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Phosphorus Binders in ESRD: Consistent Evidence From Observational Studies
Editorial Phosphorus Binders in ESRD: Consistent Evidence From Observational Studies Related Article, p. 90
T
he prescription medication burden for patients with chronic kidney disease and long-term dialysis patients is among the highest of any chronic disease, with patients receiving an average of 10 concurrent medications.1 Despite prodigious rates of prescription drug use, no medication currently is supported by outcomes-based placebo-controlled clinical trials of dialysis patients. Consequently, pharmacological care of long-term dialysis patients generally is guided by biochemistry and blood pressure data. For example, phosphorus binders are ubiquitously prescribed to dialysis patients based on the ability of these medications to decrease serum phosphorus concentrations, which are associated with mortality and cardiovascular outcomes in observational studies.2,3 In the absence of clinical trials, well-conducted observational studies of medication use (pharmacoepidemiology) can provide estimates of the risks and benefits of available medications and, in some instances, add new information beyond that of a randomized trial.4 For example, pharmacoepidemiologic studies can assess drug effectiveness in real-world clinical settings, free from the myriad exclusions and hypervigilant monitoring environment of a clinical trial. Moreover, large pharmacoepidemiologic studies may detect subtle safety signals that may otherwise be missed in a trial. However, even the highest quality pharmacoepidemiologic studies cannot fully resolve potential differences between treated and untreated individuals, leaving residual uncertainty about whether differences in study outcomes are caused by the medication or characteristics of the medication users. This residual uncertainty obscures clinical treatment decisions. In the present issue of the American Journal of Kidney Diseases, Lopes et al5 present a pharmacoepidemiologic study designed to address the hypothesis that phosphorus binders improve survival in hemodialysis patients. The study population consisted of 23,898 prevalent hemodialysis patients from the Dialysis Outcomes and Practice Patterns Study (DOPPS), which includes hemodialysis patients from North America, Europe, Australia, and Japan.6 For the primary analyses, the exposure was use versus nonuse of any phosphorus binder and the outcome was all-cause mortality. A total of 88.1% of hemodialysis patients in DOPPS were using a phosphorus binder at study entry, reflecting the near-complete penetration of these medicaAm J Kidney Dis. 2012;60(1):3-4
tions in the absence of trials based on clinical outcomes. After adjustment for demographics, estimated comorbid disease, and baseline serum phosphorus concentration, all-cause mortality was ⬃25% (95% confidence interval [CI], 17%-32%) lower in phosphorus-binder users compared with nonusers. After further adjustment for nutritional parameters, including serum albumin, serum creatinine, body mass index, and normalized protein catabolic rate, this association narrowed to an estimated 12% (95% CI, 3%-20%) lower risk of death, showing the potential confounding influence of nutritional characteristics. When mortality was evaluated as a function of both serum phosphorus concentration and phosphorus-binder status, the lowest risk of death was observed for hemodialysis patients who had a serum phosphorus concentration of 3.5-5.5 mg/dL and were receiving a phosphorus binder. These findings provide new evidence for an association of phosphorus binders with favorable nutritional status in hemodialysis patients and confirm previous findings linking phosphorus binders with improved survival in this setting. Previous observational studies also have documented associations of phosphorus-binder use with longer survival. Isakova et al7 reported an estimated 22% lower 1-year mortality associated with phosphorus-binder use in 6,372 incident hemodialysis patients in a propensity-matched and age-adjusted analysis. Winkelmayer et al8 found generally similar associations: an estimated 19% lower 1-year mortality rate comparing use versus nonuse of a calcium-containing phosphorus binder in 3,603 incident dialysis patients. However, this association was reduced to 11% and no longer met statistical significance in a propensitymatched analysis that excluded approximately half the cohort. In a study of men with advanced chronic kidney disease not on dialysis therapy, Kovesdy et al9 reported an estimated 39% lower risk of death associated with phosphorus-binder use. The present study by Lopes et al5 extends previous knowledge in several ways. First, the cohort includes patients from 12 countries, increasing the generalizability of the findings. Second, the study was conducted within the framework of a dedicated prospecAddress correspondence to Bryan Kestenbaum, MD, MS, University of Washington, 325 9th Ave, Seattle, WA 98104. E-mail: [email protected] © 2012 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2012.04.007 3
Bryan Kestenbaum
