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

Transcription

1 TITLE: Hydrochloride for the Treatment of Patients with Chronic Kidney Disease: 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 hyperphosphatemia. 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 hydrochloride is a synthetic non-aluminum, calcium-free phosphate binder. 5 It appears to be as effective as calcium-based agents in controlling serum phosphate levels, but is relatively more expensive. 1 Lanthanum carbonate 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 lanthanum carbonate? 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. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 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, 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 review 7 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 calciumphosphate product, slightly lower serum bicarbonate levels, and no difference in all cause mortality or cardiovascular mortality compared with calcium-based phosphate binders. Hydrochloride for Chronic Kidney Disease 2

3 Table 1: Pooled Estimates of Efficacy and Safety of from Tonelli et al. 7 Outcomes Number of trials Total number of patients Pooled estimates versus calcium, efficacy Serum calcium (mmol/l) 10 2,501 WMD (95% CI): (-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 (mmol 2 /l 2 ) Intact parathyroid hormone (pmol/l) Mean difference: 5.7, range: 0.7 to 9.5 Serum bicarbonate (mmol/l) WMD (95% CI): (-3.45, -2.17) 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 (%) 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 calcium acetate (nine trials ), calcium carbonate (six trials ), both calcium salts (two trials ), or aluminum hydroxide (one trial 30 ). 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 trials 10,12-15,18,24-29 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 trials 13-15,18,22 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 trials 11-15,20,22-24,26-29 showed significantly higher parathyroid hormone levels in patients receiving sevelamer compared with patients in the calcium group. Five trials 10,16,18,21,25 showed no significant difference between treatment groups. There was no significant difference in parathyroid hormone levels between sevelamer and aluminum hydroxide therapies. 30 Hydrochloride for Chronic Kidney Disease 3

4 Calcium-phosphorus products: Nine trials 10,12-16,23-28 showed a non-significant difference in calcium-phosphorous product between sevelamer and calcium salt treatments, while two trials 18,22 showed a higher level of calcium-phosphorous product in sevelamer compared with calcium group. Serum bicarbonate: Four trials 10,18,22,29 showed that treatment with sevelamer was associated with lower serum bicarbonate levels compared with calcium-based therapy, and one trial 16 reported that metabolic acidosis was more frequent with sevelamer treatment. On the other hand, two trials 12,20 showed no significant difference in serum bicarbonate between treatment groups. Serum lipid: 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 trials 11,15,24 found sevelamer therapy was associated with higher levels of bone specific alkaline phosphatase compared with calcium salt, while one trial 20 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 One trial found no significant difference in coronary calcification scores between sevelamer and calcium acetate therapy. Uric acid: Two trials 10,29 reported that patients receiving sevelamer had lower serum uric acid compared with calcium group. Mortality: The DECOR study 13,14 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 trial 10 reported that more patients treated with sevelamer experienced gastrointestinal disturbances compared with calcium acetate group. One trial 24 reported that sevelamer therapy was associated with higher events of dyspepsia compared with calcium carbonate. However, two trials 12,18 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. Hydrochloride for Chronic Kidney Disease 4

5 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 htis@cadth.ca Tel: Hydrochloride for Chronic Kidney Disease 5

6 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: Hutchison AJ. Oral phosphate binders. Kidney Int 2009;75(9): 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): 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-S Marangon N, Lindholm B, Stenvinkel P. Nonphosphate-binding effects of sevelamer--are they of clinical relevance? Semin Dial 2008;21(5): Lanthanum: new drug. Hyperphosphataemia in dialysis patients: more potential problems than benefits. Prescrire Int 2007;16(88): 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): 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): Manns B, Tonelli M, Shrive F, Wiebe N, Klarenbach S, Lee H, et al. 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; no 71. Available: (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): 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-c 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): 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): Hydrochloride for Chronic Kidney Disease 6

7 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): 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): 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): 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): 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): 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): Ferreira A, Frazao JM, Monier-Faugere MC, Gil C, Galvao J, Oliveira C, et al. Effects of sevelamer hydrochloride and calcium carbonate on renal osteodystrophy in hemodialysis patients. J Am Soc Nephrol 2008;19(2): 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-c De Santo NG, Frangiosa A, Anastasio P, Marino A, Correale G, Perna A, et al. worsens metabolic acidosis in hemodialysis patients. J Nephrol 2006;19 Suppl 9:S108-S 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): 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): 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): 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): Hydrochloride for Chronic Kidney Disease 7

