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ESC-ACCP-ACC
Guidelines in atherothrombosis
Institute of Vascular Diseases
Clinical Center University of Sarajevo
Ključni faktori razvoja aterotromboze
Oštećenje endotela
Pro-trombogena površina
Aktivirani trombociti
Leukociti, makrofagi
Oksidacija LDL
Vazokonstriktori (EDCF)
Aterotromboza
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Akutni vaskularni incidenti
Nestabilna angina/non-Q MI
Akutni MI
CVI (trombotski)
Akutna arterijska okluzija
Endovaskularne intervencije
Rekurentni vaskularni incidenti
Endotel
ISAR REACT 2
600 mg LD 2 h prior to
intervention.
Ključni faktori zaštite krvnog suda
• NO- nitrični oksid
• Inhibicija agregacije trombocita
• Prostaciklin
GP IIb/IIIa - inhibicija agregacije trombocita
Receptori
Blokiranje (inhibicija) ADP receptora
Inhibicija IP3
GP IIb/IIIa molekula oko 50.000
Inhibicija agregacije
• 20 različitih agenasa za inhibiciju
agregacije
• Inhibicija agregacije mjerena ex vivo nije
istovremeno i prevencija aterotromboze
• Acetilsalicilna kiselina, dipiridamol i
clopidogrel – long-term PO terapija
• Abciximab, tirofiban, eptifibatide – kao
short-term IV terapija
Antitrombocitni agensi - antiplatelets
• Acetilsalicilna kiselina
• Dipiridamol
• Thienopyridini (ticlopidine, clopidogrel,
prasugrel)
• Glycoprotein IIb/IIIa rec. inhibitori
(abciximab, tirofiban, eptifibatide)
ADP inhibitori
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ADP inhibitori
Ticlopidin
Clopidogrel
Prasugrel
Doziranja
ACC/AHA
Stabilna angina
75 mg
Nestabilna angina
300 mg
Akutni koronarni sindrom
300-600 mg
PCI – stent
300-600-900 mg
Aneurizma aorte
75 mg
Arterijska okluzivna bolest
75 mg
TIA i CVI
75 mg
Teška ACC stenoza (dvosudovna bolest) 75 mg
Akutni ishemični CVI
75 mg
Atrijalna fibrilacija
75 mg
Doza clopidogrela
• Uvodna doza (LD)
• Optimalna doza (OT)
• Održavanje doze (MD)
Aktivnost clopidogrel-bisulfat
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Nema signifikantnu aktivnost in vitro
Odlična bioraspoloživost
Nakon 2 sata počinje aktivnost u plazmi
75 mg/dan ostvaruje 40-60%
Puni efekat nakon 48-36 sati
Ne aficira druge plazma proteine
CAPRIE studija
Clopidogrel vs. Aspirin in Patients at Risk of
Ischemic Events
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n-19185
Koronarna, cerebralna, i/ili vaskularna bolest
Clopidogrel 75 mg/dan
Aspirin 325 mg/dan
8,7% RRR
22,5 mjeseca
CURE studija
Clopidogrel in Unstable Angina Reccurent Events
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n-12562
Nestabilna angina
MI bez elevacije ST segmenta
Clopidogrel + Aspirin
Placebo + aspirin 75-325 mg
CHARISMA studija
Clopidogrel for High Atherothrombotic Risk and
Ischemic Stabilisation
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n-15603
terapija do 42 mjeseca, medijana 28 mjeseci
17% RRR
Koronarna, cerebrovaskularna, arterijska okl.,
multipli riziko faktori
clopidogrel + aspirin vs. aspirin
Uvodna doza
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300 – 600 mg
Nakon 2 sata aktivnost u plazmi
Ostvaruje efekat nakon 6 sati
Ne aficira druge plazma proteine
Indikacija
 Inhibicija agregacije
 Antiinflamatorni efekat
 Clopidogrel 300 – 600 mg/dan, u
kombinaciji sa aspirinom,
 24 sata prije intervencije
 6 sati prije, 2 sata prije, ili 3 sata poslije
intervencije
Uvodna doza
• ISAR-REACT Study
• ISAR-COOL Study
• 600 mg clopidogrel
• Inhibicija agregacije
• Inhibicija inflamacije**
