Review of Phosphate Binders for the Treatment of Chronic Kidney Disease: A Managed Care Pharmacy Perspective

Dea Belazi, PharmD, MPH
Dr. Belazi has no actual or potential conflict of interest in relation to this program.

Dr. Belazi does not plan on discussing unlabeled/investigational uses of a commercial product.

Target Audience
This activity is designed for licensed pharmacists within both the community and managed care settings.


 
Table of Contents
 
Disclosure Statement

In accordance with the Criteria for Quality and Interpretive Guidelines of the Accreditation Council for Pharmacy Education, Massachusetts College of Pharmacy and Health Sciences will disclose any interest or affiliation a speaker may have with a supporting commercial organization, and also identify any discussion of unlabeled/investigational uses of a commercial product.
Dea Belazi, PharmD, MPH

Dr. Belazi has no actual or potential conflict of interest in relation to this program.

Dr. Belazi does not plan on discussing unlabeled/investigational uses of a commercial product.

Supporter Acknowledgement

This educational activity is supported by an educational grant from Genzyme.

 
 

Needs Assessment back to menu

The managed care environment is continuously bombarded with new pharmaceuticals that command premium prices, forcing organizations to evaluate the full value proposition of each new product. Will a new product decrease the overall cost of the disease while increasing pharmacy spend in the short-term? At the same time, will it improve outcomes and patient quality of life? Questions like these are often difficult to answer when a new product launches. However, over time, data become available that support or refute such hypotheses.

With the increase in chronic kidney disease (CKD) and dialysis treatment across the United States, focus on dialysis patient outcomes is becoming a major priority for the healthcare system. Prolonging survival, decreasing costs, reducing comorbid illnesses, and improving patient quality of life are all aspirational standards for major dialysis centers. Along these lines, recent clinical data reflect that for dialysis patients who are on calcium-based phosphate binders, calcification can lead to increased rates of cardiovascular disease; this development has become a major topic of discussion. The recent approval of non-calcium based phosphate binders provides alternative treatment options to avoid calcification in dialysis patients. Pharmacists must understand these new products and their potential benefits across the entire healthcare budget, not just by evaluating pharmacy spend.

Learning Objectives back to menu

At the conclusion of this activity, the participant should be able to:

  • Discuss the available treatment options for hyperphosphatemia in dialysis patients.
  • Identify the various stages of chronic kidney disease.
  • Compare and contrast the advantages and disadvantages of calcium and non-calcium based phosphate binders in dialysis patients.
  • Describe trends within the chronic kidney disease market.

Accreditation back to menu

The Massachusetts College of Pharmacy and Health Sciences is accredited as a provider of Continuing Education for Pharmacists by the Accreditation Council for Pharmacy Education (ACPE). In order to receive credit for this educational activity, all participants must complete a signature sheet and evaluation form. ACPE Program Number: 026-999-05-064-H01.

  • Initial Release Date: October 31, 2005
  • Planned Expiration Date: October 31, 2008

Review of Phosphate Binders for the Treatment of Chronic Kidney Disease: A Managed Care Pharmacy Perspective

Background back to menu

Healthy kidneys remove excess water and wastes from the blood, control blood pressure, keep body chemicals in balance, maintain bone strength, and produce red blood cells.i Chronic kidney disease (CKD) occurs when the kidneys are no longer able to fully perform these functions. The top 2 causes of CKD are diabetes and hypertension, respectively.

When the kidneys fail completely and permanently, the condition is classified as Stage 5 CKD, or end stage renal disease (ESRD). When ESRD occurs, the patient must undergo dialysis or receive a kidney transplant to survive.

The costs of treating CKD are high. According to the US Renal Data System (USRDS) 2004 Annual Data Report, the total costs for treating ESRD alone in 2002 were $25.2 billion (an 11% increase over 2001), consisting of $17.0 billion in Medicare costs and $8.2 billion in non-Medicare cost.1

Chronic Kidney Disease back to menu

Overview

In CKD, the kidneys seldom fail all at once. Instead, the disease progresses gradually, over a period of years. Therefore, if CKD is detected early, medication and lifestyle changes can slow or arrest its progress.