8 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): 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): 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): Katopodis KP, Andrikos EK, Gouva CD, Bairaktari ET, Nikolopoulos PM, Takouli LK, et al. hydrochloride versus aluminum hydroxide: effect on serum phosphorus and lipids in CAPD patients. Perit Dial Int 2006;26(3): Hydrochloride for Chronic Kidney Disease 8

9 APPENDIX 1: Characteristics of Randomized Controlled Trials Studying Hydrochloride Author Design Population Treatment arm(s) Control arm Co-intervention Follow-up Evenepoel et al. (2009) 10 Genzyme) Barreto et al. (2008) BriC Study 11 : ) Ferreira et al. (2008) 20 Genzyme) Qunibi et al. (2008) CARE-2 Study 12 Fresenius Medical Care and Nabi Biopharmaceuticals Takei et al. (2008) 21 (partly supported by public funding) Suki et al. (2007, 2008) DCOR 13,14 Genzyme) 143 PD ( 18 years) regimens 101 HD ( 18 years) regimens ( 3 months) 119 HD ( 18 years) regimens ( 3 months) 203 HD ( 18 years) regimens (3 months to 5 years) 42 HD ( 18 years) regimens ( 3 months) 2103 HD ( 18 years) on stable dialysis regimens (> 3 months) hydrochloride (800- mg Renagel tablets); 4.8 g/day; with adjustment hydrochloride (500- mg Renagel tablets); up to 12 g/day hydrochloride (800- mg Renagel tablets) (dosage: ) hydrochloride (500- mg Renagel tablets); 6.0±2.8 g/day Ca acetate (538-mg tablets); 4.8 g/day with adjustment Ca acetate (PhosLo 667-mg tablets); up to 2 g Ca/day CaCO 3 (Salusif 500- or 1000-mg tablets) Ca acetate (dosage: ) CaCO 3 (Caltan 500- mg tablets); 3.4±1.8g/day 6.9 g/day sevelamer 5.3 g/day Ca acetate (PhosLo ) or 4.9 g/day CaCO 3 (TUMS ) Vitamin D Atorvastatin 12 weeks 12 months 54 weeks 12 months 24 weeks Up to 45 months De Santo et al. (2006) 22 MIUR and ASI) randomized, crossover 16 HD (35-50 years) regimens (6-10 months) 2-3 capsule 3x/day sevelamer (RenaGel 800mg tablets) CaCO 3 (Metocal dividable 625 mg/half tablet) (dosage, ) 24 weeks per group per intervention Hydrochloride for Chronic Kidney Disease 9

10 Author Design Population Treatment arm(s) Control arm Co-intervention Follow-up Katopodis et al. (2006) 30 : ) Liu et al. (2006) 15 (Chugai Pharma Taiwan provided sevelamer) Pieper et al. (2006) 16 Genzyme) Block et al. (2005, 2006, 2007) Genzyme) Asmus et al. (2005) 23 Genzyme) Ferramosca et al. (2005) 17 : ) Garg et al. (2005) 29 Genzyme) Braun et al. (2004) 24 : ) randomized, crossover randomized, crossover 30 PD (mean age: 58.2±15.4 years) on stable dialysis regimens; 2-week washout 70 HD ( 20 years) regimens ( 3 months); hyperphosphatemia during 2-week washout period 18 HD or PD children or adolescents ( years) on stable dialysis regimens ( years) 129 HD (>18 years) regimens 72 HD (>19 years) regimens 108 HD ( 18 years) regimens ( 6 months) 169 HD ( 19 years) regimens 114 HD (>19 years) regimens 2-4 capsules sevelamer hydrochloride each meal (403 mg/capsule) g/day sevelamer hydrochloride (400- mg Renagel tablet) hydrochloride (400- mg Renagel tablets) hydrochloride hydrochloride (800- mg Renagel tablets); 6.9±2.6 g/day hydrochloride (800- mg Renagel tablets); 6.5±2.9 g/day hydrochloride (800- mg Renagel tablets) 5.9±2.4 g/day sevelamer 2-4 capsules aluminum hydroxide each meal (475 mg/capsule) g/day Ca acetate (667-mg Caphos tablets) Ca acetate (500-mg tablets) Ca-based phosphate binders (Ca acetate or CaCO 3 ) CaCO 3 (Sertuerner 500-mg tablets); 4.3±1.7 g/day Ca acetate (PhosLo 667-mg tablets); 4.3±2.2 g/day None Vitamin D (unchanged from prestudy dose) Vitamin D Vitamin D 8 weeks 8 weeks 8 weeks 18 months 2 years 1 year Ca-based phosphate binders (Ca acetate or CaCO 3 ) Vitamin D 52 weeks 3.9±1.7 g/day Vitamin D 52 weeks CaCO 3 Hydrochloride for Chronic Kidney Disease 10

11 Author Design Population Treatment arm(s) Control arm Co-intervention Follow-up Qunibi et al. (2004) CARE Study 18 Braintree Laboratories and Nabi Biopharmaceuticals) Raggi et al. (2004) 19 Genzyme) Shaheen et al. (2004) 25 : ) Double-blind, randomized, crossover 100 HD (adults) on stable dialysis regimens ( 3 months) 200 HD ( 19 years) regimens 20 HD (15-75 years) regimens CaCO 3 :: Calcium carbonate; HD: hemodialysis; : not reported; PD: peritoneal dialysis hydrochloride (Renagel 403-mg capsules); 2-3 capsules thrice daily hydrochloride (Renagel 800-mg tablets) hydrochloride (Renagel 800-mg tablets); 800 mg, 3x/day Ca acetate (PhosLo 667-mg capsules); 2-3 capsules thrice daily Ca acetate (PhosLo 667-mg tablets) CaCO 3 (caltrate 600-mg tablets); 600 mg, 3x/day Vitamin D Vitamin D (unchanged from prestudy dose) 8 weeks 52 weeks 8 weeks Hydrochloride for Chronic Kidney Disease 11

12 APPENDIX 2: Comparison of Clinical Effects of Hydrochloride and Other Phosphate Binders in Patients with Chronic Kidney Disease Receiving Dialysis Author Serum calcium Serum phosphorous Evenepoel et al. (2009) 10 group (change: 0.05±0.57 vs. 0.46±0.85 mg/dl, P=0.012) Barreto et al. (2008) BriC Study 11 group (1.27±0.07 vs. 1.23±0.08 mmol/l, P=0.68) Ferreira et al. (2008) 20 Lower, but NS compared with CaCO 3 group (9.1±1.1 vs. 9.3±0.7, P=0.22) group (change: -1.59±1.18 vs. 1.63±1.53 mg/dl) group (5.8±1.0 vs. 6.0±1.0 mg/dl, P=0.47) with CaCO 3 group (5.4±1.4 vs. 5.3±1.9 mg/dl, P=0.78) Parathyroid hormone with Ca acetate group (change: -44 vs. 87 pg/ml) group (498 vs. 326 pg/ml, P=0.017) Higher, but NS compared with CaCO 3 group (275 vs. 227 pg/ml, P=0.55) Calciumphosphorous product group (change: ±12.1 vs. 13.6±15.5 mg 2 /dl 2 ) Serum bicarbonate (HCO 3 ) group (P=0.008) Other clinical effects Lower total cholesterol and LDL cholesterol compared with Ca acetate group (P<0.001) Lower uric acid (P=0.01) and higher bone alkaline phosphatase (P<0.001) compared group More patients experienced gastrointestinal disturbances compared group Higher bone alkaline phosphatase compared with Ca acetate group (38±24 vs. 28±15 U/l, P=0.03) with CaCO 3 group (20.4±3.3 vs. 21.2±4.1 mmol/l, P=0.34) NSD in coronary calcification progression (35 vs. 24%, P=0.94) and bone remodeling compared group NSD in bone alkaline phosphatase compared with CaCO 3 group NSD in bone turnover or mineralization compared with CaCO 3 group Lower in total cholesterol (P=0.03) and LDL cholesterol (P<0.01) compared with CaCO 3 group Hydrochloride for Chronic Kidney Disease 12

13 Author Serum calcium Serum phosphorous Qunibi et al. (2008) CARE-2 Study 12 Takei et al. (2008) 21 group (9.0±0.7 vs. 9.4±0.7 mg/dl, P<0.05) with CaCO 3 group (10.1±0.8 vs. 10.1±0.8 mg/dl) Suki et al. (2007, 2008) 13,14 with Ca group (2.30± 0.18 vs. 2.38±0.18 mmol/l, P<0.0001) group (5.4±1.8 vs. 5.0±1.6 mg/dl) with CaCO 3 group (6.2±0.5 vs. 6.7±1.1 mg/dl) Higher compared with Ca group (1.87±0.42 vs. 1.84±0.42 mmol/l, P<0.01) Parathyroid hormone group (434 vs. 316 pg/ml, P<0.05) with CaCO 3 group in the change of intact parathyroid hormone with Ca group (278 vs. 226 pg/ml, P<0.0001) Calciumphosphorous product group (48.0±15.4 vs. 46.0±14.7 mg 2 /dl 2 ) Serum bicarbonate (HCO 3 ) group (21.6±4.3 vs. 23.1±3.9 meq/l) Other clinical effects Lower in total cholesterol compared group (123±31 vs. 134±32 mg/dl, P<0.05) 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 Lower in total cholesterol, LDL cholesterol compared with CaCO 3 group with Ca group (4.33±0.98 vs. 4.33±1.04 mmol 2 /l 2, P=0.60) Lower in progression of aortic calcification compared with CaCO 3 group (aortic calcification index mean change: 3.6±1.5% vs. 8.2±3.1%) NSD in all-cause mortality compared with Ca group (hazard ratio = 0.93, 95% CI , P=0.40) NSD in cardiovascular mortality compared with Ca group (hazard ratio = 0.93, 95% CI , 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) Hydrochloride for Chronic Kidney Disease 13

14 Author Serum calcium Serum phosphorous De Santo et al. to (2006) 22 CaCO 3 Katopodis et al. (2006) 30 with aluminum hydroxide (at both phases) Liu et al. (2006) 15 (9.11 vs mg/dl, P=0.0009) Higher compared to CaCO 3 (P<0.05) with aluminum hydroxide (- 0.38±0.03 vs ±0.05, P=NS) Higher compared with Ca acetate (5.94 vs mg/dl, P=0.05) Parathyroid hormone to CaCO 3 (P<0.05) No change compared to baseline with aluminum hydroxide (at both phases) ( vs pg/ml, P=0.0019) Calciumphosphorous product to CaCO 3 (P<0.05) Serum bicarbonate (HCO 3 ) to CaCO 3 (17.3±1.1 vs. 21.1±0.7 meq/l, P<0.01) Other clinical effects 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 , P=0.02) Lower in serum albumin compared to CaCO 3 (P<0.05) Lower in serum albumin compared to baseline (P<0.05) worsens metabolic acidosis NSD for alkaline phosphatase, serum albumin and serum insulin compared with aluminum hydroxide (at both phases) (53.34 vs mg 2 /dl 2, P=0.74) 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 ApoA 1 (P<0.05), and ApoE (P<0.05) compared with aluminum hydroxide (at both phases) Higher in alkaline phosphatase compared (88.23 vs U/l; P=0.0097) Hydrochloride for Chronic Kidney Disease 14

15 Author Serum calcium Serum phosphorous Pieper et al. (2006) 16 (change: -0.2±0.7 vs. 0.4±1.0 mg/dl) Higher incidence of hypercalcemia treatment (P<0.0005) Block et al. (2005, 2006, 2007) with Ca group (9.1±0.5 vs. 9.6±0.5 mg/dl, P<0.05) (change: - 1.5±1.6 vs ±1.7 mg/dl) with Ca group (5.2±0.9 vs. 5.1±0.8 mg/dl, P=NS) Parathyroid hormone with Ca acetate (change: -7±196 vs. -43±270 pg/ml) with Ca group (298±152 vs. 243±136 pg/dl, P<0.05) with Ca group for diabetic patients (31±14 vs. 24±16 pmol/l, P=0.038) Calciumphosphorous product (change: ±1.41 vs ±1.25 mmol 2 /l 2, P=NS) with Ca group (47±7 vs. 49±8 mg 2 /dl 2, P=NS) Serum bicarbonate (HCO 3 ) Metabolic acidosis was more frequent with sevelamer treatment (34.4% vs. 3.3%, P<0.005) Other clinical effects increased alkaline phosphatase compared with baseline (P<0.05) decreased total cholesterol and LDL cholesterol compared with baseline (P<0.05) Lower in total cholesterol (134±52 vs. 160±32 mg/dl, P<0.05), LDL cholesterol (60±34 vs. 81±26 mg/dl, P<0.001) compared with Ca group Subjects with baseline coronary artery Ca score (CACS) >30 showed 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 vs. 10.6/100 patient-years, CI , P=0.05) Hydrochloride for Chronic Kidney Disease 15

