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New Antiplatelet Therapy for Secondary STROKE Prevention :

Apakah Clopidogrel masih sebagai pilihan Pertama ? dr. Retnaningsih SpS(K) KIC
SMF/Bagian Neurologi FK UNDIP/RSUP dr.Kariadi Semarang

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

REACH DATA : ~ 40% pasien dengan CVD adalah polyvascular


~ 40% dari 18,843 pasien dengan CVD juga mengalami atherothrombotic di wilayah arterial lainnya
(%s are of total population)

REACH: The REduction of Atherothrombosis for Continued Health.

Multiple risk factors only population Patients with CVD = 27.8% of the REACH Registry population CVD 16.6%
CAD=coronary artery disease PAD=peripheral arterial disease CVD=cerebrovascular disease

CAD 8.4%

1.6% 1.2%
PAD

1. Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.

Angka kejadian CV lebih meningkat pada pasien dengan polyvascular


25.0
21.7

20.0

Single arterial bed Patients (%) Polyvascular disease


15.0
12.6

10.0
7.1

5.0
2.8 1.6 1.1 1.6 1.5

4.1 3.1

0.0

CV death

Non-fatal MI

Non-fatal stroke

CV death/ MI/stroke

CV death/ MI/stroke/hosp*

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.

Kesimpulan REACH
Analisa setelah satu tahun

Dibandingkan dengan gangguan pada vaskular tunggal atau single vascular bed, gangguan pada lebih dari satu vaskular (polyvascular) meningkatkan resiko 2x lipat terjadinya kejadian CV (CV death/MI/stroke) atau perawatan rumah sakit dalam satu tahun.

1. Steg PG et al, on behalf of the REACH Registry Investigators. JAMA 2007;297(11): 1197-1206.

Risiko Kejadian Vaskular Berulang:


( Penderta stroke 9x beresiko berulang stroke dan 3x beresiko terkena MI ) Increased risk vs. general population (%) Original event Myocardial infarction Stroke

Stroke

23 x greater risk2
(includes angina and sudden death*)

9 x greater risk3
34 x greater risk2
(includes TIA)

Myocardial infarction

57 x greater risk1
(includes death)

Peripheral arterial disease 4 x greater risk4 (includes only fatal MI and other CHD death)

23 x greater risk3
(includes TIA)

*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 1. Adult Treatment Panel II. Circulation 1994; 89:133363. 2. Kannel WB. J Cardiovasc Risk 1994; 1: 3339. 3. Wilterdink JI, Easton JD. Arch Neurol1992; 49: 85763. 4. Criqui MH et al. N Engl J Med 1992; 326: 3816.

Prediksi Angka Kejadian Cardiovaskular Berdasarkan ESSEN Score

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.

Peningkatan Angka kejadian


Berdasarkan ESSEN Score

Kesimpulan ESSEN
ESRS ( Essen ) Confirm the predictive value for recurrent stroke and the combined end point of stroke or cardiovascular death in patients with TIA or non disabling ischemic stroke

Preference should be given to simple point score ( ESRS ESSEN ), which are more likely to be used in clinical routine, where they could help to raise awareness for recurrent stroke and cardiovascular risk.
( American Stroke Association, Cristian W, Jens Banemann, 2010 )

Clinical Data update


ATC CAPRIE CHARISMA ESPRIT PROFES

TRITON PLATO

Antithrombotic Trialists Collaboration (ATC ):


Pembuktian efektivitas antiplatelet dalam menurunkan kejadian vascular
Category
Acute myocardial infarction Acute stroke Prior myocardial infarction

% odds reduction

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
0.0
* Vascular events = myocardial infarction, stroke or vascular death Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186.

22% 2
0.5 1.0 1.5
Control better

2.0

Antiplatelet better

Antithrombotic Trialists Collaboration (ATC ): Mendukung pemakaian low dose aspirin (75150mg)
ASA dose 5001500 mg daily 160325 mg daily % odds reduction ASA < 75 mg less effective

75150 mg daily
< 75 mg daily Any ASA dose

23% 2
(p < 0.0001)

0.0

0.5
ASA better

1.0

1.5
Control better

2.0

Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186.

