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PERANAN CLOPIDOGREL PADA

PENYAKIT ATHEROTHROMBOTICFOKUS PADA ACUT CORONARYSYNDROME

Oleh:

dr. KUADIHARTO, Sp.PD

BPRSUD SALATIGAIDI SALATIGA

FEBRUARI 2009

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Atherothrombosis:

The Leading Cause of Death Worldwide*

Atherothrombosis

(vascular disease)

Infectious

disease

Pulmonary

disease

Cancer

Violentdeaths

AIDS

Number of deaths (x 106)

Murray et al. Lancet 1997;349:1269-1276.

0 2 4 6 8 10 12 14 16

*

In eight defined regions of the world, including

developed and developing areas.

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Major Clinical Manifestations of

Atherothrombosis

Transientischaemic attack

Angina: Stable Unstable

Ischaemicstroke

Myocardialinfarction

Peripheral arterialdisease: Intermittent claudication Rest Pain Gangrene Necrosis

Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 16.

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Atherothrombosis Significantly Shortens Life

Analysis o f data from the Framing ham Heart Study

Healthy History of

CV disease

Historyof AMI

Historyof stroke

Peeters et al. Eur Heart J 2002; 23: 458

466

Atherothrombosis reduces life expectancy by approximately812 years in patients aged over 60 years1

Average remaining life expectancy at age 60 (men)

0

2

4

6

8

10

12

1416

18

20

Years

-9.2yrs

-7.4

yrs

-12yrs

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24.7% 29.9%

Coronary

disease7.4%

Atherothrombosis is commonly found in more

than one arterial bed in an individual patient*

Cerebrovascular

disease

Peripheral arterial

disease

3.8% 11.8%

19.2%

* Data from CAPRIE study (n=19,185)Coccheri S. Eur Heart J1998; 19(suppl): P1268.

3.3%3.3%

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Definisi Acute Coronary Syndrome (ACS)

: Sindroma klinis yang menggambarkanberbagai tingkatan sumbatan arteria

koroner (dari sub total hingga oklusi total,

serta ada tidaknya kerusakan otot jantung)

Sindrom ini mencakup :

- Angina pektoris tidak stabil (APTS)

- Non ST segmen elevation Acute Myocardial Elevation(NSTEMI)

- ST segmen elevation Acute MI (STEMI)

- Kematian mendadak

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Presentation

Working diagnosis

ECG

Biochemicalmarkers

Final diagnosis Unstable

anginaNQMI QwMI

Myocardial infarction

No ST elevation

Ischaemic discomfort

Acute coronary syndrome

ST elevation

NSTMI

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Clinical Presentation of Stable &

Unstable Plaque

Stable

Plaque

Unstable

plaque with

non-occlusive

thrombus

Unstable

plaque with

occlusive

thrombus

Stable Angina

Pectoris

Unstable Angina

/ NSTEMI

STEMI

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Pathophysiology ACS

Ruptured / erosive Plaque

Inflammation

ThrombosisVasoconstriction

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Unstable

angina

MI

Ischemic

stroke/TIA

Critical leg

ischemia

Intermitent

claudication

CV death

ACS

Atherosclerosis

Stable angina/Intermittent claudication

Atherothrombosis: A Generalized and Progressive

Process

Thrombosis

Adapted from Libby P. Circulation. 2001;104:365-372.

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Gejala-Gejala Klinis

Simptom klinis ACS secara klasik ditandai oleh

rasa tidak enak prekordial atau substernal yang

dilukiskan sebagai :

- Rasa nyeri- Terbakar

- Terhimpit

- Ditindih benda berat (membengkak)

- Rasa tidak enak menjalar ke dada depan, lengan kiri

atau kedua lengan, leher dan atau rahang. Rasa tidak

enak dapat dirasakan dipunggung, terutama di scapula.

