dr. retna-new antiplatelet for secondary stroke prevention

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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dr. retna-new antiplatelet for secondary stroke prevention

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