CAPRIE Study: Membandingkan efektivitas Clopidogrel vs. ASA


25
Events Prevented/Year/1,000 Patients

Clopidogrel mencegah 26% lebih baik atas kejadian ischemic* vs. ASA**
*(MI, ischemic stroke, and vascular death) **Berdasar studi CAPRIE dan metaanalisa APTC. 1CAPRIE Steering Committee. Lancet 1996;348:1329-1339. 2Antiplatelet Trialists Collaboration. BMJ 1994; 308:81-106.

26%
20 15

10

19

24

Clopidogrel vs Aspirin for the Prevention of ischemic Events

0 Aspirin1,2 Clopidogrel1,2

CAPRIE: Benefit Clopidogrel


Lebih meningkat pada pasien dengan resiko tinggi Vascular 13
Events Prevented/1,000 Patients/Year over ASA
34

30 25
11

28

23.8%

Event rate/year (%)

20.0%
20 15.2% 15 10 5 0
All CAPRIE patients1 (n=19,825) Prior history of any ischemic event2 (n=8,854)

20.4% 17.2% ASA Clopidogrel

14.1%

Prior history of major acute event (MI or stroke) 3 (n=4,496)

*Event rate of myocardial infarction, is chemic stroke, or vascular death 1. CAPRIE Steering Committee. Lancet 1996; 348: 132939. 2. Jarvis B, Simpson K. Drugs 2000; 60: 34777. 3. Ringleb PA et al. Eur Heart J 1999; 20: 666.

CAPRIE: Efektivitas Clopidogrel Lebih meningkat pada pasien dengan Diabetes1,2


Events Prevented/1,000 Patients/Year over ASA
38

25 20 Event rate/year (%) 15 10 5 0


All CAPRIE patients1
11

21

21.5% 17.7% 15.6% 13.7% 12.6% 17.7%


ASA Clopidogrel

Diabetes2

Diabetes treated with insulin2

*Event rate of myocardial infarction, stroke, vascular death, or hospitalization 1. Bhatt DL et al. Am Heart J 2000; 140: 6773. 2. Jarvis B, Simpson K. Drugs 2000; 60: 34777.

CAPRIE: Benefit Clopidogrel Pada pasien dengan Hypercholesterolemia1


Events Prevented/1000 Patients / Year over ASA

16 14 12

14.6%

27
11.9%

15.1%

29
12.2% ASA Clopidogrel

Event rate/year (%)

10 8 6 4 2 0 On any lipid-lowering agent On statin Overall benefit: p = 0.026; multivariate analysis

*Myocardial infaction, stroke, vascular death, or hospitalization for ischemic events/bleeding 1. Bhatt DL et al. J Am Coll Cardiol 2000; 35 (suppl A):326.

CAPRIE: Efek Samping perdarahan


clopidogrel lebih rendah dari ASA

clopidogrel

Perawatan Rumah Sakit karena ischemia dan bleeding aspirin clopidogrel

aspirin

Event rate % Intracranial Gastrointestinal bleeding bleeding CAPRIE, Lancet 1966.

-9,1

Clopidogrel vs ASA P= 0.018


Bhatt, AHJ 2000

CHARISMA : Clopidogrel + ASA efektif pada


secondary prevention, tetapi tidak pada primary
Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance

Population Established AT*


(n=12,153)

RR (95% CI)

p value

0.88 (0.77, 0.998) 0.046

Multiple Risk Factors*


(n=3,284)

1.20 (0.91, 1.59)

0.20

Overall Population
(n=15,603) 0.4 0.6 0.8 1.2

0.93 (0.83, 1.05)


1.4 1.6

0.22

Clopidogrel + ASA Better

Placebo + ASA Better

* 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 Adapted from Bhatt DL, Fox KA, Hacke W, et al. N Engl J Med 2006; 354: 1706-1717.

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 international guidelines Confounders: BP, statin, smoking control.

Perbedaan terjadi setelah 3 tahun Pemberian

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 within 90 days prior to randomization Planned dates: Oct. 2003 => Oct. 2007
Original design
PLAVIX + ASA
telmisartan n=3,875 Aggrenox telmisartan n=3,875

New design (May 2004)


PLAVIX telmisartan n=3,875 Aggrenox PLAVIX placebo n=3,875 Aggrenox

PLAVIX + ASA
placebo n=3,875 Aggrenox placebo n=3,875

telmisartan
n=3,875

placebo
n=3,875

Profess: Prevention Regimens For Effectively avoiding Second Strokes.

