Primary studies included in this systematic review

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Primary study

Unclassified

Journal Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
Year 2014
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BACKGROUND: JTT-751 is a novel phosphate binder containing ferric citrate as the active ingredient. METHODS: In this Phase 3, multicenter, randomized, open-label, parallel-group study, we compared the efficacy and safety of JTT-751 and sevelamer hydrochloride in patients undergoing hemodialysis. A total of 230 patients with a serum phosphate ≥1.97 and <3.23 mmol/L were randomized to JTT-751 (dose adjusted between 1.5 and 6.0 g/day) or sevelamer hydrochloride (dose adjusted between 3.0 and 9.0 g/day) for 12 weeks. The primary outcome was change in serum phosphate from baseline to end of treatment. Secondary outcomes included the changes in corrected serum calcium and intact parathyroid hormone (PTH). The changes in ferritin, transferrin saturation and erythropoiesis-stimulating agent dose were additional outcomes. RESULTS: Changes in serum phosphate at the end of treatment were -0.82 mmol/L in the JTT-751 group and -0.78 mmol/L in the sevelamer group, establishing non-inferiority of JTT-751 compared with sevelamer (least squares mean, -0.03 mmol/L; 95% confidence interval, -0.13 to 0.07 mmol/L). Corrected serum calcium increased and PTH decreased from baseline within both groups; changes between groups were similar. Gastrointestinal disorders were the most common adverse events in both groups; the incidence of diarrhea was higher in the JTT-751 group, while constipation occurred frequently in the sevelamer group. Treatment with JTT-751 resulted in significant relative increases in serum ferritin and transferrin saturation. CONCLUSIONS: Efficacy and safety of JTT-751 was comparable to sevelamer in patients on hemodialysis with hyperphosphatemia. Differential adverse effects were observed; biochemical markers of iron status increased in patients treated with JTT-751. TRIAL REGISTRATION NUMBER: CTI-111433 (The Japan Pharmaceutical Information Center at: http//www.clinicaltrials.jp). Date of registration: 7 March 2011.

Primary study

Unclassified

Authors Lin HH , Liou HH , Wu MS , Lin CY , Huang CC
Journal Nephrology (Carlton, Vic.)
Year 2014
AIMS: Fibroblast growth factor 23 (FGF23) and Klotho are associated with vascular calcification and cardiovascular disease in dialysis patients. Sevelamer has been shown to reduce progression of vascular calcification. This study aimed to determine the long-term effect of sevelamer treatment on serum FGF23 and Klotho levels in chronic haemodialysis (HD) patients. METHODS: In the post-hoc analysis, we measured serum FGF23, Klotho and other biochemical factors (Ca, P, i-PTH, hsCRP, LDL-C) in 50 haemodialysis patients, who completed a 48-week, open-Label, controlled randomized parallel-group study. Twenty-three patients received sevelamer and 27 patients received calcium carbonate. RESULTS: After 48-week sevelamer treatment, there were significant changes with lower LDL-C (from 2.82 ± 0.78 to 1.65 ± 0.53 mmol/L, P = 0.000), lower FGF23 (from 2465.97 (2568.88) to 795.61 (1098.39), P = 0.000) and higher s-Klotho levels (from 189.35 (161.88) to 252.94 (517.80) pg/mL, P = 0.000). In calcium carbonate group, there were no significant changes of LDL-C and FGF23, but with a borderline significant increase of s-Klotho level (from 142.34 (265.24) to 188.57 (252.38) pg/mL, P = 0.054). Multivariate analysis showed that FGF23 decrement was associated with sevelamer treatment (β = -0.277, P = 0.005), change of serum phosphate (β = 0.609, P = 0.000) and calcium levels (β = 0.635, P = 0.000). The increase of serum Klotho was associated with the decrease of serum phosphate (β = 0.490, P = 0.019). CONCLUSION: Maintenance HD patients had lower serum FGF23 levels, accompanied with significantly increased serum Klotho levels, after 48-week sevelamer treatment. The FGF23 decrement was associated with sevelamer use, the change of serum phosphate and calcium levels. The serum Klotho increment was proportional to the phosphate-lowering power of the binders.

