Continuing Education Activity

Prasugrel is a medication used to manage and treat acute coronary syndrome undergoing percutaneous intervention. Prasugrel is a thienopyridine, an irreversible antagonist of the ADP P2Y12 receptor. The antiplatelet effect of prasugrel lasts until the lifespan of platelets. Prasugrel is a prodrug that is converted to an active and inactive metabolite by the hepatic CYP system. This activity covers the indications, dosing, contraindications, mechanism of action, and management of prasugrel in cases where it can provide therapeutic benefit.

Objectives:

• Describe the mechanism of action of prasugrel.
• Review the indications of prasugrel.
• Summarize the pharmacokinetics of prasugrel.
• Explain the importance of care coordination amongst the interprofessional team to enhance patient safety for anyone using prasugrel.

Indications

Platelet adhesion, activation, and aggregation play critical roles in normal hemostasis and pathological thrombosis. These factors are pathologically crucial in initiating intracoronary thromboses that cause acute coronary syndromes (ACS) and the ischemic complications following coronary artery interventions, including stent thrombosis and recurrent myocardial infarction. The interaction of ADP with P2Y and P2Y receptors enhances and sustains platelet activation; these activated platelets expose glycoprotein IIb/IIIa receptors, which crosslink with fibrin to form platelet aggregates. These aggregates result in mechanical blood flow disruption and can potentially embolize downstream, leading to microvasculature obstruction resulting in myocardial ischemia and infarction.[1]

Prasugrel is an antiplatelet agent in the thienopyridine group.[2] Prasugrel is used to decrease the rate of cardiovascular events in patients with acute coronary syndrome (ACS) who are undergoing percutaneous coronary intervention. Prasugrel has approval for medical management of patients with unstable angina or non-ST elevation myocardial infarction (NSTEMI) and patients with ST-elevation myocardial infarction (STEMI) managed with percutaneous coronary intervention. Prasugrel is an alternative agent to clopidogrel, with greater platelet aggregation inhibition than clopidogrel.[3] It has shown an increased risk of bleeding in patients receiving prasugrel compared to clopidogrel, who require urgent or emergent CABG. However, prasugrel was associated with a lower rate of mortality when compared to clopidogrel.[4] I was approved for use in the USA by the FDA in 2009.[5]

Mechanism of Action

Prasugrel is a thienopyridine, an irreversible antagonist of the ADP P2Y12 receptor.[2] Thienopyridine antiplatelet agents interfere with platelet activation and aggregation induced by ADP.[1] The antiplatelet effect of prasugrel lasts for the lifespan of platelets.

Pharmacokinetics and Pharmacodynamics

Prasugrel is a prodrug that is converted to an active thiol metabolite and inactive metabolite by the hepatic CYP system, specifically CYP2BH6, 2C9/19 (minor), and it is a CYO3A4 substrate. The active component (R- 138727) of the metabolites irreversibly binds to and blocks P2Y12 adenosine diphosphate (ADP) receptors, preventing GPIIb/IIIa receptor complex activation, thus reducing platelet aggregation and activation. It is rapidly absorbed and metabolized, with its active metabolite peaking approximately after 30 minutes of dosing. The mean elimination half-life of the active metabolite of prasugrel is approximately 7 hours.[6] The elimination of 70 percent of the drug occurs through the kidney, with roughly 25 percent in feces.[7] With the onset of action being 30 minutes, it attains a steady-state concentration within three days.[8] Platelet aggregation returns to baseline status 5 to 9 days following discontinuation of prasugrel, which is reflective of new platelet production.

Administration

Prasugrel is only available in tablet formulation; therefore, its administration is only via the oral route. Administration can be without regard to the intake of a meal. When undergoing emergent primary PCI, crushing the tablets is associated with faster absorption and a more rapid and higher antiplatelet effect achievable within 30 minutes of administration.[9] The bioavailability of prasugrel becomes reduced when it is administered via an enteral route bypassing the stomach acidity. Clinicians should consider withholding dosing at least seven days prior to any surgical procedures.

Available Dosage Forms

5 mg and 10 mg tablets

Dosing for Acute Coronary Syndromes

Loading dose: Initial loading dose of 60 mg requires prompt administration as soon as acute coronary syndrome is known. 

Maintenance dose: The maintenance dose for people above the weight of 60 kg is 10 mg daily. There is an increased risk of bleeding in low-weight individuals (weight less than 60 kg) taking prasugrel, so a lower dose of 5 mg daily can be considered in these patients. Prasugrel 5 mg in low body weight (< 60 kg) individuals reduced platelet reactivity similarly to 10 mg in higher body weight individuals (> 60 kg).[10] Prasugrel administration should be in combination with aspirin.

Duration of Dual Antiplatelet Treatment After Stent Placement

As per ACC/AHA dual antiplatelet therapy guidelines, at least 6 to 12 months of dual antiplatelet therapy (DAPT) treatment is recommended in people with ACS receiving either a bare-metal or drug-eluting stent. A shorter duration of dual antiplatelet therapy can be considered in patients with low ischemia risk and higher bleeding risk, whereas a longer duration of DAPT treatment may be reasonable in patients with a higher risk of ischemia and lower risk of bleeding. Decisions about the discontinuation of DAPT are individualized and based on clinical judgment.[2]

Use in Renal Impairment

No dosage adjustments are required; however, there is an increased risk of bleeding with moderate to severe renal impairment due to decreased drug excretion. Dosing in end-stage renal disease and patients on peritoneal or hemodialysis is undefined.

