Mounica Vallurupalli, MD; Jean G. MacFadyen, BA; Robert J. Glynn, ScD; Tom Thuren, MD; Peter Libby, MD; Nancy Berliner, MD; Paul M Ridker, MD
Financial Support: This study was funded by Novartis Pharmaceuticals.
Disclosures: Ms. MacFadyen reports grants from Novartis during the conduct of the study. Dr. Glynn reports grants from Novartis during the conduct of the study and grants from AstraZeneca, Kowa, and Pfizer outside the submitted work. Dr. Thuren was an employee of and held stock in Novartis Pharmaceuticals during the conduct of the study. Dr. Libby reports grants from Novartis and DalCor Pharmaceuticals and has served as an unpaid consultant and/or advisory board member for Amgen, Kowa Pharmaceuticals, XBiotech, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Pfizer, Sanofi-Regeneron, Olatec Therapeutics, MedImmune, Corvidia Therapeutics, and IFM Therapeutics during the conduct of the study. Dr. Ridker reports grants and personal fees from Novartis during the conduct of the study and personal fees from Inflazome, Corvidia, and Civi Biopharma outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-2945.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Data Sharing Statement: The authors have indicated that they will not be sharing data. The CANTOS protocol is available from Dr. Ridker (e-mail, firstname.lastname@example.org).
Corresponding Author: Paul M Ridker, MD, MPH, Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue, Boston, MA 02215; e-mail, email@example.com.
Current Author Addresses: Drs. Vallurupalli and Berliner: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115.
Ms. MacFadyen and Drs. Glynn and Ridker: Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue, Boston, MA 02215.
Dr. Thuren: Novartis Pharmaceutical Corporation, One Health Plaza, East Hanover, NJ 07936.
Dr. Libby: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115.
Author Contributions: Conception and design: T. Thuren, P. Libby, N. Berliner, P.M. Ridker.
Analysis and interpretation of the data: M. Vallurupalli, J.G. MacFadyen, R.J. Glynn, T. Thuren, P. Libby, N. Berliner, P.M. Ridker.
Drafting of the article: M. Vallurupalli, P. Libby.
Critical revision for important intellectual content: P. Libby, N. Berliner, P.M. Ridker.
Final approval of the article: M. Vallurupalli, J.G. MacFadyen, R.J. Glynn, T. Thuren, P. Libby, N. Berliner, P.M. Ridker.
Statistical expertise: R.J. Glynn.
Obtaining of funding: P.M. Ridker.
Administrative, technical, or logistic support: J.G. MacFadyen, P. Libby, P.M. Ridker.
Collection and assembly of data: J.G. MacFadyen, T. Thuren, P.M. Ridker.
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.
To determine whether IL-1β inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia.
Exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846)
Many clinical sites in 39 countries.
8683 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants without anemia at trial entry and 1303 with prevalent anemia at trial entry.
Random assignment to receive placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months.
Primary outcome was incident anemia (hemoglobin level <130 g/L in men or <120 g/L in women).
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.
CANTOS was not designed to assess the cause of anemia in individual trial participants.
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.
Vallurupalli M, MacFadyen JG, Glynn RJ, et al. Effects of Interleukin-1β Inhibition on Incident Anemia: Exploratory Analyses From a Randomized Trial. Ann Intern Med. 2020;:. [Epub ahead of print 24 March 2020]. doi: https://doi.org/10.7326/M19-2945
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Published: Ann Intern Med. 2020.
Published at www.annals.org on 24 March 2020
Hematology/Oncology, Red Cell Disorders.
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