Ignite Creation Date:
2024-05-06 @ 12:06 AM
Last Modification Date:
2024-10-26 @ 10:45 AM
Study NCT ID:
NCT01493999
Status:
COMPLETED
Last Update Posted:
2014-10-08
First Post:
2011-12-14
Brief Title:
Prasugrel Versus Clopidogrel to TREAT High Platelet Reactivity
Sponsor:
University of Pecs
Organization:
University of Pecs
Study Overview
Official Title:
Prasugrel Versus Adjusted High-dose Clopidogrel to TREAT High On-clopidogrel Platelet Reactivity in Acute Coronary Syndrome Patients After PCI
Status:
COMPLETED
Status Verified Date:
2014-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
TREAT-HPR
Brief 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
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 9100 patients those with HPR had a 34-fold risk for cardiovascular death 3-fold risk for myocardial infarction MI and 4-fold risk for definiteprobable 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 34-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
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 9100 patients those with HPR had a 34-fold risk for cardiovascular death 3-fold risk for myocardial infarction MI and 4-fold risk for definiteprobable 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 34-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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None