Use in Hepatic Impairment

No dosage adjustments are necessary for mild to moderate hepatic impairment (Child-Pugh class A and B). Researchers have not studied the use of prasugrel in patients with severe hepatic impairment (Child-Pugh class C); however, it generally correlates with increased bleeding.

Pregnancy and Lactation

There is no human data regarding fetal or infant risk when using prasugrel during pregnancy or breastfeeding. The maternal risk of hemorrhage exists based on the drug's mechanism of action. There is no data on whether prasugrel affects milk production.[11]

There is no indication for dosing prasugrel in pediatric patients.

Adverse Effects

Bleeding is the most common adverse effect associated with prasugrel, and the drug carries a black box warning for potentially fatal bleeding. Increased risk of bleeding may occur in patients with a bodyweight of less than 60 kg, recent trauma, recent surgery, and active bleeding peptic ulcer. Increased risk of bleeding is also seen in renal impairment as it is associated with decreased excretion. There is no antidote available for bleeding caused by prasugrel. If bleeding does occur, theoretically, hemostasis is achievable by a platelet transfusion. However, platelet transfusion within 4 hours of administration of prasugrel may be less effective. If possible, bleeding management should take place without stopping prasugrel, as premature discontinuation of prasugrel is associated with stent thrombosis and increased incidence of adverse cardiovascular outcomes.

Thrombotic thrombocytopenic purpura (TTP) is a rare but serious adverse effect associated with thienopyridine use and usually occurs within two weeks of starting treatment.[12] TTP management requires urgent plasmapheresis. 

Indigestion is the most common gastrointestinal side effect associated with prasugrel. Other adverse effects associated with prasugrel use are headache, dizziness, epistaxis, hematoma, and bruising. 

Use of prasugrel with warfarin or NSAIDS, when used chronically, increases the risk of bleeding.

Contraindications

Hypersensitivity to prasugrel or any of the components of the formulation is a contraindication for its use. Other contraindications for starting prasugrel are any pathological bleed or history of transient ischemic attack or stroke. The use of prasugrel is not recommended in patients older than 75 due to the increased risk of bleeding.

Caution is advised when considering prasugrel in moderate to severe renal impairment, severe hepatic impairment, a patient history of GI bleeding or active GI ulcers/disease, and in patients with a history of recent surgery or trauma.

Prasugrel use is contraindicated with the concomitant use of abrocitinib (a Janus-kinase inhibitor), because of the additive effects that can lead to life-threatening bleeding risk. There are many other drugs where caution is advised and may require therapy modification; thorough medication reconciliation is required to limit bleeding risks.[13]

Monitoring

While no routine laboratory tests are required, periodic checks for hemoglobin and hematocrit for signs of bleeding are prudent on a case-by-case basis. 

Toxicity

Prasugrel causes rapid and irreversible platelet inhibition and can be associated with life-threatening bleeding in case of toxicity. Researchers observed lethality in rats with a dose of 2000 mg/kg. There is no antidote available for use in case of toxicity with prasugrel. The active metabolite of prasugrel is likely not removable via dialysis.[14]

Enhancing Healthcare Team Outcomes

Prasugrel has extensive use among cardiologists, ED physicians, mid-level practitioners (NPs and PAs), and internists. The choice of an antiplatelet medication depends upon the clinical situation. The addition of thienopyridine to aspirin is the standard of care for patients with acute coronary syndromes and patients undergoing percutaneous coronary intervention. There have been concerns about clopidogrel treatment failure, defined as the inability to achieve adequate antiplatelet effect in an individual taking clopidogrel. An individualized DAPT approach may be potentially guided by genetic or platelet function testing; however, routine screening in percutaneous coronary intervention is not recommended. However, platelet function testing merits consideration for DAPT de-escalation.[15]

Nurses are the ones to administer the drugs to the patients when the patients are inpatient and also the first responders when adverse effects occur during an inpatient stay. They can also provide patient counseling on dosing and signs of bleeding and serve as a contact point for ongoing care.

The role of a pharmacist is essential to look for any drug-drug interaction with any medication, and they can recommend discontinuation of any drugs that can alter the effectiveness of prasugrel if they are nonessential. They are the most accessible healthcare provider for patients. They can verify dosing, counsel patients on administration and adverse events, and report any concerns to other interprofessional team members.

As premature discontinuation of dual antiplatelet therapy is associated with stent thrombosis, myocardial infarctions, and increased cardiovascular events, it is crucial to educate the patient regarding compliance. Regular follow-ups are essential for the monitoring of bleeding. Discontinuation of DAPT for an elective procedure is an interdisciplinary decision, and DAPT should continue for 6 to 12 months after PCI.

Dual antiplatelet therapy requires interprofessional communication and a team approach, including primary care clinicians, specialists, nursing staff, and pharmacists, coordinating their activities and recording their findings in the patient record, so all healthcare team members operate from the same data. This approach to patient care will enhance outcomes and mitigate adverse events. [Level 5]