Primary study

Unclassified

Journal Kidney international
Year 2014
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Efficacy of PA21 (sucroferric oxyhydroxide), a novel calcium-free polynuclear iron(III)-oxyhydroxide phosphate binder, was compared with that of sevelamer carbonate in an open-label, randomized, active-controlled phase III study. Seven hundred and seven hemo- and peritoneal dialysis patients with hyperphosphatemia received PA21 1.0-3.0 g per day and 348 received sevelamer 4.8-14.4 g per day for an 8-week dose titration, followed by 4 weeks without dose change, and then 12 weeks maintenance. Serum phosphorus reductions at week 12 were -0.71 mmol/l (PA21) and -0.79 mmol/l (sevelamer), demonstrating non-inferiority of, on average, three tablets of PA21 vs. eight of sevelamer. Efficacy was maintained to week 24. Non-adherence was 15.1% (PA21) vs. 21.3% (sevelamer). The percentage of patients that reported at least one treatment-emergent adverse event was 83.2% with PA21 and 76.1% with sevelamer. A higher proportion of patients withdrew owing to treatment-emergent adverse events with PA21 (15.7%) vs. sevelamer (6.6%). Mild, transient diarrhea, discolored feces, and hyperphosphatemia were more frequent with PA21; nausea and constipation were more frequent with sevelamer. After 24 weeks, 99 hemodialysis patients on PA21 were re-randomized into a 3-week superiority analysis of PA21 maintenance dose in 50 patients vs. low dose (250 mg per day (ineffective control)) in 49 patients. The PA21 maintenance dose was superior to the low dose in maintaining serum phosphorus control. Thus, PA21 was effective in lowering serum phosphorus in dialysis patients, with similar efficacy to sevelamer carbonate, a lower pill burden, and better adherence.

Primary study

Unclassified

Authors Wada K , Wada Y
Journal Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy
Year 2014
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Vascular calcification (VC) contributes to cardiovascular disease in hemodialysis (HD) patients, especially with diabetes mellitus (DM) complications. No randomized studies have been published regarding the effect of lanthanum carbonate (LC) on VC progression in DM patients. The aim of this study was to evaluate the effects of lanthanum carbonate on the progression of VC in HD patients with type 2 DM. We conducted a randomized controlled trial comparing LC with calcium carbonate (CC) in 43 HD patients at a single dialysis center. Estimations of aortic calcification index (ACI) by abdominal computed tomography were performed twice for each patient (at baseline and 12 months). Forty-one patients completed the study (19 LC, 22 CC). When ACI at baseline was ≦0.48 (median of baseline ACI), median change in ACI (Δ%ACI) was 20.44 (11.50-36.80%) in the LC group, and 40.00 (33.30-92.60%) in the CC group (P = 0.026). On the other hand, when ACI at baseline was >0.48, the median change in ACI (Δ%ACI) was 6.42 (3.13-24.40%) in the LC group, and 8.08 (5.68-12.20%) in the CC group (P = 1.000). Serum markers of chronic kidney disease-mineral and bone disorder (CKD-MBD), HbA1c, dose of vitamin D analogues, and side-effects of medications did not change in either group throughout the study except int-PTH increased in the LC group. This study indicated that administration of LC inhibited the progression of VC in patients receiving HD for type 2 DM, only in cases of slight VC compared with CC.

Primary study

Unclassified

Journal Journal of cardiovascular pharmacology and therapeutics
Year 2013
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BACKGROUND AND OBJECTIVES: Coronary artery calcification (CAC) is associated with future cardiovascular events and/or death of patients on hemodialysis (HD). We investigated whether progression of CAC in patients on HD could be delayed by switching from a calcium (Ca)-based phosphate (Pi) binder to lanthanum carbonate. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: The CAC scores were evaluated at study enrollment and after 6 months in 52 patients on HD using calcium carbonate (CC) as a Pi binder. Patients were randomly divided into 2 groups assigned to receive either CC or lanthanum carbonate (LC), and the CAC scores were evaluated after a 6-month treatment period. Progression of CAC was assessed, as were serum levels of Ca, Pi, and intact parathyroid hormone (iPTH). RESULTS: Forty-two patients completed the study (23 receiving CC and 19 receiving LC). In the 6 months prior to randomization, all patients were treated with CC. During this 6-month period, the CAC scores increased significantly in all 42 patients. Once randomized, there was significantly less progression in the group treated with LC than with CC. Changes in CAC scores from 6 to 12 months were significantly smaller in the LC group than the CC group (-288.9 ± 1176.4 vs 107.1 ± 559.6, P = .036), and percentage changes were also significantly different (-6.4% vs 41.2%, P = .024). Serum Ca, Pi, and iPTH levels were similar in both groups during the study period. CONCLUSIONS: This pilot study suggested that LC delayed progression of CAC in patients on HD compared with CC.

