Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients
2007; Elsevier BV; Volume: 72; Issue: 9 Linguagem: Inglês
10.1038/sj.ki.5002466
ISSN1523-1755
AutoresWadi N. Suki, Raja I. Zabaneh, José L. Cangiano, John Reed, D Fischer, Leland E. Garrett, B. Ling, Scott Chasan-Taber, Maureen Dillon, Andrew T. Blair, Steven K. Burke,
Tópico(s)Magnesium in Health and Disease
ResumoElevated serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Unlike calcium-based binders, sevelamer attenuates arterial calcification but it is unknown whether sevelamer affects mortality or morbidity. In a multicenter, randomized, open-label, parallel design trial we compared sevelamer and calcium-based binders on all-cause and cause-specific mortality (cardiovascular, infection, and other) in prevalent hemodialysis patients. A total of 2103 patients were initially randomized to treatment and 1068 patients completed the study. All-cause mortality rates and cause-specific mortality rates were not significantly different. There was a significant age interaction on the treatment effect. Only in patients over 65 years of age was there a significant effect of sevelamer in lowering the mortality rate. There was a suggestion that sevelamer was associated with lower overall, but not cardiovascular-linked, mortality in older patients. We suggest that further research is needed to confirm these findings. Elevated serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Unlike calcium-based binders, sevelamer attenuates arterial calcification but it is unknown whether sevelamer affects mortality or morbidity. In a multicenter, randomized, open-label, parallel design trial we compared sevelamer and calcium-based binders on all-cause and cause-specific mortality (cardiovascular, infection, and other) in prevalent hemodialysis patients. A total of 2103 patients were initially randomized to treatment and 1068 patients completed the study. All-cause mortality rates and cause-specific mortality rates were not significantly different. There was a significant age interaction on the treatment effect. Only in patients over 65 years of age was there a significant effect of sevelamer in lowering the mortality rate. There was a suggestion that sevelamer was associated with lower overall, but not cardiovascular-linked, mortality in older patients. We suggest that further research is needed to confirm these findings. The annual mortality rate of patients undergoing hemodialysis in the United States is nearly 25%, approximately half of which is cardiovascular.1.US Renal Data System, USRDS 2004 Annual Data Report Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2004Google Scholar Hyperphosphatemia and hypercalcemia are important independent risk factors for both cardiovascular calcification2.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2436) Google Scholar, 3.Kimura K. Saika Y. Otani H. et al.Factors associated with calcification of the abdominal aorta in hemodialysis patients.Kidney Int. 1999; 56: S238-S241Abstract Full Text Full Text PDF PubMed Google Scholar, 4.Chertow G.M. Raggi P. Chasan-Taber S. et al.Determinants of progressive vascular calcification in haemodialysis patients.Nephrol Dial Transplant. 2004; 19: 1489-1496Crossref PubMed Scopus (245) Google Scholar, 5.Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (995) Google Scholar and cardiovascular morbidity and mortality in dialysis patients.6.Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2110) Google Scholar, 7.Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2207) Google Scholar, 8.Stevens L.A. Djurdjev O. Cardew S. et al.Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: evidence for the complexity of the association between mineral metabolism and outcomes.J Am Soc Nephrol. 2004; 15: 770-779Crossref PubMed Scopus (314) Google Scholar, 9.Teng M. Wolf M. Lowrie E. et al.Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy.N Engl J Med. 2003; 349: 446-456Crossref PubMed Scopus (898) Google Scholar, 10.Young E.W. Albert J.M. Satayathum S. et al.Predictors and consequences of altered mineral metabolism: the dialysis outcomes and practice patterns study.Kidney Int. 2005; 67: 1179-1187Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar Dietary restriction and conventional dialysis alone are ineffective in controlling hyperphosphatemia, thus the vast majority of dialysis patients require phosphate binders. Until recently, the predominant binders in use have been calcium acetate and calcium carbonate. However, these medications have been linked to arterial calcification.2.