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Keluhan-keluhan lain yang mungkin menyertai

adalah Sesak nafas

Keringat dingin

Mual muntah

Sendawa

Ingin BAB

Apabila keluhan ini terjadi dengan durasi lebih dari20 menit hal tersebut kemungkinan disebabkan

oleh AMI

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AMIAortic dissection

Pericarditis

Atypical anginal pain associated

with hypertrophic cardiomyopathy

Esophageal, other upper gastrointestinal,

or biliary tract disease

Pulmonary diseaseHyperventilation syndrome

Chest wall

Psychogenic

Differential Diagnosisof Prolonged Chest Pain

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Diagnostic Criterias of STEMI

Typical chest pain > 20 minutes

ECG: ST elevation > 2 mm in V1-V3 or

> 1 mm in other leadsCardiac Enzymes (CKMB): increase > 2xnormal or positive Troponin T or I

*Diagnosis of STEMI should include 2 of 3 criteriasabove

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0 8 16 24 48364

MB2/MB1Myoglobin

Hour post-AMI

Time course of Serum Protein Markers

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Enzymatic Criteria forDiagnosis of Myocardial Infarction

Serial increase, then decrease of plasma CK-MB,

with a change >25% between any two values

Increase in MB-CK activity >50% between any two

samples, separated by at least 4 hrs

If only a single sample available, CK-MB elevation

>twofold

Beyond 72 hrs, an elevation of troponin T or I or

LDH-1>LDH-2

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The Aims of STEMI Management

To minimize patients dyscomfort

To limit the extent of myocardial damage

The care can be divided into 4 phases:1. Emergency care:

- Make rapid diagnosis- Early risk stratification

- To relieve pain

- Prevent of treat cardiac death

2. Early care

- REPERFUSION THERAPY AS SOON AS POSSIBLE !3. Subsequent care

4. Risk assessment and measures to prevent progression of CAD,new infarction, heart failure and death

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The benefit of reperfusion treatment in

STEMI Patient is :

time dependent

Faster better

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Scematic picture of cross sectional area of left ventricle:

Wave Front Phenomenon: Relation of

duration of coronary occlusion and

extension of myocardial infarction

Noniskemic Iskemik Infark

40 menit 3 jam 96 jam

Reimer, Jennings

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PRINCIPLES THERAPY OF THROMBOSIS

BASED ON PATHOGENESIS

PATHOGENESIS THERAPY

RISK FACTORS PREVENTION

-PLATELET ADHESION

-PLATELET AGGREGATION

-BLOOD COAGULATION ANTICOAGULANT

-THROMBOSIS THROMBOLYTIC

ANTIPLATELET

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Major Risk Factors for Atherothrombotic Events1,2

Risk Factors

Classical Risk Factors

Obesity

Family history of CVDDiabetesLifestyle factors

Atrial fibrillation

Homocystinemia

Hyperlipidemia

Hypertension

Hypercoagulable

states

Gender

Age

Emerging Risk Factors

Elevated prothromboticfactors: fibrinogen, CRP,

PAI-1,

Elevated IMT

Genetic traits

Atherothrombotic History

Prior MI

Prior StrokeUnstable angina

TIAStable angina

PAD

MI = Myocardial infarction

TIA = Transient ischemic event

PAD = Peripheral arterial disease

CRP = C-reactive protein

PAI-1 = Plasminogen activator inhibitor-1

IMT = Intima media thickness

CVD = Cardiovascular disease

1. Grundy SM et al. Circulation 1999; 100: 14811492

2. Haffner SM et al. N Engl J Med1998; 339: 229234

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CURRENTLY AVAILABLE

ANTITHROMBOTIC DRUGS

ANTIPLATELET AGENTS ANTICOAGULANTS

ORAL PARENTERAL ORAL PARENTERAL

AspirinDipyridamol

Ticlopidin

Clopidogrel

Cilostazol

GPIIb/IIIaantagonists

Coumarin Heparin

LMWH

Hirudin

Argatroban

Fondaparinux

melagatran

THROMBOLYTIC

AGENTS

-PARENTERAL

-STREPTOKINASE

-UROKINASE

-tPA

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Door-to-needle t ime for th rom bo lyt ic therapy