Primary study

Unclassified

Journal Clinical nephrology
Year 2013
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BACKGROUND: Recent publications show that elevation of FGF23 is independently associated with progression or renal disease, left ventricular hypertrophy and cardiovascular mortality. Dietary restriction of phosphate and phosphate binders are used for control phosphate balance and elevation of serum FGF23 levels. The aim of this study is to compare the effectiveness of calcium carbonate vs. lanthanum carbonate in reducing serum FGF23 levels in Chronic Kidney Disease (CKD) patients. METHODS: 32 patients from the Nephrology outpatient clinic with CKD 4 - 5 non-dialysis were included. Patients receive a 4-month treatment period of calcium carbonate or lanthanum carbonate. Patients had normal serum calcium concentration, 25 (OH) levels >30 ng/ml and they were not on VDR activators or cinacalcet. RESULTS: As compared with calcium carbonate, patients on lanthanum carbonate had lower serum levels of FGF23 (226 ± 11 vs. 158 ± 9 pg/ml) and less urinary excretion of phosphate. No significant changes in serum calcium and PTH levels were observed in both groups. CONCLUSIONS: In conclusion, in CKD 4 - 5 patients lanthanum carbonate is effective in reducing phosphate load and FGF23 levels; this effect was not observed with calcium carbonate.

Primary study

Unclassified

Authors Lee YK , Choi HY , Shin SK , Lee HY
Journal Clinical nephrology
Year 2013
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BACKGROUND: Hyperphosphatemia is a common complication in end-stage renal disease (ESRD) patients. Reducing the serum phosphate level is crucial in management of ESRD. METHODS: This study was a randomized prospective study, designed to compare patients with hyperphosphatemia undergoing peritoneal dialysis while taking lanthanum carbonate or calcium carbonate. We divided 72 continuous ambulatory peritoneal dialysis (CAPD) patients whose serum phosphate levels were over 5.6 mg/dl into two groups to receive either lanthanum carbonate or calcium carbonate. Serum calcium, phosphate and PTH levels were examined serially for 24 weeks. RESULTS: Both lanthanum carbonate and calcium carbonate reduced serum phosphate levels, from 6.79 ± 1.05 to 5.44 ± 1.44 and from 6.31 ± 1.13 to 4.74 ± 0.78 mg/dl, respectively. The calcium × phosphate product level was reduced in the lanthanum carbonate and calcium carbonate groups from 60.23 ± 10.23 to 46.97 ± 16.42 and from 57.92 ± 11.05 to 44.50 ± 7.74 mg2/dl2, respectively. The serum parathyroid hormone (PTH) level in the lanthanum carbonate group did not change significantly compared to baseline during the study, but in the calcium carbonate group, the serum PTH level decreased significantly. Gastrointestinal complications were the main adverse effects of lanthanum carbonate and 11 out of 35 patients dropped out of the study due to this complication. CONCLUSIONS: Lanthanum carbonate was as effective as calcium carbonate in reducing serum phosphate level, and serum PTH level tended to be steadier in the lanthanum carbonate group compared to the calcium carbonate group. Though the ifference was not significant, lanthanum carbonate tended not to elevate serum calcium level in CAPD patients compared to calcium carbonate. The high incidence of gastrointestinal adverse effect in the lanthanum carbonate group will need further evaluation.

Primary study

Unclassified

Journal Journal of renal care
Year 2013
BACKGROUND: Hyperphosphataemia is a known independent risk factor for cardiovascular mortality. The objective of the study was to compare the effects of two phosphate binders, sevelamer carbonate and calcium carbonate on endothelial function (EF) and inflammation in patients on peritoneal dialysis (PD) with Type 2 diabetes mellitus (T2DM). METHODS: Fifteen subjects with hyperphosphataemia discontinued all phosphate binders to undergo a two-week washout and were assigned to sevelamer carbonate or calcium carbonate treatments for eight weeks. After a second two-week washout period, subjects crossed over to either of the alternate treatments for another eight weeks. At the beginning and end of each treatment, biomarkers of EF, pro-inflammatory cytokines, serum albumin, calcium, phosphate and lipids were measured. RESULTS: Sevelamer carbonate significantly improved lipid profile compared with calcium carbonate. Amongst the EF and pro-inflammatory biomarkers, sevelamer carbonate decreased serum endothelin-1, plasminogen activator inhibitor-1, C-reactive protein and interleukin-6. Both phosphate binders were effective in decreasing serum phosphate but sevelamer had a positive effect on EF. CONCLUSIONS: Treatment with sevelamer carbonate has beneficial effects compared with calcium carbonate in decreasing inflammation and improving EF in patients with T2DM on PD.

Primary study

Unclassified

Journal American journal of kidney diseases : the official journal of the National Kidney Foundation
Year 2013
BACKGROUND: Whether the use of sevelamer rather than a calcium-containing phosphate binder improves cardiovascular (CV) survival in patients receiving dialysis remains to be elucidated. STUDY DESIGN: Open-label randomized controlled trial with parallel groups. SETTINGS & PARTICIPANTS: 466 incident hemodialysis patients recruited from 18 centers in Italy. INTERVENTION: Study participants were randomly assigned in a 1:1 fashion to receive either sevelamer or a calcium-containing phosphate binder (although not required by the protocol, all patients in this group received calcium carbonate) for 24 months. OUTCOMES: All individuals were followed up until completion of 36 months of follow-up or censoring. CV death due to cardiac arrhythmias was regarded as the primary end point. MEASUREMENTS: Blind event adjudication. RESULTS: At baseline, patients allocated to sevelamer had higher serum phosphorus (mean, 5.6 ± 1.7 [SD] vs 4.8 ± 1.4 mg/dL) and C-reactive protein levels (mean, 8.8 ± 13.4 vs 5.9 ± 6.8 mg/dL) and lower coronary artery calcification scores (median, 19 [IQR, 0-30] vs 30 [IQR, 7-180]). At study completion, serum phosphate levels were lower in the sevelamer arm (median dosages, 4,800 and 2,000 mg/d for sevelamer and calcium carbonate, respectively). After a mean follow-up of 28 ± 10 months, 128 deaths were recorded (29 and 88 due to cardiac arrhythmias and all-cause CV death). Sevelamer-treated patients experienced lower CV mortality due to cardiac arrhythmias compared with patients treated with calcium carbonate (HR, 0.06; 95% CI, 0.01-0.25; P < 0.001). Similar results were noted for all-cause CV mortality and all-cause mortality, but not for non-CV mortality. Adjustments for potential confounders did not affect results. LIMITATIONS: Open-label design, higher baseline coronary artery calcification burden in calcium carbonate-treated patients, different mineral metabolism control in sevelamer-treated patients, overall lower than expected mortality. CONCLUSIONS: These results show that sevelamer compared to a calcium-containing phosphate binder improves survival in a cohort of incident hemodialysis patients. However, the better outcomes in the sevelamer group may be due to better phosphate control rather than reduction in calcium load.

Primary study

Unclassified

Journal Clinical journal of the American Society of Nephrology : CJASN
Year 2012
BACKGROUND AND OBJECTIVES: Dietary phosphorous overload and excessive calcium intake from calcium-containing phosphate binders promote coronary artery calcification (CAC) that may contribute to high mortality of dialysis patients. CAC has been found in patients in early stages of nondialysis-dependent CKD. In this population, no study has evaluated the potential role of phosphorus binders on mortality. This study aimed to evaluate all-cause mortality as the primary end point in nondialysis-dependent CKD patients randomized to different phosphate binders; secondary end points were dialysis inception and the composite end point of all-cause mortality and dialysis inception. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a randomized, multicenter, nonblinded pilot study. Consecutive outpatients (n=212; stage 3-4 CKD) were randomized to either sevelamer (n=107) or calcium carbonate (n=105). Phosphorus concentration was maintained between 2.7 and 4.6 mg/dl for patients with stage 3-4 CKD and between 3.5 and 5.5 mg/dl for patients with stage 5 CKD. The CAC score was assessed by computed tomography at study entry and after 6, 12, 18, and 24 months. All-cause mortality, dialysis inception, and the composite end point were recorded for up to 36 months. RESULTS: In patients randomized to sevelamer, all-cause mortality and the composite end point were lower; a nonsignificant trend was noted for dialysis inception. CONCLUSIONS: Sevelamer provided benefits in all-cause mortality and in the composite end point of death or dialysis inception but not advantages in dialysis inception. Larger studies are needed to confirm these results.