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2436) Google Scholar, 11.Guerin A.P. London G.M. Marchais S.J. et al.Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplant. 2000; 15: 1014-1021Crossref PubMed Scopus (889) Google Scholar, 12.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1509) Google Scholar Arterial calcification in hemodialysis patients is associated with arterial stiffening and with increased risk of mortality.12.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1509) Google Scholar, 13.Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Scopus (1234) Google Scholar, 14.Blacher J. Guerin A.P. Pannier B. et al.Impact of aortic stiffness on survival in end-stage renal disease.Circulation. 1999; 99: 2434-2439Crossref PubMed Scopus (1854) Google Scholar Sevelamer hydrochloride (Renagel®), a non-absorbed, phosphate-binding polymer, lowers serum phosphorus without promoting arterial calcification.2.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2436) Google Scholar, 15.Braun J. Oldendorf M. Moshage W. et al.Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients.Am J Kidney Dis. 1996; 27: 394-401Abstract Full Text PDF PubMed Scopus (737) Google Scholar, 16.Chertow G.M. Burke S.K. Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Abstract Full Text Full Text PDF PubMed Scopus (1327) Google Scholar, 17.Chertow G.M. Raggi P. McCarthy J.T. et al.The effects of sevelamer and calcium acetate on proxies of atherosclerotic and arteriosclerotic vascular disease in hemodialysis patients.Am J Nephrol. 2003; 23: 307-314Crossref PubMed Scopus (102) Google Scholar, 18.Asmus H.G. Braun J. Krause R. et al.Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density.Nephrol Dial Transplant. 2005; 20: 1653-1661Crossref PubMed Scopus (157) Google Scholar, 19.Braun J. Asmus H.G. Holzer H. et al.Long-term comparison of a calcium-free phosphate binder and calcium carbonate-phosphorus metabolism and cardiovascular calcification.Clin Nephrol. 2004; 62: 104-115Crossref PubMed Google Scholar Recently it has been shown that the presence and severity of coronary calcification is a predictor of all-cause mortality in patients new to dialysis. In addition, the use of calcium-based binders in an incident dialysis population was associated with a significantly higher mortality rate when compared to sevelamer.20.Block G.A. Raggi P. Bellasi A. et al.Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Abstract Full Text Full Text PDF PubMed Scopus (672) The DCOR (Dialysis Clinical Outcomes Revisited) trial compared all-cause mortality and cause-specific mortality (cardiovascular mortality, infection, and other causes) among hemodialysis patients treated with calcium-based phosphate binders and sevelamer. DCOR was an effectiveness trial that was designed to evaluate the treatment outcomes under usual care conditions in a prevalent population. A total of 2103 subjects were randomized (1053 to sevelamer and 1050 to calcium-based binders) and 1068 patients completed (Figure 1). Overall the treatment groups were well balanced with respect to baseline demographics and renal history for the overall study population (Table 1) as well as by age subgroup (Table 2).Table 1Demographics and renal historyVariableTotal (N=2103)Sevelamer (N=1053)Calcium (N=1050)P-value*Fisher's exact test for categorical variables and Wilcoxon rank sum test for continuous variables.Race (N (%)) Caucasian1012 (48.1)515 (48.9)497 (47.3)0.42 Black988 (47.0)494 (46.9)494 (47.0) Asian17 (0.8)6 (0.6)11 (1.0) Other86 (4.1)38 (3.6)48 (4.6)Age (years) Mean±s.d.60.0±14.759.9±14.360.1±15.20.60 Median62.061.062.0Sex (N (%)) Male1143 (54.4)574 (54.5)569 (54.2)0.90 Female960 (45.6)479 (45.5)481 (45.8)Diabetes status (N (%)) No1047 (49.8)521 (49.5)526 (50.1)0.79 Yes1056 (50.2)532 (50.5)524 (49.9)Primary cause of ESRDaPrimary cause of ESRD: unknown is displayed under miscellaneous conditions. (N (%)) Diabetes890 (42.3)447 (42.5)443 (42.2)0.63 Hypertension/large vessel disease709 (33.7)353 (33.5)356 (33.9) Glomerulonephritis213 (10.1)110 (10.4)103 (9.8) Secondary GN/vasculitis40 (1.9)16 (1.5)24 (2.3) Interstitial nephritis/pyelonephritis54 (2.6)24 (2.3)30 (2.9) Neoplasms/tumors19 (0.9)10 (0.9)9 (0.9) Cystic/hereditary/congenital disease61 (2.9)27 (2.6)34 (3.2) Miscellaneous conditions117 (5.6)66 (6.3)51 (4.9)Dialysis duration (months) Mean±s.d.38.2±39.638.8±39.637.6±39.60.53 Median24.023.924.3ESRD, end-stage renal disease; GN, glomerulonephritis.a Primary cause of ESRD: unknown is displayed under miscellaneous conditions.