Clopidogrel

Clopidogrel is an oral antiplatelet agent belonging to the thienopyridine class. It is a prodrug that inhibits platelet aggregation by irreversibly blocking the P2Y12 ADP receptor on platelets. Clopidogrel is used to prevent thrombotic cardiovascular and cerebrovascular events, especially in patients with atherosclerosis, acute coronary syndrome (ACS), recent myocardial infarction (MI), stroke, or peripheral arterial disease (PAD).

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Brand Names

• Plavix® (original brand by Sanofi/Bristol-Myers Squibb)

• Clopilet®, Deplatt®, Clovix®, Clovasca®, and other generics

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Drug Class

• Antiplatelet

• P2Y12 receptor inhibitor

• Thienopyridine derivative

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Mechanism of Action

Clopidogrel is a prodrug that requires hepatic biotransformation via cytochrome P450 (mainly CYP2C19) to its active thiol metabolite. Once activated, it:

• Irreversibly inhibits the P2Y12 subtype of ADP receptor on platelet surfaces

• This prevents ADP-mediated activation of glycoprotein IIb/IIIa complex

• Ultimately, it reduces platelet aggregation for the lifespan of the platelet (~7–10 days)

The onset of action begins within 2 hours, with maximum inhibition in 3–7 days (faster with loading dose).

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Therapeutic Indications

Clopidogrel is indicated in:

Cardiovascular Disease Prevention

• Recent myocardial infarction (MI)

• Recent ischemic stroke

• Established peripheral arterial disease (PAD)

Acute Coronary Syndrome (ACS)

• Non-ST elevation ACS (NSTEMI, UA): with aspirin

• ST-elevation MI (STEMI): with aspirin ± thrombolytic

• Post-percutaneous coronary intervention (PCI): with aspirin to prevent stent thrombosis

Atrial Fibrillation (AF)

• In patients unsuitable for oral anticoagulants, clopidogrel plus aspirin may be used

Other Uses

• Carotid artery stenting

• Off-label in certain coronary or cerebral revascularization procedures

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Dosing and Administration

Standard Dose for Secondary Prevention

• 75 mg once daily without a loading dose

ACS or PCI with Stenting

• Loading dose: 300–600 mg orally once

• Maintenance: 75 mg daily thereafter

• Often combined with aspirin (75–100 mg/day) as dual antiplatelet therapy (DAPT)

Duration of Therapy

• Post-PCI with bare-metal stent: ≥1 month

• Post-PCI with drug-eluting stent: ≥6 months (can be extended)

• ACS without stenting: typically 12 months

• Duration may vary based on risk factors for bleeding or thrombosis

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Pharmacokinetics

• Absorption: Rapid and complete

• Activation: Hepatic metabolism via CYP2C19, CYP3A4, CYP2B6, CYP1A2

• Onset: 2 hours (with loading), 3–7 days (without)

• Half-life: ~6 hours (active metabolite is short-lived)

• Excretion: Urine (50%), feces (46%)

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Genetic Polymorphism (CYP2C19)

Patients with reduced-function CYP2C19 alleles (e.g., *2 or *3) may have decreased clopidogrel activation, leading to:

• Lower platelet inhibition

• Increased risk of CV events

FDA boxed warning: Suggests genetic testing in high-risk patients

Alternatives like prasugrel or ticagrelor may be preferred in poor metabolizers.

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Contraindications

• Active bleeding (e.g., peptic ulcer, intracranial hemorrhage)

• Known hypersensitivity to clopidogrel

• Severe liver impairment

• Bleeding disorders

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Precautions

• Surgery: Stop 5–7 days before major surgery if bleeding risk outweighs thrombosis risk

• Stroke or TIA history: Avoid combination with prasugrel

• Thrombotic thrombocytopenic purpura (TTP): Rare but life-threatening

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Side Effects

Common

• Bleeding: epistaxis, bruising, GI bleeding

• Dyspepsia

• Abdominal pain

• Rash

• Diarrhea

Less Common / Serious

• Thrombocytopenia

• Leukopenia

• Liver enzyme elevation

• Severe bleeding (e.g., intracranial, retroperitoneal)

• TTP: thrombocytopenia, hemolytic anemia, fever, renal dysfunction, neurologic changes

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Drug Interactions

• Proton pump inhibitors (PPIs): Omeprazole and esomeprazole may inhibit CYP2C19 → reduce clopidogrel efficacy

  • Use pantoprazole or lansoprazole instead

• NSAIDs, SSRIs, SNRIs: ↑ risk of GI bleeding

• Warfarin/DOACs: ↑ bleeding risk

• Rifampicin: Induces CYP enzymes → ↓ clopidogrel activity

• Fluoxetine, fluvoxamine: CYP2C19 inhibitors

• Repaglinide: clopidogrel increases plasma levels, risk of hypoglycemia

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Pregnancy and Lactation

Pregnancy

• Category B (U.S. FDA): No evidence of harm in animals, but insufficient human data

• Use only if clearly needed

Lactation

• Unknown if excreted in breast milk

• Use with caution or consider alternatives

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Monitoring

• No routine lab monitoring required

• Assess bleeding risk, hemoglobin, platelet counts

• Monitor for signs of bleeding or hematologic toxicity

• Platelet function testing or CYP2C19 genotyping in select populations

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Alternatives and Comparisons

• Aspirin: Irreversible COX-1 inhibitor, often used in combo with clopidogrel

• Ticagrelor: Reversible, faster onset, not a prodrug, better CV outcomes in ACS

• Prasugrel: Prodrug like clopidogrel, more potent but higher bleeding risk

• Cangrelor: IV P2Y12 inhibitor used peri-procedurally

Clopidogrel is less potent but lower bleeding risk than prasugrel/ticagrelor, making it suitable for elderly, low-weight, or high-bleeding-risk patients.

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Patient Counseling

• Take daily at the same time, with or without food

• Do not stop suddenly, especially post-stent

• Report signs of bleeding: black stools, prolonged bruising, unusual nosebleeds

• Avoid NSAIDs unless approved

• Inform dentist or surgeon before any procedures

• Avoid alcohol, which increases bleeding risk

• Carry a medical alert card noting clopidogrel use