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Drug Reference

ticagrelor

Antiplatelet agent (P2Y12 receptor antagonist)· Brands: Brilinta, BriliquePO

Mechanism of action
Ticagrelor is a cyclopentyltriazolopyrimidine that directly and reversibly inhibits the platelet P2Y12 ADP receptor. Unlike clopidogrel and prasugrel it is an active drug and does not need hepatic bioactivation, so onset is faster and the antiplatelet effect is less variable between patients. Blocking P2Y12 prevents ADP from inhibiting adenylyl cyclase through the Gi pathway, which raises intracellular cyclic AMP and reduces activation of the glycoprotein IIb/IIIa receptor, so platelet activation, degranulation and aggregation are suppressed. Inhibition is reversible, so offset of effect depends on drug clearance rather than on platelet turnover. A circulating active metabolite formed by CYP3A contributes roughly a third of total activity. Ticagrelor also inhibits the equilibrative nucleoside transporter ENT1, reducing cellular reuptake of adenosine; the resulting rise in extracellular adenosine is thought to explain much of the drug-specific dyspnoea and possibly some of its clinical benefit. Platelet inhibition is greater and more consistent than with standard-dose clopidogrel.
Pharmacokinetics
Ticagrelor is given orally and absorbed rapidly, with peak plasma concentration about 1.5 hours after a dose. Food does not meaningfully affect absorption, and tablets may be crushed and given by nasogastric tube when swallowing is not possible. Bioavailability is about one third and plasma protein binding is high. It is metabolised mainly by CYP3A4 and CYP3A5 to an active metabolite of similar potency that reaches roughly a third to a half of parent exposure. Parent drug and metabolite are substrates of CYP3A4 and P-glycoprotein, so strong CYP3A4 inhibitors markedly raise exposure and strong inducers lower it. Elimination half-lives are about 7 hours for the parent and 9 hours for the metabolite, which supports twice-daily dosing; loss of antiplatelet effect takes about 3 to 5 days after stopping. Elimination is mainly biliary and faecal, with some renal excretion of metabolites. Mild hepatic impairment needs no adjustment, but the drug is contraindicated in severe hepatic impairment. Renal impairment, including dialysis, generally needs no dose adjustment, although experience in severe renal impairment is limited.
Indications & dosing

Acute coronary syndrome (unstable angina, NSTEMI or STEMI)

Loading dose 180 mg once, then 90 mg twice daily, usually with aspirin. Duration depends on presentation, revascularisation and bleeding risk; follow local protocols.

  • adult · PO: 90–180 mg once then BD · Loading dose 180 mg once, then 90 mg twice daily, usually with aspirin. Duration depends on presentation, revascularisation and bleeding risk; follow local protocols.

History of myocardial infarction (secondary prevention, at least 1 year after event)

For patients with prior MI and high ischaemic risk, usually with aspirin 75 to 100 mg daily. Some regimens use 90 mg twice daily; check local formulary.