The National Kidney Foundation (NKF) classifies CKD into 5 stages, as indicated by glomerular filtration rate (GFR level), which measures how well the kidneys are filtering blood. Recent NKF-published information on the various stages of CKD is contained in Table 1 below.2

Incidence and Prevalence

In the United States, the incidence and prevalence of kidney failure (and CKD) are rising, with associated poor outcomes and high cost.2 The NKF estimates that about 20 million US adults—about 1 in 9—have some degree of CKD, and that another 20 million are at increased risk. Of those patients with CKD:

  • About 300,000 patients have Stage 5 CKD—that is, kidney failure to the extent that they are on dialysis or have a GFR of less than 15 mL/min.
  • Another 400,000 patients have Stage 4 CKD (severe).
  • About 7.5 million patients have Stage 3 CKD (moderate).
  • The rest have some kidney damage, but have normal or only mildly reduced kidney function (CKD Stages 1 and 2).

As mentioned previously, Stage 5 CKD is also known as end stage renal disease (ESRD). The incidence and prevalence of ESRD have doubled in the past 10 years and are expected to continue to rise (Figure 1).1,2

The USRDS 2004 Annual Data Report did not change the projections reflected in Figure 1 (which were made in its 2000 Annual Data Report), but reported updated incidence and prevalence information. More specifically, in 20021:

  • The incident rate for ESRD was 333 per million population, representing more than 100,000 patients.
  • The prevalence rate for ESRD was 1,435 per million population, representing more than 430,000 patients.
  • Among the latter group of patients, 72% were treated by dialysis and 28% had received kidney transplants.

Prognosis, Mortality, and Morbidity

Because CKD symptoms are normally subtle until the late stages of the disease, many people with CKD do not know they have it. With early detection, the course of CKD can usually be slowed and perhaps even stopped.

However, despite advances in dialysis and transplantation, the prognosis for patients with kidney failure remains poor. The USRDS, for example, reported that in 20021:

  • More than 79,800 patients with ESRD died.
  • The annual mortality rate of dialysis patients was 248 deaths per 1,000 patient years.
  • Expected remaining lifetimes of patients treated by dialysis were far shorter than the age-matched general population, varying (depending on gender and race) from 7 to 11.5 years for patients 40 to 44 years of age, and from 3.9 to 5.6 years for patients 60 to 64 years of age.

Morbidity of kidney failure is also high. The mean number of comorbid conditions in dialysis patients is approximately 4 per patient, the mean number of hospital days per year is approximately 15, and self-reported quality of life is far lower than the general population.2

CKD and the Role of Hyperphosphatemia back to menu

CKD is associated with a variety of bone disorders and disorders of calcium and phosphorus metabolism. The major bone disorders can be classified into (1) those associated with high parathyroid hormone (PTH) levels (osteitis fibrosa cystica) and (2) those with low or normal PTH levels (adynamic bone disease). The hallmark lesion of CKD is osteitis fibrosa, due to secondary hyperparathyroidism. Now, with the advent of intensive treatments for secondary hyperparathyroidism, the prevalence of disorders associated with low or normal PTH levels has increased.

Most patients with ESRD also develop hyperphosphatemia because of their diet and insufficient elimination of phosphate through dialysis (3 times weekly). Inadequately treated hyperphosphatemia plays a central role in the pathogenesis of secondary hyperparathyroidism and extraosseous calcification.

During the past 15 years, this biochemical phenomenon has become more important. Two epidemiologic studies have, in fact, reported an association between elevated serum phosphorus and increased mortality in patients with ESRD.3,4 As a result, the National Kidney Foundation-Kidney Disease Outcome and Quality Initiative (K/DOQI) Bone Metabolism and Chronic Kidney Disease Guidelines recommend that serum phosphorous levels be maintained between 3.5 and 5.5 mg/dL.2 Notably, recent cross-sectional studies showed an average serum phosphorus level of 6.2 mg/dL in the US ESRD population.5

Given the increased focus on maintaining normal serum phosphorous and the well-known complications associated with its excess, this article will review current treatments available to treat hyperphosphatemia.


