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Evidence gathered over the past few decades indicates that atherosclerotic ischaemic heart disease can be considered an inflammatory condition in its own right. Conventional risk factors of IHD cause endothelial activation and dysfunction favouring the development of atherosclerotic changes and functional vascular abnormalities. Clinical and experimental data suggest that reducing LDL-cholesterol concentrations improve clinical outcomes.  It has been suggested that reducing inflammation without affecting lipid levels can achieve results similar to those obtained with the use of statins. The results of a recent study provide important information regarding the effects of anti-inflammatory interventions that without affecting cholesterol levels can improve clinical outcomes. (1)

The CANTOS investigators conducted a randomized, double-blind trial of canakinumab, a monoclonal antibody targeting interleukin-1β, in over 10,000 patients with a history of myocardial infarction and a high-sensitivity C-reactive protein concentration > 2 mg/L. Three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) were compared with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Canakinumab reduced  high-sensitivity C-reactive protein by 26% in the group that received the 50-mg dose, by 37% in the 150-mg group, and by 41 % in the 300-mg group compared with the placebo group. Canakinumab had no effect on cholesterol levels at any of the doses used in the study.

At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, compared with 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. Compared with placebo, hazard ratios were 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30) in the 50-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021) in the 150-mg group, and 0.86 (95% CI, 0.75 to 0.99; P = 0.031) in the 300-mg group. Only the 150-mg dose, but none of the other doses, met the prespecified threshold for statistical significance for the primary end point and the secondary end point. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31).  Of importance, and a finding that may limit the use of this kind of therapies in ischemic heart disease, was that canakinumab was associated with a higher incidence of fatal infection.

The authors concluded that antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months reduced the rate of recurrent cardiovascular events compared with placebo, and that this beneficial effect was independent of any lipid-level lowering effects. The study also showed a dramatic reduction in lung cancer mortality in the canakinumab group. The results of CANTOS open new avenues for research in the field of inflammation and atherosclerosis. More studies in large numbers of patients are required before canakinumab can be incorporated to the current anti-anginal armamentarium. Increased number of serious infections represent “collateral damage” that may limit the use of this therapeutic strategy in ischemic heart disease.

References

1. Ridker P et al. Antiinflammatory therapy with canakinumab for atherosclerotic Disease. N Engl J Med 2017; 377:1119-1131