16 Author Serum calcium Serum phosphorous Asmus et al. (2005) 23 with CaCO 3 group with CaCO 3 group Parathyroid hormone with CaCO 3 group (P<0.01) Calciumphosphorous product with CaCO 3 group Serum bicarbonate (HCO 3 ) Other clinical effects Higher in alkaline phosphatase compared with CaCO 3 group (P=0.046) Lower in total cholesterol compared with CaCO 3 group (P=0.0005) Lower in the progression in calcification of coronary arteries (P=0.018) and the aorta (P=0.004) compared with CaCO 3 group Ferramosca et al. NSD between groups in (2005) 17 coronary calcification score Garg et al. (2005) 29 Braun et al. (2004) 24 with Ca group (mean changes: vs mg/dl, P<0.0001) with CaCO 3 group (mean changes: 0.01±0.10 vs. 0.15) with Ca group (mean changes: -2.3 vs mg/dl, P=0.42) with CaCO 3 group (mean changes: ±0.68 vs ±0.50 mmol/l, P=0.62) with Ca group (values: ) with CaCO 3 group (change: -24 vs. -84 pg/ml, P=0.02) with CaCO 3 group (mean changes: - 1.4±1.7 vs ±1.2 mmpl 2 /l 2, P=0.12) to Ca group (mean changes: vs. 3.2 mg/dl, P<0.001) Lower in total cholesterol (P<0.0001), LDL cholesterol (P<0.0001) and ApoB (P<0.0001) compared with Ca acetate group Lower in serum uric acid compared with Ca group (mean changes: vs mg/dl, P=0.03) Higher in bone-specific alkaline phosphatase compared with CaCO 3 group (33 U/l vs. 20 U/l, P<0.01) Lower in total cholesterol, LDL cholesterol, and Apo B compared with CaCO 3 group (P<0.05) Higher in Apo A compared with CaCO 3 group (P<0.05) CaCO 3 patients had significant increases in coronary artery (median +34%, P<0.01) and Hydrochloride for Chronic Kidney Disease 16

17 Author Serum calcium Serum phosphorous Qunibi et al. (2004) 18 group (8.9±0.5 vs. 9.5±0.7 mg/dl, P<0.0001) Higher compared with Ca acetate (6.8±1.6 vs. 5.5±1.5 mg/dl, P=0.0006) Parathyroid hormone with Ca acetate group Calciumphosphorous product group (60.4±14.1 vs. 52.7±14.2 mg 2 /dl 2, P=0.022) Serum bicarbonate (HCO 3 ) group (19.3±2.7 vs. 21.0±2.6 meq/l, P<0.0001) Other clinical effects aortic calcification (median +32%, P<0.01) that were not observed in sevelamer patients Higher events of dyspepsia compared with CaCO 3 group (26% vs. 5%, P<0.01) NSD in adverse events compared to Ca acetate group Raggi et al. (2004) 19 Less in valvular and vascular calcification compared with Ca acetate group (P<0.05) Shaheen et al. (2004) 25 with CaCO 3 group (change: -0.2±0.9 vs. 0.5±1.3 mg/dl) with CaCO 3 group (change: -3.3±2.2 vs ±2.8 mg/dl) with CaCO 3 group (change: -45±143 vs. -53±152 pg/ml) with CaCO 3 group (change: ±24.2 vs ±34.7 mg 2 /dl 2 ) NSD in total cholesterol and triglyceride compared with CaCO 3 group Apo: apolipoprotein; Ca: calcium; CI: confidence interval; LDL: low-density lipoprotein; meq: milliequivalent; : not reported; NSD: no significant difference; RR: relative risk Hydrochloride for Chronic Kidney Disease 17