The Effect of IV Cangrelor and Oral Ticagrelor Study

The Effect of Intravenous Cangrelor and Oral Ticagrelor on Platelets, the Microcirculation and Myocardial Damage in Patients Admitted With STEMI Treated by Primary Percutaneous Coronary Intervention: A Randomized Controlled Pilot Trial

Major heart attacks are caused by a number of factors, the two major of which are furring up of a coronary artery with atheroma and then sudden clot formation on this area leading to a blockage and interruption of blood flow. The clots that lead to heart attacks are largely made of clotting blood cells (platelets) that in health repair blood vessels and inhibit spontaneous bleeding. One of the main treatment strategies for heart attacks is to make these cells less "sticky". Aspirin is a main stay of anti-platelet treatment in the United Kingdom (UK) and in addition one of three other oral antiplatelet agents acting on the same platelet activation pathway (P2Y12 receptor) is licensed for use. When a patient is admitted with a major heart attack, they are treated with emergency primary percutaneous coronary intervention (PPCI) a technique where a wire and balloon are used to reopen the coronary artery and then usually a stent (a slotted metal tube) is placed to keep the artery open. Aspirin and one of the P2Y12 inhibitor agents are given to prevent further clots and all have been shown to reduce negative events following heart attacks and angioplasty with stent insertion. There are increasing data, including from our own institution, showing that in the setting of heart attacks, the oral P2Y12 inhibitors are poorly absorbed and have little effect at the time of most need, i.e. soon after dosing while the primary PCI is being performed. All three current P2Y12 inhibitor agents are taken in tablet form immediately before the emergency PPCI procedure. It appears that in healthy stable patients these agents take at least 30 min to 2 hours to have an adequate effect. In heart attack patients the angioplasty procedure is usually performed well within this timescale. Furthermore, patients who are having a heart attack do not have normal drug absorption with blood being diverted away from the stomach and gut activity being suppressed by other drugs such as morphine. In this current study, patients with major heart attacks will be given our standard oral agent, Ticagrelor, or the newer intravenous agent Cangrelor prior to PPCI.

Acute Coronary Syndrome (ACS), High On-treatment Platelet Reactivity (HTPR), Microvascular Obstruction (MVO), ST-segment Elevation Myocardial Infarction (STEMI), Thrombolysis in Myocardial Infarction (TIMI), Unstable Angina (UA)

Adenosine Diphosphate, Cardiovascular Magnetic Resonance (CMR), Index of microvascular resistance (IMR), Vasodilator stimulated phosphoprotein phosphorylation (VASP), Pharmacodynamic, Antiplatelet, Myocardial Infarction (MI), Cangrelor, Ticagrelor, Coronary artery bypass graft (CABG), Primary percutaneous coronary intervention (PPCI)

Patients in the oral Ticagrelor arm will receive Ticagrelor at a loading dose of 180mg followed by maintenance dose of 90mg twice daily for 12 months.

Patients in the intravenous Cangrelor arm will receive Cangrelor as an initial bolus dose given as per body weight followed by an intravenous infusion for no longer than three hours, they will then switch to oral Ticagrelor given at maintenance dose of 90mg twice daily for 12 months

Degree of platelet inhibition measured with VerifyNow(R) system, rapid platelet function analyser and also VASP flow cytometry at infarct vessel open time (also known as balloon time)

Index of Microvascular Resistance (IMR) measurement using pressure wire studies immediately following the PPCI procedure.

Inclusion Criteria: Patients presenting with STEMI eligible for PPCI Able to give verbal assent pre procedure and written consent following the procedure. Age ≥18 years No contraindication to Cangrelor or Ticagrelor Thienopyridine naïve If a patient gives verbal assent but is unable to provide a written consent at a later stage due to incapacitation, presumed consent will be continued. The reasons why a patient becomes incapacitated and becomes unable to provide a written consent will be recorded during data collection. Exclusion Criteria: Be unable to provide verbal assent and written consent Allergic to Aspirin or any of the P2Y12 antagonists in the trial Have pre-existing cardiogenic shock Previous myocardial infarction Have a concurrent septic or inflammatory disease e.g. rheumatoid arthritis, lupus, and pneumonia. Already taking a P2Y12 inhibitor Known bleeding diathesis Significant active bleeding History of intracranial hemorrhage Patients who are being treated with formal anticoagulation (Vitamin K antagonist, Factor II or Xa inhibitors) or have an indication for anticoagulation during the first four hours of the study period. Example is patients known to have atrial fibrillation, pulmonary embolism or deep vein thrombosis. Known severe renal dysfunction requiring renal replacement therapy.

Ubaid S, Ford TJ, Berry C, Murray HM, Wrigley B, Khan N, Thomas MR, Armesilla AL, Townend JN, Khogali SS, Munir S, Martins J, Hothi SS, McAlindon EJ, Cotton JM. Cangrelor versus Ticagrelor in Patients Treated with Primary Percutaneous Coronary Intervention: Impact on Platelet Activity, Myocardial Microvascular Function and Infarct Size: A Randomized Controlled Trial. Thromb Haemost. 2019 Jul;119(7):1171-1181. doi: 10.1055/s-0039-1688789. Epub 2019 May 26.