NDT Advance Access originally published online on July 14, 2008
Nephrology Dialysis Transplantation 2008 23(10):3050-3052; doi:10.1093/ndt/gfn393
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Calcium-containing phosphate binders in dialysis patients with cardiovascular calcifications: should we CARE-2 avoid them?
Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
Jürgen Floege, Division of Nephrology, University Hospital, RWTH Aachen, Pauwelsstr 30, 52074 Aachen, Germany. Tel: +49-241-8089-530; Fax: +49-241-8082-446; E-mail: juergen.floege{at}rwth-aachen.de
Keywords: calcification; calcium acetate; dialysis; phosphate binder; sevelamer
Excess cardiovascular mortality is well documented in dialysis patients. Vascular calcifications, no matter where and how they are detected, are a potent predictor of mortality in such patients [1]. Many, albeit not all, studies have documented that an elevated serum calcium-phosphate product as well as the total dose of calcium-containing phosphate binders ingested correlates with the extent of vascular calcifications [2,3]. Thus, oral calcium loading might contribute to vascular calcification. This would be of particular importance in patients with serum parathyroid hormone levels <100 pg/ml, which usually indicates low-turnover bone disease [3], where the capacity of the bone to buffer calcium challenges is limited. Further evidence for a detrimental role of calcium loading is derived from the observation that the magnitude of intradialytic serum calcium increases predicts the progression of vascular calcifications [4]. Consequently, there is a good rationale to investigate whether a reduction of oral calcium loading might affect the progress of cardiovascular calcifications.
To date, three randomized prospective clinical trials have tested whether replacing calcium-containing phosphate binders in dialysis patients by a non-calcium-containing phosphate binder, namely sevelamer, alters the course of coronary and aortic calcifications. Two of them [5,6], both sponsored by the manufacturer of sevelamer, concluded that sevelamer exerted a benefit, whereas the third study [7], sponsored by a manufacturer of calcium acetate, concluded that the two phosphate binders did not differ with respect to the progression of calcification. It is the purpose of this editorial to attempt to reconcile these apparently contradictory results. Before doing so, let us briefly look at the three study designs and key findings:
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Treat-to-goal study (TTG) [5] |
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 Top Treat-to-goal study (TTG) [5] Renagel in new dialysis...Calcium acetate renagel...ConclusionReferences |
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Two hundred chronic haemodialysis patients were randomized 1:1 to receive either sevelamer (mean dose 6.5 g/day) or a calcium-containing phosphate binder (calcium acetate, mean dose 4.6 g/day, or calcium carbonate, mean dose 3.9 g/day). Vitamin D therapy and dialysate calcium were adjusted to achieve serum calcium and iPTH levels in the respective KDOQI target ranges. All subjects underwent electron beam computed tomographies (EBCT) at weeks 0, 26 and 52 to assess calcifications (Agatston scores) of the coronary arteries, aorta, mitral and aortic valve. In comparison to calcium-containing phosphate binders, sevelamer treatment led to significantly lower serum calcium, fewer hypercalcaemia episodes, less frequent suppression of PTH <150 pg/ml, lower serum LDL-cholesterol levels, and it prevented increases in aortic and coronary calcium scores.
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Renagel in new dialysis (RIND) patients’ study [6] |
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TopTreat-to-goal study (TTG) [5]Renagel in new dialysis...Calcium acetate renagel...ConclusionReferences |
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One hundred and twenty-nine patients new to haemodialysis were randomized 1:1 to receive sevelamer (mean dose 8 g/day) or calcium-containing phosphate binders (calcium acetate and/or calcium carbonate, mean dose of elemental calcium 2.3 g/day). Vitamin D therapy was flexible as in the TTG study, but dialysate calcium was fixed at 2.5 mEq/L throughout the study. EBCTs and calculations of coronary Agatston scores were performed at 0, 6, 12 and 18 months. In the subgroup of patients with detectable coronary calcifications at baseline (Agatston score >30), sevelamer retarded the progress of calcifications as compared to the calcium group. As in the TTG study, sevelamer led to significantly lower serum calcium, less frequent suppression of PTH and lower serum LDL cholesterol levels.
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Calcium acetate renagel evaluation (CARE-2) study [7] |
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TopTreat-to-goal study (TTG) [5]Renagel in new dialysis...Calcium acetate renagel...ConclusionReferences |
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Two hundred and three chronic haemodialysis patients were randomized 1:1 to receive sevelamer (mean dose 7.3 g/day) or calcium acetate (mean dose 5.5 g/day). In addition, atorvastatin (mean dose about 30 mg/day) was given to all patients of the calcium group and to 79% of the sevelamer patients to achieve LDL cholesterol levels <70 mg/dL. Vitamin D therapy was flexible, as in the TTG study, but dialysate calcium was fixed at 2.5 mEq/L throughout the study. EBCTs and calculations of coronary Agatston scores were performed at 0, 6 and 12 months. Geometric mean increases in scores were similar in the calcium group (+35%) and the sevelamer group (+39%). As in TTG and RIND, sevelamer led to significantly lower serum calcium and lesser suppression of PTH.
