Dosage

Following hospital discharge, prasugrel should be administered at a dose of 10 mg OD. Following ACS a loading dose of 60 mg of should be administered. Absorption is not affected by food and no dosing adjustment is required in patients with chronic renal disease or in patients with mild to moderate hepatic impairment. Patients taking prasugrel should also be taking ASA 75 to 325 mg daily.

Mechanism of Action

Prasugrel, a thienopyridine, exerts its antithrombotic effect by the binding of its active metabolite, in a competitive and irreversible manor, to the adenosine diphosphate (ADP) P2Y12 receptor. Natural binding of the receptor by ADP results in inhibition of cAMP-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) (VASP-P), which is known to be closely related to the inhibition of glyprotein IIb/IIIa receptor activation. Pharmacological studies with prasugrel in healthy individuals and in patients with stable coronary artery disease showed that prasugrel has a more rapid onset of action than clopidogrel and achieves more consistent and complete inhibition of ADP induced platelet aggregation.

The formation of the active metabolite of prasugrel requires a single step conversion mediated through the action of CYP2C19 and other hepatic cytochrome enzymes. Although at least 2 known loss of function alleles of CYP2C19, designated *2 and *3 exist, and CYP2C19 is known to be inhibited by other drugs, including the proton pump inhibitors omeprazole and esomeprazole, the effect on formation of the active metabolite of prasugrel is not clinically significant.

Recommendations in Vascular Prevention

Secondary CAD Prevention

Data from a large randomized clinical trial demonstrated that prasugrel provides a further 2.2% absolute benefit over clopidogrel in the reduction of the triple endpoint of MI, stroke or CV death, as well as a 1.3% absolute reduction in the rate of intra stent thrombosis, in patients with acute coronary syndromes treated with percutaneous intervention. Sub-analysis suggested that the greatest benefit was seen in patients with STEMI and with diabetes. However, no benefit was seen in total mortality and the rates of major, life threatening and fatal bleeding were increased likely due to the more potent and consistent antiplatelet effect of prasugrel over clopidogrel. Patients aged ≥75 years, weighing ≤60kg and those with a history of stroke or TIA were noted to have the highest rates of bleeding and intra-cerebral hemorrhage.

Recommendations

For patients with ACS who undergo stent implantation and have an increased risk of stent thrombosis (eg, STEMI, history of diabetes mellitus, or prior documented stent thrombosis), prasugrel 10 mg daily may be considered in addition to ASA 75 to 162 mg daily for 12 months (Class IIa, Level B).

Prasugrel should be avoided in patients with an increased bleeding risk, likely to undergo CABG within 7 days, with a history of stroke or transient ischemic attack (TIA), aged ≥75 years, or weighing ≤60kg (Class III, Level B).

Warnings & Special Considerations

Prasugrel is contraindicated in patients with a known history of cerebrovascular disease, aged ≥75 years, or weighing ≤60kg.