Platelet Inhibition to Target Reperfusion Injury

There remains a clinical need to improve health outcomes in patients with ischemic heart disease (IHD) the leading cause of death and disability in Singapore and worldwide. One neglected therapeutic target is 'myocardial reperfusion injury' in ST-segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention (PPCI). This results in microvascular obstruction (MVO) and cardiomyocyte death and contributes upto 50% of the final myocardial infarct (MI) size. Cangrelor, a potent intravenous platelet P2Y12 inhibitor with rapid onset and offset of action, has been demonstrated in experimental animal studies to reduce MI size when administered prior to reperfusion. Whether Cangrelor given together with Ticagrelor would be more effective at reducing MI size in STEMI patients treated by PPCI is not known and is investigated in the Platelet Inhibition to Target Reperfusion Injury (PITRI) trial.

The PITRI proof-of-concept clinical trial will randomise 210 STEMI patients to receive either Cangrelor (single intravenous bolus followed by a 120-minute infusion) or matching normal/saline placebo, initiated prior to PPCI on top of conventional oral dual antiplatelet therapy (Aspirin + Ticagrelor).

The primary endpoint will be acute MI size by cardiac MRI at day 2-7. Secondary endpoints will include incidence and extent of MVO by cardiac MRI; and chronic MI size, left ventricular size and ejection fraction by cardiac MRI at 6 months.

Eligibility Criteria:
Inclusion Criteria Subjects must meet all of the inclusion criteria to participate in this study.

1. Age ≥21 and \<80 years of age
2. STEMI as defined by:

   * ≥2 mm ST-segment elevation in 2 or more anterior leads (V1-V4)
   * ≥1 mV ST-segment elevation in in 2 or more limb leads (II, III and aVF, I, aVL).
   * ST elevation in II, II, aVF less than 1 mm with ST depression in aVL
   * Posterior infarction ST depression ≥ 1 mm over either V1, V2, or V3 and ST elevation ≥ 1 mm in either V7, V8 or V9
3. ≤6 hours onset of most severe chest pain to time of admission in the Emergency Medicine Department

Exclusion Criteria All subjects meeting any of the exclusion criteria at baseline will be excluded from participation.

1. History of previous MI, CVA, TIA or prior CABG surgery
2. Known contraindications to cardiac MRI (CMR) such as MRI contraindicated implanted devices, significant claustrophobia, severe allergy to gadolinium chelate contrast, severe renal insufficiency (estimated glomerular filtration rate \[eGFR\] ≤40 mL/min/1.73 m2)
3. Patients with prior therapy before admission within 7 days of anticoagulant (warfarin, phenindione, dabigatran, apixaban and rivaroxaban), glycoprotein 2B3A inhibitor, P2Y12 inhibitor (ticagrelor, prasugrel, clopidogrel, cangrelor) or thrombolytic therapy
4. Significant co-morbidities:

   * Patients with severe hepatic failure (INR\>2)
   * Cardiac arrest before randomisation
   * Cardiogenic shock
   * Poor premorbid status (bed bound / wheelchair bound)
   * Collapse / comatose / semi-conscious states
5. Contraindications to Heparinisation or Anti-Platelet Therapy:

   * History of Heparin-Induced Thrombocytopenia (HIT)
   * Increased bleeding risk (GI bleeding, traumatic head injury)
6. Pregnancy
7. Contrast allergy
8. Patients on strong CYP3A inhibitors or inducers (such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole, rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital)