The impact of improved phosphorus control: use of sevelamer hydrochloride in patients with chronic renal failure

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1 Nephrol Dial Transplant (2002) 17: The impact of improved phosphorus control: use of sevelamer hydrochloride in patients with chronic renal failure Naseem Amin Genzyme Corporation, Cambridge, MA, USA Abstract Phosphorus control is a primary goal in the care of patients with end-stage renal disease (ESRD). Sevelamer hydrochloride, a novel calcium-free, aluminum-free phosphate binder, allows physicians to control serum phosphorus in patients with ESRD without increasing serum calcium levels or contributing an excess calcium load. Clinical studies have shown that sevelamer provides sustained reduction in markers of soft-tissue and cardiac calcification, specifically serum phosphorus, calcium 3 phosphorus product, parathyroid hormone and also improves blood lipid profiles. Thus, sevelamer hydrochloride offers the promise of impacting cardiac calcification and thereby reducing patient morbidity and mortality. Long-term studies are underway to evaluate these potential benefits. This paper reviews sevelamer studies to date and addresses ongoing strategies for improving clinical management of phosphorus in ESRD. Keywords: calcium; chronic renal failure; hyperphosphataemia; phosphate binder; phosphorus; sevelamer hydrochloride Introduction Safe and effective management of serum phosphorus is a major goal of clinicians treating patients with endstage renal disease (ESRD). Consequences of inadequately controlled serum phosphorus include renal bone disease, metastatic calcification, and secondary hyperparathyroidism. Recently, hyperphosphataemia has been recognized to be an independent risk factor for mortality among dialysis patients and has been shown to be associated with cardiac-related complications and cardiac calcification w1x. Correspondence and offprint requests to: Naseem Amin, MD, Genzyme Corporation, One Kendall Square, Cambridge, MA 02139, USA. Naseem.Amin@genzyme.com Phosphate binder therapy has been a mainstay for treatment of hyperphosphataemia in ESRD patients. Calcium-based binders have been available since the 1980s, but their long-term use carries side effects that limit their effectiveness in many patients. Because large doses of calcium are required to adequately control phosphorus, hypercalcaemia is a common complication of calcium-based phosphate binders and hampers clinicians ability to control phosphorus. More insidiously, prolonged intake of high amounts of calcium may contribute to an excess calcium load and cardiac calcification w2x. Despite standard medical management for hyperphosphataemia, about 70% of haemodialysis patients in the US have serum phosphorus levels above normal ()5.0 mgudl ()1.6 mmolul)), based on data from a large epidemiological study in 1998 w3x. Elevated phosphorus levels significantly increased the risk of mortality in this patient population. Patients with serum phosphorus levels )6.5 mgudl ()2.09 mmolul) had a 27% higher risk of death, as compared with patients with serum phosphorus levels of mgudl ( mmolul). Elevated calcium 3phosphorus (Ca 3P) product also increased the risk of mortality. The relative risk of death in patients with Ca 3P )72 mg 2 udl 2 ()5.8 mmol 2 ul 2 ) was 34% higher than patients with Ca 3 P values of mg 2 udl 2 ( mmol 2 ul 2 ) w3x. The increased mortality associated with hyperphosphataemia in this study was primarily due to cardiac-related complications w3x. In a follow-up study, elevated phosphorus levels were strongly associated with an increased death risk due to cardiac causes, including coronary artery disease w4x. The relative risk of death from coronary artery disease was 52% higher for patients with serum phosphorus levels )6.5 mgudl ()2.1 mmolul), as compared with patients with levels -6.5 mgudl (O2.1 mmolul). Hyperphosphataemia was also associated with increased mortality from sudden death, other cardiac death, and cerebrovascular accidents w4x. Cardiac complications continue to represent about half of the reported causes of death in dialysis patients # 2002 European Renal Association European Dialysis and Transplant Association

2 Impacts of improved phosphorus control w5x. Cardiac risk is dramatically increased in dialysis patients, who have a 30 times greater risk of cardiovascular death as compared with the general population (Figure 1) w6x. Risk factors include hypertension, lipid abnormalities, left ventricular hypertrophy, glucose intolerance, and cardiovascular and valvular calcification. Elevated Ca 3 P and phosphorus levels in conjunction with excess calcium are seen as important risk factors for cardiac and metastatic calcification, conditions that may predispose patients to cardiac arrhythmia, conduction defects, or sudden death w1x. The morbid effects of metastatic calcification include atrioventricular block, cardiac failure w7x, pulmonary hypertension, arrhythmia, left and right ventricular hypertrophy w8,9x, bone and soft tissue necrosis w7x, pulmonary complications w2x, and tumoral calcinosis w7x. A number of recent studies indicate that cardiac calcification is common and progressive in the dialysis population, and may explain the higher risk of cardiac death in these patients w1,10 12x. For example, in a study of haemodialysis patients with documented or suspected coronary artery disease, mitral valve calcification was observed in 59% of dialysis patients, whereas aortic valve calcification was found in 55% of dialysis patients, as assessed by electron beam computed tomography (ECBT) w10x. The coronary artery calcium score was 2.5- to 5-fold higher in the dialysis patients as compared with non-dialysis patients. A study by Ribeiro et al. found similar results. These researchers reported a greater prevalence of cardiac valve calcification in dialysis patients as compared with normal patients w1x. On the basis of echocardiography, 45% of dialysis patients showed mitral annulus calcification vs 10% of normal patients, and 52% of dialysis patients had calcification of the aortic annulus vs 4% of normal patients (Figure 2). Elevated Ca 3 P levels were positively correlated to cardiac valve calcification in this study. Cardiac calcification is evident even in young nondiabetic dialysis patients. Using EBCT, Goodman et al. found that coronary artery calcification was common in a study of young adult haemodialysis patients w11x. Serum Ca 3P and intake of calcium-containing binders were significantly higher among patients with cardiac calcification. These data have led researchers to conclude that current strategies for managing hyperphosphataemia have limited effectiveness and may potentially contribute to cardiovascular morbidity and mortality among patients w13x. In a recent review, Block and Port proposed that prevention of uraemic calcification and cardiac death should be of primary concern when evaluating the risks of hyperphosphataemia and elevated parathyroid hormone (PTH) w13x. In addition, they proposed new target levels for serum phosphorus, calcium, and PTH that are closer to normal values, and suggested strategies for improved management of phosphorus that include the use of calcium-free phosphate binders, which do not add to the calcium load, induce hypercalcaemia, or promote metastatic calcification w13x. Impacts of improved phosphorus control Sevelamer hydrochloride (Renagel 1, Genzyme Corporation) is a novel, calcium-free, aluminum-free phosphate binder that prevents dietary absorption of phosphorus. Since its approval in Europe and in the US, sevelamer has demonstrated effective, long-term control of serum phosphorus and Ca 3 P in haemodialysis patients, as well as blood lipid-lowering effects, with minimal impacts on serum calcium levels. Improved control of serum phosphorus without increasing the calcium load or promoting calcification may help prevent calcific cardiac complications in ESRD patients an important goal, given the high incidence of cardiac complications and death among dialysis patients w6x. The documented benefits of sevelamer provide an opportunity to impact patient morbidity and reduce medical care costs. Specificity and properties of sevelamer 341 Sevelamer hydrochloride is a calcium-free, cationic hydrogel of cross-linked poly(allylamine hydrochoride) that binds phosphate ions through a combination of anionic and hydrogen bonding (Figure 3). Multiple Fig. 1. Cardiac risk is dramatically increased in dialysis patients by 30-fold. Fig. 2. Presence of valvular calcification in the mitral annulus and aortic annulus.

3 342 N. Amin Fig. 3. Sevelamer structure and phosphate binding. Combination of anionic and hydrogen bonding. binding sites of partially protonated amines on the polymer backbone allow efficient, selective binding of phosphate during phosphate-rich meals. Sevelamer also binds and sequesters bile acids, which may explain the blood cholesterol-lowering effects of the drug. Because of its large particle diameter size (mean 45 mm), sevelamer is not absorbed systemically due to physical barrier in the gastrointestinal tract. These properties impart a low incidence of side effects, allowing sevelamer to effectively control serum phosphorus without adding to the total body calcium load. Impact on serum phosphorus and calcium Sevelamer significantly lowers serum phosphorus in haemodialysis patients but with minimal effects on serum calcium as compared with treatment with standard calcium-based phosphate binders w14 16x. In phase III crossover studies, sevelamer reduced serum phosphorus and Ca 3 P in haemodialysis patients, with a potency equivalent to that seen with calcium acetate therapy w15x. The mean change from baseline in serum phosphorus levels after 8 weeks of sevelamer treatment was 2.0"2.3 mgudl ( 0.64"0.74 mmolul) (P ), similar to calcium acetate treatment (mean change 2.1"1.9 mgudl ( 0.67"0.61 mmolul), P ). Hypercalcaemic episodes were significantly lower with sevelamer as compared with calcium acetate treatment. Serum calcium levels )11.0 mgudl ()2.75 mmolul) occurred Fig. 4. Episodes of hypercalcemia ()2.625 and )2.750 mmolul) with sevelamer and calcium-based phosphate binders. in 5% of patients during sevelamer treatment, as compared with 22% of patients receiving calcium acetate (P ) (Figure 4) w15x. Long-term treatment with sevelamer resulted in sustained reductions in serum phosphorus and Ca 3P. In an open-label clinical trial of 192 haemodialysis patients, sevelamer treatment was associated with a mean change of 2.2"2.4 mgudl ( 0.71" 0.77 mmolul) in serum phosphorus levels, of 18.1"22.0 mg 2 udl 2 ( 1.46"1.78 mmol 2 ul 2 )inca3p, and of 0.32"0.88 mgudl (0.08"0.22 mmolul) in serum calcium levels (P ) after 44 weeks w14x. Ongoing studies are seeking to normalize serum phosphorus and calcium, and to optimize PTH levels through combined sevelamer and vitamin D therapy.

4 Impacts of improved phosphorus control Impact on parathyroid hormone Because sevelamer effectively lowers serum phosphorus levels, it has the potential to help manage secondary hyperparathyroidism, especially in combination with optimal vitamin D treatment. Long-term clinical studies found favourable changes in median serum intact PTH (ipth) levels during 44 weeks of sevelamer treatment. Changes in median ipth levels during sevelamer treatment were dependent on baseline ipth levels w14x. Patients with the highest ipth levels ()300 pguml ()31.59 pmolul)) had the greatest reduction in ipth during the study, whereas patients with below target ipth levels at baseline showed an increase in ipth levels, with a trend toward reaching target ipth levels (Figure 5). These changes in ipth levels occurred without inducing hypercalcaemia. Thus, sevelamer has the potential to positively impact patients with low levels of ipth and moderate to severe secondary hyperparathyroidism without complicating treatment by raising serum calcium levels. Impact on blood lipid profiles Clinical studies have shown that sevelamer may impact cardiovascular health in several ways. Because it is non-absorbed and calcium-free, sevelamer does not promote elevations in serum calcium and Ca 3P that are associated with vascular calcification and risk of cardiac-related death. Further, short- and long-term studies have consistently shown that sevelamer treatment results in positive changes in blood cholesterol profiles w14,16,17x. In an open-label clinical trial of 192 haemodialysis patients, serum levels of low density lipoprotein (LDL) decreased by an average of 30% from baseline (mean change, 31.7"28.6 mgudl ( 0.82"0.74 mmolul), P ) during 44 weeks of sevelamer treatment w14x. High density lipoprotein (HDL) levels increased from baseline by an average of 18% (mean change, 5.8"11.2 mgudl (0.15"0.29 mmolul), P ). These changes in lipid levels were dependent on baseline LDL levels. Those patients with the highest LDL levels showed the most dramatic changes in LDL and HDL levels after sevelamer treatment (Figure 6) w14x. These sustained effects indicate that sevelamer has the potential to significantly improve lipid profiles in ESRD patients, and especially benefit those at greater risk for cardiac complications because of diabetes, hypertension, or lipid abnormalities. Impact on risk of hospitalization and medical care costs 343 The benefits of sevelamer treatment may translate into lower risk of hospitalization and medical care costs. In a case-controlled study, the risk of hospitalization of sevelamer-treated Medicare patients was compared with randomly selected Medicare patients receiving conventional phosphate binder therapy w18x. Patients (ns152) were matched based on age, gender, race, diabetic status, and geographic location. A Cox regression, stratified on diabetic status, was used to assess the risk of all-cause hospitalization in the 17-month follow-up period. Models included increasing adjustments for patient characteristics to reduce potential treatment bias in the sevelamer-treated group. These models included: M-1 (adjustments for age, gender, and race); M-2 (M-1 plus co-morbidities); M-3 (M-2 plus prior ESRD time and total hospital days during the previous 6 months); and M-4 (M-3 plus disease severity and haematocrit levels). As compared with the control group, sevelamertreated patients had lower unadjusted first hospitalization rates and lower adjusted relative risk of first hospitalization. Risk of first hospitalization was 46 54% less in the sevelamer group as compared with the control group (P-0.03) in the follow-up period across the four models that adjusted for patient characteristics and co-morbidities (Figure 7). The reduced risk for sevelamer-treated patients was Fig. 5. Median change in PTH level, by baseline PTH groups. Patients with higher levels had greatest reduction in PTH. Fig. 6. Change in serum lipid profile with sevelamer treatment.

