Timing of thienopyridine loading and outcomes in the TRITON trial: the FDA Prasugrel Action Package outlook

Abstract

TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) was a Phase 3, randomized, double blind, parallel-group, multinational head-to-head study of prasugrel vs. clopidogrel both on top of aspirin. The primary end point was the rate of cardiovascular death, nonfatal myocardial infarction (MI), or stroke, and was reached in 12.1% of patients treated with clopidogrel and in 9.9% of patients randomized to prasugrel, suggesting impressive vascular outcome benefit of prasugrel over clopidogrel. However, this overoptimistic interpretation of the trial results was challenged by the Food and Drug Administration (FDA) Secondary Review, which revealed several shortcomings with TRITON design and data interpretation including the front-loaded nature of prasugrel benefit. Recently, following approval with black box warning, the FDA posted the complete documentation set (Action Package), revealing additional information including the timing of loading in TRITON, and how it affects vascular outcomes. The detailed FDA communications revealed highly significant correlation of the loading dose delay and primary efficacy outcomes favoring prasugrel. Indeed, when patients in TRITON were loaded early, or pretreated, the benefit of prasugrel was nonexistent. However, the longer it takes during or especially after PCI to load with thienopyridine, the more prasugrel benefit occurs. Considering that pretreatment with clopidogrel was disallowed; that three quarters of patients in TRITON were loaded during or after intervention; and that prasugrel was used at the 60-mg loading dose, which is over three times more potent than 300 mg clopidogrel, the claim of superiority of prasugrel over clopidogrel is not valid due to inappropriate use of clopidogrel.