  • adult · PO: 60 mg BD · For patients with prior MI and high ischaemic risk, usually with aspirin 75 to 100 mg daily. Some regimens use 90 mg twice daily; check local formulary.
Contraindications & precautions
  • Active pathological bleeding · Includes GI bleeding, intracranial bleeding and any current major haemorrhage. Ticagrelor is a reversible P2Y12 inhibitor and will worsen bleeding immediately.
  • History of intracranial haemorrhage · Prior spontaneous or traumatic intracranial bleed carries a high risk of recurrence with any potent antiplatelet.
  • Severe hepatic impairment · Contraindicated in the EU/UK SmPC because of limited data and expected greater exposure. US labelling advises caution rather than contraindication: check the local label and formulary.
  • Hypersensitivity to ticagrelor or any excipient · Rash and, rarely, angioedema have been reported. Avoid re-exposure if a true hypersensitivity reaction occurred.
  • Concomitant strong CYP3A4 inhibitors · Ketoconazole, clarithromycin, ritonavir and similar agents markedly increase ticagrelor exposure and bleeding risk. This is a contraindication in the EU/UK SmPC; avoid where possible and check local guidance.
  • Maintenance aspirin dose greater than 100 mg daily · Aspirin doses above 100 mg daily are not recommended with ticagrelor because they increase bleeding without added efficacy. Reduce the aspirin dose or choose another antiplatelet strategy.
  • Assess bleeding risk before starting and avoid use in active bleeding or very high bleeding risk. Keep aspirin at 100 mg daily or less and consider gastroprotection in patients with peptic ulcer disease or other GI risk factors.
  • Dyspnoea usually starts early, is mild to moderate and often settles on continued treatment. Exclude heart failure, pulmonary embolism, pneumonia or bronchospasm before attributing it to the drug.
  • Stop ticagrelor 5 days before planned surgery in most guidance, and restart only when haemostasis is secure. Do not stop prematurely after acute coronary syndrome or recent stent insertion without specialist advice.
  • Avoid strong CYP3A4 inhibitors and consider dose limits for simvastatin and atorvastatin. Monitor digoxin and ciclosporin concentrations when co-prescribed. Strong CYP3A4 inducers reduce ticagrelor exposure and may reduce efficacy.
  • Use caution with drugs that slow the heart rate, such as beta-blockers, diltiazem and verapamil, and avoid in second or third degree AV block or sick sinus syndrome without a pacemaker.
  • Serum uric acid rises with treatment: monitor and take care in patients with a history of gout or hyperuricaemia, and check renal function and urine output during therapy.
Adverse effects
  • Bleeding (including bruising, epistaxis, major and minor haemorrhage)serious
  • Dyspnoea
  • Gastrointestinal haemorrhageserious
  • Intracranial haemorrhageserious
  • Raised serum uric acid
  • Gout
  • Bradycardia and ventricular pauses
  • Headache and dizziness
  • Nausea and diarrhoea
  • Thrombotic thrombocytopenic purpuraserious
Interactions
  • simvastatinmajorAvoid concomitant use, or if deemed necessary, limit the simvastatin dose to a maximum of 40 mg daily. Alternatively, consider a statin that is not extensively metabolised by CYP3A4, such as pravastatin or rosuvastatin. Monitor patients for symptoms of myopathy and check creatine kinase levels if symptoms develop.
  • aspirinmajorUse the combination only when indicated, such as in acute coronary syndromes or after stent placement. Monitor patients closely for signs of bleeding, including occult blood loss. Consider gastroprotective strategies such as proton pump inhibitors in patients at higher risk. Review the need for continued dual therapy at regular intervals.
Renal & hepatic adjustment
  • Hepatic impairment (mild): No dose adjustment required. Use standard dosing but monitor for bleeding.
  • Hepatic impairment (moderate): No dose adjustment required. Use standard dosing but monitor for bleeding.
  • Hepatic impairment (severe): Contraindicated. Ticagrelor is not recommended in severe hepatic impairment because of increased exposure and bleeding risk. (avoid)
Monitoring, pregnancy & toxicity
  • Signs and symptoms of bleeding · At each clinical review and if bleeding is suspected
  • Haemoglobin and haematocrit · Baseline and if bleeding is suspected or clinically indicated
  • Renal function (eGFR or creatinine) · Baseline and periodically in patients with chronic kidney disease or those at risk
  • Uric acid · Baseline and if gout symptoms develop, as ticagrelor can increase uric acid
  • Dyspnoea · At each review; assess if new or worsening, as ticagrelor commonly causes dyspnoea
  • Heart rate and symptoms of bradyarrhythmia · At each review, especially in patients with sick sinus syndrome or AV block
  • Pregnancy: Ticagrelor is not recommended during pregnancy. Data are limited. Use only if the clinical need clearly outweighs the risk, and involve cardiology and obstetric specialists. If antiplatelet therapy is needed during pregnancy, an alternative agent such as aspirin or clopidogrel may be preferred depending on the indication and local guidance.
  • Toxicity: Bleeding, including epistaxis, bruising, gastrointestinal haemorrhage, haematuria, or intracranial haemorrhage. · Stop ticagrelor. Provide supportive care, monitor haemodynamics and haemoglobin, and transfuse blood products or platelets as clinically indicated. There is no specific antidote. Platelet transfusion may be considered but its effectiveness is uncertain because ticagrelor is reversible and has a short half-life.
  • Toxicity: Dyspnoea, which may be reported as breathlessness without hypoxia or bronchospasm. · Assess for other causes. If dyspnoea is severe or troublesome, consider stopping ticagrelor and switching to an alternative P2Y12 inhibitor in consultation with the treating team.
  • Toxicity: Bradycardia or vasovagal-like symptoms, including syncope. · Monitor heart rate and blood pressure. Manage symptomatically, and consider alternate antiplatelet therapy if recurrent or symptomatic.
  • Toxicity: Overdose may prolong bleeding time and increase haemorrhagic risk. · There is no antidote. Treatment is supportive. Consider activated charcoal if ingestion is recent and airway is protected. Monitor for bleeding and provide transfusion support as needed. Dialysis is unlikely to be effective because ticagrelor is highly protein bound.
Clinical notes
Ticagrelor is used with low-dose aspirin in acute coronary syndrome and after myocardial infarction, and for secondary prevention in high-risk patients with a previous myocardial infarction. Typical teaching doses are a 180 mg loading dose then 90 mg twice daily for up to 12 months; a 60 mg twice-daily maintenance dose is used for longer-term secondary prevention in selected patients. Always check local protocols, because licensed indications, dose and duration vary between regions and formularies, and the choice between ticagrelor, prasugrel and clopidogrel is often set by local pathways and bleeding-risk assessment. Bleeding is the main hazard, so it is contraindicated in active bleeding, a history of intracranial haemorrhage and severe hepatic impairment, and is avoided in patients at high bleeding risk. Dyspnoea, often occurring early and sometimes settling on continued treatment, is relatively common and adenosine-mediated, but it must still be assessed because it can also signal cardiac or pulmonary disease. Bradyarrhythmias, raised uric acid and gout flares are recognised. Stop at least 5 days before surgery where clinically possible. Avoid strong CYP3A4 inhibitors and inducers, avoid daily aspirin above about 100 mg, and review statins and other drugs that increase bleeding risk.

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BNF; local formulary; current summary of product characteristics or prescribing information