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Nephrology Dialysis Transplantation 2007 22(10):2856-2866; doi:10.1093/ndt/gfm421
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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


Systematic review of the clinical efficacy and safety of sevelamer in dialysis patients

Marcello Tonelli1,2,3,4, Natasha Wiebe1, Bruce Culleton5, Helen Lee6, Scott Klarenbach1,3,4, Fiona Shrive6, Braden Manns3,5,6 and for the Alberta Kidney Disease Network

1Department of Medicine, 2Division of Critical Care Medicine, 3Institute of Health Economics, 4Department of Public Health Sciences, University of Alberta, Edmonton, Alberta, Canada, 5Division of Nephrology, Department of Medicine and 6Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

Correspondence and offprint requests to: Braden Manns, Foothills Medical Centre, 1403, 29th Street NW, Calgary, Alberta T2N 2T9, Canada. Email: braden.manns{at}calgaryhealthregion.ca



   Abstract
Top
 Abstract
Background
 Methods
 Results
 Discussion
 Supplementary Material
 Acknowledgements
 References
 
Background. The relative effectiveness and safety of sevelamer for treatment of hyperphosphataemia in dialysis patients is uncertain, as compared with calcium-based phosphate binders.

Methods. We conducted a comprehensive search to identify all randomized cross-over or parallel group studies comparing sevelamer to any other therapy or placebo in adult dialysis patients. Study quality was assessed using the Chalmers Index. Data was extracted and checked using a standardized form and combined using a random effects model.

Results. We identified 14 primary publications of randomized trials (3193 participants) that were eligible for efficacy analysis. In analyses pooling, the 10 studies reporting on serum phosphate and calcium (2501 participants), serum phosphate was significantly lower with calcium-based phosphate binders by 0.12 mmol/l [95% confidence interval (CI) 0.05–0.19], compared with sevelamer. On-treatment calcium–phosphate product was not significantly lower in patients receiving calcium-based phosphate binders (0.12 mmol2/l2, –0.05 to 0.29), compared with sevelamer. Overall mean difference in serum calcium was significantly lower with sevelamer therapy by 0.10 mmol/l (–0.12 to –0.07) and pooled on-treatment decrease in serum bicarbonate was significantly greater with sevelamer therapy by 2.8 mmol/l (2.2 to –3.5). In the five trials which reported all-cause mortality (2429 participants), the overall risk difference for all cause mortality in these five trials was similar between therapies (–2%, 95% CI –6–2). In the three trials which reported serious adverse events (2185 participants), there was a trend towards a lower risk in patients receiving calcium-based phosphate binders (13% lower, 95% CI –2–29).

Conclusions. Compared with calcium-based phosphate binders, use of sevelamer in dialysis patients is associated with similar to slightly higher phosphate levels, similar calcium phosphate product, and slightly lower serum calcium levels. There was no evidence that sevelamer reduced all-cause mortality, cardiovascular mortality, the frequency of symptomatic bone disease or health-related quality of life.

Keywords: calcium; hyperphosphataemia; sevelamer



   Background
Top
 Abstract
 Background
Methods
 Results
 Discussion
 Supplementary Material
 Acknowledgements
 References
 
Patients with end-stage renal disease (ESRD) have high mortality rates and abnormal mineral metabolism, including hyperphosphataemia and hypocalcaemia. Observational data have linked abnormal mineral metabolism, such as hyperphosphataemia, to adverse clinical outcomes, including mortality, in patients with kidney disease. Although higher levels of serum phosphate are associated with worse outcomes, it is unclear whether better control of hyperphosphataemia would reduce morbidity or mortality in ESRD.

The treatment for hyperphosphataemia in ESRD has typically focused on the use of oral calcium-based phosphate binders taken at mealtimes, which bind dietary phosphate. Dietary phosphate binders are used by virtually all ESRD patients. Calcium-based agents have traditionally been used as first line therapy, since they correct hypocalcaemia in addition to reducing serum phosphate levels, and are inexpensive [1]. However, these agents may not be suitable for all patients because of dose-limiting hypercalcaemia and high calcium–phosphate product. In addition, recent attention has focused on the association between the cumulative dose of oral calcium and vascular calcification, which in turn may be associated with mortality in ESRD. Although magnesium- and aluminium-based agents may be useful for managing hyperphosphataemia, there is concern about adverse events including gastrointestinal intolerance and encephalopathy, respectively.

Non-calcium, non-magnesium, aluminium-free agents have recently become available for use as phosphate binders in patients with ESRD, of which sevelamer is the first such agent to be approved for use in North America. Given the large differential cost between this new agent and traditional therapies, the optimal use of this new therapy requires consideration.

