TY - JOUR
T1 - A randomized trial on the effect of phosphate reduction on vascular end points in CKD (improve-CKD)
AU - IMPROVE-CKD Trial Investigators
AU - Toussaint, Nigel D.
AU - Pedagogos, Eugenia
AU - Lioufas, Nicole M.
AU - Elder, Grahame J.
AU - Pascoe, Elaine M.
AU - Badve, Sunil V.
AU - Valks, Andrea
AU - Block, Geoffrey A.
AU - Boudville, Neil
AU - Cameron, James D.
AU - Campbell, Katrina L.
AU - Chen, Sylvia S.M.
AU - Faull, Randall J.
AU - Holt, Stephen G.
AU - Jackson, Dana
AU - Jardine, Meg J.
AU - Johnson, David W.
AU - Kerr, Peter G.
AU - Lau, Kenneth K.
AU - Hooi, Lai Seong
AU - Narayan, Om
AU - Perkovic, Vlado
AU - Polkinghorne, Kevan R.
AU - Pollock, Carol A.
AU - Reidlinger, Donna
AU - Robison, Laura
AU - Smith, Edward R.
AU - Walker, Robert J.
AU - Wang, Angela Yee Moon
AU - Hawley, Carmel M.
AU - Wyndham, Roger
AU - Vilayur, Eswari
AU - Cooper, Bruce
AU - Wong, Muh Geot
AU - Tan, Ken Soon
AU - van Eps, Carolyn
AU - Cho, Yeoungjee
AU - Barbara, Jeffrey
AU - Paizis, Kathy
AU - McMahon, Lawrence P.
AU - Nelson, Craig
AU - Gafor, Abdul Halim Abdul
AU - Meng, Ong Loke
AU - Mushahar, Lily
AU - Maher, Emad
N1 - Funding Information:
This investigator-initiated research work was supported by National Health and Medical Research Council of Australia research grants APP1044302, APP1092957, and ID 631731, and by Shire (a member of the Takeda group of companies) grant IST-AUS-000108. National Health and Medical Research Council of Australia and Shire International did not have any role in study design, collection, analysis and interpretation of data, writing the report, and the decision to submit the report for publication. The Vanderbilt Institute for Clinical and Translational Research received support from National Center for Advancing Translational Sciences grant UL1 TR000445.
Funding Information:
S. Badve reports receiving grants from National Health and Medical Research Council of Australia, personal fees from Bayer AG and Amgen Australia, and nonfinancial support from Bayer AG, unrelated to the study. G. Block reports having current equity ownership of Ardelyx and Reata. G. Block also reports being an employee of Reata Pharmaceuticals; past research funding from Keryx; and past consulting with Kirin, Amgen, Akebia, Keryx, and OPKO. N. Boudville reports personal fees from Baxter; travel grants from Amgen and Roche; and grants from Amgen and Baxter, outside the submitted work. K.L. Campbell reports consultancy fees from Nestle Health Sciences. G.J. Elder reports receiving research funding from Amgen; and travel support and honoraria from Roche and Takeda, outside the submitted work. C.M. Hawley reports research grants from National Health and Medical Research Council of Australia; research funding to her institution from Baxter Healthcare, Fresenius Medical Care, and Shire; and consultancy fees from GlaxoSmithKline, Janssen, and Otsuka paid to her institution; and personal fees from Otsuka and grants from Shire, outside the submitted work. S.G. Holt reports receiving nonfinancial support from Amgen; personal fees from Astra-Zeneca; other from Baxter; personal fees from Otsuka; grants from Sanofi; and honoraria, travel support, and research funding from Amgen, AstraZeneca, Baxter, and Sanofi, outside the submitted work. M. Jardine reports having served on advisory boards sponsored by Akebia, Baxter, Boehringer Ingelheim, and Vifor; serves on the steering committee for a trial sponsored by CSL and Janssen; and speaking at scientific meetings sponsored by Amgen, Janssen, Roche, and Vifor, with any consultancy, honoraria, or travel support paid to her institution; a Medical Research Future Fund Next Generation Clinical Researchers Program Career Development Fellowship; and unrestricted funding from Gambro, Baxter, CSL, Amgen, Eli Lilly, and MSD. D. Johnson reports grants from Baxter Healthcare, Fresenius Medical Care, and the National Health and Medical Research Council of Australia; personal fees from Baxter Healthcare, Fresenius Medical Care, AWAK, Ono, and AstraZeneca; and other support from Amgen, unrelated to the study. N.M. Lioufas reports support for research from the Australian Commonwealth with an RTP scholarship, outside the submitted work. E. Pedagogos reports honoraria, travel support, and research funding from Amgen, Shire, and Sanofi, outside the submitted work. V. Perkovic reports grants or fees from National Health and Medical Research Council of Australia, Retrophin, Janssen, Merck, Servier, AbbVie, Astellas, AstraZeneca, Bayer, Baxter, BMS, Boehringer Ingelheim, Dimerix, DURECT, Eli Lilly, Gilead, GSK, Mitsubishi Tanabe, Novartis, Novo Nordisk, Pfizer, PharmaLink, Relypsa, Sanofi, Vifor Pharma, and Tricida, outside the submitted work. K.R. Polkinghorne reports grants from National Health and Medical Research Council of Australia; personal fees from Medtronic and AstraZeneca; and travel support from Amgen, outside the submitted work. C. Pollock reports being a speaker for AstraZeneca, Janssen Cilag, Sanofi, Novartis, Vifor, and Otsuka; and reports being an advisory board member for AstraZeneca, Merck Sharp and Dohme, Eli Lilly, Novartis, Vifor, and Otsuka. E. Smith owns stock in Calciscon AG, which commercializes the T50 test. E.R. Smith reports research funding from Amgen and Sanofi, outside the submitted work. A. Yee Moon Wang reports speaker honorarium from Fresinius Kabi; and grants from Sanofi, outside the submitted work. All remaining authors have nothing to disclose.
Publisher Copyright:
Copyright © 2020 by the American Society of Nephrology
PY - 2020/11
Y1 - 2020/11
N2 - Background Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain.Methods To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate.1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism. Results A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m2; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings. Conclusions In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia. Clinical Trial registry name and registration number Australian Clinical Trials Registry, ACTRN12610000650099.
AB - Background Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain.Methods To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate.1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism. Results A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m2; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings. Conclusions In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia. Clinical Trial registry name and registration number Australian Clinical Trials Registry, ACTRN12610000650099.
UR - http://www.scopus.com/inward/record.url?scp=85094982746&partnerID=8YFLogxK
U2 - 10.1681/ASN.2020040411
DO - 10.1681/ASN.2020040411
M3 - Article
C2 - 32917784
AN - SCOPUS:85094982746
SN - 1046-6673
VL - 31
SP - 2653
EP - 2666
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 11
ER -