At first glance, these differing results would suggest that the addition of atorvastatin in the CARE-2 study somehow abolished the beneficial effects of sevelamer on the progress of vascular calcifications. Although counterintuitive, all of us have witnessed surprises in medicine and this possibility cannot be excluded. Nevertheless it is notable that consistently, serum cholesterol or serum LDL cholesterol levels did not correlate with the prevalence of cardiovascular calcifications [2]. However, before jumping for unusual conclusions, it is useful to more closely look at the patient populations in terms of risk factors for progressive cardiovascular calcifications, which have been identified in other studies (Table 1) .
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A closer look at TTG versus CARE-2
Table 2 is an attempt to compare systematically the three patient populations with regard to factors, which in most studies have been found to be associated with the occurrence or progression of cardiovascular calcifications in dialysis patients. The two studies, which are most closely related by selection of the patients and study design, are TTG and CARE-2. Table 2 shows that patients recruited for CARE-2 had a higher risk for calcifications than those in TTG as evidenced by (a) a 2-fold higher prevalence of diabetic nephropathy at baseline, (b) a 3.3-fold higher prevalence of smokers at baseline and (c) possibly higher vitamin-D and calcium intake as well as baseline iPTH. In particular, the higher prevalences of diabetic nephropathy and smoking represent two major risk factors for cardiovascular calcification that are unlikely to be affected by calcium acetate or sevelamer. In addition to higher risk at baseline, the proportion of patients lost to follow-up was also higher in CARE-2 versus TTG, rendering the interpretation of the CARE-2 outcome data somewhat more difficult than those of TTG.
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In looking at the endpoints, there is indeed a major difference between the outcomes, as judged by mean changes in calcification scores in TTG (numeric difference 197 score points between the two groups) versus CARE-2 (numeric difference 1 score point). However, in view of the huge standard deviations, a look at the medians of the score changes may be more meaningful. Here, the very notable feature is that in the two studies, the numeric difference between the sevelamer and calcium group is almost identical at 37 points in TTG versus 30 points in CARE-2. Also, it is notable that in both studies the standard deviation in mean calcification score changes was markedly higher in the sevelamer groups, suggesting that there were non-responders. Identification of factors associated with non-response may further help to identify which patients may benefit from sevelamer.
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Conclusion |
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TopTreat-to-goal study (TTG) [5]Renagel in new dialysis...Calcium acetate renagel...ConclusionReferences |
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Instead of speculating about unexpected effects of a statin to promote vascular calcification in dialysis patients, a simpler interpretation of the RIND, TTG and CARE-2 data is that RIND and TTG demonstrated a retardation of cardiovascular calcification in patients receiving sevelamer. This benefit was overrun in the CARE-2 study, in particular, by a higher prevalence of diabetic nephropathy and smoking, both calcification risk factors unlikely to be affected by the choice of phosphate binders. Despite the much faster progression of coronary calcifications in CARE-2, it is, however, notable that the numeric increase in median calcification scores revealed the same trend as in TTG, namely a lower rate of change in the sevelamer group. All of this is consistent with a fourth study, published recently, which was performed without support from the pharmaceutical industry in patients with a GFR of
30 ml/min and concluded that sevelamer retarded the progression of cardiovascular calcifications to a higher degree than the administration of calcium carbonate [8]. Taken together, these studies suggest that we should still take care to reduce oral calcium loading in patients with advanced CKD, in particular if cardiovascular calcifications have already been documented [6,9].
Conflict of interest statement. The author has received speaker honoraria from the Amgen, Fresenius, Genzyme and Shire companies. The results presented in this paper have not been published previously in whole or part, except in abstract format.
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References |
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TopTreat-to-goal study (TTG) [5]Renagel in new dialysis...Calcium acetate renagel...ConclusionReferences |
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- Ketteler M, Schlieper G, Floege J. Calcification and cardiovascular health: new insights into an old phenomenon. Hypertension (2006) 47:1027–1034.
[Free Full Text] - Floege J, Ketteler M. Vascular calcification in patients with end-stage renal disease. Nephrol Dial Transplant (2004) 19(Suppl_5):V59–V66.[CrossRef][Medline]
- London GM, Marchais SJ, Guerin AP, et al. Association of bone activity, calcium load, aortic stiffness, and calcifications in ESRD. J Am Soc Nephrol (2008) doi: 10.1681/ASN.2007050622.
- Yamada K, Fujimoto S, Nishiura R, et al. Risk factors of the progression of abdominal aortic calcification in patients on chronic haemodialysis. Nephrol Dial Transplant (2007) 22:2032–2037.
[Abstract/Free Full Text] - Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int (2002) 62:245–252.[CrossRef][ISI][Medline]
- 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][ISI][Medline]
- Qunibi W, Moustafa M, Muenz LR, 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) 51:952–965.[CrossRef][ISI][Medline]
- Russo D, Miranda I, Ruocco C, et al. The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer. Kidney Int (2007) 72:1255–1261.[CrossRef][ISI][Medline]
- Block GA, Raggi P, Bellasi A, et al. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int (2007) 71:438–441.[CrossRef][ISI][Medline]
Accepted in revised form: 20. 6.08
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