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7/30/2019 Dr. Retna-New Antiplatelet for Secondary Stroke Prevention
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New Antiplatelet Therapy for
Secondary STROKEPrevention :
Apakah Clopidogrel masih sebagaip i l ihan Pertama ?
dr. Retnaningsih SpS(K) KIC
SMF/Bagian Neurologi
FK UNDIP/RSUP dr.Kariadi
Semarang
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Pokok Bahasan
Epidemiology data Berdasarkan REACH
Penilaian Resiko atas dasar ESSEN Risk Score
Peran Antiplatelet dalam pencegahan Kejadian
berulang stroke
Clinical terbaru ( new Antiplatelet )
TRITON : Prasugrel vs. Clopidogrel
PLATO : Ticaglerol vs. Clopidogrel Guideline darai ESO & PERDOSSI
Take Home Message
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~ 40% dari 18,843 pasien dengan CVD juga mengalami
atherothrombotic di wilayah arterial lainnya
8.4%
1.6%
1.2%
REACH DATA : ~40% pasien dengan CVD adalah
polyvascular
16.6%
Patients with CVD
= 27.8% of the
REACH Registry
population
(%s are of total population)
CAD
PAD
CVD
CAD=coronary artery disease
PAD=peripheral arterial disease
CVD=cerebrovascular disease
Multiple risk
factors only
population
1. Bhatt DL et al, on behalf of the REACH Registry Investigators.
JAMA 2006;295(2):180-189.
REACH:
The REduction ofAtherothrombosis
forContinued
Health.
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Angka kejadian CV lebih meningkat pada pasien
dengan polyvascular
1.61.1
1.5
4.1
12.6
2.8
1.6
3.1
7.1
21.7
0.0
5.0
10.0
15.0
20.0
25.0
Patie
nts(%)
CV death Non-fatal MI Non-fatal
stroke
CV death/
MI/stroke
CV death/
MI/stroke/hosp*
Single arterial bed
Polyvascular disease
MI=myocardial infarction; *such as transient ischemic attack, unstable angina, worsening of
peripheral arterial disease; adjusted for age and gender
1. Steg PG et al, on behalf of the REACH Registry Investigators.
JAMA 2007;297(11): 1197-1206.
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Dibandingkan dengan gangguan pada
vaskular tunggal atau single vascularbed,
gangguan pada lebih dari satu vaskular
(polyvascular) meningkatkan resiko 2xlipat terjadinya kejadian CV (CV
death/MI/stroke) atau perawatan rumah
sakit dalam satu tahun.
Kesimpulan REACHAnalisa setelah satu tahun
1. Steg PG et al, on behalf of the REACH Registry Investigators.
JAMA 2007;297(11): 1197-1206.
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1.Adult Treatment Panel II. Circulation 1994; 89:133363. 2. Kannel WB. J Cardiovasc Risk1994; 1: 3339.3. Wilterdink JI, Easton JD.Arch Neurol1992; 49: 85763. 4. Criqui MH et al. N Engl J Med1992; 326: 3816.
*Sudden death defined as death documented within 1 hour and attributed to coronary heart disease (CHD)Includes only fatal MI and other CHD death; does not include non-fatal MI
Increased risk vs. general population (%)
Original event Myocardial infarction Stroke
Myocardial infarction
Stroke
Peripheral arterial disease
57 x greater risk1(includes death)
34 x greater risk2(includes TIA)
23 x greater risk2(includes angina and
sudden death*
)
9 x greater risk3
4 x greater risk4
(includes only fatal MIand other CHD death)
23 x greater risk3
(includes TIA)
Risiko Kejadian Vaskular Berulang:( Penderta stroke 9x beresiko berulang stroke dan 3x beresiko terkena MI )
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Prediksi Angka Kejadian Cardiovaskular
Berdasarkan ESSEN Score
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Essen Stroke Risk Score (ESRS) :Untuk kalkulasi terhadap resiko stroke berulang setelah
Ischemic stroke/ TIA
ESRS score > 3 patients with high risk for recurrent stroke Should be candidates for intensified secondary prevention
strategies.
