PERANAN CLOPIDOGREL PADA PENYAKIT ATHEROTHROMBOTIC

FOKUS PADA ACUT CORONARY SYNDROME

Oleh: dr. KUADIHARTO, Sp.PD

BPRSUD SALATIGA IDI SALATIGA
FEBRUARI 2009

Atherothrombosis: The Leading Cause of Death Worldwide*

Atherothrombosis (vascular disease) Infectious disease Pulmonary disease Cancer Violent deaths AIDS
0 2 4 6 8 10 12 14 *In eight defined regions of the world, including Number of deaths (x 106) developed and developing areas. Murray et al. Lancet 1997;349:12691276. 16

Major Clinical Manifestations of Atherothrombosis

Ischaemic stroke Myocardial infarction
Transient ischaemic attack

Angina:
Stable Unstable

Peripheral arterial disease:

Intermittent claudication Rest Pain Gangrene Necrosis

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

Atherothrombosis Significantly Shortens Life

Atherothrombosis reduces life expectancy by approximately 812 years in patients aged over 60 years1
Average remaining life expectancy at age 60 (men)
20 18 16 14

-7.4 yrs

-9.2 yrs

Years

12 10 8 6 4

-12 yrs

2
0

Healthy

History of CV disease

History of AMI

History of stroke

Analysis of data from the Framingham Heart Study

Peeters et al. Eur Heart J 2002; 23: 458466

Atherothrombosis is commonly found in more than one arterial bed in an individual patient*

Cerebrovascular disease

7.4% 24.7% 3.3% 3.3% 3.8% 11.8% 29.9%

Coronary disease

19.2% Peripheral arterial disease

* Data from CAPRIE study (n=19,185) Coccheri S. Eur Heart J 1998; 19(suppl): P1268.

Definisi Acute Coronary Syndrome (ACS) : Sindroma klinis yang menggambarkan berbagai 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

Ischaemic discomfort

Presentation
Acute coronary syndrome Working diagnosis

ECG

No ST elevation
NSTMI

ST elevation

Biochemical markers Final diagnosis Unstable angina Myocardial infarction QwMI NQMI

Clinical Presentation of Stable & Unstable Plaque

Stable Plaque
Stable Angina Pectoris

Unstable plaque with non-occlusive thrombus

Unstable plaque with occlusive thrombus

Unstable Angina / NSTEMI

STEMI

Pathophysiology ACS
Ruptured / erosive Plaque Inflammation Thrombosis Vasoconstriction

Atherothrombosis: A Generalized and Progressive Process

Thrombosis
Unstable angina ACS MI Ischemic stroke/TIA

Atherosclerosis

Critical leg ischemia Intermitent claudication

CV death

Stable angina/ Intermittent claudication

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

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.

Keluhan-keluhan lain yang mungkin menyertai adalah

Sesak nafas Keringat dingin Mual muntah Sendawa Ingin BAB

Apabila keluhan ini terjadi dengan durasi lebih dari 20 menit hal tersebut kemungkinan disebabkan oleh AMI

Differential Diagnosis of Prolonged Chest Pain

AMI Aortic dissection Pericarditis Atypical anginal pain associated with hypertrophic cardiomyopathy Esophageal, other upper gastrointestinal, or biliary tract disease Pulmonary disease Hyperventilation syndrome Chest wall Psychogenic

Diagnostic Criterias of STEMI

Typical chest pain > 20 minutes ECG: ST elevation > 2 mm in V1-V3 or > 1 mm in other leads Cardiac Enzymes (CKMB): increase > 2x normal or positive Troponin T or I
*Diagnosis of STEMI should include 2 of 3 criterias above

Time course of Serum Protein Markers

MB2/MB1 Myoglobin

048

16

24

36

48

Hour post-AMI

Enzymatic Criteria for Diagnosis 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

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.

2.

3. 4.

