antiplatelet.pptx

CASE 1

• •

Usia : 63 tahun

•

Pasien baru pertama kali mengalami hal ini, riwayat mudah lelah saat aktivitas

Pasien masuk dengan keluhan nyeri dada sejak 2 jam SM RS, terus menerus seperti ditekan benda berat, tidak menjalar, muntah (-)keringat dingin (+) hingga basah kuyup. Keluhan timbul saat sedang menunggu di bandara ,sesak (-), jan tung berdebar (-)

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

• • • •

3

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

Proprietary and Confidential. © AstraZeneca 2011. Document intended for internal discussion purposes.

Case 2 • Laki-laki 73 tahun • Dikirim dari sejawat dengan riwayat NSTEMI, DM ,C KD 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 Ischemic stroke/TIA Critical leg ischemia Intermittent claudication

Atherosclerosis

CV death

Stable angina/Intermittent claudication

From first decade

From third decade

Growth mainly by lipid accumulation Adapted from Libby P . Circulation 2001; 104: 365 –372

From fourth decade Smooth muscle and collagen

Thrombosis, haematoma

ACS

– Adhesion – Activation – Aggregation 2

3

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

Adherent platelet become activated

1 Plaque rupture leads to platelet adhesion to the exposed subendothelium

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

ACS with persistent ST segment elevation

Troponin Elevated

ACS without persistent ST segment elevation

Troponin Elevated or not

ACS with persistent ST segment elevation

ACS without persistent ST segment elevation

Management :

Management :

1. Primary PCI 2. Fibrinolytic

1. Risk Stratification 2. Optimal DAPT 3. Early i nvasive

Pr e di ct o r

Sco r e

Pr e di ct or

Age, years 40<

0

80 <

40 - 49

18

50 - 59

36

60 - 69

73

80

63

80 – 99

55

70 - 79

91

III

43

IV

64

140 - 159

26 11 0

P r e d i ct o r

S cor e

Creatinine (µmol/L) - 340

2

70-89

7

35 – 70

13

71 – 105

8

23

106 – 140

11

36

141 – 176

14

177 – 353

23

≥ 354

31

150- 199 200 >

46

Khali ll R et al. Exp Clin Cardi ol.200 9; 14(2): e25 – e30

0 21

37

90-109 110- 149

I II

47

160 - 199

Sco r e

0

58

Scor e

Killip class

120 - 139

Heart Rate , beats/min 70<

P r e di c t o r

100 - 119

200> Pr e di ct o r

Scor e

Systolic Blood Pressure (mmHg)

5

P r e d i ct o r

S co r e

Cardiac arrest at admission

43

Elevated cardiac markers

15

ST Segment deviation

30

Khali ll R et al. Exp Clin Cardi ol.200 9; 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:ACSDiagnosisdoubtful

Q#1:DefiniteACS

Aspirin : oral 150-300 or Q#4 : Invasive strategy for Admit to ICCU t Q#2 : STEMI ? c IV 80-150 mg NSTE-ACS ? Continue diagnostic tests a t No antiplatelet therapy n Q#3 : Reperfusion ? o Probable no n Invasive Definite Invasive C l a NoReperfusion Reperfusion c i Ticagrelor 180 mg d Ticagrelor 180 mg Or clopidogrel 75 mg if e Clopidogrel 75 mg Thrombolysis PrimaryPCI Or Clopidogrel 600 mg if high bleeding risk M high bleeding risk t s Ticagrelor 180 mg Or ir Age ≤ 75 : Clopidogrel 300 mg Confirmed Switch to F Age > 75 : Clopidogrel 75 mg Clopidogrel 600 mg if high bleeding risk

g n o L d rm n e a T U C I

invasive

Q#8 : normal coronary arteries?

Q#5 : Large thrombus

y r burden? to a r o Yes : Thrombectomy a b L h t a C

non invasive

Q#7 : Adequate antiplatelet Rx for PCI ?

