Prasugrel (effient) is a prodrug. It is converted in the body to its active metabolite that inhibits the aggregation of platelets by inhibiting the GPIIb/IIIa receptor complex. It reduces the incidence of thrombotic vascular events in patients with ACS including stent thrombosis in patients managed with PCI for unstable angina or myocardial infarction. Treatment with prasugrel prior to a coronary intervention in patients with Non-STEMI does not result in better outcomes and may be associated with an increased incidence of bleeding. Controversies exist regarding the concomitant use of PPIs with prasugrel and clopidogrel. However, in the PRINCIPLE-TIMI 44 trial, the concomitant use of PPIs did not affect the efficacy of the drug. [see pantoprazole vs omeprazole]

Prasugrel vs Clopidogrel vs Ticagrelor

Compared to clopidogrel, treatment with prasugrel in patients with STEMI who undergo PCI, prasugrel was found to be more effective for the prevention of ischemic events without an increased risk of bleeding. A meta-analysis comparing prasugrel, ticagrelor, and clopidogrel concluded:

• Overall, the efficacy of the three platelet inhibitors is the same
• Prasugrel may be more effective in the prevention of stent thrombosis compared to clopidogrel and ticagrelor
• Major and minor bleeding were associated with prasugrel, followed by high dose clopidogrel, and ticagrelor
• CABG related major bleeding was the same.

One study evaluated the efficacy of the three antiplatelet agents in a patient with mild hypothermia after cardiac arrest due to myocardial infarction. The proportion of patients with ineffective platelet inhibition was:

• Day 1

  • Clopidogrel: 77%
  • Prasugrel: 19%
  • Ticagrelor: 1%

• Day 2

  • Clopidogrel: 77%
  • Prasugrel: 17%
  • Ticagrelor: 0%

• Day 3

  • Clopidogrel: 85%
  • Prasugrel: 6%
  • Ticagrelor: 0%

P-value: <0.001

Compared to ticagrelor, prasugrel, clopidogrel, and vorapaxar are safer choices in patients with renal impairment. Prasugrel is inferior to ticagrelor and superior to clopidogrel in patients with high platelet reactivity following PCI Prasugrel is more efficacious than high dose clopidogrel and ticagrelor in preventing stent thrombosis. It was also seen to be most effective in preventing cardiovascular deaths compared to clopidogrel and ticagrelor at the expense of bleeding.

Table of comparison of Prasugrel vs Clopidogrel:

Prasugrel dose in Adults

Prasugrel dose in the treatment of acute coronary syndrome (ACS):

• Percutaneous coronary intervention (PCI) for ACS:

  • Loading dose:

    • 60 mg orally is administered as soon as possible but not later than one hour after PCI.

  • Maintenance dose:

    • 10 mg orally once a day (in combination with aspirin)

A loading dose may also be reasonable in patients who had a STEMI and PCI is performed more than 24 hours after treatment with the fibrinolytic agent (alteplase, reteplase, tenecteplase)

• Maintenance dosing in individuals with low body weight (<60 kg):

  • Patients weighing less than 60 kgs may continue a lower maintenance dose of 5 mg daily because of the risk of bleeding.
  • A loading dose of 30 mg followed by a maintenance dose of 5 mg daily may be reasonable in patients who weigh less than 60 kgs.

• Duration of prasugrel (in combination with aspirin) after stent placement:

  • The drug should not be prematurely stopped as it may result in thrombosis of the stents, myocardial infarction, and death.
  • The AHA/ACC recommends the use of dual antiplatelet therapy (a combination of aspirin and either of the P2Y12 inhibitor - clopidogrel, prasugrel, or ticagrelor) for a minimum of one year in patients with PCI following ACS.
  • Prescribing dual antiplatelet therapy beyond one year depends on the DAPT score
  • Furthermore, it may be reasonable to stop dual antiplatelet therapy after six months in patients who are at risk of significant bleeding.

• Switching from clopidogrel to prasugrel:

  • Patients who are being switched from clopidogrel to prasugrel should begin the treatment 24 hours after the last dose of clopidogrel.
  • It may be initiated at a dose of 10 mg once a day or a loading dose of 60 mg followed by 10 mg once a day after 24 hours.

Prasugrel pregnancy risk category: C

• This information is not available.

Prasugrel use during breastfeeding:

• It has not been proven that breastfeeding can cause the drug to be excreted.
• Manufacturers recommend weighing the benefits for the mother and the risks for the infant.

Prasugrel dose in kidney disease:

Dose adjustement is not necessary in mild renal impaiment, however, in moderate and severe renal impairment, it should be used with caution (the risks of major bleeding is high). It is not dialyzable.

Prasugrel dose in patients with liver disease:

• Mild to moderate liver impairment (Child-Pugh class A and B):

  • Adjustments in the dose is not necessary.

