Adjunctive Pharmacological Therapies in PCI : Antiplatelets and Anticoagulants

Transcription

1 Adjunctive Pharmacological Therapies in PCI : Antiplatelets and Anticoagulants Young-Hak Kim, MD Asan Medical Center, Seoul, Korea

2 Why Drug? PCI localized therapy Drug systemic effect

3 Fate of Disrupted Atherosclerotic Plaque Active fissure Intramural thrombus Cholesterol, Smoking, Age, Hypercholesterol, Hypertension Healed fissure Further angina Occlusive thrombus Acute coronary occlusion Mural thrombus Intraintimal thrombus Unstable angina pectoris

4 Pathophysiology of AMI Rupture fibrous cap with luminal and intraplaque occlusive thrombus

5 Why Drug? Adjuntive drug therapy should be combined with PCI due to generalized inflammatory process of atheromatous plaque : Panvasculits

6 Target of Drug Thrombus Coagulation cascade Platelet RBC

7 Thrombogenesis after Vascular Injury Thrombin Xa-Va Prothrombin Xa X TF-Vlla Fibrinogen Tissue Factor Fibrin

8 Inactivation of Platelet Coagulation Fibrin Formation Primary Hemostasis Platelet Function Fibrinolysis Clot Dissolution Injured Vessel Wall Endothelium

9 Coagulation Cascade XII Anions XI Intrinsic Pathway Clot XIIa Ca 2 Ca 2 XIa IX IXa VIIIa Phospholipid Ca 2 X Thrombin Fibrin Tissue Factor (TF) VIIa/TF Phospholipid Fibrinopeptide A Xa Va Ca 2 PT Fragment F1,2 Fibrinogen VII Extrinsic Pathway Vit K dependent Heparin sensitive clotting factors LMWH sensitive clotting factors Direct antithrombin Prothrombin

10 Target of Drug Thrombus Coagulation cascade Platelet RBC

11 Thrombolysis The only dissolving drug of thrombus in real sense

12 Mechanism of Thrombolysis Fibrin Rich Thrombus Streptokinase/Plasminogen Complex Nonspecific systemic activation Plasminogen Plasmin D-dimers Thrombus specific activation Utilization of fibrinogen decreased its plasma levels TNK t-pa+fibrin t-pa+fibrinr-pa+fibrin PAI-1 Fibrin Degradation Products

13 TIMI Flow Rate and Mortality Pooled data from 5498 pts with thrombolysis % P=0.003 P< P< TIMI 0 or 1 TIMI 2 TIMI 3 TIMI=Thrombolysis in Myocardial Infarction Dr. Michael Gibson, 2000

14 Thrombolytic Agents First generation Streptokinase Urokinase Second generation Anistreplase(APSAC) Third generation Reteplase(r-PA) Lanoteplase (n-pa) TNK-t-PA Fibrin specificity Direct plaminogen activation Hemorrhagic stroke Cost Tissue-type PA(t-PA: alteplase, duteplase) Prourokinase (scu-pa: Plasma saruplase) half life Noncerebral bleeding Antigenecity

15 New Plasminogen Activators Alteplase (t-pa) Lanoteplase (n-pa) Reteplase (r- PA) Increment of patency rate Prolong plasma clearance single bolus injection Tenceteplase (TNK-tPA)

16 TIMI 3 Flow Rate at 90 min % Streptokinase Conventional dose tpa Accelerated dose tpa Double bolus alteplase

17 Thirty-day Mortality Rates Mortality (%) P=NS SK(IV) SK(SubQ) t-pa + SK t-pa Days from Randomization GUSTO-I trial Catch-up

18 Thirty-day Mortality Rate % Patients Depending on Thrombolytic Agents rpa npa TNK GUSTO III tpa Bolus lytic 6.18 In Time 2 ASSENT 2

19 Mortality Reduction Depending on Thrombolysis Time Mortality Reduction (%) MITI EMIP GISSI-1 ISIS-2 GISSI-1,ISIS-2 ASSET, AIMS LATE, EMERAS Hours LATE EMERAS

20 Target of Drug Thrombus Coagulation cascade Platelet RBC

21 Anticoagulants Unfractionated heparin Low molecular weight heparin Antithrombin

22 Heparin The most widely used anticoagulant

23 Coagulation Cascade XII Anions XI Intrinsic Pathway Clot XIIa Ca 2 Ca 2 XIa IX IXa VIIIa Phospholipid Ca 2 X Thrombin Fibrin Tissue Factor (TF) VIIa/TF Phospholipid Fibrinopeptide A Xa Va Ca 2 PT Fragment F1,2 Fibrinogen VII Extrinsic Pathway Vit K dependent Heparin sensitive clotting factors LMWH sensitive clotting factors Direct antithrombin Prothrombin

