- Email: [email protected]
In Reply to ‘Progression of Calcification in the Calcium Acetate Renagel Evaluation-2 (CARE-2) Study’
Correspondence
1023
In summary, although we believe that additional studies are needed, results of our study, along with conclusions by several editorials that questioned the purported benefits of sevelamer,8,9 will undoubtedly be considered in future clinical practice guidelines. Wajeh Qunibi, MD University of Texas Health Sciences Center San Antonio, Texas Larry R. Muenz, PhD Larry R. Muenz & Associates Gaithersburg, Maryland
ACKNOWLEDGEMENTS Financial Disclosure: Dr Qunibi is a consultant and speaker for Fresenius Medical Care Advisory Board and is on the speaker’s bureau. Dr Muenz is a paid consultant to Fresenius Medical Care.
REFERENCES 1. Kestenbaum B: Calcification in CKD: No closer to the cure. Am J Kidney Dis 51:877-879, 2008 2. 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 51:952-965, 2008 3. Chertow GM, Burke SK, Raggi P: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 62:245-252, 2002 4. Block GA, Spiegel DM, Ehrlich J, et al: Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 68:1815-1824, 2005 5. Russo D, Miranda I, Ruocco C, et al: The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer. Kidney Int 72:1255-1261, 2007 6. Wanner C, Krane V, Marz W, et al: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 353:238-248, 2005 7. St Peter WL, Liu J, Weinhandl E, et al: Comparison of sevelamer and calcium-based phosphate binders on mortality, hospitalization, and morbidity in hemodialysis: A secondary analysis of the Dialysis Clinical Outcomes Revisited (DCOR) randomized trial using claims data. Am J Kidney Dis 51:445-454, 2008 8. Winkelmayer WC, Tonelli M: Phosphate binder choice in dialysis patients: A call for evidence-based rather than marketing-based clinical practice. Am J Kidney Dis 51:362365, 2008 9. Tonelli M, Wiebe N, Culleton B, et al: Systematic review of the clinical efficacy and safety of sevelamer in dialysis patients. Nephrol Dial Transplant 22:2856-2866, 2007 © 2008 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2008.07.043
IN REPLY TO TO ‘PROGRESSION OF CALCIFICATION IN THE CALCIUM ACETATE RENAGEL EVALUATION-2 (CARE-2) STUDY’ I thank Drs Qunibi and Muenz1 for their letter. I reiterate 2 important points from the editorial to Calcium Acetate Renagel Evaluation-2 (CARE-2) that are relevant to interpreting the findings from this study. Great care must be taken when interpreting results from trials that evaluate noninferiority. It is mathematically impossible to prove that 2 treatments are identical. The goal of a noninferiority trial is to show that 2 treatments differ by no more than some prespecified margin. However, this concept is complicated because errors typically found in clinical studies (dropout, noncompliance, and measurement error) and conventional analytic approaches (intention to treat) will also cause treatments to appear similar. Clinical trials are conducted in an environment that naturally favors equality between treatment groups because a statistical difference under such conditions represents credible evidence of a true treatment effect. In contrast, there is no clear interpretation of finding no statistical difference between treatment groups under conditions that promote equality; such a finding could represent true equivalence or reflect the study limitations. In CARE-2, calcium acetate and sevelamer had similar effects on progression of coronary calcification under conditions of a small sample size, considerable participant dropout, potential nonadherence, and misclassification of the outcome variable. It is difficult to dissect whether the observed similarity between calcium acetate and sevelamer in CARE-2 reflects true equivalence or 1 or more of these important study limitations. Although previous studies also had some limitations, these studies did not try to explain a statistically insignificant difference as evidence for noninferiority. CARE-2 used a statin to balance low-density lipoprotein cholesterol levels between the calcium-acetate and sevelamer groups. Although it may be tempting to account for diverse medication effects in a clinical trial, such practice confuses the primary comparison of interest and may introduce new biases. Consider a hypothetical