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Peningkatan Angka kejadianBerdasarkan ESSEN Score
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Kesimpulan ESSEN
ESRS ( Essen ) Confirm the predictive value forrecurrent stroke and the combined end point of stroke orcardiovascular death in patients with TIA or nondisabling ischemic stroke
Preference should be given to simple point score ( ESRS ESSEN ), which are more likely to be used in clinicalroutine, where they could help to raise awareness forrecurrent stroke and cardiovascular risk.
( American Stroke Association, Cristian W, Jens Banemann, 2010 )
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Clinical Data update
ATC
CAPRIE
CHARISMA
ESPRIT
PROFES
TRITON
PLATO
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Category % odds reduction
Acute myocardial infarction
Acute stroke
Prior myocardial infarction
Prior stroke/transient ischemic attack
Other high risk
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(e.g. diabetes mellitus)
All trials 22%2
Antithrombotic Trialists Collaboration (ATC ):Pembuktian efektivitas antiplatelet dalam menurunkan kejadian vascular
Antithrombotic Trialists Collaboration. BMJ2002; 324: 7186.
* Vascular events = myocardial infarction, stroke or vascular death
0.0 1.00.5 1.5 2.0Control bet terAnt iplatelet better
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Antithrombotic Trialists Collaboration (ATC ):
Mendukung pemakaian low dose aspirin (75150mg)
Antithrombotic Trialists Collaboration. BMJ2002; 324: 7186.
ASA dose % odds reduction
5001500 mg daily
160325 mg daily
75150 mg daily
< 75 mg daily
Any ASA dose 23%2
(p < 0.0001)
1.00.50.0 1.5 2.0
Contro l betterASA better
ASA < 75 mg less
effective
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CAPRIE Study: Membandingkan efektivitas
Clopidogrel vs. ASA
*(MI, ischemic stroke, and vascular death)
**Berdasar studi CAPRIE dan meta-
analisa APTC.1CAPRIE Steering Committee. Lancet
1996;348:1329-1339. 2Antiplatelet
Trialists Collaboration. BMJ 1994;
308:81-106.
Clopidogrel
mencegah 26% lebih
baik atas kejadian
ischemic* vs. ASA**
25
26%
0
5
10
15
20
2419
Events
Prevented/Year/1
,000Patients
Aspirin1,2 Clopidogrel1,2
Clopidogrel vs Aspirin for the
Prevention of ischemic Events
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CAPRIE: Benefit ClopidogrelLebih meningkat pada pasien dengan resiko tinggi Vascular13
*Event rate of myocardial infarction, is chemic stroke, or vascular death
1. CAPRIE Steering Committee. Lancet1996; 348: 132939.
2. Jarvis B, Simpson K. Drugs 2000; 60: 34777.3. Ringleb PA et al. Eur Heart J1999; 20: 666.
Events Prevented/1,000 Patients/Year over ASA
15.2%
20.0%
23.8%
14.1%
17.2%20.4%
0
5
10
15
20
25
30
All CAPRIE patients1
(n=19,825)
Prior history of any
ischemic event2
(n=8,854)
Prior history of major
acute event (MI or stroke) 3
(n=4,496)
ASA
Clopidogrel
11
28
34
Eventrate/year(%
)
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CAPRIE: Efektivitas Clopidogrel
