Elsevier

American Heart Journal

Volume 162, Issue 4, October 2011, Pages 597-605
American Heart Journal

Trial Design
Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: Rationale and Design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)

https://doi.org/10.1016/j.ahj.2011.06.012Get rights and content

Background

Inflammation contributes to all phases of the atherothrombotic process, and patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have increased vascular risk. Yet, it remains unknown whether direct inhibition of inflammation will reduce cardiovascular event rates.

Design

The CANTOS will evaluate whether interleukin-1β (IL-1β) inhibition as compared with placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable patients with coronary artery disease who remain at high vascular risk due to persistent elevations of hsCRP (>2 mg/L) despite contemporary secondary prevention strategies. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1β, a proinflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 inflammasome, a process promoted by cholesterol crystals. Canakinumab significantly reduces systemic C-reactive protein and other inflammatory biomarker levels, is generally well tolerated, and is currently indicated for the treatment of inherited IL-1β driven inflammatory diseases such as the Muckle-Wells syndrome. In a multinational collaborative effort using an event-driven intention-to-treat protocol, CANTOS will randomly allocate 17,200 stable postmyocardial infarction patients with persistent elevation of hsCRP to either placebo or to canakinumab at doses of 50, 150, or 300 mg every 3 months, administered subcutaneously. All participants will be followed up over an estimated period of up to 4 years for the trial primary end point (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) as well as for other vascular events, total mortality, adverse events, and specific clinical end points associated with inflammation including new onset diabetes, venous thrombosis, and atrial fibrillation.

Summary

If positive, CANTOS would confirm the inflammatory hypothesis of atherothrombosis and provide a novel cytokine-based therapy for the secondary prevention of cardiovascular disease and new-onset diabetes.

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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