Effects of Interleukin-1β Inhibition on Incident Anemia: Exploratory Analyses From a Randomized Trial

Abstract

Background: Inflammatory cytokines, such as interleukin (IL)-1β, alter iron homeostasis and erythropoiesis, resulting in anemia, but whether inhibition of IL-1β can reverse these effects is unclear.

Objective: To determine whether IL-1β inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia.

Design: Exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846).

Setting: Many clinical sites in 39 countries.

Participants: 8683 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants without anemia at trial entry and 1303 with prevalent anemia at trial entry.

Intervention: Random assignment to receive placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months.

Measurements: Primary outcome was incident anemia (hemoglobin level <130 g/L in men or <120 g/L in women).

Results: Anemia incidence increased with rising baseline levels of high-sensitivity C-reactive protein (hsCRP), and both hsCRP and IL-6 decreased among participants receiving canakinumab compared with the placebo group. During a median follow-up of 3.7 years, participants without baseline anemia who received canakinumab at any dosage had significantly less incident anemia than those who received placebo (hazard ratio, 0.84 [95% CI, 0.77 to 0.93]; P < 0.001). Compared with placebo, the greatest benefits of IL-1β inhibition on incident anemia were observed among participants with the most robust anti-inflammatory response, an effect corroborated in formal mediation analyses. Among those with baseline anemia, canakinumab increased mean hemoglobin levels by 11.3 g/L (P < 0.001) compared with placebo after 2 years of treatment. Canakinumab increased the risk for infection and was associated with mild cases of thrombocytopenia and neutropenia, none of which was grade 3 or higher.

Limitation: CANTOS was not designed to assess the cause of anemia in individual trial participants.

Conclusion: These exploratory analyses of randomized trial data provide proof of principle that inflammation inhibition, at least through the IL-1β/IL-6 signaling pathway, reduces the incidence of anemia and improves hemoglobin levels in patients with anemia.

Primary funding source: Novartis Pharmaceuticals.

Figures

Appendix Figure 1.

Mean hemoglobin levels over time in participants with anemia at baseline (

Appendix Figure 2.

Resolution of anemia over the course of the study among participants with anemia at baseline who received canakinumab, 50, 150, or 300 mg every 3 months, compared with the placebo group. HR = hazard ratio.

Figure 1.

Cumulative incidence of anemia (hemoglobin level top) and with the groups receiving 50, 150, or 300 mg of canakinumab once every 3 months (bottom). HR = hazard ratio.

Figure 2.

Efficacy of canakinumab versus placebo for incident anemia, according to subgroups based on baseline clinical characteristics. Data are shown as HRs for all canakinumab groups (50, 150, and 300 mg) combined compared with the placebo group. The dotted line represents the overall effect of canakinumab versus placebo for the total cohort. eGFR = estimated glomerular filtration rate; HR = hazard ratio; hsCRP = high-sensitivity C-reactive protein.

Figure 3.

Cumulative incidence of anemia (hemoglobin level

Figure 4.

Cumulative incidence of anemia (hemoglobin level