In the Literature: On Clinical Performance Measures and Outcomes Among Hemodialysis Patients
2007; Elsevier BV; Volume: 49; Issue: 3 Linguagem: Inglês
10.1053/j.ajkd.2007.01.019
ISSN1523-6838
Autores Tópico(s)Healthcare cost, quality, practices
ResumoCommentary on Rocco MV, Frankenfield DL, Hopson SD, McClellan WM: Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis. Ann Intern Med 14:512-519, 2006.The incidence and prevalence of patients treated by dialysis continues to increase.1U.S. Renal Data System2003 USRDS Annual Data Report: Atlas of End-Stage Renal Disease in the United States. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2003Google Scholar The mortality rate of dialysis patients is high, and worse than that of many cancers.1U.S. Renal Data System2003 USRDS Annual Data Report: Atlas of End-Stage Renal Disease in the United States. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2003Google Scholar Therefore it is important to identify modifiable mortality risk factors, to determine whether interventions to treat these risk factors are efficacious, to develop practice guidelines on the use of efficacious interventions in practice, and to define performance measures to monitor the outcomes of treatment. In 1997 the National Kidney Foundation developed clinical practice guidelines as part of the Dialysis Outcomes Quality Initiative (DOQI) based on appraisal of randomized controlled trials (RCTs), cohort studies, and opinion. Thereafter the US Centers for Medicare and Medicaid Services End-Stage Renal Disease (ESRD) Clinical Performance Measures Project defined and now monitors performance measures as indicators of quality of care in dialysis units. In the October 2006 issue of Annals of Internal Medicine, Rocco et al reported that attainment of multiple performance measures in dialysis patients was associated with lower mortality and hospitalization rates.2Rocco M.V. Frankenfield D.L. Hopson S.D. McClellan W.M. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis.Ann Intern Med. 2006; 14: 512-519Crossref Scopus (94) Google ScholarWhat Did This Study Show?Rocco et al2Rocco M.V. Frankenfield D.L. Hopson S.D. McClellan W.M. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis.Ann Intern Med. 2006; 14: 512-519Crossref Scopus (94) Google Scholar studied 15,287 prevalent patients, who were selected from a 5% random sample of patients receiving long-term outpatient hemodialysis in the US from 1999 and 2000. The clinical performance measure targets were hemoglobin value of 11 g/dL (110 g/L) or greater; serum albumin value of 4 g/dL (40 g/L) or greater or 3.7 g/dL (37 g/L) or greater (bromcresol green and bromcresol purple laboratory methods, respectively); use of a fistula for vascular access; and measured single-pool Kt/V urea value of 1.2 or greater. In multivariable analysis, they determined whether achieving these performance measures was associated with better mortality and hospitalization rates during the next 12 months. During the initial period, 6% of patients did not meet any target, 24% met 1 target, 39% met 2 targets, 24% met 3 targets, and 7% met all 4 targets. During the 12-month follow-up, 55% of patients were hospitalized and 20% died. Patients who met all targets were more likely to be male, younger, of white race, of Hispanic ethnicity, have hypertension or glomerulonephritis as the cause of ESRD, have a lower body mass index, and to have received dialysis for more years; they were less likely to have diabetes mellitus and comorbid conditions (both cardiovascular and noncardiovascular). In other words they were healthier and they were survivors. Adjusted hazard ratios and 95% confidence intervals were 4.6 (3.3-6.4), 3.5 (2.6-4.7), 2.6 (1.9-3.5), and 1.9 (1.4-2.6) for 0, 1, 2, or 3 targets met, respectively, compared with the reference group who met all 4 targets. The authors concluded that meeting multiple clinical measure targets was associated with a decrease in hospitalization and mortality rates. Although the authors stress that it was not possible to determine causality they do state that attainment of “individual quality indicators [was] associated with reductions in death and hospitalization.”As pointed out by the authors, the study has important limitations. It was not possible to determine the roles of severity of illness, other patient factors, or suboptimal care in failure to meet performance indicators. However achievement of targets was associated with younger age, better health, and being a survivor. It is unlikely that the multiple regression modeling can take into account all the clinical differences between achievers of targets and nonachievers. Consequently an equally tenable hypothesis, deriving from these results, is that failure to achieve targets is a marker for patients who will have adverse clinical outcomes, because they are older and sicker, and that achievement of the recommended targets will not lead to reductions in mortality and hospitalization. This conclusion is supported by the hazard associated with hypoalbuminemia, which is a marker for inflammation, malnutrition, and comorbidity. Serum albumin, a strong predictor of adverse outcomes,3Foley R.N. Parfrey P.S. Harnett J.D. Kent G.M. Murray D.C. Barre P.E. Hypoalbuminemia, cardiac morbidity, and mortality in end-stage renal disease.J Am Soc Nephrol. 