Trial DesignInterleukin-1β inhibition and the prevention of recurrent cardiovascular events: Rationale and Design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)
Section snippets
The inflammatory hypothesis of atherothrombosis and the role of hsCRP in clinical practice
Inflammation contributes to all phases of the atherothrombotic process including the rupture of plaques that underlies many acute ischemic events in the coronary and cerebral circulations. Components of both the innate and acquired immune systems contribute to atherosclerotic disease progression, and interactions between lipids and multiple facets of immune function promote premature atherogenesis and accelerate plaque fissuring. As comprehensively reviewed elsewhere, inflammatory mechanisms
The interleukin-1 family and effects on systemic inflammatory disorders
Interleukins are critical mediators of the systemic inflammatory response. Of the inflammatory molecules implicated in atherothrombosis, interleukin-1 (IL-1) plays a particularly prominent role. The IL-1 gene family encodes 3 major proteins: IL-1α and IL-1β (that exert proinflammatory effects by binding to the IL-1 type I receptor) and IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor that competitively blocks binding of IL-1α and β to the IL-1 type I receptor). The balance of pro- and
Interleukin-1 and atherothrombosis
Experimental evidence accumulating over the past quarter century has implicated IL-1 in atherothrombosis.29, 38 Studies in the early 1989s showed that IL-1 can induce procoagulant activity as well as monocyte and leukocyte adhesion in human vascular endothelial cells.39, 40 Soon thereafter, both endotoxin and tumor necrosis factors (TNFs) were found to induce IL-1 gene expression in human vascular endothelial cells41 as well as human vascular smooth muscle cells, identifying a local source of
Canakinumab as an agent to target IL-1β and potentially reduce cardiovascular event rates and new-onset diabetes: the CANTOS trial
Given the role of IL-1β in atherothrombosis described above, the use of IL-1β inhibition as a possible method to reduce vascular risk has generated considerable interest. Canakinumab is a human monoclonal antihuman IL-1β antibody of the immunoglobin G1/k isotype that is currently indicated for the treatment of IL-1β–driven inflammatory disorders such as CAPS and Muckle-Wells syndrome. Canakinumab binds human IL-1β and, thus, blocks the interaction of this cytokine with its types I and II
Disclosures
The CANTOS is a trial sponsored by Novartis and was initiated and designed by investigators at the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital, Harvard Medical School, in collaboration with Novartis. Drs Thuren and Zalewski are employees of Novartis. Drs Ridker and Libby have received research grant support form Novartis. Dr Ridker is listed as a coinventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in
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ClinicalTrial.gov ID # NCT01327846.
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On behalf of the CANTOS study group.