Acute Coronary Syndrome Clinical Trial
Official title:
Prasugrel Versus Adjusted High-dose Clopidogrel to TREAT High On-clopidogrel Platelet Reactivity in Acute Coronary Syndrome Patients After PCI
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.
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.
;
Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment
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