Available Treatments for Hyperphosphatemia back to menu

Overview

Generally, there are 3 ways to treat hyperphosphatemia (alone or in combination): through diet (by restricting intake of phosphorous), hemodialysis, and phosphate binders.

Effective dietary restriction of phosphorus—although an important treatment objective for ESRD patients—is difficult to achieve in practice because ESRD patients are encouraged to maintain a high protein diet to prevent protein malnutrition.6 Hemodialysis alone—that is, as the sole treatment modality—is not usually the definitive treatment for hyperphosphatemia, since hemodialysis alone does not adequately control serum phosphorus in most patients.7 To address this problem, researchers have been exploring hemodialysis treatment alternatives that involve the use of more frequent dialysis, such as short daily dialysis or long nocturnal dialysis. There is evidence that these hemodialysis treatment alternatives may be effective in achieving recommended serum phosphorus levels without the use of phosphate binders.8 However, these alternatives are still in the experimental stage and have not been widely applied in clinical practice.

For the reasons cited in the preceding paragraph, phosphate binders are routinely prescribed for most patients with ESRD in order to reduce intestinal absorption of dietary phosphorus and prevent hyperphosphatemia.

Phosphate Binders

Ideally, a phosphate binder would:

  • Bind most dietary phosphate in the intestine without producing significant adverse effects.
  • Be relatively inexpensive, because most dialysis patients require relatively large doses.

Unfortunately, none of the phosphate binders currently used in clinical practice (discussed in greater detail below) fully meet both of these criteria.

Aluminum Hydroxide

This less-than-ideal character of phosphate binders is perhaps best exemplified by aluminum hydroxide. Although aluminum hydroxide is probably the most cost-effective phosphate binder available, it has largely been discredited—and its use as a first line agent discarded—due to attendant risks of aluminum toxicity with encephalopathy and osteomalacia.

Aluminum hydroxide was introduced as a phosphate binder in 1970 and remained the standard of care for ESRD patients until the mid-1980s. Approximately 7 years after its introduction, powerful evidence began to mount that aluminum hydroxide caused aluminum accumulation in the brain and severe, sometimes fatal, encephalopathy.9 More specifically, several investigations demonstrated that aluminum was the cause of the debilitating effects observed in dialysis patients, including osteomalacia, pain, pathological fractures, proximal myopathy, dementia, and lack of mineralization response to vitamin D.10,11 Thus, current clinical practice guidelines advise that aluminum hydroxide be administered only in restricted situations where alternative first line agents are not appropriate.2

Calcium Binders

Because of the toxicity associated with aluminum, nephrologists aggressively sought non-aluminum alternatives. Eventually, calcium acetate and calcium carbonate— which have a better safety profile— replaced aluminum hydroxide as the most widely prescribed phosphate binders.

Despite their better safety profile, calcium salts bind dietary phosphorus less effectively than aluminum.12 There are many reasons for this long-recognized disparity, but one main reason is that calcium salts binding to phosphorus are pH dependent and therefore binding can decrease, to a greater extent than aluminum, under acidic conditions (such as those in the stomach).13

Although calcium binders are generally less effective than aluminum, numerous studies have shown that calcium binders alone are, in fact, able to normalize phosphate concentrations in a high percentage of dialysis patients. However, large doses are required to achieve this result.14,15 Consequently, treatment with calcium binders may prove relatively expensive.

As suggested above, calcium binders consist of 2 types: calcium carbonate and calcium acetate. Each is available in many dosage forms. Many of the marketed calcium carbonates fall under the category of food supplements and therefore are not required by law to meet US Pharmacopoeia (USP) standards. As food supplements, these agents are rarely covered by third party payers, including Medicaid, through which most dialysis patients are insured. Additionally, clinical trials have demonstrated the superiority of calcium acetate in binding dietary phosphorous when compared with calcium carbonate.16,17 For these reasons, calcium acetate has become the most widely prescribed calcium binder used to treat hyperphosphatemia.

