1. Non-calcium-based phosphate binders did not affect arterial stiffness or aortic calcification compared to placebo in moderate-to-severe chronic kidney disease.
Evidence Rating Level: 1 (Excellent)
Abnormal phosphate homeostasis is characteristic of chronic kidney disease, with hyperphosphatemia strongly associated with increased arterial stiffness secondary to calcification. Positive phosphate balance may contribute to rising fibroblast growth factor 23 (FGF23) levels. Both high FGF23 levels and arterial stiffness and calcification are associated with worsening kidney function and cardiovascular events and mortality. Although calcium-based phosphate binders are most commonly prescribed to treat hyperphosphatemia, non-calcium-based phosphate binders, like lanthanum carbonate, have been associated with reduced vascular calcification. Consequently, limited trials have described non-calcium-based phosphate binder therapy lowering serum phosphate and FGF23 levels; however, their effects on cardiovascular markers remain unknown. IMPROVE-CKD, or the IMpact of Phosphate Reduction on Vascular Endpoints in CKD, is an investigator-initiated, multicentre, international,double-blinded, placebo-controlled trial. 138 participants with stage 3b-4 CKD (eGFR 15-44mL/min/1.73m2) with normophosphatemia were randomized 1:1 to receive either 500mg lanthanum carbonate or matched placebo three times daily for 96 weeks. By the end of the trial, no significant differences were seen in the primary endpoint, mean pulse wave velocity (PWV), or in abdominal aortic calcification (AAC), serum phosphate, parathyroid hormone, FGF23 levels, or 24-hour urinary phosphate. At baseline, there was a greater proportion of AAC in the lanthanum arm (86% vs 77% in placebo, p=0.23). Serious adverse events occurred at similar rates between the groups (46% lanthanum vs 47% placebo), next to a significantly higher rate of life-threatening events in lanthanum (3% vs 0%, p=0.06). The study cohort in general was at a high cardiovascular risk at baseline, with a high mean PWV level (>10m/s) and a high prevalence of AAC (81%). Advanced arterial stiffness and calcification may have contributed to the lack of effect seen with the intermediate cardiovascular outcomes measured. Achievement of only 57% of target recruitment also led to underpowering of the study. Nevertheless, this is the largest and longest placebo-controlled study of its kind and its results cannot justify treating moderate-to-advanced CKD with phosphate binders to reduce cardiovascular risk in normophosphatemia. Further studies that are adequately powered could target a cohort with positive phosphate balance to assess whether phosphate-lowering therapies would improve patient outcomes.
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