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Nephrology Dialysis Transplantation 2007 22(10):2742-2745; doi:10.1093/ndt/gfm561
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Sevelamer: a promising but unproven drug

Suetonia C. Palmer1, Jonathan C. Craig2,3 and Giovanni F. M. Strippoli2,3

1Department of Medicine, University of Otago, Christchurch, New Zealand, 2School of Public Health, University of Sydney and 3Cochrane Renal Group, NHMRC Centre for Clinical Research Excellence in Renal Medicine, The Children's Hospital at Westmead, Westmead, Australia

Correspondence to: Giovanni F. M. Strippoli, MD, Mario Negri Sud Consortium, S. Maria Imbaro (Ch), Italy. Email: strippoli{at}negrisud.it

Keywords: kidney disease; mineral and bone disorder; mortality; phosphate binders; phosphorus; sevelamer

Sevelamer hydrochloride, a synthetic phosphate binder, licensed for treatment of calcium–phosphorus abnormalities in chronic kidney disease (CKD), is one of many high-cost pharmaceuticals (lanthanum carbonate, calcimimetics, vitamin D analogues) targeted specifically at patients with the CKD-Mineral and Bone Disorder (CKD-BMD) [1]. Phosphate binders, traditionally containing calcium or aluminium, improve metabolic abnormalities in CKD by reducing absorption of dietary phosphorus. Altered mineral metabolism occurs universally in people with stage 4 and 5 CKD [2], due to impaired excretion of phosphorus, reduced activation of vitamin D and a compensatory increase in parathyroid hormone (PTH) secretion [3]. These metabolic features of CKD are associated with deleterious clinical consequences, including muscle dysfunction [4], fracture [5], cardiovascular and soft tissue calcification [6] and death. Hyperphosphataemia and treatment-related hypercalcaemia have, in large-scaled cohort studies, been powerfully, consistently and independently associated with the excess all-cause and cardiovascular mortality in CKD [7,8]. Such observational research, however, is at best hypothesis-forming, and does not elucidate the mechanisms for cause of death in these patients, and more importantly, whether reversing such metabolic disturbances prevents death. The pivotal question remains—is cardiovascular calcification on the causal chain between calcium–phosphorus–PTH imbalance and cardiovascular morbidity and mortality? Are these valid surrogate outcomes for clinical research?

Administration of sevelamer, a non-aluminium and non-calcium containing phosphate binding polymer, has a potential advantage over traditional calcium-based binders, in reducing both circulating phosphorus and calcium levels, and ameliorating vascular calcification. However, the translation of these drug-specific effects into improved survival in people with CKD has not yet been demonstrated [9]. Sevelamer is not alone in this respect. Other therapies approved for the management of altered mineral metabolism in CKD, including vitamin D compounds and calcimimetics, are of as yet unproven efficacy when it comes to hard, incontrovertibly patient-relevant outcomes, such as death and major cardiovascular outcomes [10,11]. Evidence for the superior efficacy of the newer phosphate binders (sevelamer and lanthanum carbonate) over calcium-based binders continues to be debated, and nephrologists have felt obliged to defend publicly their ongoing use of calcium-based phosphate binders, in the face of allegations that they are causing harm to their patients [12]. It should be remembered that established calcium- and aluminum-based binders have not been shown to have beneficial effects on patient-centered endpoints either.

Our evidence ‘goal-posts’ have changed in renal bone disease. ‘Grandfather’ interventions such as vitamin D and calcium-based phosphate binders were licensed, subsidized and introduced widely into clinical practice, at a time when the perils of introducing new pharmaceuticals without RCTs showing benefits on patient-level outcomes were not fully appreciated. Times have changed as the marginal benefit of new pharmaceuticals shrinks, costs spiral upwards and the dangers of the broad introduction of promising but unproven or potentially hazardous interventions are now better recognized [13,14]. Full adoption of sevelamer by government drug reimbursement agencies, in place of calcium-compounds, would lead to an estimated increase in annual costs of dialysis in the United States of US$1 billion [15]. This can only be justified by the presentation of evidence for superior efficacy (and lack of toxicity) of these agents on important clinical outcomes.

