Lack of outcome benefit and clopidogrel “resistance”

Abstract

SummaryImpaired response to clopidogrel, or “resistance” is a cornerstone concept for justification of more aggressive antiplatelet regimens, and development of new more potent drugs. There are over 1,000 citations (although predominantly reviews, or case reports) in MEDLINE related to clopidogrel “resistance”, while about 100 of them attempted to link low response to adverse clinical outcomes. However, most of these studies are woefully small, and not randomised. The TRITON trial assessed head-to-head novel antiplatelet agent prasugrel versus clopidogrel in patients with acute coronary syndromes. This study was the first in a decade to challenge clopidogrel monopoly, and to indirectly test the “resistance” hypothesis. The primary endpoint was the rate of cardiovascular death, non-fatal myocardial infarction, or stroke, and occurred in 12.1% of patients treated with clopidogrel, and 9.9% of patients randomised to prasugrel, suggesting impressive vascular outcome benefit of prasugrel over clopidogrel. However, the Food and Drug Administration (FDA) presented more balanced, and realistic outlook on TRITON. While very early periprocedural benefit exists, long-term prasugrel therapy yielded identical to clopidogrel vascular outcomes among 13,608 TRITON patients challenging the postulate that clopidogrel “resistance” phenomenon is clinically relevant. Despite the fact that prasugrel 10 mg/daily cause 2.5 times more potent platelet inhibition than conventional clopidogrel 75 mg/daily, with fewer patients exhibiting broad response variability, and/or antiplatelet “resistance”, the vascular benefit beyond acute phase was identical. Keeping in mind growing over time bleeding, cancer, and mortality risks associated with chronic prasugrel use, small observational studies should be judged with skepticism as hypothesis-generating, pending confirmation in randomised trials.