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Antiplatelet and Antithrombotic Therapies in PCI – Defining the Optimal Strategy

Antiplatelet and Antithrombotic Therapies in PCI – Defining the Optimal Strategy. Franz-Josef Neumann Herz-Zentrum Bad Krozingen. Antiplatelet and Antithrombotic Therapies in PCI – Defining the Optimal Strategy. Overview of Agents and Strategies Special Subsets - Diabetics

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Antiplatelet and Antithrombotic Therapies in PCI – Defining the Optimal Strategy

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  1. Antiplatelet and Antithrombotic Therapies in PCI –Defining the Optimal Strategy Franz-Josef Neumann Herz-Zentrum Bad Krozingen

  2. Antiplatelet and Antithrombotic Therapies in PCI –Defining the Optimal Strategy Overview of Agents and Strategies Special Subsets - Diabetics - ACS without ST-elevation - Myocardial infarction with ST-elevation - Drug-eluting stents - Indication for oral anticoagulation

  3. Antiplatelet and Antithrombotic Therapies in PCI –Defining the Optimal Strategy Overview of Agents and Strategies Special Subsets - Diabetics - ACS without ST-elevation - Myocardial infarction with ST-elevation - Drug-eluting stents - Indication for oral anticoagulation

  4. Adjunctive Antithrombotic Therapy - Goals - Adjunctive Antithrombotic Therapy - Goals - Adjunctive Antithrombotic Therapy - Goals - Adjunctive Antithrombotic Therapy - Goals - Adjunctive Antithrombotic Therapy - Goals - Prevention of Restenosis Prevention of Subacute Stent Thrombosis Prevention of Acute Thrombosis and Infarction • Prevention of Restenosis • Thus far futile (except abciximab for diabetics in EPISTENT) • Prevention of Subacute Stent Thrombosis • Prevention of Acute Thrombosis and Infarction • Prevention of Restenosis • Thus far futile (except abciximab for diabetics in EPISTENT) • Prevention of Subacute Stent Thrombosis • Aspirin & thienopyridine (ISAR, STARS, FANTASTIC, MATTIS) • Prevention of Acute Thrombosis and Infarction • Prevention of Restenosis • Thus far futile (except abciximab for diabetics in EPISTENT) • Prevention of Subacute Stent Thrombosis • Aspirin & thienopyridine (ISAR, STARS, FANTASTIC, MATTIS) • Prevention of Acute Thrombosis and Infarction • Aspirin (Barnathan, Circulation 1987; Schwartz, N Engl J Med 1988) • Prevention of Restenosis • Thus far futile (except abciximab for diabetics in EPISTENT) • Prevention of Subacute Stent Thrombosis • Aspirin & thienopyridine (ISAR, STARS, FANTASTIC, MATTIS) • Prevention of Acute Thrombosis and Infarction • Aspirin (Barnathan, Circulation 1987; Schwartz, N Engl J Med 1988) • Anti-GP IIb/IIIa • Pretreatment with thienopyridine • Anticoagulants

  5. Adjunctive Antithrombotic Therapy for Prevention of Acute Thrombosis and Peri-Interventional Infarction Anti-GP IIb/IIIa Pretreatment with thienopyridine Anticoagulants

  6. Efficacy of GP IIb/IIIa Blockade for PCI Odds Ratio for 30-Day Death, MI & Urg. TVR PCI Studies Abciximab EPIC (bolus arm) EPILOG EPISTENT (stent arms) Eptifibatide IMPACT-II ESPRIT Tirofiban RESTORE PCI Subgroups Eptifibatide PURSUIT (death&MI) Tirofiban PRISM-PLUS Comparison Abciximab vs. Tirofiban TARGET 0.0 0.5 1.0 2.0

  7. Efficacy of GP IIb/IIIa Blockade Depending on Risk Positive Troponin T Negative Troponin T 30 30 P=0.001 P=0.002 n.s. n.s. 20 20 Rate of Death & MI [%] Rate of Death & MI [%] 10 10 0 0 Day 30 Day 180 Day 30 Day 180 Placebo Abciximab Hamm et al., N Engl J Med 1999