Lebih meningkat pada pasien dengan Diabetes1,2
1. Bhatt DL et al.Am Heart J2000; 140: 6773.
2. Jarvis B, Simpson K. Drugs 2000; 60: 34777.
Events Prevented/1,000 Patients/Year over ASA
13.7%
17.7%
21.5%
12.6%
15.6% 17.7%
0
5
10
15
20
25
All CAPRIE patients1 Diabetes2 Diabetes treated withinsulin2
Ev
entrate/year(%)
11
21
38
*Event rate of myocardial infarction, stroke, vascular death, or hospitalization
ASA
Clopidogrel
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CAPRIE: Benefit Clopidogrel Pada pasien
dengan Hypercholesterolemia1
*Myocardial infaction, stroke, vascular death, or hospitalization for ischemic events/bleeding
1. Bhatt DL et al. J Am Coll Cardiol2000; 35 (suppl A):326.
Events Prevented/1000 Patients / Year over ASA
Overall benefit:p = 0.026; multivariate analysis
15.1%14.6%
12.2%11.9%
0
2
4
6
8
10
12
14
16
On any lipid-lowering agent On statin
2927
ASA
Clopidogrel
Eventrate/year(%)
CAPRIE
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CAPRIE: Efek Samping perdarahanclopidogrel lebih rendah dari ASA
.
Eventrate%
Intracranial
bleeding
Gastrointestinal
bleeding
clopidogrel
aspirin
Perawatan Rumah Sakit karena
ischemia dan bleeding
clopido
grel
aspirin
Clopidogrel vs ASAP= 0.018
CAPRIE, Lancet 1966. Bhatt, AHJ 2000
-9,1
CHARISMA
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Population RR (95% CI) p value
Established AT* 0.88 (0.77, 0.998) 0.046
(n=12,153)
Multiple Risk Factors* 1.20 (0.91, 1.59) 0.20
(n=3,284)
Overall Population 0.93 (0.83, 1.05) 0.22(n=15,603)
CHARISMA : Clopidogrel + ASA efektif padasecondary prevention, tetapi tidak pada primary
* A statistical test for interaction showed marginally significant heterogeneity
(p=0.045) in treatment response for the pre-specified subgroups of symptomatic
and asymptomatic patients
AT=Atherothrombosis (Qualifying CAD, CVD or PAD) 166 patients did not meet any of the main inclusion criteria
0.6 0.8 1.41.2Clopidogrel + ASA
BetterPlacebo + ASA
Better
1.60.4
Adapted from Bhatt DL, Fox KA, Hacke W, et al. N Engl J Med2006; 354: 1706-1717.
Clopidogrel forHighAtherothrombotic Risk and Ischemic
Stabilization, Management andAvoidance
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ESPRIT (open label study)
Lancet 2006 May 20;1638
Aspirin (30-325 mg) vs Aspirin plus dipyridamole
Stroke /Tia within 6 months n=2,739
Vascular death, stroke, MI or bleeding
16% aspirin alone
13% asp + dipyrimadole
Withdrawal
34% A+D vs 13% A alone
Those withdrew had higher risk reduction
40% on Aspirin 30 mg only - against most internationalguidelines
Confounders: BP, statin, smoking control.
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Perbedaan terjadi setelah 3 tahu n
Pemberian
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PROFESS: NEJM, April 2008. Randomized, multicenter (600), multinational study:
2x2 factorial design, double-blind, double-dummy
Duration of treatment: 2-4 years
In 15,500 patients (20,666 screened)
Presenting a qualifying ischemic stoke within 90 days prior to randomization
Inclusion criteria:
Male, female >55 years old
With an ischemic stroke (neurologically and clinically stable and occurrence within90 days prior to randomization
Planned dates: Oct. 2003 => Oct. 2007
Original design New design (May 2004)
PLAVIX
telmisartan
n=3,875
PLAVIX
placebo
n=3,875
telmisartan
n=3,875
placebo
n=3,875
PLAVIX + ASA
telmisartan
n=3,875
PLAVIX + ASA
placebo
n=3,875
Aggrenox
telmisartan
n=3,875
Aggrenox
placebo
n=3,875
Aggrenox Aggrenox
Profess: Prevention Regimens For Effectively avoiding Second Strokes.
