General Information

Efient (prasugrel) works by reducing the tendency of platelets, the blood particles responsible for clotting, from sticking or clumping together. Prasugrel blocks a specific receptor on the platelet surface, P2Y12 adenosine diphosphate (ADP), and prevents platelets from clumping, which can result in clogged arteries and may lead to heart attack.

Efient is specifically indicated to reduce the rate of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention (PCI) as follows:
Patients with unstable angina or non-ST-elevation myocardial infarction (NSTEMI)
Patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.

Efient is supplied as a 5 mg or 10 mg tablet for oral administration. The recommended initial dose of the drug is as a single 60 mg oral loading dose which may be continued at 10 mg orally once daily. Patients taking Effient should also take aspirin (75 mg to 325 mg) daily.
Dosing in Low Weight Patients Patients weighing < 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once daily maintenance dose. Consider lowering the maintenance dose to 5 mg in this population.

Clinical Results

FDA Approval
The FDA approval of Efient was based on the results of TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel). This multicenter, international, randomized, double-blind, parallel-group study enrolled 13,608 subjects with ACS (UA, NSTEMI, or STEMI) who were to be managed with PCI. The subjects were randomized to receive Effient (60 mg loading dose followed by 10 mg once daily) or clopidogrel (300 mg loading dose followed by 75 mg once daily), with administration and follow-up for a minimum of 6 months (actual median 14.5 months). Patients also received aspirin (75 mg to 325 mg once daily). The primary outcome measure was the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in the UA/NSTEMI population. Success in this group allowed analysis of the same endpoint in the overall ACS and STEMI populations. Efient produced a statistically significant reduction in this primary endpoint of 19% when compared to Plavix (p=0.0004). This was observed as early as three days into treatment. In a subgroup of subjects with diabetes, prasugrel reduced each of the endpoints by 21% in subjects with STEMI (p=0.02) and 18% in subjects with unstable angina (p=0.002), compared to Plavix. In addition, prasugrel resulted in a 34% decline in urgent target vessel revascularization (p<0.001) and a 42% reduction in heart attack with subsequent death from cardiovascular causes (p=0.02). Prasugrel treated subjects also had a statistically significant increase in non-CABG (coronary artery bypass grafting) major bleeding compared to Plavix-treated subjects (2.4% vs. 1.8%, p=0.03). Fatal bleeding was statistically more frequent among prasugrel-treated than clopidogrel-treated subjects (0.4% vs. 0.1%, p=0.002). Overall, prasugrel showed a higher clinical benefit over Plavix, with a significant 13% reduction in overall events (12.2 vs. 13.9, p=0.004).

Ongoing Study Commitments

• Eli Lilly has agreed to conduct an open-label trial of ex vivo reversal of platelet inhibition by exogenous platelets as a function of time and plasma level of prasugrel active metabolite in 28 normal volunteers administered a single 60-mg loading dose of prasugrel plus aspirin 325 mg.
  Final Protocol Submission: 09/2009
  Trial Completion Date: 08/2011
  Final Report Submission: 09/2011
• Eli Lilly has agreed to gather baseline cancer history and cancer adverse event data from the ongoing trial TRILOGY, a 10,300-subject trial being conducted in patients with acute coronary syndrome who are being managed medically (without coronary revascularization).
  Protocol Submission: 06/2008
  Trial Completion Date: 12/2012
  Final Report Submission: 01/2013
• Eli Lilly has agreed to perform a clinical trial in the fasting and fed state, to compare the pharmacokinetics of single 60-mg doses of the marketed and new prasugrel formulations with respect to concentrations of the prasugrel active metabolite and effects on platelet inhibition.
  Trial Completion Date: 08/2009
  Final Report Submission: 12/2009
• perform, in the presence and absence of a proton pump inhibitor, a clinical trial to compare the pharmacodynamics of single 60-mg doses of the marketed and new prasugrel formulations with respect to concentrations of the prasugrel active metabolite and effects on platelet inhibition.
  Final Report Submission: 12/2009
• Eli Lilly has commited to the collection of samples at baseline for genotyping CYP450 enzymes in TRILOGY subjects, to allow a comparison of effectiveness and bleeding in prasugrel and clopidogrel subgroups by metabolizer status.
  Trial Completion Date: 12/2012
  Final Report Submission: 01/2013

Side Effects

Adverse events associated with the use of Efient may include, but are not limited to, the following:

• TIMI major or minor bleeding
• Hypertension
• Hypercholesterolemia/Hyperlipidemia
• Headache
• Back Pain
Dyspnea
• Nausea
• Dizziness

Mechanism of Action

Efient contains prasugrel, a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor. Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.

Literature References

Michelson AD, Frelinger AL 3rd, Braunwald E, Downey WE, Angiolillo DJ, Xenopoulos NP, Jakubowski JA, Li Y, Murphy SA, Qin J, McCabe CH, Antman EM, Wiviott SD; TRITON-TIMI 38 Investigators Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial. European Heart Journal 2009 Jul;30(14):1753-63

Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH, Antman EM; TRITON-TIMI 38 investigators Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009 Feb 28;373(9665):723-31

Scott DM, Norwood RM, Parra D P2Y(12) inhibitors in cardiovascular disease: focus on prasugrel.The Annals of Pharmacotherapy 2009 Jan;43(1):64-76.

Braun OO, Johnell M, Varenhorst C, James S, Brandt JT, Jakubowski JA, Winters KJ, Wallentin L, Erlinge D, Siegbahn A Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease. Thrombosis and Haemostasis 2008 Oct;100(4):626-33

Wiviott SD, Trenk D, Frelinger AL, O'Donoghue M, Neumann FJ, Michelson AD, Angiolillo DJ, Hod H, Montalescot G, Miller DL, Jakubowski JA, Cairns R, Murphy SA, McCabe CH, Antman EM, Braunwald E; PRINCIPLE-TIMI 44 Investigators Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007 Dec 18;116(25):2923-32

Jakubowski JA, Matsushima N, Asai F, Naganuma H, Brandt JT, Hirota T, Freestone S, Winters KJ A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans. British Journal of Clinical Pharmacology 2007 Apr;63(4):421-30

Wiviott SD, Antman EM, Winters KJ, Weerakkody G, Murphy SA, Behounek BD, Carney RJ, Lazzam C, McKay RG, McCabe CH, Braunwald E; JUMBO-TIMI 26 Investigators Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation 2005 Jun 28;111(25):3366-73

Additional Information

For additional information regarding Efient or thrombotic cardiovascular events in patients with acute coronary syndrome managed with PCI, please visit the Efient web page.