In this issue of Nephrology Dialysis and Transplantation, Marcello Tonelli and colleagues present two timely analyses of sevelamer efficacy and cost-effectiveness [16,17] in people requiring dialysis. Their meta-analysis of efficacy identifies 10 randomized trials comparing sevelamer with calcium carbonate, calcium acetate or either drug, in nearly 3000 patients on dialysis. The meta-analysis also reviews the safety of sevelamer, in 31 controlled and single-arm studies in 4000 patients. No difference was found between sevelamer and calcium-based phosphate binders for all-cause mortality, cardiovascular mortality, adverse events or hospitalization. Data were not reported, in any trial, on the effect of sevelamer treatment on bone pain and fracture. The lack of difference between sevelamer and standard phosphate binders on clinical endpoints is strengthened by the inclusion of the Dialysis Clinical Outcomes Revisited (DCOR) trial, a large (n = 2103) but as yet unpublished multicentre US study of sevelamer versus calcium-based phosphate binders, in haemodialysis patients [18] where the primary outcome was all-cause mortality. The trial report, released in poster format only, identified no difference between study groups for death (relative risk [RR] 0.91, CI not available). Despite the incomplete reporting of mortality data in the current meta-analysis (only 5 out of 10 trials), the conclusion is clear regarding the relative effects of sevelamer and calcium-based phosphate binders on clinically relevant end-points in people receiving dialysis; no difference between treatment groups has been shown.

Following treatment with sevelamer, the risk of hypercalcaemia (calcium >2.6–2.75 mmol/l) was reduced by 20%, serum phosphorus levels were higher (0.12 mmol/l, CI 0.05–0.19), serum calcium levels were lower (–0.1 mmol/l, CI –0.12 to –0.17), and the serum calcium by phosphorus product unchanged compared with calcium-based phosphate binders. The effect of treatment on vascular calcification was not assessed in the current meta-analysis, despite arterial calcification being the focus of two small recent trials, the RIND study [19] and the Treat-to-Goal study [20], and the importance placed by some authors on the role of sevelamer in slowing the progression of vascular calcification as the point of difference from calcium-based therapies [21]. This emphasis on surrogate biomarkers such as circulating calcium, phosphorus, PTH levels and vascular calcification, as primary outcomes of interest, is common in controlled studies of interventions for bone disease in CKD. The current group of trials is no exception and brings into focus the issues of surrogate and patient-centred outcomes in nephrology trials.

For renal bone disease, it is proposed that research interventions produce effects on biomarkers (calcium, phosphorus and PTH levels), which result in improved patient-level outcomes (mortality, cardiac and cerebrovascular events). This rationale is built on the premise that improvements in calcium and phosphorus metabolism and levels of PTH are valid surrogates of such clinically important outcomes as mortality. However, not all biomarkers are legitimate proxies of patient-centred end-points. The medical literature is littered with misleading surrogates, which have led to the use of ineffective or possibly harmful interventions [22]. First, a valid surrogate marker must show a robust, independent and consistent association with the clinical outcome [23]. This requirement has clearly been met for calcium and phosphorus, and for survival in CKD in large-scaled cohort analyses. Secondly, and more importantly, evidence is required that an intervention both alters the surrogate marker of interest (e.g. decrease in serum phosphorus with a phosphate binder), and results in an expected improvement in the clinical outcome of importance (e.g. improved survival with phosphate binders). For interventions in renal bone disease, including phosphate binders, this second criterion remains unproven after nearly 40 years of research. The clinical consequences of the biochemical effects of sevelamer on calcium and phosphorus metabolism remain very unclear.

The second report regarding sevelamer in today's issue is a comprehensive economic analysis comparing sevelamer with calcium carbonate modeled on North American cohorts of adults requiring dialysis (peritoneal and haemodialysis) for renal replacement therapy [17]. The analyses are necessarily complex, due to the ‘life-saving’ but expensive nature of dialysis and renal transplantation. The modelling, performed through the eyes of the health-care purchaser, is designed to incorporate the actual costs accrued by prescription of sevelamer, in place of calcium carbonate, against the economic benefits achieved by a potentially lower hospitalization rate, derived from sevelamer use during a patient's lifetime. The analyses are informed by the DCOR trial using data on hospitalization rates in the 2100 participants [18]. The study, in fact, found no difference between treatment groups for days in hospital per year or rates of hospitalization. Sevelamer, using the manufacturer's pricing, would cost in excess of {euro}2900 more than calcium carbonate to prescribe each year for a dialysis patient, and would result in a cost per quality- adjusted life year (QALY) in CKD of {euro}110 000. In short, the risk of hospitalization resulting from the prescription of sevelamer would need to be reduced by over 30% to generate cost savings to justify the drug-alone expense of sevelamer. While most are aware of the challenge that health systems face ensuring patients access to expensive, but potentially effective treatments for life-threatening conditions, newer and costly pharmaceuticals developed for the management of hyperphosphataemia have yet to prove greater efficacy ahead of their inexpensive counterparts.

