Antiplatelet and Antithrombotic Therapies in PCI Defining the Optimal Strategy

Transcription

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 - 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 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 Odds Ratio for 30-Day Death, MI & Urg. TVR

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

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 (%) 10 8 PCI-CURE CREDO P=0.05 No Pretreatment Pretreatment P= mg + 75 mg for 300 mg median of 10 days < 6 h 6-24 h

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

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

12 Bleeding Risk of CABG After Clopidogrel Early Major/Life Threatening Bleeding (%) 10 P= P= Placebo Clopidogrel Fox KA et al., Circulation < 4 Days > 4 Days After Discontinuation of Study Drug

13 Risk/Benefit Ratio of Clopidogrel in CURE CV Death, MI, Stroke & Life Threatening Bleeding (%) 15 P< Events Prevented/Incurred per Life Threatening 5 Bleeding Placebo Clopidogrel Fox KA et al., Circulation CV Death, Infarction, Stroke

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

15 Efficacy of Thienopyridines with GP IIb/IIIa Blockade Ticlopidin EPISTENT (Abciximab), n=794 Clopidogrel ESPRIT* (Eptifibatid), n=1040 Pooled, n=7,021 TARGET (Abciximab), n=2411 TARGET (Tirofiban), n=2398 CREDO (Mixed), n=378 Steinhubl SR, Circulation 2001 & JAMA 2002; Chan AW et al., J Am Coll Cardiol 2003; Tcheng JE, pers. comm. Relative 30-Day Risk of Death, MI & Urg. TVR *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 (%) 6 P=0.91 P= P= 0.37 P=0.007 Placebo Abciximab Death & MI Urgent TVR Major bleed 0.9 Transfusion Kastrati A et al., N Engl J Med 2004

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

20 ISAR-REACT: 1-Year Outcome Event-free survival, % 100 P= Death: 2.1% vs 2.4%, P=0.66 MI: 4.2% vs 4.3%, P= Abciximab Placebo 0 Schömig A et al., Eur Heart J, in press Months after randomisation

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 30-Day Rate (%) 15 P=0.27 P= Bivalirudin In-Hospital Rate (%) 15 P=0.42 P< Heparin Enoxaparin Bivalirudin 5 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% P= P=0.26 P=0.43 P=0.44 P< Composite Death 6.2 MI Urgent TVR Major bleeding Lincoff et al., JAMA 2003

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

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= Abciximab Placebo Diabetes No Diabetes Marso et al., Circulation 1999

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

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

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

33 Improved Survival After PCI with Abciximab Cumulative incidence of death (%) P = 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 ISAR-SWEET: Abciximab After Clopidogrel Loading in Diabetics? 6-month rate of death, MI and TVR (%) 50 P=0.01 P= Abciximab Placebo 10 0 Mehilli J et al., Circulation 2004 Restenosis 6 months TLR 12 months

36 REPLACE-2: Outcome in Diabetics 30-days Diabetes No Diabetes 1-year Diabetes No Diabetes Relative Risk of Death, MI, Urgent TVR Bivalirudin better Anti GPIIb/IIIa 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 6% 4% 2% N=12,296 P= % 2.9% Control Pooled GP IIb/IIIa-Antagonist 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 Lower Thrombus Load After GP IIb/IIIa Inhibition Lesions with Moderate/Large Thrombus (%) 30 P= % 17.1% 0 Zhao et al., Circulation 1999 Heparin alone Tirofiban + Heparin

42 Cooling-off before PTCA and Risk of Death and Infarction day 2-3 days 4-7 days 8-30 days Simoons Eur Heart J 2000 Peri- & Postinterventional

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 Antithrombotic Regimen Aspirin: Pretreatment: (Duration as randomized) initial iv-bolus of 500 mg, 100 mg bid. Clopidogrel: 600 mg loading dose 75 mg bid Tirofiban: Heparin: 10 µg/kg Bolus, 0,10 µg/kg/min 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 Neumann et al., JAMA 2003

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

46 ISAR-COOL: Primary Endpoint After Catheterization Combined incidence of death and MI (%) Early intervention P=0.96 Cooling-off 0 Neumann et al., JAMA Days after randomization

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

48 Cooling-off before PTCA and Risk of Death and Infarction day 2-3 days 4-7 days 8-30 days Simoons Eur Heart J 2000 Preinterventional Peri- & Postinterventional

49 Cooling-off before PTCA and Risk of Death and Infarction day 2-3 days 4-7 days 8-30 days Simoons Eur Heart J 2000 Total Preinterventional Peri- & Postinterventional

50 Clinical Outcome and Duration of Pretreatment - TACTICS - Patients with primary endpoint within 6 months [%] >48 Duration of pretreatment [h] Cannon et al., ESC 2001

51 ISAR-COOL: Primary Endpoint Before and After Catheterization Number of events (death & MI) 15 P=0.002 P= Cooling-off Early intervention 5 0 Before Neumann et al., JAMA Catheterization After

