Project Grant R33HL171775

A NOVEL TICAGRELOR COATED STENT TO ELIMINATE THE NEED FOR DUAL ANTI PLATELET THERAPY POST PCI - THERE ARE MORE THAN 1.8 MILLION PERCUTANEOUS CORONARY INTERVENTIONS (PCI) PERFORMED ANNUALLY TO TREAT CORONARY ARTERY STENOSIS. STENT THROMBOSIS IS A CATASTROPHIC MECHANISM FOR STENT FAILURE, COMPRISING 11% OF CASES OF ACUTE MYOCARDIAL INFARCTION, AND CARRIES A HIGH MORBIDITY AND MORTALITY; ITS PREVENTION REQUIRES THE USE OF PROLONGED DUAL ANTIPLATELET THERAPY, WHICH SIGNIFICANTLY INCREASES BLEEDING RISK, RENDERING PCI THERAPY OF PROHIBITIVELY HIGH RISK IN CERTAIN PATIENTS. THIS IS PARTICULARLY TRUE WITH CO-EXISTING CONDITIONS, SUCH AS ATRIAL FIBRILLATION, WHICH COMPRISES 5% OF PCI PATIENTS AND REQUIRES ADDITIONAL ANTICOAGULANT THERAPY TO PREVENT LEFT ATRIAL THROMBI. YET, A CONTEMPORARY STENT SYSTEM THAT PROVIDES LOCAL ANTIPLATELET ACTIVITY, OBVIATING THE NEED FOR SYSTEMIC THERAPY TO MITIGATE BLEEDING RISK, DOES NOT EXIST. TO FILL THIS URGENT UNMET NEED, WE HAVE DEVELOPED SUCH A STENT: THE TICAGRELOR COATED STENT (TCS). THE TCS IS COATED WITH THE POTENT ANTIPLATELET AGENT TICAGRELOR, UTILIZING A SELF-ASSEMBLED MONOLAYER. WE HAVE ESTABLISHED IN VITRO PROOF OF CONCEPT FOR THIS NEW STENT PLATFORM. WE ALSO IMPLANTED THE TCS IN RABBITS FOR UP TO 35 DAYS AND DEMONSTRATED SUPERIOR PERFORMANCE IN COMPARISON WITH STANDARD NON-COATED STENTS. IN A RECENT PORCINE EX VIVO AV FISTULA MODEL, WE DEMONSTRATED WIDELY PATENT TCS WITH NO THROMBUS, MINIMAL PLATELET ACTIVATION AND ADHERENCE, AND A MARKED DECREASE IN INFLAMMATION, IN COMPARISON TO CONTROL STENTS. THUS, THE TCS PROVIDES LOCAL ANTIPLATELET ACTIVITY TO NOT ONLY PREVENT STENT THROMBOSIS, BUT ALSO TO MINIMIZE BLEEDING RISK BY ELIMINATING THE NEED FOR SYSTEMIC DUAL ANTIPLATELET THERAPY. MOREOVER, THIS STENT IS EXPECTED TO PROVIDE A SAFE REVASCULARIZATION OPTION FOR PATIENTS WHO HAVE LIMITED ACCESS TO OR WHO ARE UNABLE TO TAKE DAILY MEDICATIONS. GIVEN OUR PROMISING PRELIMINARY DATA, WE ARE NOW POISED TO MOVE FORWARD WITH A DETAILED CHEMICAL CHARACTERIZATION OF THE TCS AND SAFETY TESTING IN PORCINE CORONARY ARTERY IMPLANT STUDIES, TO FURTHER ASSESS SAFETY, PRIOR TO POTENTIAL CLINICAL TRANSLATION. WE HAVE DIVIDED THE PROPOSED WORK INTO THE FOLLOWING THREE SPECIFIC AIMS: (1) PRECISE MEASUREMENT OF DRUG CONCENTRATION PER TCS AREA PRE- AND POST-IMPLANTATION, TCS SHELF LIFE AND STABILITY, USING MASS SPECTROSCOPY AND UV SPECTROSCOPY TECHNIQUES; (2) ASSESSMENT OF PLATELET ACTIVITY AND INFLAMMATION IN A PORCINE EX VIVO MODEL AS MEASURED BY SCANNING ELECTRON MICROSCOPY, CONFOCAL MICROSCOPY, AND HISTOPATHOLOGY; (3) SAFETY OF STENT IMPLANTATION ASSESSED IN PORCINE SURVIVAL STUDIES AT 7, 28, AND 180 DAYS AND A HEAD-TO-HEAD COMPARISON WITH INDUSTRY STANDARD CORONARY DRUG ELUTING STENTS. SAFETY TESTING IN OUR PORCINE GROUPS WILL SERVE AS THE FRAMEWORK TO TRANSLATE OUR WORK TO HUMAN SUBJECTS.