Prasugrel (Effient): mechanism of action, indications and adverse effects

This post is an overview on the mechanism of action, clinical trials, indications, adverse effects profile of prasugrel. It also features a video interview with Steve D. Wiviott, MD, FACC; from the TIMI Study Group, Brigham and Women’s Hospital.

The antiplatelet agent prasugrel (Effient in the US, Efient in the EU) was approved by the FDA on July 10, 2009. Like clopidogrel and ticlopidine, prasugrel is a platelet inhibitor of the thienopyridine class. All drugs in this class act as ADP receptor antagonists,  what makes them different is their safety profile and pharmacokinetic properties. Although clopidogrel is a widely prescribed agent, it has limitations such as: a modest antiplatelet effect, a delayed onset of action and considerable interpatient variability in drug response. All these disadvantages motivated the development of more effective and predictable agents, such as the novel prasugrel.

Much controversy has surrounded the approval of prasugrel . There is uncertainty about the role this drug will play in the prevention of myocardial infarction, as well as its optimal dosing and adverse effects profile.

Mechanism of action

prasugrel_mechanism_of_action Prasugrel is a prodrug, oxidation by intestinal and hepatic cytochrome P-450 enzymes convert prasugrel into its active metabolite. Prasugrel has a rapid and almost complete absorption after oral ingestion of a loading dose. Its active form binds irreversibly to the adenosine diphosphate (ADP) P2Y12 receptor on platelets for their lifespan, thereby inhibiting their activation and decreasing subsequent platelet aggregation.

Prasugrel has a greater antiplatelet effect than clopidogrel because it is metabolized more efficiently.  Some of the differences in metabolism between clopidogrel and prasugrel may be explained by genetic polymorphisms affecting the cytochrome P-450 system.

Indications

Co-administered with aspirin,  prasugrel is approved by the European Commission for the prevention of atherothrombotic events in patients with acute coronary syndromes (unstable angina, non-ST segment elevation myocardial infarction or ST segment elevation myocardial infarction) undergoing primary or delayed percutaneous coronary intervention (PCI).

Adverse effects and limitations

Prasugrel will include a boxed warning alerting prescribers that the drug can cause significant, sometimes fatal, bleeding.

The drug should not be used in patients with active pathological bleeding, a history of TIAs (transient ischemic attacks) or stroke, or urgent need for surgery, including coronary artery bypass graft surgery.

Some have argued that this boxed warning will make much harder for prasugrel to become a successful drug (in marketing terms).

Which trials lead to prasugrel approval?

TRITON – TIMI 38 is the name of the trial that lead to the approval of prasugrel. TRITON-TIMI 38 was a head to head (prasugrel vs. clopidogrel), randomized, double blind  trial; instead of prasugrel vs. placebo. You can read further details on the official presentation below.

Download: “TRITON TIMI 38 Stent Analysis” PPT

Dr. Victor Serebruany, who is a patent application holder for prasugrel and who worked on early clinical studies for the drug, issued a letter urging the FDA to halt its review of prasugrel. In that letter he requested the FDA to halt its review for prasugrel until a “properly-designed Phase 3 study has been performed with a lower, safer dose of prasugrel and properly defined clinical outcomes”.

MTRAC verdict on prasugrel

The Midlands Therapeutics Review and Advisory Committee (MTRAC) is a UK based independent professional committee of GPs and representatives of other key decision-makers in the use of medicines in primary care.  They conclude that:

Treatment with prasugrel should be initiated in secondary care. It is then appropriate for continued prescribing in primary care. Prasugrel may be suitable for a limited number of patients(e.g. patients who require immediate percutaneous coronary intervention or patients who have experienced stent thrombosis despite previous clopidogrel treatment). However, for each individual, the potential benefits of prasugrel must be carefully balanced against the risk of bleeding. Prasugrel is not recommended for patients over the age of 75 years or patients weighing less that 60 kg because these patients have a high risk of bleeding. It is contraindicated in patients with a history of stroke or transient ischemic attack.

Download PDF: MTRAC, Medicines Management, Keele University. Verdict and summary: Prasugrel

Interview with Steve D. Wiviott, MD, FACC; from the TIMI Study Group

Dr. Cannon, editor in Chief of Cardiosource, interviews one of the TRITON-TIMI 38 investigators: Dr. Steve D. Wiviott.

References and further reading

Wallentin L., P2Y12 inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. European Heart Journal Advance Access published on July 24, 2009
Bhatt, D. L. & Topol, E. J. Scientific and therapeutic advances in antiplatelet therapy. Nature Rev. Drug Discov. 2, 15–28 (2003).

Wiviott SD, Braunwald E, McCabe CH, et al. ; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001–2015. FREE Full Text.

European Medicines Agency (EMEA). European Public Assessment Report — Efient. EMEA website (2009).

Huber, K. Fresh from the pipeline: Prasugrel. Nature Reviews Drug Discovery 8, 449-450 (June 2009).

Bhatt DL. Prasugrel in Clinical Practice. N Engl J Med Published at www.nejm.org July 15, 2009. Free full text.

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