* Fisher's exact test for categorical variables and Wilcoxon rank sum test for continuous variables. Open table in a new tab Table 2Patient demographics and renal history by age subgroupVariable<65 years of age≥65 years of ageTotal (N=1176)Sevelamer (N=598)Calcium (N=578)P-value*Fisher's exact test for categorical variables and Wilcoxon rank sum test for continuous variables.Total (N=927)Sevelamer (N=455)Calcium (N=472)P-value*Fisher's exact test for categorical variables and Wilcoxon rank sum test for continuous variables.Race (N (%)) Caucasian448 (38.1)236 (39.5)212 (36.7)0.61564 (60.8)279 (61.3)285 (60.4)0.53 Black663 (56.4)333 (55.7)330 (57.1)325 (35.1)161 (35.4)164 (34.7) Asian6 (0.5)3 (0.5)3 (0.5)11 (1.2)3 (0.7)8 (1.7) Other59 (5.0)26 (4.3)33 (5.7)27 (2.9)12 (2.6)15 (3.2)Age (years) (mean±s.d.)49.4±10.349.8±10.149.0±10.50.2173.4±6.073.1±5.773.7±6.20.22(Median)51.051.051.073.073.073.0Sex (N (%)) Male684 (58.2)354 (59.2)330 (57.1)0.48459 (49.5)220 (48.4)239 (50.6)0.51 Female492 (41.8)244 (40.8)248 (42.9)468 (50.5)235 (51.6)233 (49.4)Diabetes status (N (%)) No626 (53.2)317 (53.0)309 (53.5)0.91421 (45.4)204 (44.8)217 (46.0)0.74 Yes550 (46.8)281 (47.0)269 (46.5)506 (54.6)251 (55.2)255 (54.0)Primary cause of ESRDaPrimary cause of ESRD: unknown is displayed under miscellaneous conditions. (N (%)) Diabetes465 (39.5)235 (39.3)230 (39.8)0.49425 (45.8)212 (46.6)213 (45.1)0.66 Glomerulonephritis151 (12.8)82 (13.7)69 (11.9)62 (6.7)28 (6.2)34 (7.2) Secondary GN/vasculitis32 (2.7)13 (2.2)19 (3.3)8 (0.9)3 (0.7)5 (1.1) Interstitial Nephritis/pyelonephritis32 (2.7)17 (2.8)15 (2.6)22 (2.4)7 (1.5)15 (3.2) Neoplasms/tumors8 (0.7)5 (0.8)3 (0.5)11 (1.2)5 (1.1)6 (1.3) Hypertension/large vessel disease385 (32.7)195 (32.6)190 (32.9)324 (35.0)158 (34.7)166 (35.2) Miscellaneous conditions65 (5.5)37 (6.2)28 (4.8)52 (5.6)29 (6.4)23 (4.9) Cystic/hereditary/congenital disease38 (3.2)14 (2.3)24 (4.3)23 (2.5)13 (2.9)10 (2.1)Dialysis duration (mean±s.d., median (months))44.9±44.745.0±44.144.7±45.30.9329.9±30.030.8±31.028.9±29.10.4731.330.831.520.019.820.0ESRD, end-stage renal disease; GN, glomerulonephritis.a Primary cause of ESRD: unknown is displayed under miscellaneous conditions.* Fisher's exact test for categorical variables and Wilcoxon rank sum test for continuous variables. Open table in a new tab ESRD, end-stage renal disease; GN, glomerulonephritis. ESRD, end-stage renal disease; GN, glomerulonephritis. A total of 502 and 533 subjects discontinued early in the sevelamer and calcium groups, respectively. There was no difference between the groups regarding time to early discontinuation (log-rank P=0.15). The follow-up time was similar for the sevelamer and calcium groups (mean 20.3±13.9, median 19.6 vs mean 19.6±13.6, median 18.5 months, respectively). Overall, 38% of subjects were treated for 36 months. More subjects randomized to calcium never took study medication, more dropped due to investigator decision (defined in Figure 1), and the discontinuations due to adverse events were mainly related to hypercalcemia. In contrast, more subjects randomized to sevelamer were discontinued due to adverse events that were mainly gastrointestinal. The baseline demographics and renal history among subjects who discontinued early were similar. Of the subjects randomized to calcium, 70% took calcium acetate as PhosLo® tablets and 30% took calcium carbonate as TUMS®. Ninety-four percent remained on calcium acetate and 87% remained on calcium carbonate. The other subjects switched formulations but remained on calcium-based phosphate binders. The mean prescribed daily dose at study completion was 5.3 g for calcium acetate, 4.9 g for calcium carbonate, and 6.9 g for sevelamer. There was no difference between treatment groups with respect to