Platelet Inhibition With Cangrelor and Crushed Ticagrelor in STEMI

In STEMI patients undergoing PPCI there is a delayed onset of action of oral P2Y12 receptor
inhibitors, including prasugrel and ticagrelor, which require more than 2 hours to exert
their full antiplatelet effects, and thus exposing these high-risk patients to an increased
risk of early thrombotic complications. The mechanism of this delayed onset of antiplatelet
effect is likely multifactorial due to the presence in the setting of STEMI of specific
conditions that translate into delayed drug absorption which in turn affect the
pharmacokinetic (PK) and pharmacodynamic (PD) profiles of oral P2Y12 receptor inhibitors.
Crushing prasugrel and ticagrelor improves their PK and PD profiles as it favors drug
absorption and onset of antiplatelet effects and because of this, it is commonly used in
STEMI patients undergoing PPCI. However, despite the use of crushed tablets, up to one-third
of patients may still have high on-treatment platelet reactivity (HPR) within the first 2
hours after loading dose (LD) administration of these oral agents. Cangrelor is a potent
intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a
greater reduction in ischemic events compared with clopidogrel in P2Y12 receptor naïve
patients undergoing PCI. To date most studies have explored cangrelor in the setting of PCI
subjects treated with clopidogrel and the clinical profile of cangrelor among patients
treated with prasugrel or ticagrelor is currently unknown. This is noteworthy because ACS
patients, in particular STEMI undergoing PPCI, are commonly treated with either prasugrel or
ticagrelor. PD investigations conducted in vitro or ex vivo in stable patients have shown
cangrelor to be associated with enhanced platelet inhibition compared with that induced by
prasugrel and ticagrelor. However, the PD effects of cangrelor in STEMI patients undergoing
PPCI treated with a newer generation P2Y12 receptor inhibitor and how this compares with a
crushed formulation of the oral drug is unexplored. The aim of this prospective randomized
study is to investigate the PD effects of cangrelor in STEMI patients undergoing PPCI treated
with crushed ticagrelor.

Inclusion criteria:

- Patients with STEMI undergoing primary PPCI

- Age > 18 years old

Exclusion criteria:

- Inability to provide written informed consent

- Known history of prior intracranial bleeding

- On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel,
ticagrelor) in the prior 10 days

- Known allergies to aspirin, ticagrelor or cangrelor

- On treatment with oral anticoagulant

- Treatment with glycoprotein IIb/IIIa inhibitors

- Fibrinolytics within 24 hours

- Active bleeding

- High risk of bleeding

- Known platelet count <80x106/mL

- Known hemoglobin <10 g/dL

- Intubated patients (prior to randomization)

- Known creatinine clearance <30 mL/minute or on hemodialysis.

- Known severe hepatic dysfunction

- Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker
protection

- Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction
with ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin,
nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and
telithromizycin.

- Pregnant or lactating females.