Therapeutics
Review: Non–calcium-based phosphate binders reduce mortality compared with calcium-based binders in CKD
Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet. 2013;382:1268-77.
Clinical impact rating: n ★★★★★★✩ Question
Source of funding: No external funding.
In patients with chronic kidney disease (CKD), what is the relative effect of non–calcium-based and calcium-based phosphate binders on mortality?
For correspondence: Dr. S.A. Jamal, Women’s College Hospital Research Institute, Toronto, ON, Canada. E-mail [email protected]. ■
Commentary
Review scope Included studies compared non–calcium-based phosphate binders (sevelamer hydrochloride, sevelamer carbonate, or lanthanum) with calcium-based phosphate binders (calcium carbonate or calcium acetate) in patients with CKD (at any stage of disease and receiving any type of dialysis). Outcomes included all-cause mortality and coronary artery calcification (Agatston score, higher score = more severe atherosclerosis).
Review methods This was an update of a previous review. MEDLINE, EMBASE/ Excerpta Medica, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and CINAHL (all Aug 2008 to Oct 2012) were searched for published randomized controlled trials (RCTs) and non-RCTs. 18 studies, including 10 from the previous review and 8 new studies (n = 3230), met selection criteria. 14 were RCTs (n = 4715, mean age range 47 to 67 y, follow-up range 5 to 44 mo, 48% to 99% men) comparing the non–calcium-based phosphate binders sevelamer (11 RCTs), lanthanum (2 RCTs), or sevelamer or lanthanum (1 RCT) with calcium-based phosphate binders. Risk for bias was low (5 RCTs), unclear (3 RCTs), and high (6 RCTs). Only RCT results are presented here.
Main results Non–calcium-based phosphate binders reduced all-cause mortality (Table) and coronary artery calcification (7 RCTs, n = 704, mean difference in Agatston score −95, 95% CI −147 to −44) compared with calcium-based phosphate binders.
Conclusion In patients with chronic kidney disease, non–calcium-based phosphate binders reduce all-cause mortality compared with calcium-based phosphate binders. All-cause mortality for non–calcium-based vs calcium-based phosphate binders in patients with chronic kidney disease* Non– calciumbased phosphate binder
Number of trials (n)
Weighted event rates
Non– Calciumcalcium- based based
At 5 to 44 mo
RRR (95% CI)
NNT (CI)
All
11 (4622)
17%
22%
22% (2 to 39)
21 (12 to 231)
Sevelamer
10 (4518)†
21%
23%†
11% (−1 to 22)
NS
Lanthanum
1 (1354)
17%
23%
26% (−13 to 51)
NS
*NS = not significant; other abbreviations defined in Glossary. Weighted event rates, RRR, NNT, and CI calculated from control event rates and risk ratios in article using a DerSimonian and Laird random-effects model.
Hyperphosphatemia is inevitable in patients with CKD who receive conventional dialysis; it is treated with intestinal phosphate-binding agents. Whether older, calcium-based or newer, noncalcium formulations, which are 4 to 10 times more expensive (1), are the ideal option for phosphate binders is an unresolved clinical problem. Non–calcium-based binders are believed to decrease positive calcium balance (as calcium is present as part of dialysate composition) and delay coronary artery calcification, which may have beneficial effects on cardiovascular and overall mortality in these patients. Jamal and colleagues updated their prior meta-analysis from 2009 and reported a 22% relative reduction in all-cause mortality in patients who were randomly assigned to non–calcium–based phosphate binders compared with those assigned to calcium-based binders (11 RCTs, n = 4622, risk ratio 0.78, 95% CI 0.61 to 0.98). Length of follow-up in most trials was surprisingly short, with most ranging from < 1 to 2 years. Meta-analysis of 7 trials showed less vascular calcification with non–calcium-based phosphate binders, suggesting that the reduction in calcification could be a surrogate for mortality benefit. However, this conclusion is limited by the lack of information on cause of death (cardiovascular vs noncardiovascular) in the included trials. Unfortunately, the review could not evaluate whether the difference between groups resulted from benefit from non–calcium-based binders or harm from calcium-based binders; whether there were differences between the non–calcium-based free binders sevelamer or lanthanum, or differences between available calcium binders (carbonate vs acetate); or the impact of varying calcium concentrations in dialysate. The reported effects on vascular calcification may be exaggerated with the absorption of alkali along with calcium (2). The review by Jamal and colleagues could have important implications for treatment of patients with CKD. Although non–calcium-based binders may be preferred in patients receiving dialysis, only 64 deaths separate the 2 groups, and the data are not robust. It is also not clear from this review whether the expensive noncalcium agents should be the first choice in patients with CKD who are not receiving dialysis. Additional evidence needs to be generated in this larger group of patients who have impaired ability to excrete excess calcium. Chirag R. Parikh, MD, PhD Program of Applied Translational Research, Yale University New Haven, Connecticut, USA References 1. Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney failure. N Engl J Med. 2010;362:1312-24. 2. Bushinsky DA, Monk RD. Electrolyte quintet: calcium. Lancet. 1998; 352:306-11.
†Information provided by author.
JC2
© 2013 American College of Physicians
Downloaded From: http://annals.org/ by a Fudan University User on 12/11/2016
19 November 2013 | ACP Journal Club | Volume 159 • Number 10
Review: Non–calcium-based phosphate binders reduce mortality compared with calcium-based binders in CKD
Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet. 2013;382:1268-77.