tive study that used standardized approaches to data collection with a particular focus on practice patterns. Third, the study specifically highlights a set of nutritional parameters that were linked with phosphorusbinder use and, through adjustment, attenuates potential confounding by these characteristics. In the present study, phosphorus-binder users had higher serum concentrations of albumin and creatinine and greater body mass and normalized protein catabolic rates compared with nonusers. As markers of malnutrition and inflammation, these differences could suggest better nutritional status or less chronic inflammation and oxidative stress in phosphorusbinder users. The cross-sectional assessment of phosphorus binders and nutritional status does not permit distinction of whether phosphorus binders actually improve these nutritional parameters or binders simply are withheld from sicker patients. Nevertheless, these results may help inform future observational studies about the importance of carefully measuring and adjusting for nutritional parameters as potential confounders. This study, like previous observational studies of phosphorus binders, has important limitations. First, unmeasured differences in characteristics of phosphorus-binder users versus nonusers may have been responsible for the observed survival benefit. The high penetration of phosphorus-binder use in this population further raises the possibility of systematic differences in the level of standard clinical care. Second, the presence and severity of comorbid disease processes are imprecisely captured, raising the possibility of unmeasured confounding. Third, the study is limited by prevalent user bias, in which exposed individuals are selected based on stable use of a particular medication. Capturing new medication users when they initiate a drug therapy minimizes this potential bias and more closely resembles the approach of a clinical trial. Prevalent user bias may exert particularly strong bias in observational studies of phosphorusbinder use because acute illness, infection, or prolonged hospitalization may lead to cachexia and decreased serum phosphorus concentrations, prompting discontinuation of phosphorus-binder therapy. This sequence of events could induce a false association of current phosphorus-binder use with improved survival. Evaluating incident phosphorus-binder users in an intention-to-treat analysis mitigates this potential problem and is the preferred solution for most pharmacoepidemiologic studies. An outcomes-centered placebo-controlled trial of phosphorus binders versus placebo in dialysis patients who have moderate elevations of serum phosphorus levels is the best way to determine whether these
4
medications improve the health of this population. Objections to such an approach have been raised on ethical grounds due to consistent associations of higher serum phosphorus concentrations with adverse clinical outcomes. Similar ethical arguments were raised about anemia prior to TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy), the amount of urea clearance prior to the HEMO (Hemodialysis) Study, and serum lipid levels prior to 4D (Die Deutsche Diabetes Dialyse Studie). Given that phosphorus binders are already prescribed to most dialysis patients, pharmaceutical companies have little incentive to conduct such a trial. It is up to nephrologists, the treating physicians, to conceive and carry out this next step. Bryan Kestenbaum, MD, MS University of Washington Seattle, Washington
ACKNOWLEDGEMENTS Financial Disclosure: The author declares that he has no relevant financial interests.
REFERENCES 1. Pai AB, Boyd A, Depczynski J, Chavez IM, Khan N, Manley H. Reduced drug use and hospitalization rates in patients undergoing hemodialysis who received pharmaceutical care: a 2-year, randomized, controlled study. Pharmacotherapy. 2009;29(12): 1433-1440. 2. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. 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(4):607-617. 3. Stevens LA, Djurdjev O, Cardew S, Cameron EC, Levin A. 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(3):770779. 4. Avorn J. In defense of pharmacoepidemiology—embracing the yin and yang of drug research. N Engl J Med. 2007;357(22): 2219-2221. 5. Lopes AA, Tong L, Thumma J, et al. Phosphate binder use and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS): evaluation of possible confounding by nutritional status. Am J Kidney Dis. 2012; 60(1):90-101. 6. Goodkin DA, Mapes DL, Held PJ. The Dialysis Outcomes and Practice Patterns Study (DOPPS): how can we improve the care of hemodialysis patients? Semin Dial. 2001;14(3):157-159. 7. Isakova T, Gutierrez OM, Chang Y, et al. Phosphorus binders and survival on hemodialysis. J Am Soc Nephrol. 2009;20(2):388396. 8. Winkelmayer WC, Liu J, Kestenbaum B. Comparative effectiveness of calcium-containing phosphate binders in incident U.S. dialysis patients. Clin J Am Soc Nephrol. 2011;6(1):175-183. 9. Kovesdy CP, Kuchmak O, Lu JL, Kalantar-Zadeh K. Outcomes associated with phosphorus binders in men with non– dialysis-dependent CKD. Am J Kidney Dis. 2010;56(5):842-851.
