Plaque Regression and Progenitor Cell Mobilization with Intensive Lipid Elimination Regimen (PREMIER) Abstract The rate of recurrent cardiovascular events is unacceptably high in patients who experience acute coronary syndrome (ACS). The use of statins to lower lipid levels is a fundamental part of the treatment of these patients. However, even the most intensive pharmacologic lipid lowering therapy, though proven superior to standard dose regimens, is still associated with an unacceptably high rate of recurrent CV events. Progression or rupture of lipid rich necrotic core (NC) elements of atherosclerotic vulnerable plaque (VP) leads to a majority of recurrent CV events. Vascular healing by endothelial progenitor cells (EPC) plays a crucial role in repair following ischemic injury primarily by endothelialization of (VP) and neovascularization of ischemic myocardium. In fact, EPC mobilization while on statin therapy has been shown to enhance coronary blood flow in patients with stable coronary artery disease (CAD), and reduce myocardial ischemia and CV events in patients with ACS within a few weeks of treatment. This has prompted a continuous drive towards lowering of total cholesterol and specifically low-density lipoprotein (LDL). However, what still remains uncertain is whether the most intensive LDL-lowering therapy (ILLT) with LDL-apheresis could lead to a rapid and detectable reduction in VP atheroma volume, along with a more robust EPC mobilization compared to standard statin therapy in ACS patients. In this multi-center trial 114 ACS patients undergoing percutaneous coronary intervention (PCI) will be randomized to either initial LDL-apheresis and an oral daily dose of 20mg of Atorvastatin (ILLT group) or to standard statin monotherapy (SMT) with daily dose of up to 40mg of Atorvastatin without LDL-apheresis. Patients will undergo intravascular ultrasound with virtual histology (IVUS-VH) to determine whether ILLT reduces total atheroma volume and %NC in the target coronary artery at 12 weeks. Cell culture and flow- cytometer (FACS) analysis will be used to determine if there is a greater increase in EPC- colony forming units (EPC-CFU/ml), of peripheral blood, compared to SMT group from baseline to four and 12 weeks post- PCI. The study will also look for a reduction in major adverse CV events (MACE) at 12 weeks and at end of study (at least six months follow-up). If successful, this trial will provide evidence that in ACS patients, ILLT with LDL-apheresis plus statin therapy will significantly reduce the total atheroma volume of vulnerable plaque and augment mobilization of peripherally circulating EPC-CFU/ml, compared to guideline based standard statin monotherapy alone (SMT) 1

Public Health Relevance

Plaque Regression and Progenitor Cell Mobilization with Intensive Lipid Elimination Regimen (PREMIER) Veterans presenting with a heart attack are at an unacceptably high risk of recurrent heart attacks. Progression or rupture of cholesterol rich vulnerable plaque leads to a majority of recurrent heart attacks. This study is designed to test a novel paradigm of heart artery plaque regression and healing by intensive, and rapid, one-time, removal of the harmful low density cholesterol from blood by LDL- apheresis filtering along with statin therapy, following a heart attack. Only patients that have been successfully treated with stent placements, as advised by their physician, will be considered and enrolled for the study. This unique treatment paradigm will be compared to standard medical therapy with statin drugs in randomized clinical trial. We propose to stimulate and harness the endogenous ability of patients to release specialized stem cells known as endothelial progenitor cells, important to blood vessel repair and regeneration, by rapid cholesterol reduction, thereby avoiding all compatibility and ethical issues related with stem cell therapies.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Clinical Trials (CLIN)
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VA North Texas Health Care System
United States
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