Prevention: Meta- analysis Turpie et al. Arch Intern Med. 2002;162:1833-40.

14. 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. 1464-76.

15. Majority of Patients Undergoing Catheterization in OASIS-5 Went Early Mehta et al. JACC 2006; abstract 821-5 44.2% 17.4% 38.4% 0 5 10 15 20 25 30 35 40 45 50 <24 hrs24-48 hrs>48 hrs Patients (%) N = 14,206

16. Similar Efficacy Outcome Rates in Both Groups at Day 9 OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76. 5.8%5.7%Death/MI/RI 1.9% Refractory Ischemia 2.6%2.7%MI 1.8%1.9%Death 4.1% Death/MI FondaparinuxEnoxaparin 0.81.01.2 Non-inferiority Margin = 1.185 Hazard Ratio Fondaparinux better Enoxaparin better

17. Major Bleeding: 9 Days Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0123456789 HR 0.52 95% CI 0.44-0.61 P<<0.00001 Enoxaparin Fondaparinux

18. Mortality: Day 30 Days Cumulative Hazard 0.0 0.01 0.02 0.03 036912151821242730 HR 0.83 95% CI 0.71-0.97 P=0.02 Enoxaparin Fondaparinux

19. Efficacy at 6 Months OASIS 5 Investigators. N Engl J Med. 2006;354:1464-76. 0.811.2 11.3%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 0.06 0.05 NS 0.04 0.007 P value Fondaparinux betterEnoxaparin better Enoxaparin FondaparinuxHazard Ratio

20. All Types of Bleeding were Reduced in the Fondaparinux Group at Day 9 OutcomeEnoxaparin (%) Fondaparinux (%) p value No. Randomized10,02110,057 Total bleeds7.33.3<0.001* Major bleeds4.12.1<0.001 TIMI major + fatal bleeds 1.30.7<0.001** Fatal bleeds0.20.10.005 Minor bleeds3.21.1<0.001 * HR (95% CI): 0.44 (0.39-0.50);**HR (95% CI): 0.55 (0.41-0.74) OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

21. The Reduction in Major Bleeding with Fondaparinux was Consistent in Almost All Categories Major bleeding at day 9 Enoxaparin (No. patients) Fondaparinux (No. Patients) p value No. Randomized10,02110,057 Total Major Bleeds412 (4.1%)212 (2.1%)<0.001 Intracranial77NS Requiring surgery7741<0.001 Retroperitoneal379<0.001 Transfusion282160<0.001 Associated with death at study end 7938<0.001 OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

22. OASIS-5 – The Reduction in Major Bleeding at Day 9 Was Independent of Renal Function OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76. *88 µmol/L Creatinine 1.9%3.4% <1.04 mg/dL* (n = 8871) 2.4%4.7% >1.04 mg/dL* (n = 11,124) FondaparinuxEnoxaparin 0.61.01.2 Interaction p value = 0.71 Hazard Ratio Fondaparinux betterEnoxaparin better 0.80.4

23. Major Bleeding was Reduced with Fondaparinux Irrespective of Creatinine Clearance CrCl (mL/min) Enoxaparin* (%) Fondaparinux (%) P value < 30 (n = 535) 9.92.40.001 > 30 (n = 19442) 4.02.2<0.001 OASIS 5 Investigators. N Engl J Med. 2006;354:1464-76. *Enoxaparin dose reduced to 1 mg/kg od according to label if clearance of creatinine was below 30 mL/min

24. The Reduction in Major Bleeding at Day 9 with Fondaparinux was Consistent in All Subgroups OASIS-5 Investigators. N Engl J Med 2006;354:1464-76 Characteristics N Enoxaparin Fondaparinux % Age ≥ 65 yr12,2615.52.7 < 65 yr78142.11.40.11 Sex Male12,3793.32.0 Female76995.52.50.07 Creatinine At or above median*11,1244.72.4 Less than median*88713.41.90.71 Heparin at randomization Yes 35665.03.0 No16,5124.02.00.35 Revascularization in 9 days Yes73726.04.2 No12,7063.01.0< 0.001 Catheterization laboratory in center Yes 14,0285.02.6 No60502.31.20.88 1.01.40.2 Fondaparinux betterEnoxaparin better 0.40.60.81.2 * The median value for creatinine was 88 µmol/L (1.04 mg/dL) Interaction p value

25. Major Bleeding at Day 30 and GP IIb/IIIa Use HR 0.63 P<0.0001 HR 0.60 P = 0.0001 N = 16448N = 3630

26. Fondaparinux Superior to Enoxaparin for Bleeding Irrespective of Rx Duration HR 0.69 P = 0.001 HR 0.55 P <0.0001 HR 0.67 P = 0.018 N = 5581N = 8712N = 5785

27. Incidence of Major Bleeds with Enoxaparin in OASIS-5 is Consistent with Previous Trials EnoxaparinEnoxFondaEnoxFonda SYNERGY 1 In-hospital ESSENCE 2 Day 30 A to Z 3 Day 6 Meta- analysis 4 Day 7 OASIS 5 Day 9 OASIS 5 Day 9 OASIS 5 Day 30 OASIS 5 Day 30 TIMI major+ fatal bleeds 9.1%-0.9%- 1.3%0.7%1.5%1.0% Major bleeds -6.5%-4.7% 4.1%2.2%5.0%3.1% 1.SYNERGY Investigators. JAMA. 2004;292:45-54. 2.Cohen et al. N Engl J Med. 337:447-52. 3. Blazing et al. JAMA 2004;292:55-64 4.Petersen et al. JAMA. 2004;292:89-96.

28. Fondaparinux-Associated Reduction of Bleeding Translated into Long-Term Mortality Benefit Patients withEnoxaparinFondaparinuxDifference No Bleed526523-3 Minor Bleeds3313-20 Major Bleeds7938-41 Total638574-64 No. of deaths at 180 days OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

29. Days Cumulative Hazard 0.0 0.05 0.10 0.15 020406080100120140160180 Enoxaparin Fondaparinux HR 0.86 95% CI 0.81-0.93 P<<0.00001 Net Clinical Benefits at 6 Months (Death, MI, RI, Major Bleeding)

30. Efficacy and Safety in PCI Patients Outcome Day 9Enox N = 3072 Fonda N = 3105 HR (95% CI)P value Death, MI or Stroke190 (6.2)197 (6.3)1.03 (0.84-1.25) 0.79 Death38 (1.2)37 (1.2)0.96 (0.61-1.52) 0.87 MI154 (5.0)160 (5.2)1.03 (0.82-1.28) 0.80 Stroke13 (0.4)12 (0.4)0.91 (0.42-2.00) 0.82 Major Bleeding155 (5.1)73 (2.4)0.46 (0.35-0.61) <0.00001 Death, MI, stroke, major bleeding 318 (10.4)255 (8.2)0.78 (0.67-0.93) 0.004 Mehta et al. JACC. 2006;abstract 821-5.

31. PCI < 24 Hours of Randomization Outcome Day 9 Enox N = 1420 Fonda N = 1414 HR (95% CI)P value Death, MI or Stroke77 (5.4)75 (5.3)0.98 (0.71-1.34) 0.89 Death19 (1.3) 1.01 (0.53-1.90) 0.98 MI55 (3.9)53 (3.8)0.97 (0.66-1.41) 0.86 Stroke8 (0.6)6 (0.4)0.76 (0.23-2.18) 0.60 Major Bleeding69 (4.9)33 (2.3)0.48 (0.31-0.72) 0.0005 Death, MI, stroke, major bleeding 135 (9.5)103 (7.3)0.76 (0.59-0.98) 0.035 Mehta et al. JACC. 2006;abstract 821-5