PROFES : K bi i D i id l + ASA
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PROFES : Kombinasis Dypiridamole + ASA samaefektifnya dibandingkan Clopidogrel, tetapi bermakna
meningkatkan intracranial haemorrhage
Note: Slides reproduced accurately based on data orally presented. Not validated with a published
source. This data curve have been redrawn.R Sacco. Presented at ESCo 2008.
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Secara Bermakna Kejadian Major
Hemorrhagic lebih tinggi pada Aggrenox
R. Sacco, presented at ESCo 2008Adapted from http://european-stroke-conference.com/2008/Nice/webcast/1_clinical_trials_I/index.html, 20/05/2008
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Summary
Single therapy denganclopidogrel lebih efektif secara bermaknadibandingkan aspirin dengan efek samping perdarahan
lambung yang lebih minimal pada kelompok clopidogrel
Kombinasi ASA dan Dypiridamole ( Aggrenox ), sama efektifnyadengan clopidogrel, tetapi efek samping perdarahan ICH secara
bermakna lebih tinggi pada kelompok Aggrenox
Clopidogrel memiliki bukti yang kuat ( EBM ) dalam mencegahkejadian stroke berulang dan menurunkan kejadian cardiovascular,
harus dipertimbangkan sebagai pilihan pertama pada terapi pasien
iskemik stroke
M t K A ti l
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Menurut Key Article
Postgrad Med J 2012
Stroke merupakan heterogeneous disease, dengan subtypes yang berbeda dimana
setiap type berbeda pathophisiology, riwayat klinis dan kematian
Cerebrovascular disease dan ischaemic heart disease sangat erat kaitannya,
dimana banyak pasien stroke adalah multivascular disease
Clopidogrel harus diberikan sebagai first line antiplatelet untuk secondary prevention
ischaemic stroke karena terbukti efficacy pada semua type iskemik stroke , pada
coronary heart disease dan pada peripheral arterial disease
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BAGAIMANA DENGAN
New Anti Platelet Pada Stroke1. ( Prasugrel )
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Prasugrel vs. Clopidogrel pada ACS
13,608 pasien, risiko sedang sampai tinggi ACSdirencanakan percutaneous coronary intervention. 60
mg prasugrel + 10 mg maintenance, atau 300 mg
clopidogrel + 75 mg maintenance, 6 hingga 15 bulan.
Terbukti menurunkan kejadian ischemic events 19%,
tetapi meningkatkan 32% major bleeding, termasuk fatal
bleeding.
Total mortality tidak berbeda secara bermakna
Triton-TIMI 38. NEJM.2007; 357: 2001-15 Trial to assess improvement in therapeutic
outcomes by optimizing platelet inhibition with Prasugrel-Thrombolysis in Myocardial Infarction.
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TRITON-TIMI: Prasugrel efektif menurunkan gabungan
CV death, MI atau stroke secara bermakna, tetapi meningkatkan
major bleeding 1
1. Wiviott SD et al. N Engl J Med2007;357:20012015.
TRITON Cl id l l bih b ik d i d i t
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TRITON: Clopidogrel lebih baik ada pasien dengan riwayatstroke/TIA
prasugrel meningkatkan resiko kejadian stroke 37%
1. Antman EM. Presented at AHA 2007.
Available at http://www.timi.org/files/slides/TRITON%20TIMI%2038%20AHA%202007.ppt.Last accessed 17 December 2008.
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New Antiplatelet2. (Ticaglerol )
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Tidak ada perbedaan yang bermakna pada pasien stroke/TIA
Ti l l S b k i k tk
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Ticaglerol Secara bermakna meningkatkan
perdarahan pasien Non CABG 25 %
Non-CABG and CABG-related major bleeding
7
0
K-M
estimatedrate(%
peryear)
9
8
6
5
4
3
2
1
Non-CABG
PLATO
major
bleeding
4.5
3.8
P=0.03
HR 1.19
(1.02-1.38)
2.8
2.2
P=0.03
HR 1.25
(1.03-1.53)
7.47.9
NS
5.35.8
NS
Ticagrelor
Clopidogrel
Non-CABG
TIMI major
bleeding
CABG
PLATO
major
bleeding
CABG
TIMI major
bleeding
Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57.
