1. OASIS 5 Access AHA 2006 Martial Hamon, Shamir Mehta, Gabriel Steg, David Faxon, Prafulla Kerkar, Hans-Jürgen Rupprecht, Jean-Francois Tanguay, Rizwan Afzal, Salim Yusuf On behalf of the Oasis 5 investigators Major bleeding in patients with acute coronary syndrome undergoing early invasive management can be reduced by fondaparinux, even in the context of trans-radial coronary intervention: Insights from OASIS-5 Trial. OASIS 5

2. Fondaparinux: AT Xa IIIIa THROMBIN Fibrinogen Fibrin Fondaparinux Antithrombin Intrinsic pathway Extrinsic pathway  Synthetic pentasaccharide  Pure factor Xa inhibitor  Selective binding to antithrombin  Rapid and predictable inhibition of factor Xa

3. OASIS-5 20,078 patients with Non ST-ACS 2 of 3 criteria : Age > 60. Δ ST. rise of biol. makers Fondaparinux 2.5 mg / d Randomization Enoxaparin 1 mg/kg X 2/d PEP: Efficacy : death, MI, refract. Ischemia @ day 9 Safety : major bleeding Net clinical outcome : death, MI, refract. Ischemia, major bleeding Secondary EP: Individual PEP (death) @ day30 & day180   Hypothesis : non-inferiority test then superiority test ASA. Clopidogrel. GP IIb/IIla IV

4. Primary Endpoint OASIS 5 Death/MI/RI day 9 Cumulative Hazard 0123456789 0.0 0.01 0.02 0.03 0.04 0.05 0.06 NS Days from randomization Fondaparinux Enoxaparin N Engl J Med 2006;354:1464-76

5. Major bleeding at day 9 0123456789 0.0 0.01 0.02 0.03 0.04 Days from randomization Enoxaparin Fondaparinux HR 0.53 IC 95% 0.45-0.62 p << 0.00001 Cumulative Hazard N Engl J Med 2006;354:1464-76

6. Net clinical outcome at Day 9 Enoxaparin Fondaparinux HR 0.82 IC 95 % 0.74-0.90 p << 0.00001 0123456789 0.0 0.02 0.04 0.06 0.08 Days from randomization Cumulative Hazard N Engl J Med 2006;354:1464-76

7. Death through day 30 Mortality at Day 30 N Engl J Med 2006;354:1464-76

8. Background The use of combined antithrombotic therapies and routine invasive procedures in ACS has decreased the risk of ischemic events substantially but remains associated with a significant increase in bleeding risk.The use of combined antithrombotic therapies and routine invasive procedures in ACS has decreased the risk of ischemic events substantially but remains associated with a significant increase in bleeding risk. Recently Fondaparinux in the OASIS 5 trial has been shown to be a preferred alternative to enoxaparin in this setting because it preserves efficacy and by significantly reducing major bleeding provides for better long-term event-free survival.Recently Fondaparinux in the OASIS 5 trial has been shown to be a preferred alternative to enoxaparin in this setting because it preserves efficacy and by significantly reducing major bleeding provides for better long-term event-free survival. The impact of a trans-radial approach to percutaneous coronary intervention (PCI) on efficacy and bleeding in ACS patients treated with a contemporary pharmacological regimen remains unknown.The impact of a trans-radial approach to percutaneous coronary intervention (PCI) on efficacy and bleeding in ACS patients treated with a contemporary pharmacological regimen remains unknown.

9. Objectives  The aim of this post hoc analysis was to examine the impact of the trans-radial approach (TRA), in comparison to the trans-femoral approach (TFA) on PCI-related: -major bleeding -and patients’outcomes in a contemporary pharmacological environnement in the 7,885 patients with ACS who underwent PCI in the OASIS-5 trial (TRA or TFA)

10. Patient selection-Methods   Analyses include all patients who underwent PCI (Brachial access excluded).   Hazard ratio and two sided 95% CI were calculated with use of a cox proportional-hazards model with the access site as the only covariate (day 9, day 30 and at 6 months Fup)   Rates presented are Kaplan-Meier rates.   Adjusted Hazard ratio have also been calculated. Major Bleeding definition: Clinically overt bleeding that is either fatal, intracranial, ≥ retroperitoneal, intraocular, drop in Hb ≥ 3g/dL ≥ or requiring transfusion ≥ 2U RBC

11. Baseline Characteristics Femoral(N=7,013)Radial(N=872)p-value Male68.8%74.5%0.001 Diabetes23.8%20.4%0.025 Heart Failure 7.9%6.2%0.079 Prior MI 23.1%18.0%<0.001 Prior PCI 15.7%14.2%0.260 Prior CABG 9.5%3.9%<0.001 DemographicsFemoral(N=7,013)Radial(N=872)p-value Biomarker + 77.3%82.5%0.001 ST dep. > 1mm 43.0%40.3%0.117 High Risk Features TFA 89% and TRA 11%

