Prasugrel
P2Y12 antagonist in acute coronary syndrome with PCI
Prasugrel is a third generation thienopyridine and an irreversible P2Y12 receptor antagonist. Eli Lilly and Daiichi Sankyo launched the compound in 2009 under the brand name Efient; generics are now available. Prasugrel is approved for platelet aggregation inhibition in combination with acetylsalicylic acid in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).
The pivotal TRITON TIMI 38 trial compared prasugrel with clopidogrel in more than 13,600 patients with ACS and planned PCI. Prasugrel reduced the composite endpoint of cardiovascular death, non fatal myocardial infarction and non fatal stroke by 19 percent compared with clopidogrel, although with a markedly increased rate of major bleeding. In patients with a previous stroke or TIA the net benefit was negative, which is why this group is excluded from use.
Mechanism of Action
Like clopidogrel, prasugrel is a prodrug. After absorption it is metabolised to the active metabolite in two steps: first by intestinal and plasma esterases to a thiolactone intermediate, then by hepatic CYP enzymes (mainly CYP3A4 and CYP2B6, and to a lesser extent CYP2C19 and CYP2C9) to the active metabolite. This binds irreversibly and covalently to the P2Y12 receptor on platelets.
The P2Y12 receptor is activated by adenosine diphosphate (ADP) and mediates ADP dependent platelet activation and aggregation. Irreversible blockade prevents platelet activation and the release of further mediators. The effect lasts about 7 to 10 days (platelet lifespan) until new platelets are formed.
Compared with clopidogrel, prasugrel is activated much faster and more effectively. Platelet inhibition begins 30 minutes after the loading dose and reaches its maximum after 4 hours. The CYP2C19 genetic variability, which leads to inadequate platelet inhibition in up to 30 percent of clopidogrel patients, plays no relevant role with prasugrel because its CYP2C19 dependence is minimal.
Indications
- Acute coronary syndrome with planned percutaneous coronary intervention (PCI): STEMI, NSTEMI and unstable angina in combination with acetylsalicylic acid
- Stent thrombosis prophylaxis after elective PCI in ACS patients, dual antiplatelet therapy typically for 12 months
Prasugrel is not indicated in stable coronary artery disease without an acute event, in patients with previous stroke or TIA (contraindication), in patients at high bleeding risk, or in severe hepatic impairment.
Dosage and Administration
Adults under 75 years of age with body weight of at least 60 kg: a single 60 mg loading dose before PCI, followed by 10 mg once daily as the maintenance dose. Adults over 75 years or with body weight below 60 kg: the 60 mg loading dose is unchanged; the maintenance dose is reduced to 5 mg once daily because of the increased bleeding risk.
The tablet is taken in the morning or evening at the same time of day, independent of meals, with a glass of water. Concomitant intake of 75 to 100 mg acetylsalicylic acid is standard. Treatment duration is usually 12 months after PCI, and in individual cases shorter or longer depending on risk benefit assessment.
Renal impairment: no dose adjustment required, caution with haemodialysis. Hepatic impairment: no adjustment for mild to moderate impairment; contraindicated in severe impairment. CYP3A4 inhibitors: no clinically relevant influence.
Side Effects
Common: bleeding of any location including skin and mucosal bleeding, epistaxis, gingival bleeding, increased menstrual bleeding, haematomas, gastrointestinal bleeding, microscopic haematuria, headache, dizziness.
Uncommon: major gastrointestinal bleeding, intracranial haemorrhage, retroperitoneal bleeding, skin rash, pruritus, occasionally thrombocytopenia.
Rare to very rare: thrombotic thrombocytopenic purpura (TTP), severe hypersensitivity reactions, angioedema, severe liver dysfunction.
Bleeding risk: in TRITON TIMI 38 the risk of major bleeding with prasugrel was about 32 percent higher than with clopidogrel. Patients over 75 years of age, patients with low body weight under 60 kg, and patients with previous stroke or TIA are particularly at risk. For the last group prasugrel is contraindicated.
Interactions
- NSAIDs, acetylsalicylic acid: additive bleeding risk, low dose ASA is part of the standard combination, avoid NSAIDs where possible
- Other antiplatelet agents (clopidogrel, ticagrelor, cilostazol): combination with prasugrel is not useful and carries an increased bleeding risk
- Oral anticoagulants (warfarin, DOACs), heparins: combine only with a clear indication (e.g. atrial fibrillation plus ACS), shortest reasonable duration, increased bleeding risk
- SSRIs, SNRIs: increased gastrointestinal bleeding risk
- Proton pump inhibitors: no clinically relevant interaction with prasugrel, unlike clopidogrel (where CYP2C19 inhibition has been discussed)
- Opioids: may delay absorption of the loading dose, relevant in the emergency setting
Special Notes
Contraindications: previous stroke or transient ischaemic attack, active pathological bleeding, severe hepatic impairment, known hypersensitivity to prasugrel.
Surgery: for elective surgery prasugrel should be stopped at least 7 days before the procedure to reduce the bleeding risk. When PCI or a cardiovascular intervention is required the benefit usually outweighs the risk, and a joint decision between cardiology and surgery is standard. After stent implantation dual antiplatelet therapy should not be ended prematurely because of the risk of stent thrombosis.
Dental procedures: minor procedures such as tooth extractions can usually be performed while continuing therapy, in agreement with the dentist and cardiologist. A temporary pause can be considered for more extensive procedures.
Pregnancy: experience is limited; use on a case by case basis when the cardiological indication is compelling, after a risk benefit assessment. Breastfeeding: no data on passage into breast milk, use not recommended.
Monitoring: observe clinically for signs of bleeding and perform regular blood counts (haemoglobin, platelets). With unexplained bleeding check coagulation status. Patients should carry a medication card and inform all medical staff before procedures.
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Frequently Asked Questions
What is the difference compared with clopidogrel?
Prasugrel acts faster, more strongly and more reliably than clopidogrel, because its activation does not depend on CYP2C19. In return the bleeding risk is higher. In TRITON TIMI 38 prasugrel reduced ischaemic events after ACS by 19 percent, but increased major bleeding by 32 percent. Careful patient selection is therefore decisive.
Why is prasugrel contraindicated after stroke?
In the subgroup with previous stroke or TIA in TRITON TIMI 38 the risk of intracranial bleeding clearly outweighed the benefit. For these patients clopidogrel or ticagrelor is the better choice. The contraindication is absolute, even in apparently good overall health.
How long do I take prasugrel after a heart attack?
The standard duration is 12 months in combination with acetylsalicylic acid after PCI with a stent. In individual cases the duration can be shortened (at high bleeding risk) or extended (for complex stent implantation or persisting high ischaemic risk). The cardiologist decides individually.
What should be done in case of surgery or accident?
For elective surgery stop prasugrel at least 7 days beforehand in agreement with the cardiologist. In case of accident or urgent surgery, platelet transfusion can partly offset the effect; the benefit is limited because the binding is irreversible. In stent patients continuation often outweighs the risk, so the balance is individual.
Sources
- EMA, Efient (Prasugrel) EPAR
- AWMF, ESC Guidelines ACS and PCI
- Gelbe Liste, Prasugrel active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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