37,514.

022 / Sept 2014

Translating updated ACS guidelines into

clinical practice : Right Patient for The Right
OAP

The spectrum of ACS

Hamm CW, et al. European Heart Journal . 2011; 32: 29993054

Updated Guidelines ACS

2011

ESC Guidelines for the management of acute coronary

syndromes in patients presenting without persistent STsegment elevation 1

2012

ESC Guidelines for the management of acute myocardial

infarction in patients presenting with ST-segment elevation 2

2012

ACCF/AHA Focused Update of the Guideline for the

Management of Patients With UA/NSTEMI 3

2013

ACCF/AHA Guideline for the Management of ST-Elevation

Myocardial Infarction 4

1. Hamm CW, et al. European Heart Journal . 2011; 32: 29993054 ; 2. Steg PG et al. Eur Heart J 2012;33:2569-619; 3.
Jneid H et al. Circulation 2012; 126: 875 910; 4. OGara PT et al. Circulation 2013;127:529-555

Platelet play a pivotal role in ACS

Platelets do 3 things that promote thrombus formaton
Adhesion
Activation
Aggregation

2
1

Adherent platelet become activated

Plaque rupture leads

to platelet adhesion
to the exposed
subendothelium

Vorchheimer DA, et al. Mayo Clin Proc. 2006;81:59-68; Davies MJ. Heart. 2000;83:361-366.

Activated platelets aggregate

and assemble a critical mass
of activated, pro-thrombotic
platelet membrane at the site
of injury

Dual Antiplatelet Therapy is the STANDARD for ACS

Recommendation

Class &
level

Aspirin should be given to all patients without

contraindications at an initial loading dose of 150300 mg,
and at a maintenance dose of 75100 mg daily long-term
regardless of treatment strategy.

1A

A P2Y12 inhibitor should be added to aspirin as soon as

possible and maintained over 12 months, unless there are
contraindications such as excessive risk of bleeding.

1A

Hamm CW et al. Eur Heart J 2011;32:2999 3054

Profile of P2Y12 inhibitor

Hamm CW et al. Eur Heart J 2011;32:2999 3054

Metabolism of P2Y12 inhibitor

Adapted from Schomig A. N Engl J Med 2009;361:11081111

Limitation of clopidogrel
Dual antiplatelet therapy (DAPT) with aspirin &
clopidogrel is the current standard treatment in patients
with ACS1
With or without ST segment elevation1

Poor platelet inhibition response to clopidogrel is seen in

approximately 15% - 40% of patients2
Contribute to residual high risk of recurrent results

Clopidogrel has slow onset of action1

Prodrug that requires conversion to active metabolite1

Variable metabolism results in interindividual variability in

inhibition of platelet agregation1
Irreversible binds to platelet P2Y12 reseptors

1. Bassand JP . European Heart Journal Supplements (2008) 10 (Supplement D), D3D11; 2.

Gurbel PA, Tantry US. Thrombosis Research. 2007;120: 311321

Ticagrelor in reducing CV death in ACS patient

Trial &
population

Primary endpoint

CV DEATH

Safety endpoint (bleeding)

CURE (2001)
NSTE-ACS
patients
n = 12,562

Clopidogrel vs
plasebo : 9.3 % vs
11.4%
P < 0.001

Clopidogrel vs
plasebo : 5.1% vs
5.5% ; NNT =
250
P value : N/A

Major bleeding*
Clopidogrel 3.7%
Placebo 2.7%
(P = 0.001)
NNH: 100

TRITON (2007)
Undergoing PCI
NSTE-ACS 74%
STEMI 26%
n = 13 608

Prasugrel vs
Clopidogrel : 9.9%
vs 12.1% ;
P value < 0.001

Prasugrel vs
Clopidogrel :
2.1% vs 2.4% ;
NNT = 333
P value = 0.31
(NS)

