TITLE: Sevelamer Hydrochloride for the Treatment of Patients with : A Review of the Clinical Effectiveness

DATE: 08 September 2009

CONTEXT AND POLICY ISSUES:

Patients with end-stage chronic kidney disease receiving dialysis have mineral abnormalities, including .1 The inadequate phosphorous control is associated with increased risk of morbidity and mortality.2 Dietary restriction of phosphate and current dialysis methods are not sufficient to maintain serum phosphate levels within the recommended range and most dialysis patients require taking oral phosphate binders.2 Aluminum based agents are relatively efficient for managing hyperphosphatemia, but they are no longer widely used due to concern of adverse events and toxicity.3 The calcium-based phosphate binders are relatively inexpensive and have been used as first line therapy.2 However, the use of calcium-based agents can result in hypercalcemia, which may be associated with vascular calcification.4 Sevelamer hydrochloride is a synthetic non-aluminum, calcium-free .5 It appears to be as effective as calcium-based agents in controlling serum phosphate levels, but is relatively more expensive.1 Lanthanum is also a non-aluminum, non-calcium based binder.6 This report reviews the clinical effectiveness of sevelamer hydrochloride in managing hyperphosphatemia in dialysis patients.

RESEARCH QUESTIONS:

1. What is the clinical effectiveness of sevelamer hydrochloride for the treatment of patients with chronic kidney disease?

2. What is the comparative clinical effectiveness of sevelamer hydrochloride and ?

Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report.

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3. What is the evidence that sevelamer hydrochloride is more effective in a sub-group of patients with chronic kidney disease?

METHODS:

A limited literature search was conducted on key health technology assessment resources, including PubMed, The Cochrane Library (Issue 3, 2009), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English language articles published between 2004 and August, 2009. Filters were applied to limit the retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, and controlled clinical trials.

SUMMARY OF FINDINGS:

Three systematic reviews/meta-analyses and 21 reports describing 18 randomized controlled trials (RCTs) were identified.

Systematic reviews and meta-analyses

Three systematic reviews and meta-analyses were identified.7-9 Since these were all from the same research group and contain the same information, only the most recent review7 is summarized here. Tonelli et al. (2007)7 reviewed the clinical efficacy and safety of sevelamer in dialysis patients compared with calcium-based phosphate binders. Fourteen trials (3193 participants) were included for efficacy analysis. Table 1 summarizes the pooled estimates from Tonelli et al. Patients treated with sevelamer had significantly lower serum calcium and serum bicarbonate, but higher serum phosphorous compared with patients treated with calcium-based phosphate binders. There was no significant difference in serum calcium phosphate product between treatment groups. Although data on intact parathyroid hormone could not be pooled, all trials showed the mean of intact parathyroid hormone was numerically higher in sevelamer recipients compared with patients in the calcium group. There was a 13% higher risk of serious adverse events associated with sevelamer therapy compared with calcium-based therapy, although no significant difference between groups was detected. One trial showed that sevelamer had a significantly higher risk of serious gastrointestinal events compared with the calcium group. The absolute risk of hypercalcemia was 21% higher in calcium-based phosphate binder treated recipients. The overall risk difference for all cause mortality or cardiovascular mortality was similar between treatments. There was no evidence in health-related quality of life, cardiovascular events, or the frequency of symptomatic bone disease. Thus, Tonelli et al. concluded that treatment with sevelamer in dialysis patients was associated with slightly higher serum phosphate levels, slightly lower serum calcium levels, similar calcium- phosphate product, slightly lower serum bicarbonate levels, and no difference in all cause mortality or cardiovascular mortality compared with calcium-based phosphate binders.

Sevelamer Hydrochloride for Chronic Kidney Disease 2

Table 1: Pooled Estimates of Efficacy and Safety of Sevelamer from Tonelli et al.7

Outcomes Number Total Pooled estimates of trials number of patients Sevelamer versus calcium, efficacy • Serum calcium (mmol/l) 10 2,501 WMD (95% CI): -0.10 (-0.12, -0.07) • Serum phosphorous (mmol/l) 10 2,501 WMD (95% CI): 0.12 (0.09, 0.19) • Serum Calcium-phosphate 9 2,271 WMD (95% CI): 0.12 (-0.05, 0.29) product (mmol2/l2) • Intact parathyroid hormone 10 2501 Mean difference: 5.7, range: 0.7 to (pmol/l) 9.5 • Serum bicarbonate (mmol/l) 4 338 WMD (95% CI): -2.81 (-3.45, -2.17) Sevelamer versus calcium, safety • Serious adverse events (%) 3 2,185 RD (95% CI): 13 (-2, 29) • Serious gastrointestinal events 1 31 RD (95% CI): 33 (9-58) (%) • Hypercalcemia (%) 7 554 RD (95% CI): -21 (-29, -13) • All cause mortality (%) 5 2,429 RD (95% CI): -2 (-6, 2) • Cardiovascular mortality (%) 3 2,102 RD (95% CI): -1 (-4, 2) CI: confidence interval; RD: risk difference; WMD: weighted mean difference