1996; 7: 728-736PubMed Google Scholar could not be targeted for quality improvement interventions, because no efficacious interventions were available. As a result serum albumin levels had not changed during the 10-year period of observation.How Does This Study Compare With Other Studies?Prospective longitudinal studies of cohorts of patients have been used to identify risk factors, but in dialysis patients these studies are prone to multiple methodologic problems including survivor bias caused by enrolling prevalent rather than incident patients, unmeasured comorbidity, multiple interventions, selection bias for interventions, and inadequate power to take account of multiple known risk factors. In addition, identification of risk in a cohort study does not indicate that reduction in outcomes will occur by treating the risk factor, because the identified risk factor may only be a marker for some other associated factor which is causing death. Consequently the treatment hypothesis produced by a cohort study must be proven (where possible) by an RCT in which the new intervention is compared to conventional therapy in an adequately powered study of groups of patients considered to be similar because they were randomly allocated to either the intervention or control group. In the absence of an RCT proving efficacy of an intervention to improve an outcome, demonstration of an association between achievement of a performance measure and an outcome is subject to the same methodologic problems as in a cohort study demonstrating an association between the risk factor and the outcome. In addition, another limitation, dose-targeting bias, must be considered in observational studies relating achievement of performance measures to outcomes. Dose-targeting bias describes the likelihood that failure to achieve the performance measure is a marker for some other risk factor which is associated with both unresponsiveness to therapy and subsequent adverse outcomes. Dose-targeting bias is a likely explanation for the divergent results of cohort studies which examined the risk of anemia4Foley R.N. Parfrey P.S. Harnett J.D. Kent G.M. Murray D.C. Barre P.E. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease.Am J Kidney Dis. 1996; 28: 53-61Abstract Full Text PDF PubMed Scopus (682) Google Scholar, 5Collins A.J. Influence of target hemoglobin in dialysis patients on morbidity and mortality.Kidney Int (Suppl). 2002; 80: 44-48Crossref PubMed Scopus (76) Google Scholar and of different quantities of dialysis (as measured by Kt/V),6Port F.K. Ashby V.B. Dhingra R.K. Roys E. Wolfe R.A. Dialysis dose and body mass index are strongly associated with survival in hemodialysis patients.J Am Soc Nephrol. 2002; 13: 1061-1066PubMed Google Scholar and subsequent RCTs which examined the effect of anemia therapy7Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1864) Google Scholar, 8Parfrey P.S. Foley R.N. Wittreich B.H. Sullivan D.J. Zagari M.J. Frei D. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease.J Am Soc Nephrol. 2005; 16: 2180-2189Crossref PubMed Scopus (320) Google Scholar, 9Drüeke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1761) Google Scholar, 10Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2249) Google Scholar and of increasing dose of dialysis.11Eknoyan G. Beck G.J. Cheung A.K. et al.Effect of dialysis dose and membrane flux in maintenance dialysis.N Eng J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1560) Google Scholar, 12Greene T. Daugirdas J. Depner T. et al.Association of achieved dialysis dose with mortality in the hemodialysis study: an example of “dose targeting in bias”.J Am Soc Nephrol. 2005; 16: 3371-3380Crossref PubMed Scopus (74) Google ScholarMultiple cohort studies have confirmed that anemia is a cardiac and mortality risk factor,4Foley R.N. Parfrey P.S. Harnett J.D. Kent G.M. Murray D.C. Barre P.E. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease.Am J Kidney Dis. 1996; 28: 53-61Abstract Full Text PDF PubMed Scopus (682) Google Scholar, 5Collins A.J. Influence of target hemoglobin in dialysis patients on morbidity and mortality.Kidney Int (Suppl). 2002; 80: 44-48Crossref PubMed Scopus (76) Google Scholar but multiple RCTs comparing normalization of hemoglobin with erythropoietin to partial correction of anemia failed to demonstrate a clinical benefit, and produced a signal of potential harm in the higher hemoglobin group.7Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1864) Google Scholar, 8Parfrey P.S. Foley R.N. Wittreich B.H. Sullivan D.J. Zagari M.J. Frei D. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease.J Am Soc Nephrol. 2005; 16: 2180-2189Crossref PubMed Scopus (320) Google Scholar, 9Drüeke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1761) Google Scholar, 10Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2249) Google Scholar While the hazard in the high hemoglobin group was opposite to that anticipated from the cohort studies (Fig 1A), the relationships between achieved hemoglobin and primary outcome in both the intervention and control groups were similar to those observed in cohort studies7Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1864) Google Scholar (Fig 1B). It is likely that failure to achieve the higher hemoglobin level in either the intervention or the control group was a marker for some other adverse risk factor unresponsive to anemia therapy.A very similar observation was made in the Hemodialysis (HEMO) Study, an RCT where higher dose of dialysis did not prevent adverse clinical events compared to a lower dose, but higher achieved Kt/V in both intervention and control groups was associated with better clinical outcomes11Eknoyan G. Beck G.J. Cheung A.K. et al.Effect of dialysis dose and membrane flux in maintenance dialysis.N Eng J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1560) Google Scholar, 12Greene T. Daugirdas J. Depner T. et al.Association of achieved dialysis dose with mortality in the hemodialysis study: an example of “dose targeting in bias”.J Am Soc Nephrol. 2005; 16: 3371-3380Crossref PubMed Scopus (74) Google Scholar (Fig 2). Again the latter results from these 2 cohorts were consistent with those reported in previous cohort studies.6Port F.K. Ashby V.B. Dhingra R.K. Roys E. Wolfe R.A. Dialysis dose and body mass index are strongly associated with survival in hemodialysis patients.J Am Soc Nephrol. 2002; 13: 1061-1066PubMed Google Scholar Thus failure to achieve the higher Kt/V in either group was likely associated with some adverse risk factor unresponsive to increasing dialysis dose.Figure 2(A) Cumulative survival in hemodialysis patients randomly allocated to high dose of dialysis (urea reduction of about 75% or single pool Kt/V of about 1.65) and to standard dose (urea reduction of about 65% or single pool Kt/V of 1.25). Reproduced with permission from Eknoyan et al11Eknoyan G. Beck G.J. Cheung A.K. et al.Effect of dialysis dose and membrane flux in maintenance dialysis.N Eng J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1560) Google Scholar; copyright © 2002 Massachusetts Medical Society, all rights reserved. (B) Association of mortality with the most recent 4 month mean equilibrated Kt/V (e Kt/V). Shown are the adjusted relative risks (RR; and 95% confidence intervals[CI]) of mortality within each of the 5 quintiles of the 4-month average e KT/V values of the standard-dose group and the first, second, fourth, and fifth quintiles of the high dose group, with the middle quintile of the high-dose group as reference. Reproduced with permission from Greene et al12Greene T. Daugirdas J. Depner T. et al.Association of achieved dialysis dose with mortality in the hemodialysis study: an example of “dose targeting in bias”.J Am Soc Nephrol. 2005; 16: 3371-3380Crossref PubMed Scopus (74) Google Scholar; copyright © 2005 American Society of Nephrology.View Large Image Figure ViewerDownload Hi-res image Download (PPT)What Should Clinicians and Researchers Do?Of the 4 quality indicators studied by Rocco et al,2Rocco M.V. Frankenfield D.L. Hopson S.D. McClellan W.M. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis.Ann Intern Med. 2006; 14: 512-519Crossref Scopus (94) Google Scholar only a higher dialysis dose has RCT evidence to support the expectations that achievement of these targets would be associated with better hard clinical outcomes.13Lowrie E.G. Laird N.M. Parker T.F. Sargent J.A. Effect of the hemodialysis prescription on patient morbidity: report from the National Co-operative Dialysis Study.N Eng J Med. 1981; 305: 1176-1181Crossref PubMed Scopus (602) Google Scholar Thus, a clinical performance measure to achieve Kt/V > 1.2 is justified. One cannot conclude from the Rocco et al analyses that achievement of other clinical performance targets will lead to reduction in mortality and hospitalization. However achievement of some targets should be associated with other clinical benefits. RCTs demonstrate that treatment of anemia to a target hemoglobin value of 11 g/dL (110 g/L) or greater will improve quality of life and limit blood transfusions.14Canadian Erythropoietin Study GroupAssociation between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving hemodialysis.BMJ. 1990; 300: 573-578Crossref PubMed Google Scholar It is likely that preferential use of fistulas rather than grafts should lead to better vascular access outcomes.15Woods J.D. Turenne M.N. Strawderman R.L. et al.Vascular access survival among incident hemodialysis patients in the United States.Am J Kidney Dis. 1997; 30: 50-57Abstract Full Text PDF PubMed Scopus (234) Google Scholar Consequently quality assurance initiatives to achieve these targets can be supported. However, a serum albumin target of 4 g/dL (40g/L) as a clinical performance measure is illusory at present, as it is not currently modifiable.Questions on the efficacy of and target levels for interventions should be answered using RCTs. Effect sizes derived from cohort studies should not be used to influence clinical practice, but to create hypotheses to test in RCTs, except in those situations where the intervention is clearly a dominant strategy as in the provision of dialysis in ESRD, cessation of smoking, or provision of defibrillators in inherited arrhythmogenic right ventricular cardiomyopathy.16Hodgkinson K.A. Parfrey P.S. Bassett A.S. et al.The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cariomyopathy (ARVD5).J Am Coll Cardiol. 2005; 45: 400-408Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar As Rocco et al2Rocco M.V. Frankenfield D.L. Hopson S.D. McClellan W.M. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis.Ann Intern Med. 2006; 14: 512-519Crossref Scopus (94) Google Scholar suggest, the premise that achievement of multiple clinical performance measures will lead to improvement in mortality and hospitalization is testable, but will require an experimental trial which randomly allocates patients to intervention and control groups. Commentary on Rocco MV, Frankenfield DL, Hopson SD, McClellan WM: Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis. Ann Intern Med 14:512-519, 2006. Commentary on Rocco MV, Frankenfield DL, Hopson SD, McClellan WM: Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis. Ann Intern Med 14:512-519, 2006. Commentary on Rocco MV, Frankenfield DL, Hopson SD, McClellan WM: Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis. Ann Intern Med 14:512-519, 2006. The incidence and prevalence of patients treated by dialysis continues to increase.1U.S. Renal Data System2003 USRDS Annual Data Report: Atlas of End-Stage Renal Disease in the United States. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2003Google Scholar The mortality rate of dialysis patients is high, and worse than that of many cancers.1U.S. Renal Data System2003 USRDS Annual Data Report: Atlas of End-Stage Renal Disease in the United States. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2003Google Scholar Therefore it is important to identify modifiable mortality risk factors, to determine whether interventions to treat these risk factors are efficacious, to develop practice guidelines on the use of efficacious interventions in practice, and to define performance measures to monitor the outcomes of treatment. In 1997 the National Kidney Foundation developed clinical practice guidelines as part of the Dialysis Outcomes Quality Initiative (DOQI) based on appraisal of randomized controlled trials (RCTs), cohort studies, and opinion. Thereafter the US Centers for Medicare and Medicaid Services End-Stage Renal Disease (ESRD) Clinical Performance Measures Project defined and now monitors performance measures as indicators of quality of care in dialysis units. In the October 2006 issue of Annals of Internal Medicine, Rocco et al reported that attainment of multiple performance measures in dialysis patients was associated with lower mortality and hospitalization rates.2Rocco M.V. Frankenfield D.L. Hopson S.D. McClellan W.M. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis.Ann Intern Med. 2006; 14: 512-519Crossref Scopus (94) Google Scholar What Did This Study Show?Rocco et al2Rocco M.V. Frankenfield D.L. Hopson S.D. McClellan W.M. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis.Ann Intern Med. 2006; 14: 512-519Crossref Scopus (94) Google Scholar studied 15,287 prevalent patients, who were selected from a 5% random sample of patients receiving long-term outpatient hemodialysis in the US from 1999 and 2000. The clinical performance measure targets were hemoglobin value of 11 g/dL (110 g/L) or greater; serum albumin value of 4 g/dL (40 g/L) or greater or 3.7 g/dL (37 g/L) or greater (bromcresol green and bromcresol purple laboratory methods, respectively); use of a fistula for vascular access; and measured single-pool Kt/V urea value of 1.2 or greater. In multivariable analysis, they determined whether achieving these performance measures was associated with better mortality and hospitalization rates during the next 12 months. During the initial period, 6% of patients did not meet any target, 24% met 1 target, 39% met 2 targets, 24% met 3 targets, and 7% met all 4 targets. During the 12-month follow-up, 55% of patients were hospitalized and 20% died. Patients who met all targets were more likely to be male, younger, of white race, of Hispanic ethnicity, have hypertension or glomerulonephritis as the cause of ESRD, have a lower body mass index, and to have received dialysis for more years; they were less likely to have diabetes mellitus and comorbid conditions (both cardiovascular and noncardiovascular). In other words they were healthier and they were survivors. Adjusted hazard ratios and 95% confidence intervals were 4.6 (3.3-6.4), 3.5 (2.6-4.7), 2.6 (1.9-3.5), and 1.9 (1.4-2.6) for 0, 1, 2, or 3 targets met, respectively, compared with the reference group who met all 4 targets. The authors concluded that meeting multiple clinical measure targets was associated with a decrease in hospitalization and mortality rates. Although the authors stress that it was not possible to determine causality they do state that attainment of “individual quality indicators [was] associated with reductions in death and hospitalization.”As pointed out by the authors, the study has important limitations. It was not possible to determine the roles of severity of illness, other patient factors, or suboptimal care in failure to meet performance indicators. However achievement of targets was associated with younger age, better health, and being a survivor. It is unlikely that the multiple regression modeling can take into account all the clinical differences between achievers of targets and nonachievers. Consequently an equally tenable hypothesis, deriving from these results, is that failure to achieve targets is a marker for patients who will have adverse clinical outcomes, because they are older and sicker, and that achievement of the recommended targets will not lead to reductions in mortality and hospitalization. This conclusion is supported by the hazard associated with hypoalbuminemia, which is a marker for inflammation, malnutrition, and comorbidity. Serum albumin, a strong predictor of adverse outcomes,3Foley R.N. Parfrey P.S. Harnett J.D. Kent G.M. Murray D.C. Barre P.E. Hypoalbuminemia, cardiac morbidity, and mortality in end-stage renal disease.J Am Soc Nephrol. 1996; 7: 728-736PubMed Google Scholar could not be targeted for quality improvement interventions, because no efficacious interventions were available. As a result serum albumin levels had not changed during the 10-year period of observation. Rocco et al2Rocco M.V. Frankenfield D.L. Hopson S.D. McClellan W.M. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis.Ann Intern Med. 2006; 14: 512-519Crossref Scopus (94) Google Scholar studied 15,287 prevalent patients, who were selected from a 5% random sample of patients receiving long-term outpatient hemodialysis in the US from 1999 and 2000. The clinical performance measure targets were hemoglobin value of 11 g/dL (110 g/L) or greater; serum albumin value of 4 g/dL (40 g/L) or greater or 3.7 g/dL (37 g/L) or greater (bromcresol green and bromcresol purple laboratory methods, respectively); use of a fistula for vascular access; and measured single-pool Kt/V urea value of 1.2 or greater. In multivariable analysis, they determined whether achieving these performance measures was associated with better mortality and hospitalization rates during the next 12 months. During the initial period, 6% of patients did not meet any target, 24% met 1 target, 39% met 2 targets, 24% met 3 targets, and 7% met all 4 targets. During the 12-month follow-up, 55% of patients were hospitalized and 20% died. Patients who met all targets were more likely to be male, younger, of white race, of Hispanic ethnicity, have hypertension or glomerulonephritis as the cause of ESRD, have a lower body mass