NonCABG-related
major bleeding**: Prasugrel 2.4%;
Clopidogrel 1.8% ; (P = 0.03) ; NNH: 167
CABG-related major bleeding** Prasugrel
13.4% vs Clopidogrel 3.2% (P < 0.001)
NNH: 10

PLATO (2009)
All ACS both
invasive and
non invasive
n = 18.624

Ticagrelor vs
clopidogrel : 9.8% vs
11.7%
P value < 0.001

Ticagrelor vs
clopidogrel : 4.0%
vs 5.1%; NNT =
91, P value
=0.001

Major bleeding :
PLATO definition*** : Ticagrelor 11.6% vs
clopidogrel 11.2% ; NNH 250; , p = 0.43
(NS)
TIMI definition** : Ticagrelor 7.9% vs
clopidogrel 7.7% ; NNH 500; p = 0.57 (NS)

* CURE Definition; **TIMI definition ; ***PLATO definition

1.Yusuf S et al. N Engl J Med 2001;345; Wiviott SD e tal. N Engl J Med 2007;357:2001-15; Wallentin L, et al. N Engl J Med. 2009;361:10451057.

PLATO study design

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)

Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)

Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)

In combination with aspirin

612-month exposure
Pretreated with clopidogrel
Invasive and non invasive management (except fibrinolytic 24 hours)
Additional dose up to 600 mg for clopidogrel and 90 mg for ticagrelor
prior to PCI
Wallentin L, et al. N Engl J Med. 2009;361:10451057.
James S, et al. Am Heart J. 2009;157:599605.

Cumulative incidence (%)

Composite CV event Ticagrelor vs Clopidogrel

13
12
11
10
9
8
7
6
5
4
3
2
1
0

9.8
Ticagrelor

HR 0.84 (95% CI 0.770.92), p < 0.001

0

No. at risk
Ticagrelor

11.7

Clopidogrel

60

120

180

240

300

360

Days after randomisation

9,333

8,628

8,460

8,219

6,743

5,161

4,147

Clopidogrel 9,291

8,521

8,362

8,124

6,650

5,096

4,047

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Wallentin L, et al. N Engl J Med. 2009;361:10451057.

RRR

16%

K-M estimated rate (% per year)

Primary Safety Endpoint :

No increase in major bleeding
15
Ticagrelor
10

Clopidogrel

11.6
11.2

HR 1.04 (95% CI 0.951.13), p=0.43

0
0

60

120

180

240

Days from first IP dose

Wallentin L, et al. N Engl J Med. 2009;361:10451057.

300

360

Case Study
57 years old male, retired
technician
Coronary Risk Factors
Hypertension
Dyslipidaemia
Smoker (30 pack years history)
Present History
Three days history of on and off
chest pain initially thought to be
indigestion
Severe chest pain at 10 am on the
day of presentation
Associated breathlessness worse
on exertion

1st ECG
Sinus rhythm
T wave inversion in lead V5 and
V6
Tall R wave in V1 to 3
Q waves in II & AVF
2nd ECG (10 mins apart)
Sinus rhythm
T wave inversion in lead V6 and
I, dynamic T wave on V5
Lab
Troponin T 3.830 ug/l (Elevated
consistent with myocardial
damage)

Which P2Y12 Inhibitor ?

How to choose the right OAP ?

1.
2.

Clinical setting ?
Patient related factor ?
ischemic risk
bleeding risk
other baseline characteristic age,
stroke/TIA

Damman P et al. J Thromb Thrombolysis (2012) 33:143 - 153

weight, history of

STEMI patient
The preferred treatment for patients with STEMI is
mechanical reperfusion by primary PCI
Fast acting P2Y12 inhibitors are of paramount importance
in these high-risk patients who require urgent intervention

An ADP-receptor blocker is recommended in addition to

aspirin. Options are:

1A

Prasugrel in clopidogrel-naive patients, if no history of prior stroke/

TIA, age <75 years.

1B

Ticagrelor.

