Inhibition of inflammation through interleukin pathway may be protective against anemia

1. In this secondary analysis of data from the CANTOS trial in 2017, canakinumab significantly reduced the incidence of anemia in patients with a history of myocardial infarction.

2. Among participants with baseline anemia, those who received canakinumab had significantly higher hemoglobin levels versus placebo.

Evidence Rating Level: 3 (Average)

Study Rundown: Cytokines such as interleukins contribute to anemia pathogenesis by exerting numerous effects including myelosuppression, erythropoietin resistance, and decreased erythrocyte survival. While this link is well-characterized, it is unknown whether cytokine inhibition is sufficient to spur reversal of these trends. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) investigated the effect of canakinumab, a monoclonal antibody, on cardiovascular outcomes in patients with a history of myocardial infarction. This exploratory analysis of CANTOS found that inhibition of the interleukin-1β signaling pathway, in addition to conferring cardiovascular benefit, also improved hemoglobin levels in anemic patients and reduced overall incidence of anemia by over 15 percent. The greatest effects were observed in participants with the greatest anti-inflammatory responses, reinforcing the association between cytokine signaling and anemia development. One limitation of this study was that the analysis was conducted on data from a study designed for the purpose of specifically assessing the cardiovascular effects of canakinumab. Thus, the study protocol was not designed to evaluate the findings of the exploratory analysis. Additionally, generalizability was limited due to the study population’s relative homogeneity, meaning that prospective studies are needed to extend these findings to other groups. Further, the clinical relevance of increase in hemoglobin levels remains to be determined.

Click here to read the study in Annals of Internal Medicine

Click here to read an accompanying editorial in Annals of Internal Medicine

Relevant Reading: Heme Catabolic Pathway in Inflammation and Immune Disorders

In-Depth [randomized controlled trial]: CANTOS was a multinational, double-blind, placebo-controlled trial that recruited 10,061 participants with a history of myocardial infarction and high-sensitivity C-reactive protein (hsCRP) levels of 2 mg/L or greater despite receiving secondary preventive care. Patients were stratified according to time from the most recent myocardial infarction and randomly assigned to receive standard care plus either placebo or one of three dosages of canakinumab: 50, 150, or 300 mg administered subcutaneously every 3 months. Among patients who did not have anemia at baseline, each group had similar clinical characteristics including age, kidney function, and underlying inflammation. All three treatment groups experienced lowered hsCRP and interleukin-6 levels, and the combined canakinumab groups had a significantly lower likelihood of developing anemia versus placebo (HR, 0.84 [95% CI, 0.77 to 0.93]; P < 0.001). This protective effect was determined to be independent of sex, presence of hypertension, diabetes, or heart failure, among other variables. After stratification by hsCRP level at 3 months, it was discovered that participants with stronger anti-inflammatory responses had greater reductions in incident anemia (HR, 0.74; CI, 0.66 to 0.83; P < 0.001) compared to those whose hsCRP levels remained above 2 mg/L (HR, 0.98; CI, 0.88 to 1.09; P = 0.71). Participants who already had anemia at baseline also derived significant benefits from the trial regimens, exhibiting a 11.3 g/L (1.13 g/dL) increase in mean hemoglobin levels versus placebo at 2 years (P < 0.001).

Image: PD

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