Effect of Prasugrel Versus Clopidogrel on Platelet Function After Bivalirudin Cessation

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 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.

Inclusion Criteria:

1. Signed informed consent before initiation of any study related procedures

2. Male or non-pregnant female aged 18 to ≤ 75 years

3. Referred for PCI or structural cardiac intervention and planned to receive
bivalirudin treatment

4. Only subjects in whom the treating physician feels that clopidogrel and prasugrel are
equivalent on the basis of available clinical literature will be included.

Exclusion Criteria:

1. Currently receiving glycoprotein IIb/IIIa inhibitors.

2. Have received prasugrel or clopidogrel within 2 weeks

3. Serum creatinine level >2.0

4. Hypersensitivity to bivalirudin, prasugrel, clopidogrel or aspirin

5. Currently on heparin administration or administered ≤ 4.5 h prior to intervention

6. Thrombocytopenia (<50,000/µL)

7. Severe systemic hypertension defined as systolic blood pressure >180 mm Hg and/or
diastolic blood pressure >110 mm Hg

8. Body weight < 60 kg

9. Cardiogenic shock

10. Acute pericarditis

11. Active internal bleeding

12. History of bleeding diathesis within previous thirty days

13. Any history of intracranial hemorrhage, TIA or stroke

14. Arteriovenous malformations or aneurysms

15. Major surgical procedures or severe physical trauma within last thirty days.

16. Symptoms or findings suggestive of aortic dissection

17. Pregnancy

18. Participation in other clinical research studies involving the evaluation of
investigational drugs or devices within 30 days of enrollment

19. Incompetent subjects or subjects otherwise unable to provide informed consent

20. Subjects in whom the treating physician believes that one agent (prasugrel or
clopidogrel) is preferable over the other will be excluded from study participation.