1B

Clopidogrel, preferably when prasugrel or ticagrelor are either not

available or contraindicated.

1C

Damman P et al. J Thromb Thrombolysis (2012) 33:143153; Steg PG et al. Eur Heart J 2012;33:2569-619

NSTEMI patient
The choice of P2Y12 inhibition in patients presenting with
NSTE-ACS depends on the chosen treatment strategy
Current guidelines recommend a routine invasive
strategy, consisting of routine coronary angiography and
PCI if suitable, in high-risk NSTE-ACS patients
High risk of ischemic heart disease is associated with STsegment changes, elevated troponin, diabetes, and a
GRACE risk score of more than 140
Regardless of the intended treatment strategy in
NSTEACS, a large proportion of the patients do not
undergo revascularization during initial hospitalization

Damman P et al. J Thromb Thrombolysis (2012) 33:143153;

MORE potent Oral Antiplatelet is the preferred options

NSTEMI
Ticagrelor (180-mg loading dose, 90 mg twice daily) is recommended for
all patients at moderate-to-high risk of ischaemic events (e.g. elevated
troponins) , regardless of initial treatment strategy and including those
pre-treated with clopidogrel (which should be discontinued when
ticagrelor is commenced)
Prasugrel (60-mg loading dose, 10-mg daily dose) is recommended for
P2Y12-inhibitor-nave patients (especially diabetics) in whom coronary
anatomy is known and who are proceeding to PCI unless there is a high
risk of lifethreatening bleeding or other contraindications
Clopidogrel (300-mg loading dose, 75-mg daily dose) is recommended for
patients who cannot receive ticagrelor or prasugrel.

A 600-mg loading dose of clopidogrel (or a supplementary 300-mg dose at

PCI following an initial 300-mg loading dose) is recommended for patients
scheduled for an invasive strategy when ticagrelor or prasugrel is not an
option.

Hamm CW et al. Eur Heart J 2011;32:2999 3054

Class

Level

Class

Level

Class

Level

Class

Level

GRACE risk score

Hamm CW, et al. European Heart Journal . 2011; 32: 29993054

Guidelines recommendation P2Y12 Inhibitor

based on treatment approach
Conservative
strategy
ESC
Ticagrelor (1B) or
Clopidogrel (1A) or

AHA
Clopidogrel (1B) or
ticagrelor (1B)

PCI
Strategy
ESC
Ticagrelor (1 B)
Prasugrel (1 B) no
prior stroke/TIA , age
< 75 years old
Clopidogrel 600 mg
(1 C)

Fibrinolytic
ESC dan AHA
Clopidogrel I A

AHA (1 B)
Clopidogrel (600 mg/
75 mg BID)
Prasugrel (60 mg/10
mg BID)
Ticagrelor (180 mg/
90 mg BID

1. Hamm CW et al. Eur Heart J 2011;32:2999 3054; 2 Jneid H et al. Circulation 2012; 126: 875 910; 3. Steg PG et al. Eur
Heart J 2012;33:2569-619; 4. OGara PT et al. Circulation 2013;127:529-555

Other clinical consideration in the choice of

P2Y12 inhibitor
A. High risk for (recurrent) ischemic events

Diabetic patients
B. High risk subgroup for bleeding events

Impaired renal function

Damman P et al. J Thromb Thrombolysis (2012) 33:143153

Platelet Dysfunction in DM: The Diabetic Platelet

Ferreiro JL , Angiolillo DJ. Circulation. 2011;123:798-813

Platelet Response to Clopidogrel Is Attenuated in

Diabetic Patients Undergoing Coronary Stent
Implantation
ADP aggregation after a 600-mg clopidogrel loading dose

Geisler T et al. Diabetes Care. 2007;30 (2): 372 - 374

Increased risk of ischaemic events in

diabetic patients

CV death, MI or
stroke
All-cause mortality

MI

1.0
HR (95% CI)
Decreased risk
for diabetics

Increased risk
for diabetics

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.
Adapted from James S, et al. Eur Heart J 2010;31:30063016.

