Giuseppe Biondi Zoccai Divisione di Cardiologia, Università di Torino 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

Introductory remarks 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? G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>Introduction

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

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

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

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

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

ACS pathophysiology Plaque rupture Old terms New terms Stable angina Unstable angina Non-Q MI Q-MI New terms Atherothrombosis UA/NSTEMI STEMI Days Weeks Minutes Hours Antithrombotic therapy & (selectively) invasive management Reperfusion (thrombolysis and/or PTCA) G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>Scope

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

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

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

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

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

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

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

Variability in clopidogrel response Change in ADP-Induced platelet aggregation 75 mg chronic dosing Maximal aggregation 5 µmol/L ADP (%) following 600 mg loading dose 100 N=544 N=1001 80 Number of Patients 60 40 20 2 4 6 8 10 Relative change in aggregation Time from loading dose to cath (h) Serebruany et al, J Am Coll Cardiol 2005 Hochholzer et al, Circulation 2005 G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>Scope

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

Aspirin in unstable angina 0.25 Placebo 0.20 Risk ratio after 1 year 0.52 95% Cl 0.37–0.72 (P=0.0001) 0.15 Probability of death or MI 0.10 ASA 75 mg Slide 4 Long-term Efficacy of ASA in Reducing Death or MI in Patients With Unstable Angina These results reinforce the need for long-term antiplatelet therapy and show the long-term efficacy of ASA. In this trial 796 male patients with unstable angina or non-Q-wave MI were randomized to receive either ASA (75 mg/day) or placebo. There was a significant reduction in the risk of death or MI in ASA-treated patients. After 1 year, the risk was reduced by 48%. Revascularization for severe angina was also less common in the ASA-treated patients. 0.05 0.00 3 6 9 12 Wallentin et al, JACC 1991 Months G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>Antiplatelet Rx Reference Wallentin LC and the Research Group of Instability in Coronary Artery Disease in Southeast Sweden. J Am Coll Cardiol 1991;18:1587–1593.

PCI-CURE Substudy Placebo Clopidogrel 12.6% 1.9% ARR 31% RRR P=0.002 N=2,658 0.15 8.8% 0.10 Cumulative hazard rates for CV death/MI 0.05 PCI-CURE1 was a prospectively designed sub-study of patients undergoing percutaneous coronary intervention (PCI) who were randomized to double-blind therapy with clopidogrel* or placebo* in the CURE† trial. The objectives were to test the hypothesis that pre-treatment with clopidogrel* would be superior to placebo* in reducing major ischemic events within the first 30 days after PCI, and to determine if long-term treatment (up to 1 year) with clopidogrel after PCI would provide additional clinical benefit. In PCI-CURE, patients underwent a PCI at a median 10 days from randomization into the trial. Following PCI, all stented patients received open label ADP receptor antagonist (clopidogrel or ticlopidine) in combination with ASA for 2-4 weeks. PCI-CURE demonstrated the long-term efficacy of clopidogrel on top of standard therapy including ASA in patients undergoing PCI. For the endpoint of myocardial infarction (MI) or cardiovascular death from time of randomization to end of follow-up, treatment with clopidogrel* resulted in a 31% relative risk reduction (8.8% clopidogrel vs 12.6% placebo; p = 0.002).‡ The use of clopidogrel on top of standard therapy including ASA was safe. There was a non-significant and small excess in major, but not life-threatening, bleeding in the group treated with clopidogrel on top of standard therapy including ASA. Clopidogrel plus ASA was associated with an increase in minor bleeding compared with placebo to end of follow-up. * On top of standard therapy (including ASA) † Clopidogrel in Unstable angina to prevent Recurrent Events ‡ This endpoint included events that were prevented prior to PCI as well as those following the procedure Reference: 1. Mehta SR et al. Lancet 2001: 358: 527–33. 0.0 10 40 100 200 300 400 Days of follow-up a b a = median time PCI (10 days) b = 30 days after median time of PCI Mehta et al, Lancet 2001 G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>Antiplatelet Rx

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

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

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

% of subjects having DES thrombosis Prasugrel vs 300/75 mg clopidogrel in ACS 2.31% 2 CLOPIDOGREL 1.5 % of subjects having DES thrombosis Hazard ratio 0.36 [0.22-0.58] P<0.0001 1 0.84% PRASUGREL 0.5 Days 50 100 150 200 250 300 350 400 450 G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>Antiplatelet Rx

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

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

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

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

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

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

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

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

ESC guidelines: a synthesis ASPIRIN: 500 mg oral or 300 mg IV loading dose ASAP, 75-100 mg lifelong CLOPIDOGREL: 300-600 mg loading dose ASAP, 75 mg for 9-12 months DIRECT 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 FONDAPARINUX: 2.5 mg SC daily in patients managed non-urgently or conservatively GPIIB/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 HEPARIN (eg 10 mg/Kg SC enoxaparin twice daily): if invasive strategy is not applicable or deferred UNFRACTIONED 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/CANGRELOR: not yet CE-marked Bassand et al, EHJ 2007 Bertrand et al, EHJ 2002; Silber et al, EHJ 2005 G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>>When and how

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

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

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

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

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

What about tougher cases?

Predicting ischemic risk TIMI Score VARIABLE MULTI-VARIABLE P ODDS RATIO POINT Age>65 years <0.001 1.75 1 >2 risk factors for CAD 0.003 1.54 Significant CAD 1.70 ST deviation 0.005 1.51 Severe angina 0.001 1.53 Aspirin in last week 0.006 1.74 Raised cardiac markers 1.56 * * all-cause mortality, myocardial infarction, and severe recurrent ischemia prompting urgent revascularization Antman et al, JAMA 2000;284:835-42 G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>>>Sizing

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

A new composite end-point: net adverse clinical events (NACE) ALL CAN IMPACT ON PROGNOSIS, SYMPTOMS, AND COSTS! BUT EACH MAY IMPACT THESE IN DIFFERENT DIRECTIONS MAJOR BLEEDING DEATH PCI/ CABG MI STROKE Ndrepepa et al, J Am Coll Cardiol 2008;51:690-7

A new composite end-point: net adverse clinical events (NACE) ALL CAN IMPACT ON PROGNOSIS, SYMPTOMS, AND COSTS! BUT EACH MAY IMPACT THESE IN DIFFERENT DIRECTIONS MAJOR BLEEDING DEATH NACE: composite of all cause death, non-fatal myocardial infarction, non-fatal stroke, PCI/CABG, and non-fatal major bleeding* PCI/ CABG MI STROKE *in several cases, stroke is not included in NACE definition

Take home messages

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

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

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

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