index, and to have received dialysis for more years; they were less likely to have diabetes mellitus and comorbid conditions (both cardiovascular and noncardiovascular). In other words they were healthier and they were survivors. Adjusted hazard ratios and 95% confidence intervals were 4.6 (3.3-6.4), 3.5 (2.6-4.7), 2.6 (1.9-3.5), and 1.9 (1.4-2.6) for 0, 1, 2, or 3 targets met, respectively, compared with the reference group who met all 4 targets. The authors concluded that meeting multiple clinical measure targets was associated with a decrease in hospitalization and mortality rates. Although the authors stress that it was not possible to determine causality they do state that attainment of “individual quality indicators [was] associated with reductions in death and hospitalization.” As pointed out by the authors, the study has important limitations. It was not possible to determine the roles of severity of illness, other patient factors, or suboptimal care in failure to meet performance indicators. However achievement of targets was associated with younger age, better health, and being a survivor. It is unlikely that the multiple regression modeling can take into account all the clinical differences between achievers of targets and nonachievers. Consequently an equally tenable hypothesis, deriving from these results, is that failure to achieve targets is a marker for patients who will have adverse clinical outcomes, because they are older and sicker, and that achievement of the recommended targets will not lead to reductions in mortality and hospitalization. This conclusion is supported by the hazard associated with hypoalbuminemia, which is a marker for inflammation, malnutrition, and comorbidity. Serum albumin, a strong predictor of adverse outcomes,3Foley R.N. Parfrey P.S. Harnett J.D. Kent G.M. Murray D.C. Barre P.E. Hypoalbuminemia, cardiac morbidity, and mortality in end-stage renal disease.J Am Soc Nephrol. 1996; 7: 728-736PubMed Google Scholar could not be targeted for quality improvement interventions, because no efficacious interventions were available. As a result serum albumin levels had not changed during the 10-year period of observation. How Does This Study Compare With Other Studies?Prospective longitudinal studies of cohorts of patients have been used to identify risk factors, but in dialysis patients these studies are prone to multiple methodologic problems including survivor bias caused by enrolling prevalent rather than incident patients, unmeasured comorbidity, multiple interventions, selection bias for interventions, and inadequate power to take account of multiple known risk factors. In addition, identification of risk in a cohort study does not indicate that reduction in outcomes will occur by treating the risk factor, because the identified risk factor may only be a marker for some other associated factor which is causing death. Consequently the treatment hypothesis produced by a cohort study must be proven (where possible) by an RCT in which the new intervention is compared to conventional therapy in an adequately powered study of groups of patients considered to be similar because they were randomly allocated to either the intervention or control group. In the absence of an RCT proving efficacy of an intervention to improve an outcome, demonstration of an association between achievement of a performance measure and an outcome is subject to the same methodologic problems as in a cohort study demonstrating an association between the risk factor and the outcome. In addition, another limitation, dose-targeting bias, must be considered in observational studies relating achievement of performance measures to outcomes. Dose-targeting bias describes the likelihood that failure to achieve the performance measure is a marker for some other risk factor which is associated with both unresponsiveness to therapy and subsequent adverse outcomes. Dose-targeting bias is a likely explanation for the divergent results of cohort studies which examined the risk of anemia4Foley R.N. Parfrey P.S. Harnett J.D. Kent G.M. Murray D.C. Barre P.E. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease.Am J Kidney Dis. 1996; 28: 53-61Abstract Full Text PDF PubMed Scopus (682) Google Scholar, 5Collins A.J. Influence of target hemoglobin in dialysis patients on morbidity and mortality.Kidney Int (Suppl). 2002; 80: 44-48Crossref PubMed Scopus (76) Google Scholar and of different quantities of dialysis (as measured by Kt/V),6Port F.K. Ashby V.B. Dhingra R.K. Roys E. Wolfe R.A. Dialysis dose and body mass index are strongly associated with survival in hemodialysis patients.J Am Soc Nephrol. 