trial comparing metformin with sulfonylureas for cardiovascular disease prevention. In addition to effects on glucose metabolism, metformin may also cause modest weight loss. Adding a second weight-loss medication to maintain equal weights between treatment groups would introduce another complex medication into the study, with differences in timing and dosage between treatment groups. Although most participants in CARE-2 eventually received a statin, differences in the timing and dosage of statins, which have diverse actions beyond lowering cholesterol levels, obscures the comparison of interest. For this reason, it is not unfortunate that previous trials allowed for differences in low-density lipoprotein cholesterol levels between sevelamer- and calciumtreated patients. These studies adhered to the accepted conduct of randomized clinical trials. Current evidence does not provide a clear choice for selection of a phosphate binder in dialysis patients. There is scant trial evidence for a clinical benefit of any phosphate binder in this setting. Instead, phosphate binders are pre-
1024
Correspondence
scribed based on scientific understanding of calciumphosphate metabolism, associations of phosphate levels with adverse outcomes, and, unfortunately, the marketing practices of companies that manufacture these products. In my view, limitations in the design and conduct of CARE-2 prevent meaningful changes to our current understanding of this common clinical problem. Bryan R. Kestenbaum, MD, MS University of Washington Seattle, Washington
ACKNOWLEDGEMENTS
between diabetics and non-diabetics: The respective importance of glycemic and phosphorus control. Kidney Blood Press Res 31:10-15, 2007 2. 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 51:952-965, 2008 © 2008 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2008.06.034
Financial Disclosure: Dr Kestenbaum has received grant support from Amgen.
REFERENCE
BINDER WARS
1. Qunibi W, Muenz LR: Progression of calcification in the Calcium Acetate Renagel Evaluation-2 (CARE-2) Study. Am J Kidney Dis 52:1022-1023, 2008 (ltr)
To the Editor: Qunibi et al1 report that a combination of atorvastatin and calcium acetate in hemodialysis patients achieves similar progression of coronary artery calcification (CAC) compared with sevelamer-treated patients. My concern is that the use of atorvastatin in patients with diabetes receiving hemodialysis was associated with doubling of the relative risk of fatal stroke (while not changing the effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke).2 In these days of escalating drug copays and increasing pill burdens, how can one justify using a combination therapy that possibly increases the risk of fatal stroke when similar CAC results can be achieved with 1 medication that has been associated with a significant survival benefit compared with the use of calcium-containing phosphate binders?3
© 2008 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2008.08.014
HYPERPHOSPHATEMIA IN THE CALCIUM ACETATE RENAGEL EVALUATION-2 (CARE-2) STUDY To the Editor: Hyperphosphatemia has been associated with progression of vascular calcification.1 In the recent Calcium Acetate Renagel Evaluation-2 (CARE-2) Study,2 serum phosphate control appeared better in the calcium-acetate group than the sevelamer group (see Fig 6A of2). Unfortunately, the statistical test for serum phosphorus values compared serum phosphorus values at only the beginning and end of the trial. It would be beneficial if the investigators could provide timeaveraged serum phosphorus values for the first 6 months of the trial (at the time of first measurement of vascular calcification) and also for the 12 months of the trial with the appropriate statistical comparison. Differences in phosphorus control could affect the rates of vascular calcification. Anthony J. Bleyer, MD, MS Wake Forest University School of Medicine Winston-Salem, North Carolina
ACKNOWLEDGEMENTS Financial Disclosure: Dr Bleyer has participated in clinical trials and has received speaking honoraria from Genzyme.
REFERENCES 1. Ishimura E, Okuno S, Taniwaka H, et al: Different risk factors for vascular calcification in end-stage renal disease
David G. Martinez, MD United Health Services Hospitals Binghamton, New York
ACKNOWLEDGEMENTS Financial Disclosure: None.