52 ISAR-COOL: Incidence of Primary Endpoint Combined incidence of death and MI (%) 15 Cooling-off 10 P= Early intervention 0 Neumann et al., JAMA Days after randomization

53 Cumulative Incidence of Primary Endpoint Combined incidence of death and MI (%) % Cooling-off 5.6% Early intervention 0 Kastrati et al., TCT Months after randomization

54 Left Ventricular Function %LV % P=0.13 Perfusion Defect Size at 30-Day SPECT 0 P=0.005 LV Ejection Fraction at 6-Month Angiography Cooling-off Early intervention Kastrati et al., TCT 2004

55 Benefit of GP IIb/IIIa Blockade in ACS Meta-Analysis of Six Major Trials (31,402 Patients) All patients with ACS Patients with ACS, undergoing PCI within 5 days Relative 30-Day Risk of Death and MI Anti GPIIb/IIIa better Boersma E et al. Lancet 2002

56 Clopidogrel and/or anti-gp IIb/IIIa: Differential Efficacy Depending on Risk Profil Event rate [%] 15 P< P<0.05 Event rate [%] 15 n.s. 10 P<0.05 Control Tirofiban Heeschen et al., Lancet 1999 Clopidogrel 5 5 CURE, ACC PRISM CURE Marker positive 0 PRISM CURE Marker negative

57 GP IIb/IIIa Blockade While on Thienopyridines Relative 30-Day Risk of Death, Infarction, Urgent Reintervention TARGET: Pretreatment with Clopidogrel Abciximab vs. Tirofiban Topol et al., N Engl J Med 2000

58 Are GP IIb/IIIa antagonists needed in high-risk ACS, if the patient is on clopidogrel? ISAR-REACT-2

59 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

60 ADMIRAL - Angiographic Patency TIMI 3 Flow (% of Patients) 100 p = p = p = Placebo Abciximab p = Prior To PCI Immediately Post-PCI 24 hour Post-PCI 6 month Post-PCI Montalescot et al., N Engl J Med 2001

61 Abciximab for PCI in AMI: Microvascular Reperfusion and Recovery of Contraction D 30 Peak flow velocity (cm/s) p=0.024 D 0.8 Wall motion index (SD/chord) p= Neumann et al., Circulation 1998 Abciximab Heparin 95%-confidence interval

62 Abciximab and ST-Resolution After Stenting: Results from ACE Antoniucci et al., J Am Coll Cardiol 2003

63 Infarct Size in ACE Infarct Size (% of LV) 30 p= Antoniucci et al., J Am Coll Cardiol Stent Stent + Abciximab

64 RAPPORT, Brener et al. (PTCA) Circulation 1999 ISAR-2 Neumann et al. (Stent) J Am Coll Cardiol 2000 ADMIRAL Montalescot et al (Stent) N Engl J Med, 2001 CADILLAC Abciximab for PCI in AMI: Clinical Outcome Stone et al. (Stent/PTCA) N Engl J Med, Days 6 Months ACE Antoniucci et al. (Stent) J Am Coll Cardiol 2003 Pooled Relative Risk of Death+MI+TVR Abciximab vs Control

65 Abciximab for PCI in AMI: 6 to 12-Month Mortality ADMIRAL 300 CADILLAC 2082 RAPPORT 483 ISAR ACE 394 Petronio et al. 89 Pooled Abciximab better Placebo better De Luca G et al., submitted

66 Are GP IIb/IIIa antagonists needed in acute myocardial infarction, if the patient is on clopidogrel or receives bivalirudin? BRAVE-3 HORIZONS

67 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

68 Duration of Clopidogrel Administration in Various Studies Ravel: Sirius: E-Sirius: C-Sirius Taxus I: Taxus II: Taxus IV: 8 weeks 3 months 2 months 2 months 6 months 6 months 6 months

69 Mortality Within 6-12 Months after DES Babapulle MN et al., Lancet 2004

70 Incidence of Myocardial Infarction within 6-12 Months after DES Babapulle MN et al., Lancet 2004

71 Incidence of Stent Thrombosis within 6-12 Months after DES Ravel Sirius C-Sirius E-Sirius pooled Taxus-I Taxus-II Taxus-IV pooled Babapulle MN et al., Lancet Rate of Stent Thrombosis (%) DES BMS

72 Rate of Stent Thrombosis [%] Rate of Stent Thrombosis within 6-12 Months after DES x SIRIUS (n=1510) TAXUS IV (n=1314) TAXUS VI (n=219) ARTS II (n=606) Cypher- Bifurcation (n=86)

73 Stent Thrombosis TAXUS IV (n=625) % (n=7) p 0.77 Control (n=613) % (n=5) 0 0,5 1 1,5 30 days 30 days to 1 year 1 year to 2 years

