1. 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
Aggiornamenti in tema di fibrillazione atriale, imaging 3D ed infarto acuto - Torino, 18/10/2008

2. 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

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. 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

6. 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

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

8. 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

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
SES
BMS
Guagliumi et al, Ital Heart J 2003
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
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

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. Aspirin in unstable angina
0.25
Placebo
0.20
Risk ratio after 1 year % 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.

19. 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

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

21. 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

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

23. % 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 [ ]
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

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

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

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

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

29. 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

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. ESC guidelines: a synthesis
ASPIRIN: 500 mg oral or 300 mg IV loading dose ASAP, mg lifelong
CLOPIDOGREL: 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: 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

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

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

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

38. What about tougher cases?

39. 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

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

41. 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

42. 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

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: For further slides on these topics feel free to visit the metcardio.org website: