Treatment of hyperphosphatemia with sevelamer hydrochloride in dialysis patients: effects on vascular calcification, bone and a close look into the survival data
2008; Elsevier BV; Volume: 74; Linguagem: Inglês
10.1038/ki.2008.544
ISSN1523-1755
Autores Tópico(s)Pharmacological Effects and Toxicity Studies
ResumoIn chronic kidney disease patients, bone and mineral abnormalities have a major impact on morbidity and mortality. Hyperphosphatemia has been associated with increased mortality and with the development of cardiovascular calcification, an independent predictor of mortality. Vascular calcifications have been associated with low bone turnover, low bone volume and lower activation frequency. In dialysis patients, the treatment of hyperphospathemia with calcium based compounds, when compared with sevelamer, is associated with more frequent episodes of hypercalcemia, suppression of intact parathyroid hormone and with progression of coronary calcifications. In the presence of adynamic bone disease, calcium load has a significantly higher impact on aortic calcifications and stiffening. A randomized, prospective, open label study, evaluated patients with bone biopsies at the beginning and after 1 year treatment period with sevelamer hydrochloride or calcium carbonate. Sevelamer treatment resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation rate increased and trabecular architecture improved only with sevelamer. In incident dialysis patients, treatment with sevelamer has been associated with better survival, while in prevalent patients a clear benefit could only be demonstrated in older patients and in patients treated for more than 2 years. In conclusion, the treatment of hyperphosphatemia with sevelamer hydrochloride, a non-calcium and non-metal containing phosphate binder, is associated with a beneficial effect on vascular calcification progression, bone disease and most likely with a survival benefit in some hemodialysis patients populations. In chronic kidney disease patients, bone and mineral abnormalities have a major impact on morbidity and mortality. Hyperphosphatemia has been associated with increased mortality and with the development of cardiovascular calcification, an independent predictor of mortality. Vascular calcifications have been associated with low bone turnover, low bone volume and lower activation frequency. In dialysis patients, the treatment of hyperphospathemia with calcium based compounds, when compared with sevelamer, is associated with more frequent episodes of hypercalcemia, suppression of intact parathyroid hormone and with progression of coronary calcifications. In the presence of adynamic bone disease, calcium load has a significantly higher impact on aortic calcifications and stiffening. A randomized, prospective, open label study, evaluated patients with bone biopsies at the beginning and after 1 year treatment period with sevelamer hydrochloride or calcium carbonate. Sevelamer treatment resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation rate increased and trabecular architecture improved only with sevelamer. In incident dialysis patients, treatment with sevelamer has been associated with better survival, while in prevalent patients a clear benefit could only be demonstrated in older patients and in patients treated for more than 2 years. In conclusion, the treatment of hyperphosphatemia with sevelamer hydrochloride, a non-calcium and non-metal containing phosphate binder, is associated with a beneficial effect on vascular calcification progression, bone disease and most likely with a survival benefit in some hemodialysis patients populations. The last few years have seen major developments in the management of bone and mineral disorders associated with chronic kidney disease (CKD). Acknowledgment of the fact that these bone and mineral abnormalities in CKD patients have a major impact on morbidity and mortality drove nephrologists' attention to the importance of controlling these alterations. In addition, new compounds have been developed for the control of hyperphosphatemia and for the treatment of secondary hyperparathyroidism, raising many questions toward the use of non-calcium-containing phosphate binders. Until recently, the only phosphate binders available were aluminum or calcium-based compounds. These compounds were efficacious but were also associated with significant side effects. The use of aluminum-containing phosphate binders is associated with bone disease as well as hematologic and central nervous system toxicity, whereas the use of calcium-containing phosphate binders is associated with increased risk of hypercalcemia and cardiovascular calcification.1.Guerin A. London G. Marchais S. et al.Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplant. 2000; 15: 1014-1021Crossref PubMed Scopus (889) Google Scholar,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.London G.M. Guérin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1509) Google Scholar,4.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group. 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 It is now known that serum calcium levels are not accurate in predicting the calcium balance and burden. The excessive amount of calcium ingested from diet and calcium-containing binders has been associated with cardiovascular calcifications, even in the presence of normal calcium serum levels.1.Guerin A. London G. Marchais S. et al.Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplant. 2000; 15: 1014-1021Crossref PubMed Scopus (889) Google Scholar,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.London G.M. Guérin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1509) Google Scholar,4.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group. 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 The non-calcium, non-metal-containing, and non-absorbed phosphate binder, sevelamer hydrochloride, has provided an effective way to bind phosphorus in the gut without the risks of hypercalcemia, soft tissue or vascular calcifications, or heavy metal accumulation. In recent years, it has become clear that the presence of elevated serum phosphorus levels in CKD stage 5 patients is positively associated with increased mortality.5.Block G. Hulbert-Shearon T. Levin N. et al.Association of serum phosphorus and calcium x 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,6.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 Hyperphosphatemia and elevated calcium-phosphorus product (Ca X P) are associated with cardiovascular calcification.1.Guerin A. London G. Marchais S. et al.Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplant. 2000; 15: 1014-1021Crossref PubMed Scopus (889) Google Scholar,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 Cardiovascular calcification is an independent predictor of mortality. Several authors have now reported a strong positive association between the presence and extent of vascular calcification and both cardiovascular and all-cause mortality.3.London G.M. Guérin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1509) Google Scholar,7.Blacher J. Guérin 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,8.Adragão T. Pires A. Lucas C. et al.A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients.Nephrol Dial Transplant. 2004; 19: 1480-1488Crossref PubMed Scopus (258) Google Scholar Raggi et al.9.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 reported that previous myocardial infarction, angina, and known coronary artery disease were all more common in CKD stage 5 patients with extensive calcification. Most stage 5 CKD patients present with hyperphosphatemia. The clinical outcomes of this mineral abnormality include secondary hyperparathyroidism with consequent renal bone disease, extra-osseous calcification, and increased mortality. Therapeutic strategies to control phosphorus levels include dietary restrictions, dialysis, and the use of phosphate-binding agents. Reduction of phosphate intake in the diet is often difficult and is also limited by the associated protein restriction, as all proteins contain phosphate. Phosphate is also difficult to remove by dialysis. Increased dialysis time or frequency may be effective, but it is often difficult to implement because of logistic problems and poor patient acceptance. Sevelamer hydrochloride has been widely studied and shown to be effective in reducing phosphorus levels and Ca X P without causing hypercalcemia and soft tissue calcification in stage 5 CKD population on hemodialysis, with the added benefit of cholesterol reduction (total and low-density lipoprotein cholesterol). This compound is well tolerated with few side effects, the more frequently reported ones being diarrhea, constipation, dyspepsia, nausea, and vomiting. Chertow et al.4.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group. 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 reported the results of a randomized parallel design clinical trial comparing sevelamer with calcium-based phosphorus binders in 200 hemodialysis patients. Sevelamer and calcium-based compounds provided similar control of serum phosphorus and Ca X P. Adherence to the prescribed dose of binder in the sevelamer and calcium-containing binder groups was similar: 86 vs 80%, respectively. The group treated with sevelamer received an average binder dose of 6.5±2.9 g per day and the group treated with calcium-based binders, 4.3±1.9 g per day (4.6 and 3.9 g per day of calcium acetate or calcium carbonate, respectively). The calcium-based group had more frequent episodes of hypercalcemia when compared with the sevelamer group: 43 and 17%, respectively. Suppression of intact parathyroid hormone secretion below the 150–300 pg/ml range was more common at the end of the study in the calcium-based binders group, 57 vs 30%, despite the protocol-specified reduction or cessation of vitamin D for intact parathyroid hormone below 150 pg/ml. Twelve percent of patients in the calcium group required rescue therapy with aluminum-containing binders for a calcium-phosphorus product above 72 mg2/100ml2, compared with 4% of patients in the sevelamer group. Total and low-density lipoprotein cholesterol decreased significantly in the sevelamer-treated group compared with a non-change in the calcium binders group. It is relevant that, the electron beam computed tomography (EBCT) performed at the beginning of the study detected a prevalence of coronary artery calcification of 83% and aortic calcification of 80% of the study patients. There was significant progression of the coronary artery and aortic calcification EBCT score, at weeks 26 and 52, in the calcium-containing binders-treated group, despite the use of an average dose of calcium-containing binders of only 4.3±1.9 g per day, which corresponds to values of elemental calcium under the Kidney Disease Outcomes Quality Initiative recommendations. There was no significant progression in the sevelamer-treated group. The high prevalence of vascular calcification seen in the dialysis population in the Chertow study4.