| | Benefits and Harms of Phosphate Binders in CKD: A Systematic Review of Randomized Controlled TrialsReceived 13 February 2009; accepted 5 June 2009. published online 19 August 2009. BackgroundPhosphate binders are widely used to control serum phosphorus levels in patients with chronic kidney disease (CKD). We analyzed the effects of phosphate binders on biochemical and patient-level end points in patients with CKD. Study DesignSystematic review and meta-analysis by searching MEDLINE (1966 to April 2009), EMBASE (1980 to April 2009), and the Cochrane Renal Group Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL). Setting & PopulationPatients with CKD. Selection Criteria for StudiesRandomized controlled trials. InterventionPhosphate binders. OutcomesSerum phosphorus, calcium, and parathyroid hormone levels; incidence of hypercalcemia; all-cause mortality; adverse effects. Results40 trials (6,406 patients) were included. There was no significant decrease in all-cause mortality (10 randomized controlled trials; 3,079 patients; relative risk [RR], 0.73; 95% confidence interval [CI], 0.46 to 1.16), hospitalization, or end-of-treatment serum calcium-phosphorus product levels with sevelamer compared with calcium-based agents. There was a significant decrease in end-of-treatment phosphorus and parathyroid hormone levels with calcium salts compared with sevelamer and a significant decrease in risk of hypercalcemia (RR, 0.47; 95% CI, 0.36 to 0.62) with sevelamer compared with calcium-based agents. There was a significant increase in risk of gastrointestinal adverse events with sevelamer in comparison to calcium salts (RR, 1.39; 95% CI, 1.04 to 1.87). Compared with calcium-based agents, lanthanum significantly decreased end-of-treatment serum calcium and calcium-phosphorus product levels, but with similar end-of-treatment phosphorus levels. Effects of calcium acetate on biochemical end points were similar to those of calcium carbonate. Existing data are insufficient to conclude for a differential impact of any phosphate binder on cardiovascular mortality or other patient-level outcome. LimitationsFew long-term studies of the efficacy of phosphate binders on mortality and musculoskeletal morbidity, significant heterogeneity for many surrogate outcomes, and suboptimal reporting of study methods to determine trial quality. ConclusionCurrently, there are insufficient data to establish the comparative superiority of non–calcium-binding agents over calcium-containing phosphate binders for such important patient-level outcomes as all-cause mortality and cardiovascular end points. Additional trials are still required to examine the differential effects of phosphate-binding agents on these end points and the mineral homeostasis pathway. The incidence of chronic kidney disease (CKD) is increasing worldwide, with about $23 billion (6.6% of the Medicare budget) spent on the care of patients with end-stage renal disease in 2006 in the United States alone.1 Worsening kidney function results in impaired clearance of the dietary phosphorus load,2 which directly and indirectly increases parathyroid hormone (PTH) secretion.2, 3, 4 Secondary hyperparathyroidism is characterized by high bone turnover, exaggerated marrow fibrosis, and increased musculoskeletal morbidity. Recently, epidemiological data have shifted the focus of altered mineral metabolism in CKD from renal bone disease to a broader recognition that hyperphosphatemia is associated with increased morbidity, mortality, and hospitalization; reduced quality of life; and increased costs of care.5, 6, 7 Cardiovascular disease accounts for more than half the deaths in dialysis patients,1 and the development of vascular calcification of the arterial media has been advocated as a major contributing factor.8, 9 Because abnormalities in mineral metabolism involve a paradigm incorporating bone disease and vascular and soft-tissue calcification that have potential effects on fracture, cardiovascular outcomes, and mortality, the concept of CKD-mineral and bone disorder has been introduced. This condition is the target of several interventions, including phosphate binders, vitamin D analogues, and calcimimetics, all of which may suppress the development or progression of CKD-mineral and bone disorder.10, 11 Phosphate binders containing aluminum and calcium have been used widely since 1970, and the non–calcium- or aluminum-based agents, sevelamer hydrochloride and lanthanum carbonate, more recently have become available. Their use is increasing in current practice, and although they are more expensive, the potential decrease in risk of vascular calcification and toxicity advocates for broader adoption. For control of hyperphosphatemia, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) recommends the use of calcium-based binders in patients with CKD stages 3 and 4 (glomerular filtration rate, 30 to 59 and 15 to 29 mL/min/1.73 m2, respectively) and both calcium-based and calcium- and aluminum-free binders in patients with CKD stages 5 and 5D (glomerular filtration rate < 15 mL/min/1.73 m2 and dialysis).12 The relative merits of available phosphate-binding agents are controversial.13, 14 We have conducted a systematic review of the benefits and harms of phosphate binders compared with calcium salts or placebo to