Emergency care: - Make rapid diagnosis - Early risk stratification - To relieve pain - Prevent of treat cardiac death Early care - REPERFUSION THERAPY AS SOON AS POSSIBLE ! Subsequent care Risk assessment and measures to prevent progression of CAD, new infarction, heart failure and death

The benefit of reperfusion treatment in STEMI Patient is : time dependent

Faster better

Wave Front Phenomenon: Relation of duration of coronary occlusion and extension of myocardial infarction
Scematic picture of cross sectional area of left ventricle:

40 menit

3 jam

96 jam

Noniskemic

Iskemik

Infark
Reimer, Jennings

PRINCIPLES THERAPY OF THROMBOSIS BASED ON PATHOGENESIS

PATHOGENESIS RISK FACTORS - PLATELET ADHESION
ANTIPLATELET

THERAPY PREVENTION

-PLATELET AGGREGATION

-BLOOD COAGULATION

ANTICOAGULANT

-THROMBOSIS

THROMBOLYTIC

Major Risk Factors for Atherothrombotic Events1,2

Classical Risk Factors
Obesity Family history of CVD Diabetes Lifestyle factors Atrial fibrillation Homocystinemia Hyperlipidemia Hypertension Hypercoagulable states Gender Age

Atherothrombotic History Prior MI Prior Stroke Unstable angina TIA Stable angina PAD

Risk Factors

Emerging Risk Factors

Elevated prothrombotic factors: fibrinogen, CRP, PAI-1,

Elevated IMT Genetic traits
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 Med 1998; 339: 229234

CURRENTLY AVAILABLE ANTITHROMBOTIC DRUGS

ANTIPLATELET AGENTS

ANTICOAGULANTS

THROMBOLYTIC AGENTS

ORAL Aspirin Dipyridamol Ticlopidin Clopidogrel Cilostazol

PARENTERAL

ORAL Coumarin melagatran

PARENTERAL Heparin LMWH Hirudin Argatroban Fondaparinux

GPIIb/IIIa antagonists

-PARENTERAL -STREPTOKINASE -UROKINASE -tPA

Door-to-needle time for thrombolytic therapy

Pasien sakit dada, tiba di UGD: anamnesa, O2, infus 10 menit Rekam EKG, nilai adanya elevasi ST 10 menit Nilai ada / tidaknya kontraindikasi trombolitik: - Perdarahan - TD menetap > 180/110 mmHg - Riwayat stroke - Bedah mayor < 2 minggu - Peny. Berat (mis. Kanker) 10 menit Tidak Berikan Th/ trombolitik Ya
Pertimbangkan PCI primer: - Pasien dengan stroke & resiko perdarahan - Syok kardiogenik

Indikasi Trombolitik
1.
2.

3.

Nyeri dada khas infark ( > 20 menit, Gejala sistemik) Perubahan EKG : Elevasi segmen ST > 1 mm, minimal pada 2 lead ekstremitas atau 2 mm pada lead dada atau adanya BBB (Bundle Branch Block) baru Waktu terhitung mulai nyeri dada: - < 6 jam : sangat bermanfaat - 6 12 jam : bermanfaat - > 12 jam : sedikit bermanfaat

Dosis Trombolitik
Steptokinase 1500 IU dilarutkan dalam D5% 100 cc dalam waktu 1 jam digunakan bersama dengan pemberian aspirin 100mg Pemberian trombolitik dapat dilakukan di UGD bahkan dalam ambulance untuk transportasi menuju ke RS Selama tindakan dinilai tekanan darah, irama jantung, kesadaran dan keluhan penderita Terapi trombolitik merupakan tindakan yang aman dengan risiko yang minimal.

Kontraindikasi
Absolut
Perdarahan internal aktif Tersangka diseksi aorta Resisutasi yang traumatis & lama Trauma kepala baru / neoplasma intrakranial Retinopati diabet berdarah / semua perdarahan mata Kehamilan Reaksi alergi trombolitik, untuk pemberian ulang jenis yang sama Hipertensi > 180/110 mmHg yang tidak dapat segera diturunkan Riwayat stroke hemoragik

Relatif
Bedah mayor / trauma berat > 2 minggu Hipertensi berat > 180/110 mmHg dan dapat segera diturunkan Ulkus peptikum Riwayat serebrovaskular accident Adanya gangguan sistem pembekuan darah / pengguna antikoagulan Disfungsi liver berat

Pre-hospital or In-hospital thrombolytic treatment ?