REFERENCES 1. 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 51:952-965, 2008 2. Wanner C: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 353:18581860, 2005 3. Block GA: Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 71:438-441, 2007 © 2008 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2008.07.042
1023
In summary, although we believe that additional studies are needed, results of our study, along with conclusions by several editorials that questioned the purported benefits of sevelamer,8,9 will undoubtedly be considered in future clinical practice guidelines. Wajeh Qunibi, MD University of Texas Health Sciences Center San Antonio, Texas Larry R. Muenz, PhD Larry R. Muenz & Associates Gaithersburg, Maryland
ACKNOWLEDGEMENTS Financial Disclosure: Dr Qunibi is a consultant and speaker for Fresenius Medical Care Advisory Board and is on the speaker’s bureau. Dr Muenz is a paid consultant to Fresenius Medical Care.
REFERENCES 1. Kestenbaum B: Calcification in CKD: No closer to the cure. Am J Kidney Dis 51:877-879, 2008 2. 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 51:952-965, 2008 3. Chertow GM, Burke SK, Raggi P: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 62:245-252, 2002 4. Block GA, Spiegel DM, Ehrlich J, et al: Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 68:1815-1824, 2005 5. Russo D, Miranda I, Ruocco C, et al: The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer. Kidney Int 72:1255-1261, 2007 6. Wanner C, Krane V, Marz W, et al: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 353:238-248, 2005 7. St Peter WL, Liu J, Weinhandl E, et al: Comparison of sevelamer and calcium-based phosphate binders on mortality, hospitalization, and morbidity in hemodialysis: A secondary analysis of the Dialysis Clinical Outcomes Revisited (DCOR) randomized trial using claims data. Am J Kidney Dis 51:445-454, 2008 8. Winkelmayer WC, Tonelli M: Phosphate binder choice in dialysis patients: A call for evidence-based rather than marketing-based clinical practice. Am J Kidney Dis 51:362365, 2008 9. Tonelli M, Wiebe N, Culleton B, et al: Systematic review of the clinical efficacy and safety of sevelamer in dialysis patients. Nephrol Dial Transplant 22:2856-2866, 2007 © 2008 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2008.07.043
IN REPLY TO TO ‘PROGRESSION OF CALCIFICATION IN THE CALCIUM ACETATE RENAGEL EVALUATION-2 (CARE-2) STUDY’ I thank Drs Qunibi and Muenz1 for their letter. I reiterate 2 important points from the editorial to Calcium Acetate Renagel Evaluation-2 (CARE-2) that are relevant to interpreting the findings from this study. Great care must be taken when interpreting results from trials that evaluate noninferiority. It is mathematically impossible to prove that 2 treatments are identical. The goal of a noninferiority trial is to show that 2 treatments differ by no more than some prespecified margin. However, this concept is complicated because errors typically found in clinical studies (dropout, noncompliance, and measurement error) and conventional analytic approaches (intention to treat) will also cause treatments to appear similar. Clinical trials are conducted in an environment that naturally favors equality between treatment groups because a statistical difference under such conditions represents credible evidence of a true treatment effect. In contrast, there is no clear interpretation of finding no statistical difference between treatment groups under conditions that promote equality; such a finding could represent true equivalence or reflect the study limitations. In CARE-2, calcium acetate and sevelamer had similar effects on progression of coronary calcification under conditions of a small sample size, considerable participant dropout, potential nonadherence, and misclassification of the outcome variable. It is difficult to dissect whether the observed similarity between calcium acetate and sevelamer in CARE-2 reflects true equivalence or 1 or more of these important study limitations. Although previous studies also had some limitations, these studies did not try to explain a statistically insignificant difference as evidence for noninferiority. CARE-2 used a statin to balance low-density lipoprotein cholesterol levels between the calcium-acetate and sevelamer groups. Although it may be tempting to account for diverse medication effects in a clinical trial, such practice confuses the primary comparison of interest and may introduce new biases. Consider a hypothetical trial comparing metformin with sulfonylureas for cardiovascular disease