Prasugrel

Effient (Eli Lilly)
5 mg and 10 mg tablets
Approved indication: recurrent myocardial infarction
Australian Medicines Handbook section 7.2.2

Patients with myocardial infarction are at high risk of recurrence. Dual antiplatelet therapy, such as aspirin and clopidogrel, has been shown to reduce this risk.

Prasugrel, an adenosine diphosphate receptor antagonist of the thienopyridine class, is a new antiplatelet drug. It works by inhibiting platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y₁₂ receptor on platelets. After oral administration, prasugrel is metabolised mainly by cytochrome P450 3A4 and 2B6. Its elimination half-life is 7.4 hours with the majority of the dose being excreted in the urine.

In a pharmacodynamic study of patients with acute coronary syndrome, prasugrel (60 mg loading dose, then 10 mg daily) was found to be a more potent inhibitor of platelet aggregation than clopidogrel (600 mg loading dose then 150 mg daily) in ex vivo blood tests.¹

The approval of prasugrel is based on a comparative trial with clopidogrel in 13 608 patients. These people had acute coronary syndrome (10 074 with unstable angina or non-ST-elevation myocardial infarction and 3534 with ST-elevation myocardial infarction) and nearly all of them were undergoing percutaneous coronary intervention. Both prasugrel (60 mg loading dose, then 10 mg daily) and clopidogrel (300 mg loading dose then 75 mg daily) were given in conjunction with aspirin (75-162 mg). The median duration of treatment was 14.5 months. The primary end point was a composite of cardiovascular death, non-fatal myocardial infarction or stroke. Significantly fewer patients receiving prasugrel had a cardiovascular event compared to those receiving clopidogrel (9.9% vs 12.1%). This was mostly due to the reduced incidence of myocardial infarction. Rates of stroke and death from cardiovascular causes not involving myocardial infarction were similar between groups. There were also significant reductions in the rates of stent thrombosis and urgent target-vessel revascularisation procedures with prasugrel. In the 3146 people with diabetes, less patients in the prasugrel group had a cardiovascular event than in the clopidogrel group (12.2% vs 17%).²

Obviously with antiplatelet drugs there is a risk of bleeding. The incidence of major haemorrhage in the trial was greater with prasugrel than with clopidogrel (2.4% vs 1.8%). This was fatal for 21 (0.4%) patients taking prasugrel and 5 (0.1%) patients taking clopidogrel. A post hoc analysis of harm versus benefit (based on bleeding and cardiovascular events) found that certain groups of patients did not benefit from prasugrel treatment. This included patients aged 75 or older and those weighing less than 60 kg. Prasugrel is not generally recommended for patients over 75 years but if the doctor decides it would benefit the patient, a lower maintenance dose (5 mg) is advised. Similarly, a lower maintenance dose is recommended if prasugrel is given to patients weighing less than 60 kg. Doctors should be aware that there is no evidence for the safety or efficacy of the lower dose of prasugrel. The post hoc analysis found that patients who had had a previous stroke or transient ischaemic attack had net harm and should not be given prasugrel.

Other adverse events included severe thrombocytopenia (0.3%), neutropenia (less than 0.1%) and colonic neoplasms (0.2%). Colonic cancers were reported twice as often with prasugrel than with clopidogrel, possibly because they were more likely to be detected due to the increased bleeding risk.¹

Caution is urged when giving prasugrel to patients who have an increased risk of bleeding. This includes patients taking concomitant drugs, such as oral anticoagulants, non-steroidal anti-inflammatory drugs and fibrinolytics. Care should also be taken in patients who have had recent surgery, recurrent gastrointestinal bleeding or active peptic ulcers. To prevent bleeding complications, prasugrel should be stopped at least seven days before elective surgery. Premature discontinuation of prasugrel can increase the risk of thrombosis, myocardial infarction and death so in this situation patients should be monitored for cardiac events. It is contraindicated in patients with severe hepatic impairment.

Although prasugrel is metabolised by CYP3A4 it can be used concomitantly with other drugs metabolised by this pathway, such as the statins. It can also be given with digoxin, proton pump inhibitors and H₂ blockers. As prasugrel is a weak inhibitor of CYP2B6, a clinically significant effect may be seen when it is co-administered with drugs that are solely metabolised by CYP2B6 and have a narrow therapeutic window (such as cyclophosphamide or efavirenz).

When used with aspirin, prasugrel provides an alternative to other antiplatelet drugs for preventing atherothrombotic events in some patients with acute coronary syndrome who are undergoing percutaneous coronary intervention. However, there are only short-term clinical data for this drug (up to 15 months). Prasugrel appears to have more potent antiplatelet effects than clopidogrel so the risk of bleeding is higher.

manufacturer provided additional useful information

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

Note on references

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).