Paul M Ridker1, Jean G MacFadyen2, Robert J Glynn2, Wolfgang Koenig3, Peter Libby4, Brendan M Everett5, Martin Lefkowitz6, Tom Thuren6, Jan H Cornel7. 1. Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: pridker@bwh.harvard.edu. 2. Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 3. Deutsches Herzzentrum München, Technische Universität München, DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; University of Ulm Medical Center, Department of Internal Medicine II-Cardiology, Ulm, Germany. 4. Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 5. Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 6. Novartis Pharmaceutical Corporation, East Hanover, New Jersey, and Basel, Switzerland. 7. Noordwest Ziekenhuisgroep, Alkmaar, the Netherlands.
Abstract
BACKGROUND: Inflammation contributes to chronic kidney disease (CKD), in part mediated through activation of interleukin (IL)-1β by the NLRP3 inflammasome within the kidney. This process also likely contributes to the accelerated atherosclerosis associated with nephropathy. OBJECTIVES: The authors hypothesized that canakinumab, a human monoclonal antibody targeting IL-1β, might reduce cardiovascular event rates and improve renal function among post-myocardial infarction patients with CKD. METHODS:Stable post-myocardial infarction patients with high-sensitivity C-reactive protein (hsCRP) ≥ 2mg/l were randomly allocated to placebo or to 1 of 3 doses of canakinumab (50, 150, or 300 mg) given subcutaneously once every 3 months. Participants were followed for incident myocardial infarction, stroke, hospitalization for unstable angina requiring urgent revascularization, cardiovascular death, or death from any cause over a median follow-up period of 3.7 years (maximum 5 years). All patients additionally had serial monitoring of estimated glomerular filtration rate (eGFR), creatinine, the urine albumin to creatinine ratio (uACR), and were monitored for adverse renal and urinary events. RESULTS:Of 10,061 participants, 1,875 (18.6%) had baseline eGFR <60 ml/min/1.73 m2. These moderate CKD patients had higher incidence rates for major adverse vascular events compared with those with eGFR ≥60 ml/min/1.73 m2 (6.92 vs. 4.13 per 100 person-years; p < 0.0001). Random allocation to canakinumab reduced the risk of major adverse cardiovascular events among those with CKD (hazard ratio: 0.82; 95% confidence interval: 0.68 to 1.00; p = 0.05) with the largest cardiovascular benefits accruing among those who achieved on-treatment hsCRP levels below 2 mg/l measured after taking the first dose (hazard ratio: 0.68; 95% confidence interval: 0.53 to 0.86; p = 0.0015). Comparable effects were observed among those with baseline albuminuria or diabetes. Canakinumab had neither clinically meaningful benefits nor substantive harms with respect to serial measures of eGFR, creatinine, the uACR, or reported adverse renal events during trial follow-up. CONCLUSIONS:IL-1β inhibition with canakinumab reduces major adverse cardiovascular event rates among high-risk atherosclerosis patients with CKD, particularly among those with a robust anti-inflammatory response to initial treatment. These cardiovascular benefits accrued with no adverse clinical renal events. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846).
RCT Entities:
BACKGROUND: Inflammation contributes to chronic kidney disease (CKD), in part mediated through activation of interleukin (IL)-1β by the NLRP3 inflammasome within the kidney. This process also likely contributes to the accelerated atherosclerosis associated with nephropathy. OBJECTIVES: The authors hypothesized that canakinumab, a human monoclonal antibody targeting IL-1β, might reduce cardiovascular event rates and improve renal function among post-myocardial infarctionpatients with CKD. METHODS: Stable post-myocardial infarctionpatients with high-sensitivity C-reactive protein (hsCRP) ≥ 2mg/l were randomly allocated to placebo or to 1 of 3 doses of canakinumab (50, 150, or 300 mg) given subcutaneously once every 3 months. Participants were followed for incident myocardial infarction, stroke, hospitalization for unstable angina requiring urgent revascularization, cardiovascular death, or death from any cause over a median follow-up period of 3.7 years (maximum 5 years). All patients additionally had serial monitoring of estimated glomerular filtration rate (eGFR), creatinine, the urine albumin to creatinine ratio (uACR), and were monitored for adverse renal and urinary events. RESULTS: Of 10,061 participants, 1,875 (18.6%) had baseline eGFR <60 ml/min/1.73 m2. These moderate CKDpatients had higher incidence rates for major adverse vascular events compared with those with eGFR ≥60 ml/min/1.73 m2 (6.92 vs. 4.13 per 100 person-years; p < 0.0001). Random allocation to canakinumab reduced the risk of major adverse cardiovascular events among those with CKD (hazard ratio: 0.82; 95% confidence interval: 0.68 to 1.00; p = 0.05) with the largest cardiovascular benefits accruing among those who achieved on-treatment hsCRP levels below 2 mg/l measured after taking the first dose (hazard ratio: 0.68; 95% confidence interval: 0.53 to 0.86; p = 0.0015). Comparable effects were observed among those with baseline albuminuria or diabetes. Canakinumab had neither clinically meaningful benefits nor substantive harms with respect to serial measures of eGFR, creatinine, the uACR, or reported adverse renal events during trial follow-up. CONCLUSIONS: IL-1β inhibition with canakinumab reduces major adverse cardiovascular event rates among high-risk atherosclerosispatients with CKD, particularly among those with a robust anti-inflammatory response to initial treatment. These cardiovascular benefits accrued with no adverse clinical renal events. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846).
Authors: Yuliya Lytvyn; Petter Bjornstad; Daniel H van Raalte; Hiddo L Heerspink; David Z I Cherney Journal: Endocr Rev Date: 2020-04-01 Impact factor: 19.871
Authors: Adriana M Hung; Yohei Tsuchida; Kristen L Nowak; Sudipa Sarkar; Michel Chonchol; Victoria Whitfield; Natjalie Salas; Anna Dikalova; Patricia G Yancey; Jiansheng Huang; MacRae F Linton; T Alp Ikizler; Valentina Kon Journal: Clin J Am Soc Nephrol Date: 2019-04-23 Impact factor: 8.237
Authors: Quiana McKnight; Sarah Jenkins; Xiuqi Li; Tracy Nelson; Arnaud Marlier; Lloyd G Cantley; Karin E Finberg; Jackie A Fretz Journal: J Bone Miner Res Date: 2020-05-27 Impact factor: 6.741
Authors: Stephanie M Cicalese; Josiane Fernandes da Silva; Fernanda Priviero; R Clinton Webb; Satoru Eguchi; Rita C Tostes Journal: Circ Res Date: 2021-04-01 Impact factor: 17.367