Impact of Colchicine on Peri-Operative Major Adverse Cardiovascular Events in Patients with Prior Coronary Revascularization

Patients with prior coronary revascularization have a high risk of major adverse cardiovascular events (MACE) after major surgery, up to more than 2-fold when compared to patients without prior coronary revascularization. The pro-inflammatory and hypercoagulable states induced by surgery and the hemodynamic changes caused by fluid shifts and anesthesia are all important triggers of perioperative myocardial ischemia. Indeed, peri-operative systemic inflammation is associated with a nearly 4-fold increase in the risk of perioperative MACE. Neutrophils, the most abundant of inflammatory cells, adhere to inflamed or injured endothelium, migrate into the vessel wall, release proteolytic enzymes that can lead to erosion or rupture of plaque. Peri- operative cytokine generation may also activate the inflammasome and, thereby, macrophage- mediated synthesis of interleukin (IL)-1β, a known target for therapy for secondary prevention of MACE, particularly in the setting of high C-reactive protein (CRP) concentration. Colchicine is a safe, well-tolerated anti-inflammatory agent that preferentially accumulates in neutrophils compared with other inflammatory cells. Colchicine inhibits chemotaxis, endothelial adhesion, and extravasation of neutrophils at sites of endothelial injury or inflammation; suppresses the inflammasome-mediated production of IL-1β by macrophages; and reduces inflammation and MACE in patients with cardiovascular disease. The Colchicine Cardiovascular Outcomes Trial and Low Dose Colchicine 2 Trial demonstrated a reduction in MACE with colchicine in about 4000 patients with prior myocardial infarction and about 5000 patients with stable coronary artery disease, respectively. My VA CDA-funded Colchicine-PCI trial demonstrated for the first time that administration of colchicine prior to injury dampens the inflammatory response measured by CRP. The effects of colchicine on peri-operative MACE in patients with prior coronary revascularization undergoing major surgery, remains unknown. The aims of this proposal are to 1) assess the effect of colchicine on peri-operative MACE in response to intermediate- or high-risk non-cardiac surgery in patients with prior coronary revascularization; 2) characterize the level of systemic inflammation and profile of peri-operative neutrophils in this population; and 3) determine the clinical and genetic predictors of peri- operative MACE and examine factors that determine heterogeneity of treatment response in this population. This proposal offers the opportunity to use colchicine to delineate the role of inflammation in the development of post-operative inflammation, as well as test this potentially cost-effective therapy in the reduction of peri-operative MACE with minimal systemic immunosuppression. The proposal also aims to foster a personalized medicine approach to peri-operative cardiovascular optimization based on use of inflammatory markers and pharmacogenetics to identify factors that predict patients who are at risk of peri-operative MACE despite the use of colchicine and may, therefore, require alternative anti-inflammatory or anti- thrombotic therapy. Finally, findings from this study may also open a door to novel therapeutic strategies in other settings of cardiovascular inflammation and injury (e.g., peripheral artery disease, stroke) and other disease states in which neutrophils play a pivotal role (e.g., vasculitis, wound healing).