Trial Questions Safety and Efficacy of Phosphate Binders in CKD

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The longest placebo-controlled trial of phosphate binders conducted to date challenges the drugs’ utility in patients with chronic kidney disease (CKD) and points to the drugs’ potential harm to patients’ cardiovascular health. The findings, which were published recently in the Journal of the American Society of Nephrology, indicate that additional studies of the safety and efficacy of phosphate binders are needed.

Surprising trial results

Given the association between higher levels of phosphorus and mortality in patients with CKD, phosphate binders are commonly prescribed to patients with the disease even though they are approved only for patients with kidney failure.

“In the last several years there have been no less than a dozen observational reports demonstrating that higher serum phosphorus values within the normal range are associated with cardiovascular events, progression of CKD, and mortality,” said Geoffrey Block, MD, of Denver Nephrology, who is the lead author of the study. “This has been shown in patients with or without kidney disease but of course, patients with kidney disease are much more prone to having serum phosphorus at the high end of normal given the reduction in renal excretion of phosphorus.”

To determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with CKD, Block and his colleagues evaluated the effects of different phosphate binders in patients with moderate to advanced CKD and normal or near-normal serum phosphorus levels.

The investigators randomly assigned 148 patients with estimated GFRs of 20 to 45 mL/min per 1.73 m2 to receive calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus level from baseline to the average of months 3, 6, and 9.

“The results of the trial were quite surprising,” said Block. “Despite using substantial doses of all three medications and achieving the expected reduction in urinary phosphate excretion, serum phosphorus levels were reduced very modestly.”

Specifically, serum phosphorus decreased from a baseline mean level of 4.2 mg/dL in both active and placebo arms to 3.9 mg/dL with active therapy and 4.1 mg/dL with placebo. Phosphate binders, but not placebo, decreased the mean level of 24-hour urine phosphorus by 22 percent. The median level of serum intact parathyroid hormone remained stable with active therapy and increased with placebo. Active therapy did not significantly affect plasma levels of C-terminal fibroblast growth factor 23, which has been associated with progression of kidney disease, left ventricular hypertrophy, and all-cause mortality. Active therapy significantly increased calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1 percent versus 0.6 percent; abdominal aorta: median increases of 15.4 percent versus 3.4 percent). “There appeared to be substantial differences among the three different phosphate binders on the progression of vascular calcification and on levels of fibroblast growth factor 23; however the trial was not powered to examine specific binders versus placebo nor versus each other,” said Block.

Future of phosphate binders in patients with CKD

The results reveal that treatment with phosphate binders can significantly lower urinary phosphorus levels, moderately lower blood phosphorus levels, and slow the progression of secondary hyperparathyroidism in patients with CKD who have normal or near-normal levels of serum phosphorus. Despite these positive effects, phosphate binders do not seem to have any effect on the blood levels of a hormone that regulates phosphate excretion in the urine, and the drugs cause vascular calcification, which can lead to heart problems. Heart disease is the leading cause of death in patients with CKD.

“It was our expectation that effective reductions in phosphorus absorption would lower serum phosphorus more substantially, result in a reduction of fibroblast growth factor 23 levels, result in an increase in endogenous 1-25 vitamin D3 levels, and attenuate the progression of calcification relative to placebo in patients who were already calcified,” Block said. “In all of these areas our results contradicted our expectations.” The increased calcification observed in the study was seen not only in patients receiving calcium-containing phosphate binders, suggesting that phosphate binding therapy may have adverse health consequences not previously recognized in the short-term clinical trials used for approval.

These findings call into question the safety and effectiveness of phosphate binders in patients with CKD.

“While we continue to believe that serum phosphorus is a key component of the increased cardiovascular risk associated with kidney disease, our results suggest the use of the currently approved phosphate binding drugs does not result in substantial reductions in serum phosphorus and may be associated with harm in this population,” said Block.

Csaba Kovesdy, MD, who is the Fred Hatch Professor of Medicine in Nephrology at the University of Tennessee Health Science Center, in Memphis, said that the results regarding the biochemical effects of the binders are not surprising, but the effects on vascular calcification are more difficult to interpret.

“The results of this study should not be used to conclude that phosphorus binders are harmful. The study was not powered to assess changes in vascular calcification, and only 81 patients (55 percent of the total enrolled) were assessed for changes in this end point,” he said. Kovesdy, who was not involved with the study, added that because it is unclear how the baseline characteristics of these 81 patients differed from one another, it is possible that patients in the phosphate binder arm had baseline characteristics that predisposed them to more progressive calcification independently of treatment.

Tamara Isakova, MD, an assistant professor at the University of Miami Miller School of Medicine and an expert in mineral metabolism abnormalities in CKD, noted that additional studies, including those that investigate alternatives to phosphate binders, are needed. “The report by Dr. Block et al. and other recent studies should further motivate the nephrology community to continue to define the safety and efficacy of binders in CKD and to further investigate the role of dietary phosphate restriction as a potentially safe and effective sole or adjunctive risk-reduction strategy in this population,” she said.

Notes

[1] Study co-authors include David C. Wheeler, MD, Martha S. Persky, Bryan Kestenbaum, MD, Markus Ketteler, MD, David M. Spiegel, MD, Matthew A. Allison, MD, John Asplin, MD, Gerard Smits, PhD, Andrew N. Hoofnagle, MD, PhD, Laura Kooienga, MD, Ravi Thadhani, MD, Michael Mannstadt, MD, Myles Wolf, MD, and Glenn M. Chertow, MD.

[2] The article, entitled “A randomized trial of phosphate binders in patients with moderate chronic kidney disease,” is available online at http://jasn.asnjournals.org/; doi: 10.1681/ASN.2012030223.

September 2012 (Vol. 4, Number 9)