Randomized Crossover Trial of Phosphate-binding Medication on Serum Phosphate Levels in Patients With Aortic Stenosis

David S Wald,John Chambers,Jonathan P Bestwick,Nicholas J Wald

doi:10.1016/j.clinthera.2019.08.004

David S Wald, John Chambers + Show 2 more

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https://doi.org/10.1016/j.clinthera.2019.08.004

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Abstract

PurposeAortic stenosis is a common cause of valvular heart disease with no means of prevention. The recognized association between aortic stenosis and serum phosphate raises the possibility of preventing progression of the disorder by using phosphate-binding drugs, but there is uncertainty whether such treatment lowers serum phosphate levels in patients without diagnosed renal failure. This pilot study was conducted to answer this question in patients with aortic stenosis. MethodsA randomized, double-blind, crossover trial of the phosphate-binding drug sevelamer was conducted in 72 patients. Patients were prescribed sevelamer 0.8 g (low-dose), sevelamer 2.4 g (high-dose), and matching placebo, 3 times daily with food; each regimen lasted 6 weeks and was allocated at random. Serum phosphate levels were measured at the end of each treatment period, and within-person levels were compared. FindingsSixty-one patients completed the 3 treatment periods. There was no significant difference in the mean end-treatment phosphate levels across all patients (3.38, 3.36, and 3.31 mg/dL with placebo, low-dose sevelamer, and high-dose sevelamer, respectively). Post hoc analysis showed a reduction in phosphate levels with increasing sevelamer dose in the highest baseline phosphate quartile group; a 0.3 mg/dL reduction (mean, 4.09 mg/dL with placebo, 3.95 mg/dL with low-dose sevelamer, and 3.79 mg/dL with high-dose sevelamer; Ptrend = 0.027). ImplicationsSevelamer had no overall statistically significant effect in lowering serum phosphate levels, but a reduction was observed in patients with phosphate levels in the highest quartile group of the population distribution. This hypothesis-generating result requires confirmation in an independent study. If confirmed, a trial of sevelamer in preventing the progression of aortic stenosis may be justified in patients with high phosphate levels. ISRCTN Registry identifier: ISRCTN17365679.

Highlights

Aortic stenosis affects ~3% of people aged >75 years[1,2] and is the most common indication for heart valve replacement and cause of death from valvular heart disease in Western countries.[3,4] Calcium phosphate crystals accumulate on the aortic valve,[5] leading to progressive obstruction of blood flow from the heart and death in symptomatic cases, unless the valve is surgically replaced.[6]
There was a suggestion of a reduction in serum phosphate at the end of the sevelamer periods, but this finding was not statistically significant (P values for low-dose sevelamer vs placebo, P 1⁄4 0.720; high-dose sevelamer vs placebo, P 1⁄4 0.306; and Ptrend 1⁄4 0.807)
Estimated 24-h urine phosphate measurements revealed reductions in excretion of phosphate during the low-dose and highdose sevelamer periods (P < 0.001 for each dose compared with placebo)

Summary

Introduction

Aortic stenosis affects ~3% of people aged >75 years[1,2] and is the most common indication for heart valve replacement and cause of death from valvular heart disease in Western countries.[3,4] Calcium phosphate crystals accumulate on the aortic valve,[5] leading to progressive obstruction of blood flow from the heart and death in symptomatic cases, unless the valve is surgically replaced.[6]. Phosphate-lowering drugs such as sevelamer, which bind dietary phosphate in the gut, are used in patients with renal failure undergoing dialysis to lower raised serum phosphate levels, typically >5.5 mg/dL, but it is not known whether such treatment lowers serum phosphate levels in people not on dialysis. It is uncertain whether treatment, in the absence of diagnosed renal failure, will lower phosphate levels because preserved renal function may counter the effect of reduced dietary phosphate absorption.[8] This uncertainty prompted us to conduct a randomized, double-blind, placebo-controlled crossover trial to determine whether sevelamer reduces serum phosphate levels in patients without diagnosed renal failure.

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