Phosphate-Binding Agents Regulate Serum Phosphate and Lower Mortality Risk

The use of phosphate-binding agents (PBAs) in patients on hemodialysis is associated with reduced mortality risk regardless of other factors, according to results from the large European Current Management of Secondary Hyperparathyroidism—a Multicenter Observational Study (COSMOS). The association applied to all types of PBAs except those containing aluminum, said trial chairman Jorge Cannata-Andia, MD, of the Hospital Universitario Central de Asturias in Oviedo, Spain.

The study, conducted at 220 centers across the European Union, investigated the association between treatments affecting bone metabolic parameters and clinical outcomes among patients on hemodialysis. Specifically, the researchers looked at the association between the use of a single PBA or a combination of PBAs and mortality.

COSMOS was an observational study with 3 years of follow-up that enrolled patients from a wide geographic area in Europe in numbers approximately proportional to the number of patients on hemodialysis in each country.

COSMOS essentially confirmed the relationship of phosphorus levels and mortality risk seen in previous studies, with the lowest risk of all-cause mortality occurring at a serum phosphorus level near 4.0 mg/dL. Below 3.0 mg/dL, the mortality risk doubled (hazard ratio [HR], 2.0). An elevated serum phosphorus level also conferred a higher mortality risk, increasing at a phosphorus level greater than 5.5 mg/dL. The mortality risk was about 50 percent higher (HR of about 1.5) when the serum phosphorus exceeded 6.5 mg/dL.

Similarly, for cardiovascular mortality the lowest risk was at about 4.0 mg/dL, with higher risks observed at both low and high serum phosphorus levels.

The use of PBAs reduced the risk of all-cause and cardiovascular mortality, in many cases by as much as 50 percent.

The findings held regardless of age, sex, history of diabetes or cardiovascular disease, time on hemodialysis, or baseline serum parathyroid hormone, calcium, or phosphorus levels.

The investigators developed three statistical models to study the association between mortality rates and the use of phosphate binders. The models took into account and adjusted for differences in the case mix, case mix plus therapies other than PBAs, and case mix plus other therapies plus blood chemistries.

For each model, all PBAs (except those containing aluminum) were associated with significantly lower risks of all-cause and cardiovascular mortality. A wide range of PBAs were included, encompassing those containing calcium or lanthanum, calcium and lanthanum, polyanionic gels, calcium or lanthanum plus polyanionic gels, polyanionic gels plus a lanthanum-containing PBA, a calcium plus aluminum-containing PBA, and polyanionic gels plus an aluminum-containing PBA. The greatest risk reduction (73 percent) occurred with the use of a polyanionic gel plus a lanthanum-containing PBA.

“The main message is that PBAs are ... related with a lower mortality,” Cannata-Andia concluded. “We can say that this effect is from the phosphate binder and is not the effect of vitamin D or a calcium mimetic.”

He emphasized that the combination of PBAs, which is a common practice, did better than agents used singly.

Cannata-Andia noted “huge differences in price” for PBAs, with the oldest and least expensive PBAs (those containing aluminum) having lesser efficacy in terms of mortality risk, and the newer and more expensive PBAs having more efficacy but also a higher cost. Still, he said it is “very reassuring” that combinations of calcium-containing and non–calcium containing PBAs “did very well.”

Notes

[1] The study was supported by Fundación Renal Iñigo Alvarez de Toledon and by Amgen. Dr. Cannata-Andia had no other disclosures.