Pasien sakit dada, tiba di UGD: anamnesa, O2, infus

Rekam EKG, nilai adanya elevasi ST

Nilai ada / tidaknya kontraindikasi trombolitik:

- Perdarahan- TD menetap > 180/110 mmHg

- Riwayat stroke

- Bedah mayor < 2 minggu

- Peny. Berat (mis. Kanker)

Tidak Ya

Berikan Th/ trombolitik

Pertimbangkan PCI primer:

- Pasien dengan stroke &

resiko perdarahan

- Syok kardiogenik

10 menit

10 menit

10 menit

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Indikasi Trombolitik

1. Nyeri dada khas infark ( > 20 menit, Gejala sistemik)

2. Perubahan EKG : Elevasi segmen ST > 1 mm, minimal

pada 2 lead ekstremitas atau 2 mm pada lead dada atau

adanya BBB (Bundle Branch Block) baru3. Waktu terhitung mulai nyeri dada:

- < 6 jam : sangat bermanfaat

- 6 12 jam : bermanfaat

- > 12 jam : sedikit bermanfaat

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Dosis Trombolitik

Steptokinase 1500 IU dilarutkan dalam D5% 100cc dalam waktu 1 jam digunakan bersamadengan pemberian aspirin 100mg

Pemberian trombolitik dapat dilakukan di UGDbahkan dalam ambulance untuk transportasimenuju ke RS

Selama tindakan dinilai tekanan darah, irama

jantung, kesadaran dan keluhan penderitaTerapi trombolitik merupakan tindakan yangaman dengan risiko yang minimal.

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Kontra indikasi

Perdarahan internal aktif

Tersangka diseksi aorta

Resisutasi yang traumatis & lama

Trauma kepala baru / neoplasma

intrakranialRetinopati diabet berdarah / semuaperdarahan mata

Kehamilan

Reaksi alergi trombolitik, untukpemberian ulang jenis yang sama

Hipertensi > 180/110 mmHg yang tidakdapat segera diturunkan

Riwayat stroke hemoragik

Bedah mayor / trauma berat > 2

minggu

Hipertensi berat > 180/110 mmHg

dan dapat segera diturunkan

Ulkus peptikumRiwayat serebrovaskular accident

Adanya gangguan sistem

pembekuan darah / pengguna

antikoagulan

Disfungsi liver berat

Absolut Relatif

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Pre-hospital or In-hospital

thrombolytic treatment ?

17% mortality reduction of

pre-hospital thrombolytictreatment

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Algoritma Infark Miokard Akut (1)

Di Komunitas

ditekankan pada:

Panggil dulu, panggil cepat, panggil ambulan

Program nasional Kewaspadaan Serangan

Jantung

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Algoritma tatalaksana IMA (2)

Sistim Emergency Medical Service (EMS)

O2 IV Cardiac monitor tanda2 vital

Nitrogliserin

Analgetik narkotik

Pemberitahuan ke UGD

Kirim segera ke UGD

Skrining prehospital utk th/ trombolitikEKG 12 lead, kirim dg fax ke UGD

Mulai terapi trombolitik

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Algoritma INfark miokard akut (3)

Di UGD

Pendekatan team utk protokol door-to-drug

Triase cepat pasien dengan nyeri dadaPengambil keputusan ditentukan oleh

institusi (dr. jaga UGD/ Internist/

Cardiologist/ dsb)

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Kri ter ia K l inis Keberhasi lan