all-cause mortality, the primary end point (Figure 2a). There were 267 deaths in the sevelamer group and 275 deaths in the calcium group. The sevelamer group mortality rate was 15.0 per 100 patient-years and the calcium group mortality rate was 16.1 per 100 patient-years (hazard ratio=0.93, 95% confidence interval (CI): 0.79–1.10; log-rank P=0.40). The Kaplan–Meier curve (Figure 2a) reveals no difference in mortality risk for those patients on study for less than 2 years. However, for those patients remaining on study for at least 2 years (43% of the population), a difference between groups, favoring sevelamer, appears to emerge (time–treatment interaction P=0.02). Of the deaths, 53% were attributable to cardiovascular causes (289 (142 sevelamer and 147 calcium) of 542 total deaths; Figure 2d). Among sevelamer and calcium subjects, the cardiovascular mortality rate was 8.0 per 100 patient-years and 8.6 per 100 patient-years, respectively (hazard ratio=0.93, 95% CI: 0.74–1.17; log-rank P=0.53). There were 47 deaths due to infection in the sevelamer group with a rate of 2.6 per 100 patient-years and 41 deaths due to infection in the calcium group with a rate of 2.4 per 100 patient-years (log-rank P=0.68). There were 78 deaths due to other causes in the sevelamer group, with a rate of 4.4 per 100 patient-years, and 87 deaths due to other causes in the calcium group, with a rate of 5.1 per 100 patient-years (log-rank P=0.33). The adjusted hazard ratios and P-values were not notably different for any analyses presented above. In a pre-specified analysis, a significant interaction between treatment and age (<65 years, ≥65 years) was observed for all-cause mortality (P=0.02), but not with other baseline characteristics (race, sex, diabetes status, cause of kidney disease, and dialysis duration). In subjects ≥65 years of age (44% of the study population), the all-cause mortality rate was 18.2 per 100 patient-years for the sevelamer group and 23.4 per 100 patient-years for the calcium group (hazard ratio=0.77, 95% CI: 0.61–0.96; Figure 2b). In subjects <65 years of age, the all-cause mortality rate was 12.5 per 100 patient-years for the sevelamer group and 10.6 per 100 patient-years for the calcium group; there was no difference between groups (hazard ratio=1.18, 95% CI: 0.91–1.53). No treatment-by age interaction was observed for cardiovascular mortality; however, subgroup results are presented to help better understand the all-cause mortality results. Among older sevelamer- and calcium-treated subjects, the cardiovascular mortality rate was 10.5 per 100 patient-years and 13.3 per 100 patient-years, respectively (hazard ratio=0.78, 95% CI: 0.58–1.05). Among younger sevelamer and calcium subjects, the cardiovascular mortality rate was 6.1 per 100 patient-years and 5.1 per 100 patient-years, respectively (hazard ratio=1.19, 95% CI: 0.82–1.73). The mean number of hospitalizations/patient-year was 2.1 (median 1.0) for the sevelamer-treated patients and 2.3 (median 1.3) for the calcium-treated patients (P=0.0738). In patients ≥65 years old, the mean number of hospitalizations/patient-year was 2.1 (median 1.3) for the sevelamer-treated patients and 2.9 (median 1.6) for the calcium-treated patients. In patients <65 years old, the mean number of hospitalizations/patient-year was 2.1 (median 0.9) for the sevelamer-treated patients and 1.8 (median 0.9) for the calcium-treated patients. The mean hospital days/patient-year was 14.8 (median 5.0) for the sevelamer-treated patients and 17.4 (median 5.8) for the calcium-treated patients (P=0.0897). In patients ≥65 years old, the mean hospital days/patient-year was 16.6 (median 6.9) for the sevelamer-treated patients and 21.8 (median 7.9) for the calcium-treated patients. In patients ≤65 years old, the mean hospital days/patient-year was 13.4 (median 3.4) for the sevelamer-treated patients and 13.8 (median 4.0) for the calcium-treated patients. Table 3 displays the time-weighted average levels of post-baseline serum phosphorus, calcium, calcium–phosphorus product, intact parathormone, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, and Kt/V obtained from each dialysis provider's central laboratory. Laboratory values were consistent with what is typically seen in US hemodialysis patients. The data