P2Y12 Inhibitors

P2Y12 inhibitors block the platelet ADP receptor P2Y12, preventing the amplification of platelet activation and the conformational change of glycoprotein IIb/IIIa that allows aggregation. Combined with aspirin they form dual antiplatelet therapy, the basis of treatment after acute coronary syndrome and coronary stenting. Used alone, clopidogrel is an option for long-term secondary prevention after stroke, myocardial infarction and in peripheral artery disease.

Members. Clopidogrel, prasugrel and ticlopidine (thienopyridines, irreversible); ticagrelor (cyclopentyltriazolopyrimidine, reversible); cangrelor (intravenous, reversible).

Mechanism. Thienopyridines are prodrugs whose active metabolites bind covalently to P2Y12 for the life of the platelet (7 to 10 days). Ticagrelor and cangrelor are active drugs that bind reversibly. Ticagrelor also inhibits adenosine reuptake, which explains dyspnoea and bradycardia.

Pharmacokinetics. Clopidogrel needs two-step activation, mainly by CYP2C19, so loss-of-function alleles (carried by a large share of people of Asian ancestry and a smaller share of people of African ancestry) lower response. Onset is 2 to 6 hours with a 300 to 600 mg load. Prasugrel is activated in one step with onset within 30 minutes. Ticagrelor acts within 30 minutes with a half-life of about 7 to 9 hours, so it is given twice daily. Cangrelor acts within 2 minutes, with recovery of platelet function within 1 hour.

• Clopidogrel: least potent and most variable; the only drug with evidence in stroke and peripheral artery disease alone; low cost and widely available.
• Prasugrel: more potent and predictable than clopidogrel; used after angiography in acute coronary syndrome managed with stenting; higher bleeding risk.
• Ticagrelor: potent and reversible; used in acute coronary syndrome managed with or without stenting; dyspnoea in 10% to 15%.
• Cangrelor: intravenous bridging when oral absorption is uncertain, for example in an intubated patient or before surgery.
• Ticlopidine: obsolete because of neutropenia and thrombotic thrombocytopenic purpura.

• Acute coronary syndrome: ticagrelor 180 mg load then 90 mg twice daily, or prasugrel 60 mg load then 10 mg daily (5 mg if under 60 kg or over 75 years), or clopidogrel 300 to 600 mg load then 75 mg daily. Continue with aspirin 75 to 100 mg daily for 12 months, then single therapy.
• Elective stenting: clopidogrel 300 to 600 mg load then 75 mg daily, with aspirin for 6 months, or 1 to 3 months in high bleeding risk.
• STEMI treated with thrombolysis: clopidogrel 300 mg (75 mg if over 75 years) then 75 mg daily.
• Minor ischaemic stroke or high-risk transient ischaemic attack: clopidogrel 300 mg load then 75 mg daily with aspirin for 21 days, then clopidogrel or aspirin alone.
• Peripheral artery disease and long-term secondary prevention: clopidogrel 75 mg daily.
• Cangrelor: 30 micrograms/kg bolus, then 4 micrograms/kg/minute for at least 2 hours or the length of the procedure.
• Selection: use ticagrelor or prasugrel in acute coronary syndrome when available and bleeding risk allows. Clopidogrel when cost or supply limit access, bleeding risk is high, an oral anticoagulant is also needed, or stroke is the indication.
• Switching: moving from clopidogrel to a more potent drug in the first month is safe with a loading dose. Moving to clopidogrel (de-escalation) after the first 1 to 3 months is used to cut bleeding.

Contraindications. Active bleeding, history of intracranial haemorrhage, severe hepatic impairment, and hypersensitivity. Prasugrel is also contraindicated after stroke or transient ischaemic attack. Ticagrelor is also avoided with strong CYP3A4 inhibitors or inducers and in bradyarrhythmia without a pacemaker.

Adverse effects. Bleeding, bruising, dyspnoea and ventricular pauses (ticagrelor), raised uric acid and creatinine (ticagrelor), rash, diarrhoea, and rarely thrombotic thrombocytopenic purpura (clopidogrel, ticlopidine).

Interactions. Omeprazole and esomeprazole reduce clopidogrel activation; pantoprazole is preferred. Anticoagulants, NSAIDs and SSRIs raise bleeding risk. Ketoconazole, itraconazole, clarithromycin, ritonavir (raise ticagrelor), and rifampicin, carbamazepine, phenytoin (lower ticagrelor). Ticagrelor raises simvastatin and lovastatin levels, with simvastatin limited to 40 mg daily. Morphine delays absorption of oral P2Y12 inhibitors.

Peri-procedural stopping. Clopidogrel 5 days, ticagrelor 3 to 5 days and prasugrel 7 days before elective surgery, with cardiology advice if a stent was placed in the past 6 to 12 months.

Management of bleeding. Stop the drug and give local measures and tranexamic acid. Platelet transfusion helps with thienopyridines but is less effective for ticagrelor while active drug is present.

Monitoring. Haemoglobin, platelets, signs of bleeding, adherence, and for ticagrelor symptoms of dyspnoea and heart rate.

Referral and escalation. Bleeding that is major, recurrent ischaemic events, or any request to stop therapy within the first months after stenting needs cardiology advice.

Special groups. Older adults and low body weight: prefer clopidogrel or reduced-dose prasugrel. Pregnancy and breastfeeding: avoid unless essential. Kidney disease: higher bleeding risk, no dose change. CYP2C19 loss-of-function carriers: ticagrelor or prasugrel perform better than clopidogrel where available.