Clopidogrel pre Rx

Low Bleeding Risk ? If yes, then GPIIb/IIIa inhibitor according to renal function

Confirmed ACS ? If not, stop DAPT

Q#10 : Stent Thombosis Risk ?

Clopidogrel or switch to Ticagrelor Discuss Tirofiban or Eptifibatide

No Clopidogrel Ticagrelor or Clopidogrel Discuss Tirofiban or Eptifibatide

Q#6 : Surgery ?

Stop P2Y12 : Clopidogrel or ticagrelor 5 days before. Resume DAPT after CABG

Q#9 : Low Bleeding Risk ?

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. Euro ean Heart Journal: Acute Cardiovascular Care 1 2 170–176

Dual Antiplatelet Therapy is the STANDARD for ACS

Recommendation

Clas& s level

Aspirin should be given to all patients without contraindications at an initial loading dose of 150 –300 mg, and at a maintenance dose of 75 –100 mg daily long-term regardless of treatment strategy.

1A

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

4 .0 0

d r a z a H e v it la u m u C

3 .0 0

HR 0.96 (0.851.08) P = 0.489

2 0 . 0

1 0 . 0

ASA 81-100 mg ASA 300-325 mg

.0 0

0

3

6

9

12

15 Days

18

Mehta SR et al. N Engl J Med. 2010;10:930-42

21

24

27

30

ESC STEMI GUIDELINES : P2Y12 Inhibitor

Aspirin oral or iv (if unable to swallow) is recommended

Kel as

Level

1

B

Kelas

Level

1

B

Kelas

Level

1

C

P2Y12 inhibitor is recommended in addition to aspirin :

Ticagrelor

Clopidogrel, preferably when prasugrel or ticagrelor are either not available or contraindicated

Steg GS et al. doi:10.1093/e urheart j/ehs21 5

NSTEMI ACS Guidelines : P2Y12 Inhibitor 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).

Kel as

Level

1

B

Clopidogrel (300-mg loading dose, 75-mg daily dose) is recommended for patients who cannot receive ticagrelor or prasugrel.

Kel as

Level

1

A

Kelas

Level

1

B

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. European Heart Journal (2011) 32, 2999–3054

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 1

•

Clopidogrel has slow onset of action – 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), –D11; D3 2. Gurbel PA, Tantry US. Thrombosis Research. 2007;120:–311 321

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 withticagrelor than with clopidogrel (final extent) Clopidogrel 75 mg od

Ticagrelor 100 mg bd

100

100

80

80

DAY 1

60 40

% , n 20 o it i ib 0 h n I n 100 a e M 80

0

2

4

8

60

% , n o it i ib h n I n a e M

12

40 20

0 0

2

4

8

12

100 80 60

60

DAY 14

40 20

40 20

2nd dose 0

0 0

2

4

8

12

Time, h

24

0 2

4

81

2

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.

24

P2Y12 inhibitor

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

Ticagrelor is direct acting whereas all thienopyridines are pro-drugs Active compound Intermediate metabolite

No in vivo biotransformation

Pro-drug

Ticagrelor

CYP-dependent oxidation CYP3A4/5 CYP2B6 CYP2C19 CYP2C9 Hydrolysis CYP2D6 by esterase

Binding Platelet

Prasugrel

P2Y12

Clopidogrel CYP-dependent oxidation CYP1A2 CYP2B6 CYP2C19

Figure adapted from Schömig A (2009). CYP, c ytochrome P450. Schömig A. N Engl J Med 2009;361:1108–1111.

CYP-dependent oxidation CYP2C19 CYP3A4/5 CYP2B6

21 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 Last HIGH DOSE CLOPIDOGREL Maintenance Dose 100 90 80

90 mg bid

Loading Dose 180 mg

*

*

75 mg qd

*

*

*

Ticagrelor (n=54)

*

†

*

600 mg

Clopidogrel (n=50)



*

* †

70

‡

P