NNH = 143
Kejadian ICH dan FATAL ICH secara bermakna
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Kejadian ICH dan FATAL ICH secara bermakna
meningkat pada pemberian Ticaglerol
P=0.06
HR 1.87
P=0.02
HR=5.47
K-M
estimatedrate
(%p
eryear)
ICH
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
Fatal ICH
0.28
0.15
0.12
0.01
TicagrelorClopidogrel
Ticagrelor (N=9235) 26 11
Clopidogrel (N=9186) 14 1
Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57.
FDA website CardiovascularandRenalDru sAdvisor Committee/ucm192863.htm. Accessed on Au ust 23rd 2010.
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Summary New Antiplatelet
PRASUGREL Antiplatelet baru Prasugrel efektif pada pasien ACS
dengan PIC, tetapi secara bermakna meningkatkanperdarahan ~ 32% lebih tinggi dari clopidogrel
Meningkatkan kejadian stroke hingga 37 %
Tidak di indikasikan pada pasien stroke
TICAGLEROL Antiplatelet baru Ticaglerol efektif pada pasien ACS
termasuk pasien dengan PCI, tetapi secara bermakna
meningkatkan perdaraan pada pasien non CABG ~ 25 % Meningkatkan kejadian ICH dan Fatal ICH secara
bermakna
Belum mendapatkan persetujuan untuk indikasi Stroke
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Guideline ESO dan PERDOSSI
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ESO: European Stroke Organization
Guideline for Management of Ischemic Stroke and TIA
( update Jan 2009 )
It is recommended that patients receive anti-thrombotictherapy ( Class 1, level A)
It is recommended that patients not requiring anticoagulation
should receive anti-platelet therapy ( class 1 level A), where
possible combine aspirin and dipyridamole or clopidogrelalone Alternatively, aspirin alone or trifusal alone, may be
used (class 1, level A)
The combination of aspirin and clopidogrel is not
recommended in patient with recent ischemic stroke, exceptin patients with specific condition ( eq unstable angina, or
non Q wave MI, or recent stenting). Treatment should be
given for up to 9 months after the event ( Class 1, level A)
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PERDOSSI: Guideline Stroke 2011
Pasien dengan stroke iskemik atau TIA yang tidak
mendapatkan antikoagulan harus diberikan antiplatelet,seperti aspitin ( 80 325 mg ) atau clopidogrel 75 mg, atauterapi kombinasi aspirin dosis rendah 25 mg denganextended release dipyridamole 200 mg ( AHA/ASA, Class 1,level of evidence A )
Kombinasi aspirin dan clopidogrel tidak direkomendasikan
pada pasien dengan stroke iskemik akut, kecual ipadapasien dengan indikasi spesifik ( Pasien dengan angina tdk
stabil, dengan Non Q wave MI, pasien dengan stenting ).Pengobatan diberikan sampai 9 bulan sesudah kejadian (
AHA/ASA. Class 1, level of evidence A )
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TAKE HOME MESSAGES
40 % pasien stroke, merupakan poly-vascular disease
Anti- platelet berperanan penting dalam menurunkan secondary preventionstroke
Penelitian TRITON menunjukkan clopidogrel lebih superior dari generasibaru Prasugrel dalam menurunkan resiko stroke karena lebih sedikitkomplikasi perdarahan.
Penelitian PLATO menunjukkan Ticaglerol meningkatkan perdarahan ICHdan Fatal ICH secara bermakna, dan belum dapat persetujuan untukdigunakan pada stroke
ESO 2009 dan PERDOSSI 2011 merekomendasikan clopidogrel sebagaiklass 1A pada secondary prevention stroke
Clopidog rel be the f irs t choice
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