1. www.metcardio.org Giuseppe Biondi Zoccai University of Turin, Turin, Italy METCARDIO, Turin, Italy gbiondizoccai@gmail.com BMS & Sanofi Aventis Sponsored Symposium: State of art of dual antiplatelet therapy in ACS Bologna, 25/9/2008 – 13.05-13.25 THE IMPORTANCE OF AN ADEQUATE RISK-BENEFIT RATIO IN THE ANTIPLATELET TREATMENT OF ACS PATIENTS

2. www.metcardio.org Thrombotic events Bleeding SCOPE OF THE PROBLEM

3. www.metcardio.org Thrombotic events Bleeding SCOPE OF THE PROBLEM

4. www.metcardio.org SCOPE OF THE PROBLEM

5. www.metcardio.org LEARNING GOALS What is the risk and the impact of atherothrombotic events in ACS? What is the risk and the impact of bleeding events in ACS? How can we strike a balance between risk and benefit of antiplatelet therapy in ACS?

6. www.metcardio.org LEARNING GOALS What is the risk and the impact of atherothrombotic events in ACS? What is the risk and the impact of bleeding events in ACS? How can we strike a balance between risk and benefit of antiplatelet therapy in ACS?

7. www.metcardio.org IN OTHER WORDS… WHAT ELSE SHOULD I EXPECT FROM ATHEROTHROMBOSIS AFTER THE INDEX EVENT?

8. www.metcardio.org WHAT IS THE CLINICAL BURDEN OF ATHEROTHROMBOSIS? DEATH STROKE MI TVR RE-HOSPITALIZATION My main tool to avoid athero- thrombosis: antithrombotic Rx

9. www.metcardio.org ATHEROTHROMBOTIC EVENTS AFTER ADMISSION FOR AMI Capewell et al,Heart 2006

10. www.metcardio.org Capewell et al, Heart 2006 ATHEROTHROMBOTIC EVENTS AFTER ADMISSION FOR UA

11. www.metcardio.org Antman et al, JAMA 2000;284:835-42 PREDICTORS OF ATHERO- THROMBOTIC EVENTS: TIMI Score (n=7081) * all-cause mortality, myocardial infarction, and severe recurrent ischemia prompting urgent revascularization * VARIABLE MULTI- VARIABLE P ODDS RATIOPOINT Age>65 years<0.0011.751 >2 risk factors for CAD 0.0031.541 Significant CAD<0.0011.701 ST deviation0.0051.511 Severe angina0.0011.531 Aspirin in last week 0.0061.741 Raised cardiac markers <0.0011.561

12. www.metcardio.org Antithrombotic therapy & (selectively) invasive management Stable angina Unstable angina Reperfusion (thrombolysis and/or PTCA) Minutes Hours Days Weeks STEMI UA/NSTEMI Atherothrombosis New terms Old terms Plaque rupture Non-Q MI Q-MI EXTREMELY VARIABLE PATHOPHYSIOLOGY

13. www.metcardio.org EXTREMELY VARIABLE IMPACT OF MYOCARDIAL INFARCTION: case study from the PURSUIT trial Akkerhuis et al, Circulation 2002;105:554-556

14. www.metcardio.org ON TOP OF THIS: VARIABILITY IN RESPONSE TO ANTITHROMBOTIC THERAPY

15. www.metcardio.org VARIABILITY IN CLOPIDOGREL RESPONSE Change in ADP-Induced Platelet Aggregation 75 mg chronic dosing Serebruany et al, J Am Coll Cardiol 2005 Hochholzer et al, Circulation 2005 Time from loading dose to cath (h) Maximal aggregation 5 µmol/L ADP (%) following 600 mg loading dose 0246810 0 20 40 60 80 100 N=1001 Number of Patients N=544 Relative change in aggregation

16. www.metcardio.org LEARNING GOALS What is the risk and the impact of atherothrombotic events in ACS? What is the risk and the impact of bleeding events in ACS? How can we strike a balance between risk and benefit of antiplatelet therapy in ACS?

17. www.metcardio.org IN OTHER WORDS… WHEN IS MUCH TOO MUCH?

18. www.metcardio.org THE CASE FOR FOCUSING ON BLEEDING It is common It is expensive Patients remember bleeding events more than asymptomatic enzyme leaks It is associated with increased mortality

19. www.metcardio.org THE CASE FOR FOCUSING ON BLEEDING It is common It is expensive Patients remember bleeding events more than asymptomatic enzyme leaks It is associated with increased mortality Strategies that prevent or reduce bleeding may reduce mortality

20. www.metcardio.org THE CASE FOR FOCUSING ON BLEEDING It is common It is expensive Patients remember bleeding events more than asymptomatic enzyme leaks It is associated with increased mortality Strategies that prevent or reduce bleeding may reduce mortality Minimizing bleeding should be an essential part of modern therapy of CAD