An earlier review [1] included seven randomized trials with a total of 756 participants, and largely considered biochemical outcomes such as change in serum calcium level. Since that time, several trials which report the effect of sevelamer on all-cause or cardiovascular mortality have been published, as well as relatively large single-arm trials permitting the evaluation of adverse events. Given recent attention to the potential benefits of sevelamer in the nephrology literature and popular media, it appears that an updated summary of evidence would be potentially useful to clinicians and decision-makers. We performed a systematic review of the effectiveness and safety of sevelamer (compared with calcium-based phosphate binders) in patients with ESRD.



   Methods
Top
 Abstract
 Background
 Methods
Results
 Discussion
 Supplementary Material
 Acknowledgements
 References
 
This systematic review was conducted and reported in accordance with available guidelines as described subsequently [2,3]. Detailed study methodology is reported in the Web Appendix.

Search strategy
We conducted a comprehensive search to identify all relevant studies or registries of sevelamer use. MEDLINE (1966—19 January 2007), EMBASE (1988—19 January 2007), all EBM Reviews (includes CENTRAL, the Cochrane Database of Systematic Reviews and DARE), the National Health Service Economic Evaluation Database, TOXNET, BIOSIS Previews®, and a variety of grey literature sources (n = 43) were searched. Studies in all languages were included, regardless of publication status. The citations of existing reviews and trials identified were reviewed by two reviewers to identify pertinent studies.

Selection criteria and method
Each potentially relevant study was independently assessed by two reviewers for inclusion in the review. For assessing clinical benefit, studies meeting the following criteria were eligible for inclusion: randomized controlled trials (RCTs) or randomized crossover trials studying adults with ESRD (chronic kidney disease, on dialysis, or kidney transplant recipients) and comparing sevelamer to any calcium-based phosphate binder. For assessing harm, studies (controlled or uncontrolled) meeting the following criteria were eligible for inclusion: prospective clinical trial or registry of adult patients with ESRD who received sevelamer.

Data extraction
A standardized data extraction method was used to record trial characteristics into a database. A second reviewer checked the extracted data for accuracy.

Adverse events (AE) were considered serious if the authors described the event as serious or if it was the reason given for withdrawal from the trial. All other AE were considered non-serious.

Quality assessment
The study quality of RCTs was assessed using a condensed version of the Chalmers Index [4], and included other items also known to be associated with study quality [5,6]. Single-arm trials were not assessed for quality.

Data analysis
Data were analysed using Review Manager 4.2.7 (Oxford, England) and Stata 8.2 (College Station, TX, USA). Weighted mean difference (WMD) was used to pool results for continuous efficacy outcomes (e.g. serum phosphate, serum calcium). For trials with fewer than 100 participants, change-from-baseline results were used in place of final value results [7]. Pooling methods that account for the within-patient correlation from crossover trials were used to combine crossover and parallel continuous trial data [8]. Adverse event rates were tabulated but not pooled since the quality of reporting was poor (e.g. descriptions of ascertainment and event severity were absent) [9,10].

Where appropriate, results were combined using a random effects model, and statistical heterogeneity was quantified using the I2 statistic [11,12]. Publication bias was assessed using weighted regression [13].



   Results
Top
 Abstract
 Background
 Methods
 Results
Discussion
 Supplementary Material
 Acknowledgements
 References
 
Quantity of research available
Figure 1 shows trial flow among those studies considered for inclusion. Multiple publications were excluded from the count of included studies because they were secondary publications of previous reports; however, any relevant and unique results were extracted and included [14–20]. Koiwa et al. [21,22] were excluded because the time of randomization occurred after subjects had already been treated with sevelamer for 4 weeks, meaning that changes in clinical parameters during the study might be smaller than expected (biasing against sevelamer). Several trials accrued many of the same participants and so were only included in each outcome once [23–26]. One study (RIND) [27] initially reported biochemical outcomes and subsequently compared mortality between treatment groups after extended follow-up of the original cohort [20]. Both have been included in this review, although during the extended follow-up period, participants in this trial did not necessarily receive the treatment that was assigned by randomization.


Figure 1
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  		Fig. 1. Flow diagram of studies considered for inclusion.

 
Trial characteristics
We identified 10 primary publications of randomized trials with a total of 2991 participants eligible for efficacy analysis [27–36]; one was an abstract [32] and a second was a poster [36]. They compared sevelamer to either calcium acetate [28,33,31], calcium carbonate [30,32,34,35] or either (based on physician preference) [27,29,36]. Two were randomized crossover trials with reportedly no carryover effect [28,35]; two were randomized crossover trials that did not report whether there was a carryover effect [30,37]. One had no baseline washout period [34]. One other accrued only patients who had recently initiated dialysis [27]. All were haemodialysis patients except for two studies: one study [34] did not specify a dialytic modality, the other [37] included peritoneal patients.

