A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD)
Authors: Toussaint Nigel D. , Pedagogos Eugenia , Lioufas Nicole M. , Elder Grahame J. , Pascoe Elaine M. , Badve Sunil V. , Valks Andrea , Block Geoffrey A. , Boudville Neil , Cameron James D. , Campbell Katrina L. , Chen Sylvia S.M. , Faull Randall J. , Holt Stephen G. , Jackson Dana , Jardine Meg J. , Johnson David W. , Kerr Peter G. , Lau Kenneth K. , Hooi Lai-Seong , Narayan Om , Perkovic Vlado , Polkinghorne Kevan R. , Pollock Carol A. , Reidlinger Donna , Robison Laura , Smith Edward R. , Walker Robert J. , Wang Angela Yee Moon , Hawley Carmel M. ,   IMPROVE-CKD Trial Investigators
Published: September 2020

Significance Statement
In patients with CKD, higher serum phosphate levels are associated with increased fibroblast growth factor 23 (FGF23) levels, arterial calcification, and cardiovascular mortality. Limited trials assessing phosphate-lowering therapy have reported modest efficacy in lowering serum phosphate and FGF23 levels during short-term follow-up in patients with CKD; the effect of these agents on cardiovascular markers remains uncertain. This randomized trial involving 278 participants with stage 3b or 4 CKD (mean age 63 years) found no significant differences between the phosphate binder lanthanum carbonate and placebo for pulse wave velocity, abdominal aortic calcification, serum phosphate, or FGF23 levels at 96 weeks, nor did lanthanum carbonate attenuate intermediate markers of cardiovascular risk. This suggests a need for clinical trials to assess the utility of phosphate-lowering strategies in more highly targeted patients with nondialysis CKD.

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 principal 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