21. www.metcardio.org PREVALENCE OF MAJOR BLEEDING: GRACE Registry (n=24045) Moscucci et al, Eur Heart J 2003;24:1815-1823

22. www.metcardio.org Moscucci et al, Eur Heart J 2003;24:1815-1823 PREDICTORS OF MAJOR BLEEDING: GRACE Registry (n=24045)

23. www.metcardio.org Rao et al, Am J Cardio 2005;96:1200-1206 IMPACT* ON MORTALITY OF BLEEDING IN ACS Survival P<0.0001 P=0.20 P<0.0001 *at both univariate and multivariable analyses

24. www.metcardio.org Aronson et al, Am J Cardiol 2008;102:115-119 SIMILAR PREDICTORS AND IMPACT* FOR BLOOD TRANSFUSIONS IN AMI *at both univariate and multivariable analyses

25. www.metcardio.org Cohen et al, J Am Coll Cardio 2004;44:1792-1800 EVENTCOST (USD)P VALUE Myocardial infarction >10 x ULN 5-10 x ULN 3 x ULN 4,084 2,233 1,165 <0.05 Repeat revascularization PCI CABG 8,187 29,506 <0.05 Stroke?? Major bleeding 6,300<0.05 IMPACT ON COSTS: case study from the REPLACE-2 trial

26. www.metcardio.org LEARNING GOALS What is the risk and the impact of atherothrombotic events in ACS? What is the risk and the impact of bleeding events in ACS? How can we strike a balance between risk and benefit of antiplatelet therapy in ACS?

27. www.metcardio.org OVERWHELMING COMPLEXITY?

28. www.metcardio.org FINDING THE BALANCE: AN EASY CASE

29. www.metcardio.org FINDING THE BALANCE: ANOTHER EASY CASE

30. www.metcardio.org WHAT ABOUT TOUGHER CASES?

31. www.metcardio.org Ndrepepa et al, J Am Coll Cardiol 2008;51:690-7 RATIONALE FOR QUADRUPLE END-POINT IN PCI

32. www.metcardio.org RATIONALE FOR QUADRUPLE END-POINT IN PCI Ndrepepa et al, J Am Coll Cardiol 2008;51:690-7

33. www.metcardio.org DEFINITION OF NET ADVERSE CLINICAL EVENTS (NACE) Ndrepepa et al, J Am Coll Cardiol 2008;51:690-7 DEATH MI STROKE PCI/ CABG MAJOR BLEEDING ALL CAN IMPACT ON PROGNOSIS, SYMPTOMS, AND COSTS! BUT EACH MAY IMPACT THESE IN DIFFERENT DIRECTIONS

34. www.metcardio.org DEFINITION OF NET ADVERSE CLINICAL EVENTS (NACE) *in several cases, stroke is not included in NACE definition DEATH MI STROKE PCI/ CABG MAJOR BLEEDING ALL CAN IMPACT ON PROGNOSIS, SYMPTOMS, AND COSTS! BUT EACH MAY IMPACT THESE IN DIFFERENT DIRECTIONS NACE: composite of all cause death, non- fatal myocardial infarction, non-fatal stroke, PCI/CABG, and non-fatal major bleeding*

35. www.metcardio.org WHAT ABOUT CLOPIDOGREL IN REAL LIFE ? Alexander et al, Am Heart J 2008;156:606-612

36. www.metcardio.org SUMMARY OF EVIDENCE ON CLOPIDOGREL LOADING

37. www.metcardio.org SUMMARY OF EVIDENCE ON CLOPIDOGREL LOADING Lotrionte et al, Am J Cardio 2007;100:1199-1206

38. www.metcardio.org DO-IT-YOURSELF ANTIPLATELET THERAPY?

39. www.metcardio.org DO-IT-YOURSELF ANTIPLATELET THERAPY! Bonello et al, J Am Coll Cardiol 2008;51:1404-11

40. www.metcardio.org DO-IT-YOURSELF ANTIPLATELET THERAPY! Bonello et al, J Am Coll Cardiol 2008;51:1404-11 26 patients receiving 4 600 mg loading doses of clopidogrel 24 hours apart (2.4 g)!

41. www.metcardio.org A GLIMPSE AT THE FUTURE

42. www.metcardio.org TAKE HOME MESSAGES

43. www.metcardio.org 1. A COMPREHENSIVE APPRAISAL OF THROMBOTIC & BLEEDING RISKS IS NEEDED IN PATIENTS WITH ACS THROMBOSIS BLEEDING

44. www.metcardio.org 2. BETTER YET PRACTICAL RISK- STRATIFICATION TOOLS FOR BLEEDS AND THROMBOSES ARE WARRANTED

45. www.metcardio.org 3. EVERY PATIENT WILL HAVE AN INDIVIDUALIZED TREATMENT, DEPENDING ON OVERALL RISK PROFILE AND ACUITY

46. www.metcardio.org For further slides on these topics please feel free to visit the metcardio.org website: http://www.metcardio.org/slides.html http://www.metcardio.org/slides.html