12. Baseline Characteristics Femoral(N=7,013)Radial(N=872)p-value ASA98.6%98.4%0.701 Clopidogrel85.6%88.0%0.062 GPIIb/IIIa Inhibitor 32.5%43.8%<0.001 Betablocker89.2%89.0%0.817 ACE inhibitor 68.9%60.4%<0.001 ARB7.6%9.2%0.092 Statins83.9%86.4%0.066 Other Lipid lower agents 3.3%2.3%0.117 In Hospital Medications

13. Procedural Details Femoral 10048 lesions Radial 1268 lesions p-value Complete success 91.6%92.4%0.331 Stent84.4%86.2%0.103 Bare stent 62.0%61.6%0.798 Drug eluting stent 22.5%24.6%0.089 No stent 15.4%13.3%0.049 Angio thrombus pre-pci 13.0%13.2%0.871 Percutaneous coronary interventions (analysis per lesion)

14. Endpoint Measures at Day 9 Radial vs. Femoral 10.5%8.4%0.79 (0.62-1.00)0.05 Hazard ratio ±95% CI Hazard ratio ±95% CI Endpoint Net clinical outcome Death/MI/RI Major bleeding Radial better Femoral better Radial(n=872) Femoral(n=7013) HR (95% CI) p-value 7.7%7.1%0.92 (0.70-1.19) 0.52 3.5%1.6%0.45 (0.26-0.77)0.004

15. Days 0.0 0.02 0.04 0.06 0.08 0123456789 Femoral Radial Death/MI/RI at Day 9 Radial vs. Femoral HR 0.92 95% CI [0.70-1.19] p=0.52 Cumulative Hazard

16. HR 0.45 95% CI [0.26-0.77] p=0.004 Major Bleeding at Day 9 Radial vs. Femoral Days Cumulative Hazard 0.0 0.01 0.02 0.03 0123456789 Femoral Radial

17. Net clinical outcome at Day 9 Radial vs. Femoral HR 0.79 95% CI [0.62-1.00] p=0.05 Days Cumulative Hazard 0.0 0.02 0.04 0.06 0.08 0.10 0123456789 Femoral Radial

18. Endpoint Measures at Day 30 Radial vs. Femoral 13.1%10.3%0.78 (0.62-0.96)0.021 Hazard ratio ±95% CI Hazard ratio ±95% CI Endpoint Net clinical outcome Death/MI/RI Major bleeding Radial better Femoral better Radial(n=872) Femoral(n=7013) HR (95% CI) p-value 10.0%8.9%0.89 (0.70-1.12) 0.316 4.1%2.1%0.50 (0.31-0.80)<0.004

19. Death/MI/RI at Day 30 Radial vs. Femoral HR 0.89 95% CI [0.70-1.12] p=0.31 Days Cumulative Hazard 0.0 0.02 0.04 0.06 0.08 0.10 036912151821242730 Femoral Radial

20. Major Bleeding at Day 30 Radial vs. Femoral HR 0.50 95% CI [0.31-0.80] p=0.004 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 036912151821242730 Femoral Radial

21. Net clinical outcome at Day 30 Radial vs. Femoral HR 0.78 95% CI [0.62-0.96] p=0.021 Days Cumulative Hazard 0.0 0.02 0.04 0.06 0.08 0.10 0.12 0.14 036912151821242730 Femoral Radial

22. Endpoint Measures at 6 months Radial vs. Femoral 17.5%13.5%0.76 (0.63-0.92)0.005 Hazard ratio ±95% CI Hazard ratio ±95% CI Endpoint Net clinical outcome Death/MI/RI Major bleeding Radial better Femoral better Radial(n=872) Femoral(n=7013) HR (95% CI) p-value 13.9%11.8%0.84 (0.69-1.04) 0.103 5.1%2.7%0.52 (0.34-0.79)0.002

23. Death/MI/RI at 6 months Radial vs. Femoral HR 0.84 95% CI [0.69-1.04] p=0.10 Days Cumulative Hazard 0.0 0.05 0.10 0.15 0306090120150180 Femoral Radial

24. Major Bleeding at 6 months Radial vs. Femoral HR 0.52 95% CI [0.34-0.79] p=0.002 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0.05 0306090120150180 Femoral Radial

25. Net clinical outcome at 6 months Radial vs. Femoral HR 0.76 (adjusted) 95% CI [0.63-0.92] p=0.005 Days Cumulative Hazard 0.0 0.05 0.10 0.15 0306090120150180 Femoral Radial

26. Mortality at 6 months Radial vs. Femoral HR 0.68 95% CI [0.43-1.07] p=0.09 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0306090120150180 Femoral Radial

27. Protocol Major Bleeding in PCI patients at Day 9 3,5% 4,8% 2,3% 0,9% 1,6% 2,4% OverallEnoxaparinFondaparinux 9 day events (%) FemoralRadial P =0.03P=0.026 P =0.048 (during blind study drug administration)