determine whether newer agents deliver improved biochemical and patient-level outcomes, with particular reference to musculoskeletal and cardiovascular morbidity, hospitalization, and mortality. Methods  Inclusion Criteria Randomized controlled trials (RCTs) and quasi-RCTs (trials that use a method of allocating participants to different forms of care that are not truly random, such as allocation by date of birth, alternate medical records, day of the week, or other forms of alternation) of phosphate binders in people with CKD, alone or in combination with other nonrandomized cointerventions (eg, vitamin D compounds), were included. Studies enrolling adult patients (age > 18 years) with CKD stages 3 to 5 and 5D (dialysis) were included. Search Strategy RCTs of phosphate binders in patients with CKD were searched in MEDLINE (1966 to April 2009), EMBASE (1980 to April 2009), and the Cochrane Renal Group Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) with optimally sensitive search strategies developed by the Cochrane Collaboration15 and using relevant medical subject terms (Item S1, provided as online supplementary material with this article at www.ajkd.org). Trials were considered without language restriction. Titles and abstracts of search results were screened according to inclusion criteria. Studies that did not meet inclusion criteria (ie, animal studies, non-RCTs, and RCTs of interventions that were not relevant to the review) were excluded. Data Extraction, Quality Assessment, and Statistical Analysis We followed Cochrane methods and Quality of Reporting of Meta-analyses (QUOROM) guidelines for conduct and reporting of this systematic review.16 Two authors independently assessed each trial, and data were extracted for characteristics of participants, interventions, comparisons, and the following outcomes when reported in trials: all-cause mortality, cardiovascular mortality, nonfatal cardiovascular events, vascular calcification by any imaging modality, end-of-treatment PTH concentration (intact PTH and PTH 1-84 as reported in the studies), serum calcium (milligrams per deciliter), serum phosphorus (milligrams per deciliter), serum calcium-phosphorus product (Ca × P; milligrams squared per deciliter squared), alkaline phosphatase (international units per liter), serum bicarbonate (milliequivalents per liter), total cholesterol (milligrams per deciliter), bone mineral density, bone mineral content, bone histomorphometry, occurrence of hypercalcemia (defined as serum calcium level > 10.2 mg/dL or as defined by the study investigators), and treatment-related toxicity (gastrointestinal side effects). Investigators were contacted if data related to mortality and levels of phosphorus, calcium, PTH, or Ca × P were not available or not reported in the published reports. The quality of RCTs was assessed by using a checklist that included allocation concealment; blinding of participants, investigators, outcome assessors, and data analysts; use of intention-to-treat analyses; and completeness of follow-up.17 Discrepancies between the 2 data extractors (S.D.N. and S.C.P.) were resolved by discussion with an arbitrator (G.F.M.S.). Dichotomous data were analyzed by using the relative risk (RR) measure and its 95% confidence intervals (CIs). Risk estimates from individual trials were pooled by using the Der Simonian-Laird random-effects model.18 When continuous measurements of outcomes were used, the weighted mean difference (WMD) and its CI were computed by using end-of-treatment values. Heterogeneity across included trials was analyzed by means of visual analysis of the forest plot and formally using the heterogeneity χ2 (Cochran Q) statistic and the I2 statistic. Subgroup analyses were performed as applicable based on a predefined study protocol and were reported when significant.19 Sources of heterogeneity to be explored in subgroup analyses were the following: older versus newer phosphate-binding agents; baseline PTH levels; baseline phosphorus levels; type of calcium assay used in the study; use of washout of phosphate binder; study duration; quality items, including allocation concealment, blinding, and use of intention-to-treat analysis; number of patients lost to follow-up; and number of trial participants. Analyses were performed using Review Manager (RevMan) [Computer program]. Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008), and Comprehensive Meta-analysis version 2 (Biostat, NJ, USA). Results Search Results The combined search of MEDLINE, EMBASE, and the Cochrane Library identified 2,381 citations, of which 2,298 were excluded after title and abstract review (Fig 1). Full-text assessment of 83 potentially relevant articles identified 40 eligible trials reported in 46 publications and enrolling 6,406 patients (Fig 1).20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 Investigators of 19 trials were contacted for additional information and clarification relating to study methods and additional unreported data, with 8 responding. Trial Characteristics Characteristics of participants and interventions of the included trials are listed in Table 1. Three different groups of trials were identified. The first group of trials compared any calcium salt with another calcium salt or placebo.20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 Seven trials (307 patients) compared calcium acetate with calcium carbonate,20, 23, 24, 25, 26, 28, 29 and 2 trials (47 patients) compared calcium ketoglutarate with calcium carbonate.21, 22 One trial (18 patients) compared calcium acetate with placebo,30 and 2 trials (65 patients) compared different doses of calcium acetate.27, 31 Two studies included patients with CKD stages 3 and 4,23, 27 and the rest enrolled hemodialysis patients. Concomitant vitamin D analogues (intravenous or oral) were administered in most of these studies. | | |  | Study Type/Reference | Kidney Disease Stage | Intervention | Cointervention | Dialysate Calcium (mEq/L)/% Patients | No. of Patients | Follow-up (wk) | |
