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CASE 1

Usia : 63 tahun
Pasien masuk dengan keluhan nyeri dada sejak 2 jam SMRS, terus
menerus seperti ditekan benda berat, tidak menjalar, muntah (-)keringat
dingin (+) hingga basah kuyup. Keluhan timbul saat sedang menunggu di
bandara ,sesak (-), jantung berdebar (-)
Pasien baru pertama kali mengalami hal ini, riwayat mudah lelah saat
aktivitas

Faktor risiko
Hipertensi
Kolesterol tinggi
Merokok (-)
DM (-)
FH (-)

Proprietary and Confidential. AstraZeneca 2011. Document intended for internal discussion purposes.
Physical Examination and ECG

KU nyeri dada
TD 134/78 mmHg
Nadi 90 x / menit
RR 16 x / menit

Lab

Hb 13.6 mg/dl
Lekosit 11.450
Hs Trop T 32
GDS 173

3 Proprietary and Confidential. AstraZeneca 2011. Document intended for internal discussion purposes.
Case 2

Laki-laki 73 tahun
Dikirim dari sejawat dengan riwayat NSTEMI, DM ,CKD
CABG 1996
EF 63 %
Diagnostik Angio
RCA distal CTO stent patent, LM stenosis 95%, LAD CTO, LCx CTO. LIMA
Patent, SVG-RCA total oklusi, SVG-LCx total oklusi, LIMA patent

Proprietary and Confidential. AstraZeneca 2011. Document intended for internal discussion purposes.
Atherothrombosis: A Generalized and Progressive
Disease
Atherothrombosis

Unstable angina
MI ACS

Ischemic
stroke/TIA
Critical leg
ischemia
Atherosclerosis
Intermittent
claudication
CV death

Stable angina/Intermittent claudication

From first decade From third decade From fourth decade

Smooth muscle Thrombosis,


Growth mainly by lipid accumulation haematoma
and collagen
Adapted from Libby P. Circulation 2001; 104: 365372
Adhesion Activated platelets aggregate
and assemble a critical mass
Activation 3
of activated, pro-thrombotic
platelet membrane at the site
Aggregation of injury

Adherent platelet become activated


2

1
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.
ACS with persistent ACS without persistent
ST segment elevation ST segment elevation

Troponin Elevated Troponin Elevated or not


ACS with persistent ACS without persistent
ST segment elevation ST segment elevation

Management : Management :
1. Primary PCI 1. Risk Stratification
2. Fibrinolytic 2. Optimal DAPT
3. Early invasive
Predictor Score Predictor Score Predictor Score

Age, years Systolic Blood Pressure (mmHg) Killip class

< 40 0 < 80 63 I 0

40 - 49 18 80 99 58 II 21

50 - 59 36 100 - 119 47 III 43

60 - 69 55 120 - 139 37 IV 64

70 - 79 73 140 - 159 26
80 91 160 - 199 11
> 200 0

Predictor Score Predictor Score Predictor Score


Heart Rate , beats/min Creatinine (mol/L) Cardiac 43
< 70 0 arrest at
0 - 34 2
admission
70-89 7 35 70 5
Elevated 15
90-109 13 71 105 8 cardiac
110 - 149 23 markers
106 140 11
150 - 199 36 ST Segment 30
141 176 14 deviation
> 200 46 177 353 23
354 31

Khalill R et al. Exp Clin Cardiol.2009; 14(2): e25 e30


Khalill R et al. Exp Clin Cardiol.2009; 14(2): e25 e30
Play a major role in the early care of acute myocardial
infarction
Often the first to be contacted by patients
What GP should do
Can perform and interpret the ECG
Alert EMS
Administer opioids and antithrombotic drugs (including
fibrinolytic)
Undertake defibrillation if needed

Steg PG, et al. European Heart Journal. 2012;33:2569-2619


10-questions strategy in selecting oral antiplatelet in ACS
Q#1:ACS Diagnosis doubtful Q#1:Definite ACS

Admit to ICCU Aspirin : oral 150-300 or Q#4 : Invasive strategy for


Q#2 : STEMI ?

