The trial was presented here today at the American Heart Association 2007 Scientific Sessions and simultaneously published online in the New England Journal of Medicine. In the paper, the authors, led by Dr Stephen Wiviott (Brigham and Women's Hospital, Boston, MA), note that for every 1000 patients treated with prasugrel as compared with clopidogrel, 23 MIs were prevented, with an excess of six non-CABG-related TIMI major hemorrhages. They conclude: "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."

In an accompanying editorial, Dr Deepak Bhatt (Cleveland Clinic, OH) notes that for each death from cardiovascular causes prevented by prasugrel as compared with clopidogrel, approximately one additional episode of fatal bleeding was caused by prasugrel [2]. He suggests: "Prasugrel would probably benefit patients with ACS who are undergoing PCI and who are at high risk of ischemic events and low risk for bleeding, although those with a lower risk for ischemic events and a high risk of bleeding may be better served with clopidogrel."

Bhatt further points out that among those with a history of stroke or transient ischemic attack (TIA), there was an excess of intracranial hemorrhage with prasugrel; therefore, it should not be used at the dose studied in TRITON-TIMI 38 in patients with known cerebrovascular disease. He concludes: "In carefully selected patients, prasugrel may be an advance in the treatment of patients with ACS who are undergoing PCI, although if the drug should gain regulatory approval, the results of TRITON-TIMI 38 should not be extrapolated to other clinical scenarios in which clopidogrel is currently used."

Commenting on the results for heartwire, Dr Eric Topol (Scripps Translational Science Institute, La Jolla, CA) pointed out that the ACS patients enrolled in TRITON-TIMI 38 had already had a diagnostic angiogram and had been scheduled for PCI. "In this select indication, the combination of prasugrel and aspirin (compared with clopidogrel and aspirin) reduces about two MIs per 100 patients treated but induces one major bleeding complication. Prasugrel appears to be particularly potent, with the danger of serious bleeding in patients who undergo CABG or who have cerebrovascular disease. It will also be interesting to see how well this drug is tolerated in the real treatment world, as opposed to the context of a well-conducted, rigorous randomized clinical trial," he said.

The TRITON-TIMI 38 trial randomized 13 608 moderate- to high-risk ACS patients scheduled for PCI to receive prasugrel (60-mg loading dose and then 10-mg daily maintenance dose) or clopidogrel (300-mg/75-mg) for six to 15 months. Results showed a significant reduction in the primary efficacy end point (cardiovascular death/MI/stroke), as well as in MI, urgent target vessel revascularization (TVR), and stent thrombosis. But this was at the expense of a significant increase in major bleeding, life-threatening bleeding, and fatal bleeding.

The increased bleeding with prasugrel has caused some doubt as to whether the drug will now reach the market. Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) commented to heartwire: "The holy grail of antithrombotic drug development is balancing improved efficacy against the risk of increased bleeding. It appears that prasugrel has fallen short in this regard. The sponsors might tout better efficacy compared with clopidogrel as a major advantage. However, judging by the recent regulatory climes, safety issues might trump efficacy."

Kaul believes that if prasugrel is approved on the basis of these data, it will have only a limited role. "A desirable benefit/risk profile for prasugrel would be patients at high risk for periprocedural ischemic events (such as diabetics), but without the potential for high bleeding risk, such as the elderly, patients with history of cerebrovascular events (stroke, TIA), patients weighing less than 60 kg, and possibly patients with renal dysfunction. Furthermore, an absolute risk increase in major bleeding of 10.2% (reflecting a nearly fivefold increase) in patients undergoing CABG precludes prasugrel as a potential candidate for pretreatment, prior to defining coronary anatomy. One potential but untested hypothesis would be to assess the role of prasugrel in patients who demonstrate 'hyporesponsiveness' to clopidogrel therapy."

He added: "Generally speaking, safety issues are underestimated in clinical trials, just as efficacy is overestimated, compared with clinical practice. This would potentially make the benefit/risk profile of prasugrel even less desirable in clinical practice and pose a tougher challenge to the practicing clinician."