5 344 N. Amin mainly due to a lower incidence of hospitalization for cardiovascular and vascular access complications w18x. Death rates in the sevelamer group from all causes appeared lower than in the control group (67 vs 101 deaths per 1000 patient years); however, prospective, randomized studies with a larger number of patients are required to confirm these results. A 2000 patient prospective, randomized study (D-COR) comparing sevelamer to calcium-based phosphate binder treatment has been initiated. Analysis of Medicare allowable expenditures in this study showed that the treatment costs were substantially less for those patients receiving sevelamer as compared with conventional binder therapy. The costs per member per month (PMPM) was about US$1400 less for sevelamer-treated patient as compared with the non-sevelamer group in the 17-month follow-up period (Part A expenses, US$3368 vs 4745; total expenses US$4422 vs 5866) (Figure 8) w18x. The lower costs in the sevelamer group were mainly due to lower inpatient expenses. While further prospective studies are required, the data suggest that sevelamer treatment substantially reduces the risk of hospitalization and the associated medical costs for haemodialysis patients w18x. Other studies Ongoing studies are evaluating the potential impact of sevelamer on morbidity and mortality in patients with ESRD. Prospective, randomized, long-term studies employing EBCT are assessing the effect of sevelamer, as compared with calcium-based phosphate binders, on cardiac and aortic calcification, serum phosphorus, calcium, Ca 3P product, and PTH levels. Other studies are evaluating the effect of sevelamer on bone morphology, vascular access, and use in peritoneal dialysis patients and paediatric patients. These studies will address the role of sevelamer in optimizing renal care. Conclusions Fig. 7. Adjusted risk of first hospitalization by detailed Cox regression analyses. Controlling serum phosphorus levels in ESRD patients is vital to minimize the development of renal bone disease, secondary hyperparathyroidism, and metastatic calcification. Hyperphosphataemia, excess calcium load, and elevated Ca 3P appear to contribute to the high incidence of calcific cardiac disease and mortality in chronic dialysis patients. Dietary phosphate restriction alone is not generally sufficient to control serum phosphorus levels, thus daily administration of oral phosphate binding agents is necessary in almost all dialysis patients. During the past decade, the most commonly used phosphate binders were calciumbased compounds. However, chronically high levels of calcium intake have been recognized to contribute to excess calcium load, soft-tissue calcification, and cardiac calcification in ESRD patients. Since it has become commercially available, sevelamer has been shown to effectively control serum phosphorus with minimal effects on calcium levels. Its ability to improve blood lipid profiles, without increasing the risk of metastatic calcification, associated with a high calcium load makes this phosphate binder an important tool in improving the management of phosphorus in dialysis patients. Further studies will evaluate its potential to positively impact patient survival and morbidity and to reduce medical care costs. References Fig. 8. Medicare allowable expenditures, per patient per month. 1. Ribeiro S, Ramos A, Brandao A et al. Cardiac valve calcification in hemodialysis patients: role of calcium-phosphate metabolism. Nephrol Dial Transplant 1998; 13: Hsu C. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis 1997; 29:

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