Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Brilinta (AstraZeneca)
90 mg tablets
Approved indication: prevention of atherothrombotic events in acute coronary syndrome
Australian Medicines Handbook section 7.2.3

Approximately one third of patients with acute coronary syndrome die, have another myocardial infarction or are rehospitalised within six months. Drugs that inhibit platelet aggregation such as clopidogrel can reduce this risk. Similar to clopidogrel, ticagrelor inhibits blood clotting by directly blocking the P2Y12 adenosine diphosphate receptor on platelets. However unlike clopidogrel, this interaction is direct and reversible. Ticagrelor has a rapid onset of action – almost 90% of platelet aggregation is inhibited within 2–4 hours of a 180 mg loading dose.

The approval of ticagrelor is mainly based on a phase III multicentre (42 countries) comparative trial with clopidogrel (PLATelet inhibition and patient Outcomes – PLATO trial). 1 In the study, 18 624 patients who had been hospitalised for an acute coronary syndrome with or without ST-segment elevation were randomised to receive ticagrelor (180 mg loading dose, if treatment-naïve, then 90 mg twice daily) or clopidogrel (300 mg loading dose, if treatment-naïve, then 75 mg daily). All patients were given concomitant aspirin 75–100 mg. Variations in drug doses were allowed depending on the patient's medications before the trial and on what coronary procedure they were having. After 12 months, the composite outcome of cardiovascular death, myocardial infarction or stroke occurred less with ticagrelor than with clopidogrel (9.8% vs 11.7%, p 1

Although ticagrelor was significantly more effective than clopidogrel in the trial, its efficacy varied between countries. In Canada (401 patients), the USA (1413 patients) and Australia (83 patients), clopidogrel was more effective than ticagrelor (hazard ratios 1.17, 1.27 and 2.45), whereas in countries such as Poland (2666 patients) and the Czech Republic (1021 patients) ticagrelor was favoured (hazard ratios 0.69 and 0.84). 2

As with other antiplatelet drugs, bleeding is a risk and patients with an increased risk were excluded from the trial. Despite this, the rates of major bleeding were high, but similar for ticagrelor and clopidogrel (11.6% vs 11.2%). The number of major bleeds not associated with coronary artery bypass grafting was slightly higher for ticagrelor than clopidogrel (4.5% vs 3.8%, p=0.03). There were also more intracranial bleeds with ticagrelor – 11 bleeds were fatal with ticagrelor versus 1 bleed with clopidogrel. 1

Ticagrelor is therefore contraindicated if a patient is bleeding or has a history of intracranial bleeding. It should not be given with drugs that may increase bleeding such as clopidogrel and should be used cautiously with non-steroidal anti-inflammatory drugs. Ticagrelor should be stopped five days before elective surgery.

Other adverse effects of ticagrelor include dyspnoea (13.8% of patients), headache (6.5%) and nosebleeds (6%). In the ticagrelor group, 0.8% of patients withdrew because of dyspnoea and 0.4% because of a nosebleed. Patients with asthma or chronic obstructive pulmonary disorder have an increased risk of dyspnoea. There were significantly more discontinuations due to adverse effects with ticagrelor than with clopidogrel (7.4% vs 6.0%). 1

Creatinine elevations were observed in some patients so monitoring of renal function is recommended particularly in patients over 75 years, those with moderate or severe renal impairment or patients taking angiotensin II receptor blockers. Ticagrelor is not recommended for patients on renal dialysis. As increases in uric acid have occurred with ticagrelor, caution is urged in patients with a history of hyperuricaemia. Ticagrelor is discouraged in patients with uric acid nephropathy.

Caution is recommended in patients with an increased risk of bradycardia as these people were excluded from the trial. Ventricular pauses of three or more seconds (detected during Holter monitoring) were more common in the ticagrelor group than the clopidogrel group in the first week of the trial. 1 These were more common in patients with congestive heart failure but were rarely associated with clinical symptoms.

Oral ticagrelor is rapidly absorbed. After metabolism in the liver, ticagrelor is eliminated mainly by biliary excretion. It is contraindicated in moderate to severe hepatic impairment.

As ticagrelor is a substrate for cytochrome P450 3A4, it has the potential to interact with other drugs metabolised by this enzyme such as ketoconazole and diltiazem. Ticagrelor increases concentrations of simvastatin and atorvastatin, so patients may be at increased risk of adverse effects. Ticagrelor is also a substrate for P-glycoprotein and increases the levels of drugs such as digoxin and cyclosporin.

Overall, ticagrelor plus aspirin prevented more myocardial infarctions and cardiovascular deaths (but not strokes) than clopidogrel plus aspirin, without increasing the bleeding risk. However in some countries participating in the trial, including Australia, clopidogrel was more effective than ticagrelor. The reason for this discrepancy is not clear. The safety of ticagrelor use beyond one year is not currently known.

manufacturer provided the product information

The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.