Randomized controlled trials

Twenty-one reports describing 18 RCTs were selected for inclusion. Appendix 1 summarizes the design and characteristics of trials comparing sevelamer hydrochloride with (nine trials10-19), (six trials20-25), both calcium salts (two trials26-29), or aluminum hydroxide (one trial30). Trials with direct comparison of sevelamer hydrochloride and lanthanum carbonate were not identified. The study populations in the included trials consisted of adults undergoing stable peritoneal dialysis in two trials(N=173),10,30 adults undergoing stable hemodialysis in 15 trials (N=3,566),11-15,17-29 and children or adolescents undergoing peritoneal and hemodialysis in one trial(N=18).16 The follow-up duration ranged from 8 weeks to 45 months. Thirteen studies reported receiving financial support from pharmaceutical companies. The reported clinical effects from the RCTs of sevelamer hydrochloride compared with the other phosphate binders are summarized in Appendix 2. Serum calcium: In comparison with calcium salts, treatment with sevelamer was associated with significantly lower serum calcium levels in nine trials10,12-15,18,24-29 and a non-significant difference in six trials.11,16,20-23 There was no significant difference in serum calcium levels in sevelamer compared with aluminum hydroxide.30 Serum phosphorus: Four trials13-15,18,22 showed that sevelamer therapy was associated with slightly and significantly higher serum phosphorus levels compared with calcium salt therapy, while 11 trials 10-12,16,20,21,23-29 showed no significant difference between treatment groups. There was no significant difference in serum phosphorous levels between sevelamer and aluminum hydroxide therapies.30 Intact parathyroid hormone: Ten trials11-15,20,22-24,26-29 showed significantly higher parathyroid hormone levels in patients receiving sevelamer compared with patients in the calcium group. Five trials10,16,18,21,25 showed no significant difference between treatment groups. There was no significant difference in parathyroid hormone levels between sevelamer and aluminum hydroxide therapies.30

Sevelamer Hydrochloride for Chronic Kidney Disease 3

Calcium-phosphorus products: Nine trials10,12-16,23-28 showed a non-significant difference in calcium-phosphorous product between sevelamer and calcium salt treatments, while two trials18,22 showed a higher level of calcium-phosphorous product in sevelamer compared with calcium group. Serum bicarbonate: Four trials10,18,22,29 showed that treatment with sevelamer was associated with lower serum bicarbonate levels compared with calcium-based therapy, and one trial16 reported that metabolic acidosis was more frequent with sevelamer treatment. On the other hand, two trials12,20 showed no significant difference in serum bicarbonate between treatment groups. Serum lipid: Sevelamer therapy was associated with a significant reduction in total cholesterol and LDL cholesterol compared with calcium salts in eight trials,10,12,14,17,20,21,24,26-28 or aluminum hydroxide.30 One trial found no significant difference in total cholesterol between sevelamer and calcium carbonate groups.25 The serum level of ApoB, a protein marker of LDL particle, was also found significantly lower in sevelamer recipients in three trials.17,24,30 Bone alkaline phosphatase: Three trials11,15,24 found sevelamer therapy was associated with higher levels of bone specific alkaline phosphatase compared with calcium salt, while one trial20 found no significant difference between treatment groups. There was no significant difference in alkaline phosphatase levels between sevelamer and aluminum hydroxide therapy. Aortic calcification: Patients treated with sevelamer had a lower progression of aortic calcification compared with patients treated with calcium salts,19,21,23,26-28 particularly in diabetic patients.26-28 One trial found no significant difference in coronary calcification scores between sevelamer and calcium acetate therapy. : Two trials10,29 reported that patients receiving sevelamer had lower serum uric acid compared with calcium group. Mortality: The DECOR study13,14 with the largest population of hemodialysis patients (N=2103) found no significant difference in all-cause mortality or cardiovascular mortality between sevelamer and calcium salt treated groups. The numbers of hospitalizations were also not significantly different between interventions. However, older patients (≥65 years) who received sevelamer had lower risk of death compared with calcium group.

Adverse events: One trial10 reported that more patients treated with sevelamer experienced gastrointestinal disturbances compared with calcium acetate group. One trial24 reported that sevelamer therapy was associated with higher events of dyspepsia compared with calcium carbonate. However, two trials12,18 found similar rates of adverse events between sevelamer and calcium acetate group.