• Severe liver impairment (Child-Pugh class C):

  • It should be used with caution because of the increased risk of bleeding, although, the manufacturer has not recommended any dose adjustment in these patients (it has not been studied)

Prasugrel side effects :

• Cardiovascular:

  • Hypertension
  • Hypotension
  • Atrial Fibrillation
  • Bradycardia
  • Peripheral Edema

• Central Nervous System:

  • Headache
  • Dizziness
  • Fatigue
  • Noncardiac Chest Pain

• Dermatologic:

  • Skin Rash

• Endocrine & Metabolic:

  • Hypercholesterolemia
  • Hyperlipidemia

• Gastrointestinal:

  • Nausea
  • Diarrhea
  • Gastrointestinal Hemorrhage

• Hematologic & Oncologic:

  • Leukopenia
  • Anemia
  • Major Hemorrhage
  • Minor Hemorrhage
  • Major Hemorrhage

• Neuromuscular & Skeletal:

  • Back Pain
  • Limb Pain

• Respiratory:

  • Epistaxis
  • Dyspnea
  • Cough

• Miscellaneous:

  • Fever

Prasugrel contraindications:

• Very severe allergic reactions to the drug
• Active major bleeding
• Prior stroke or TIA.

Warnings and precautions

• Bleeding: [US Boxed Warning]

  • Sometimes, severe bleeding can occur and may prove fatal.
  • You should not use it if you have had strokes, TIAs, or active bleeding.
  • Patients at higher risk for major bleeding include:
    • Patients who are less than 60kg in body weight
    • Recent trauma
    • recent surgery,
    • Recent or recurrent gastrointestinal bleeding
    • Active peptic ulcer disease
    • Grave hepatic impairment
    • Moderate to severe renal impairment
    • Concomitant use heparin, warfarin, fibrinolytic treatment, and NSAIDs can increase bleeding risk.
  • Patients who have had CABG, PCI or coronary angiography should be concerned about bleeding if they become hypotensive.
  • Patients with minor bleeding may continue the drug, as patients who have had a history of acute coronary syndrome may be at greater risk.
  • Patients who have suffered major bleeding should not take the medicine. They may need transfusions of platelets or RCC.

• Hypersensitivity

  • Patients who have had severe allergic reactions, including angioedema, to thienopyridines (clopidogrel or ticlopidine) in the past have been reported.
  • Patients with severe allergies to prasugrel should avoid it.

• TTP:Thrombotic thrombocytopenic purpura

  • Prasugrel has been used in rare cases of TTP (thrombotic-thrombocytopenic purpura).
  • These patients must be identified immediately and plasmapheresis may possibly be necessary.

• GI disease:

  • Patients who have had recent gastrointestinal surgery or bleeding or those with active pepticul disease should be cautious when taking the drug.

• Hepatic impairment

  • Patients suffering from liver disease have a higher risk of bleeding. They should be closely monitored.
  • These patients should use it with caution.

• Renal impairment

  • Patients suffering from renal failure are at greater risk of bleeding. This drug should be used with caution.

Prasugrel: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

How to monitor the patient?

Monitor hemoglobin, hematocrit, and for bleeding diathesis periodically.

How to administer Prasugrel?

• It can be administered with or without a meal. In emergency situations such as in the settings of percutaneous intervention, the drug can be crushed and mixed with 25 ml of water for it to rapidly absorb.
• The response after the ingestion of the crushed tablet is quicker and a more potent effect may be seen in as early as 30 minutes.
• The tablet can be swallowed, chewed, crushed and mixed with water, juice, food, or other liquids and immediately administered by a nasogastric tube or orally.
• When the drug is administered via an enteral tube, its bioavailability may be reduced because the acidic environment of the stomach is bypassed.

Prasugrel Mechanism of action:

• Prasugrel, a drug that can be metabolized into active and inactive metabolites, is a prodrug. 
• R-138727, an active metabolite, blocks irreversibly the P2Y12 portion of ADP receptors on platelets.
• It also inhibits activation of GPIIb/IIIa. Prasugrel indirectly inhibits platelet activation, aggregation.
• A 60 mg loading dose will inhibit platelet aggregation in 30 minutes.
• The median time it takes to get more than 20% platelet inhibition is around 30 minutes.

The Time to achieve maximum inhibition The dose that is given will determine the number of platelets. Maximum platelet inhibition takes approximately 4 hours after a 60 mg loading dose. After 5 to 9 days, the platelets will return to their baseline function. The drug is being used in rapid succession at more than 79%. absorbed. Around 98% of active metabolites are protein-bound. It is Metabolized In the intestine and serum, thiolactone is converted via esterase-mediated hydrolysis to active metabolite. This happens via CYP450 mediated oxidation (mainly CYP3A4 or CYP2B6). The active metabolite is a Half-life It takes approximately 7 hours, with a range of 2 - 15 hour. The active metabolite needs to reach its peak serum concentration in about 30 minutes. When it is given with high-fat meals, this time is reduced further to 1.5 hours. It is excreted Primarily in the urine (68%), and feces (27%).

Prasugrel Brands (International):

• Effient
• Apagrel
• Effient
• Eficlot
• Efient
• Hemagrel
• Jasugrel
• Nefagrel
• Prasucard
• Prasudoc
• Prasuva
• Reclap
• Targol
• Trocal
• Ugral