Plavix as Medical Necessity in

Unstable Angina
(Plavix sebagai Kebutuhan Medis di
Angina Tidak Stabil)

Manisfestasi klinik Atherothrombosis

Ischemic
stroke
Myocardial
infarction

Transient
ischemic attack

Angina:
Stable
Unstable

Peripheral arterial
disease:

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

Intermittent claudication
Rest Pain
Gangrene
Necrosis

arteri perifer
penyakit:

Perawatan Rumah Sakit di US

Karena ACS1
Acute coronary syndromes

1.5 juta perawatan di rumah sakit per tahun

Unstable angina (UA)

Myocardial infarction
(Q-wave and non-Q-wave)

750,000 penderita

750,000 penderita

1. Cairns J et al. Can J Cardiol 1996; 12: 127992.

Atherothrombosis Secara bermakna

menurunkan harapan hidup
Atherothrombosis reduces life expectancy by approximately
812 years in patients aged over 60 years 1

20
18

Average remaining life expectancy at age 60 (men)

Rata-rata harapan hidup yang tersisa pada usia 60
(laki-laki)

16

-7.4
years

Years

14
12

-9.2
years
-12
years

10
8
6
4
2
0
Healthy

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

History of
cardiovascular disease

History of
AMI

History of
stroke

Analysis of data from the Framingham Heart Study

AMI = Acute myocardial infarction

Acute Coronary Syndrome: Biaya rata-rata di

Negara Eropa (selama 6 bulan)*1
12,000

Cost per patient (Euros)

10,000
8,000
6,000
4,000
2,000

*Initial hospital stay accounts for > 80% of the costs

1. Brown RE et al. Eur Heart J 2002; 23: 508.

UK

Italy

Netherlands

Spain

Germany

France

Tantangan Penanganan ACS

Angka kematian dalam 30 hari 8% hingga 16% sekalipun

heparin/aspirin telah diberikan.

Adanya issue aspirin resistance

Bila terjadi Recurrent ischemia, akan menurunkan survival pasien

Kemampuan identifikasi Pasien ACS apakah medium/high-risk

Menginplementasikan strategi pengobatan baru dengan menggunakan

potent anti platelet pada medium- hingga high-risk ACS pasien

Peranan Antiplatelet

Obat - Obat Antiplatelet

Thromboxane A2 inhibitor
Acetylsalicylic acid (ASA)
Phosphodiesterase inhibitor
Dipyridamole
Glycoprotein (GP) IIb/IIIa blockers
Parenteral: abciximab, eptifibatide, tirofiban
ADP-receptor antagonists
Clopidogrel ( Plavix )
Ticlopidine ( Ticlid , Agulan , Ticuring )

Cara Kerja Antiplatelet 1

CLOPIDOGREL

C
ADP
ADP

GPllb/llla

Activation

(Fibrinogen receptor)
ASA

COX
TXA2

COX (cyclo-oxygenase)
ADP (adenosine diphosphate)
TXA2 (thromboxane A2)
1. Schafer AI. Am J Med 1996; 101: 199209.

Collagen thrombin
TXA2

BUKTI ILMIAH YANG KUAT:

Antithrombotic Trialists Collaboration1

Objective:
Untuk menentukan efek pengobatan anti platelet pada pasien
pasien dengan resiko tinggi untuk terjadi Kejadian Vaskular.

Data diteliti dari:

287 Penelitian:
135,000 pasien dibandingkan dengan anti platelet lain atau
dengan control.
77,000 pasien merupakan penelitian perbandingan antiplatelet

Hasil yang diukur

Kejaian vascular yang serius: non-fatal myocardial infarction,
non-fatal stroke atau vascular death

1. Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186.

Antithrombotic Trialists Collaboration:

Menurunkan Resiko Non-Fatal Myocardial Infarction 1
Category

% odds reduction

Acute MI
Prior MI
Prior stroke/TIA
Other high risk*

34% 3

All trials

(p < 0.0001)

0.0

0.5

Antiplatelet better

1.0

1.5

2.0

Control better

*Coronary artery disease, peripheral arterial disease, high risk of embolism and other high
risk conditions (including hemodialysis, diabetes mellitus, carotid disease)
1. Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186.