There are disadvantages and risks associated with use of calcium binders. For example, despite its popularity, calcium acetate has been shown in one study to cause more nausea and diarrhea than calcium carbonate agents.18 In addition, the use of calcium binders in high doses to control serum phosphorus in dialysis patients results in positive calcium balance. Positive calcium balance can be a factor in a very complex cascade of pathologic and comorbid conditions leading to an increase in cardiovascular disease among these patients. Calcification of tissues and organs has been associated with myocardial infarction, cardiac valvular disease, angina, aortic aneurysm, and even death.19-22 The impact of positive calcium balance is currently an area of discussion and debate.

The NKF recommends that the total dose of elemental calcium from phosphate binders not exceed 1.5 grams per day.2 The NKF guidelines further recommend avoiding calcium phosphate binders altogether when serum calcium levels exceed 10.2 mg/dL or when intact parathyroid hormone levels are 150 pg/mL or less. Lastly, the guidelines advocate avoiding calcium in hemodialysis patients with existing soft-tissue calcification.2

Sevelamer Hydrochloride

Sevelamer hydrochloride was introduced in 1998. In contrast to the other agents previously used to control hyperphosphatemia, sevelamer hydrochloride was considered the first to be free of potentially toxic metals. Moreover, studies have shown that sevelamer hydrochloride effectively controls serum phosphate in hemodialysis patients without developing hypercalcemia.23,24 In addition, the drug has had an unanticipated beneficialeffect on binding bile salts and reducing LDL cholesterol.25-27

The use of calcium binders compared to non-calcium binders (sevelamer) has been compared in several clinical trials. The ability to control serum phosphorous appears to be similar between the two modalities. Patients treated with sevelamer experience a beneficial reduction in total and LDL cholesterol, while in one trial there was some presence of low serum bicarbonate. Those treated with calcium containing agents appeared to be at greater risk for hypercalcemia, and in one trial were associated with higher coronary artery and aortic calcification scores.28-32

Sevelamer hydrochloride has been shown to be an effective binder that decreases the incidence of hypercalcemic episodes relative to patients on calcium treatment.29,33-35 A recent (2002) randomized, controlled, multicenter, prospective clinical trial involving 200 hemodialysis patients demonstrated that, compared with calcium binders, sevelamer hydrochloride provides similar control of serum phosphorus levels while attenuating the progression of cardiovascular calcification.36 Similar results were reported in a follow-up randomized, controlled clinical trial involving 108 hemodialysis patients who were given either sevelamer hydrochloride or calcium acetate.37 In sum, these studies show that substituting sevelamer hydrochloride for calcium acetate as a phosphate binder can reduce a patient’s total calcium load and also reduce progressing vascular calcification.

More evidence regarding the use of sevelamer hydrochloride became available on July 28, 2005 (full results yet to be published), when the results from the Dialysis Clinical Outcomes Revisited (DCOR) trial were announced. The 3-year DCOR trial (an industry sponsored trial)-—the largest outcomes study ever conducted in the hemodialysis population—involved more than 2,100 adult hemodialysis patients at 75 sites in the United States and compared the difference in mortality and morbidity outcomes for patients receiving sevelamer hydrochloride with those using calcium-based phosphate binders.38 Patients were randomly assigned to either sevelamer or calcium-based binders (calcium acetate or calcium carbonate). Approximately 27% of patients in the calcium group opted to use calcium carbonate rather than calcium acetate. Patients were treated according to the usual treatment guidelines in their dialysis center in order to capture the real world experience of those on dialysis. Patients were followed for up to 45 months. The study population for both treatment groups was similar for demographics and baseline clinical characteristics, and similar to the overall US dialysis population. The median age of patients in the study was 62 years old. Dropout rates throughout the study were similar for each group.38

The DCOR study found that sevelamer hydrochloride use resulted in the strongest clinical benefit in 2 specific groups of patients: those who were treated for 2 years or more, and those who were 65 years of age or older. The results reported for these groups make DCOR the first large-scale, prospective, randomized clinical trial to demonstrate a mortality or morbidity benefit for specific patient types on hemodialysis. While not all clinical endpoints met statistical significance, important DCOR endpoints of mortality and morbidity are summarized as follows38:

  • A 9% reduced mortality risk was seen in patients using sevelamer compared with calcium phosphate binders, but this was not statistically significant (p=0.3). It was found that the mortality outcome was influenced by age and treatment duration. Patients using sevelamer for 2 years or more had a reduced all cause mortality of 34% compared with those on calcium (p=0.02). These patients made up 43% of the study population.
  • Patients in the study who were 65 years or older had a reduced mortality risk of 22% compared with calcium (p=0.03). Those 65 years or older who were on sevelamer hydrochloride more than 2 years had a reduced mortality risk of 54% compared with calcium binder users (p=0.0009).
  • Patients using sevelamer had a 23% reduction in hospitalizations compared with calcium binder users (p=0.06). In patients 65 years and older, this did reach statistical significance (p=0.03).
  • Although not significant, patients using sevelamer hydrochloride had a 14% reduction in the number of days hospitalized per year compared with calcium binder users (p=0.09).

Sevelamer hydrochloride does, however, have potential drawbacks. One potential drawback is cost; sevelamer hydrochloride is approximately 2 to 3 times more expensive than its predecessors. Adverse effects are another concern: sevelamer hydrochloride generally requires large doses to achieve adequate control (5 to 7 grams or 6 to 18 tablets per day). These high doses can generate gastrointestinaldiscomfort at rates similar to calcium binders and in one trial, low serum bicarbonate.27,32,39

Lanthanum Carbonate

The most recent phosphate binder to come to market is lanthanum carbonate. Lanthanum is a naturally occurring element that binds to phosphate, allowing for the removal of phosphate from the body. The Food and Drug Administration (FDA) spent 2.5 years reviewing lanthanum prior to giving approval in October 2004. Lanthanum carbonate is available in the United States in 250 and 500 mg strengths. Most patients require a daily dose of 1,500 to 3,000 mg to lower serum phosphate levels below 6 mg/dL.

Compared with aluminum, lanthanum carbonate does not accumulate as much in the body of dialysis patients because of its low gastrointestinal absorption and elimination.40 However, in animal studies, lanthanum carbonate has been shown to accumulate with long-term exposure. Furthermore, studies have shown that in humans, lanthanum carbonate accumulates in bone.41 Due to limited experience with the use of lanthanum carbonate, it is unknown if the accumulation in human tissue or organs poses any harmful long-term effects.

Compared with calcium phosphate binders, lanthanum carbonate has been associated with a significantly lower incidence of hypercalcemia.42 In the lanthanum carbonate phase III study, approximately 126 patients received daily doses of lanthanum carbonate for 6 weeks, ranging from 750 to 3,000 mg per day. This study showed that lanthanum carbonate was effective over placebo in reducing serum phosphate and PTH levels.43

In addition, a phase III multi-center study was conducted to compare treatment with lanthanum carbonate versus calcium carbonate, and to determine the differences in associated bone disorders, such as osteomalacia or adynamic bone disease. The study group consisted of 98 patients who were starting renal dialysis for the first time. Those patients were randomized to receive either lanthanum carbonate or calcium carbonate, titrated to a dose that was well tolerated and gave acceptable control of serum phosphate (up to 3,750 mg per day of lanthanum carbonate or up to 9,000 mg per day of calcium carbonate); treatment lasted for approximately 12 months.43 The study reported no differences in osteomalacia, but reported that lanthanum carbonate demonstrated a larger reduction in adynamic bone disease than calcium carbonate.

The cost of lanthanum carbonate is slightly less than sevelamer, but like sevelamer, it is significantly more expensive than calcium acetate. Lanthanum carbonate, although shown to be effective, does not have long-term safety and effectiveness data to support its use as a preferred first-line agent over calcium acetate or sevelamer hydrochloride. As experience increases with the use of lanthanum carbonate, its long-term safety and effectiveness will be better elucidated.

