Effect of Prasugrel Versus Clopidogrel on Platelet Function After Bivalirudin Cessation
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease
Study type: Interventional
Phase: Phase 4

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) IIb/IIIa 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 IIb/IIIa 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 IIb/IIIa 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 IIb/IIIa 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 IIb/IIIa inhibitor treated patients. The investigators have recently documented
      that the half life of bivalirudin, at the currently utilized dose during cardiac
      interventions is 29.3 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, i.e. prasugrel, when
      combined with bivalirudin treatment has the potential to reduce bleeding (compared with GP
      IIb/IIIa 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, i.e. 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.
    

Intervention name(s): Prasugrel; Clopidogrel
Intervention type(s): Drug; Drug
Intervention description(s): Patients will be randomized to prasugrel or clopidogrel to assess the effect of these drugs on inhibition of platelet aggregation following the cessation of bivalirudin therapy.; Clopidogrel 600 mg as a loading dose immediately prior to the start of procedure and 75 mg daily thereafter
Other intervention name(s): Effient; Plavix
Intervention MeSH terms: Clopidogrel; Prasugrel Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; bivalirudin