Patients requiring dialysis for renal replacement therapy suffer a higher rate of death from cardiovascular disease than the general population [24]. They also demonstrate a high prevalence of progressive and premature vascular calcification, including coronary artery calcification [6]. Vascular calcification is not a passive process in uremia, but a tightly regulated event where the phenotype of vascular smooth muscle cells evolves into osteogenic cells which induce formation of a mineral matrix within vascular tissues [25]. Circulating phosphorus is a potent inducer of differentiation of smooth vascular cells into osteoblasts [26]. What remains undetermined is the actual relationship between vascular calcification and cardiovascular death in CKD. In other words, do people with CKD die of their vascular calcification? Nearly three quarters of people commencing dialysis have left ventricular hypertrophy, compared with 10% recording a prior history of myocardial infarction. Only 20% of cardiac deaths in the US dialysis population are directly attributed to active myocardial ischaemia, with the remainder assigned to arrhythmias or sudden death, possibly reflecting myocardial, rather than arterial disease [27]. Recent association data have shown that coronary artery [28] and abdominal aorta calcification [29] are significant predictors of death in dialysis patients. Given the absence of data to prove that raised phosphorus causes calcification, and, in turn, that vascular calcification causes death in CKD, it is imperative that future randomized trials in this area rely on validated end-points, such as parathyroidectomy, fracture, hospitalization and death.

All novel pharmaceuticals and devices must meet stringent safety and efficacy standards before they are licensed for human use. This regulatory process is required to balance safety data with timely access by the community to novel therapeutic advances, and is concerned primarily with the safety, quality and performance of medicines. It is, however, the separate role of policy makers, to decide whether these approved pharmaceuticals should be funded fully, or in part, by government, or delegated authorities, Despite continued approval for license of sevelamer hydrochloride by the US Food and Drug Administration (FDA) since 1998, and subsequently by other international agencies, no funding agency has approved full reimbursement of sevelamer for people with CKD (Pharmaceutical Benefits Scheme Australia; National Institute of Clinical Excellence (NICE), United Kingdom; Medicare, United States). In their publicly available summary decision on sevelamer, the Australian Pharmaceutical Benefits Advisory Committee (PBAC) estimated the annual cost of sevelamer for all dialysis patients in Australia to approximate {euro}20–40 million, and doubted whether the reduction in vascular calcification with sevelamer reported in the recently conducted RIND and Treat-to-Goal studies [19,20] would translate into improved cardiovascular outcomes [30]. They rejected the manufacturer's submission to fund sevelamer ‘because of uncertain clinical benefit and uncertain cost-effectiveness’, although a more recent decision has allowed the use of sevelamer in a subgroup of patients in whom hyperphosphataemia cannot be controlled with standard phosphate binders.

A sea change for interventions for abnormalities of bone and mineral metabolism in CKD may at last be occurring with the registration by Amgen in 2006 of the ‘Evaluation of cinacalcet HCl therapy to lower cardiac events’ (EVOLVE) trialTM in 3800 dialysis patients [31]. The trial defines a primary outcome measure of time to a composite event comprising all-cause mortality or non-fatal cardiovascular events and secondary measures of non-fatal cardiovascular events, parathyroidectomy and fracture. This responsible use of resources to find out whether a drug for bone disease has an effect on outcomes that really matter should be applauded. Is this a sign of changing times? We certainly hope so.

Conflict of interest statement: None declared.

(See related articles by Tonelli et al. Systematic review of the clinical efficacy and safety of sevelamer in dialysis patients Nephrol Dial Transplant 2007; 22: 2856–2866.)

(See related articles by Manns et al. Economic evaluation of sevelamer in patients with end-stage renal disease. Nephrol Dial Transplant 2007; 22: 2867–2878.)



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Received for publication: 22. 7.07
Accepted in revised form: 24. 7.07


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