Antithrombotic therapy in
acute coronary syndromes:
which agent and when?
Giuseppe Biondi Zoccai
Divisione di Cardiologia, Università di Torino
[email protected]
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
Scope of the problem
Thrombotic events
Bleeding
Myocardial
ischemia
Peri-procedural
complications
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando
>>>>Scope
Scope of the problem
Thrombotic events
Bleeding
Myocardial
ischemia
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
Atherothrombosis
Non-Q MI
Q-MI
STEMI
UA/NSTEMI
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
60
40
20
0
Relative change in aggregation
Serebruany et al, J Am Coll Cardiol 2005
0
2
4
6
8
10
Time from loading dose to cath (h)
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
Probability of death or MI
0.25
Placebo
0.20
Risk ratio after 1 year 0.52
95% Cl 0.37–0.72 (P=0.0001)
0.15
0.10
ASA 75 mg
0.05
0.00
0
3
6
Months
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando
9
12
Wallentin et al, JACC 1991
>>>>>Antiplatelet Rx
Cumulative hazard rates for CV death/MI
PCI-CURE Substudy
Placebo
Clopidogrel
0.15
12.6%
8.8%
0.10
1.9% ARR
31% RRR
P=0.002
N=2,658
0.05
0.0
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
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando
Mehta et al, Lancet 2001
>>>>>Antiplatelet Rx
Clopidogrel loading in highrisk 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
*
600 mg clopidogrel
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
Prasugrel vs 300/75 mg
clopidogrel in ACS
% of subjects having
DES thrombosis
2.31%
Days
2
CLOPIDOGREL
1.5
Hazard ratio 0.36 [0.22-0.58]
P<0.0001
0.84%
1
PRASUGREL
0.5
0
0
50
100
150
200
250
300
G. Biondi Zoccai – Terapia antitrombotica: quale farmaco e quando
350
400
>>>>>Antiplatelet Rx
450
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
4
3,7
3
Serious
bleeding 2
(%)
1,7
Theroux et al, NEJM 1988
1
0
ASA+UFH
ASA
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
VARIABLE
MULTIVARIABLE P
ODDS 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
*
TIMI Score
* 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)
MAJOR
BLEEDING
DEATH
PCI/ CABG
MI
STROKE
ALL CAN
IMPACT ON
PROGNOSIS,
SYMPTOMS,
AND COSTS!
BUT EACH
MAY IMPACT
THESE IN
DIFFERENT
DIRECTIONS
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
MAJOR
PROGNOSIS,
DEATH
BLEEDING
SYMPTOMS,
NACE: composite of all cause
death,
nonAND
COSTS!
myocardial infarction, non-fatal
stroke,
BUT
EACH
PCI/fatal
CABG
MI
PCI/CABG, and non-fatal
major bleeding*
MAY IMPACT
THESE IN
STROKE
DIFFERENT
DIRECTIONS
*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 riskstratification 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