First Medical Contact


Continue diagnostic tests IV 80-150 mg NSTE-ACS ?
No antiplatelet therapy
Q#3 : Reperfusion ?
Probable non Invasive Definite Invasive

No Reperfusion Reperfusion
Ticagrelor 180 mg
Or clopidogrel 75 mg if Ticagrelor 180 mg
Clopidogrel 75 mg Thrombolysis Primary PCI
high bleeding risk Or Clopidogrel 600 mg if
high bleeding risk
Age 75 : Clopidogrel 300 mg Ticagrelor 180 mg Or
Confirmed Switch to
Age > 75 : Clopidogrel 75 mg Clopidogrel 600 mg if
non invasive invasive
high bleeding risk

Q#5 : Large thrombus Q#8 : normal Q#6 : Surgery ?


Q#7 : Adequate antiplatelet
Cath Laboratory

burden? coronary arteries?


Rx for PCI ?

Clopidogrel pre Rx No Clopidogrel


Yes : Thrombectomy Stop P2Y12 :
Clopidogrel or Clopidogrel or
Confirmed Ticagrelor or
switch to ticagrelor 5
Low Bleeding Risk ? ACS ? Clopidogrel
Ticagrelor days before.
If yes, then GPIIb/IIIa If not, stop Discuss
Discuss Resume DAPT
inhibitor according to DAPT Tirofiban or
Tirofiban or after CABG
renal function Eptifibatide
Eptifibatide
ICU and Long

Q#10 : Stent Thombosis Risk ? Q#9 : Low Bleeding Risk ?


Term

If yes, continue Ticagrelor 90 mg/12h if ongoing OR switch from clopidogrel to ticagrelor 90 mg/12h.
If no, Clopidogrel 75 mg/d if ongoing OR discuss switch from Prasugrel to Clopidogrel

Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170176
Dual Antiplatelet Therapy is the STANDARD for ACS

Recommendation Class &


level
Aspirin should be given to all patients without 1A
contraindications at an initial loading dose of 150300 mg,
and at a maintenance dose of 75100 mg daily long-term
regardless of treatment strategy.
A P2Y12 inhibitor should be added to aspirin as soon as 1A
possible and maintained over 12 months, unless there are
contraindications such as excessive risk of bleeding.

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


0.04
0.03
Cumulative Hazard

HR 0.96 (0.85-
0.02

1.08)
P = 0.489
0.01

ASA 81-100 mg
ASA 300-325 mg
0.0

0 3 6 9 12 15 18 21 24 27 30

Days
Mehta SR et al. N Engl J Med. 2010;10:930-42
ESC STEMI GUIDELINES : P2Y12 Inhibitor
Kelas Level
Aspirin oral or iv (if unable to swallow) is recommended
1 B

P2Y12 inhibitor is recommended in addition to aspirin :

Kelas Level
Ticagrelor
1 B
Clopidogrel, preferably when prasugrel Kelas Level
or ticagrelor are either not available or
contraindicated 1 C

Steg GS et al. doi:10.1093/eurheartj/ehs215


NSTEMI ACS Guidelines : P2Y12 Inhibitor
Ticagrelor (180-mg loading dose, 90 mg twice daily) is recommended Kelas Level
for all patients at moderate-to-high risk of ischaemic events (e.g.
elevated troponins) , regardless of initial treatment strategy and 1 B
including those pre-treated with clopidogrel (which should be
discontinued when ticagrelor is commenced).

Clopidogrel (300-mg loading dose, 75-mg daily dose) is Kelas Level


recommended for patients who cannot receive ticagrelor or
prasugrel. 1 A

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


dose at PCI following an initial 300-mg loading Kelas Level
dose) is recommended for patients scheduled for an invasive strategy 1 B
when ticagrelor or prasugrel is not an option.

Hamm CW, et al. European Heart Journal (2011) 32, 29993054


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

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


2. Gurbel PA, Tantry US. Thrombosis Research. 2007;120: 311321
GRAVITAS Study (clopidogrel low responders) :
No improve in CV outcome with increase dose of
clopidogrel

Observed event rates are listed; P value by log rank test.