Reperfusi Trombo l is is

Nyeri dada berkurang hilang

Aritmia reperfusi

EKG : ST elevasi menurun > 40%

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Terapi rutin pada ACS

1. Oksigenasi 3-5 lt/menit

2. Aspirin150-325 mg (no enteric-coated) dikunyah3. Nitrat (ISDN, Cedocard, Isoket) dihisap bawah lidah

4. Morfin 2-4 mg (iv) dapat diulang setengah jam

berikutnyaNo. 1,2,3,4MONA

5. Clopidogrel (Clopisan) recomendasi AHA 2007

No, 1,2,3,4,5MONACO

6. Heparin : unfractionated heparin dan low molecular-weight heparin (LMWH)

7. Beta-Blocker bila tidak ada kontraindikasi

8. Ace-Inhibitor bila tidak ada kontraindikasi

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Clopidogrel Clinical Trial Program Covers All

Manifestations of Atherothrombosis

1. CAPRIE Steering Committee. Lancet1996; 348: 132913392. The CURE Trial Investigators. N Engl J Med2001; 345: 4945023. Bertrand ME et al. Circulation 2000; 102: 624

629

4. Steinhubl SR et al. JAMA 2002; 288: 24112420

StrokeTIA

Acute MIUnstable angina

Prior MIPCI/stenting

Atrial fibrillation

Intermittentclaudication

Peripheral

vascularintervention

CHARISMACAPRIE1

ACTIVECOMMITCLARITYCURE2

CLASSICS3

CREDO4

CHARISMACAPRIE1

CAMPER

CHARISMACAPRIE1

MATCHACTIVECARESS

TIA = Transient ischemic attack

MI = Myocardial infarctionPCI = Percutaneous coronary intervention

Teri J McDermott CMI 2003

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Beberapa Studi Klinis

ClopidogrelCURE

(Clopidogrel In Unstable Angina To Prevent

Recurrent Events)

CAPRIE

(Clopidogrel vs Aspirin in Patients at Risk of

Ischaemic Events)

CREDO

(The Clopidogrel for the Reduction of Events

During Observation)

CURE (Clopidogrel in Unstable Angina to Prevent

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CURE (Clopidogrel in Unstable Angina to Prevent

Recurrent Events) : Early and Long-Term Efficacy of

Clopidogrel

*On top of standard therapy (including ASA)

1. The CURE Trial Investigators. N Engl J Med2001; 345: 494502

2. Data on file, 2002, p73 internal CSR-EFC 3307

p= 0.00009

Cumulative events (MI, stroke, or cardiovascular death)

Months of follow-up

20%*Relative

riskreduction

Placebo (+ASA)*(n =6,303)

Clopidogrel* (+ ASA)(n = 6,259)

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 3 6 9 12

Cumulativehaz

ardrate

op ogre vs sp r n n at ents at s o

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Cumulative Event Rate(Myocardial Infarction, Ischemic Stroke or Vascular Death)

8.7%*Overallrelative

risk

reductionClopidogrel

Months of follow-up

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30 33 36

Cum

ulativeeventrate

(%)

ASA

p = 0.043, n = 19,185

ASA = acetylsalicylic acid *Intention to treat analysis

CAPRIE Steering Committee. Lancet1996; 348: 13291339.

op ogre vs sp r n n at ents at s oIschaemic Events): Long-Term Efficacy of Clopidogrel vs

ASA

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CREDO (The Clopidogrel for the Reduction of Events During

Observation) : Long-term Efficacy of Clopidogrel

27%

RelativeRisk

Reduction

p= 0.02

Clopidogrel (+ ASA)*

Placebo (+ ASA) *

Co

mbinedendpointoccurrence(%

)

Months from randomization

0 3 6 9 12

8.5%

11.5%

1-year results (Stroke, MI or death)

0

5

10

15

Steinhubl S et al. JAMA 2002; 288(19): 24112420

* On top of standard therapy including acetylsalicylic acid

All patients received clopidogrel post-PCI up to Day 28

MI = myocardial infarction

PCI = percutaneous coronary intervention

n = 2,116

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TERIMA KASIH