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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
• 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
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
Scope of the problemThrombotic eventsThrombotic events
Myocardial Myocardial ischemiaischemia
BleedingBleeding
Peri-procedural Peri-procedural complicationscomplications
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>Scope
Scope of the problemThrombotic eventsThrombotic events
Myocardial Myocardial ischemiaischemia
BleedingBleeding
Peri-procedural Peri-procedural complicationscomplications
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>Scope
Scope of the problem
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>Scope
Antithrombotictherapy &
(selectively)invasive
management
Stable angina
Unstableangina
Reperfusion(thrombolysis and/or PTCA)
Minutes Hours
DaysWeeks
STEMISTEMIUA/NSTEMIUA/NSTEMIAtherothrombosisAtherothrombosisNew terms
Old terms
Plaque rupture
Non-Q MI Q-MI
ACS pathophysiology
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
Guagliumi et al, Ital Heart J 2003
SES BMS
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 responseChange in ADP-Induced
platelet aggregation75 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
0 2 4 6 8 100
20
40
60
80
100
N=1001
Num
ber
of P
atie
nts N=544
Relative change in aggregation
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
0.00
0.05
0.10
0.15
0.20
0.25
0 3 6 9 12
Months
Pro
bab
ility
of
de
ath
or
MI Placebo
ASA 75 mg
Risk ratio after 1 year 0.5295% 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
Cu
mu
lati
ve h
azar
d r
ates
fo
r C
V d
eath
/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
0.00
40 100 200 300 400
a b
PlaceboClopidogrelClopidogrel
12.6%
8.8%8.8%
1.9% ARR31% RRRP=0.002N=2,658
Mehta et al, Lancet 2001
PCI-CURE Substudy
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>Antiplatelet Rx
10
Lotrionte et al,
AJC 2007
Clopidogrel loading in high-risk patients undergoing PCI
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>Antiplatelet Rx
Kastrati et al, JAMA 2006
Abciximab in ACS with 600 mg clopidogrel pretreatment
*Death/MI/urgent TVR
*
600 mg clopidogrel500 mg ASA
>2 h before PCI
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
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
0 50 100 150 200 250 300 350 400 450
% o
f sub
ject
s ha
ving
D
ES
thro
mbo
sis
Hazard ratio 0.36 [0.22-0.58]P<0.0001
2.31%
0.84%
Days
CLOPIDOGREL
PRASUGREL
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
3,7
1,7
0
1
2
3
4
Serious bleeding
(%)
ASA+UFH ASA
Theroux et al, NEJM 1988
UF Heparin in NSTEACS
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>Antiplatelet Rx
LMW heparin in NSTEACS
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>Antiplatelet Rx
Bassand et al, EHJ 2007
Direct thrombin inhibitors in ACS
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>>Anticoagulant Rx
Bassand et al, EHJ 2007
The HORIZONS trial
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>>Anticoagulant Rx
Stone et al, NEJM 2008
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
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
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
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
Antman et al, JAMA 2000;284:835-42
TIMI Score
* all-cause mortality, myocardial infarction, and severe recurrent ischemia prompting urgent revascularization
*
VARIABLEMULTI-
VARIABLE PODDS RATIO POINT
Age>65 years <0.001 1.75 1
>2 risk factors for CAD
0.003 1.54 1
Significant CAD <0.001 1.70 1
ST deviation 0.005 1.51 1
Severe angina 0.001 1.53 1
Aspirin in last week
0.006 1.74 1
Raised cardiac markers
<0.001 1.56 1
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>>>Sizing
Nikolski et al, EHJ 2007
Predicting bleeding risk
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando >>>>>>>Sizing
A new composite end-point: net adverse clinical events (NACE)
Ndrepepa et al, J Am Coll Cardiol 2008;51:690-7
DEATHDEATH
MIMI
STROKESTROKE
PCI/ CABGPCI/ CABG
MAJOR MAJOR BLEEDINGBLEEDING
ALL CAN ALL CAN IMPACT ON IMPACT ON
PROGNOSIS, PROGNOSIS, SYMPTOMS, SYMPTOMS, AND COSTS!AND COSTS!BUT EACH BUT EACH
MAY IMPACT MAY IMPACT THESE IN THESE IN
DIFFERENT DIFFERENT DIRECTIONSDIRECTIONS
*in several cases, stroke is not included in NACE definition
DEATHDEATH
MIMI
STROKESTROKE
PCI/ CABGPCI/ CABG
MAJOR MAJOR BLEEDINGBLEEDING
ALL CAN ALL CAN IMPACT ON IMPACT ON
PROGNOSIS, PROGNOSIS, SYMPTOMS, SYMPTOMS, AND COSTS!AND COSTS!BUT EACH BUT EACH
MAY IMPACT MAY IMPACT THESE IN THESE IN
DIFFERENT DIFFERENT DIRECTIONSDIRECTIONS
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)
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: [email protected]
For further slides on these topics feel free to visit the metcardio.org website:
http://www.metcardio.org/slides.html