17% mortality reduction of pre-hospital thrombolytic treatment

Algoritma Infark Miokard Akut (1)

Di Komunitas ditekankan pada:
Panggil dulu, panggil cepat, panggil ambulan Program nasional Kewaspadaan Serangan Jantung

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/ trombolitik EKG 12 lead, kirim dg fax ke UGD Mulai terapi trombolitik

Algoritma INfark miokard akut (3)

Di UGD Pendekatan team utk protokol door-to-drug Triase cepat pasien dengan nyeri dada Pengambil keputusan ditentukan oleh institusi (dr. jaga UGD/ Internist/ Cardiologist/ dsb)

Kriteria Klinis Keberhasilan Reperfusi Trombolisis

Nyeri dada berkurang hilang Aritmia reperfusi EKG : ST elevasi menurun > 40%

Terapi rutin pada ACS

1.

2. 3. 4.

5. 6. 7. 8.

Oksigenasi 3-5 lt/menit Aspirin 150-325 mg (no enteric-coated) dikunyah Nitrat (ISDN, Cedocard, Isoket) dihisap bawah lidah Morfin 2-4 mg (iv) dapat diulang setengah jam berikutnya No. 1,2,3,4 MONA Clopidogrel (Clopisan) recomendasi AHA 2007 No, 1,2,3,4,5 MONACO Heparin : unfractionated heparin dan low molecularweight heparin (LMWH) Beta-Blocker bila tidak ada kontraindikasi Ace-Inhibitor bila tidak ada kontraindikasi

Clopidogrel Clinical Trial Program Covers All Manifestations of Atherothrombosis

Stroke TIA CHARISMA CAPRIE1 MATCH ACTIVE CARESS

Acute MI Unstable angina Prior MI PCI/stenting Atrial fibrillation

CHARISMA CAPRIE1 ACTIVE COMMIT CLARITY CURE2 CLASSICS3 CREDO4

Intermittent claudication Peripheral vascular intervention

CHARISMA CAPRIE1 CAMPER

Teri J McDermott CMI 2003 1. CAPRIE Steering Committee. Lancet 1996; 348: 13291339 2. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502 3. Bertrand ME et al. Circulation 2000; 102: 624629 4. Steinhubl SR et al. JAMA 2002; 288: 24112420

TIA = Transient ischemic attack MI = Myocardial infarction PCI = Percutaneous coronary intervention

 CURE

Beberapa Studi Klinis Clopidogrel

(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 Recurrent Events) : Early and Long-Term Efficacy of Clopidogrel
Cumulative events (MI, stroke, or cardiovascular death)
0.14

20%*
Placebo (+ASA)*
(n =6,303)

Cumulative hazard rate

0.12 0.10 0.08 0.06 0.04 0.02 0.00

Relative risk reduction p = 0.00009 Clopidogrel* (+ ASA)

(n = 6,259)

12

Months of follow-up
*On top of standard therapy (including ASA)

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502 2. Data on file, 2002, p73 internal CSR-EFC 3307

CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events): Long-Term Efficacy of Clopidogrel vs ASA
Cumulative Event Rate (Myocardial Infarction, Ischemic Stroke or Vascular Death)
ASA
16

8.7%*
Overall relative risk reduction

Cumulative event rate (%)

12

Clopidogrel

p = 0.043, n = 19,185
0 0 3 6 9 12 15 18 21 24 27 30 33 36

Months of follow-up
ASA = acetylsalicylic acid *Intention to treat analysis CAPRIE Steering Committee. Lancet 1996; 348: 13291339.

CREDO (The Clopidogrel for the Reduction of Events During Observation) : Long-term Efficacy of Clopidogrel
Combined endpoint occurrence (%) 15 1-year results (Stroke, MI or death)

11.5%

27%
Relative Risk Reduction p = 0.02

10

n = 2,116
8.5%

5
Placebo (+ ASA) * Clopidogrel (+ ASA)*

0 0 3 6 9 12
* 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

Months from randomization

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

TERIMA KASIH