32. RR 0.42 95% CI 0.26-0.65 P <0.0001 RR 0.96 95% CI 0.73-1.26 P = 0.78 RR 0.39 95% CI 0.22-0.67 P <0.0001 RR 1.40 95% CI 1.00-1.97 P = 0.048 Major Bleeding 48 hours after PCI Abrupt/threatened abrupt closure N = 1277 N = 1275 N = 1633 N = 1648 N = 1275 RR 0.94 95% CI 0.63-1.33 P=0.62 RR 0.70 95% CI 0.51-0.96 P=0.026 OASIS 5: Fonda vs Enox alone and vs UFH + Enox Mehta et al. Presented at WCC/ESC Hotline Session, Barcelona, 2006 3.8 3.4 6.2 4.3 1.3 5.9 6 0 2 4 5 6 7 % Events Fonda Enox alone UFH + Enox Fonda Enox alone UFH + Enox 1 N = 1633 N = 1648 1.6 3 N = 1277 N = 1633 N = 1648 N = 1277 N = 1275

33. Open Label UFH Prior to PCI Data After Protocol Amendment No UFH Prior to PCIUFH Prior to PCI Enox (%) Fonda (%) HR (95% CI) Enox (%) Fonda (%) HR (95% CI) Number randomized8107938075 Death/MI/Stroke/Maj or Bleed 90 (11.1)80 (10.1)0.90 (0.67-1.22) 9 (11.2)4 (5.3)0.45 (0.14-1.47) Death/MI/Stroke60 (7.4)57 (7.2)0.97 (0.68-1.40) 5 (6.3)3 (4.0)0.62 (0.15-2.61) Major Bleed35 (4.3)26 (3.3)0.75 (0.45-1.25) 5 (6.2)1 (1.3)0.21 (0.02-1.79) Abrupt Closure13 (1.6)15 (1.9)1.18 (0.56-2.5) 01 (1.3)-- Threatened abrupt closure 38 (4.7)31 (3.9)0.83 (0.52-1.32) 2 (2.5)4 (5.3)2.13 (0.40-11.3) Catheter Thrombus4 (0.5)9 (1.1)2.30 (0.71-7.4) 01 (1.3)*-- Vascular Access Site complication 56 (6.9)22 (2.8)0.40 (0.25-0.65) 5 (6.3)1 (1.3)0.21 (0.03-1.8) 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

34. Adding UFH to Fondaparinux is Safe and Preserves the Lower Bleeding with Fondaparinux vs Enoxaparin EnoxFondaHRCI No UFH post- Randomization 1.2 (n = 1277) 0.5 (n = 1313) 0.450.18-1.11 UFH or equivalent placebo mandated by protocol during PCI 1.1 (n = 1229) 0.4 n = 1279) 0.340.12-0.95 Open Label UFH2.7 (n = 598) 1.3 (n = 543) 0.480.20-1.17 Overall1.5 (n = 3104) 0.6 (n = 3135) 0.420.24-0.71 Yusuf S. et al. N Engl J Med. 2006; 354:2829.

35. PCI-Related Complications and MACE (death, MI or stroke) HR 0.79 P<<0.0001 HR 0.81 P<0.0001 HR 0.75 P<<0.0001 Mehta et al. JACC 2006;abstract 821-5

36. Advantage of a Single Dose with Fondaparinux The advantage of a single dose for all patients is clear; in this era of recognition of the common occurrence of medical errors that lead to harm, a single dose would result in fewer medical errors because complex calculations of the type identified in the CRUSADE registry would not be needed Califf. JAMA. 2006;295:1579-80.

37. ACUITY Study Design – Patient Flow UFH/Enox + GP IIb/IIIa (N = 4,603) Bivalirudin + GP IIb/IIIa (N = 4,604) Bivalirudin Alone (N = 4,612) R* 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 Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.

38. ACUITY Primary Outcome: No Difference in Ischemic Outcomes or Major Bleeding with Bivalirudin vs Heparin in Presence of GPI P Sup = 0.93P Sup = 0.39 P Sup = 0.38 Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.

39. ACUITY Primary Endpoint: Lower Bleeding with BIV vs Hep+IIb/IIIa P NI <0.0001 P Sup = 0.015 P NI = 0.011 P Sup = 0.32 P NI <0.0001 P Sup <0.0001 Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.

