Prasugrel Versus Clopidogrel to TREAT High Platelet Reactivity
Condition: Acute Coronary Syndrome
MeSH terms: Acute Coronary Syndrome; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      MAIN AIM: To compare the pharmacological potency of administering adjusted 600 mg clopidogrel
      loading doses and 60 mg prasugrel in patients with high on-clopidogrel platelet reactivity
      (HPR) after PCI.

      SECONDARY OBJECTIVES: To define the optimal maintenance dose with both prasugrel (5 mg vs. 10
      mg) and clopidogrel (75 mg vs. 150 mg) in patients with HPR for chronic therapy.

      DESIGN: Prospective, Randomized, Open-label, Single-center trial.

      PRIMARY ENDPOINT: Platelet reactivity measured with Multiplate between clopidogrel and
      prasugrel arm at day 4.
    

Detailed description: 
      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.

      Thereby, we aim to compare the achievable platelet inhibition after 60 mg prasugrel with
      adjusted loading doses of 600 mg clopidogrel tailored according to a platelet function
      assessment in patients after PCI. Moreover, we aim to compare the antiplatelet potency of
      different clopidogrel (75 vs. 150 mg) and prasugrel (5 mg vs. 10 mg) maintenance doses during
      the chronic phase of PCI.

      Previous work:

      Our research team in the University of Pécs, Hungary has been involved in platelet function
      experiments since more than five years. We described the large inter-individual variability
      in response to clopidogrel and demonstrated that high on-treatment ADP reactivity is
      associated with recurrent ischemic events after PCI. We performed a meta-analysis to
      summarize the clinical significance of high platelet reactivity and described that these
      patients have 3-fold risk to MI, 4-fold risk to stent thrombosis and 3,4-fold risk for CV
      death. We also tried to determine the efficacy of 150 mg clopidogrel among patients with high
      platelet reactivity, together with the clinical and laboratory predictors of good response to
      the higher maintenance dose. We compared more sophisticated methods of platelet aggregation
      to light transmission aggregometry.

      Study hypothesis:

      We hypothesise that prasugrel will provide more rapid and more potent platelet aggregation
      inhibition compared to repeated loading doses of clopidogrel in patients with HPR after PCI.
      We also test the efficacy of 5 mg and 10 mg prasugrel as well as 75 and 150 mg clopidogrel in
      sustaining platelet inhibition in the maintenance phase.
    

Intervention name(s): Clopidogrel reloading; Prasugrel
Intervention type(s): Drug; Drug
Intervention description(s): Up to three times 600 mg clopidogrel; 60 mg prasugrel in patients with HPR
Other intervention name(s): Clopidogrel = KARDOGREL; Prasugrel = EFIENT
Intervention MeSH terms: Clopidogrel; Prasugrel Hydrochloride
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Clopidogrel; prasugrel; HPR; loading dose; maintenance dose; stent thrombosis; platelet reactivity; Coronary intervention; stent implantation