Am J Kidney Dis. 2012;60(1):3-4
T
he prescription medication burden for patients with chronic kidney disease and long-term dialysis patients is among the highest of any chronic disease, with patients receiving an average of 10 concurrent medications.1 Despite prodigious rates of prescription drug use, no medication currently is supported by outcomes-based placebo-controlled clinical trials of dialysis patients. Consequently, pharmacological care of long-term dialysis patients generally is guided by biochemistry and blood pressure data. For example, phosphorus binders are ubiquitously prescribed to dialysis patients based on the ability of these medications to decrease serum phosphorus concentrations, which are associated with mortality and cardiovascular outcomes in observational studies.2,3 In the absence of clinical trials, well-conducted observational studies of medication use (pharmacoepidemiology) can provide estimates of the risks and benefits of available medications and, in some instances, add new information beyond that of a randomized trial.4 For example, pharmacoepidemiologic studies can assess drug effectiveness in real-world clinical settings, free from the myriad exclusions and hypervigilant monitoring environment of a clinical trial. Moreover, large pharmacoepidemiologic studies may detect subtle safety signals that may otherwise be missed in a trial. However, even the highest quality pharmacoepidemiologic studies cannot fully resolve potential differences between treated and untreated individuals, leaving residual uncertainty about whether differences in study outcomes are caused by the medication or characteristics of the medication users. This residual uncertainty obscures clinical treatment decisions. In the present issue of the American Journal of Kidney Diseases, Lopes et al5 present a pharmacoepidemiologic study designed to address the hypothesis that phosphorus binders improve survival in hemodialysis patients. The study population consisted of 23,898 prevalent hemodialysis patients from the Dialysis Outcomes and Practice Patterns Study (DOPPS), which includes hemodialysis patients from North America, Europe, Australia, and Japan.6 For the primary analyses, the exposure was use versus nonuse of any phosphorus binder and the outcome was all-cause mortality. A total of 88.1% of hemodialysis patients in DOPPS were using a phosphorus binder at study entry, reflecting the near-complete penetration of these medicaAm J Kidney Dis. 2012;60(1):3-4
tions in the absence of trials based on clinical outcomes. After adjustment for demographics, estimated comorbid disease, and baseline serum phosphorus concentration, all-cause mortality was ⬃25% (95% confidence interval [CI], 17%-32%) lower in phosphorus-binder users compared with nonusers. After further adjustment for nutritional parameters, including serum albumin, serum creatinine, body mass index, and normalized protein catabolic rate, this association narrowed to an estimated 12% (95% CI, 3%-20%) lower risk of death, showing the potential confounding influence of nutritional characteristics. When mortality was evaluated as a function of both serum phosphorus concentration and phosphorus-binder status, the lowest risk of death was observed for hemodialysis patients who had a serum phosphorus concentration of 3.5-5.5 mg/dL and were receiving a phosphorus binder. These findings provide new evidence for an association of phosphorus binders with favorable nutritional status in hemodialysis patients and confirm previous findings linking phosphorus binders with improved survival in this setting. Previous observational studies also have documented associations of phosphorus-binder use with longer survival. Isakova et al7 reported an estimated 22% lower 1-year mortality associated with phosphorus-binder use in 6,372 incident hemodialysis patients in a propensity-matched and age-adjusted analysis. Winkelmayer et al8 found generally similar associations: an estimated 19% lower 1-year mortality rate comparing use versus nonuse of a calcium-containing phosphorus binder in 3,603 incident dialysis patients. However, this association was reduced to 11% and no longer met statistical significance in a propensitymatched analysis that excluded approximately half the cohort. In a study of men with advanced chronic kidney disease not on dialysis therapy, Kovesdy et al9 reported an estimated 39% lower risk of death associated with phosphorus-binder use. The present study by Lopes et al5 extends previous knowledge in several ways. First, the cohort includes patients from 12 countries, increasing the generalizability of the findings. Second, the study was conducted within the framework of a dedicated prospecAddress correspondence to Bryan Kestenbaum, MD, MS, University of Washington, 325 9th Ave, Seattle, WA 98104. E-mail: [email protected] © 2012 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2012.04.007 3
Bryan Kestenbaum
