The new antiplatelet agent, prasugrel (Lilly/Daiichi Sankyo), has been approved in the European Union for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI).
This follows a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency at the end of last year.
Prasugrel, which will be marketed in Europe as Efient“, will be the first major competitor to clopidogrel, which has a much broader range of indications and is one of the world’s best selling pharmaceuticals. Prasugrel is a more potent antiplatelet agent than clopidogrel and is not thought to be associated with so much variability as clopidogrel.
The increased antiplatelet potency of prasugrel would be expected to translate into a higher efficacy in preventing ischaemic events, but also a higher risk of bleeding.
This is exactly what was seen in the large-scale TRITON-TIMI 38 trial, on which the approval of prasugrel is based.
In the trial, which was conducted in 13,608 moderate-to-high-risk ACS patients scheduled for PCI, prasugrel given at a 60 mg loading dose followed by a 10 mg daily maintenance dose) was compared to clopidogrel (300 mg loading dose /75 mg maintenance dose). Results showed a significant reduction in the primary end point (cardiovascular death/non-fatal myocardial infarction/non-fatal stroke), but at the expense of a significant increase in major bleeding, life-threatening bleeding, and fatal bleeding.
In the paper, published in 2007 (N Engl J Med 2007;357:2001-15), the TRITON-TIMI 38 authors report that for every 1,000 patients treated with prasugrel as compared with clopidogrel, 23 myocardial infarctions were prevented, with an excess of six non-CABG-related TIMI major bleeds. They concluded that: “When considering the choice of antiplatelet regimens for the treatment of patients with ACS who are undergoing PCI, clinicians need to weigh the benefits and risks of intensive inhibition of platelet aggregation”.
Writing in an accompanying editorial, Dr Deepak Bhatt (Cleveland Clinic, US) suggested that: “Prasugrel would probably benefit patients with ACS who are undergoing PCI and who are at high risk of ischaemic events and low risk for bleeding, although those with a lower risk for ischaemic events and a high risk of bleeding may be better served with clopidogrel”.
In the TRITON-TIMI 38 trial, an increased risk of serious bleeding with prasugrel was seen in certain patient groups; patients who weighed less than 60 kg, patients who were 75 years of age or older and those who had had a prior transient ischaemic attack (TIA) or stroke. Consequently, it is recommended that patients with prior TIA or stroke should not be treated with prasugrel, and the drug is also generally not recommended for use in patients aged 75 years or older; but if it is used in this elderly group, a lower maintenance dose (5 mg) should be used. This lower maintenance dose is also recommended if prasugrel is given to patients who weigh less than 60 kg.
Approval also likely in the US
Prasugrel also received a positive recommendation from the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee in early February for a similar indication, suggesting that US approval will follow shortly. But the FDA advisory committee meeting attracted some controversy when it was revealed that one expert, Dr Sanjay Kaul, an outspoken critic of prasugrel, was dropped from the committee after a phone call to the FDA from Lilly, questioning his inclusion.