Aernoud Fiolet

107 The LoDoCo2 trial rationale, design, and baseline characteristics DISCUSSION There is a need to develop safe effective well-tolerated and affordable therapies for secondary prevention of CV disease, which remains among the major causes of morbidity and mortality throughout the world. 39 Even after lowering LDLc to extremely low levels and optimization of anti-thrombotic therapies, considerable residual risk remains. Encouragingly, the CANTOS trial demonstrated that targeting the IL-1 β inflammatory cytokine pathway further improved clinical outcomes in high risk patients with stable coronary disease suggesting that it may be possible to modify the inflammatory processes that drive the atherosclerosis, however the reduction in major adverse CV events was modest and accompanied by a small increase in fatal infections. The CV registration of canakinumab has been halted by Novartis. 40 It is now appreciated that once cholesterol crystallizes in atherosclerotic plaque, it can initiate an innate immune response by triggering complement and by activating macrophages to produce IL-1 β . 41 In addition, larger cholesterol crystals that are not readily ingested can induce a cycle of frustrated phagocytosis that results in an indolent, and at times a more intense acute inflammatory response. 10 Hence, extracellular cholesterol crystals trigger inflammatory processes up and downstream of the IL-1 β pathway, suggesting that a much broader approach is required to more fully address the inflammatory processes that may drive the atherosclerotic process. 42 In contrast to canakinumab, which selectively inhibits IL-1 β , colchicine has broad cellular effects that targets multiple aspects of the innate immune response (Figure 1) and long-term colchicine has proven effective in gout and FMF in which these same inflammatory processes are active. 43,44 The LoDoCo pilot that used a prospective randomized observer-blinded endpoint (PROBE) design in 532 patients demonstrated that low-dose colchicine was safe and effective in reducing the risk of CV events in patients with stable coronary disease when used in combination with statins and anti-platelet therapy. The results showed that the colchicine group had a robust reduction in the primary endpoint (HR 0.33, 95% CI 0.18-0.59). 30 The second LoDoCo trial (LoDoCo2) has been designed to confirm the safety and benefit of colchicine 0.5 mg daily for secondary prevention of CV events. The trial