Thirty-one prospective trials with a total of 4085 participants were identified and eligible for the review of safety [23–25,27–29,31–36,37–55] (Table 1; abbreviated version, full version available in the Web Appendix). Most (n = 16) were single-arm trials. No registries were identified. Three studied peritoneal dialysis patients [37,40,50]; two were conducted in Spain and the remaining was conducted in Greece. All the RCTs that were included in the efficacy analysis were also included in the safety analysis except for De Santo et al. [30] which report no relevant harm data.


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  		Table 1. Characteristics of included studies

 
The reporting of study design in RCTs was weak in a number of areas (Table 2; abbreviated version, full version available in the Web Appendix). Non-eligible patients were not described in 10/16 trials. Double-blind treatment assignment was reported by two trials [24,33]. The description of withdrawals and dropouts was incomplete or not reported in 11 trials. Furthermore, as shown in Table 2 the percentage of loss to follow-up was >10% in 7/10 trials (percentage of loss to follow-up could not be calculated from the remainder), and only 4/16 RCTs reported a sample size calculation. Four trials [24,25,28,33] reported an intention-to-treat design and a further trial reported [29] a method for handling missing data. Only two RCTs [29,45] reported side effects adequately (number and type of side effect was listed individually and by treatment group). Two trials [30,31] reported a public source of funding and one [37] reported having no funding.


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  		Table 2. Quality assessment of RCTs

 
Publication bias
To assess the potential for publication bias in RCTs, we used results from the most frequent outcome studied (serum phosphate). Our funnel plot was asymmetrical (not shown) and the weighted regression test detected statistical evidence of publication bias (bias=1.9, P = 0.01).

Sevelamer vs calcium-based phosphate binders—effect on serum measures
Ten RCTs with 2501 participants reported serum phosphate, serum calcium and intact parathyroid hormone (iPTH). The duration of follow-up ranged from 8 weeks to 45 months. In pooled analyses, serum phosphate was significantly lower with calcium-based phosphate binders by 0.12 mmol/l [95% confidence interval (CI) 0.05–0.19; Figure 2] and the between-study heterogeneity was large (I2 = 64%). All RCTs favoured calcium-based phosphate binders. Removing the unpublished studies [32,36], increased the overall effect slightly (0.17 mmol/l, 0.07–0.27). The overall weighted mean difference in serum calcium was significantly lower with sevelamer therapy by 0.10 mmol/l (–0.12 to –0.07; Table 3). Between-study variance was also large (I2 = 53%).


Figure 2
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  		Fig. 2. Metagraph of serum phosphate (mmol/l) for sevelamer vs calcium-based phosphate binders. WMD, weighted mean difference; SE, standard error; CI, confidence interval.

 

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  		Table 3. Overall outcome summaries

 
The data for iPTH was skewed so that results could not be combined. Mean (or median) differences of iPTH ranged from 0.7 to 9.5 pmol/l. All RCTs demonstrated numerically lower mean on-treatment iPTH (or in some cases, a smaller increase in PTH) in calcium recipients, although only two [27,36] were statistically significant.

Nine RCTs with 2271 participants reported serum calcium–phosphate product. On-treatment calcium–phosphate product was non-significantly lower in patients receiving calcium-based phosphate binders (WMD 0.12 mmol2/l2, –0.05 to 0.29; Table 3) and the between-study heterogeneity was large (I2 = 57%). Four RCTs with 338 participants reported serum bicarbonate. The overall weighted mean difference was significant and was lower with sevelamer therapy by 2.8 mmol/l (–3.5 to –2.2; I2 = 0%).

Sevelamer vs calcium-based phosphate binders—effect on hypercalcaemia
The rate of hypercalcaemia (defined in all trials as a calcium >2.6–2.75 mmol/l), reported in 13 trials (634 participants; median 12 weeks; Table 3), was a median of 7% and ranged from 0 to 36. Eight RCTs (570 participants) reported the number of patients who became hypercalcemic during the course of follow-up. The absolute risk of hypercalcaemia was 21% lower in sevelamer recipients (95% CI 13–29; I2 = 36%). The number needed to harm (i.e. to result in one participant experiencing at least one episode of hypercalcaemia) was 5 (3–8). The median duration of hypercalcaemia or its clinical consequences were not reported for any trial.

