Inflammation and cardiovascular diseases: lessons from seminal clinical trials

Inflammation has been long regarded as a key contributor to atherosclerosis. Inflammatory cells and soluble mediators play critical roles throughout arterial plaque development and accordingly, targeting inflammatory pathways effectively reduces atherosclerotic burden in animal models of cardiovascular (CV) diseases. Yet, clinical translation often led to inconclusive or even contradictory results. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) followed by the Colchicine Cardiovascular Outcomes Trial (COLCOT) were the first two randomized clinical trials (RCTs) to convincingly demonstrate the effectiveness of specific anti-inflammatory treatments in the field of CV prevention, while other phase III trials - including the Cardiovascular Inflammation Reduction Trial (CIRT) one using methotrexate - were futile. This manuscript reviews the main characteristics and findings of recent anti-inflammatory phase III trials in cardiology and discusses their similarities and differences in order to get further insights into the contribution of specific inflammatory pathways on CV outcomes. CANTOS and COLCOT demonstrated efficacy of two anti-inflammatory drugs (canakinumab and colchicine, respectively) in the secondary prevention of major adverse CV events (MACE) thus providing the first confirmation of the involvement of a specific inflammatory pathway in human atherosclerotic CV disease (ASCVD). Also, they highlighted the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-related pathway as an effective therapeutic target to blunt ASCVD. In contrast, other trials interfering with a number of inflammasome-independent pathways failed to provide benefit. Lastly, all anti-inflammatory trials underscored the importance of balancing the risk of impaired host defence with an increase in infections and the prevention of MACE in CV patients with residual inflammatory risk.