Clopidogrel vs. Prasugrel in Medically Managed ACS

Clopidogrel (famous by its brand name Plavix) is now generic and while prices vary from one pharmacy to another, it is very likely that very soon its price will come down. On the other hand, Prasugrel (which works the same way as clopidogrel) has a long way to go before it becomes generic and thus is likely to remain costly for next several years.

Prasugrel has one advantage over clopidogrel; its metabolism is not dependent on CYP2C19 (a member of cytochrome P450 system). A mutation within the gene of this particular enzyme decreases its function and decreases the conversion of the pro-drug, clopidogrel, into its active metabolite. The metabolism is shunted towards inactive metabolites and hence individuals with certain mutations in this gene are associated with increased platelet reactivity while on clopidogrel. This was shown conclusively in a GWAS by Alan Shuldiner and his team.

Prasugrel does seem to be superior to clopidogrel in individuals who undergo percutaneous coronary intervention (PCI) however, it was not clear if prasugrel is also superior to clopidogrel in individuals who are managed conservatively.

The results of the TRILOGY-ACS trial (double blind, randomized, double-dummy, active control, event-driven), announced today at the ESC Congress 2012 suggest that there is no difference. In this study, investigators randomized >9,000 patients with acute coronary syndromes (ACS) to either clopidogrel+acetyl salicylic acid (ASA or aspirin) or prasugrel+ASA. The primary end point of the trial was cardiovascular death, myocardial infarction, or stroke. The study did not find a benefit of prasugrel over clopidogrel for either the primary outcome or individual components of the primary outcome (p = 0.21). Post-hoc analysis suggests some interesting hypothesis that may be worth looking into in future studies.

Ticagrelor, another anti-platelet agent that also works by inhibiting the same ADP receptors (P2Y12), on the other hand, was shown to be superior to clopidogrel in a similar type of medically managed population in the PLATO trial. It will be interesting to see how they do in their head-to-head comparison (if ever done).