Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes
NEJM — Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes
Following up Oct 24th’s post reporting on the news of Phase 1 trial suspensions of prasugrel to adjust dosage, we have today’s results of the TRITON-TIMI 38 Phase 3 pivotal trial of prasugrel vs. clopidogrel, published online in the NEJM to coincide with a presentation at the AHA annual meeting.
The editorial accompanying the detailed trial results, written by Deepak Bhatt of the Cleveland Clinic, sums up the study findings and implications nicely and sheds some light on the decision to study the antiplatelet pharmacodynamic effects at lower doses in subgroups of patients with differing baseline risks for serious bleeding:
The degrees of reduction in all these important ischemic events were substantial and robust [~19% in the primary efficacy endpoint, up to 52% for reduction in stent thrombosis with drug-eluting stents]. Beyond comparing one drug with another, the TRITON–TIMI 38 study validates the hypothesis that greater degrees of adenosine diphosphate–mediated platelet inhibition are indeed associated with a greater suppression of clinical ischemic events. This is a major scientific contribution to our understanding of antiplatelet therapy….
Of concern, however, was the excess in TIMI major bleeding not related to coronary-artery bypass grafting that was life-threatening in the prasugrel group (1.4%, vs. 0.9% in the clopidogrel group; P=0.01), even fatally so (0.4% vs. 0.1%, P=0.002)….Thus, there is a price to pay for greater platelet inhibition and the accompanying reduction in ischemic events: higher rates of serious bleeding. In TRITON–TIMI 38, for each death from cardiovascular causes prevented by the use of prasugrel as compared with clopidogrel, approximately one additional episode of fatal bleeding was caused by prasugrel…..[I]n a “real-world” setting, such as in an elderly patient with multiple coexisting conditions, the risk of major bleeding and even fatal bleeding may be increased to an even greater degree than was seen in TRITON–TIMI 38. Correspondingly,the benefits may also be greater in actual practice….
Bottom line: Prasugrel more effectively prevents acute coronary syndromes than clopidgrel at its approved dosage, probably by stronger ADP-mediated platelet inhibition at the one size-fits-all dose of prasugrel studied. However, one-size-fits-all appears to be an undesirable approach to this form of therapy, as evidenced by the significantly higher bleeding risk with prasugrel. A more personalized approach, perhaps to the level of an individual patient, is necessary to improve on the efficacy of clopidogrel in the real world. Thus, further clinical study of prasugrel , perhaps in conjunction with a point-of-care theranostic, will be needed to guide its tailored prescription. That said, I see nothing in these results that would preclude FDA approval of prasugrel now, without further clinical study, albeit with limitations on its use to low bleeding-risk patients. Realistically, though, Lilly and DaiichiSankyo must perform additional studies to justify prescription of prasugrel to broader populations of patients and reap the financial rewards they are seeking.