LIMITATIONS

Three systematic reviews and meta-analyses from the same research group were identified and only the most recent one was summarized in this report. Thirteen out of 18 RCTs reported receiving financial support from pharmaceutical industries. The clinical outcome results appear to be inconsistent between trials comparing the efficacy and safety of sevelamer hydrochloride with calcium-based phosphate binders. However, the systematic review/meta-analysis by Tonelli et al. (2007)7 provided some pooling data on the efficacy of sevelamer compared with calcium based agents.

Sevelamer Hydrochloride for Chronic Kidney Disease 4

CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING:

The published literature shows that sevelamer appears to as effective as calcium-based phosphate binders in the management of hyperphosphatemia in dialysis patients without elevating serum calcium levels, although the phosphate levels in sevelamer treated patients were slightly higher than those receiving calcium based agents. Elevation of serum calcium is believed to be associated vascular calcification. The systematic review and RCT results suggest that sevelamer may slow down the progression of vascular calcification although its impact on total mortality or cardiovascular mortality has not clinically been proven. The clinical data on aortic calcification were inconsistent between trials. From the included RCTs, the apparent benefits of sevelamer are its lipid lowering effect, particularly total cholesterol and LDL cholesterol, and its uric acid lowering effect. Two trials raised concern that sevelamer may worsen metabolic acidosis that may be an important risk factor for bone metabolism and the prognosis of dialysis patients. Taken together, apart from its comparable control of serum phosphate levels with a lower risk of hypercalcemia compared with calcium-based agents, there is no evidence in the published literature that sevelamer improves morbidity and mortality in dialysis patients. Studies on direct comparison of sevelamer and lanthanum carbonate were not identified and therefore conclusions about comparative clinical effectiveness are not possible. One trial suggested that sevelamer may be beneficial for patients over 65 years of age, but further information about effectiveness in other subgroups was not identified. The studies did not indicate a difference in outcomes between patients on hemodialysis or peritoneal dialysis. The inconsistent data are a consideration and the routine use of sevelamer in dialysis patients does not appear to be supported by the current literature.

PREPARED BY: Khai Tran, MSc, PhD, Research Officer Raymond Banks, MLIS, Information Specialist Health Technology Inquiry Service Email: [email protected] Tel: 1-866-898-8439

Sevelamer Hydrochloride for Chronic Kidney Disease 5

REFERENCES:

1. Mohammed I, Hutchison AJ. Oral phosphate binders for the management of serum phosphate levels in dialysis patients. J Ren Care 2009;35 Suppl 1:65-70.

2. Hutchison AJ. Oral phosphate binders. Kidney Int 2009;75(9):906-14.

3. Sprague SM. A comparative review of the efficacy and safety of established phosphate binders: calcium, sevelamer, and lanthanum carbonate. Curr Med Res Opin 2007;23(12):3167-75.

4. Frazao JM, Adragao T. Treatment of hyperphosphatemia with sevelamer hydrochloride in dialysis patients: effects on vascular calcification, bone and a close look into the survival data. Kidney Int Suppl 2008;(111):S38-S43.

5. Marangon N, Lindholm B, Stenvinkel P. Nonphosphate-binding effects of sevelamer--are they of clinical relevance? Semin Dial 2008;21(5):385-9.

6. Lanthanum: new drug. Hyperphosphataemia in dialysis patients: more potential problems than benefits. Prescrire Int 2007;16(88):47-50.

7. Tonelli M, Wiebe N, Culleton B, Lee H, Klarenbach S, Shrive F, et al. Systematic review of the clinical efficacy and safety of sevelamer in dialysis patients. Nephrol Dial Transplant 2007;22(10):2856-66.

8. 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(3):1239-47.

9. Manns B, Tonelli M, Shrive F, Wiebe N, Klarenbach S, Lee H, et al. Sevelamer in patients with end-stage renal disease: a systematic review and economic evaluation. In: Technology report [database online]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2006. no 71. Available: http://www.cadth.ca/media/pdf/HTA_349_sevelamer_tr_e.pdf (accessed 2009 Aug 19).

10. Evenepoel P, Selgas R, Caputo F, Foggensteiner L, Heaf JG, Ortiz A, et al. Efficacy and safety of sevelamer hydrochloride and calcium acetate in patients on peritoneal dialysis. Nephrol Dial Transplant 2009;24(1):278-85.

11. Barreto DV, Barreto FC, de Carvalho AB, Cuppari L, Draibe SA, Dalboni MA, et al. Phosphate binder impact on bone remodeling and coronary calcification--results from the BRiC study. Nephron Clin Pract 2008;110(4):c273-c283.

12. Qunibi W, Moustafa M, Muenz LR, He DY, Kessler PD, az-Buxo JA, et al. A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: the Calcium Acetate Renagel Evaluation-2 (CARE-2) study. Am J Kidney Dis 2008;51(6):952-65.