Managed Care Perspective back to menu

The Challenge for Decision Makers

ESRD is a chronic illness, but because of advanced therapies and treatments, it can be managed and patients’ survival rates improved. As newer and more costly agents become readily available, making decisions about disease management and formulary placement for these products will become more complicated: to gauge the value proposition for each product, the cost, benefits, and side effects of each must be artfully evaluated, compared, and balanced.

For example, and as stated earlier, newer agents like sevelamer hydrochloride or lanthanum carbonate are much more expensive compared with older agents like calcium acetate. However, no data are available to compare reduced calcification and cardiovascular events of calcium binders versus sevelamer hydrochloride or lanthanum carbonate. It is therefore difficult to determine the complete value proposition for sevelamer hydrochloride or lanthanum carbonate for meaningful comparison to the other available agents.

Pricing

The following table describes pricing based on First Data Bank average wholesale price (as of August 2005) and daily dose (from package inserts).

As reflected in Table 3, sevelamer hydrochloride and lanthanum carbonate are significantly more expensive than calcium acetate. However, the value of the more expensive agents, as suggested above, may lay in their effectiveness in reducing cardiovascular disease and hospitalizations. These benefits must be taken into account.

Comparing Sevelamer Hydrochloride and Calcium Acetate

Sevelamer hydrochloride and calcium acetate have been studied and compared extensively. Data are available, for instance, to show the effects of each on calcification and cardiovascular events.24-28 Managed care payers can utilize this information to determine the clinical and economic value of sevelamer and calcium binders.ii

In the Treat-to-Goal study, Chertow and colleagues conducted a 52-week head-to-head trial comparing sevelamer hydrochloride and calcium acetate.26 Efficacy and calcification of coronary arteries and the aorta were measured. It was shown that sevelamer hydrochloride attenuated the progression of calcification. In contrast, patients treated with calcium acetate had significant (p=0.02) increases in both coronary and aortic calcification compared with sevelamer hydrochloride. Moreover, 37% of sevelamer-treated patients had hospitalizations compared with 48% of patients on calcium acetate.26

Supporting the Treat-to-Goal study, both clinically and economically, is a 2000 study published by Collins. This study assessed a claims database of Medicare patients. The outcomes evaluated were risk of all cause hospitalization and per member/per month (PMPM) Medicare expenditures.44 This retrospective analysis consisted of 152 ESRD patients in 2 different arms: a sevelamer arm and a non-sevelamer arm. Patients on sevelamer hydrochloride received on average about 5 grams per day. Cox-regression statistical analysis was used. The Collins study found that:

  • Within 17 months, patients taking sevelamer were 46% to 54% less likely to be hospitalized.
  • Sevelamer patients had a PMPM of $3,368 versus $4,745 for non-sevelamer patients, equating a savings of $16,500 per year.

Moreover, based on the Chertow study,26 one can calculate a crude number needed to treat to avoid a hospitalization event. Because there is a 10% hospitalization rate difference between the sevelamer and calcium acetate group, it would require nine patients to be treated with sevelamer to avoid 1 hospitalization. It is therefore important for payers to determine if the higher acquisition cost of sevelamer hydrochloride compared with calcium acetate outweighs the costs of a hospitalization.


Conclusion back to menu

Head-to-head studies have demonstrated that all of the products discussed above are comparably efficacious in reducing phosphate serum levels. While not fully understood, the role of positive calcium balance potentially associated with calcium binders remains a topic of debate and may impact treatment decisions. Although limited experience exists, lanthanum carbonate has been shown to accumulate in the body and the long-term efficacy has yet to be determined. Sevelamer's impact on attenuating cardiovascular calcification while providing phosphate binding activity must be balanced with its cost and associated adverse effect profile. From a pure cost perspective, the Collins study noted medical cost savings within 1 to 1 1/2 years of therapy with sevelamer.

Payers who must make formulary decisions in the phosphate binder class must therefore consider more than price. Decision makers must also assess the medical costs associated with complications of treatment in this class and the potential impact that each class of agents can have on those escalating medical costs.

i. Healthy kidneys are also critical in development of children.
ii. As suggested, in light of the dearth of data on lanthanum carbonate, only sevelamer hydrochloride and calcium acetate can be meaningfully compared at this time.

References back to menu

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