Sevelamer vs calcium-based phosphate binders—effect on mortality
Five RCTs with 2429 participants reported all-cause mortality. The duration of follow-up varied from 2 to 45 months. Only one RCT [36] specified all-cause mortality as the primary outcome. The overall risk difference was non-significant (–2%, 95% CI –6 to 2; Figure 3). The point estimate for three RCTs [27,34,36] favoured sevelamer over calcium-based phosphate binders, and the percent of variance due to between-study variance was modest (I2 = 22%). Two of the RCTs with 89% of the weight did not follow all participants until the end of the study or death [29,36]. Both of these RCTs had losses to follow-up which considerably exceeded 10% (range 15–48%; Table 2). The most recent trial had median follow-up of 44 months, and found significantly reduced mortality among sevelamer recipients in both adjusted and unadjusted analyses. Results were similar when the unpublished study [36], was excluded (–5%, –15 to 5). Three RCTs with 2102 participants reported cardiovascular mortality and the overall risk difference was non-significant (–1%, –4 to 2; Figure 3).


Figure 3
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  		Fig. 3. Metagraph of mortality for sevelamer vs calcium-based phosphate binders.RD, risk difference; CI, confidence interval.

 
Sevelamer vs calcium-based phosphate binders—effect on hospitalizations
Two unblinded RCTs reported the number of days hospitalized but these results could not be pooled due to differences in the reporting of hospitalization days. Chertow et al. [29] reported the number of patients hospitalized during the 52-week trial. The difference was non-significant (total 567 vs 980 days in recipients of sevelamer and calcium-based binders, respectively; P = 0.23; 200 participants). Suki et al. [36] reported the number of days hospitalized per patient year; this difference was also non-significant (median 5.0 in sevelamer recipients vs 5.8 days in recipients of calcium-based binders; P = 0.09; 2040 participants) but again favoured sevelamer therapy.

Sevelamer vs calcium-based phosphate binders—effect on health-related quality of life and other clinical outcomes
No RCTs reported a measure of health-related quality of life. No RCTs reported CVD events, or the frequency of symptomatic bone disease such as fractures or bone pain. Two RCTs [27,29] (217 participants) reported change-from-baseline Agatston calcification scores [56]. The data were skewed so non-parametric statistics are reported here. Using the last timepoints available (1.5 years and 1 year, respectively), the two median change-from-baseline differences were –56 and –116. Both Wilcoxon tests were significant (P's ≤ 0.04) and favoured smaller increases in the sevelamer groups.

Sevelamer vs calcium-based phosphate binders—effect on adverse events
Seventeen sevelamer trials with 1834 participants reported serious adverse events (Table 3). Frequencies of SAE ranged from 2% to 33% for an approximate median duration of follow-up of <2 years. The median frequency of SAE was 15%. The frequency of serious adverse gastrointestinal events ranged from 0% to 40% (median 24 weeks duration of follow-up). Three trials with 260 participants reported chest pain; one trial (n = 34; median follow-up 6 months) reported one incident as serious, while the other two trials reported frequencies of 7 and 8% (median follow-up 8 weeks) but did not distinguish between serious and non-serious events.

Controlled comparisons of AE were less frequent
Three RCTs with 2185 participants reported SAE totals. The pooled risk difference was non-significant (13% lower in patients receiving calcium-based phosphate binders, 95% CI –2% higher to 29% lower; I2 = 78%; Table 3) and all three RCTs favoured calcium-based phosphate binders. A further three RCTs plus another report [15] of the Treat-to-Goal RCT with 248 participants reported all adverse events. This risk difference was also non-significant (–1%, –12 to 10). One report (31 participants) of serious gastrointestinal complaints found a significant risk difference of 33% (9–58%) favouring calcium-based phosphate binders.



   Discussion
Top
 Abstract
 Background
 Methods
 Results
 Discussion
Supplementary Material
 Acknowledgements
 References
 
We performed a comprehensive search according to published recommendations, and identified 32 trials including more than 4000 participants in total. Compared with oral calcium-based phosphate binders, there was no evidence that sevelamer reduced all-cause mortality, cardiovascular mortality or the frequency of symptomatic bone disease, and no evidence that sevelamer improved quality of life. Two studies reported a non-significant reduction in hospitalization associated with sevelamer therapy. However, potentially significant limitations in the design of these studies suggest that additional trials are required to confirm this finding.

Our review updates the findings of an earlier systematic review from our group [1], and includes 25 new studies (with a total of 3345 additional participants). Notably, the current review includes results from the Dialysis Clinical Outcomes Revisited (DCOR) study—the largest randomized trial of sevelamer conducted to date. This randomized, unblinded study allocated 2103 haemodialysis patients at 75 US centres to receive sevelamer or calcium-based phosphate binders. The intended duration of follow-up was 3 years, but was extended for an additional year following a lower than expected mortality rate at an interim analysis [36]. Forty-eight percent of participants (47% of sevelamer recipients and 49% of calcium recipients) terminated the study early, and information on clinical events for these patients after early study termination is unknown. As reported above, the primary analysis from DCOR did not show a difference in survival overall between patients treated with sevelamer and those receiving calcium-based phosphate binders (RR 0.91, P = 0.30). A pre-specified secondary analysis suggested that sevelamer was associated with better survival in patients aged ≥65 years. However, this finding will require confirmation in future studies, since the high frequency of loss to follow-up means that a significant increase in mortality due to sevelamer cannot be excluded even in this subgroup.