PLATO diabetes:
Primary composite endpoint

CV death, MI, or stroke (%)

20

Diabetes
Ticagrelor (n=2326)
Clopidogrel (n=2336)
HR (95% CI) = 0.88(0.761.03)

15

16.2%
14.1%
p for interaction = 0.49

10

10.2%
8.4%

No diabetes
Ticagrelor (n=6999)
Clopidogrel (n=6952)
HR (95% CI) = 0.83(0.740.93)

0
0

60

120

180

240

300

360

Days after randomisation

Primary endpoint benefit with ticagrelor was consistent with the

overall PLATO trial results
No interaction between diabetes status and treatment was observed (p=0.49)
CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.
Adapted from James S, et al. Eur Heart J 2010;31:30063016.

PLATO diabetes:
Major bleeding
14.8%
14.1%

Major bleeding (%)

15

p for interaction = 0.21

10.8%
10.0%

10

Diabetes
Ticagrelor (n=2305)
Clopidogrel (n=2316)
HR (95% CI) = 0.95(0.811.12)

No diabetes
Ticagrelor (n=6928)
Clopidogrel (n=6870)
HR (95% CI) = 1.08(0.971.20)

0
0

60

120

180

240

300

360

Days after randomisation

Bleeding occurred with similar frequency in the ticagrelor and clopidogrel groups,
independent of diabetes status
No interaction between diabetes status and treatment was observed (p=0.21)
CI, confidence interval; HR, hazard ratio.
Adapted from James S, et al. Eur Heart J 2010;31:30063016.

Disorders of Hemostasis in CKD

1. Prothrombotic tendency
excessive cardiovascular events
2. Platelet dysfunction increased
bleeding tendency

Jalal DI et al. Semin Thromb Hemost 2010;36:3440

Responsiveness of clopidogrel and CV

event in patient with CKD
Response of clopidogrel in CKD
patients

CV event in clopidogrel response

vs low response

Percentage of low responders to clopidogrel

increase according to deterioration of renal
function

Clopidogrel low responders significantly increases risk

for CV events in patients with poor renal function

Htun P et al. J Am Soc Nephrol. 2011 April; 22(4): 627633

Renal function and outcomes in PLATO:

Primary composite endpoint by CrCl

Increasing renal impairment

CrCl
(mL/min)

Risk of CV death, stroke or MI

HR (95% CI)

30
40
50
60
70
80
90
100
0.4

0.5

0.6

0.7

0.8

0.9
Ticagrelor
better

CI, confidence interval; CrCl, creatinine clearance; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.
James S, et al. Circulation 2010;122:10561067.

1.0

1.1

Clopidogrel
better

1.2

Renal function and outcomes in PLATO:

Major bleeding
CKD
Ticagrelor
Clopidogrel
HR (95% CI) = 1.07(0.881.30)

25

Major bleeding (%)

20

p for interaction = 0.92

15

15.1%
14.3%
10.6%
9.8%

10

Normal renal function

Ticagrelor
Clopidogrel
HR (95% CI) = 1.08(0.961.22)

0
0

60

120
180
240
Days after randomisation

300

Bleeding occurred with similar frequency

in the ticagrelor and clopidogrel groups
NB: Figure labeled Non-CABG TIMI bleeding in manuscript.
CABG, coronary artery bypass graft; CI, confidence interval; CKD, chronic kidney disease HR, hazard ratio; TIMI, Thrombolysis in Myocardial Infarction.
Adapted from James S, et al. Circulation 2010;122:10561067.

360

Summary
Updated ACS guidelines has recommended new P2Y12
inhibitor as a first line treatment
Evidence Based Medicine provide guidance to translate
guidelines into clinical practice
Right OAP for the right ACS patient will help patient to
achieve better CV outcomes
Ticagrelor has recommended as first line therapy in ACS
Guidelines both ESC and AHA