Ignite Creation Date:
2024-05-06 @ 1:21 AM
Last Modification Date:
2024-10-26 @ 11:02 AM
Study NCT ID:
NCT01789814
Status:
COMPLETED
Last Update Posted:
2017-04-04
First Post:
2013-02-04
Brief Title:
Effect of Prasugrel Versus Clopidogrel on Platelet Function After Bivalirudin Cessation
Sponsor:
Tufts Medical Center
Organization:
Tufts Medical Center
Study Overview
Official Title:
The Effect of Prasugrel as Compared to Clopidogrel on Platelet Function Immediately Following the Termination of Intravenous Bivalirudin in Patients Undergoing Percutaneous Coronary and Structural Cardiac Intervention
Status:
COMPLETED
Status Verified Date:
2017-03
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:
None
Brief Summary:
Early stent thrombosis has been noted with increased frequency in acute coronary syndrome ACS patients undergoing percutaneous coronary intervention PCI who are treated with bivalirudin and clopidogrel The brief half life of bivalirudin acting in concert with the delayed action of clopidogrel likely exposes patients to thrombosis during a vulnerable period of reduced antiplatelet effect in the immediate post stenting period Combination therapy with bivalirudin and prasugrel is conceptually attractive as the more rapid onset of action of prasugrel could potentially significantly diminish the vulnerable period likely reducing the potential for acute stent thrombosis The trials which have documented the efficacy of prasugrel as compared to clopidogrel have in general not reported on patients in whom bivalirudin was utilized Currently in the United States bivalirudin is the most commonly used adjunctive agent used during PCI Using light transmission aggregometry this study will examine the inhibition of platelet aggregation in patients randomized to treatment with clopidogrel vs prasugrel during the vulnerable period following the discontinuation of bivalirudin therapy The investigators anticipate that this study will document significant enhancement of inhibition of platelet aggregation in patients randomized to prasugrel treatment
Detailed Description:
Percutaneous coronary intervention PCI targeting coronary lesions in patients with coronary syndromes leads to iatrogenic endothelial disruption and heightened platelet activation and aggregation Blocking platelet aggregation with glycoprotein GP IIbIIIa inhibitors has been demonstrated to be of unequivocal benefit when combined with heparin in patients undergoing PCI Heparin-mediated thrombin inhibition is an established therapy for safely performing PCI however there are several well known limitations of heparin including its variable anticoagulant effect due to nonlinear pharmacokinetics and inconsistent binding to blood proteins In addition heparin does not effectively block clot-bound thrombin and may cause thrombocytopenia
The direct thrombin inhibitor DTI bivalirudin which binds with high affinity to exosite I of thrombin may be a safer alternative to other commonly used pharmacologic PCI adjuncts with an expert consensus document defining it as reasonable to use as an alternative to unfractionated heparin and GP IIbIIIa antagonists in low-risk patients undergoing elective PCI The ACUITY trial has supported the use of bivalirudin in patients with unstable coronary syndromes This study showed similar rates of ischemic events and less bleeding when compared with patients treated with heparin and GP IIbIIIa inhibitors Similar results were reported in the REPLACE-2 randomized trial which studied a patient population with a lower prevalence of acute coronary syndromes Recent results from our laboratory suggest that at least a part of the salutary effects of DTIs are due to a reduction of thrombin and to a lesser extent collagen-mediated platelet activation
Inhibition of the platelet P2Y12 Adenosine Diphosphate ADP receptor is standard of care when added to aspirin in patients undergoing coronary stenting A 600 mg loading dose of clopidogrel led to enhanced inhibition of platelet aggregation and a reduction in adverse clinical outcomes in Non-ST-Segment Elevation Myocardial Infarction NSTEMI patients undergoing coronary stenting when compared to 300 mg Other studies have documented that when compared with both 300 and 600 mg loading doses of clopidogrel a 60 mg loading dose of prasugrel has been documented to eventuate in faster onset greater magnitude and more consistent levels of platelet inhibition as measured by light transmission aggregometry Several studies have documented significantly greater platelet inhibition with prasugrel treatment when compared to high-dose clopidogrel therapy The more potent P2Y12 ADP receptor antagonist prasugrel significantly reduced the composite endpoint of cardiovascular death nonfatal MI and nonfatal stroke in higher-risk ACS patients referred for PCI The salutary effects referable to prasugrel treatment in this study were mostly due to a reduction in the incidence of myocardial infarction
