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Published on: March 1, 2011
Effects of Interleukin-1β Inhibition on Incident Anemia: Exploratory Analyses From a Randomized Trial
Mounica Vallurupalli1, Jean G MacFadyen1, Robert J Glynn1
1Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (M.V., J.G.M., R.J.G., P.L., N.B., P.M.R.).
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.
