Current pharmaceutical options for atherosclerotic disease focus almost exclusively on reducing plasma levels of cholesterol, but a new study suggests that anti-inflammatory therapy may significantly lower the incidence of recurrent cardiovascular events.
Previous research has shown that downstream biomarkers of inflammation, such as high-sensitivity C-reactive protein (CRP) and interleukin-6, are associated with an increased risk of cardiovascular events, independent of cholesterol level.
Canakinumab, a fully human monoclonal antibody, lowers CRP level and targets interleukin-1β, a cytokine central to inflammatory response that drives the interleukin-6 signaling pathway. Previously investigated for the treatment of rheumatoid arthritis, canakinumab currently is approved for clinical use in rheumatologic disorders, such as systemic juvenile idiopathic arthritis.
Prior to this study, there was no evidence to show that reducing vascular inflammation could reduce rates of cardiovascular events in the absence of concomitant lipid lowering. Led by Paul Ridker, MD, of Brigham and Women’s Hospital in Boston, researchers writing in the New England Journal of Medicine hypothesized that canakinumab could be used to test the inflammatory hypothesis of atherothrombosis directly.
The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) was designed to evaluate whether canakinumab could prevent recurrent vascular events. The randomized, double-blind, placebo-controlled trial enrolled 10,061 patients who had a history of myocardial infarction with a CRP level of 2 mg/L or higher. The mean age of participants who underwent randomization was 61 years; 25.7% were women and 40.0% had diabetes. The trial compared 3 doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo.
Canakinumab significantly reduced CRP levels from baseline, as compared with placebo. In particular, the 150-mg dose of canakinumab resulted in a significantly lower incidence of recurrent cardiovascular events than placebo, independent of lipid-level lowering.
In the 150 mg group, the risk of nonfatal myocardial infraction, nonfatal stroke, or cardiovascular death was 15% lower than the risk in the placebo group (3.86 vs 4.50 events per 100 person-years). The risk of these events plus hospitalization for unstable angina that led to urgent revascularization was 17% lower in the 150 mg group than in the placebo group (4.29 vs 5.13 events per 100 person-years).
Ridker PM, Everett BM, Thuren T, et al. “Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.” N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914. [Epub ahead of print]