DISPERSE: Greater and more consistent IPA with ticagrelor
than with clopidogrel (final extent)
Clopidogrel 75 mg od Ticagrelor 100 mg bd
100 100

80 80

60 DAY 1 60

40 40

Mean Inhibition, %
Mean Inhibition, %

20 20

0 0
0 2 4 8 12 0 2 4 8 12
100 100

80 80

60 60

40
DAY 14 40

20 20
2nd dose
0 0
0 2 4 8 12 24 0 2 4 8 12 24
Time, h Time, h
IPA = inhibition of platelet aggregation; od = once daily; bd = twice daily.
Adapted from Husted SE, et al. Presented at: European Society of Cardiology Annual Congress 2005; 3-7 September, 2005; Stockholm, Sweden.
P2Y12 inhibitor

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


Ticagrelor is direct acting whereas all thienopyridines
are pro-drugs
No in vivo
Active compound biotransformation
Intermediate metabolite
Pro-drug
CYP-dependent
oxidation
CYP3A4/5
Ticagrelor CYP2B6
CYP2C19
Hydrolysis CYP2C9 Binding
by esterase CYP2D6
Prasugrel Platelet

P2Y12
Clopidogrel
CYP-dependent CYP-dependent
oxidation oxidation
CYP1A2 CYP2C19
CYP2B6 CYP3A4/5
CYP2C19 CYP2B6

Figure adapted from Schmig A (2009). CYP, cytochrome P450. 21


Schmig A. N Engl J Med 2009;361:11081111. APPROVED NOV 2013 FOR USE BY ASTRAZENECA MEDICAL AFFAIRS PERSONNEL. MAY NOT BE USED FOR PRODUCT
PROMOTIONAL PURPOSES. NOT FOR USE BY ASTRAZENECA SALES PERSONNEL.
ONSET/OFFSET STUDY :
TICAGRELOR FASTER ONSET and FASTER OFFSET VS
HIGH DOSE CLOPIDOGREL Maintenance
Last
Dose
Loading 90 mg bid
100
Dose 75 mg qd Ticagrelor (n=54)
* * *
90 180 mg
* *
* * Clopidogrel (n=50)
600 mg


80
* * P<0.0001
P<0.005
70
P<0.05

60
IPA %

50 *

40

30

20

10

0 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240

Onset Maintenance Offset


Time (Hours) Time (Hours)
Gurbel PA et al. Circulation 2009;120:2577-2585
All OAP proven to reduce CV event
(CV death, MI dan Stroke )
CURE1 TRITON TIMI 382 PLATO3

(CV death, MI atau Stroke)%)


Rate of composite CV event

11.4 12.1 11.7

9.3 9.9 9.8

P < 0.001 P < 0.001 P < 0.001

Plasebo Clopidogrel Clopidogrel Prasugrel Clopidogrel BRILINTA

n = 12.562 n = 13.608 n = 18.624

23

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.
Only ticagrelor proven to have mortality benefit vs
clopidogrel
CURE1 TRITON TIMI 382 PLATO3
P = N/A
(%)death (%)

5.50
5.10 5.10
CV deathCV

4.00
composite
of of

2.40
Rate

2.10
Rate

Clopidogrel Ticagrelor
Plasebo Clopidogrel Clopidogrel Prasugrel

n = 12.562 n = 13.608 n = 18.624


NNT = 250 NNT = 333 NNT = 91

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.
P = 0.008
Ticagrelor (n=9,235)
K-M Estimated Rate (% Per Year)
18
16.1 Clopidogrel (n=9,186)
16 NS
14.6
14
11.6
12 11.2 NS
10
NS
7.9
8 P = 0.03 7.4
5.8 5.8
6
4.5
3.8
4
NS
2
0.3 0.3
0
Major Bleeding Life-threatening/ Fatal Bleeding Major and Minor Non-CABG- CABG-Major
Fatal Bleeding Bleeding Major Bleeding Bleeding

All values presented by PLATO criteria.


Both groups included aspirin.

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


Interruption and/or neutralization of both CLASS LEVEL
anticoagulant and antiplatelet therapies is
indicated in case of major bleeding, unless 1 C
it can be adequately controlled by specific
haemostatic measures

CLASS LEVEL
Minor bleeding should preferably be
managed without interruption of active
1 C
treatments.

CLASS LEVEL
Co-medication of PPI and antithrombotic
agents is recommended in patients at
1 B
increased risk of GI haemorrhage.

