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Antithrombotic therapy in acute coronary syndromes: which agent and when? Giuseppe Biondi Zoccai Divisione di Cardiologia, Università di Torino

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Presentation on theme: "Antithrombotic therapy in acute coronary syndromes: which agent and when? Giuseppe Biondi Zoccai Divisione di Cardiologia, Università di Torino"— Presentation transcript:

1 Antithrombotic therapy in acute coronary syndromes: which agent and when? Giuseppe Biondi Zoccai Divisione di Cardiologia, Università di Torino gbiondizoccai@gmail.com Aggiornamenti in tema di fibrillazione atriale, imaging 3D ed infarto acuto - Torino, 18/10/2008

2 Were you ever feeling uncertain on the most appropriate combination antithrombotic agents in acute coronary syndromes (ACS)? And what about their most appropriate timing of administration? Introductory remarks G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>Introduction

3 Learning goals What is the scope of ACS? What is the role of antiplatelet agents in ACS? What is the role of anticoagulants in ACS? When and how should antithrombotic agents be given? Does on size fit all? G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>Learning goals

4 Learning goals What is the scope of ACS? What is the role of antiplatelet agents in ACS? What is the role of anticoagulants in ACS? When and how should antithrombotic agents be given? Does on size fit all? G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

5 Scope of the problem Thrombotic events Myocardial ischemia Bleeding Peri-procedural complications G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

6 Scope of the problem Thrombotic events Myocardial ischemia Bleeding Peri-procedural complications G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

7 Scope of the problem G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

8 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 ACS pathophysiology G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

9 Scope of the problem: AMI Capewell et al, Heart 2006 G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

10 Scope of the problem: unstable angina Capewell et al, Heart 2006 G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

11 Pathways to thrombosis * * * * Myers, BUMC Proceedings 2005 G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

12 Multiple vulnerable coronary plaques in patients with AMI Asakura et al, J Am Coll Cardiol 2001 G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

13 Multiple ruptured coronary plaques in patients with ACS G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

14 Endothelialization of stent struts Guagliumi et al, Ital Heart J 2003 SESBMS G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

15 On top of this: variability in response to antithrombotic therapy G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

16 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 G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>Scope

17 Learning goals What is the scope of ACS? What is the role of antiplatelet agents in ACS? What is the role of anticoagulants in ACS? When and how should antithrombotic agents be given? Does on size fit all? G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>Antiplatelet Rx

18 0.00 0.05 0.10 0.15 0.20 0.25 036912 Months Probability of death or MI Placebo ASA 75 mg Risk ratio after 1 year 0.52 95% Cl 0.37–0.72 (P=0.0001) Wallentin et al, JACC 1991 Aspirin in unstable angina G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>Antiplatelet Rx

19 Cumulative hazard rates for CV death/MI Days of follow-up a = median time PCI (10 days) b = 30 days after median time of PCI 0.15 0.10 0.05 0.0 0 40 100200300400 ab PlaceboClopidogrel 12.6% 8.8% 1.9% ARR 31% RRR P=0.002 N=2,658 Mehta et al, Lancet 2001 PCI-CURE Substudy G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>Antiplatelet Rx 10

20 Lotrionte et al, AJC 2007 Clopidogrel loading in high- risk patients undergoing PCI G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>Antiplatelet Rx

21 Kastrati et al, JAMA 2006 Abciximab in ACS with 600 mg clopidogrel pretreatment *Death/MI/urgent TVR * 600 mg clopidogrel 500 mg ASA >2 h before PCI G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>Antiplatelet Rx

22 Invasive vs conservative approach: stents AND antiplatelet Rx G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>>>Sizing

23 Prasugrel vs 300/75 mg clopidogrel in ACS G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>Antiplatelet Rx 0 0.5 1 1.5 2 050100150200250300350400450 % of subjects having DES thrombosis Hazard ratio 0.36 [0.22-0.58] P<0.0001 2.31% 0.84% Days CLOPIDOGREL PRASUGREL