40. ACUITY: Components of the Ischemic Composite UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone P Sup = 0.32P Sup = 0.34P Sup = 0.35P Sup = 0.78 Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.

41. ACUITY: Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Men (n = 6444) Women (n = 2771) Diabetes (n = 2585) No diabetes (n = 6630) CrCl ≥60 (n = 6993) CrCl <60 (n = 1644) Age <65 (n = 5051) Age ≥65 (n = 4164) Risk ratio ±95% CI Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa 7.8% 12.9% US (n = 5224) OUS (n = 3991) 10.6% 9.5% 8.9% 16.1% 10.8% 9.8% 9.5% 11.6% 9.2% 14.7% 11.8% 11.5% 10.4% 16.8% 13.7% 10.9% 13.5% PP int 0.86 (0.71-1.03) 0.88 (0.75-1.02) 0.90 (0.77-1.05) 0.82 (0.68-0.98) 0.86 (0.74-0.99) 0.96 (0.77-1.19) 0.79 (0.64-0.97) 0.90 (0.78-1.04) 0.87 (0.75-1.00) 0.86 (0.70-1.04) 0.09 0.16 0.03 0.71 0.02 0.16 0.05 0.12 0.89 0.47 0.43 0.28 0.91 RR (95% CI) Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.

42. ACUITY: Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Yes (n = 3197) No (n = 6008) Low (0-2) (n = 1291) Intermed (3-4) (n = 4407) High (5-7) (n = 2449) Elevated (n = 5368) Normal (n = 3841) Risk ratio ±95% CI Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa 9.2% 11.3% 12.2% 11.1% PP int 0.76 (0.65-0.89) 1.02 (0.86-1.21) 12.2% 7.1% 13.3% 9.4% 0.92 (0.80-1.06) 0.75 (0.61-0.93) 0.23 0.01 <0.001 0.83 0.35 0.02 0.18 13.0% 8.6% 13.7% 10.6% 0.96 (0.80-1.14) 0.81 (0.69-0.95) 0.61 0.01 0.42 Biomarkers (CK/Trop) ST Deviation TIMI Risk Score Pre Thienopyridine 6.4%10.2%0.63 (0.43-0.91)0.01 9.4%10.2%0.92 (0.77-1.10) 0.34 13.9%15.2%0.92 (0.76-1.11)0.36 Yes (n = 5192) No (n = 4023) RR (95% CI) Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.

43. ACUITY: Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Bivalirudin alone better UFH/Enox + IIb/IIIa better Bival Alone UFH/Enox + IIb/IIIa PP int 0.59 11.6%13.3%0.87 (0.75-1.00)0.09 10.6%18.2%0.97 (0.75-1.26) 0.84 5.1%6.5%0.78 (0.58-1.04)0.09 0.62 8.3%9.8%0.85 (0.67-1.06)0.15 9.2%9.4%0.98 (0.78-1.23) 0.86 12.5%14.4%0.87 (0.73-1.05)0.14 0.56 9.1%10.0%0.91 (0.73-1.12)0.36 6.7%7.1%0.94 (0.80-1.10) 0.46 10.6%12.6%0.84 (0.65-1.10)0.21 RR (95% CI) PCI (n = 5170) CABG (n = 1048) Medical (n = 2989) No prior AT (n = 3290) Consistent Rx (n = 5519) Crossover (n = 3211) A-thrombin crossover Early (<3.0 h) Intermediate (3.0-19.7 h) Late (≥19.7 h) Risk ratio ±95% CI Risk ratio ±95% CI Actual treatment Rand. to angio/interv. tertiles Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.

44. Summary Fondaparinux reduces bleeding and mortality in patients with NSTEACS compared with enoxaparin including those undergoing early intervention (<24 hours) Standard UFH +/- GPI is recommended in those receiving a PCI Bivalirudin is no different than UFH/enoxaparin in reducing ischemic outcomes or bleeding in presence of a GPI Bivalirudin reduces bleeding compared with UFH/enox + GPI but patients need to be pre-treated with a thienopyridine to maintain efficacy The two agents may be complementary—fondaparinux for initial upstream therapy and bivalirudin in those needing a PCI.