PROFES : Kombinasis Dypiridamole + ASA sama


efektifnya 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.

Secara Bermakna Kejadian Major Hemorrhagic lebih tinggi pada Aggrenox

R. Sacco, presented at ESCo 2008 Adapted from http://european-stroke-conference.com/2008/Nice/webcast/1_clinical_trials_I/index.html, 20/05/2008

Summary
Single therapy dengan clopidogrel lebih efektif secara bermakna dibandingkan aspirin dengan efek samping perdarahan lambung yang lebih minimal pada kelompok clopidogrel Kombinasi ASA dan Dypiridamole ( Aggrenox ), sama efektifnya dengan clopidogrel, tetapi efek samping perdarahan ICH secara bermakna lebih tinggi pada kelompok Aggrenox Clopidogrel memiliki bukti yang kuat ( EBM ) dalam mencegah kejadian stroke berulang dan menurunkan kejadian cardiovascular, harus dipertimbangkan sebagai pilihan pertama pada terapi pasien iskemik stroke

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

BAGAIMANA DENGAN New Anti Platelet Pada Stroke 1. ( Prasugrel )

Prasugrel vs. Clopidogrel pada ACS


13,608 pasien, risiko sedang sampai tinggi ACS direncanakan 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.

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 Med 2007;357:20012015.

TRITON: Clopidogrel lebih baik ada pasien dengan riwayat


stroke/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.

New Antiplatelet 2. (Ticaglerol )

Tidak ada perbedaan yang bermakna pada pasien stroke/TIA

Ticaglerol Secara bermakna meningkatkan perdarahan pasien Non CABG 25 %


Non-CABG and CABG-related major bleeding
9 K-M estimated rate (% per year) 8 7 6 5 4 3 2 1 0 Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding P=0.03 HR 1.19 (1.02-1.38) 4.5 3.8 P=0.03 HR 1.25 (1.03-1.53) 2.8 2.2 NS NNH = 143 7.9 7.4 NS 5.8 5.3 Ticagrelor Clopidogrel

Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57.

Kejadian ICH dan FATAL ICH secara bermakna meningkat pada pemberian Ticaglerol
0.35 P=0.06 HR 1.87
0.28

K-M estimated rate (% per year)

Ticagrelor Clopidogrel

0.3 0.25 0.2

P=0.02 HR=5.47
0.15

0.15 0.1 0.05

0.12

0.01

ICH Ticagrelor (N=9235) Clopidogrel (N=9186)

Fatal ICH

26 14

11 1

Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57. FDA website CardiovascularandRenalDrugsAdvisoryCommittee/ucm192863.htm. Accessed on August 23rd, 2010.

Summary New Antiplatelet


PRASUGREL
Antiplatelet baru Prasugrel efektif pada pasien ACS dengan PIC, tetapi secara bermakna meningkatkan perdarahan ~ 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

Guideline ESO dan PERDOSSI

ESO: European Stroke Organization Guideline for Management of Ischemic Stroke and TIA ( update Jan 2009 ) It is recommended that patients receive anti-thrombotic therapy ( 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 clopidogrel alone 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, except in 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)

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, atau terapi kombinasi aspirin dosis rendah 25 mg dengan extended release dipyridamole 200 mg ( AHA/ASA, Class 1, level of evidence A ) Kombinasi aspirin dan clopidogrel tidak direkomendasikan pada pasien dengan stroke iskemik akut, kecuali pada pasien 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 )

TAKE HOME MESSAGES


40 % pasien stroke, merupakan poly-vascular disease Anti- platelet berperanan penting dalam menurunkan secondary prevention stroke Penelitian TRITON menunjukkan clopidogrel lebih superior dari generasi baru Prasugrel dalam menurunkan resiko stroke karena lebih sedikit komplikasi perdarahan.

Penelitian PLATO menunjukkan Ticaglerol meningkatkan perdarahan ICH dan Fatal ICH secara bermakna, dan belum dapat persetujuan untuk digunakan pada stroke

ESO 2009 dan PERDOSSI 2011 merekomendasikan clopidogrel sebagai klass 1A pada secondary prevention stroke

Clopidogrel be the first choice