24 Learning goals What is the scope of ACS? What is the role of antiplatelet agents in ACS? What is the role of anticoagulants in ACS? When and how should antithrombotic agents be given? Does on size fit all? G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>>Anticoagulant Rx

25 Theroux et al, NEJM 1988 UF Heparin in NSTEACS G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>Antiplatelet Rx

26 LMW heparin in NSTEACS G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>Antiplatelet Rx Bassand et al, EHJ 2007

27 Direct thrombin inhibitors in ACS G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>>Anticoagulant Rx Bassand et al, EHJ 2007

28 The HORIZONS trial G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>>Anticoagulant Rx Stone et al, NEJM 2008

29 Fondaparinux in ACS: combined analysis of OASIS-5 (NSTEACS) and OASIS-6 (STEMI) G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>>Anticoagulant Rx Mehta et al, Circ 2008

30 Learning goals What is the scope of ACS? What is the role of antiplatelet agents in ACS? What is the role of anticoagulants in ACS? When and how should antithrombotic agents be given? Does on size fit all? G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>>When and how

31 Overwhelming complexity? G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>>When and how

32 Bertrand et al, EHJ 2002; Silber et al, EHJ 2005 ESC guidelines: a synthesis ASPIRINASPIRIN: 500 mg oral or 300 mg IV loading dose ASAP, 75-100 mg lifelong CLOPIDOGRELCLOPIDOGREL: 300-600 mg loading dose ASAP, 75 mg for 9-12 months DIRECT THROMBIN INHIBITORSDIRECT THROMBIN INHIBITORS (eg bivalirudin): as replacement of UFH or LWM for HIT, in NSTEACS patients at high-risk of bleeding but low risk of ischemic events, and in most STEMI FONDAPARINUXFONDAPARINUX: 2.5 mg SC daily in patients managed non-urgently or conservatively GPIIB/IIIA INHIBITORSGPIIB/IIIA INHIBITORS: in high-risk patients, provisionally in others (abciximab or eptifibatide in the cath lab if angio<2.5 h or provisional use; eptifibatide or tirofiban if angio<48 h) LMW HEPARINLMW HEPARIN (eg 10 mg/Kg SC enoxaparin twice daily): if invasive strategy is not applicable or deferred UNFRACTIONED HEPARINUNFRACTIONED HEPARIN: 50-100 IU/Kg IV bolus and additional doses aiming for target ACT (250–350 s without GpIIb/IIIa inhibitors, and 200–250 with them) if immediate or early invasive strategy PRASUGREL/CANGRELORPRASUGREL/CANGRELOR: not yet CE-marked G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>>When and how Bassand et al, EHJ 2007

33 Learning goals What is the scope of ACS? What is the role of antiplatelet agents in ACS? What is the role of anticoagulants in ACS? When and how should antithrombotic agents be given? Does on size fit all? G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>>>Sizing

34 Finding the balance between ischemic and bleeding risk: an easy case

35

36 Finding the balance between ischemic and bleeding risk: another easy case

37

38 What about tougher cases?

39 Predicting ischemic risk Antman et al, JAMA 2000;284:835-42 TIMI Score * 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 G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>>>Sizing

40 Nikolski et al, EHJ 2007 Predicting bleeding risk G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando>>>>>>>Sizing

41 A new composite end-point: 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

42 *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* A new composite end-point: net adverse clinical events (NACE)

43 Take home messages

44 1. A comprehensive appraisal of thrombotic & bleeding risks is needed in patients with ACS THROMBOSIS BLEEDING

45 2. Better yet practical risk- stratification tools for bleeds and thromboses are warranted

46 3. Every patient will have an individualized treatment with different agents, timing and dosage of administration, depending on overall risk profile and acuity

47 Thank you for your attention For any correspondence: gbiondizoccai@gmail.com For further slides on these topics feel free to visit the metcardio.org website: http://www.metcardio.org/slides.html gbiondizoccai@gmail.com http://www.metcardio.org/slides.html


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