Prasugrel, which is in development by Lilly and Sankyo, belongs to the same class as clopidogrel—thienopyridine P2Y₁₂ receptor antagonists—and will be the first major competitor for clopidogrel.

At the meeting, scientists from Lilly and Sankyo reported data from a pooled analysis of three early-phase studies. The studies involved 112 healthy volunteers who were randomized to receive either a 60-mg loading dose of prasugrel or a 300-mg loading dose of clopidogrel in a two-way crossover design. Adenosine-diphosphate (ADP)-induced platelet aggregation was measured in blood samples taken from the volunteers at four to five hours and 24 hours after the medications were administered.

Results showed that all subjects responded effectively to prasugrel, but when the same subjects were given clopidogrel, between 22% and 43% were classed as nonresponders, depending on the defintion of nonresponder used. The definition of nonresponsiveness of "subjects achieving less than 25% inhibition of platelet aggregation or a difference of less than 20% in maximum platelet aggregation in response to 5-µM adenosine diphosphate" applied to 22% of patients with clopidogrel. But if the definition "less than 20% inhibition of platelet aggregation or a difference of less than 15% in maximum platelet aggregation in response to 20-µM ADP" were used, 43% of patients were classed as nonresponders to clopidogrel.

Prasugrel is currently being studied in a phase 3 trial in ACS patients undergoing PCI. The TRITON-TIMI 38 study is comparing prasugrel and clopidogrel in up to 13 000 patients. The study design incorporates a loading dose before PCI, followed by once-daily maintenance dosing starting after the PCI procedure. The study is expected to be completed in early 2007, with regulatory submissions for prasugrel to follow in the second half of 2007.

Commenting on the current data for heartwire, Dr Paul Gurbel (Johns Hopkins University, Baltimore, MD), who is a TRITON-TIMI 38 investigator, said it does appear that prasugrel has less interpatient variability in responsiveness than clopidogrel. "These results underscore the variable response that can be seen with clopidogrel and suggests that prasugrel provides a more uniform platelet inhibition." He explained that this is probably because prasugrel is less affected by esterases in the circulation than clopidogrel.

But Gurbel added that the "big question" was whether this lower variability with prasugrel would translate into better outcomes. "Preliminary data do suggest that there is a relationship between the degree of platelet aggregation and clinical outcome. High platelet reactivity when on an inhibitor does appear to be associated with a high risk of clinical events. But more will be learned about this from the TRITON-TIMI-38 study."

Gurbel believes prasugrel has "huge promise" but cautions that its bleeding profile needs to be studied carefully. "Of course we have to look at bleeding. There is the question of whether better platelet inhibition will lead to more bleeding, but this will all be scrutinized in TRITON-TIMI-38," he commented to heartwire.