Clinical impact rating: n ★★★★★★✩ Question
Source of funding: No external funding.
In patients with chronic kidney disease (CKD), what is the relative effect of non–calcium-based and calcium-based phosphate binders on mortality?
For correspondence: Dr. S.A. Jamal, Women’s College Hospital Research Institute, Toronto, ON, Canada. E-mail [email protected]. ■
Commentary
Review scope Included studies compared non–calcium-based phosphate binders (sevelamer hydrochloride, sevelamer carbonate, or lanthanum) with calcium-based phosphate binders (calcium carbonate or calcium acetate) in patients with CKD (at any stage of disease and receiving any type of dialysis). Outcomes included all-cause mortality and coronary artery calcification (Agatston score, higher score = more severe atherosclerosis).
Review methods This was an update of a previous review. MEDLINE, EMBASE/ Excerpta Medica, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and CINAHL (all Aug 2008 to Oct 2012) were searched for published randomized controlled trials (RCTs) and non-RCTs. 18 studies, including 10 from the previous review and 8 new studies (n = 3230), met selection criteria. 14 were RCTs (n = 4715, mean age range 47 to 67 y, follow-up range 5 to 44 mo, 48% to 99% men) comparing the non–calcium-based phosphate binders sevelamer (11 RCTs), lanthanum (2 RCTs), or sevelamer or lanthanum (1 RCT) with calcium-based phosphate binders. Risk for bias was low (5 RCTs), unclear (3 RCTs), and high (6 RCTs). Only RCT results are presented here.
Main results Non–calcium-based phosphate binders reduced all-cause mortality (Table) and coronary artery calcification (7 RCTs, n = 704, mean difference in Agatston score −95, 95% CI −147 to −44) compared with calcium-based phosphate binders.
Conclusion In patients with chronic kidney disease, non–calcium-based phosphate binders reduce all-cause mortality compared with calcium-based phosphate binders. All-cause mortality for non–calcium-based vs calcium-based phosphate binders in patients with chronic kidney disease* Non– calciumbased phosphate binder
Number of trials (n)
Weighted event rates
Non– Calciumcalcium- based based
At 5 to 44 mo
RRR (95% CI)
NNT (CI)
All
11 (4622)
17%
22%
22% (2 to 39)
21 (12 to 231)
Sevelamer
10 (4518)†
21%
23%†
11% (−1 to 22)
NS
Lanthanum
1 (1354)
17%
23%
26% (−13 to 51)
NS
*NS = not significant; other abbreviations defined in Glossary. Weighted event rates, RRR, NNT, and CI calculated from control event rates and risk ratios in article using a DerSimonian and Laird random-effects model.
Hyperphosphatemia is inevitable in patients with CKD who receive conventional dialysis; it is treated with intestinal phosphate-binding agents. Whether older, calcium-based or newer, noncalcium formulations, which are 4 to 10 times more expensive (1), are the ideal option for phosphate binders is an unresolved clinical problem. Non–calcium-based binders are believed to decrease positive calcium balance (as calcium is present as part of dialysate composition) and delay coronary artery calcification, which may have beneficial effects on cardiovascular and overall mortality in these patients. Jamal and colleagues updated their prior meta-analysis from 2009 and reported a 22% relative reduction in all-cause mortality in patients who were randomly assigned to non–calcium–based phosphate binders compared with those assigned to calcium-based binders (11 RCTs, n = 4622, risk ratio 0.78, 95% CI 0.61 to 0.98). Length of follow-up in most trials was surprisingly short, with most ranging from < 1 to 2 years. Meta-analysis of 7 trials showed less vascular calcification with non–calcium-based phosphate binders, suggesting that the reduction in calcification could be a surrogate for mortality benefit. However, this conclusion is limited by the lack of information on cause of death (cardiovascular vs noncardiovascular) in the included trials. Unfortunately, the review could not evaluate whether the difference between groups resulted from benefit from non–calcium-based binders or harm from calcium-based binders; whether there were differences between the non–calcium-based free binders sevelamer or lanthanum, or differences between available calcium binders (carbonate vs acetate); or the impact of varying calcium concentrations in dialysate. The reported effects on vascular calcification may be exaggerated with the absorption of alkali along with calcium (2). The review by Jamal and colleagues could have important implications for treatment of patients with CKD. Although non–calcium-based binders may be preferred in patients receiving dialysis, only 64 deaths separate the 2 groups, and the data are not robust. It is also not clear from this review whether the expensive noncalcium agents should be the first choice in patients with CKD who are not receiving dialysis. Additional evidence needs to be generated in this larger group of patients who have impaired ability to excrete excess calcium. Chirag R. Parikh, MD, PhD Program of Applied Translational Research, Yale University New Haven, Connecticut, USA References 1. Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney failure. N Engl J Med. 2010;362:1312-24. 2. Bushinsky DA, Monk RD. Electrolyte quintet: calcium. Lancet. 1998; 352:306-11.
†Information provided by author.
JC2
© 2013 American College of Physicians
Downloaded From: http://annals.org/ by a Fudan University User on 12/11/2016
19 November 2013 | ACP Journal Club | Volume 159 • Number 10