13. Suki WN, Zabaneh R, Cangiano JL, Reed J, Fischer D, Garrett L, et al. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int 2007;72(9):1130-7.

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14. Suki WN. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients: results of a randomized clinical trial. J Ren Nutr 2008;18(1):91-8.

15. Liu YL, Lin HH, Yu CC, Kuo HL, Yang YF, Chou CY, et al. A comparison of sevelamer hydrochloride with calcium acetate on biomarkers of bone turnover in hemodialysis patients. Ren Fail 2006;28(8):701-7.

16. Pieper AK, Haffner D, Hoppe B, Dittrich K, Offner G, Bonzel KE, et al. A randomized crossover trial comparing sevelamer with calcium acetate in children with CKD. Am J Kidney Dis 2006;47(4):625-35.

17. 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(5):820-5.

18. Qunibi WY, Hootkins RE, McDowell LL, Meyer MS, Simon M, Garza RO, et al. Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study). Kidney Int 2004;65(5):1914-26.

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(1):134-41.

20. Ferreira A, Frazao JM, Monier-Faugere MC, Gil C, Galvao J, Oliveira C, et al. Effects of sevelamer hydrochloride and calcium carbonate on in hemodialysis patients. J Am Soc Nephrol 2008;19(2):405-12.

21. Takei T, Otsubo S, Uchida K, Matsugami K, Mimuro T, Kabaya T, et al. Effects of sevelamer on the progression of vascular calcification in patients on chronic haemodialysis. Nephron Clin Pract 2008;108(4):c278-c283.

22. De Santo NG, Frangiosa A, Anastasio P, Marino A, Correale G, Perna A, et al. Sevelamer worsens metabolic acidosis in hemodialysis patients. J Nephrol 2006;19 Suppl 9:S108-S114.

23. Asmus HG, Braun J, Krause R, Brunkhorst R, Holzer H, Schulz W, et al. Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density. Nephrol Dial Transplant 2005;20(8):1653-61.

24. Braun J, Asmus HG, Holzer H, Brunkhorst R, Krause R, Schulz W, et al. Long-term comparison of a calcium-free phosphate binder and calcium carbonate--phosphorus metabolism and cardiovascular calcification. Clin Nephrol 2004;62(2):104-15.

25. 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 Med J 2004;25(6):785-91.

26. Block GA, Spiegel DM, Ehrlich J, Mehta R, Lindbergh J, Dreisbach A, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 2005;68(4):1815-24.

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27. Galassi A, Spiegel DM, Bellasi A, Block GA, Raggi P. Accelerated vascular calcification and relative hypoparathyroidism in incident haemodialysis diabetic patients receiving calcium binders. Nephrol Dial Transplant 2006;21(11):3215-22.

28. 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):438-41.

29. Garg JP, Chasan-Taber S, Blair A, Plone M, Bommer J, Raggi P, et al. Effects of sevelamer and calcium-based phosphate binders on uric acid concentrations in patients undergoing hemodialysis: a randomized clinical trial. Arthritis Rheum 2005;52(1):290-5.

30. Katopodis KP, Andrikos EK, Gouva CD, Bairaktari ET, Nikolopoulos PM, Takouli LK, et al. Sevelamer hydrochloride versus aluminum hydroxide: effect on serum phosphorus and lipids in CAPD patients. Perit Dial Int 2006;26(3):320-7.

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APPENDIX 1: Characteristics of Randomized Controlled Trials Studying Sevelamer Hydrochloride

Author Design Population Treatment arm(s) Control arm Co-intervention Follow-up

Evenepoel et al. Open-label, 143 PD (≥18 years) Sevelamer Ca acetate (538-mg Vitamin D 12 weeks (2009)10 randomized, two on stable dialysis hydrochloride (800- tablets); 4.8 g/day parallel groups regimens mg Renagel tablets); with adjustment (supported by 4.8 g/day; with Genzyme) adjustment Barreto et al. (2008) Open-label, 101 HD (≥18 years) Sevelamer Ca acetate NR 12 months BriC Study11 randomized, two on stable dialysis hydrochloride (500- (PhosLo® 667-mg parallel groups regimens (≥ 3 mg Renagel tablets); tablets); up to 2 g (supported by: NR) months) up to 12 g/day Ca/day Ferreira et al. Open-label, 119 HD (≥18 years) Sevelamer CaCO3 (Salusif 500- NR 54 weeks (2008)20 randomized, two on stable dialysis hydrochloride (800- or 1000-mg tablets) parallel groups regimens (≥ 3 mg Renagel tablets) (supported by months) Genzyme) Qunibi et al. (2008) Open-label, 203 HD (≥18 years) Sevelamer (dosage: Ca acetate (dosage: Atorvastatin 12 months CARE-2 Study12 randomized, two on stable dialysis NR) NR) parallel groups regimens (3 months (supported by to 5 years) Fresenius Medical Care and Nabi Biopharmaceuticals 21 Takei et al. (2008) Open-label, 42 HD (≥18 years) Sevelamer CaCO3 (Caltan 500- NR 24 weeks randomized, two on stable dialysis hydrochloride (500- mg tablets); (partly supported by parallel groups regimens (≥ 3 mg Renagel tablets); 3.4±1.8g/day public funding) months) 6.0±2.8 g/day Suki et al. (2007, Open-label, 2103 HD (≥18 6.9 g/day sevelamer 5.3 g/day Ca acetate NR Up to 45 months 2008) DCOR13,14 randomized, two years) on stable (PhosLo®) or 4.9 parallel groups dialysis regimens (> g/day CaCO3 (supported by 3 months) (TUMS®) Genzyme)