prevention. In addition to effects on glucose metabolism, metformin may also cause modest weight loss. Adding a second weight-loss medication to maintain equal weights between treatment groups would introduce another complex medication into the study, with differences in timing and dosage between treatment groups. Although most participants in CARE-2 eventually received a statin, differences in the timing and dosage of statins, which have diverse actions beyond lowering cholesterol levels, obscures the comparison of interest. For this reason, it is not unfortunate that previous trials allowed for differences in low-density lipoprotein cholesterol levels between sevelamer- and calciumtreated patients. These studies adhered to the accepted conduct of randomized clinical trials. Current evidence does not provide a clear choice for selection of a phosphate binder in dialysis patients. There is scant trial evidence for a clinical benefit of any phosphate binder in this setting. Instead, phosphate binders are pre-
1024
Correspondence
scribed based on scientific understanding of calciumphosphate metabolism, associations of phosphate levels with adverse outcomes, and, unfortunately, the marketing practices of companies that manufacture these products. In my view, limitations in the design and conduct of CARE-2 prevent meaningful changes to our current understanding of this common clinical problem. Bryan R. Kestenbaum, MD, MS University of Washington Seattle, Washington
ACKNOWLEDGEMENTS
between diabetics and non-diabetics: The respective importance of glycemic and phosphorus control. Kidney Blood Press Res 31:10-15, 2007 2. 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 51:952-965, 2008 © 2008 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2008.06.034
Financial Disclosure: Dr Kestenbaum has received grant support from Amgen.
REFERENCE
BINDER WARS
1. Qunibi W, Muenz LR: Progression of calcification in the Calcium Acetate Renagel Evaluation-2 (CARE-2) Study. Am J Kidney Dis 52:1022-1023, 2008 (ltr)
To the Editor: Qunibi et al1 report that a combination of atorvastatin and calcium acetate in hemodialysis patients achieves similar progression of coronary artery calcification (CAC) compared with sevelamer-treated patients. My concern is that the use of atorvastatin in patients with diabetes receiving hemodialysis was associated with doubling of the relative risk of fatal stroke (while not changing the effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke).2 In these days of escalating drug copays and increasing pill burdens, how can one justify using a combination therapy that possibly increases the risk of fatal stroke when similar CAC results can be achieved with 1 medication that has been associated with a significant survival benefit compared with the use of calcium-containing phosphate binders?3
© 2008 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2008.08.014
HYPERPHOSPHATEMIA IN THE CALCIUM ACETATE RENAGEL EVALUATION-2 (CARE-2) STUDY To the Editor: Hyperphosphatemia has been associated with progression of vascular calcification.1 In the recent Calcium Acetate Renagel Evaluation-2 (CARE-2) Study,2 serum phosphate control appeared better in the calcium-acetate group than the sevelamer group (see Fig 6A of2). Unfortunately, the statistical test for serum phosphorus values compared serum phosphorus values at only the beginning and end of the trial. It would be beneficial if the investigators could provide timeaveraged serum phosphorus values for the first 6 months of the trial (at the time of first measurement of vascular calcification) and also for the 12 months of the trial with the appropriate statistical comparison. Differences in phosphorus control could affect the rates of vascular calcification. Anthony J. Bleyer, MD, MS Wake Forest University School of Medicine Winston-Salem, North Carolina
ACKNOWLEDGEMENTS Financial Disclosure: Dr Bleyer has participated in clinical trials and has received speaking honoraria from Genzyme.
REFERENCES 1. Ishimura E, Okuno S, Taniwaka H, et al: Different risk factors for vascular calcification in end-stage renal disease
David G. Martinez, MD United Health Services Hospitals Binghamton, New York
ACKNOWLEDGEMENTS Financial Disclosure: None.
REFERENCES 1. 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 51:952-965, 2008 2. Wanner C: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 353:18581860, 2005 3. Block GA: Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 71:438-441, 2007 © 2008 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2008.07.042