Clopidogrel

Clopidogrel is an oral P2Y12 receptor antagonist given as a prodrug. It is used after acute coronary syndrome, after coronary stenting, after ischaemic stroke or transient ischaemic attack, and in peripheral artery disease, usually with aspirin for a limited time. It needs activation by CYP2C19, so reduced function alleles and interacting drugs lower its effect. It is available in most East African hospitals and is cheaper than newer agents.

Classification. Antiplatelet; thienopyridine P2Y12 inhibitor (irreversible).

Mechanism. The active thiol metabolite binds irreversibly to the platelet P2Y12 receptor, blocking ADP induced platelet activation and aggregation for the life of the platelet.

Pharmacodynamics. Onset 2 to 6 hours after a 300 mg dose and within 2 hours after 600 mg; steady state inhibition after 3 to 7 days of 75 mg. Platelet function recovers over 5 to 7 days after stopping. Response varies between patients.

Pharmacokinetics. Absorbed to about 50%; about 85% is hydrolysed to an inactive acid, and 15% is converted by CYP2C19 (and CYP3A4, CYP1A2, CYP2B6) to the active metabolite. Half life of the parent 6 hours and the active metabolite 30 minutes (irreversible effect). Excreted in urine (50%) and faeces (46%).

Acute coronary syndrome (with aspirin), adult.

• Loading 300 mg (600 mg when planning percutaneous coronary intervention).

• Then 75 mg once daily for up to 12 months (6 months after a drug eluting stent in stable disease).

• With fibrinolysis for ST elevation myocardial infarction in patients 75 years or younger: 300 mg loading; older than 75 years: 75 mg loading, then 75 mg daily.

Secondary prevention after recent myocardial infarction, ischaemic stroke or established peripheral artery disease, adult. 75 mg once daily.

Minor ischaemic stroke or high risk transient ischaemic attack (with aspirin), adult. Loading 300 mg, then 75 mg daily with aspirin for 21 days; then 75 mg alone.

Atrial fibrillation unsuitable for anticoagulation (with aspirin), adult. 75 mg once daily; bleeding risk is high.

Children (specialist). 0.2 mg/kg once daily for stent or shunt protection.

Contraindications. Active bleeding (peptic ulcer, intracranial haemorrhage); severe hepatic impairment; hypersensitivity; concurrent omeprazole or esomeprazole (reduced effect).

Warnings. Bleeding; thrombotic thrombocytopenic purpura (rare, within 2 weeks; stop and seek urgent help); reduced response in CYP2C19 poor metabolisers (and in some patients with diabetes, obesity or kidney impairment); stop 5 to 7 days before elective surgery; premature stopping after stenting risks stent thrombosis. Cross reaction with other thienopyridines.

Adverse effects. Bleeding, bruising, epistaxis, gastrointestinal bleeding, dyspepsia, diarrhoea, rash, rarely thrombotic thrombocytopenic purpura or neutropenia.

Interactions. Omeprazole and esomeprazole: reduce activation (use pantoprazole). Warfarin, direct oral anticoagulants, aspirin and other non steroidal anti-inflammatory drugs: bleeding. CYP2C19 inhibitors (fluconazole, voriconazole, fluoxetine, fluvoxamine, ticlopidine, chloramphenicol): reduced effect. CYP2C19 inducers (rifampicin, carbamazepine): increased bleeding. Repaglinide and paclitaxel: raised levels (CYP2C8). Opioids (morphine): delay absorption. Selective serotonin reuptake inhibitors: bleeding.

Special groups.

• Pregnancy: avoid unless essential; limited data.

• Breastfeeding: no data; avoid.

• Patients of African ancestry: CYP2C19 loss of function alleles are present in a minority; consider an alternative if a stent thrombosis or recurrent event occurs.

• Older adults: 75 mg; lower loading dose with fibrinolysis in those over 75 years.

• Kidney impairment: no adjustment; limited experience in severe disease.

• Liver impairment: use with care; avoid in severe disease (bleeding).

Formulations. Tablets 75 and 300 mg.

Administration. Oral once daily with or without food. For loading, swallow whole tablets.

Baseline. Haemoglobin, platelet count, creatinine, liver function, history of bleeding, drug history for omeprazole and CYP2C19 inhibitors.

Monitoring. Signs of bleeding; haemoglobin and platelets at 1 month and with any symptoms; adherence (especially in the first year after stenting). Fever, bruising, neurological change or kidney injury in the first weeks: check for thrombotic thrombocytopenic purpura.

Stopping. Do not stop within 6 to 12 months of a stent without cardiology advice. Stop 5 to 7 days before elective surgery when safe.

Common prescribing errors. Prescribing omeprazole or esomeprazole with it; stopping early after stenting; omitting a loading dose in acute coronary syndrome; combining with a direct oral anticoagulant and aspirin for longer than needed; missing a CYP2C19 inhibitor such as fluconazole.