Antithrombotic therapy in acute coronary syndromes: which agent and when? Giuseppe Biondi Zoccai...

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

• 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






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


Scope of the problem


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


Scope of the problem: AMI

Capewell et al, Heart 2006


Scope of the problem: unstable angina

Capewell et al, Heart 2006


Pathways to thrombosis

****

** **Myers, BUMC Proceedings 2005


Multiple vulnerable coronary

plaques in patients with AMI

Asakura et al, J Am Coll Cardiol 2001


Multiple ruptured coronary

plaques in patients with ACS


Endothelialization of stent struts

Guagliumi et al, Ital Heart J 2003

SES BMS


On top of this: variability in response to antithrombotic therapy


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


Learning goals






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


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


10

Lotrionte et al,

AJC 2007

Clopidogrel loading in high-risk patients undergoing PCI


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


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


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






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


LMW heparin in NSTEACS


Bassand et al, EHJ 2007

Direct thrombin inhibitors in ACS



The HORIZONS trial


Stone et al, NEJM 2008

Fondaparinux in ACS: combined analysis of OASIS-5 (NSTEACS)

and OASIS-6 (STEMI)


Mehta et al, Circ 2008

Learning goals






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

Overwhelming complexity?


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



Learning goals







Finding the balance between ischemic and

bleeding risk: an 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


Nikolski et al, EHJ 2007

Predicting bleeding risk


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

Antithrombotic therapy in acute coronary syndromes: which agent and when? Giuseppe Biondi Zoccai...

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