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group. 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 has been confirmed by other reports and is of major concern because of the positive association between the presence and severity of calcification and mortality in this population. There is also some evidence that most of the patients develop vascular calcifications while on hemodialysis treatment. In fact, a report from Spiegel et al.10.Spiegel D.M. Raggi P. Metha R. et al.Coronary and aortic calcification in patients new to dialysis.Hemodialysis Int. 2004; 8: 265-272Crossref PubMed Scopus (29) Google Scholar revealed that only 34% of patients with advanced CKD starting dialysis had coronary artery calcifications scores that placed them above the 90th percentile for age and sex. In the same patient population initiating dialysis, 109 patients underwent baseline and at least one additional measurement of coronary artery calcification.11.Block G.A. Spiegel D.M. Ehrlich J. et al.Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar At baseline, 37% of the patients who underwent treatment with sevelamer and 31% of the patients who underwent treatment with calcium-based binders had no evidence of calcification. The authors report that no patients with a zero coronary calcium score progressed to a coronary artery calcium score >30, using EBCT, in an 18-month period of time. Patients already having a coronary artery calcium score >30 at baseline progressed during the time of the study in both arms. The patients treated with calcium-based binders showed a more rapid and severe progression when compared with those receiving sevelamer. It can be noted that, during this study, all the patients were maintained on dialysis with a calcium dialysate concentration of 2.5 mEq/l. The authors conclude that patients new to dialysis, with no evidence of coronary calcification, showed little evidence of disease development over a period of 18 months independent of the phosphate binder used. Patients with even little evidence of coronary calcification progress with both binders; however, the group treated with calcium-based binders have a much more severe progression when compared with the patients treated with sevelamer.11.Block G.A. Spiegel D.M. Ehrlich J. et al.Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar Without any doubt, this study confirms the importance of the Kidney Disease Outcomes Quality Initiative clinical practice guidelines for bone metabolism and disease in CKD, recommending that calcium-based binders should be avoided in patients with evidence of severe calcification.12.National Kidney Foundation KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney disease.Am J Kidney Dis. 2003; 42: S1-S201Crossref PubMed Scopus (667) Google Scholar ‘Kidney Disease: Improving Global Outcomes’ has recommended a new classification for CKD mineral and bone disorder that includes for the first time the evaluation of vascular calcifications.13.Moe S. Drueke T. Cunningham J. et al.Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2006; 69: 1945-1953Abstract Full Text Full Text PDF PubMed Scopus (1457) Google Scholar In hemodialysis patients, vascular calcifications may be evaluated by different techniques: EBCT,14.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 multislice computed tomography (MSCT),15.Moe S.M. O'Neill K.D. Fineberg N. et al.Assessment of vascular calcification in ESRD patients using spiral CT.Nephrol Dial Transplant. 2003; 18: 1152-1158Crossref PubMed Scopus (146) Google Scholar ultrasonography,7.Blacher J. Guérin 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 and plain X-ray.3.London G.M. Guérin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1509) Google Scholar,8.Adragão T. Pires A. Lucas C. et al.A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients.Nephrol Dial Transplant. 2004; 19: 1480-1488Crossref PubMed Scopus (258) Google Scholar,16.Belasi A. Ferramosca E. Muntner P. et al.Correlation of simple imaging tests and coronary artery calcium measured by computed tomography in hemodalysis patients.Kidney Int. 2006; 70: 16Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar EBCT and MSCT allow a quantitative measurement and are considered the gold standard for evaluating vascular calcification, but are very expensive. The utilization of plain X-ray for screening vascular calcifications has been suggested by Kidney Disease Outcomes Quality Initiative12.National Kidney Foundation KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney disease.Am J Kidney Dis. 2003; 42: S1-S201Crossref PubMed Scopus (667) Google Scholar and ‘Kidney Disease: Improving Global Outcomes’.13.Moe S. Drueke T. Cunningham J. et al.Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2006; 69: 1945-1953Abstract Full Text Full Text PDF PubMed Scopus (1457) Google Scholar We have developed a vascular calcification score evaluated in plain X-ray of hands and pelvis (Figure 1), which was a predictor of cardiovascular death and cardiovascular morbidity in dialysis patients (Figure 2).8.Adragão T. Pires A. Lucas C. et al.A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients.Nephrol Dial Transplant. 2004; 19: 1480-1488Crossref PubMed Scopus (258) Google Scholar This simple vascular calcification score has been also correlated with valvular calcifications17.Adragao T. Pires A. Lucas C. et al.Vascular and valvular calcifications in dialysis patients: the same pathogenesis?.Port J Nephrol Hypert. 2007; 21: 281-285Google Scholar and with arterial stiffness.18.Adragao T. Pires A. Lucas C. et al.A simple vascular calcification score is a predictor of pulse wave velocity in hemodialysis patients.J Am Soc Nephrol. 2005; 16 (PO638): 473AGoogle ScholarFigure 2Calcification score from plain X-ray of hands and pelvis was a predictor of cardiovascular death and cardiovascular morbidity in dialysis patients. After 3 years of follow-up vascular score ≥3 was associated with higher cardiovascular mortality and morbidity.8.Adragão T. Pires A. Lucas C. et al.A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients.Nephrol Dial Transplant. 2004; 19: 1480-1488Crossref PubMed Scopus (258) Google ScholarView Large Image Figure ViewerDownload Hi-res image Download (PPT) Plain X-ray and ultrasonography are semiquantitative, less expensive, and useful for screening the presence of vascular calcifications. They can be used to identify patients at higher risk of a cardiovascular event. EBCT and MSCT are useful for evaluating the progression of vascular calcification and the effect of different treatments on progression of vascular calcification. These two techniques do not differentiate intimal from medial calcification, and the explanation for the very high scores evaluated in dialysis patients is the presence of both types of calcification. In a randomized prospective, open label study, 119 hemodialysis patients were evaluated with bone biopsies performed at the beginning and after a 1-year treatment period, to compare the effects of sevelamer hydrochloride and calcium carbonate on bone.19.Ferreira A. Frazão J.M. Monier-Faugere M.C. et al.Effects of sevelamer hydrochloride and calcium carbonate on renal osteodystrophy in hemodialysis patients.J Am Soc Nephrol. 2008; 19: 405-412Crossref PubMed Scopus (143) Google Scholar Biopsy-proven adynamic bone disease was the most frequent bone abnormality at baseline (59%). The serum phosphorus levels were similarly controlled in both groups, although the serum calcium level was consistently lower and intact parathyroid hormone higher in patients treated with sevelamer. Compared with baseline values, there were no changes in mineralization lag time or measures of bone turnover after 1 year of treatment with both sevelamer and calcium carbonate. Bone formation rate per bone surface increased significantly from baseline only in the sevelamer-treated patients. In addition, of those with abnormal microarchitecture at baseline (that is, trabecular separation), 7 of 10 in the sevelamer group normalized after 1 year compared with 0 of 3 in the calcium group. In summary, this study showed that sevelamer treatment resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation rate increased and trabecular architecture improved only with sevelamer. In a group of 42 hemodialysis patients submitted to bone biopsies,20.Adragao T. Ferreira A. Frazão J.M. et al.Vascular Calcifications and bone turnover in hemodialysis patients.Nephrol Dial Transp. 2006; 21 (MO014): iv 292Google Scholar we have verified that low bone volume was associated with vascular calcifications evaluated by MSCT or by plain X-ray and with higher pulse wave velocity. Adynamic bone disease was present in 50% of patients. There were no cases of osteomalacia and no aluminum deposits in bone. London et al.21.London G.M. Marty C. Marchais S.J. et al.Arterial calcifications and bone histomorphometry in end-stage renal disease.J Am Soc Nephrol. 2004; 15: 1943-1951Crossref PubMed Scopus (519) Google Scholar showed the existence of an association between vascular calcifications and low bone turnover. In this study, 58 hemodialysis patients were evaluated; 23 patients had been submitted to parathyroidectomy and 33 patients had aluminum deposits in bone. Vascular calcifications were evaluated by ultrasonography. More calcifications were associated with lower osteoblast surface and with other markers of low bone turnover, with lower parathyroid hormone levels and with higher calcium dose. Asci et al.22.Asci G. Ozkahya M. Duman S. et al.The link between cardiovascular and bone disease in hemodialysis patients.Nephrol Dial Transp. 2007; 22 (MO014): vi 217Google Scholar showed, in a group of 224 patients, that vascular calcifications evaluated by MSCT were associated with lower activation frequency evaluated in bone biopsies. A recent study was performed to assess the impact of bone activity on the relationships between the dosage of calcium-containing binders and aortic stiffness or abdominal aorta calcification score.23.London G.M. Marchais S.J. Gérin A.P. et al.Association of bone activity, calcium load, aortic sitfness, and calcifications in ESRD.J Am Soc Nephrol. 