Our review also included a follow-up analysis [20] of an earlier study which compared sevelamer with calcium-based binders [27]. During the extension phase, physicians were free to prescribe the phosphate-binder of their choice. After a median follow-up of 44 months, sevelamer was associated with significantly lower mortality with or without adjustment for potential confounders (adjusted hazard ratio 0.32, 95% CI 0.13–0.81). The authors of this study suggest that the explanation for its different findings as compared with DCOR might have been due to the longer follow-up period, or differences in study population. Although these explanations are plausible, this study was relatively small, and bias introduced by the open label design or incomplete follow-up for mortality among sevelamer recipients remains a possibility.

Sevelamer therapy results in a smaller increase in serum calcium levels and fewer episodes of hypercalcaemia, compared with calcium-based phosphate binders. However, sevelamer appears to be slightly inferior to oral calcium-based phosphate binders for control of hyperphosphataemia, although the clinical significance of the difference (0.12 mmol/l) is uncertain. Sevelamer therapy also leads to lower serum bicarbonate levels (~2.8 mmol/l), which is also of uncertain clinical significance but warrants further examination. The comparative efficacy of sevelamer for control of hyperparathyroidism could not be assessed. Finally, sevelamer therapy results in smaller increases in vascular calcification scores, compared with calcium-based binders although the significance of this is uncertain.

The safety analyses demonstrate that the incidence of adverse events among sevelamer recipients is relatively high (median frequencies of serious and non-serious adverse events 15 and 30%, respectively), but this must be interpreted in the context of the clinical population. When we restricted our observations to data from the available RCTs, there was a trend towards an increased risk of serious adverse events with sevelamer (13% higher; 95% CI 2% lower to 29% higher). Unfortunately, the clinical significance of these adverse events (and their impact on quality of life) cannot be assessed from the available data.

The populations studied include both incident and prevalent dialysis patients drawn from a wide range of countries and practice settings. Therefore, the findings of the current review are likely to be externally valid, although the two largest RCTs were both conducted in American haemodialysis patients. The internal validity of the available data is less certain. Overall, quality of trial conduct and/or reporting was low, with only one study describing adequate allocation concealment, uncommon use of an intention-to-treat design, lack of patient blinding, infrequent blinding of care providers/outcome assessors, short follow-up duration (especially for trials not designed to compare mortality between treatments) and considerable loss to follow-up in most studies. As noted in the body of the review, loss to follow-up in the two largest RCTs substantially exceeded 20%, which has the potential to introduce significant bias.

The theoretical rationale underpinning the preferential use of non-calcium-based binders such as sevelamer is intellectually appealing, especially in view of data from randomized trials indicating that sevelamer reduces vascular and cardiac calcification [17,27,29]. To date, the hypothesis that improvements in these surrogate outcomes will translate into clinically meaningful benefits remains unproven. In addition, the risk of serious adverse events with sevelamer treatment warrant further scrutiny. Therefore, available clinical practice guidelines which recommend the preferential use of sevelamer do not appear to be supported by available data.

On the other hand, the available studies cannot exclude a clinically relevant beneficial effect of sevelamer, especially in certain clinical subpopulations. Given that sevelamer may reduce the risk of hypercalcaemia compared with calcium-based phosphate binders, patients with higher levels of serum calcium at baseline also appear worthy of detailed study. Future trials should also attempt to address the deficits in trial quality and reporting outlined above.

To our knowledge, this is the most comprehensive systematic review of the clinical and safety effects of sevelamer. Our findings and the strength of our conclusions are limited by the available evidence. There is a relative paucity of large RCTs which address this important clinical topic, and as noted above the quality of the available trials is poor. In addition, our pooled results are potentially prone to the well-known limitations of meta-analysis. Although our statistical testing suggested the possibility of publication bias, this is unlikely to have affected our conclusions, since such trials (if they exist) would likely reinforce the finding of no demonstrated benefit due to sevelamer treatment. Despite these caveats, we took care to reduce the likelihood of bias by following recommendations for the conduct of systematic reviews, including conducting an a priori review protocol, using a well-defined, comprehensive literature search strategy designed by an expert librarian, performing quality assessment and data extraction with duplicate reviewers and using rigorous statistical methodology. We believe that these steps have reduced susceptibility to bias and have led to robust conclusions.

In summary, although sevelamer provides comparable control of serum phosphate levels with a lower risk of hypercalcaemia than calcium-based phosphate binders, we found no convincing evidence that sevelamer improves clinically relevant outcomes in ESRD patients. Therefore, recommendations for the routine use of sevelamer in dialysis patients are not supported by current data.



   Supplementary Material
Top
 Abstract
 Background
 Methods
 Results
 Discussion
 Supplementary Material
Acknowledgements
 References
 
For Supplementary Material, please refer to NDT Online.’



   Acknowledgements
Top
 Abstract
 Background
 Methods
 Results
 Discussion
 Supplementary Material
 Acknowledgements
References
 
We thank Genzyme Canada, Paul Kessler from Nabi Biopharmaceuticals and Dolores Prados Garrido for sending us additional information. We also thank Ellen Crumley for librarian support, Denise Adams and Maria Ospina for additional reviewer support and Alex Stewart for text retrieval. This study was funded by the Canadian Agency for Drugs and Technologies in Health.

Conflict of interest statement. None declared.

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

(See related article by S. C. Palmer et al. Sevelamer: apromising but unproven drug. Nephrol Dial Transplant 2007; 22: 2742–2745.)



   References
Top
 Abstract
 Background
 Methods
 Results
 Discussion
 Supplementary Material
 Acknowledgements
 References
 

  1. Manns B, Stevens L, Miskulin D, Owen WF Jr, Winkelmayer WC, Tonelli M. A systematic review of sevelamer in ESRD and an analysis of its potential economic impact in Canada and the United States. Kidney Int (2004) 66:1239–1247.[CrossRef][Web of Science][Medline]
  2. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses of randomised controlled trials: The QUOROM statement. Lancet (1999) 354:1896–1900.[CrossRef][Web of Science][Medline]
  3. Guidelines for authors of CCOHTA Health Technology Assessments Reports. (2003) Ottawa: The Canadian Coordinating Office for Health Technology Assessments.
  4. Juni P, Altman DG, Egger M. Assessing the quality of randomised controlled trials. In: Systematic Reviews In Health Care—Egger M, Davey Smith G, Altman DG, eds. (2001) London, UK: BMJ Books. ;87–108.
  5. Jadad AR, Moore RA, Carrol D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials (1996) 17:1–12.[CrossRef][Web of Science][Medline]
  6. Schulze KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. J Am Med Assoc (1995) 273:408–412.[Abstract/Free Full Text]
  7. Friedman LM, Furberg CD, DeMets DL, eds. The randomization process. In: Fundamentals of Clinical Trials. (1998) New York: Springer-Verlag, Inc. 61–81.
  8. Curtin F, Altman DG, Elbourne D. Meta-analysis combining parallel and cross-over trials. I: continuous outcomes. Stat Med (2002) 21:2131–2144.[CrossRef][Web of Science][Medline]
  9. Ioannidis JP, Evans SJ, Gotzsche PC, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med (2004) 141:781–788.[Abstract/Free Full Text]
  10. Ioannidis JP, Lau J. Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas. JAMA (2001) 285:437–443.[Abstract/Free Full Text]
  11. Higgins JPT, Thompson SG. Quanitifying heterogeneity in a meta-analysis. Stat Med (2002) 21:1538–1558.
  12. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Br Med J (2003) 327:557–560.[Free Full Text]
  13. Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Br Med J (1997) 315:629–634.[Abstract/Free Full Text]
  14. Asmus HG, Braun J, Krause R, et al. Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density. Nephrol Dial Transplant (2005) 20:1653–1661.[Abstract/Free Full Text]
  15. Braun J, Asmus HG, Holzer H, et al. Long-term comparison of a calcium-free phosphate binder and calcium carbonate–phosphorus metabolism and cardiovascular calcification. Clin Nephrol (2004) 62:104–115.[Web of Science][Medline]
  16. Chertow GM, Raggi P, Chasan-Taber S, Bommer J, Holzer H, Burke SK. Determinants of progressive vascular calcification in haemodialysis patients. Nephrol Dial Transplant (2004) 19:1489–1496.[Abstract/Free Full Text]
  17. Chertow GM, Raggi P, McCarthy JT, et al. The effects of sevelamer and calcium acetate on proxies of atherosclerotic and arteriosclerotic vascular disease in hemodialysis patients. Am J Nephrol (2003) 23:307–314.[CrossRef][Web of Science][Medline]
  18. Ferramosca E, Burke S, Chasan-Taber S, Ratti C, Chertow GM, Raggi P. Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients. Am Heart J (2005) 149:820–825.[CrossRef][Web of Science][Medline]
  19. Raggi P, Bommer J, Chertow GM. Valvular calcification in hemodialysis patients randomized to calcium-based phosphorus binders or sevelamer. J Heart Valve Dis (2004) 13:134–141.[Web of Science][Medline]
  20. Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int (2007) 71(5):1–4.[CrossRef]
  21. Koiwa F, Onoda N, Kato H, et al. Prospective randomized multicenter trial of sevelamer hydrochloride and calcium carbonate for the treatment of hyperphosphatemia in hemodialysis patients in Japan. Ther Apher Dial (2005) 9:340–346.[CrossRef][Web of Science][Medline]
  22. Koiwa F, Kazama JJ, Tokumoto A, et al. Sevelamer hydrochloride and calcium bicarbonate reduce serum fibroblast growth factor 23 levels in dialysis patients. Ther Apher Dial (2005) 9:336–339.[CrossRef][Web of Science][Medline]
  23. Chertow GM, Burke SK, Dillon MA, Slatopolsky E. Long-term effects of sevelamer hydrochloride on the calcium x phosphate product and lipid profile of haemodialysis patients. Nephrol Dial Transplant (1999) 14:2907–2914.[Abstract/Free Full Text]
  24. Chertow GM, Burke SK, Lazarus JM, et al. Poly[allylamine hydrochloride] (RenaGel): a noncalcemic phosphate binder for the treatment of hyperphosphatemia in chronic renal failure. Am J Kidney Dis (1997) 29:66–71.[Web of Science][Medline]
  25. Chertow GM, Dillon M, Burke SK, et al. A randomized trial of sevelamer hydrochloride (RenaGel) with and without supplemental calcium. Clin Nephrol (1999) 51:18–26.[Web of Science][Medline]
  26. Chertow GM, Dillon MA, Amin N, Burke SK. Sevelamer with and without calcium and vitamin D: observations from a long-term open-label clinical trial. J Ren Nutr (2000) 10:125–132.[CrossRef][Medline]
  27. Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int (2005) 68:1815–1824.[CrossRef][Web of Science][Medline]
  28. Bleyer AJ, Burke SK, Dillon M, et al. A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients. Am J Kidney Dis (1999) 33:694–701.[Web of Science][Medline]
  29. Chertow GM, Burke SK, Raggi P, Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int (2002) 62:245–252.[CrossRef][Web of Science][Medline]
  30. De Santo NG, Frangiosa A, Anastasio P, et al. Sevelamer worsens metabolic acidosis in hemodialysis patients. J Nephrol (2006) 19([Suppl 9]):S108–S114.[Web of Science][Medline]
  31. Hervas JG, Prados D, Cerezo S. Treatment of hyperphosphatemia with sevelamer hydrochloride in hemodialysis patients: a comparison with calcium acetate. Kidney Int (2003) 63([Suppl 2]):S69–S72.
  32. Kinugasa E, Koshikawa S, The PBSG. Effects of PB-94 (sevelamer hydrochloride), a phosphate binder, on the treatment of hyperphosphatemia in hemodialysis patients - a randomized, open label, dose titration study of PB-94 versus Caltan tablet 500 (calcium carbonate). J Am Soc Nephrol (2001) 12:755A.
  33. Qunibi WY, Hootkins RE, McDowell LL, et al. Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study). Kidney Int (2004) 65:1914–1926.[CrossRef][Web of Science][Medline]
  34. Sadek T, Mazouz H, Bahloul H, et al. Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study. Nephrol Dial Transplant (2003) 18:582–589.[Abstract/Free Full Text]
  35. Shaheen FA, Akeel NM, Badawi LS, Souqiyyeh MZ. Efficacy and safety of sevelamer. Comparison with calcium carbonate in the treatment of hyperphosphatemia in hemodialysis patients. Saudi Medical Journal (2004) 25:785–791.[Web of Science][Medline]
  36. Suki W, Zabaneh R, Cangiano J, et al. The DCOR Trial: a prospective, randomized trial assessing the impact on outcomes of sevelamer in dialysis patients. In: American Society of Nephrology (2005) Pennsylvania: Philadelphia.
  37. Katopodis KP, Andrikos EK, Gouva CD, et al. Sevelamer hydrochloride versus aluminum hydroxide: effect on serum phosphorus and lipids in CAPD patients. Perit Dial Int (2006) 26:320–327.[Abstract/Free Full Text]
  38. Akizawa T, Kinugasa E, Nagai T, et al. Effect of sevelamer hydrochloride (PB-94) on hyperphosphatemia in Japanese hemodialysis (HD) patients. J Am Soc Nephrol (2000) 11:557A.
  39. Almirall J, Lopez T, Vallve M, Ruiz A, Llibre J, Betriu A. Safety and efficacy of sevelamer in the treatment of uncontrolled hyperphosphataemia of haemodialysis patients. Nephron Clinical Practice (2004) 97:c17–c22.[CrossRef][Web of Science][Medline]
  40. Borras M, Marco MP, Fernandez E. Treatment with sevelamer decreases bicarbonate levels in peritoneal dialysis patients. Perit Dial Int (2002) 22:737–738.[Free Full Text]