74 Reports on Late Stent Thrombosis after DES Mc Fadden EP et al., Lancet 2004 Paclitaxel-eluting stent: Day 343 Paclitaxel-eluting stent: Day 442 Sirolimus-eluting stent: Day 335 Sirolimus-eluting stent: Day 375 After discontinuation of aspirin and clopidogrel Virmani R et al., Circulation 2004 Sirolimus-eluting stent: Day 550 Hypersensitivity reaction with occlusive thrombus

75 Hypersensitivity Reaction after Sirolimus-Eluting Stent Late Occlusive Thrombus Inflammation within media Giant cells around polymer remnant Virmani R et al., Circulation 2004

76 Open Thienopyridine Benefit of Long-Term Therapy with Clopidogrel - PCI-CURE - Vasc. Death or Myocardial Infarction [%] Placebo Clopidogrel Days Mehta SR et al., Lancet 2001

77 Risk Reduction by Clopidgrel: Day 30 to End of Study - PCI-CURE - Relative Risk Vasc. Death and Infarction Vasc. Death, Infarction, Rehospitalisation Mehta SR et al., Lancet 2001

78 Benefit of Long-Term Therapy with Clopidogrel in CREDO Cumulative Incidence of Death, Infarction and Stroke [%] 6 Placebo Clopidogrel 2 1 Relative Risk: 0.63 ( ); P = Days Steinhubl et al., JAMA 2002

79 CHARISMA: Clopidogrel for Secondary Prevention Patients 45 years R with high risk of athero-thrombotic complications Randomisation: n = 15,200 (event driven) Clopidogrel 75 mg daily (n = 7,600) Placebo (n = 7,600) All Patients receive additional aspirin ( mg daily).

80 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

81 Efficacy of Dual Antiplatelet Therapy Anticoagulation plus Aspirin ISAR STARS MATTIS FANTASTIC pooled Odds Ratio for death, myocardial infarction and target vessel revascularization Ticlopidine plus Aspirin better Control therapy better

82 Fibrinogen Receptor Activation After Stenting percentage of LIBS1-positive platelets 40 aspirin group ticlopidine group P= days after stent implantation Neumann et al., J Am Coll Cardiol 1997

83 Inadequate Platelet Inhibition by Ticlopidine Alone Platelet aggregation (%) Ticlopidine + aspirin Ticlopidine alone 50 0 Collagen-induced ADP-induced Rupprecht HJ et al., Circulation 1998

84 Clopidogrel versus Aspirin in CAPRIE Caprie Investigators, Lancet 1996

85 Clopidogrel versus Aspirin in CAPRIE: No Benefit in Cardiac Patients Caprie Investigators, Lancet 1996

86 Anticoagulation and Dual Antiplatelet Therapy Mayo-Clinic Experience 66 Patients No MACE 6 Patients with Readmission for Bleeding: Bleeding from colon polyps, transfusion Day 14 Hematuria secondary to urolithiasis Day 15 Peptic ulcer Day 9 Groin haematoma Day 2 (INR 1.0) Nose bleeding Minor ear bleeding Orford JL et al., Am Heart J 2004

87 Anticoagulation and Dual Antiplatelet Therapy Herz-Zentrum Bad Krozingen 161 Patients from Oct until Oct (2.0 % of all PCI) 30-day MACE: n = 7 (4.3 % [95%-CI: 1.2 % %]) Death: n=4 (2.5 %) unknown ischemic stroke intracerebral bleeding after fall stent thrombosis No lethal infarction: n = 0 Reintervention: n = 3 (1.9%) Bleeding complications: n=4 (2.5 % [95%-CI: 0.1%-4.9%]) Intracerebral bleeding after fall n = 1 Surgical revision for groin bleeding n = 2 Gastro-intestinal bleeding n = 1

88 ACTIVE Study Design Atrial Fibrillation Increased Risk of vascular events Contraindication to oral anticoagulation Clopidrogrel + Aspirin vs oral anticoagulation (INR 2-3) Clopidrogrel + Aspirin vs Placebo + Aspirin n = 6,000 completed Irbesartan vs Placebo Follow-up after 3 years about 4,000 still running

89 Adjunctive Antithrombotic Therapy Low-to-intermediate risk patients Effective clopidogrel pretreatment (ISAR-REACT-regimen) or bivalirudin (REPLACE-2 regimen) can replace GP IIb/IIIa blockade Insulin-Treated Diabetics Effective clopidogrel pretreatment or bivalirudin are potential alternatives to GP IIb/IIIa blockade High Risk Acute Coronary Syndromes (incl. STEMI) Based on currently available evidence: Triple antiplatelet therapy plus heparin

90 Continuation of Antithrombotic Treatment Duration of Dual Antiplatelet Therapy Optimal: 1 year Minimal: Bare stents 4 weeks Sirolimus-eluting stents 2 months Paclitaxel-eluting stents 6 months Atrial fibrillation with low intermediate risk Withholding of oral anticoagulation for the duration of dual antiplatelet therapy Patients with strict indication for oral anticoagulation Combination with dual antiplatelet therapy