2008; 19: 1827-1835Crossref PubMed Scopus (230) Google Scholar A significant interaction was found between the dosage of calcium-containing phosphate binders and bone activity such that the calcium load had a significantly higher impact on aortic calcifications and stiffening in the presence of adynamic bone disease. The data presented suggest that sevelamer treatment has a beneficial effect on bone, with an increase in the bone formation rate and an improvement in the trabecular architecture. There is an association between vascular calcifications and low bone volume and with low bone turnover in dialysis patients. Finally, in dialysis patients with adynamic bone, calcium load has a greater influence on aortic calcifications and stiffening. Patients whose bone is not able to retain calcium or phosphorus have higher vascular calcification scores. One added risk factor for the development of vascular calcifications in the setting of low bone turnover is the administration of calcium-containing phosphate binders. The promise of a survival benefit with the use of sevelamer hydrochloride has been evaluated in two randomized prospective, controlled studies with interesting results that generate some controversy and certainly have not completely solved the issue. The first was the ‘Dialysis Clinical Outcomes Revisited (DCOR)’ study.24.Suki W.N. Zabaneh R. Cangiano J.L. et al.Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.Kidney Int. 2007; 72: 1130-1137Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar This 3-year trial involving more than 2100 patients compared the difference in mortality and morbidity outcomes for patients receiving sevelamer hydrochloride and those receiving calcium-containing phosphate binders. This was the largest outcomes study ever conducted in the hemodialysis population. This study showed that the patients treated with sevelamer hydrochloride experienced a reduction of 7% in the risk of death from all causes when compared with the patients treated with calcium-based phosphate binders, which was statistically not significant (P=0.3). The patients aged 65 years or more (a predefined analysis) were 23% less likely to die when treated with sevelamer hydrochloride, as compared with treatment with calcium-based binders. In addition, patients treated with sevelamer hydrochloride for more than 2 years had a 34% reduction of the mortality risk for all causes compared with those treated with the calcium-containing binders. The second study was the ‘Renagel in New to Dialysis Patients.’25.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) Google Scholar This was a randomized controlled, prospective, open label study with 127 patients incident to dialysis, assigned to 18 months treatment with sevelamer hydrochloride or calcium-containing phosphate binders, to assess coronary artery calcification progression. Mortality was a predetermined secondary end point.25.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) Google Scholar Twenty-three deaths in the calcium-containing phosphate binders group and 11 deaths in the sevelamer hydrochloride-assigned patients occurred during the median 44 months of follow-up time after randomization, a significantly lower mortality for patients treated with sevelamer hydrochloride. The survival benefit observed with sevelamer hydrochloride treatment persisted after full multivariate adjustment. It is very important to analyze the reasons for the differences observed in the outcomes of these two trials. The DCOR trial evaluated prevalent patients probably with a more important burden of calcification, whereas ‘Renagel in New to Dialysis Patients’ trial was performed in patients new to dialysis. It is probably very difficult to reverse already existing vascular calcifications. The DCOR trial has been criticized for the short follow-up time of less than 2 years. The median follow-up was shorter in the DCOR trial compared with the ‘Renagel in New to Dialysis Patients’ trial, 19 vs 44 months, respectively. The short follow-up time in the DCOR trial did not allow the differences in mortality to appear. In fact, for the patients followed for more than 2 years, the difference in mortality became significant. In the DCOR trial, the number of previewed cardiovascular events necessary to demonstrate a difference between the two treatment groups was not reached. The annual mortality rate in the DCOR trial was inferior to the annual mortality rate reported in United States Renal Data System.26.U.S. Renal Data System USRDS 2005 Annual Data Report National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2005Google Scholar The results of these two studies strongly suggest that the use of sevelamer as a phosphate binder decreases mortality in incident and in elderly hemodialysis patients and reinforces the importance of earlier initiation of treatment with sevelamer hydrochloride in hemodialysis patients. A final comment is on the systematic review of the clinical efficacy and safety of sevelamer hydrochloride in dialysis patients published by Tonelli et al.27.Tonelli M. Wiebe N. Culleton B. et al.Systematic review of the clinical efficacy and safety of sevelamer in dialysis patients.Nephrol Dial Transplant. 