|---|
| Calcium salt v other calcium salt/placebo | | | | | | | | |  Almirall et al,20 1994 | HD | Calcium acetate, 3.8 g/d, v calcium carbonate, 4 g/d | Oral calcitriol | NA | 10 | 24 | | | Bro et al,21 1998 | HD | Calcium ketoglutarate v calcium carbonate to achieve serum phosphorus < 5.3 mg/dL | Oral alfacalcidol | 3.5/100 | 19 | 12 | | | Birck et al,22 1999 | HD | Calcium ketoglutarate v calcium carbonate to achieve serum phosphorus < 5.3 mg/dL | NA | 2.5/100 | 28 | 12 | | | Borrego et al,23 2000 | Predialysis | Calcium acetate, 1.0 g/d, v calcium carbonate, 2.5 g/d | NA | 2.5-3.5/100 | 28 | 6 | | | Caravaca et al,24 1992 | HD | Calcium acetate, 6.5 g/d, v calcium carbonate, 3.75 g/d | None | NA | 80 | 16 | | | Emmett et al,25 1991 | HD | Calcium acetate v calcium carbonate to achieve serum phosphorus of 4.5-5.5 g/dL | Oral or IV vitamin D | 3.25/100 | 91 | 2 | | | d'Almeida Filho et al,26 2000 | HD | Calcium acetate, 5.6 g/d, v calcium carbonate, 6.2 g/d | None | 3.0-3.5/100 | 52 | 4 | | | Phelps et al,27 2002 | Predialysis | Calcium acetate, 2.0 g/d, v calcium acetate, 6.0 g/d | NA | 3.5/100 | 18 | 8 | | | Pflanz et al,28 1994 | HD | Calcium acetate, 6.0 g/d, v calcium carbonate, 3.75 g/d | None | NA | 31 | 6 | | | Ring et al,29 1993 | HD | Calcium acetate, 3.8 g/d, v calcium carbonate, 4 g/d | None | 2.5/100 | 15 | 3 | | | Rudnicki et al,30 1994⁎ | HD | Calcium, 2.0 g/d, v placebo | Oral vitamin D | 3.5/100 | 18 | 24 | | | Schaeffer et al,31 1991 | HD | Calcium acetate (6 g/d) v calcium acetate + calcitriol (4 μg, 2×/wk) v calcium acetate + calcitriol (0.5 μg, 2×/wk) v aluminum hydroxide + calcitriol (4 μg, 2×/wk) | Oral calcitriol | NA | 47 | 7 | | | Sevelamer v calcium salts | | | | | | | | | Barreto et al,32 2008 | HD | Sevelamer v calcium acetate or achieve serum phosphorus of 3.5-5.5 mg/dL | IV vitamin D | NA | 101 | 52 | | | Bleyer et al,33 1999 | HD | Sevelamer v calcium acetate to achieve serum phosphorus of 2.5-5.5 mg/dL | Oral calcitriol | 2.26-2.5/65 2.5-3.0/1.2 3.0-3.5/22.9 | 83 | 16 | | | Block et al,34 2005 | HD | Sevelamer v calcium acetate or calcium carbonate to achieve serum phosphorus < 6.5 mg/dL and serum calcium < 10.2 mg/dL | Oral or IV vitamin | 2.5/100 | 129 | 72 | | | Qunibi et al (CARE-2),35 2008 | HD | Sevelamer + atorvastatin v calcium acetate + atorvastatin to achieve serum phosphorus of 3.5-5.5 mg/dL and LDL cholesterol < 70 mg/dL | NA | 2.5/10 | 203 | 52 | | | Chertow et al,36 1999 | HD | Sevelamer v sevelamer + calcium carbonate to achieve serum phosphorus of 2.5-5.5 mg/dL | Oral or IV vitamin D | | 71 | 12 | | | Chertow et al,37 2002 | HD | Sevelamer v calcium acetate or calcium carbonate to achieve serum phosphorus of 3.0-5.0 mg/dL and calcium of 8.5-10.5 mg/dL | Oral or IV vitamin D | NA | 200 | 52 | | | Suki et al (DCOR),38 2007 | HD | Sevelamer v calcium acetate or calcium carbonate | NA | NA | 2,103 | 156 | | | DeSanto et al,39 2006 | HD | Sevelamer v calcium carbonate | NA | NA | 16 | 24 | | | Evenepoel et al,40 2009 | PD | Sevelamer v calcium acetate to achieve serum phosphorus of 3.0-5.5 mg/dL | IV vitamin D | NA | 143 | 12 | | | Ferreira et al,41 2008 | HD | Sevelamer v calcium carbonate to achieve serum phosphorus of 3.2-5.0 mg/dL | IV vitamin D | NA | 91 | 52 | | | Kingusa et al,42 2001 | HD | Sevelamer v calcium carbonate | NA | NA | 230 | 8 | | | Hervas et al,43 2003 | HD | Sevelamer v calcium acetate | Oral or IV vitamin D | | 51 | 34 | | | Koiwa et al,44 2005 | HD | Sevelamer, 6 g/d, v sevelamer, 3 g/d, + calcium carbonate, 3 g/d, v calcium carbonate, 3 g/d | IV or oral calcitriol | 3.0/100 | 86 | 8 | | | Qunibi et al,45 2004 | HD | Sevelamer v calcium acetate to achieve serum phosphorus < 5.5 mg/dL | IV vitamin D | 2.5/100 | 98 | 8 | | | Russo et al,46 2007 | Predialysis | Sevelamer, 1,600 mg/d, v calcium carbonate, 2 g/d, v low-phosphate diet alone | NA | NA | 90 | 104 | | | Sadek et al,47 2003 | HD | Sevelamer, 4.4 g/d, v calcium carbonate, 4.8 g/d | IV vitamin D | Varied | 42 | 20 | | | Shaheen et al,48 2004 | HD | Sevelamer v calcium carbonate to achieve serum phosphorus, 2.5-5.5 mg/dL | Oral or IV vitamin D | 3.5/100 | 20 | 8 | | | Sevelamer v placebo | | | | | | | | | Chertow et al,49 1997 | HD | Sevelamer v placebo | Oral or IV vitamin D | NA | 36 | 8 | | | Lanthanum carbonate v calcium salts | | | | | | | | | D'haese et al,50 2003 | HD | Lanthanum carbonate up to 3,750 mg/d v calcium carbonate up to 9,000 mg/d | Oral or IV vitamin D | NA | 98 | 52 | | | Hutchison et al,51 2003 | HD | Lanthanum carbonate v calcium carbonate to achieve serum phosphorus < 5.58 mg/dL | Oral or IV vitamin D | NA | 800 | 20 | | | Shigmetsu et al,52 2008 | HD | Lanthanum carbonate v calcium carbonate | Oral or IV vitamin D | 3.0/100 | 259 | 8 | | | Spasovski et al,53 2006 | HD | Lanthanum carbonate v calcium carbonate | Oral or IV vitamin D | NA | 24 | 104 | | | Lanthanum carbonate v placebo | | | | | | | | | Al-Baaj et al,54 2003 | HD | Lanthanum carbonate v placebo in patients with serum phosphorus of 4.03-5.58 mg/dL | Oral or IV vitamin D | NA | 36 | 4 | | | Chiang et al,55 2005 | HD | Lanthanum carbonate, 375 mg-3.0 g/d, v placebo to achieve serum phosphorus < 5.6 mg/dL | Oral or IV vitamin D | NA | 61 | 4 | | | Finn et al,56 2004† | HD | Lanthanum carbonate v placebo to achieve serum phosphorus < 5.9 mg/dL | NA | NA | 144 | 4 | | | Joy et al,57 2003 | HD | Lanthanum carbonate v placebo to achieve serum phosphorus < 5.9 mg/dL | Oral or IV vitamin D | NA | 93 | 4 | | | Lanthanum carbonate v others | | | | | | | | | Malluche et al,58 2008 | HD | Lanthanum carbonate v standard phosphate binder (sevelamer or calcium salts) to achieve serum phosphorus < 5.9 mg/dL | Oral or IV vitamin D | 2.5/100 | 211 | 104 | | | Mehrotra et al,59 2008‡ | HD | Lanthanum carbonate, 3,000 v 3,750 v 4,500 mg/d | NA | NA | 513 | 8 | | | | |
| ⁎ All patients were continued on aluminum-containing phosphate binders. †This study analyzed the efficacy of various doses of lanthanum carbonate. ‡This study had a 4-month open-label extension. |
The second group compared the efficacy of sevelamer hydrochloride against calcium salts or placebo.32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 Five trials (476 patients) compared sevelamer with calcium acetate,32, 33, 40, 43, 45 6 trials (489 patients) compared sevelamer with calcium carbonate,39, 41, 42, 46, 47, 48 2 trials (157 patients) compared sevelamer directly with sevelamer and calcium carbonate,36, 44 3 trials (2,369 patients) compared sevelamer with calcium acetate and calcium carbonate,34, 37, 38 1 trial compared sevelamer plus atorvastatin with calcium acetate plus atorvastatin,35 and 1 trial (36 patients) compared sevelamer with placebo.49 All these trials were performed in patients on hemodialysis therapy, and oral or intravenous vitamin D compounds were used as cointervention in most patients. The third group of trials (10 trials; 2,239 patients) compared lanthanum carbonate with calcium carbonate (4 studies; 1,181 patients),50, 51, 52, 53 lanthanum carbonate with placebo (4 studies; 334 patients),54, 55, 56, 57 different doses of lanthanum carbonate, and lanthanum carbonate with standard phosphate binders (sevelamer and calcium salts) in dialysis patients.58, 59 The majority of trials included in this review were of short duration (1 to 18 months of treatment administration), except for the Dialysis Clinical Outcomes Revisited (DCOR) trial,38 which analyzed the efficacy of phosphate binders to decrease serum phosphorus levels, in which 42% of patients had follow-up longer than 24 months. The number of participants ranged from 10 to 2,103, with 27 of 40 (67%) trials enrolling fewer than 100 participants. Coadministration of vitamin D analogues and route of administration of these agents varied among studies. Assays used to measure PTH also differed in the included studies. Most studies defined hypercalcemia as serum calcium level greater than 10.2 mg/dL, whereas some used greater than 10.5 mg/dL and some used greater than 11.0 mg/dL as a cutoff value to define hypercalcemia. Trial Quality According to current method standards for reporting, trial quality was variable. Allocation concealment was adequate in 10 of 40 (25%) trials and unclear in others. Participants and investigators were blinded in 8 of 40 (20%) trials, and outcome assessors were blinded in no trial. Only 13 of the 40 (33%) trials were analyzed on an intention-to-treat basis. Patients lost to follow-up ranged from 0% to 31%, but did not differ between the treatment and control groups of the trials. Trial Results Patient-Level Outcomes All-cause Mortality There was no significant reduction in risk of all-cause mortality with calcium acetate in comparison to calcium carbonate. Similarly, there was no significant reduction in risk of all-cause mortality with sevelamer in comparison to calcium salts (10 trials; 3,079 patients; RR, 0.73; 95% CI, 0.46 to 1.16; Fig 2); data for mortality primarily derive from 1 large trial (DCOR).36 No deaths were reported in the included studies that compared lanthanum carbonate with placebo or calcium carbonate; thus, mortality could not be ascertained for this comparison. Hospitalization Two trials reported hospitalization details. However, these reports could not be pooled because of differences in reporting methods. In 1 trial, the number of patients hospitalized within 52 weeks was reported, with no significant difference in risk of hospitalization between sevelamer and calcium salts (P = 0.15).37 In another trial, the number of days hospitalized per patient-year was reported, with no difference between sevelamer and calcium salts for this outcome (P = 0.09).38 Gastrointestinal Events There was no significant difference in risk of adverse gastrointestinal events with calcium acetate in comparison to calcium carbonate or with lanthanum carbonate in comparison to placebo or calcium carbonate (Table 2). However, there was a significant increase in risk of gastrointestinal events with sevelamer in comparison to calcium salts (RR, 1.39; 95% CI, 1.04 to 1.87; Table 2). Gastrointestinal side effects reported with sevelamer included abdominal bloating, diarrhea, and constipation. Biochemical and Other Surrogate End Points Serum Phosphorus There was no significant difference in end-of-treatment serum phosphorus levels with calcium acetate in comparison to calcium carbonate or with lanthanum carbonate in comparison to calcium carbonate (Fig 3). There was a significantly greater end-of-treatment serum phosphorus level with sevelamer in comparison to calcium salts (WMD, 0.21 mg/dL; 95% CI, 0.01 to 0.41; Fig 3). There was a significant decrease in end-of-treatment phosphorus level with calcium in comparison to placebo (2 trials; 90 patients; WMD, −1.41 mg/dL; 95% CI, −2.52 to −0.29). Similarly, there was a significant decrease in end-of-treatment phosphorus level with sevelamer in comparison to placebo (1 trial; 36 patients; WMD, −1.80 mg/dL; 95% CI, −3.32 to −0.28). Combination treatment with sevelamer and calcium carbonate had no synergistic effect on serum phosphorus level compared with sevelamer alone (1 trial; 71 patients; WMD, −0.20 mg/dL; 95% CI, −1.14 to 0.74). Serum PTH There was no significant difference in end-of-treatment PTH level with calcium acetate in comparison to calcium carbonate or with lanthanum carbonate compared with calcium carbonate (Fig 4). There was a significantly greater end-of-treatment PTH level with sevelamer compared with calcium salts (WMD, 55.57 pg/mL; 95% CI, 26.69 to 84.45) and a decrease in end-of-treatment PTH level with lanthanum carbonate in comparison to placebo (WMD, −83.00 pg/mL; 95% CI, −154.63 to −11.37). Ca × P There was no significant difference in end-of-treatment Ca × P level with calcium acetate in comparison to calcium carbonate and sevelamer in comparison to calcium salts (Table 3). There was a significantly lower end-of-treatment Ca × P level with lanthanum carbonate in comparison to placebo (WMD, −14.20 mg2/dL2; 95% CI, −21.03 to −7.37) and with lanthanum carbonate in comparison to calcium carbonate (WMD, −3.82 mg2/dL2; 95% CI, −7.47 to −0.16). Serum Bicarbonate There was no significant difference in end-of-treatment serum bicarbonate level between calcium acetate and calcium carbonate. There was a significantly lower end-of-treatment serum bicarbonate level with sevelamer in comparison to calcium salts (WMD, −1.43 mEq/L; 95% CI, −2.07 to −0.79; Table 3). Other Biochemical End Points There was no significant difference in end-of-treatment alkaline phosphatase level with sevelamer in comparison to calcium salts (Table 3). There was a significant difference in end-of-treatment total cholesterol level with sevelamer in comparison to calcium salts (WMD, −20.55 mg/dL; 95% CI, −29.15 to −11.96; Table 3). Vascular Calcification Five studies reported the effects of sevelamer and calcium salts on vascular calcification32, 34, 35, 37, 41 (Table 4). One study reported slower progression of coronary, aortic, and heart valve calcification (measured by using electron beam computed tomography) with use of sevelamer in comparison to calcium acetate37 by using the Agatston scoring system. Similarly, another study showed decreased progression of coronary artery calcification with sevelamer compared with calcium salts in incident hemodialysis patients34 (Table 4). In contrast, a third study compared sevelamer plus atorvastatin with calcium acetate plus atorvastatin and reported similar coronary artery calcification progression in both groups.35 There also was a study that reported coronary artery calcium scores in 101 dialysis patients (using a modified Agatston scoring system) and reported no difference in coronary artery calcification progression between the sevelamer and calcium groups (P = 0.59).32 Included studies used different scoring systems to assess vascular calcification and thus could not be pooled. | | | | Reference | Comparisons | Study Duration (mo) | No. of Participants | Outcomes Analyzed | Key Findings | |
|---|
| Barreto et al,32 2008 | Sevelamer v calcium acetate | 12 | 101 | (1) CAC scores using electron beam computed tomography, (2) bone histomorphometry | CAC progression and bone remodeling did not differ between the 2 groups | | | Block et al,34 2005 | Sevelamer v calcium carbonate + calcium acetate | 18 | 129 | CAC scores by using electron beam computed tomography | Calcium-containing phosphate binders increased CAC scores compared with sevelamer (P = 0.01) | | | Chertow et al,37 2002 | Sevelamer v calcium acetate | 12 | 132 | Vascular calcification scores⁎ (Agatston scores) using electron beam computed tomography | Coronary, aortic, and valvular calcification progressed in calcium-treated patients, but no significant progression was noted in the sevelamer-treated group | | | Qunibi et al (CARE-2),35 2008 | Sevelamer + atorvastatin v calcium acetate + atorvastatin | 12 | 203 | Vascular calcification scores (Agatston scores) using electron beam computed tomography | Coronary calcification scores were similar in both groups | | | Raggi et al,62 2005† | Sevelamer v calcium acetate | 12 | 111 | Thoracic vertebral bone attenuation using electron beam computed tomography | Trabecular bone attenuation decreased significantly in sevelamer-treated patients (P < 0.05) Cortical bone attenuation did not decrease significantly with sevelamer (P = 0.05) | | | Russo et al,46 2007 | Sevelamer v calcium carbonate v low-phosphorus diet | 24 | 90 | CAC scores using electron beam computed tomography | Sevelamer reduced the progression of CAC, whereas calcium carbonate did not increase or decrease CAC progression | | | D'Haese et al,50 2003 | Lanthanum carbonate v placebo | 12 | 98 | Bone histomorphometry analyzing:(1) Development or improvement in various types of renal osteodystrophy (adynamic bone disease, osteomalacia, mixed renal osteodystrophy, hyperparathyroidism) (2) Lanthanum content in bone | (1) Prevalence of renal osteodystrophy decreased from 36% to 18% in the lanthanum carbonate group and increased from 43% to 53% in calcium carbonate patients (2) Bone lanthanum levels were higher in lanthanum carbonate than calcium carbonate patients | | | Phelps et al,27 2002 | Calcium acetate, 2 g/d, v calcium acetate, 6 g/d | 18 | 24 | BMD at lumbar spine, femoral neck, and greater trochanter by using DEXA | No significant difference between treatment groups | | | Ferreira et al,41 2008 | Sevelamer v calcium carbonate | 12 | 91 | Mineralization lag time, changes in bone turnover, development of osteomalacia, adynamic bone disease | Bone formation and trabecular architecture increased with sevelamer, with no changes in bone turnover or mineralization | | | Malluche et al,58 2008 | Lanthanum carbonate v standard phosphate-binder therapy | 24 | 211 | Bone histomorphometry analyzing changes in bone turnover, mineralization, bone volume, and lanthanum content in bone | Patients administered lanthanum carbonate had improvement in bone turnover and bone volume | | | | |
| ⁎ Agatston score was obtained by multiplying the area of calcified focus by a weighted density coefficient based on the peak density of the calcification noted on electron beam computed tomography. †Substudy of Chertow 2002.37 |
Bone Outcomes Lanthanum carbonate decreased the number of patients developing low-turnover bone disease in comparison to calcium carbonate53 and resulted in improvement in bone volume in comparison to standard phosphate-binder therapy58 (Table 4). Aluminum-like effects on bone were not noted in follow-up studies that assessed the safety of lanthanum carbonate.53 Based on electron beam computed tomographic results, 1 study reported a significant decrease in trabecular bone attenuation and a trend toward a decrease in cortical bone attenuation (P = 0.05) in thoracic vertebrae with sevelamer compared with calcium salts.62 In another study enrolling 101 dialysis patients, there was no difference in bone remodeling between the sevelamer and calcium groups at the end of 1 year of follow-up.31 Another study reported increased bone formation and improved trabecular architecture, but no significant change in bone turnover or mineralization, with sevelamer in comparison to calcium salts.41 A formal meta-analysis could not be performed for the incidence of fracture because of insufficient data. Discussion Our systematic review has identified a large number of RCTs that examine phosphate binders in people with CKD. These trials have not shown that phosphate binders compared with placebo or calcium salts compared with non–calcium- or aluminum-containing agents decrease all-cause or cardiovascular mortality. As expected, all phosphate binders decreased serum phosphorus levels compared with placebo; however, newer agents (lanthanum carbonate and sevelamer) did not result in consistently superior biochemical outcomes compared with calcium-based therapies. Rather, in direct comparisons (head-to-head studies), calcium salts were superior to sevelamer for reduction of serum phosphorus levels. Compared with calcium salts, sevelamer and lanthanum carbonate were associated with significantly lower rates of treatment-related hypercalcemia, which may result in decreased vascular calcification. The differential effect on serum calcium and phosphorus levels resulted in increased PTH suppression by treatment with calcium compared with sevelamer. The efficacy of available phosphate-binding agents on the surrogate outcomes of bone mineral density or histomorphometry and vascular calcification have been reported heterogeneously in few studies, and reliable conclusions could not be drawn through meta-analysis. Sevelamer was associated with lower serum calcium, higher phosphorus, and higher PTH levels at the end-of-treatment period compared with calcium salts. This may be caused by noncompliance, resulting in less phosphorus reduction with sevelamer, or because it is less effective at the relative doses used. Various gastrointestinal adverse effects, such as constipation, abdominal bloating, dyspepsia, nausea, and vomiting, were reported with sevelamer and calcium salts in clinical trials. Although most individual studies reported no significant difference in gastrointestinal side effects between sevelamer and calcium salts, there was significantly greater occurrence with sevelamer when studies were pooled. This also might have contributed to lower compliance and higher pill burdens reported for sevelamer. Sevelamer resulted in lower end-of-treatment serum calcium