Research 3

By group 1: Dela rosa, Andrew Bugnosen, christan Carino, jescyl Llamido, robert Valencerina, cheska Free Powerpoint Templates

alcid, lorenzo miranda, pearl florendo, martina dy, yvanna

Page 1

What is inhibation Of platelet aggregation?

Inhibition of platelet aggregation (IPA) has been a drug development target in acute coronary syndrome (ACS) for almost 2 decades. The relationship between IPA and cardiovascular (CV) events has not been quantified. Cardiovascular (non fatal myocardial infarction, death) and major bleeding events were extracted from phase 2 or 3 randomized, double-blind trials that evaluated oral and intravenous glycoprotein antagonists and thienopyridines.

Free Powerpoint Templates

Page 2

IPA was extracted from different sources that studied a similar regimen in a similar population. Events were correlated to IPA using a linear relative-risk mixedeffects model. Covariates included type of drug, mean age, gender percentage, and ADP. Clinical trial simulations were conducted to evaluate the relationship between IPA and the likelihood of observing a CV event in a 6-month end point trial. Data from 81918 subjects in 20 studies were extracted from the literature. To achieve a 20% relative reduction in CV events would require a further 77% absolute increase in IPA or a further 27absolute increase for thienopyridines. CV risk reduction was less in studies with older subjects and greater in studies with greater percentages of male subjects.
Free Powerpoint Templates Page 3

Assuming a 3% major bleeding rate in the control group, these drugs had a 1% increase in absolute risk as absolute platelet inhibition increases by 60%. This relationship in intrinsic bleeding may be different in different population subtypes. Assuming a 12% event rate, a 6-month active-controlled thienopyridine trial with 3000 subjects could detect a relationship between CV events and IPA with 80% likelihood. Target IPA increases in ACS are an absolute increase of 80% for IV GP2b/3a antagonists and 30% for thienopyridines. Quantitative models using literature data on IPA and CV events can be used to select dose regimens in early stages of drug development.

Free Powerpoint Templates

Page 4

Most cases of acute coronary syndromes (ACS) are caused by the formation of a platelet-rich arterial thrombus at the site of atherosclerotic plaque rupture or erosion, and antiplatelet therapy is a standard part of their management. Aspirin irreversibly inactivates platelet cyclooxygenase-1, preventing the formation and release of the platelet agonist thromboxane. However, this positive feedback loop plays a limited role in platelet reactivity to soluble platelet agonists, so that, although aspirin is effective in reducing the incidence of thromboembolic complications of ACS, a substantial risk of arterial thromboembolism remains.

Free Powerpoint Templates

Page 5

Background:
Clopidogrel is a thienopyridine antiplatelet agent that is inactive until absorbed and converted to its active metabolite by hepatic cytochrome P450 enzymes. This active metabolite binds irreversibly to platelet P2Y12 receptors, which play a major role in amplifying the platelet responses that underlie arterial thrombosis and associated inflammation. The addition of clopidogrel to aspirin in the management of ACS yields greater protection against arterial thromboembolic events than aspirin alone.

Free Powerpoint Templates

Page 6

However, some patients have little detectable response to clopidogrel therapy and appear to have a higher risk of major adverse cardiac events. Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with clopidogrel may be less well protected.

Free Powerpoint Templates

Page 7

End of slide show!

Free Powerpoint Templates

Page 8