24 Optimal Activated Clotting Time During PCI Circulation. 2001;103:

25 Optimal Activated Clotting Time During PCI Circulation. 2001;103:

26 Low-Molecular Weight Heparin New drug expected to replace heparin

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28 Coagulation Cascade XII Anions XI Intrinsic Pathway Clot XIIa Ca 2 Ca 2 XIa IX IXa VIIIa Phospholipid Ca 2 X Thrombin Fibrin Tissue Factor (TF) VIIa/TF Phospholipid Fibrinopeptide A Xa Va Ca 2 PT Fragment F1,2 Fibrinogen VII Extrinsic Pathway Vit K dependent Heparin sensitive clotting factors LMWH sensitive clotting factors Direct antithrombin Prothrombin

29 LMWH Preparation Ardeparin (Normiflo) Dalteparin (Fragmin) Enoxaparin (Lovenox) Nadroparin (Fraxiparine) Reviparin (Clivarine) Tinzaparin (Innohep)

30 Anti-Xa Activity After Enoxaparin in Pts Undergoing CAG & PCI Sustained antiplatelet activity Circulation 2001;103:658

31 ESSENCE trial ACS N=3171 Enoxaparin 1mg/kg bid 2-8 days (vs. UFH bolus infusion 2-8 days) End point:death, myocardial infarction, recurrent angina

32 ESSENCE / TIMI IIB ACS Comparison of Enoxaparin versus UFH in Patients with ACS having Subsequent PCI Group Death/MI/Urgent Revascularization at Day 43 Treatment n N % OR Treatment Effect 95% CI of OR p Value In-hospital UFH PCI Enoxaparin Ontreatment PCI UFH Enoxaparin

33 ESSENCE / TIMI IIB ACS Comparison of Enoxaparin versus UFH in Patients with ACS having Subsequent PCI Death/MI/Urgent Revascularization at One Year Treatment Effect Group Treatment n N % OR 95% CI of OR p Value In-hospital UFH PCI Enoxaparin Ontreatment PCI UFH Enoxaparin Am J Cardiol 2002;90:477

34 Short Term LMWH vs. ACS Unfractionated Heparin LMWH UFH OR 95% Cl Gurfinkel 0/68 4/70 (4 2%) FRIC 29/751 (3 9%) 26/731 (3 6%) ESSENCE 17/1607 (1 1%) 20/1564 (1 3%) TIMI 11B 33/1953 (1 7%) 42/1959 (2 1%) FRAXIS 69/2317 (3 0%) 36/1151 (3 1%) Pooled results 148/6696 (2 2%) 128/5475 (2 3%) LMWH better UFH better

35 ASSENT-3 PLUS AMI Death P=0.234 Recurrent MI P=0.028 Refractory Ischemia P=0.067 ICH P= % 7.5% 8% 8% 3% 6% 6.0% 6% 5.9% 6% 4.4% 6.5% 2% 2.2% 4% 4% 3.6% 4% 2% 2% 2% 1% 1.0% 0% 0% 0% 0% Enoxaparin UFH + TNK + TNK Enoxaparin UFH + TNK + TNK Enoxaparin UFH + TNK + TNK Enoxaparin UFH + TNK + TNK Wallentin et al, AHA 2002

36 A to Z study 3987 high-risk ACS patients were included (with ST changes or a positive cardiac marker) Pts obtained baseline therapy with tirofiban and aspirin Pts were randomized to enoxaparin (1mg/kg every 12 hours) or weight-adjusted UFH Treatment was given for a maximum of 120 hours but could be stopped or switched at any time at the treating physician s discretion 60% of the patients went for angiography ACC, 2003

37 Clinical end points End point Death MI Refractory ischemia Urgent revascularzation Multiple MI events Composite of secondary end points Enoxaparin (%) UFH (%) HR No significant reduction of cardiac events However, no sampling and expected efficacy 95% CI ACC, 2003

38 Direct Antithrombin Theoretically most attractive anticoagulant

39 Coagulation Cascade XII Anions XI Intrinsic Pathway Clot XIIa Ca 2 Ca 2 XIa IX IXa VIIIa Phospholipid Ca 2 X Thrombin Fibrin Tissue Factor (TF) VIIa/TF Phospholipid Fibrinopeptide A Xa Va Ca 2 PT Fragment F1,2 Fibrinogen VII Extrinsic Pathway Vit K dependent Heparin sensitive clotting factors LMWH sensitive clotting factors Direct antithrombin Prothrombin