tive study that used standardized approaches to data collection with a particular focus on practice patterns. Third, the study specifically highlights a set of nutritional parameters that were linked with phosphorusbinder use and, through adjustment, attenuates potential confounding by these characteristics. In the present study, phosphorus-binder users had higher serum concentrations of albumin and creatinine and greater body mass and normalized protein catabolic rates compared with nonusers. As markers of malnutrition and inflammation, these differences could suggest better nutritional status or less chronic inflammation and oxidative stress in phosphorusbinder users. The cross-sectional assessment of phosphorus binders and nutritional status does not permit distinction of whether phosphorus binders actually improve these nutritional parameters or binders simply are withheld from sicker patients. Nevertheless, these results may help inform future observational studies about the importance of carefully measuring and adjusting for nutritional parameters as potential confounders. This study, like previous observational studies of phosphorus binders, has important limitations. First, unmeasured differences in characteristics of phosphorus-binder users versus nonusers may have been responsible for the observed survival benefit. The high penetration of phosphorus-binder use in this population further raises the possibility of systematic differences in the level of standard clinical care. Second, the presence and severity of comorbid disease processes are imprecisely captured, raising the possibility of unmeasured confounding. Third, the study is limited by prevalent user bias, in which exposed individuals are selected based on stable use of a particular medication. Capturing new medication users when they initiate a drug therapy minimizes this potential bias and more closely resembles the approach of a clinical trial. Prevalent user bias may exert particularly strong bias in observational studies of phosphorusbinder use because acute illness, infection, or prolonged hospitalization may lead to cachexia and decreased serum phosphorus concentrations, prompting discontinuation of phosphorus-binder therapy. This sequence of events could induce a false association of current phosphorus-binder use with improved survival. Evaluating incident phosphorus-binder users in an intention-to-treat analysis mitigates this potential problem and is the preferred solution for most pharmacoepidemiologic studies. An outcomes-centered placebo-controlled trial of phosphorus binders versus placebo in dialysis patients who have moderate elevations of serum phosphorus levels is the best way to determine whether these
4
medications improve the health of this population. Objections to such an approach have been raised on ethical grounds due to consistent associations of higher serum phosphorus concentrations with adverse clinical outcomes. Similar ethical arguments were raised about anemia prior to TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy), the amount of urea clearance prior to the HEMO (Hemodialysis) Study, and serum lipid levels prior to 4D (Die Deutsche Diabetes Dialyse Studie). Given that phosphorus binders are already prescribed to most dialysis patients, pharmaceutical companies have little incentive to conduct such a trial. It is up to nephrologists, the treating physicians, to conceive and carry out this next step. Bryan Kestenbaum, MD, MS University of Washington Seattle, Washington
ACKNOWLEDGEMENTS Financial Disclosure: The author declares that he has no relevant financial interests.
REFERENCES 1. Pai AB, Boyd A, Depczynski J, Chavez IM, Khan N, Manley H. Reduced drug use and hospitalization rates in patients undergoing hemodialysis who received pharmaceutical care: a 2-year, randomized, controlled study. Pharmacotherapy. 2009;29(12): 1433-1440. 2. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. 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(4):607-617. 3. Stevens LA, Djurdjev O, Cardew S, Cameron EC, Levin A. 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(3):770779. 4. Avorn J. In defense of pharmacoepidemiology—embracing the yin and yang of drug research. N Engl J Med. 2007;357(22): 2219-2221. 5. Lopes AA, Tong L, Thumma J, et al. Phosphate binder use and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS): evaluation of possible confounding by nutritional status. Am J Kidney Dis. 2012; 60(1):90-101. 6. Goodkin DA, Mapes DL, Held PJ. The Dialysis Outcomes and Practice Patterns Study (DOPPS): how can we improve the care of hemodialysis patients? Semin Dial. 2001;14(3):157-159. 7. Isakova T, Gutierrez OM, Chang Y, et al. Phosphorus binders and survival on hemodialysis. J Am Soc Nephrol. 2009;20(2):388396. 8. Winkelmayer WC, Liu J, Kestenbaum B. Comparative effectiveness of calcium-containing phosphate binders in incident U.S. dialysis patients. Clin J Am Soc Nephrol. 2011;6(1):175-183. 9. Kovesdy CP, Kuchmak O, Lu JL, Kalantar-Zadeh K. Outcomes associated with phosphorus binders in men with non– dialysis-dependent CKD. Am J Kidney Dis. 2010;56(5):842-851.
Am J Kidney Dis. 2012;60(1):3-4