Anti-inflammatory Therapy for Atherosclerotic Disease

September 12, 2017
Mariah Zebrowski Leach, JD, MS

Canakinumab lowers CRP level and may significantly lower the incidence of recurrent cardiovascular events.

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 study

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.

The findings

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).

In the 150 mg group, the P values for both hazard ratios met the prespecified multiplicity-adjusted thresholds for statistical significance. Although the hazard ratios were similar in the 300 mg group and in the placebo group, the prespecified thresholds for significance were not met in that case. Still, “both a pooled analysis of all canakinumab doses and a trend analysis suggested a beneficial effect of canakinumab with regard to cardiovascular outcomes,” the researchers concluded.

Consistent with the known effects of interleukin-1β inhibition, canakinumab also resulted in significantly fewer reports of arthritis, gout, and osteoarthritis than did the placebo group. Although significantly more deaths were attributed to infection or sepsis in the pooled canakinumab groups than in the placebo groups, cancer mortality was found to be significantly lower with canakinumab than with placebo.

Implications

The results of this study suggest that reducing vascular inflammation may significantly lower the incidence of recurrent cardiovascular events. Inhibition of interleukin-1β represents only one of many potential anti-inflammatory pathways that might serve as targets for atheroprotection.

“Our data suggests that other antiinflammatory interventions, such as those that directly inhibit NLRP3 function or that alter downstream interleukin-6 signaling, may also be beneficial in reducing cardiovascular risk,” the researchers observed.

The lowered cancer risk among patients assigned to receive canakinumab is consistent with experimental data that relate interleukin-1 to the progression and invasiveness of certain tumors, particularly lung cancer. This finding may present another promising lead for future research.

References:

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]