40 Anti-thrombin Agents Direct Thrombin Inhibitors Do not require a cofactor Not inhibited by PF-4 or antiheparin proteins Effective against clot-bound thrombin No platelet aggregation Predictable anticoagulation No thrombocytopenia

41 Clinical Outcomes in PCI Bivalirudin Heparin better better Bivalirudin Heparin N=3277 N=2857 Death, MI or revasc. Death or MI MI Revascularization Hemorrhage 7.4% 13.0% 5.7% 7.5% 3.4% 4.4% 3.3% 4.3% 3.3% 4.8% 2.8% 7.6%

42 REPLACE PCI Patients Urgent or Elective PCI 1 : 1 randomization Aspirin Plavix Stent ANGIOMAX 0.75 mg/kg bolus 1.75mg/kg/h procedure Provisional abciximab or eptifibatide Heparin 65 U/kg Abciximab Or Eptifibatide Endpoints 30-day Death MI Revasc Hemorrhage Economics 1-year follow-up

43 Overall Outcome REPLACE - 2

44 REPLACE 2 : Drug Cost Drug Cost Heparin n=3008 Treated Total cost Aniomax n=2994 Treated Total cost Heparin Bivalirudin Abciximab Eptifibatide $ 10 $ 395 $ 1350 $ $28,960 $0 $1,741,500 $963, $0 $1,182,630 $143,100 $66,600 Total $2,734,060 $1,392,330 Average per patient Saving per patient $909 $465 > $400

45 Target of Drug Thrombus Coagulation cascade Platelet RBC

46 Thrombogenesis after Vascular Injury Thrombin Xa-Va Prothrombin Xa X TF-Vlla Fibrinogen Tissue Factor Fibrin

47 Antiplatelet Aspirin Clopidogrel or Ticlopidine Glycoprotein IIb/IIIa inhibitor

48 Pathways of Platelet Activation Epi PAF Thrombin Platelet ADP TXA2 Vasopressin 5HT GPIIb/IIIA Collagen Thrombus

49 Action of Antithrombotic Drug LMWH Heparin AT AT Bivalirudin Hirudins Argatroban Tissue factor Plasma clotting ADP cascade Thromboxane A 2 Prothrombin Factor Xa Thrombin Fibrinogen Aspirin Collagen Platelet activation Platelet aggregation Fibrin Ticlopidine Clopidogrel GP IIb/IIIa receptors Thrombolytics Thrombus

50 Aspirin Traditionally most important drug

51 Action of Antithrombotic Drug LMWH Heparin AT AT Bivalirudin Hirudins Argatroban Tissue factor Plasma clotting ADP cascade Thromboxane A 2 Prothrombin Factor Xa Thrombin Fibrinogen Aspirin Collagen Platelet activation Platelet aggregation Fibrin Ticlopidine Clopidogrel GP IIb/IIIa receptors Thrombolytics Thrombus

52 Cumulative Number of Vascular Deaths ISIS Control (13.2%) Aspirin (10.7%) Streptokinase (10.4%) Streptokinase + aspirin (8.0%) day ISIS-2 2 Investigators, LANCET 1988;2:

53 Clopidogrel or Ticlopidine New replacing drug of aspirin Plavix and Ticlid

54 Action of Antithrombotic Drug LMWH Heparin AT AT Bivalirudin Hirudins Argatroban Tissue factor Plasma clotting ADP cascade Thromboxane A 2 Prothrombin Factor Xa Thrombin Fibrinogen Aspirin Collagen Platelet activation Platelet aggregation Fibrin Ticlopidine Clopidogrel GP IIb/IIIa receptors Thrombolytics Thrombus

55 Platelet 1. Platelet Adhesion GP Ib 2. Platelet Activation Plaque rupture ASA, Clopidogrel/Ticlopidine Activated Platelet GP IIb/IIIa 3. Platelet Aggregation GP IIb/IIIa Inhibitors Cannon, Braunwald, Heart Disease 2001

56 Indirect Comparisons ASA Doses on Vascular Events in High Risk Patients ASA Dose # Trials OR mg 34 19% mg 19 26% mg 12 32% <75 mg 3 13% Overall 65 23% Antiplatelet Antiplatelet Better Worse Antithrombotic Trialists Collaboration BMJ 2002; 324:71-86