demonstrate a higher serum calcium and lower intact parathormone level in the calcium subjects, and a lower total and LDL cholesterol in the sevelamer subjects. The laboratory values were also examined by age. Older subjects tended to have lower phosphorus values than the younger subjects (in subjects <65 years, sevelamer 1.97±0.42 and calcium 1.94±0.45 mmol/l (6.1±1.3 and 6.0±1.4 mg/dl); in subjects ≥65 years, sevelamer 1.78±0.39 and calcium 1.68±0.36 mmol/l (5.5±1.2 and 5.2±1.1 mg/dl)).Table 3Time-weighted average of post-baseline assessments for serum phosphorus, calcium, calcium–phosphorus product, intact parathormone, total cholesterol , LDL-, HDL-cholesterol, and Kt/VSevelamerCalciumNTime weighted mean±s.d.NTime weighted mean±s.d.P-value*Wilcoxon rank sum test.Phosphorus (mmol/l)8431.87±0.428431.84±0.42<0.01Calcium (mmol/l)8352.30±0.188372.38±0.18<0.0001Calcium × phosphorus product (mmol2/l2)8354.33±0.988334.33±1.040.60Intact parathormoneaPresented as median (interquartile range). (pg/ml)774278 (200, 476)768226 (142, 387)<0.0001Total cholesterol (mmol/l)5263.77±0.875294.16±0.90<0.0001LDL cholesterol (mmol/l)1971.78±0.672022.20±0.80<0.0001HDL cholesterol (mmol/l)2471.17±0.392481.15±0.410.62Kt/V8231.6±0.38271.6±0.30.11HDL, high-density lipoprotein; LDL, low-density lipoprotein.To convert values for phosphorus to mg/dl, divide by 0.3229. To convert values for calcium to mg/dl, divide by 0.25. To convert values for calcium × phosphorus product to mg2/dl2 divide by 0.0807. To convert values for cholesterol to mg/dl, divide by 0.02586.a Presented as median (interquartile range).* Wilcoxon rank sum test. Open table in a new tab HDL, high-density lipoprotein; LDL, low-density lipoprotein. To convert values for phosphorus to mg/dl, divide by 0.3229. To convert values for calcium to mg/dl, divide by 0.25. To convert values for calcium × phosphorus product to mg2/dl2 divide by 0.0807. To convert values for cholesterol to mg/dl, divide by 0.02586. There were eight subjects with a total of 11 possibly drug-related serious adverse events in the study. Eight related serious adverse events occurred in five subjects in the calcium group (calciphylaxis (three subjects); hypercalcemia, nausea, and vomiting (one subject); and cholecystitis and acute pancreatitis (one subject)), and three related serious adverse events occurred in three subjects in the sevelamer group (constipation (one subject), vomiting (one subject), and osteoporosis (one subject)). The sevelamer subject diagnosed with osteoporosis was a 72-year-old woman who had been treated intermittently for asthma with both oral and inhaled steroids and was diagnosed with osteoporosis during the trial. Elevations of serum phosphorus and serum calcium in dialysis patients are independently associated with increased risk of arterial calcification2.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2436) Google Scholar, 3.Kimura K. Saika Y. Otani H. et al.Factors associated with calcification of the abdominal aorta in hemodialysis patients.Kidney Int. 1999; 56: S238-S241Abstract Full Text Full Text PDF PubMed Google Scholar, 4.Chertow G.M. Raggi P. Chasan-Taber S. et al.Determinants of progressive vascular calcification in haemodialysis patients.Nephrol Dial Transplant. 2004; 19: 1489-1496Crossref PubMed Scopus (245) Google Scholar, 5.Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (995) Google Scholar and death.6.Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2110) Google Scholar, 7.Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2207) Google Scholar, 8.Stevens L.A. Djurdjev O. Cardew S. et al.Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: evidence for the complexity of the association between mineral metabolism and outcomes.J Am Soc Nephrol. 2004; 15: 770-779Crossref PubMed Scopus (314) Google Scholar, 9.Teng M. Wolf M. Lowrie E. et al.Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy.N Engl J Med. 2003; 349: 446-456Crossref PubMed Scopus (898) Google Scholar, 10.Young E.W. Albert J.M. Satayathum S. et al.Predictors and consequences of altered mineral metabolism: the dialysis outcomes and practice patterns study.Kidney Int. 2005; 67: 1179-1187Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar The dose of calcium-based phosphate binders has been linked with the severity of arterial calcification,2.