Aernoud Fiolet

30 Chapter 1 One of the first inflammatory targets in coronary disease risk was the inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA 2 ). Lp-PLA 2 is bound to LDL cholesterol and plays a role in oxidative modification within the vascular wall, and it increases vascular inflammation in atherosclerosis. The Lp-PLA 2 inhibitor darapladip was tested in two major trials in almost 20,000 patients with chronic coronary disease and recent acute coronary syndrome. Both trials did not demonstrate a reduction in the risk of major cardiovascular events. 106,107 A variant of the compound inhibiting the secretory formof PLA 2 , varespladib,was associated with a higher rate of recurrent myocardial infarction. 108 Parallel to these efforts, inhibition of the broad p38 mitogen-activated protein (MAP) kinases system was proposed. The p38 MAP kinase system takes part in various intracellular signaling routes and is active in endothelial cells, smooth muscle cells and leucocytes. The p38 MAP kinase system inhibitor losmapimod however did not show any clinical effect. 109 Methotrexate is a broad-acting immunomodulating drug that inhibits DNA synthesis by competing with folate synthesis and by inhibiting T-cell adhesion molecules and T-cell activity. The drug is used in a wide array of autoimmune and oncological conditions. The ability of methotrexate to dampen atherosclerotic inflammation was studied in over 4,500 patients with chronic coronary disease and type 2 diabetes or metabolic syndrome. The trial was ended prematurely for reasons of futility, as accruing more data would unlikely be able to demonstrate any signal of clinical benefit. 110 One of the common denominators in these trials was the absence of any evident biochemical response to the treatment. These data strengthened the hypothesis that effective inhibition of the inflammatory pathways in atherosclerosis should comprise targeted and detectable interleukin – 1 and interleukin – 6 inhibition, confirming the earlier experimental findings. Promising therapeutic developments The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) was the first to prove that modulating the inflammatory pathway in atherosclerosis reduces major adverse cardiovascular events in patients with a recent history of myocardial infarction and an hsCRP level equal or above 2 mg/liter. The CANTOS trial randomised 10,061 patients to receive three subcutaneous doses of canakinumab, a selective interleukin – 1 β inhibitor, or placebo. Canakinumab (150 mg) reduced the risk for the composite end point of nonfatal myocardial infarction, nonfatal