Antithrombotic Trialists Collaboration:

Menurunkan Resiko Non-Fatal Stroke1

Category

% odds reduction

Acute MI
Acute stroke
Prior MI
Prior stroke/TIA
Other high risk*

25% 3

All trials

(p < 0.0001)
0.0

0.5

Antiplatelet better

1.0

1.5

2.0

Control better

*Coronary artery disease, peripheral arterial disease, high risk of embolism and other high
risk conditions (including hemodialysis, diabetes mellitus, carotid disease)
1. Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186.

Antithrombotic Trialists Collaboration:

Menurunkan Resiko Vascular Deaths1

Category

% odds reduction

Acute MI
Acute stroke
Prior MI
Prior stroke/TIA
Other high risk*

15% 2

All trials

(p < 0.0001)
0.0

0.5

Antiplatelet better

1.0

1.5

2.0

Control better

*Coronary artery disease, peripheral arterial disease, high risk of embolism and other high
risk conditions (including hemodialysis, diabetes mellitus, carotid disease)
1. Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186.

Antithrombotic Trialists Collaboration:

Kesimpulan

Pemberian Antiplatelet harus dipertimbangkan untuk diberikan secara rutin

pada pasien yang beresiko tinggi.
Pemberian Antiplatelet menurunkan kejadian vascular pada pasien resiko
tinggi dari:
acute myocardial infarction (MI) dan acute stroke
prior MI and prior stroke/transient ischemic attack
coronary artery disease (e.g. unstable angina, heart failure)
peripheral arterial disease (e.g. intermittent claudication)
high risk of embolism (e.g. atrial fibrillation)
Other high risk factors (e.g diabetes) 1

Pemberian Antiplatelet harus diberikan secara kontinyu dan jangka

panjang.

1. Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186. 2. Braunwald E et al.

J Am Coll Cardiol 2000; 36: 9701062. 3. Bertrand ME et al. Eur Heart J 2000; 21: 140632.

Clopidogrel pada Unstable Angina

dan
Non Q- Wave MI

CAPRIE: Benefit Clopidogrel lebih baik dari ASA

dalam menurunkan Myocard Infark1
ASA

19.2%*
Relative
risk
reduction
Clopidogrel

Cumulative event rate (%)

ASA 3.6%
4

Clopidogrel 2.9%

p = 0.008, n = 19,185
0
0

12

15

18

21

24

Months of follow-up
*ITT analysis
1. Gent M. Circulation 1997; 96(suppl 8): I-467.

27

30

33

36

C
30 lop
do 0m id
se g og
lo re
ad l
in
g

CURE: Design1
n = 12,562
28 countries

Double-blind treatment up to 12 months

ASA 75325 mg o.d.

1. The CURE Study Investigators. Eur Heart J 2000; 21: 203341.

or 12 m
fin o
al nth
vis
it

Placebo

th
vis
3m
it
on
th
vis
it
6m
on
th
vis
it
9m
on
th
vis
it

Pl
ac
eb
o
lo Day
Di
sc adin 1
ha
g
d
rg
e v ose
isi
t

(unstable angina
or non-Q-wave
myocardial
infarction)

75mg o.d.
(n = 6,259)

ASA 75325 mg o.d.

1m
on

Patients with
acute coronary
syndrome

Clopidogrel

1 tab o.d.
(n = 6,303)

R = Randomization

CURE: Benefits Clopidogrel

Cumulative Events
(Myocardial Infarction, Stroke, or Cardiovascular Death)

kumulatif Acara
(Myocardial Infarction, Stroke, atau Kematian Kardiovaskular)

Cummulative hazard rate

0.14

Placebo*
(n = 6,303)

0.12
0.10

Clopidogrel*
(n = 6,259)

0.08
0.06

20% Relative
risk reduction
p = 0.00009

0.04
0.02
0.00
0

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.