In the HORIZONS AMI trial patients with ST-segment elevation myocardial infarction who underwent primary PCI anticoagulation with bivalirudin alone as compared with heparin plus GP IIbIIIa inhibitors resulted in significantly reduced 30-day rates of major bleeding and net adverse clinical events Despite these results and those from our laboratory documenting a profound bivalirudin-mediated effect on platelet aggregation closer analysis of the HORIZONS AMI trial has documented a higher acute stent thrombosis rate in bivalirudin as opposed to GP IIbIIIa inhibitor treated patients The investigators have recently documented that the half life of bivalirudin at the currently utilized dose during cardiac interventions is 293 minutes The relatively short half life of this DTI in concert with the relatively long time period required to activate clopidogrel from a prodrug to its active metabolite likely exposes patients to a vulnerable period when there is suboptimal platelet inhibition It is plausible that this vulnerable period when platelet activity is not inhibited was the proximate cause of early stent thrombosis in the HORIZONS trial Consequently earlier acting more potent thienopyridine therapy ie prasugrel when combined with bivalirudin treatment has the potential to reduce bleeding compared with GP IIbIIIa inhibitors while preventing peri-procedural MI as well as providing protection from platelet-mediated stent thrombosis compared with clopidogrel during the vulnerable period following PCI
The overwhelming majority of published data examining clinical outcomes or in-vivo pharmacodynamic and pharmacokinetic differences between clopidogrel and prasugrel have done so in PCI patients in whom bivalirudin was either not used or used very infrequently ie in less than 10 of studied patients However at the present time in the United States bivalirudin is the preeminent antithrombotic adjunctive therapy used during PCI Consequently comparative data regarding the effect of prasugrel and clopidogrel on platelet function in bivalirudin-treated patients is of significant clinical importance
The direct thrombin inhibitor DTI bivalirudin which binds with high affinity to exosite I of thrombin may be a safer alternative to other commonly used pharmacologic PCI adjuncts with an expert consensus document defining it as reasonable to use as an alternative to unfractionated heparin and GP IIbIIIa antagonists in low-risk patients undergoing elective PCI The ACUITY trial has supported the use of bivalirudin in patients with unstable coronary syndromes This study showed similar rates of ischemic events and less bleeding when compared with patients treated with heparin and GP IIbIIIa inhibitors Similar results were reported in the REPLACE-2 randomized trial which studied a patient population with a lower prevalence of acute coronary syndromes Recent results from our laboratory suggest that at least a part of the salutary effects of DTIs are due to a reduction of thrombin and to a lesser extent collagen-mediated platelet activation
Inhibition of the platelet P2Y12 Adenosine Diphosphate ADP receptor is standard of care when added to aspirin in patients undergoing coronary stenting A 600 mg loading dose of clopidogrel led to enhanced inhibition of platelet aggregation and a reduction in adverse clinical outcomes in Non-ST-Segment Elevation Myocardial Infarction NSTEMI patients undergoing coronary stenting when compared to 300 mg Other studies have documented that when compared with both 300 and 600 mg loading doses of clopidogrel a 60 mg loading dose of prasugrel has been documented to eventuate in faster onset greater magnitude and more consistent levels of platelet inhibition as measured by light transmission aggregometry Several studies have documented significantly greater platelet inhibition with prasugrel treatment when compared to high-dose clopidogrel therapy The more potent P2Y12 ADP receptor antagonist prasugrel significantly reduced the composite endpoint of cardiovascular death nonfatal MI and nonfatal stroke in higher-risk ACS patients referred for PCI The salutary effects referable to prasugrel treatment in this study were mostly due to a reduction in the incidence of myocardial infarction
In the HORIZONS AMI trial patients with ST-segment elevation myocardial infarction who underwent primary PCI anticoagulation with bivalirudin alone as compared with heparin plus GP IIbIIIa inhibitors resulted in significantly reduced 30-day rates of major bleeding and net adverse clinical events Despite these results and those from our laboratory documenting a profound bivalirudin-mediated effect on platelet aggregation closer analysis of the HORIZONS AMI trial has documented a higher acute stent thrombosis rate in bivalirudin as opposed to GP IIbIIIa inhibitor treated patients The investigators have recently documented that the half life of bivalirudin at the currently utilized dose during cardiac interventions is 293 minutes The relatively short half life of this DTI in concert with the relatively long time period required to activate clopidogrel from a prodrug to its active metabolite likely exposes patients to a vulnerable period when there is suboptimal platelet inhibition It is plausible that this vulnerable period when platelet activity is not inhibited was the proximate cause of early stent thrombosis in the HORIZONS trial Consequently earlier acting more potent thienopyridine therapy ie prasugrel when combined with bivalirudin treatment has the potential to reduce bleeding compared with GP IIbIIIa inhibitors while preventing peri-procedural MI as well as providing protection from platelet-mediated stent thrombosis compared with clopidogrel during the vulnerable period following PCI
The overwhelming majority of published data examining clinical outcomes or in-vivo pharmacodynamic and pharmacokinetic differences between clopidogrel and prasugrel have done so in PCI patients in whom bivalirudin was either not used or used very infrequently ie in less than 10 of studied patients However at the present time in the United States bivalirudin is the preeminent antithrombotic adjunctive therapy used during PCI Consequently comparative data regarding the effect of prasugrel and clopidogrel on platelet function in bivalirudin-treated patients is of significant clinical importance
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| TMCcardintervCK2013 | OTHER | Tufts Medical Center | None |