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


Consistent result of ticagrelor in efficacy primary
endpoint despite of PPI treatment

Proton Pump Inhibitors (Rand.) P value interaction 0.69

Hazard Ratio KM % at
Month 12 HR (95% CI)
(95% CI)
Ti. Cl.
No 9.2 11.0 0.83 (0.74, 0.93)
n = 12,249

Yes 11.0 12.9 0.86 (0.75, 1.00)


n = 6375 0.2 0.5 1.0 2.0

Ticagrelor better Clopidogrel better


KM : KaplanMeier

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


CASE 1
Q#1:Definite ACS

Aspirin : oral 150-300 or


Q#2 : STEMI ?

First Medical Contact


IV 80-150 mg

Q#3 : Reperfusion ?

Reperfusion

Primary PCI

Which P2Y12 inhibitor preferred for


Ticagrelor 180 mg Or
Clopidogrel 600 mg if this case ?
high bleeding risk

Q#5 : Large thrombus


1. Faster onset
Cath Laboratory

burden? 2. Low inter individual variability


3. No issue with low responders
Yes : Thrombectomy

Low Bleeding Risk ?


If yes, then GPIIb/IIIa
inhibitor according to Reduced risk of stent thrombosis
renal function Reduced CV mortality
ICU and Long

Q#10 : Stent Thombosis Risk ? Q#9 : Low Bleeding Risk ?


Term

If yes, continue Ticagrelor 90 mg/12h if ongoing OR switch from clopidogrel to ticagrelor 90 mg/12h.
If no, Clopidogrel 75 mg/d if ongoing OR discuss switch from Prasugrel to Clopidogrel

Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170176
Case 2
Q#1:Definite ACS

Aspirin : oral 150-300 or Q#4 : Invasive strategy for

First Medical Contact


Check GRACE RISK Score IV 80-150 mg NSTE-ACS ?

Definite Invasive
Age : 73 years old
CKD, Elevated CardiACS maker, ST Ticagrelor 180 mg
segment deviation Or Clopidogrel 600 mg if
high bleeding risk

Moderate high risk patients

Guidelines Q#7 : Adequate antiplatelet


Cath Laboratory

Rx for PCI ?
Ticagrelor 1B
Mod high risk NSTEMI patient Clopidogrel pre Rx No Clopidogrel

Pre treated with clopi or nave Clopidogrel or


Ticagrelor or
switch to
PCI or MM Ticagrelor
Clopidogrel
Discuss
Discuss
Tirofiban or
Tirofiban or
Clopidogrel 1A Eptifibatide
Eptifibatide
If ticagrelor or prasugrel not available
ICU and Long

Q#10 : Stent Thombosis Risk ? Q#9 : Low Bleeding Risk ?


Term

If yes, continue Ticagrelor 90 mg/12h if ongoing OR switch from clopidogrel to ticagrelor 90 mg/12h.
If no, Clopidogrel 75 mg/d if ongoing OR discuss switch from Prasugrel to Clopidogrel

Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170176
ESC STEMI Guidelines 2012
DAPT and antithrombotic combination therapies after STEMI
Primary PCI and Fibrinolytic is up to 12 months
No reperfusion at least 1 month up to 12 months

NTEMI Guidelines 2012


Continue for 12 months (unless at high risk of bleeding)

Cessation of DAPT in Surgery patients


The risk of bleeding related to surgery must be balanced against
the risk of recurrent ischaemic events related to discontinuation
of therapy
it is reasonable to restart DAPT as soon as considered safe in
relation to bleeding risk
Steg GS et al. doi:10.1093/eurheartj/ehs215; Hamm CW, et al. European Heart Journal (2011) 32, 29993054
Antiplatelet therapy key to reducing thrombus burden and
plaque stabilisation during ACS
In STEMI patients, a loading dose of P2Y12 receptor
inhibitor should be given as early as possible or at time of
primary PCI
In NSTEMI patients, a strategy of risk stratification,
optimal potent dual antiplatelet therapy (including the new
oral P2Y12 inhibitors and early invasive approach is
appropriate
Ticagrelor + aspirin has recommended in ESC and AHA
guidelines as first line treatment in ACS and proven to
reduced CV mortality