Presenting the data from a small platelet study of the drug, Dr Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD), said that prasugrel was clearly a more potent antiplatelet agent than clopidogrel, but "this was not necessarily a good thing." He reported a nine-patient platelet substudy of the phase 2 JUMBO trial [1], in which two patients taking prasugrel showed profound platelet inhibition, which he said is not seen with clopidogrel and which "raises the possibility of higher bleeding risks, especially during long-term prasugrel use." Serebruany pointed out that both these patients were receiving a 10-mg maintenance dose of prasugrel, which is the dose being tested in the phase 3 TRITON trial.

To heartwire, Serebruany commented: "These two patients had complete inhibition of collagen-induced aggregation at 30 days, which is an extreme degree of platelet inhibition. I have never seen this before in 30 years of work with antiplatelet agents. This leads me to believe that the 10-mg dose will cause bleeding problems if used as the maintenance dose."

In response, another antiplatelet expert, Prof Lars Wallentin (University Hospital, Uppsala, Sweden), says that more-effective antithrombotic agents are often associated with a raised risk of bleeding, but he adds that the TRITON trial is now almost fully recruited and has not been stopped for safety issues, which is reassuring in this regard.

Serebruany explained that although clopidogrel is a widely used and effective antiplatelet agent, it has several shortcomings, such as delayed platelet inhibition and response variability, so the ongoing search for more efficient and safe antiplatelet agents is well justified. He added that prasugrel has the potential to achieve higher levels of inhibition of ADP-induced platelet aggregation than currently approved doses of clopidogrel, and in the phase 2 (JUMBO)-TIMI 26 study, prasugrel did indeed show faster and less-variable platelet inhibition than clopidogrel.

As part of the JUMBO substudy, Serebruany performed detailed platelet studies on nine patients in the prasugrel group who underwent coronary stenting. They had received one of three doses of the drug—40 mg loading and 7.5 mg maintenance, 60 loading and 10 mg maintenance, or 60 loading and 15 mg maintenance. Platelet activity was assessed at baseline, at four and 24 hours, and at 30 days after stent implantation in substudy participants and compared with 124 historic controls who received clopidogrel.

Serebruany reported that there were many significant differences in the degree of platelet inhibition between prasugrel- and clopidogrel-treated patients, all of which clearly suggested that prasugrel is a much more potent antiplatelet agent than clopidogrel. But he added that "more potent platelet inhibition may not necessarily result in better clinical outcomes." Serebruany describes the complete inhibition of collagen-induced aggregation seen with the 10-mg prasugrel dose as "alarming" and calls for more dose-finding studies. He says he "has no problem" with the 60-mg loading dose but that a lower-dose maintenance dose (between 3 and 5 mg) would likely give similar efficacy with fewer safety issues.

He also pointed out that if a drug causes an increased risk of bleeding, even if the bleeding itself is not a major problem, this can greatly increase the rate of noncompliance, which can lead to a rebound increase in cardiac events [2]. He notes that many patients stop treatment because of adverse effects, which is a particular problem for antiplatelet and anticoagulant therapies, where routine tasks like shaving or toothbrushing can produce annoying minor bleeding. "Obviously, the risks for noncompliance are higher for more potent antiplatelet regimens and probably contributed substantially to the higher rates of mortality due to thrombotic events reported previously with oral GP IIb/IIIa inhibitors," he suggests.

Whether stronger platelet inhibition will yield better clinical outcomes and/or increased bleeding will be determined in the phase 3 TRITON-TIMI 38 study, which is comparing one-year treatment with prasugrel or clopidogrel in ACS patients taken to PCI.

In response to these comments, Wallentin says that more effective antiplatelet agents are needed and that both prasugrel and another similar agent in development by AstraZeneca completely abolish the existence of low or nonresponders, which is seen in 20% to 40% of patients treated with clopidogrel. "At the Barcelona meeting, several abstracts highlighted that low responders to clopidogrel had a raised risk of thrombotic complications in association with PCI procedures. Thus, there is a strong rationale for an improved protection against ischemic events with the use of the new agents as compared with clopidogrel," he told heartwire.

But Wallentin adds that "almost always" the use of a more effective antithrombotic agent is associated with a raised risk of bleeding. However, he points out that doses of prasugrel and AZD6140 (the AstraZeneca compound) currently being tested phase 3 trials did not show any significant increase in major bleeds in previous phase 2 trials. And while the final evaluation of the benefit/risk ratio of these new compounds needs to await the results of the ongoing phase 3 trials, he says it is "comforting that the TRITON trial will soon have concluded its recruitment goals without any intervention of the [data safety and monitoring board]. Therefore, it seems unlikely that there is any dramatic increase in the risk of bleeding that is not compensated by a reduction in ischemic events by more effective platelet inhibition."