28. Protocol Major Bleeding at Day 9 (during blind study drug administration) P = 0.08P = <0.0001 (N=416)(N=456)(N=3,523)(N=3,490) HR 0.36 95% CI [0.11-1.16] HR 0.48 95% CI [0.37-0.62]

29. Protocol Major Bleeding Enoxaparin versus Fondaparinux FondaparinuxEnoxaparin Enox. Fonda. P P int 0.65 4.8%2.3%0.48 (0.37-0.62)<0.001 2.4%0.9%0.36 (0.11-1.16) 0.086 0.37 5.2%3.0%0.56 (0.44-0.72)<0.001 3.1%1.1%0.35 (0.12-0.98) 0.045 0.31 6.1%4.0%0.64 (0.51-0.79)<0.001 3.9%1.5%0.39 (0.16-0.96) 0.040 HR (95% CI) Femoral (n=7013) Radial (n=872) Femoral (n=7013) Radial (n=872) Major Bleed day 180 Femoral (n=7013) Radial (n=872) Hazard Ratio ±95% CI Hazard Ratio ±95% CI Major Bleed day 9 Major Bleed day 30

30. Bleeding & Access complications at Day 9 Femoral(N=7013)Radial(N=872)p-value Major Bleed 3.5%1.6%0.002 Retroperitoneal Hem. 0.3%0%0.124 Pseudoaneurysm1.2%0%0.001 Large hematoma 3.1%0.3%<0.001 GI Bleeding 0.5%0%0.042 Other site 2.8%1.6%0.038 Hb drop ≥ 3g/dL 2.8%1.1%0.004 Hb dop ≥ 5 g/dL 1.1%0.5%0.082 Blood transfusion 3.6%1.5%0.001 Blood transfusion >2 U 2.3%0.6%0.001 Radial versus Femoral Major Bleeding definition: Clinically overt bleeding that is either fatal, intracranial, retroperitoneal, intraocular, drop in Hb ≥ 3g/dL or requiring transfusion ≥ 2U RBC

31. (Gender, Diabetes, GPI, Prior MI, Biomarkers) Endpoint Measures Adjusted Femoral better Femoral better Endpoint Net clinical outcome Death/MI/RI Major bleeding Radial better Radial better Femoral better Femoral better Hazard ratio ±95% CI Hazard ratio ±95% CI Hazard ratio ±95% CI Hazard ratio ±95% CI Radial better Radial better Femoral better Femoral better Hazard ratio ±95% CI Hazard ratio ±95% CI Radial better Radial better Day 9 Day 30 Day 180 P=0.03 P=0.36 P=0.003 P=0.02 P=0.31 P=0.003 P=0.009 P=0.18 P=0.002

32. Femoral(N=7013)Radial(N=872)p-value Day 9 Net clinical outcome 10.5%8.4%0.030 Death/MI/RI7.7%7.1%0.364 Major Bleed 3.5%1.6%0.003 Day 30 Net clinical outcome 13.1%10.3%0.019 Death/MI/RI10.0%8.9%0.311 Major Bleed 4.1%2.1%0.003 Day 180 Net clinical outcome 17.5%13.5%0.009 Death/MI/RI13.9%11.8%0.180 Major Bleed 5.1%2.7%0.002 (Gender, Diabetes, GPI, Prior MI, Biomarkers) Endpoint Measures Adjusted At 6 months NNT Net clinical outcome 25 Death/MI/RI48 Major Bleed 42

33. Mortality at 6 Months Radial vs. Femoral HR 0.68 95% CI [0.43-1.07] p=0.09 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0306090120150180 Non-adjusted: HR 0.68 [0.43-1.07] p=0.09 Adjusted: HR 0.71 [0.45-1.13] p=0.15 3.4% 2.3% NNT~100 Femoral Radial

34. Conclusions In ACS patients undergoing PCI, radial access was associated with similar rates of ischemia and significantly reduced major bleeding compared with femoral access, leading to better net clinical outcome.In ACS patients undergoing PCI, radial access was associated with similar rates of ischemia and significantly reduced major bleeding compared with femoral access, leading to better net clinical outcome. Our results suggest that TRA by reducing major bleeding may be associated with 6 months mortality reduction as compared to TFA.Our results suggest that TRA by reducing major bleeding may be associated with 6 months mortality reduction as compared to TFA. Randomized trials are warranted to confirm the impact of access site on event-free survivalRandomized trials are warranted to confirm the impact of access site on event-free survival A fondaparinux strategy:A fondaparinux strategy:  Reduces major bleeding both in femoral and radial access  Improves net clinical outcome in femoral approach compared to an enoxaparin based regimen

35. Acknowledgements  Shamir Metha and Salim Yusuf  Rizwan Afzal (statistical analysis) Thank you for your attention