De Santo et al. Open-label, 16 HD (35-50 years) 2-3 capsule 3x/day CaCO3 (Metocal NR 24 weeks per group (2006)22 randomized, on stable dialysis sevelamer (RenaGel dividable 625 per intervention crossover regimens (6-10 800mg tablets) mg/half tablet) (supported by MIUR months) (dosage, NR) and ASI)

9 Sevelamer Hydrochloride for Chronic Kidney Disease

Author Design Population Treatment arm(s) Control arm Co-intervention Follow-up

Katopodis et al. Open-label, 30 PD (mean age: 2-4 capsules 2-4 capsules None 8 weeks (2006)30 randomized, 58.2±15.4 years) on sevelamer aluminum hydroxide crossover stable dialysis hydrochloride each each meal (475 (supported by: NR) regimens; 2-week meal (403 mg/capsule) washout mg/capsule) Liu et al. (2006)15 Open-label, 70 HD (≥20 years) 2.4 – 3.6 g/day 2.0 – 4.0 g/day Ca Vitamin D 8 weeks randomized, two on stable dialysis sevelamer acetate (667-mg (unchanged from (Chugai Pharma parallel groups regimens (≥3 hydrochloride (400- Caphos tablets) prestudy dose) Taiwan provided months); mg Renagel tablet) sevelamer) hyperphosphatemia during 2-week washout period Pieper et al. (2006)16 Open-label, 18 HD or PD Sevelamer Ca acetate (500-mg Vitamin D 8 weeks randomized, children or hydrochloride (400- tablets) (supported by crossover adolescents (0.9- mg Renagel tablets) Genzyme) 17.3 years) on stable dialysis regimens (0.1-3.1 years) Block et al. (2005, Open-label, 129 HD (>18 years) Sevelamer Ca-based NR 18 months 2006, 2007)26-28 randomized, two on stable dialysis hydrochloride phosphate binders parallel groups regimens (Ca acetate or (supported by CaCO3) Genzyme) Asmus et al. Open-label, 72 HD (>19 years) Sevelamer CaCO3 (Sertuerner Vitamin D 2 years (2005)23 randomized, two on stable dialysis hydrochloride (800- 500-mg tablets); parallel groups regimens mg Renagel tablets); 4.3±1.7 g/day (supported by 6.9±2.6 g/day Genzyme) Ferramosca et al. Open-label, 108 HD (≥18 years) Sevelamer Ca acetate (PhosLo NR 1 year (2005)17 randomized, two on stable dialysis hydrochloride (800- 667-mg tablets); parallel groups regimens (≥ 6 mg Renagel tablets); 4.3±2.2 g/day (supported by: NR) months) 6.5±2.9 g/day Garg et al. (2005)29 Open-label, 169 HD (≥19 years) Sevelamer Ca-based Vitamin D 52 weeks randomized, two on stable dialysis hydrochloride (800- phosphate binders (supported by parallel groups regimens mg Renagel tablets) (Ca acetate or Genzyme) CaCO3) Braun et al. (2004)24 Open-label, 114 HD (>19 years) 5.9±2.4 g/day 3.9±1.7 g/day Vitamin D 52 weeks randomized, two on stable dialysis sevelamer CaCO3 (supported by: NR) parallel groups regimens