57 Antiplatelet Therapy Trialists and CAPRIE Studies ASA and Clopidogrel in Secondary Prevention Cumulative Event Rate - % (Vascular Death, MI, or Stroke p = Time from Randomization (mo) 1 Antiplatelet Trialists Collaboration. BMJ. 1994; 308: CAPRIE Steering Committee, Lancet ;348: Placebo 1 Aspirin 1,2 Clopidogrel 2 25% 8.7% Relative Risk Reduction

58 Efficacy of Clopidogrel or Ticlopidine in Reducing Coronary Events after Stenting 30-Day Major Adverse Cardiac Events Trial N Relative Risk & 95% CI Clopid. Ticl. CLASSICS 1, % 0.9% TOPPS % 3.5% Müller % 1.7% CCF 2, % 8.9% Lenox Hill 2, % 3.8% Mayo 2, % 1.6% N. Memorial 1, % 2.2% S. Illinois % 1.4% Wash. Hosp % 0.5% Wessex % 5.2% Overall 13,827 OR = 0.73, p= % 3.9% Clopidogrel Better Ticlopidine Better Bhatt, DL. JACC. 2002

59 Benefit of Pre-treatment with Clopidogrel 30 Days (D/MI/UTVR) 6 Months (D/MITVR) Clopidogrel No Clopidogrel

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61 Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events Randomized, Double-blind 12, 562 patients Clopidogrel 300mg loading dose, 75 mg daily Patients with Non-ST elevation Acute Coronary Syndrome R Aspirin mg 3 months of double-blind Rx, 12 months of F/U Aspirin mg Placebo Months CURE Investigators NEJM 2001

62 Cumulative Hazard Rates for CV Death/MI/Stroke CURE Investigators NEJM 2001 Cumulative Cumulative Hazard Hazard Rates Placebo P < Clopidogrel No of Pts of Follow-up Months of Follow-up Plac Clop

63 PCI- CURE Study Design CURE PCI-CURE PLACEBO + ASA * Pretreatment N = 2,658 patients undergoing PCI Open-label thienopyridine N = 1345 R PCI 30 days post PCI End of follow-up Up to 12 months after randomization CLOPIDOGREL + ASA * Pretreatment Open-label thienopyridine N = 1313 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:

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65 PCI- CURE Overall Long-term Results Cumulative Hazard Rate CV Death or MI from randomization to end of follow-up * In addition to other standard therapies. Placebo + ASA* Clopidogrel + ASA* Mehta et al for the CURE Investigators. Lancet. 2001;358: % 8.8% P = N = Days of follow-up 31% Relative Risk Reduction

66 Major/Life-Threatening Bleeds within 7 Days of CABG Surgery Plac Clop RR p Stopped < 5 days prior to CABG Pts with Maj/LT Bleeds N = % N = % Stopped > 5 days prior to CABG Pts with Maj/LT Bleeds N = % N = %

67 Clopidogrel timing Early treatment - Reduced early ischemic events - Potential for bleeding if early CABG needed Wait until catheterization - Avoid treatment of patients pre-cabg - Lost opportunity for early benefit

68 Clinical Events Post-PCI Elective PCI STENT ACS - Invasive Traditional clopidogrel Evidence-Based: CURE/ PCI-CURE/ CURE/ CREDO 24 Hours Acute Incidence: Stent 0.6% Thrombosis Subacute Stent Thrombosis Stent: Restenosis Coronary tree: recurrent events Up to 30 days Incidence: 6.4% Up to 12 Months Incidence: 20-25%* Incidence: 6-15% Major Adverse Cardiac Events Years Incidence: ~ 20%

69 Glycoprotein IIb/IIIa Inhibitors Abciximab : Reopro Tirofiban : Agrastat

70 Embolized Platelet Aggregate in a Small Myocardial Arteriole Stains intensely red for the IIb/IIIa IIIa receptor

71 Potent Antiplatelet Effect Epi 5HT PAF Thrombin Platele t GPIIb/IIIa Thrombus ADP TXA2 Vasopress in Collagen GPIIb/IIIa Blocker

72 Fibrinogen or vwf Platelet GP IIb/IIIa Vitronectin Endothelium Collagen vwf

73 GP IIb/IIIa Inhibitor During Medical Management and After PCI: CAPTURE, PURSUIT, PRISM-PLUS Medical Rx Post PCI Death or MI 10% 8% 6% 4% 2% N=12,296 N=2754 P=0.001 Control P=0.001 GP IIb/IIIa inhibitor 4.3% 2.9% 8.0% 4.9% 0% h +48 h +72 h +24 h +48 h PCI Boersma et al. Circulation ;100:

