Aernoud Fiolet

95 The LoDoCo2 trial rationale, design, and baseline characteristics INTRODUCTION A therosclerosis remains the major cause of death, disability and rising health care costs in many parts of the world. Reducing the global burden of cardiovascular (CV) disease requires the development and widespread deployment of effective and affordable therapies for secondary prevention of atherosclerosis that are safe and well tolerated when used over decades. Aggressive secondary prevention can improve CV outcomes in patients with established atherosclerosis. Lifestyle changes and intensive combinedmodification of multiple risk factors, including lowering low-density lipoprotein-cholesterol (LDLc), blood pressure and glucose, as well as antithrombotic therapy, have been demonstrated to significantly improve the long-term outcomes among patients with coronary artery disease. 1-7 Despite this, a considerable residual CV risk persists. Atherosclerosis is a complex inflammatorydisease. In spite of the recognition of the central role of inflammation in unstable coronary syndromes, the lack of complete understanding of the underlying mechanisms leading to plaque instability has hampered efforts for the development of anti-inflammatory treatments to prevent CV events. Recent evidence suggests an important role of the NOD-like receptor family pyrin containing domain 3 (NLRP3) inflammasome by various triggers. Complement activation also triggers an inflammatory response activating endothelium to produce selectins thereby promoting entry of circulating leucocytes into the vascular bed, which may predispose to plaque instability (Figure 1). 8-11 The proof of concept CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) study supports the hypothesis that dampening the downstream effects of activation of the NLRP3 inflammasome by specifically targeting interleukin-1 β (IL-1 β ) with the monoclonal antibody canakinumab can reduce the risk of major adverse CV events. 12 In contrast to canakinumab, colchicine is a microtubule inhibitor with broad cellular effects and has additional actions both up and downstream of the NLRP3 inflammasome (Figure 1, Figure 2). Microtubules are involved in various cellular processes including maintenance of cell shape, intracellular trafficking, cytokine and chemokine secretion, cell migration, and cell division. Colchicine is a classical anti-mitotic drug that blocks mitotic cells in metaphase. Colchicine can therefore