12

CURE: Efektifitas SEGERA dengan

Clopidogrel Loading Dose1
Event rate (primary endpoint) within first 24 hours after randomization
Acara tingkat (titik akhir primer ) dalam 24 jam pertama setelah pengacakan

Cumulative hazard rates

0.025

0.020

Placebo

0.015

0.010

Clopidogrel

0.005

P=0.003

0.0
0

10

12

14

16

18

20

22

24

Hours after randomization

1. Yusuf S et al. Circulation 2003; 107: 966972

Cardiovascular death, myocardial infarction, stroke and

severe ischemia

19

CURE: Efektifitas SEGERA dan JANGKA

PANJANG dengan Clopidogrel1
030 days

31 days to 12 months

1.00

1.00

0.98

Clopidogrel

0.96

Proportion event-free

Proportion event-free

0.98

Placebo

0.94
0.92

RR: 0.79 (0.670.92)

p=0.003

0.90

Clopidogrel

0.96
Placebo

0.94

RR: 0.82 (0.70 0.95)

p=0.009

0.92

0.90
0

Weeks
1. Yusuf S et al. Circulation 2003; 107: 966972

10

12

Months
Impact of clopidogrel compared with placebo on cardiovascular death, myocardial
20
infarction, stroke within first 30 days and from 30 days to 12 months
RR = Relative risk

CURE: Benefit yang Konsisten tak Tergantung

Dari Riwayat Pasien
Baseline
characteristics

Percent events
N

Overall

12,562

9.3

11.4

3,295

12.7

15.5

Unstable angina 8,298

7.3

8.7

968

15.1

19.7

No

9,381

8.8

10.9

Yes

3,176

10.7

13.0

No

7,273

7.5

8.9

Yes

5,288

11.8

14.8

No

9,721

7.9

9.9

Yes

2,840

14.2

16.7

No

8,517

7.8

9.5

Yes

4,044

12.5

15.4

No

12,055

8.9

11.0

Yes

506

17.9

22.4

Diagnosis

Non-Q-W MI

Other
Elev card enzy

ST depr >1.0 mm

Diabetes

Previous myocardial
infarction
Previous stroke

Clopidogrel* Placebo*

0.4
*On top of standard therapy (including ASA)
1. Clopidogrel Prescribing Information, US, February 2002.

Clopidogrel better

0.6

0.8

1.0

Placebo better

1.2

CURE: Benefit yang konsisten on Top of

Therapy Standard Trombosis
Concomitant
medication/therapy
Heparin/LMWH

ASA

GPIIb/IIIa Antag

Events (%)

N
No

951

4.9

7.7

Yes

11611

9.7

11.7

< 100 mg

1927

8.5

9.7

100200
mg

7428

9.2

10.9

3201

9.9

13.7

11739

8.9

10.8

823

15.7

19.2

2032

9.9

12.0

10530

9.2

11.3

4813

6.3

8.1

7749

11.2

13.5

4461

10.9

13.1

8101

8.4

10.5

7977

8.1

10.0

4585

11.4

13.8

> 200 mg
No

Beta-blocker

Yes
No

ACEI

Yes
No

Lipid-lowering

Yes
No

PTCA/CABG

Clopidogrel* Placebo*

Yes
No
Yes

*On top of standard therapy (including ASA)

1. Clopidogrel Prescribing Information, US, February 2002.

Clopidogrel better

0.4

0.6
0.8
1.0
Hazard ratio (95% CI)

Placebo better

1.2

CURE: Benefit Clopidogrel Pada Semua

Resiko Selama 12 Bulan
MI, stroke or vascular death (%)

ARR*
RRR

1.6
29%

1.6
15%

25

4.8
27%

n = 1,989

20.7
20
15.9
15

11.4
10

n = 3,276

5.7
5

Placebo

n = 7,297

9.8

p = 0.003

Clopidogrel

p = 0.02

4.1

p = 0.03

0
Low risk

Moderate risk

High risk

*Absolute risk reduction

Relative risk reduction

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502. 2. Budaj AJ et al J Am Coll
Cardiol 2002; 39, (suppl B): 441B.