Sevelamer Hydrochloride for Chronic Kidney Disease 10

Author Design Population Treatment arm(s) Control arm Co-intervention Follow-up

Qunibi et al. (2004) Double-blind, 100 HD (adults) on Sevelamer Ca acetate Vitamin D 8 weeks CARE Study18 randomized, two stable dialysis hydrochloride (PhosLo® 667-mg parallel groups regimens (≥ 3 (Renagel® 403-mg capsules); 2-3 (supported by months) capsules); 2-3 capsules thrice daily Braintree capsules thrice daily Laboratories and Nabi Biopharmaceuticals) Raggi et al. (2004)19 Open-label, 200 HD (≥19 years) Sevelamer Ca acetate NR 52 weeks randomized, two on stable dialysis hydrochloride (PhosLo® 667-mg (supported by parallel groups regimens (Renagel® 800-mg tablets) Genzyme) tablets) Shaheen et al. Open-label, 20 HD (15-75 years) Sevelamer CaCO3 (caltrate Vitamin D 8 weeks (2004)25 randomized, on stable dialysis hydrochloride 600-mg tablets); 600 (unchanged from crossover regimens (Renagel® 800-mg mg, 3x/day prestudy dose) (supported by: NR) tablets); 800 mg, 3x/day

CaCO3:: Calcium carbonate; HD: hemodialysis; NR: not reported; PD: peritoneal dialysis

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APPENDIX 2: Comparison of Clinical Effects of Sevelamer Hydrochloride and Other Phosphate Binders in Patients with Chronic Kidney Disease Receiving Dialysis

Author Serum calcium Serum Parathyroid Calcium- Serum Other clinical effects phosphorous hormone phosphorous bicarbonate product (HCO3) Evenepoel et al. Lower compared NSD compared NSD compared with NSD compared Lower compared Lower total cholesterol and 10 (2009) with Ca acetate with Ca acetate Ca acetate group with Ca acetate with Ca acetate LDL cholesterol compared with group (change: group (change: (change: -44 vs. –87 group (change: - group (P=0.008) Ca acetate group (P<0.001) 0.05±0.57 vs. -1.59±1.18 vs. – pg/ml) 15.0±12.1 vs. – 0.46±0.85 mg/dl, 1.63±1.53 13.6±15.5 Lower uric acid (P=0.01) and P=0.012) mg/dl) mg2/dl2) higher bone alkaline phosphatase (P<0.001) compared with Ca acetate group More patients experienced gastrointestinal disturbances compared with Ca acetate group Barreto et al. (2008) NSD compared NSD compared Higher compared NR NR Higher bone alkaline BriC Study11 with Ca acetate with Ca acetate with Ca acetate phosphatase compared with group (1.27±0.07 group (5.8±1.0 group (498 vs. 326 Ca acetate group (38±24 vs. vs. 1.23±0.08 vs. 6.0±1.0 pg/ml, P=0.017) 28±15 U/l, P=0.03) mmol/l, P=0.68) mg/dl, P=0.47) NSD in coronary calcification progression (35 vs. 24%, P=0.94) and bone remodeling compared with Ca acetate group Ferreira et al. Lower, but NS NSD compared Higher, but NS NR NSD compared NSD in bone alkaline 20 (2008) compared with with CaCO3 compared with with CaCO3 phosphatase compared with CaCO3 group group (5.4±1.4 CaCO3 group (275 group (20.4±3.3 CaCO3 group (9.1±1.1 vs. vs. 5.3±1.9 vs. 227 pg/ml, vs. 21.2±4.1 9.3±0.7, P=0.22) mg/dl, P=0.78) P=0.55) mmol/l, P=0.34) NSD in bone turnover or mineralization compared with CaCO3 group Lower in total cholesterol (P=0.03) and LDL cholesterol (P<0.01) compared with CaCO3 group

Sevelamer Hydrochloride for Chronic Kidney Disease 12

Author Serum calcium Serum Parathyroid Calcium- Serum Other clinical effects phosphorous hormone phosphorous bicarbonate product (HCO3) Qunibi et al. (2008) Lower compared NSD compared Higher compared NSD compared NSD compared Lower in total cholesterol CARE-2 Study12 with Ca acetate with Ca acetate with Ca acetate with Ca acetate with Ca acetate compared with Ca acetate group (9.0±0.7 vs. group (5.4±1.8 group (434 vs. 316 group (48.0±15.4 group (21.6±4.3 group (123±31 vs. 134±32 9.4±0.7 mg/dl, vs. 5.0±1.6 pg/ml, P<0.05) vs. 46.0±14.7 vs. 23.1±3.9 mg/dl, P<0.05) P<0.05) mg/dl) mg2/dl2) mEq/l) Similar progression in coronary artery calcification (CAC) between treatment groups with intensive lowering of LDL cholesterol levels for 1 year Similar rates of adverse events between treatment groups Takei et al. (2008)21 NSD compared NSD compared NSD compared with NR NR Lower in total cholesterol, LDL with CaCO3 group with CaCO3 CaCO3 group in the cholesterol compared with (10.1±0.8 vs. group (6.2±0.5 change of intact CaCO3 group 10.1±0.8 mg/dl) vs. 6.7±1.1 parathyroid hormone mg/dl) Lower in progression of aortic calcification compared with CaCO3 group (aortic calcification index mean change: 3.6±1.5% vs. 8.2±3.1%) Suki et al. (2007, Lower compared Higher Higher compared NSD compared NR NSD in all-cause mortality 2008)13,14 with Ca group compared with with Ca group (278 with Ca group compared with Ca group (2.30± 0.18 vs. Ca group vs. 226 pg/ml, (4.33±0.98 vs. (hazard ratio = 0.93, 95% CI 2.38±0.18 mmol/l, (1.87±0.42 vs. P<0.0001) 4.33±1.04 0.79-1.10, P=0.40) P<0.0001) 1.84±0.42 mmol2/l2, P=0.60) mmol/l, P<0.01) NSD in cardiovascular mortality compared with Ca group (hazard ratio = 0.93, 95% CI 0.74-1.17, P=0.53) NSD in number of hospitalizations/patient-year compared with Ca group (2.1 vs. 2.3, P=0.07) Lower in total cholesterol compared with Ca group (3.77±0.87 vs. 4.16±0.90 mol/l, P<0.0001)

