CANTOS Trial Validates the Inflammatory Pathogenesis of Atherosclerosis
Setting the Stage for a New Chapter in Therapeutic Targeting
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Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.
The CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) provides intriguing support for the inflammatory hypothesis of atherosclerosis and cancer in man, demonstrating diverse clinical benefits of inhibiting IL (interleukin)-1β for cardiovascular events and lung cancer. Limited effects on cardiovascular mortality and safety concerns raised by a higher incidence of fatal infection warrant further studies to identify patient subgroups which profit most from anti-inflammatory therapy and a careful pursuit of alternative targets.
Abundant evidence from experimental and clinical studies has lend strong support to the hypothesis that inflammation contributes to the pathogenesis of atherosclerotic disease in conjunction with or beyond elevated lipid levels; however, ultimate proof by selective anti-inflammatory treatment in a clinical trial remained elusive for decades. This has now changed with the results of the CANTOS, a double-blind trial involving high-risk patients with prior myocardial infarction (MI) and a residual inflammatory response (defined by hsCRP [high-sensitivity C-reactive protein] levels >2 mg/L despite intensive statin therapy), who were randomized to canakinumab (50, 150, or 300 mg every 3 months) or placebo.1 Canakinumab, a human monoclonal antibody targeting IL-1β as the master cytokine of innate immunity, dose dependently reduced hsCRP and IL-6 levels by ≤43% from baseline. At 150 mg (but not the other doses), canakinumab significantly lowered the risk for the primary (MI, stroke, cardiovascular death) and secondary end points (hazard ratio [HR], 0.85 and 0.83, respectively). Adversely, canakinumab was associated with leukopenia and a higher incidence of fatal infection. Whereas no significant difference in all-cause or cardiovascular mortality was observed, canakinumab strikingly reduced cancer mortality (exploratory results indicating HR 0.23, for lung cancer), supporting a role of inflammation in cancer progression. …