PCI-CURE Study Design

Day 30

12 months

Day 30

Placebo 1 tab od

12 months + standard therapy

(n=1345)

PCI
Open-label
therapy*
24 weeks

Clopidogrel 75 mg od
+ standard therapy
(n=1313)

PCI=Percutaneous Coronary Intervention

*Open-label therapy could include ADP-receptor antagonist in combination with ASA
Standard therapy always included ASA, and could also include heparin, LMWH, GP IIb/IIIa inhibitors
post-randomization, beta-blockers, ACE inhibitors, lipid-lowering agents, and/or other therapies or
interventions (e.g. PTCA, CABG) at physicians discretion
LMWH, low-molecular-weight heparin; GP, glycoprotein;
PTCA, percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass graft

The CURE Investigators. N Eng J Med August 2001

PCI-CURE Hasil setelah 30 hari

Gabungan dari cardiovascular death, MI, atau urgent

revascularization
Cumulative hazard rates
0.08

Standard therapy
Clopidogrel
+ standard therapy

0.06
0.04

30% RRR
p=0.03
n=2658

0.02
0.0
0

10
15
20
Days of follow-up

25

30

including ASA

The CURE Investigators. Lancet August 2001

PCI-CURE Keseluruhan Hasil Jangka Panjang

Sejak Randomize
Gabungan dari cardiovascular death atau MI dari randomization hingga akhir follow-up

Cumulative hazard rates

0.15

12.6%

0.10

8.8%
Standard therapy
Clopidogrel
+ standard therapy

0.05

31% RRR
p=0.002
n=2658

0.0
010 40
a

100

200

300

400

Days of follow-up

a = median time from randomization to PCI (10 days)

b = 30 days after median time of PCI

The CURE Investigators. Lancet August 2001

up to 12 months including ASA

PCI-CURE Keamanan Komplikasi perdarahan

Clopidogrel +
standard therapy
%

Standard therapy
alone
%

p value

1.6

1.4

NS

Life-threatening

0.7

0.7

Other Major

0.9

0.7

1.0

0.7

NS

2.7

2.5

NS

Life-threatening

1.2

1.3

Other Major

1.5

1.1

3.5

2.1

Major

Minor
PCI to end of follow-up
Major

Minor
including ASA

0.03

The CREDO Trial

Clopidogrel for the Reduction of Events
During Observation
Results

Study Design

Placebo Arm

Clopidogrel Arm

PCI

28 Days

12 Months

Pretreatment
LD Clopidogrel#

Clopidogrel#

Clopidogrel*

R
Clopidogrel#
LD Placebo#

LD=loading dose, PT= Pretreatment, R= Randomization

# on top standard therapy including ASA (325 mg)
on top standard therapy including ASA (81-325 mg)
Steinhubl S, et al. JAMA, November 20, 2002 Vol 288, No 19: 2411 2420

Placebo*

Benefits Clopidogrel Jangka Panjang pada pasien

PCI
1 year results

COMBINED ENDPOINT OCCURRENCE (%)

15

(MI, Stroke, or Death)

11.5%
27% RRR

10

8.5%

5
Placebo*#
Clopidogrel*

0
0

6
MONTHS FROM RANDOMIZATION

* On top of standard therapy including ASA

#
All patients received clopidogrel post PCI up to day 28
Steinhubl S, et al. JAMA, November 20, 2002 Vol 288, No 19: 2411 2420

12

p = 0.02

CLARITY: Design
Objectives:
Mengevaluasi efektifitas dan keamanan clopidogrel, on top of standard
therapy (termasuk low-dose ASA, heparin dan thrombolytic), pada pasien
dengan acute myocardial infarction (MI)

Methodology:
Double-blind, randomized, prospective, multi-center trial

Populasi:
Follow-up pada 3,000 pasien dengan ST-elevation acute MI diberikan terapi
selama empat minggu

Hasil utama :
Primary endpoint adalah rate dari TIMI derajat 0 atau 1 , atau kematian atau
MI melalui pengamatan angiography, atau melalui index hospitalization
atau hari ke 8 , mana yang lebih dulu jika angiography tidak dilakukan.