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Author Serum calcium Serum Parathyroid Calcium- Serum Other clinical effects phosphorous hormone phosphorous bicarbonate product (HCO3) Lower in LDL cholesterol compared with Ca group (1.78±0.67 vs. 2.20±0.80 mol/l, P<0.0001) Lower in risk of death among patients ≥65 years of age compared with Ca group (RR=0.77; 95% CI 0.62-0.97, P=0.02) De Santo et al. NSD compared to Higher Higher compared to Higher compared Lower compared Lower in serum albumin 22 (2006) CaCO3 compared to CaCO3 (P<0.05) to CaCO3 to CaCO3 compared to CaCO3 (P<0.05) CaCO3 (P<0.05) (P<0.05) (17.3±1.1 vs. No change 21.1±0.7 mEq/l, Lower in serum albumin compared to P<0.01) compared to baseline (P<0.05) baseline Sevelamer worsens metabolic acidosis Katopodis et al. NSD compared NSD compared NSD compared with NR NR NSD for alkaline phosphatase, (2006)30 with aluminum with aluminum aluminum hydroxide serum albumin and serum hydroxide (at both hydroxide (- (at both phases) compared with phases) 0.38±0.03 vs. - aluminum hydroxide (at both 0.40±0.05, phases) P=NS) Lower in total cholesterol (P<0.05), LDL cholesterol (P<0.001) and ApoB (P<0.05) compared with aluminum hydroxide (at both phases)

Higher in ApoA1 (P<0.05), and ApoE (P<0.05) compared with aluminum hydroxide (at both phases) Liu et al. (2006)15 Lower compared Higher Higher compared NSD compared NR Higher in alkaline phosphatase with Ca acetate compared with with Ca acetate (- with Ca acetate compared with Ca acetate (9.11 vs. 9.86 Ca acetate 69.0 vs. –178.0 (53.34 vs. 52.49 (88.23 vs. 64.53 U/l; mg/dl, P=0.0009) (5.94 vs. 5.38 pg/ml, P=0.0019) mg2/dl2, P=0.74) P=0.0097) mg/dl, P=0.05)

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Author Serum calcium Serum Parathyroid Calcium- Serum Other clinical effects phosphorous hormone phosphorous bicarbonate product (HCO3) Pieper et al. (2006)16 NSD compared NSD compared NSD compared with NSD compared Metabolic Sevelamer increased alkaline with Ca acetate with Ca acetate Ca acetate (change: with Ca acetate acidosis was phosphatase compared with (change: -0.2±0.7 (change: - -7±196 vs. -43±270 (change: - more frequent baseline (P<0.05) vs. 0.4±1.0 mg/dl) 1.5±1.6 vs. - pg/ml) 1.37±1.41 vs. - with sevelamer 1.7±1.7 mg/dl) 1.12±1.25 treatment (34.4% Sevelamer decreased total Higher incidence mmol2/l2, P=NS) vs. 3.3%, cholesterol and LDL of hypercalcemia P<0.005) cholesterol compared with with Ca acetate baseline (P<0.05) treatment (P<0.0005) Block et al. (2005, Lower compared NSD compared Higher compared NSD compared NR Lower in total cholesterol 2006, 2007)26-28 with Ca group with Ca group with Ca group with Ca group (134±52 vs. 160±32 mg/dl, (9.1±0.5 vs. (5.2±0.9 vs. (298±152 vs. (47±7 vs. 49±8 P<0.05), LDL cholesterol 9.6±0.5 mg/dl, 5.1±0.8 mg/dl, 243±136 pg/dl, mg2/dl2, P=NS) (60±34 vs. 81±26 mg/dl, P<0.05) P=NS) P<0.05) P<0.001) compared with Ca group Higher compared with Ca group for Subjects with baseline diabetic patients coronary artery Ca score (31±14 vs. 24±16 (CACS) >30 showed pmol/l, P=0.038) progressive increase in CACS in both treatment arms. Treatment with Ca containing phosphate binders showed more rapid and more severe increases in CACS compared with sevelamer. Slower in CACS progression in diabetic patients treated with sevelamer compared with Ca group (median increase: 27 vs 177, P=0.05) Borderline lower mortality compared to Ca group (5.3/100 CI 2.2-8.5 vs. 10.6/100 patient-years, CI 6.3- 14.9, P=0.05)