74 Benefit of GP IIb/IIIa inhibitors by PCI Treatment for 12 hours Roffi M. et al. EHJ 2002; 105:

75 Upstream vs. Downstream GP IIb/IIIa inhibition Upstream demonstrated benefits Thrombus, TIMI 3, MI size (PRISM-PLUS) PLUS) Death/MI pre-cath (meta-analysis) analysis) Events Med Rx, PCI, or CABG TACTICS-TIMI TIMI 18 benefit of strategy Downstream with abciximab potential in ACS 50% benefit in PCI (EPISTENT) Abciximab mortality (EPISTENT, meta) Abcixmab restenosis/tvr in DM (EPISTENT) BUT: TARGET No diff mortality, TVR

76 PRISM-PLUS: Improvement in Thrombus Grade and TIMI Flow Grade with IIb/IIIa inhibition % Odds Ratio: 0.77 P=0.022 Possible Small Moderate Large Occlusion Tirofiban + Heparin (n=608) 17% Possible Small Moderate Large Occlusion Heparin (n=622) 24% Effective in large thrombotic burden 5 0 Odds Ratio 0.65 P= % Partial Perfusion (TIMI 2) Total Occlusion (TIMI 0) Tirofiban + Heparin (n=570) 25.5% Partial Perfusion (TIMI 2) TIMI 1 Total Occlusion (TIMI 0) Heparin (n=580) Zhao et al. Circulation 1999;100:

77 IIb/IIIa IIIa Inhibition in TnI + patients by Revasc: PRISM Study Death / MI at 30 Days 0.37 ( ) 0.93) P= ( ) 0.84) P=0.004 Heeschen, et al. Lancet 1999;354:

78 PRISM-PLUS: Risk of D/MI/RI by TIMI Risk Score and PCI No PCI TIMI RISK High N 664 P 0.04 Low PCI High Low Tiro + Hep 1 Heparin 10 Better Better Morrow DA et al. AHA 2001

79 TIMI 3 Flow Rate CADILAC Trial 2681 pts with AMI < 12hr % P=NS 20 0 PTCA N=518 PTCA+Abc N=528 Stent N=512 Stent+Abc N=524 Stone GW et al, NEJM 2002;346:

80 12-Month Mortality in Primary Angioplasty for Acute Myocardial Infarction CADILAC Trial 6% 5.5% 5.4% 4% 2% No significant benefit of reopro 3.4% 3.1% 0% Months to Event P=0.10 Stone GW et al, NEJM 2002;346:

81 12-Month MACE in Primary Angioplasty for Acute Myocardial Infarction CADILAC Trial MACE=death, MI, Target lesion revascularization 25% 20% PTCA, no Ab PTCA, Ab Stent, no Ab 22.4% 20.6% 15% 10% 5% 0% 0 No significant benefit of reopro Months to Event P=0.10 P< % 13.3% Stone GW et al, NEJM 2002;346:

82 Angiographic Restenosis Restenosis P< % 40.8% % % 20.8 CADILLAC Trial Reocclusion No significant benefit of reopro % P= % P P+A S S+A P P+A S S+A Stone GW et al, NEJM 2002;346:

83 30-Day Subacute Thrombosis CADILLAC Trial % P=0.05 Slight benefit of reopro P= PTCA PTCA+Abc Stent Stent+Abc Stone GW et al, NEJM 2002;346:

84 30-Day Hemorrhagic Complications Abciximab (+) % 8 Abciximab (-) P= Thrombocytopenia CADILLAC Trial 5.4 P=0.05 Increased bleeding rate of reopro 3.4 Transfusion Stone GW et al, NEJM 2002;346:

85 Based on Site of Initiation of Treatment % 30 P<0.05 ADMIRAL Trial Death, MI, and TVR P<0.05 Stent + placebo (n=151) Stent + Abciximab (n= Early treatment is important P=NS P=NS days In Ambulance or ER (n=86) In Cath lab or CCU (n=214) TVR=Target vessel revascularization months 30 days 6 months Montalescot et al, NEJM 2001;344:

86 Conclusions Anticoagulants Heparin Low molecular weight heparin Direct thrombin inhibitor Antiplatelets Aspirin Ticlopidine Clopidogrel Glycoprotein IIb/IIIa inhibitor Antithrombotic activity Bleeding risk