Ticagrelor

Ticagrelor is an oral P2Y12 receptor antagonist that binds reversibly and does not need metabolic activation. It acts faster than clopidogrel and lowers cardiovascular death, myocardial infarction and stent thrombosis in acute coronary syndrome. It causes dyspnoea and bradyarrhythmias and has important interactions. It is expensive and limited in East Africa.

Classification. Antiplatelet; cyclopentyltriazolopyrimidine P2Y12 inhibitor (reversible).

Mechanism. Binds the platelet P2Y12 receptor at a site separate from ADP, causing a conformational change that blocks signalling. It also raises extracellular adenosine by blocking its uptake, which explains dyspnoea and some bradycardia.

Pharmacodynamics. Onset within 30 minutes of 180 mg; peak at 2 hours. Platelet function recovers within 3 to 5 days after stopping. More consistent than clopidogrel.

Pharmacokinetics. Bioavailability about 36%; food has little effect. Half life 7 hours (the active metabolite 9 hours). Metabolised by CYP3A4 to an active metabolite; excreted mainly in bile and faeces. A weak inhibitor of CYP3A4 and P-glycoprotein.

Acute coronary syndrome (with aspirin), adult.

• Loading 180 mg.

• Then 90 mg twice daily for 12 months.

• After 12 months in patients with a prior myocardial infarction and high risk, 60 mg twice daily for up to 3 years.

• Keep the aspirin dose at 75 to 100 mg daily; higher doses reduce benefit.

Minor ischaemic stroke or high risk transient ischaemic attack (with aspirin), adult. Loading 180 mg, then 90 mg twice daily for 30 days.

Chronic coronary disease with diabetes and previous stent (specialist). 60 mg twice daily with aspirin.

Children. Not established.

Contraindications. Active pathological bleeding; previous intracranial haemorrhage; moderate to severe hepatic impairment; concurrent strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir) or inducers (rifampicin, carbamazepine, phenytoin); hypersensitivity.

Warnings. Bleeding; dyspnoea (in about 14%, usually mild and within the first week); bradyarrhythmia and ventricular pauses (sick sinus syndrome, second or third degree block without a pacemaker); raised uric acid and creatinine; central sleep apnoea; stop 5 days before surgery. Not for use in those with prior intracranial haemorrhage.

Adverse effects. Dyspnoea, bleeding, bruising, epistaxis, bradycardia, ventricular pauses, raised creatinine and uric acid, gastrointestinal upset, headache, dizziness.

Interactions. Strong CYP3A4 inhibitors and inducers: contraindicated. Moderate CYP3A4 inhibitors (diltiazem): modest rise. Simvastatin and lovastatin: limit to 40 mg daily. Digoxin: monitor levels. Ciclosporin: raised levels. Anticoagulants, non steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors: bleeding. Aspirin above 100 mg daily: reduced efficacy.

Special groups.

• Pregnancy: avoid; no data.

• Breastfeeding: no data; avoid.

• Patients of African ancestry: no dose change.

• Older adults: no adjustment; bleeding risk is higher.

• Kidney impairment: no adjustment; monitor creatinine because of the rise after starting.

• Liver impairment: mild: no change; moderate to severe: avoid.

Formulations. Tablets 60 and 90 mg.

Administration. Oral twice daily with or without food. Tablets can be crushed and given by nasogastric tube.

Baseline. Haemoglobin, platelet count, creatinine, uric acid, liver function, ECG for conduction disease, drug history for CYP3A4 interactions.

Monitoring. Bleeding; dyspnoea; heart rate; creatinine and uric acid at 1 month; adherence (twice daily dosing).

Stopping. Do not stop within 12 months of an acute coronary event or stent without cardiology advice. Stop 5 days before elective surgery when safe.

Common prescribing errors. Giving aspirin above 100 mg daily; combining with clarithromycin or ketoconazole; using in prior intracranial haemorrhage; missing the second daily dose; stopping early because of mild dyspnoea.