  8. Adjunctive Antithrombotic Therapy for Prevention of Acute Thrombosis and Peri-Interventional Infarction Anti-GP IIb/IIIa Pretreatment with thienopyridine Anticoagulants

  9. Clopidogrel Pretreatment and Early Risk of PCI 30-Day Death, MI & Urg. TVR (%) No Pretreatment 10 PCI-CURE CREDO Pretreatment 8.3 8 P=0.05 8.0 P=0.01 6.4 6 5.8 4.5 4 2 0 300 mg + 75 mg for median of 10 days 300 mg < 6 h 6 - 24 h

  10. n=10 n=10 Rapid Effect with High Loading Dose of Clopidogrel Platelet aggregation (%) Platelet aggregation (%) 300 mg 60 60 P<0.01 n.s. n.s. 600 mg 40 40 20 20 n=514 n=204 n=10 n=10 0 0 48 h 2 – 6 h > 6 h 2 h Müller et. al., Heart 2001 Hochholzer et. al., Circulation in press

  11. Pretreatment with Thienopyridine and Early Risk of PCI Relative 30-Day Risk of Death, MI, Urg. TVR PCI-CURE, n = 2658 CREDO (full effect), n = 473 EPISTENT, n = 809 ESPRIT*, n = 1024 Pooled, n = 4964 0 0.5 1 1.5 *1-year Death&MI Mehta SR, Lancet 2001; Steinhubl SR, Circulation 2001 & JAMA 2002; Tcheng JE, pers. comm.

  12. P=0.52 5.3 4.4 > 4 Days Bleeding Risk of CABG After Clopidogrel Early Major/Life Threatening Bleeding (%) Placebo 10 P=0.06 Clopidogrel 9.6 7.5 6.3 5 2.5 0 < 4 Days After Discontinuation of Study Drug Fox KA et al., Circulation 2004

  13. Risk/Benefit Ratio of Clopidogrel in CURE Events Prevented/Incurred per 1000 CV Death, MI, Stroke & Life Threatening Bleeding (%) 10 Life Threatening Bleeding 15 P<0.001 5 4 12.5 0 10 10.6 -5 - 10 5 -15 -21 -20 CV Death, Infarction, Stroke 0 -25 Placebo Clopidogrel Fox KA et al., Circulation 2004

  14. 30-Day Death, MI & Urg. TVR (%) 15 P=0.17 P=0.28 P=0.02 12.8 10 8.4 8.7 7.3 6.9 5.9 5 0 Eptifibatide Abciximab Tirofiban ESPRIT* TARGET Clopidogrel Pretreatment Plus GP IIb/IIIa Blockade? No Pretreatment Pretreatment *1-year Death&MI Chan AW et al., J Am Coll Cardiol 2003; Tcheng JE, pers. comm.

  15. Efficacy of Thienopyridines with GP IIb/IIIa Blockade Relative 30-Day Risk of Death, MI & Urg. TVR Ticlopidin EPISTENT (Abciximab), n=794 Clopidogrel ESPRIT*(Eptifibatid), n=1040 TARGET (Abciximab), n=2411 TARGET (Tirofiban), n=2398 CREDO (Mixed), n=378 Pooled, n=7,021 0 0.5 1 1.5 Steinhubl SR, Circulation 2001 & JAMA 2002; Chan AW et al., J Am Coll Cardiol 2003; Tcheng JE, pers. comm. *1-year Death&MI

  16. Are GP IIb/IIIa antagonists needed, if the patient is on clopidogrel? ISAR-REACT

  17. Major Selection Criteria Included Elective percutaneous coronary intervention Pretreatment with 600 mg clopidogrel at least 2 hours before PCI Not Included ST-segment displacement Troponin-T level > 0.03 ng/mL, recent (<14 days) MI Insulin-dependent diabetes mellitus Kastrati A et al., N Engl J Med 2004

  18. ISAR-REACT: Efficacy and Safety Analysis 30-Day Rate (%) Placebo 6 P=0.91 P=0.46 P= 0.37 P=0.007 Abciximab 5 4 4.0 3.9 3 2.4 2 1 1.1 0.9 0.9 0.7 0.7 0 Death & MI Urgent TVR Major bleed Transfusion Kastrati A et al., N Engl J Med 2004

