A Gigantic Proof-of-Concept Trial
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Cumulative evidence links inflammation with atherothrombotic disease. Conversely, the role of modulating the inflammatory process as a therapeutic target has remain an unproven hypothesis until the execution of the CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study). On the one hand, this trial provides robust evidence that interleukin-1β (IL-1β) inhibition by canakinumab reduces the incidence of repetitive atherothrombotic events in patients with postmyocardial infarction already on state-of-the-art treatment but with a residual inflammatory risk. On the other hand, the absolute antiatherothrombotic effect size of this intervention seems small (189 patients had to be intervened during 1 year to prevent 1 myocardial infarction episode) and associated with a mild increase in the incidence of serious adverse events (≈1 in 750 patients intervened during 1 year developed a fatal infection or sepsis). Beyond all these considerations, CANTOS represents a gigantic (10 000 patients) proof-of-concept trial.
Atherosclerosis is a systemic disease with a long clinically silent phase. Arterial wall lipid deposition, the hallmark of atherosclerosis, begins early in life. Atherosclerotic plaques grow gradually for several years, the disease becoming clinically overt only when the plaque is large enough to restrict blood flow or becomes unstable and ruptures, causing a thrombus. From its earliest asymptomatic phase through to the late clinical manifest stages, atherosclerosis is predominantly an inflammatory disease, featuring leukocyte activation, cytokine release, and infiltration by eosinophils, neutrophils, and macrophages. Epidemiological studies have revealed that circulating inflammatory biomarkers, especially C-reactive protein (CRP) measured by a high sensitivity (hs) assay, are associated with a higher incidence of atherothrombotic events (myocardial infarction, stroke, etc.).1 All these observations suggested that strategies to reduce inflammation would lead to a reduction in atherothrombotic events. However, it is important to note that the evidence linking inflammation to atherosclerosis is associative, and evidence for a causal role of inflammation in atherothrombotic …