Prasugrel Versus Adjusted High-dose Clopidogrel to TREAT High On-clopidogrel Platelet Reactivity in Acute Coronary Syndrome Patients After PCI

Study rationale:

After coronary stent implantation, aspirin plus thienopyridine therapy has been proven to be superior to aspirin alone or aspirin plus warfarin in reducing adverse thrombotic events. Due to the lower rate of haematopoietic side effects, once daily administration and faster onset of action, clopidogrel has replaced ticlopidine as the thienopyridine of choice in patients after acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI). However, clopidogrel has many known limitations that might carry important clinical consequences. First, the onset of action of clopidogrel is relatively slow; even a loading dose of 600 mg requires 4-6 hours to achieve the full antiplatelet effect. Second, the antiplatelet potency of clopidogrel is moderate, and platelet reactivity after clopidogrel treatment shows wide inter-patient variability. As a result, a substantial proportion (25-30%) of patients is not receiving proper ADP-receptor inhibition after a fixed-dose clopidogrel regimen and high on-clopidogrel platelet reactivity (HPR) might persist despite clopidogrel administration. In a meta-analysis comprising 20 studies and more than 9,100 patients, those with HPR had a 3.4-fold risk for cardiovascular death, 3-fold risk for myocardial infarction (MI), and 4-fold risk for definite/probable stent thrombosis. According to our current knowledge, the development of HPR is multifactorial: clinical conditions (diabetes, acute coronary syndrome, renal insufficiency, low ejection fraction), laboratory parameters (platelet count, baseline platelet reactivity), patient compliance and genetic predisposition might contribute to the evolution of HPR. (13) Out of these factors, the clinical importance of genetic interaction in clopidogrel-treated subjects was recently emphasized by multiple studies and by a black-boxed warning of the FDA. (14) Based on these, not all clopidogrel-treated patients get the full clinical benefit from clopidogrel therapy and those carrying a loss-of-function allele (LOF: *2 and *3) in the CYP2C19 gene have higher risk to adverse thrombotic events. All these evidences highlight that the currently recommended, fixed-dose clopidogrel treatment is insufficient to prevent the development of HPR and thrombotic events in a significant proportion of patients after PCI.

Up to now, there is limited information on the optimal strategy to overcome HPR. Increasing the maintenance dose of clopidogrel to 150 mg might decrease to rate of HPR; however, it might help in less than 50% of the patients. In one study, the administration of repeated loading doses of 600 mg clopidogrel - based on the results of the vasodilator stimulated phosphoprotein phosphorylation (VASP) assessment - was successful to overcome HPR in 86% of the patients. Importantly, this was the first and only strategy with clopidogrel that was associated with an improvement in the clinical outcome among patients with non-ST segment elevation MI, as the reloaded group had significantly lower rate of major adverse cardiac events compared to conventional fixed dose clopidogrel.

Beyond clopidogrel, there are newer antiplatelet agents that might also be attractive candidates to overcome HPR. Prasugrel is a novel, third-generation thienopyridine that can eliminate many drawbacks of clopidogrel. Compared to clopidogrel, prasugrel leads to a more rapid and greater formation of its active metabolite after absorption as it is not inactivated by the non-specific estherases in the portal circulation. These features result in a more rapid, more uniform and more potent platelet inhibition both after the loading dose and during the maintenance phase with prasugrel compared to even a high-dose of clopidogrel.

However, there is no direct comparison in platelet inhibition between a strategy of administering repeated loading doses of clopidogrel and prasugrel in patients with HPR. Moreover, the optimal maintenance doses of clopidogrel and prasugrel to maintain proper platelet inhibition during the chronic phase of antiplatelet therapy is also unknown.