  19. Relative Risk Diabetes (non-insulin dep.) Yes No Angina class III/IV or Prior myocardial infarction Yes No PCI in complex lesions Yes No 0 0.5 1.0 1.5 2.0 2.5 3.0 Placebo better Abciximab better ISAR-REACT: Outcome in Higher Risk Subgroups Kastrati et al., N Engl J Med 2004

  20. ISAR-REACT: 1-Year Outcome Event-free survival, % 100 P=0.92 80 Death: 2.1% vs 2.4%, P=0.66 MI: 4.2% vs 4.3%, P=0.92 60 40 Abciximab 20 Placebo 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomisation Schömig A et al., Eur Heart J, in press

  21. Adjunctive Antithrombotic Therapy for Prevention of Acute Thrombosis and Peri-Interventional Infarction Anti-GP IIb/IIIa Pretreatment with thienopyridine Anticoagulants

  22. Anticoagulants: Alternatives to Heparin Enoxaparin Bivalirudin In-Hospital Rate (%) 30-Day Rate (%) P=0.42 P<0.001 P=0.27 P=0.02 15 15 Heparin 14.2 13.1 Enoxaparin 10 10 9.8 Bivalirudin 5 5 5.1 4.6 3.8 3.7 2.5 0 0 Death & MI Major bleed Death, MI & emerg. CABG Major bleed SYNERGY-PCI, TCT 2004; Bittl et al., N Engl J Med 1995

  23. Can bivalurudin replace GP IIb/IIIa blockade? REPLACE-2

  24. Major Selection Criteria Included Urgent or elective percutaneous coronary intervention Not Included Acute myocardial infarction Lincoff et al., JAMA 2003

  25. REPLACE-2: Primary Endpoint Heparin + Anti GP IIb/III Bivalirudin + bail-out 7.2% 12 P=0.32 P=0.26 P<0.001 P=0.43 P=0.44 10 10.0 9.2 8 7.0 6 6.2 4 4.1 2 2.4 0.4 0.2 1.4 1.2 0 Composite Death MI Urgent TVR Major bleeding Lincoff et al., JAMA 2003

  26. Outcome in Various Subgroups Relative Risk of Death, MI, Urgent TVR Diabetes Yes No ACS present Yes No Thienopyridine pretreatment Yes No Abciximab Eptifibatide 0.5 1.0 1.5 2.0 Anti GPIIb/IIIa better Bivalirudin better Lincoff et al., JAMA 2003

  27. REPLACE-2: Long-Term Outcome 6-month rates MI: 7.4% vs 8.2%, P=0.24 TVR: 11.4% vs 12.1%, P=0.66 Lincoff et al., JAMA 2004

  28. Antiplatelet and Antithrombotic Therapies in PCI –Defining the Optimal Strategy Overview of Agents and Strategies Special Subsets - Diabetics - ACS without ST-elevation - Myocardial infarction with ST-elevation - Drug-eluting stents - Indication for oral anticoagulation

  29. Abciximab and Stent in Diabetics 6-month rate of death, MI and TVR (%) 30 P=0.005 P=0.062 Abciximab 25 25.2 Placebo 20 15 16.5 13.0 13.0 10 5 0 Diabetes No Diabetes Marso et al., Circulation 1999

  30. Abciximab and Stent in Diabetics Marso et al., Circulation 1999

  31. Abciximab and Stent in Diabetics Marso et al., Circulation 1999

  32. Abciximab and Stent in Diabetics Marso et al., Circulation 1999

  33. Improved Survival After PCI with Abciximab Cumulative incidence of death (%) P = 0.031 Diabetics, placebo Non-diabetics, placebo Diabetics, abciximab Non-diabetics, abciximab Bhatt DL et al., J Am Coll Cardiol 2000

  34. ISAR-SWEET: Abciximab After Clopidogrel Loading in Diabetics? Mehilli J et al., Circulation 2004

  35. 50 40 30 20 10 0 ISAR-SWEET: Abciximab After Clopidogrel Loading in Diabetics? 6-month rate of death, MI and TVR (%) P=0.062 P=0.01 Abciximab Placebo 37.8 30.4 28.9 23.2 Restenosis 6 months TLR 12 months Mehilli J et al., Circulation 2004

