Dervin Ariansyah

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Antiplatelet Therapy

Acetysalicylic •Aspirin
Acid

•Ticlopidine
Thienopyridines •Clopidogrel
•Prasugrel

•Cilostazol
Novel Agents •Dipyridamole

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 Platelet Activation
■ Mechanism

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 Platelet Activation
■ Mechanism

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 ASPIRIN
■ Mechanism Of Action

Acetylating a serine
platelet is unable to
residue on the COX or Decreased COX enzymes
synthesize COX
prostaglandin anucleate

inhibition of intrinsic NO
Decreased production of synthase & transcription
thromboxane A2 factors involved in
inflammation

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 ASPIRIN
■ Secondary Prevention

ATC (Antiplatelet Trialists Collaboration)

• Meta-analysis of 31 randomized trials in patients who had sustained prior MI, stroke,TIA or UAP
• 25% reduction in the odds of suffering a recurrent vascular event, 18% reduction in the odds of
vascular death among patients at high risk
ISIS-2 (Second International Study of Infarct Survival)
• 17.187 patients with IMA
• Aspirin 162.5 mg/daily for 1 month signifcantly reduced early vascular mortality, 324 mg
/daily for 12 weeks resulted 51% reduction in myocardial infarction or death
RISC (Research Group on Instability in Coronary Artery Diseases)
• 796 men with unstable angina or non–Qwave myocardial infarction
• 57% to 69% reduction in the rate of the combined endpoint of myocardial infarction or death
among who were treated with low-dose aspirin
CATS (Chinese Acute Shock Trial)
• In more than 20,000 patients
• 60 mg of aspirin given within 48 hours of an ischemic stroke prevented 6.8 deaths or recurrent
nonfatal strokes per 1000 patients treated
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 ASPIRIN
■ Primary Prevention

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 ASPIRIN
■ Dosing

CURE

• Increasing dosage of aspirin (< 100 mg, 101 to 199 mg, >200mg daily) were not associated with
greater clinical benefit
• higher rates of major bleeding were observed with escalating dosages of aspirin compared with
placebo

CHARISMA

• A meta-analysis of 31 randomized trials : the risk of major bleeding events was lowest in patients
who took the lowest aspirin dosage
• > 50 y.o,Clopidogrel monotherapy >> Aspirin monotherapy on bleeding events

CURRENT – OASIS 7

• 25,000 patients with ACS treated with an early invasive strategy were randomly assigned to
receive conventional clopidogrel dosages
• High-dose clopidogrel was associated with a signifcant reduction in the composite of death,
myocardial infarction, or stroke at 30 days in patients undergoing PCI
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 ASPIRIN
■ Formulations

Systemic circulation peak within 40

Aspirin is rapidly absorbed in the
minutes after ingestion of regular aspirin
stomach and small intestine after
and 3 to 4 hours after ingestion of an
ingestion
enteric coat

Enteric-coated aspirin does not seem to

Maximal platelet thromboxane inhibitio, confer protection against
,achieved at 13.6 minutes,most efficient gastrointestinal bleeding in comparison
325-mg aspirin tablet is chewed withbuffered or regular preparations of
the same dose

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 ASPIRIN
■ Hemorragic Complications

The majority of bleeding complications arise from the gastrointestinal tract; upper
gastrointestinal hemorrhage was 1.5% over 2 years of follow-up

The relative risk of intracranial hemorrhage was increase in major bleeding of 0.12%

ACCF, ACG and AHA recommend reducing chronic aspirin dosages to 81 mg daily with
the addition of a daily dose of a PPI in patients with a history of gastrointestinal
hemorrhage or maintenance steroid medication, elderly patients and dyspepsia

Replacing aspirin with clopidogrel is not recommended as a strategy for reducing the risk of
recurrent gastrointestinal complications

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 ASPIRIN
■ Drug Interactions

Aspirin+NSAID

Mitigate the protective effect of aspirin

Excess risk of mortality and cardiovascular death

the administration of aspirin 2 hours before a single dose of

ibuprofen resulted in expected irreversible COX-1 inhibition
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 ASPIRIN
■ Guidelines

