Sevelamer Doesn't Protect the Heart in Early CKD: Study

April 26, 2013

By Megan Brooks

NEW YORK (Reuters Health) Apr 26 - The phosphate binder sevelamer didn't have any favorable cardiovascular effects in a randomized controlled trial of patients with stage 3 chronic kidney disease (CKD), as the UK study team had hoped.

High blood levels of serum phosphate, even in the normal range, are associated with an increased risk of dying from cardiovascular-related causes in the general population and in patients with CKD. Phosphate's ability to promote calcification and stiffening of blood vessels and its potential to cause structural changes in the heart, such as increased wall thickness, may be the reason.

Sevelamer is indicated for the management of hyperphosphatemia in adult patients with stage 4 and 5 CKD on hemodialysis. Evidence from hemodialysis patients suggests that lowering serum phosphate may reduce left ventricular (LV) mass.

Dr. Charles Ferro of Queen Elizabeth Hospital Birmingham and colleagues designed their study to test the hypothesis that reducing the phosphate absorbed from the diet would improve surrogate markers of cardiovascular health in patients with early stage 3 CKD.

"We were aiming to show this in the general population and chose to use patients with mild CKD to increase the power of the pilot study as they would already have mildly deranged phosphate handling. The patients we studied were selected to have no biochemical evidence of mineral bone disorder," Dr. Ferro explained.

During a four-week open-label run-in period, 120 adults (mean age 55 years) with stage 3 nondiabetic CKD received sevelamer carbonate (1600 mg with each meal). Eleven patients withdrew during the run-in phase (five withdrew consent, two were intolerant to the medication, one had hypophosphatemia and three were non-compliant with the study).

After the run-in period, 55 patients were randomly assigned to continue sevelamer and 54 to take placebo for an additional 36 weeks. An additional 12 patients withdrew from this phase of the study (five in the sevelamer group and seven in the placebo group) for similar reasons.

Intention-to-treat analysis at 40 weeks showed "no statistically significant differences between sevelamer and placebo with regard to LV mass, systolic and diastolic function, or pulse wave velocity," the researchers reported online April 18 in the Journal of the American Society of Nephrology.

Only 56% of patients took 80% or more of their prescribed therapy, despite repeated reminders. In this compliant subgroup, treatment with sevelamer was associated with lower urinary phosphate excretion and serum fibroblast growth factor-23 (FGF-23) but not serum phosphate, klotho, vitamin D, or cardiovascular-related outcomes of interest, the researchers say.

"It would appear that for now it would be better to lower the amount of phosphate in the diet rather than rely on pharmacological interventions," Dr. Ferro commented in a statement. "Fast food and ready-to-eat processed foods are the main contributors to today's rising dietary consumption of phosphate."

But, he told Reuters Health, "More study is definitely worthwhile. The evidence linking phosphate to cardiovascular disease continues to grow. Several well-respected investigators are currently working in this area. Our group in Birmingham is still keen to take this work forward and several lines of investigation are being planned."

In an editorial, Dr. Rajiv Agarwal of Indiana University School of Medicine in Indianapolis agrees that this study "should not serve as a death knell to investigations on phosphorus in progressive CKD, but should instead serve as a cr�che for future investigations on the value of phosphorus reduction in preventing cardiovascular disease and CKD progression."

Dr. Agarwal also "congratulates the investigators for adding another randomized trial to the meager number of trials in nephrology. Their well conducted trial and transparent reporting are evident in their study. The editors also need to be congratulated for having the courage to publish a null trial in a prestigious journal."

The study was presented as an abstract at the 2012 American Heart Association Scientific Sessions in Los Angeles, California. It was funded by an unrestricted grant from Genzyme Corporation, which markets sevelamer. Two of the authors have received lecture and advisory board fees from Genzyme. Dr. Agarwal has several financial disclosures, all listed with the original article.

SOURCE: https://bit.ly/14WimqN

J Am Soc Nephrol 2013.

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