• ISAR-REACT Study (Intracoronary Stenting and Antithrombotic
Regimen-Rapid Early Action for Coronary Treatment)
• ISAR-COOL Study (Intracoronary Stenting with Antithrombotic Regimen
Cooling-off Trial)
ISAR-REACT Study
ISAR-COOL Study
 600 mg inhibicija agregacije +
antiinflamatorni efekat
 signifikantno izraženiji u odnosu na 300
mg/dan
CREDO
MATCH
FASTER
SPS3
ARCH
CLARITY
Indikacija
• High-risk pacijenti
• Produžena terapija - redukcija non-fatal MI,
CVI, ili VD za 25%
Apsolutna redukcija rizika
• High-risk pacijenti
• Seriuos vascular events
(prethodni MI)
36 na 1000 pac. tretiranih 2 godine
Apsolutna redukcija rizika
• High-risk pacijenti
• Seriuos vascular events
(prethodni AMI)
38 na 1000 pac. tretiranih 1 mjesec
Apsolutna redukcija rizika
• High-risk pacijenti
• Seriuos vascular events
(prethodni CVI ili TIAs)
36 na 1000 pac. tretiranih 2 godine
Apsolutna redukcija rizika
• High-risk pacijenti
• Seriuos vascular events
(prethodni akutni CVI)
9 na 1000 pac. tretiranih 1 mjesec
Apsolutna redukcija rizika
• High-risk pacijenti
• Seriuos vascular events
(stabilna angina, PAD, AF)
22 na 1000 pac. tretiranih 2 godine
FDA approval - licensed
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Reduction of atherosclerotic events (MI,
CVI, VD) in pts with recent MI, recent CVI,
or established PAD
For pts with ACS whether or not PCI (with
or without stent) or CABG is performed.
Additional use in STEMI treated by
fibrinolysis and aspirin, early clopidogrel
reduced major events by 20%.
Prevention of late post-stent thrombosis
after DES should be used 12 months
For aspirin resistance
ACC/AHA guidelines
 For AMI, clopidogrel 75 mg daily
added to aspirin (75 mg-325 mg
once daily) for at least 7 days (Class
IA)
 Dual antiplatelet therapy for at least
12 month after DES
ACC/AHA guidelines
 Non-ST-segment elevation acute
coronary syndrome (unstable
angina/non-Q-wave MI)
 Clopidogrel should be initiated with a
single 300 mg loading dose and then
continued at 75 mg once daily.
Aspirin (75 mg-325 mg once daily)
should be initiated and continued in
combination with clopidogrel.
AHA/ACC guidelines
 For patients with ST-segment elevation
acute myocardial infarction, clopidogrel
has been shown to reduce the rate of
death from any cause and the rate of a
combined endpoint of death, reinfarction or stroke
 It is not given when urgent CABG is
likely
European Society of Cardiology
• post MI, CVI, AOD
• clopidogrel 75 mg/day
European Society of Cardiology
• Cardiovascular disease
• Multiple risk factors
• clopidogrel 75 mg/day
FDA approval 2007.
LD 300 or 600 mg. daily
MD 75 mg clopidogrela
+ aspirin 75 mg daily
Non responder or poor responder
5 - 44% patients
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Gurbel Pa, Tantry US: Clopidogrel resistance?
Thrombosis Res. 2007. 120: 311-321.
Gurbel PA et al. Platelet Reactivity in Patients and
Reccurent Events Post-Stenting: Results of
PREPARE POST-STENTING Study. J Am Coll.Card.
2005. 46: 1820-1826.
 Light transmission aggregometry
(LTA)
 Vasodilator-stimulated
phosphoprotein (VASP)
Maintenance dose (MD)Doza održavanja?
150 or 75 mg clopidogrel daily.
van Beckerath N, et al.
Eur Heart J. 2007. On-line published. February 1.
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Aspirin,
25 mg aspirina + 2 x 200 dipiridamol
Clopidogrel 75 mg dn. Prednost nad
aspirinom (2B)
Ako je plasiran stent, aspirin +
clopidogrel
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