  36. REPLACE-2: Outcome in Diabetics Relative Risk of Death, MI, Urgent TVR 30-days Diabetes No Diabetes 1-year Diabetes No Diabetes 0.5 1.0 1.5 2.0 Anti GPIIb/IIIa better Bivalirudin better Lincoff et al., JAMA 2003 & 2004

  37. Antiplatelet and Antithrombotic Therapies in PCI –Defining the Optimal Strategy Overview of Agents and Strategies Special Subsets - Diabetics - ACS without ST-elevation - Myocardial infarction with ST-elevation - Drug-eluting stents - Indication for oral anticoagulation

  38. Preinterventional Rate of Death and Infarction Pooled 6% N=12,296 P=0.0001 4.4% Control 4% GP IIb/IIIa-Antagonist 2% 2.9% 0% 0h 24h 48h 72h Boersma et al., Circulation 1999

  39. Does Antithrombotic Pretreatment Reduce the Risk of Subsequent PCI ?

  40. Intracoronary Thrombi in Unstable Angina Zhao et al., Circulation 1999

  41. 24.1% 17.1% Tirofiban + Heparin Heparin alone Lower Thrombus Load After GP IIb/IIIa Inhibition Lesions with Moderate/Large Thrombus (%) 30 P=0.022 20 10 0 Zhao et al., Circulation 1999

  42. “Cooling-off“ before PTCA and Risk of Death and Infarction 30-day rate [%] 18 16 14 12 Simoons Eur Heart J 2000 10 8 6 4 2 0 Peri- &Postinterventional 1 day 2-3 days 4-7 days days 8-30 duration of preinterventional therapy

  43. Randomization Cooling-off: Antithrombotic pretreatment for 72 to 120 hours Early intervention: Antithrombotic pretreatment for less than 6 hours Neumann et al., JAMA 2003

  44. Pretreatment: (Duration as randomized) Aspirin: initial iv-bolus of 500 mg, 100 mg bid. Clopidogrel: 600 mg loading dose 75 mg bid Tirofiban: 10 µg/kg Bolus, 0,10 µg/kg/min Heparin:60 U/kg bolus infusion (PTT 60-85s) Peri/Postinterventional: 2 x 100 mg 75 mg bid for 3 d, 1 x 75 mg 0,15 µg/kg/min für 24h 60 U/kg bolus Antithrombotic Regimen Neumann et al., JAMA 2003

  45. Study Population Early Intervention n=203 Cooling-Off n=207 Troponin T ST-segment 32% 34% 35% 34% Both 32% 32% Neumann et al., JAMA 2003

  46. ISAR-COOL: Primary Endpoint After Catheterization Combined incidence of death and MI (%) 15 10 Early intervention „Cooling-off“ 5 P=0.96 0 0 5 10 15 20 25 30 Days after randomization Neumann et al., JAMA 2003

  47. Risk of Pretreatment Death and MI 5% TACTICS:CONSERVATIVE 4,4% 4% CAPTURE PRISM-PLUS PURSUIT 3% 2% 1,7% 1% TACTICS: INVASIVE 0% 0 1 2 3 4 5 6 7 8 Boersma et al., Circulation 1999; Cannon et al., ESC 2001

  48. “Cooling-off“ before PTCA and Risk of Death and Infarction 30-day rate [%] 18 16 14 12 Simoons Eur Heart J 2000 10 8 6 4 2 Preinterventional 0 Peri- &Postinterventional 1 day 2-3 days 4-7 days days 8-30 duration of preintervenional therapy

  49. “Cooling-off“ before PTCA and Risk of Death and Infarction 30-day rate [%] Simoons Eur Heart J 2000 Total Preinterventional Peri- &Postinterventional days duration of preintervenional therapy

  50. Clinical Outcome and Duration of Pretreatment - TACTICS - Patients with primary endpoint within 6 months [%] 25 20 20.5 15 15.0 14.8 13.9 10 5 0 4-12 12-24 24-48 >48 Duration of pretreatment [h] Cannon et al., ESC 2001

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