2007; 22: 2856-2866Crossref PubMed Scopus (88) Google Scholar In the mortality analysis, the authors included five studies (Table 1), with only one of them having mortality as the primary end point.25.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) Google Scholar The other three studies included (Table 1) in the mortality analysis involved a small number of patients, had a short follow-up, and mortality was not an end point. These studies4.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group. 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,28.Sadek T. Mazouz H. Bahloul H. et al.Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study.Nephrol Dial Transplant. 2003; 18: 582-589Crossref PubMed Scopus (81) Google Scholar,29.Shaheen F.A. Akeel N.M. Badawi L.S. et al.Efficacy and safety of sevelamer. Comparison with calcium carbonate in the treatment of hyperphosphatemia in hemodialysis patients.Saudi Med J. 2004; 25: 785-791PubMed Google Scholar were not powered in terms of follow-up time, number of patients, and end points to evaluate mortality. In our view, it is impossible to withdraw any mortality information in studies with 42 patients and a 5-month follow-up, or a crossover study with 20 patients and a total follow-up of 18 weeks. The Chertow study's4.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group. 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 primary end point was vascular calcification; mortality was not even an end point and received 24% weight in the analysis. Regarding the ‘Renagel in New to Dialysis Patients’ study, with a long follow-up for the secondary end point mortality and evidence of survival benefit in the sevelamer-treated group, the weight attributed was only 4.26%.Table 1Summary of the studies used for mortality analysisAuthorNumber of patientsFollow-upPrimary end pointsBlock et al.25.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) Google Scholar12718 months for the primary end point (calcifications) and 44 months for the secondary end point (mortality)Progression of calcificationsChertow et al.4.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group. 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 Scholar20052 weeksProgression of calcificationsSadek et al.28.Sadek T. Mazouz H. Bahloul H. et al.Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study.Nephrol Dial Transplant. 2003; 18: 582-589Crossref PubMed Scopus (81) Google Scholar425 monthsBiochemical parametersShaheen et al.29.Shaheen F.A. Akeel N.M. Badawi L.S. et al.Efficacy and safety of sevelamer. Comparison with calcium carbonate in the treatment of hyperphosphatemia in hemodialysis patients.Saudi Med J. 2004; 25: 785-791PubMed Google Scholar20Crossover study 18 weeksBiochemical parametersSuki et al.24.Suki W.N. Zabaneh R. Cangiano J.L. et al.Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.Kidney Int. 2007; 72: 1130-1137Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar210322 monthsMortality Open table in a new tab In our opinion, the available data on mortality benefit with sevelamer hydrochloride treatment from two randomized prospective controlled trials constitute a very positive fact that is certainly innovative in the nephrology field. We are not aware of any other pharmacological intervention in dialysis patients with such ground in terms of hard outcome data. In a recent editorial,30.Farkouh M.E. Fuster V. Meta-analysis of small trials: proceed with caution.Nat Clin Pract nephrol. 2008; 4: 115Crossref PubMed Scopus (11) Google Scholar the authors state that ‘to cultivate a balanced approach to understanding results generated by meta-analysis of data from small trials it is important to accept the limitations implicit in this method.’ Meta-analysis only generates hypotheses and certainly should be carefully interpreted. One should always keep in mind that well-designed, randomized controlled trials are the strong bases for evidence-based medicine. There is mounting evidence from basic science,31.Giachelli C.M. Vascular calcification mechanisms.J Am Soc Nephrol. 2004; 15: 2959-2961Crossref PubMed Scopus (453) Google Scholar observational studies,32.Kalantar-Zadeh K. Kuwae N. Regidor D.L. et al.Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.Kidney Int. 2006; 70: 771-780Abstract Full Text Full Text PDF PubMed Scopus (798) Google Scholar and randomized trials with surrogate end points such as cardiovascular calcification4.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group. 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,11.Block G.A. Spiegel D.M. Ehrlich J. et al.Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar and mortality25.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) Google Scholar that calcium can be toxic for dialysis patients. With this level of information, the nephrology community should be asking what level of scientific evidence is needed to convince us to discontinue, or at least to be extremely cautious with the use of calcium-containing phosphate binders, a potentially harmful therapy. João M Frazão has received consulting and lecture fees from Amgen and Genzyme. Teresa Adragão has declared no financial interests.
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