Dervin Ariansyah 1

Antiplatelet Therapy Aspirin Acetysalicylic Acid Ticlopidine Clopidogrel Prasugrel Thienopyridines Cilostazol Dipyridamole Novel Agents 2

Platelet Activation 3 ■Mechanism

Platelet Activation 4 ■Mechanism

ASPIRIN ■Mechanism Of Action 5 Acetylating a serine residue on the COX or prostaglandin anucleate platelet is unable to synthesize COX Decreased COX enzymes Decreased production of thromboxane A2 inhibition of intrinsic NO synthase & transcription factors involved in inflammation

ASPIRIN ■Secondary Prevention 6 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) patients with IMA Aspirin 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

7 ASPIRIN ■Primary Prevention

8 ASPIRIN ■Dosing CURE Increasing dosage of aspirin ( 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

9 ASPIRIN ■Formulations Aspirin is rapidly absorbed in the stomach and small intestine after ingestion Systemic circulation peak within 40 minutes after ingestion of regular aspirin and 3 to 4 hours after ingestion of an enteric coat Maximal platelet thromboxane inhibitio,,achieved at 13.6 minutes,most efficient 325-mg aspirin tablet is chewed Enteric-coated aspirin does not seem to confer protection against gastrointestinal bleeding in comparison withbuffered or regular preparations of the same dose

10 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

11 ASPIRIN Aspirin+NSAID Mitigate the protective effect of aspirinExcess 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 ■Drug Interactions

12 ASPIRIN ■Aspirin Resistance

13 ASPIRIN ■Guidelines

14 ASPIRIN ■Guidelines

THIENOPYRIDINES ■Mechanism Of Action 15

16 THIENOPYRIDINES ■CLOPIDOGREL : Secondary Prevention

17 THIENOPYRIDINES ■CLOPIDOGREL : Secondary Prevention

18 THIENOPYRIDINES ■CLOPIDOGREL : Resistance TRITON TIMI 38 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 that of noncarriers. Presence of the CYP2C19 allele was also associated with a threefold increase in the risk of stent thrombosis FAST MI 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 in the risk of adverse cardiovascular events OCLA a marker of clopidogrel-induced platelet inhibition, the investigators demonstrated greater mean platelet reactivity in patients treated with omeprazole COGENT There was no evidence of cardiovascular harm from the combination of clopidogrel with proton pump inhibitors.

19 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.

20 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 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 Clopidogrel (75 mg daily) or prasugrel (10 mg daily) is recommended for 12 months after placement of a BES or DES In patients scheduled to undergo elective CABG, discontinuation of clopidogrel and prasugrel for a minimum of 5 and 7 day

21 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

22 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 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 Clopidogrel (75 mg daily) or prasugrel (10 mg daily) is recommended for 12 months after placement of a BES or DES 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. 24

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