CLARITY: Design
ASA loading dose + heparin + thrombolytic
n = 3,000

Clopidogrel
loading dose

ASA 75162 mg/day

ASA 75100 mg/day

Double-blind treatment for 30 days

ASA loading dose + heparin

+ thrombolytic

ASA 75100 mg/day

An
g
pr
e- iogra
dis
ch phy
Da arg
y3 e
8

ASA 75162 mg/day

ASA = 150325 mg (if no ASA within prior 24 hours) or 150162 mg, as

loading dose
Heparin = Unfractioned or low-molecular weight heparin
Thrombolytic = Recombinant plasminogen activator, tenecteplase, tissue
plasminogen activator, or streptokinase

30
da
ys

Patients with acute

STEMI
<6 hours

Clopidogrel
75 mg/day
(n =1,500)

Placebo
1 tab/day
(n =1,500)

R = Randomization
ASA = Acetylsalicylic acid
STEMI = ST-elevation myocardial infarction

ACC/AHA 2002 Guidelines Update

Untuk UA dan NSTEMI1
Rekomendasi Class I
Diduga ACS

Aspirin

Didiagnosa ACS

ACS dengan
ischemia atau terlihat resiko tinggi
atau direncanakan untuk PCI

SC LMWH
or
IV heparin

Aspirin
+
IV heparin/SC LMWH
+
IV GP IIb/IIIa antagonist

+ Clopidogrel

+ Clopidogrel

Aspirin

During hospital care

Clopidogrel should be administered to hospitalized patients who are unable to take ASA
because of hypersensitivity or major GI intolerance
Class IIa: enoxaparin preferred over unfractionated heparin, unless CABG is planned within 24 hours
*

1. Braunwald E et al. American College of Cardiology (ACC) and the American Heart Association
(AHA) Guidelines, USA: ACC/AHA; 2002.

ACC/AHA 2002 Guidelines Update

Untuk UA dan NSTEMI1
Class I Recommendations for Long Term Therapy*

ASA

+
Clopidogrel for 9 months

+
Beta-blockers

+
Lipid lowering therapy

+
ACE I

At hospital discharge and post-hospital discharge

In the absence of contraindications
Clopidogrel should be administered to hospitalized patients who are unable to take
ASA because of hypersensitivity or major GI intolerance
*

1. Braunwald E et al. American College of Cardiology (ACC) and the American Heart Association
(AHA) Guidelines, USA: ACC/AHA; 2002.

The Ongoing Clopidogrel Clinical Trials Program

MELIPUTIAll
SEMUA
ASPEK KEJADIAN
Covers
Manifestations
of ATHEROTHROMBOSIS
Atherothrombosis
Stroke
TIA

Acute MI
Unstable angina
Prior MI
PCI/stenting
Atrial fibrillation

Intermittent
claudication
Peripheral
vascular
intervention

CHARISMA
CAPRIE1
MATCH
ACTIVE
CARESS
CHARISMA
CAPRIE1
ACTIVE
COMMIT
CLARITY
CURE2
CLASSICS3
CREDO4
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

Plavix Sebagai MEDICAL

NECESSITY Pada UA

Plavix terbukti Lebih efektif dari standard therapi UA saat ini

Efektifitas terjadi segera ( dalam Jam ) dan terbukti menurunkan

kematian dan angka kejadian atherothrombosis sebesar ~ 20 %

Efektifitas dipertahankan jangka panjang hingga satu tahun ( 20

37,4 % RRR ) bila tetap menggunakan Plavix.

Tingkat keamanan yang menguntungkan dan efek perdarahan

yang terjadi setara dengan therap standard.

Plavix sinergis dikombinasikan dengan pengobatan UA yang ada

dan tidak tergantung pada riwayat penyakit pasien, sangat
sinergis dengan ASA.

Dosis Praktis 1 X 1

PLAVIX Indications:
UNSTABLE ANGINA
Non -Q- Wave MI
RECENT MI
RECENT STROKE
ESTABLISH PAD

Dosis Plavix:
Loading Dose 300 mg ( 4 tab )
Maintenance 1 x 1 ( 75 mg )

TERIMA KASIH
THANK YOU