levels, which might have contributed to the greater PTH levels noted. The DCOR Study, the largest trial (n = 2,103) conducted to date, reported no difference in risk of all-cause mortality between sevelamer and calcium salts,38 except for a subgroup analysis in patients older than 65 years who completed a 2-year follow-up. Because of the size of this study, DCOR was very influential and contributed 46% of the weight in our all-cause mortality analysis. Exclusion of this study resulted in a similar, but smaller, risk of all-cause mortality (RR, 0.59 [95% CI, 0.35 to 1.01] versus RR, 0.75 [95% CI, 0.48 to 1.16]). Given the limitations of the analysis by Suki et al,38 we also conducted a sensitivity analysis using data from St Peters et al,66 who used Centers for Medicare & Medicaid Services claims data to reassess the DCOR trial results. The risk of all-cause mortality was unchanged (RR, 0.75; 95% CI, 0.56 to 1.33) by using these data. The occurrence, progression, and prognostic importance of vascular calcification are important questions in CKD, and the influence of calcium-based binders on progression of vascular calcification is a matter of intense debate.67, 68, 69, 70 Two studies in the present analysis reported a greater rate of progression of vascular calcification with calcium salts compared with sevelamer,34, 37 whereas 1 study showed no difference in calcium scores between sevelamer and calcium salts.32 The possibility that the cholesterol-lowering effect of sevelamer may contribute to this effect (rather than hypercalcemia from calcium salts) cannot be excluded based on the recently published CARE-2 (The Calcium Acetate Renagel Evaluation-2) study.35 Although vascular calcification is associated with increased risk of mortality in hemodialysis patients, the impact of decreasing vascular calcification on survival outcomes has not been shown in randomized intervention trials.69 As shown by the recent negative results of the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) study (analyzing the beneficial effects of statins in dialysis patients), even such a universally accepted surrogate end point as low-density lipoprotein cholesterol level may not predict such patient-centered end points as mortality in a different setting, such as dialysis, in which the causal pathway to cardiovascular end points and death may be different.71, 72 A surrogate end point must be validated and tested in specific settings before validating assumptions that modifying the surrogate marker will reduce clinical outcomes. Sevelamer has not been well studied in patients with CKD stages 3 to 5 (not requiring dialysis), except for a single study.46 Therefore, this systematic review can only inform the therapeutic use of sevelamer and calcium salts in dialysis patients and for only surrogate biochemical end points; it is still uncertain whether sevelamer reduces hypercalcemia and cardiovascular disease in patients with stages 3 to 5 CKD compared with calcium-based agents. Calcium salts are recommended in predialysis patients by various international guideline agencies for the control of hyperphosphatemia.12, 73 Our review confirms that calcium carbonate and calcium acetate are equally effective in decreasing phosphorus and PTH levels with a similar incidence of hypercalcemia and gastrointestinal adverse events; we identified only 2 studies conducted in predialysis patients.23, 27 Because few studies are available, there currently is no strong RCT evidence (for the outcomes of mortality and morbidity) for the use of calcium-based phosphate binders in patients with earlier stages of CKD. Few studies have analyzed the use of lanthanum carbonate alone or in conjunction with calcium salts for phosphate binding in patients with CKD. Lanthanum carbonate has been compared with placebo and calcium carbonate in dialysis patients, and available data confirm their efficacy in decreasing phosphorus levels, similar to calcium carbonate, with a decreased incidence of hypercalcemia. Accumulation of lanthanum in bone has been assessed in 1 study by means of bone biopsy at the end of 2 years of treatment, and no evidence of aluminum-like toxicity was observed.53 To the best of our knowledge, this is the first comprehensive systematic review of RCTs that has assessed the benefits and harms of all phosphate-binding agents in patients with CKD. A previous meta-analysis (including 17 prospective and retrospective studies comparing sevelamer hydrochloride with placebo) showed that sevelamer compared with placebo or no treatment improved biochemical end points (serum phosphorus, Ca × P, PTH, and lipid levels) without increased serum calcium levels. However, data for survival, hospitalization, and vascular calcification were not included.74 The inclusion of both observational studies and RCTs in that review decreased the strengths of its conclusions through potential for bias and unknown confounding. A second systematic review of 7 RCTs (746 patients) concluded that sevelamer had similar effects on phosphorus and Ca × P levels, with a lower incidence of hypercalcemia.75 Similar to the previous analysis, that review focused on only the effects of sevelamer and included some, but not all, available trials. A more recent analysis by Tonelli et al76 (an update of their previous