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 ASPIRIN
■ Guidelines

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 THIENOPYRIDINES
■ Mechanism Of Action

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 THIENOPYRIDINES
■ CLOPIDOGREL : Secondary Prevention

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 THIENOPYRIDINES
■ CLOPIDOGREL : Secondary Prevention

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 THIENOPYRIDINES
■ CLOPIDOGREL : Resistance
• 54% increase in the risk of the composite endpoint of myocardial infarction,
cardiovascular death, or stroke among carriers of at least one CYP2C19 allele over
TRITON that of noncarriers. Presence of the CYP2C19 allele was also associated with a
TIMI 38 threefold increase in the risk of stent thrombosis

• In patients with an acute myocardial infarction who underwent PCI, the presence of
two copies of the CYP2C19 allele was associated with more than a threefold increase
FAST MI in the risk of adverse cardiovascular events

• a marker of clopidogrel-induced platelet inhibition, the investigators demonstrated

greater mean platelet reactivity in patients treated with omeprazole
OCLA

• There was no evidence of cardiovascular harm from the combination of clopidogrel

with proton pump inhibitors.
COGENT

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 THIENOPYRIDINES
■ PRASUGREL

TRITON-TIMI 38

19% relative rate reduction in the composite endpoint of CVD

death, nonfatal IM, or stroke but 32% increase in the rate of
major bleeding

30 % reduction in major cardiovascular events was observed

in patients with diabetes treated with prasugrel, in
comparison with a 14% reduction in those without diabetes

In patients with stents, prasugrel was also associated with a

58% relative reduction in stent thrombosis.
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 THIENOPYRIDINES
■ PRASUGREL
the ACC/AHA : 300- to 600-mg
loading dose of clopidogrel or
60 mg loading dose of
prasugrel in all patients with
STEMI who were undergoing
PCI
Clopidogrel (75 mg daily) or
prasugrel (10 mg daily) is
recommended for 12 months
after placement of a BES or
DES
In patients receiving fbrinolytic
therapy and nonprimary PCI,
clopidogrel is favored as the
thienopyridine of choice,
because of the lack of data for
prasugrel in the setting of
fbrinolytic therapy
In patients scheduled to
undergo elective CABG,
discontinuation of clopidogrel
and prasugrel for a minimum
of 5 and 7 day
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 NOVEL AGENTS
■ Cilostazol

Selective inhibition of PIE3 and vasculer smooth muscle cell

Increase level of platelet cyclic adenosin monophosphat (cAMP) and ultimately

result in inhibition of platelet aggregation and arteriolar vasodilatation

Antimitogenic effect and inhibition of CAMP uptake

Randomazid placebo control trial : 50 mg or 100 mg twice daily, signifcantly Improved

pain-free walking distance in comparison with placebo trials that included 2702 patients
with moderate to severe claudication, cilostazol resulted in a 67% increase in pain-free
walking distance and 50% increase in maximal walk

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 NOVEL AGENTS
■ Dipyridamole
the ACC/AHA : 300- to 600-mg
loading dose of clopidogrel or
60 mg loading dose of
prasugrel in all patients with
STEMI who were undergoing
PCI
Clopidogrel (75 mg daily) or
prasugrel (10 mg daily) is
recommended for 12 months
after placement of a BES or
DES
In patients receiving fbrinolytic
therapy and nonprimary PCI,
clopidogrel is favored as the
thienopyridine of choice,
because of the lack of data for
prasugrel in the setting of
fbrinolytic therapy
In patients scheduled to
undergo elective CABG,
discontinuation of clopidogrel
and prasugrel for a minimum
of 5 and 7 day
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Conclusion
Platelets play a fundamental role in thrombosis and inflammation, processes germane to
the development of cardiovascular disease.

Inhibition of thromboxane synthesis through aspirin has formed the basis of modern
cardiovascular disease prevention

ADP inhibition by thienopyridines has proved an essential adjunct in the treatment of

patients with ACS, cerebrovascular disease, and peripheral artery disease

New strategies for platelet inhibition must be developed to achieve greater successes in
the treatment of cardiovascular disease.

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