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2436) Google Scholar,12.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1509) Google Scholar necessitating that limitations be placed on the use of these agents.21.National Kidney Foundation (NKF)K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S201PubMed Google Scholar,22.National Kidney Foundation (NKF)K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients.Am J Kidney Dis. 2005; 45: S1-S153Google Scholar Sevelamer has been shown to lead to less calcification progression than calcium-based binders.16.Chertow G.M. Burke S.K. Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Abstract Full Text Full Text PDF PubMed Scopus (1327) Google Scholar, 17.Chertow G.M. Raggi P. McCarthy J.T. et al.The effects of sevelamer and calcium acetate on proxies of atherosclerotic and arteriosclerotic vascular disease in hemodialysis patients.Am J Nephrol. 2003; 23: 307-314Crossref PubMed Scopus (102) Google Scholar, 18.Asmus H.G. Braun J. Krause R. et al.Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density.Nephrol Dial Transplant. 2005; 20: 1653-1661Crossref PubMed Scopus (157) Google Scholar, 19.Braun J. Asmus H.G. Holzer H. et al.Long-term comparison of a calcium-free phosphate binder and calcium carbonate-phosphorus metabolism and cardiovascular calcification.Clin Nephrol. 2004; 62: 104-115Crossref PubMed Google Scholar In subjects new to dialysis, calcium-based binders have recently been shown to be associated with higher all-cause mortality rate compared to sevelamer.20.Block G.A. Raggi P. Bellasi A. et al.Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Abstract Full Text Full Text PDF PubMed Scopus (672) This study was conducted to determine whether these treatments differ with regards to clinical outcomes, and represents the largest prospective randomized clinical trial conducted among a prevalent dialysis population. In this study, all-cause mortality was not significantly different in the overall population. However, the results suggest that sevelamer was associated with a lower mortality rate than calcium in older subjects (sevelamer: 18.2 per 100 patient-years; calcium: 23.4 per 100 patient-years; P=0.02). Among younger subjects, sevelamer was associated with a higher mortality rate than calcium, though these rates were substantially lower than those for older subjects, and the difference was not statistically significant (sevelamer: 12.5 per 100 patient-years; calcium: 10.6 per 100 patient-years; P=0.21). The findings in older subjects are consistent with earlier literature documenting that older hemodialysis patients tend to have greater calcification burden than younger patients. Therefore, it may be that a calcium effect on mortality could occur over a shorter follow-up time in older as compared with younger patients.2.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2436) Google Scholar, 3.Kimura K. Saika Y. Otani H. et al.Factors associated with calcification of the abdominal aorta in hemodialysis patients.Kidney Int. 1999; 56: S238-S241Abstract Full Text Full Text PDF PubMed Google Scholar, 5.Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (995) Google Scholar, 11.Guerin A.P. London G.M. Marchais S.J. et al.Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplant. 2000; 15: 1014-1021Crossref PubMed Scopus (889) Google Scholar, 12.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1509) Google Scholar, 13.Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Scopus (1234) Google Scholar Furthermore, progression of calcification is greater among those patients with higher levels of arterial calcification at baseline.16.Chertow G.M. Burke S.K. Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Abstract Full Text Full Text PDF PubMed Scopus (1327) Google Scholar Although not statistically significant, the potential benefit in younger subjects treated with calcium-based binders deserves further investigation. Cardiovascular mortality was not found to be different between the treatment groups. The study, however, was not powered to detect differences in cardiovascular or other specific causes of death. There was a trend for less hospitalization burden in the
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