review) analyzed the benefits of sevelamer in comparison to calcium alone and included 10 trials.75 This review did not assess the role of other phosphate binders and did not explore the risk of vascular calcification.77 Our systematic review has a number of strengths and some weaknesses. It is based on prior publication of a prospectively designed peer-reviewed protocol78 and a systematic search of medical databases, data extraction, analysis, and trial quality assessment by 2 independent reviewers with supervision by a third experienced investigator. The key findings are limited by the lack of long-term studies analyzing the efficacy of phosphate binders on mortality and musculoskeletal morbidity. Most included studies enrolled few patients (except for the large DCOR trial), and all were powered to observe differences in surrogate end points, rather than patient-focused outcomes. This attention to surrogate rather than patient-level end points in patients with CKD is not new and should be superseded by focus on major patient-level end points in future trials.79, 80, 81 The strength of conclusions drawn from this review also is limited by suboptimal reporting of study methods to determine trial quality and significant heterogeneity observed for many outcomes. The primary advantage for more recently developed phosphate binders (lanthanum carbonate and sevelamer) is a decrease in hypercalcemia in dialysis patients. Existing trials using patient-focused end points in predialysis patients are inadequate to inform clinical recommendations for any phosphate binder and are required before advocating that newer agents are superior to existing lower cost interventions. Full adoption of sevelamer and lanthanum by government drug reimbursement agencies in place of calcium salts would lead to a large increase in health care expenditure.82, 83 This can be justified only by presenting evidence for improved clinical outcomes of these agents compared with calcium salts. Additionally, it should be remembered that to date, no clinical trial has shown a survival advantage for calcium salts (compared with placebo or other agents). Further research using an RCT design is required to assess the effect of surrogate biochemical end points (phosphorus, calcium, and PTH levels) on mortality and morbidity in patients with CKD. These might include trials of: (1) direct comparisons between sevelamer, calcium salts, and lanthanum carbonate in patients with CKD with primary outcomes of all-cause and cardiovascular mortality, fractures, hospitalization, and parathyroidectomy; (2) any phosphate binder to control hyperphosphatemia in patients with CKD stages 3 and 4; or (3) the efficacy of combination therapy (such as sevelamer with or without calcium salts) on both surrogate and patient-level end points. Acknowledgements Author affiliations are as follows. Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH: Sankar D. Navaneethan, MD, MPH; Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand: Suetonia C. Palmer, MBChB; Cochrane Renal Group, NHMRC Centre for Clinical Research Excellence in Renal Medicine, The Children’s Hospital at Westmead, Westmead: Suetonia C. Palmer, MBChB, Jonathan C. Craig, MBChB, PhD, Giovanni F.M. Strippoli, MD, PhD, MPH, MM; School of Public Health, University of Sydney, Sydney, Australia: Jonathan C. Craig, MBChB, PhD, Giovanni F.M. Strippoli, MD, PhD, MPH, MM; Centre for Transplant and Renal Research, Westmead Millennium Institute, Sydney, Australia: Grahame J. Elder, PhD; Department of Pharmacology and Clinical Epidemiology, Renal Division, Mario Negri Sud Consortium, S Maria Imbaro (Ch), Italy: Giovanni F.M. Strippoli, MD, PhD, MPH, MM; and DIAVERUM Medical Scientific Office, Lund, Sweden: Giovanni F.M. Strippoli, MD, PhD, MPH, MM. We thank Narelle Willis (Review Group Coordinator of the Cochrane Renal Group), Ruth Mitchell (Trials Search Coordinator of the Cochrane Renal Group), and the Cochrane Renal Group for assistance with preparation of this study. Support: None. Financial Disclosure: None. Supplementary Material Supplementary Item S1 (PDF) Description of search strategy. References 1. 1US Renal Data System. USRDS 2008 Annual Data Report (Chapter 11: Costs of End-Stage Renal Disease). http://www.usrds.org/2008/pdf/V2_11_2008.pdf. 2. 2Hruska KA, Mathew S, Lund R, Qiu P, Pratt R. Hyperphosphatemia of chronic kidney disease. Kidney Int. 2008;74:148–157.
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A list of author affiliations appears at the end of this article  Address correspondence to Sankar D. Navaneethan, MD, MPH, Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Euclid Ave, Q7, Cleveland, OH 44122
Giovanni F.M. Strippoli, MD, PhD, MPH, MM, Department of Pharmacology and Clinical Epidemiology, Renal Division, Mario Negri Sud Consortium, S Maria Imbaro (Ch), Italy This review is excerpted from a Cochrane Review to be published in The Cochrane Library (http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/HOME). Cochrane Reviews are regularly updated as new evidence emerges in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the review. PII: S0272-6386(09)00865-8 doi:10.1053/j.ajkd.2009.06.004 © 2009 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved. | |
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