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Author Serum calcium Serum Parathyroid Calcium- Serum Other clinical effects phosphorous hormone phosphorous bicarbonate product (HCO3) Asmus et al. (2005)23 NSD compared NSD compared Higher compared NSD compared NR Higher in alkaline phosphatase with CaCO3 group with CaCO3 with CaCO3 group with CaCO3 group compared with CaCO3 group group (P<0.01) (P=0.046) Lower in total cholesterol compared with CaCO3 group (P=0.0005) Lower in the progression in calcification of coronary arteries (P=0.018) and the aorta (P=0.004) compared with CaCO3 group Ferramosca et al. NR NR NR NR NR NSD between groups in (2005)17 coronary calcification score Lower in total cholesterol (P<0.0001), LDL cholesterol (P<0.0001) and ApoB (P<0.0001) compared with Ca acetate group Garg et al. (2005)29 Lower compared NSD compared Higher compared NR Lower compared Lower in serum uric acid with Ca group with Ca group with Ca group to Ca group compared with Ca group (mean changes: - (mean changes: (values: NR) (mean changes: - (mean changes: -0.64 vs. - 0.01 vs. 0.43 -2.3 vs. -2.1 0.05 vs. 3.2 0.26 mg/dl, P=0.03) mg/dl, P<0.0001) mg/dl, P=0.42) mg/dl, P<0.001) Braun et al. (2004)24 Lower compared NSD compared Higher compared NSD compared NR Higher in bone-specific with CaCO3 group with CaCO3 with CaCO3 group with CaCO3 group alkaline phosphatase (mean changes: group (mean (change: -24 vs. -84 (mean changes: - compared with CaCO3 group 0.01±0.10 vs. changes: - pg/ml, P=0.02) 1.4±1.7 vs. - (33 U/l vs. 20 U/l, P<0.01) 0.15) 0.58±0.68 vs. - 0.9±1.2 mmpl2/l2, 0.52±0.50 P=0.12) Lower in total cholesterol, LDL mmol/l, P=0.62) cholesterol, and Apo B compared with CaCO3 group (P<0.05) Higher in Apo A compared with CaCO3 group (P<0.05)

CaCO3 patients had significant increases in coronary artery (median +34%, P<0.01) and

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Author Serum calcium Serum Parathyroid Calcium- Serum Other clinical effects phosphorous hormone phosphorous bicarbonate product (HCO3) aortic calcification (median +32%, P<0.01) that were not observed in sevelamer patients Higher events of dyspepsia compared with CaCO3 group (26% vs. 5%, P<0.01) Qunibi et al. (2004)18 Lower compared Higher NSD compared with Higher compared Lower compared NSD in adverse events with Ca acetate compared with Ca acetate group with Ca acetate with Ca acetate compared to Ca acetate group group (8.9±0.5 vs. Ca acetate group (60.4±14.1 group (19.3±2.7 9.5±0.7 mg/dl, (6.8±1.6 vs. vs. 52.7±14.2 vs. 21.0±2.6 P<0.0001) 5.5±1.5 mg/dl, mg2/dl2, P=0.022) mEq/l, P<0.0001) P=0.0006) Raggi et al. (2004)19 NR NR NR NR NR Less in valvular and vascular calcification compared with Ca acetate group (P<0.05) Shaheen et al. Lower compared NSD compared NSD compared with NSD compared NR NSD in total cholesterol and 25 (2004) with CaCO3 group with CaCO3 CaCO3 group with CaCO3 group triglyceride compared with (change: -0.2±0.9 group (change: (change: -45±143 vs. (change: - CaCO3 group vs. 0.5±1.3 mg/dl) -3.3±2.2 vs. - -53±152 pg/ml) 31.7±24.2 vs. - 3.9±2.8 mg/dl) 37.5±34.7 mg2/dl2) Apo: apolipoprotein; Ca: calcium; CI: confidence interval; LDL: low-density lipoprotein; mEq: milliequivalent; NR: not reported; NSD: no significant difference; RR: relative risk

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