  41. Castro R, Herman A, Ferreira C, Travassos F, Nunes-Azevedo J, Oliveira M. RenaGel efficacy in severe secondary hyperparathyroidism. Nefrologia (2002) 22:448–455.[Web of Science][Medline]
  42. Fischer D, Cline K, Plone MA, Dillon M, Burke SK, Blair AT. Results of a randomized crossover study comparing once-daily and thrice-daily sevelamer dosing. Am J Kidney Dis (2006) 48:437–444.[CrossRef][Web of Science][Medline]
  43. Gallieni M, Cozzolino M, Carpani P, Zoni U, Brancaccio D. Sevelamer reduces calcium load and maintains a low calcium-phosphorus ion product in dialysis patients. J Nephrol (2001) 14:176–183.[CrossRef][Web of Science][Medline]
  44. Goldberg DI, Dillon MA, Slatopolsky EA, et al. Effect of RenaGel, a non-absorbed, calcium- and aluminium-free phosphate binder, on serum phosphorus, calcium, and intact parathyroid hormone in end-stage renal disease patients. Nephrol Dial Transplant (1998) 13:2303–2310.[Abstract/Free Full Text]
  45. Iwasaki Y, Takami H, Tani M, et al. Efficacy of combined sevelamer and calcium carbonate therapy for hyperphosphatemia in Japanese hemodialysis patients. Ther Apher Dial (2005) 9:347–351.[CrossRef][Web of Science][Medline]
  46. Izumi M, Shirai K, Ito K, et al. Is 2.5 mEq/l the optimal calcium concentration of dialysate in the use of sevelamer hydrochloride? A study of the dialysate calcium concentration recommended by K/DOQI guidelines. Ther Apher (2005) 9:24–31.[CrossRef][Web of Science]
  47. McIntyre CW, Patel V, Taylor GS, Fluck RJ. A prospective study of combination therapy for hyperphosphataemia with calcium-containing phosphate binders and sevelamer in hypercalcaemic haemodialysis patients. Nephrol Dial Transplant (2002) 17:1643–1648.[Abstract/Free Full Text]
  48. Mitsopoulos E, Griveas I, Zanos S, et al. Increase in serum magnesium level in haemodialysis patients receiving sevelamer hydrochloride. Int Urol Nephrol (2005) 37:321–328.[CrossRef][Medline]
  49. Ogata H, Koiwa F, Shishido K, Kinugasa E. Combination therapy with sevelamer hydrochloride and calcium carbonate in Japanese patients with long-term hemodialysis: Alternative approach for optimal mineral management. Ther Apher (2005) 9:11–15.[CrossRef][Web of Science]
  50. Ortiz A, Rios F, Melero R, Reyero A, Gazapo R, Casado S. [Experience with sevelamer in peritoneal dialysis]. Nefrologia (2003) 23:432–436.[Web of Science][Medline]
  51. Paz Marco MP, Muray S, Betriu A, Craver L, Belart M, Fernandez E. Treatment with sevelamer decreases bicarbonate levels in hemodialysis patients. Nephron (2002) 92:499–500.[CrossRef][Web of Science][Medline]
  52. Slatopolsky EA, Burke SK, Dillon MA, The RenaGel Study Group. RenaGel, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. Kidney Int (1999) 55:299–307.[CrossRef][Web of Science][Medline]
  53. Sturtevant JM, Hawley CM, Reiger K, et al. Efficacy and side-effect profile of sevelamer hydrochloride used in combination with conventional phosphate binders. Nephrology (2004) 9:406–413.[CrossRef][Medline]
  54. Wilkes BM, Reiner D, Kern M, Burke S. Simultaneous lowering of serum phosphate and LDL-cholesterol by sevelamer hydrochloride (RenaGel) in dialysis patients. Clin Nephrol (1998) 50:381–386.[Web of Science][Medline]
  55. Yamada K, Fujimoto S, Tokura T, et al. Effect of sevelamer on dyslipidemia and chronic inflammation in maintenance hemodialysis patients. Ren Fail (2005) 27:361–365.[CrossRef][Web of Science][Medline]
  56. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol (1990) 15:827–832.[Abstract]
  57. Slatopolsky EA, Burke SK, Dillon MA, et al. RenaGel(TM), a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. Kidney Int (1999) 55:299–307.[CrossRef][Web of Science][Medline]
  58. Cho MK, Bero LA. The quality of drug studies published in symposium proceedings. Ann Intern Med (1996) 124:485–489.[Abstract/Free Full Text]
  59. Follmann D, Elliot P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol (1992) 45:769–773.[CrossRef][Web of Science][Medline]
  60. Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol (2002) 31:140–149.[Abstract/Free Full Text]
Received for publication: 7. 3.07
Accepted in revised form: 5. 6.07


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