2002; 13: 1061-1066PubMed Google Scholar and subsequent RCTs which examined the effect of anemia therapy7Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1864) Google Scholar, 8Parfrey P.S. Foley R.N. Wittreich B.H. Sullivan D.J. Zagari M.J. Frei D. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease.J Am Soc Nephrol. 2005; 16: 2180-2189Crossref PubMed Scopus (320) Google Scholar, 9Drüeke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1761) Google Scholar, 10Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2249) Google Scholar and of increasing dose of dialysis.11Eknoyan G. Beck G.J. Cheung A.K. et al.Effect of dialysis dose and membrane flux in maintenance dialysis.N Eng J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1560) Google Scholar, 12Greene T. Daugirdas J. Depner T. et al.Association of achieved dialysis dose with mortality in the hemodialysis study: an example of “dose targeting in bias”.J Am Soc Nephrol. 2005; 16: 3371-3380Crossref PubMed Scopus (74) Google ScholarMultiple cohort studies have confirmed that anemia is a cardiac and mortality risk factor,4Foley R.N. Parfrey P.S. Harnett J.D. Kent G.M. Murray D.C. Barre P.E. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease.Am J Kidney Dis. 1996; 28: 53-61Abstract Full Text PDF PubMed Scopus (682) Google Scholar, 5Collins A.J. Influence of target hemoglobin in dialysis patients on morbidity and mortality.Kidney Int (Suppl). 2002; 80: 44-48Crossref PubMed Scopus (76) Google Scholar but multiple RCTs comparing normalization of hemoglobin with erythropoietin to partial correction of anemia failed to demonstrate a clinical benefit, and produced a signal of potential harm in the higher hemoglobin group.7Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1864) Google Scholar, 8Parfrey P.S. Foley R.N. Wittreich B.H. Sullivan D.J. Zagari M.J. Frei D. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease.J Am Soc Nephrol. 2005; 16: 2180-2189Crossref PubMed Scopus (320) Google Scholar, 9Drüeke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1761) Google Scholar, 10Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2249) Google Scholar While the hazard in the high hemoglobin group was opposite to that anticipated from the cohort studies (Fig 1A), the relationships between achieved hemoglobin and primary outcome in both the intervention and control groups were similar to those observed in cohort studies7Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1864) Google Scholar (Fig 1B). It is likely that failure to achieve the higher hemoglobin level in either the intervention or the control group was a marker for some other adverse risk factor unresponsive to anemia therapy.A very similar observation was made in the Hemodialysis (HEMO) Study, an RCT where higher dose of dialysis did not prevent adverse clinical events compared to a lower dose, but higher achieved Kt/V in both intervention and control groups was associated with better clinical outcomes11Eknoyan G. Beck G.J. Cheung A.K. et al.Effect of dialysis dose and membrane flux in maintenance dialysis.N Eng J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1560) Google Scholar, 12Greene T. Daugirdas J. Depner T. et al.Association of achieved dialysis dose with mortality in the hemodialysis study: an example of “dose targeting in bias”.J Am Soc Nephrol. 2005; 16: 3371-3380Crossref PubMed Scopus (74) Google Scholar (Fig 2). Again the latter results from these 2 cohorts were consistent with those reported in previous cohort studies.6Port F.K. Ashby V.B. Dhingra R.K. Roys E. Wolfe R.A. Dialysis dose and body mass index are strongly associated with survival in hemodialysis patients.J Am Soc Nephrol. 2002; 13: 1061-1066PubMed Google Scholar Thus failure to achieve the higher Kt/V in either group was likely associated with some adverse risk factor unresponsive to increasing dialysis dose. Prospective longitudinal studies of cohorts of patients have been used to identify risk factors, but in dialysis patients these studies are prone to multiple methodologic problems including survivor bias caused by enrolling prevalent rather than incident patients, unmeasured comorbidity, multiple interventions, selection bias for interventions, and inadequate power to take account of multiple known risk factors. In addition, identification of risk in a cohort study does not indicate that reduction in outcomes will occur by treating the risk factor, because the identified risk factor may only be a marker for some other associated factor which is causing death. Consequently the treatment hypothesis produced by a cohort study must be proven (where possible) by an RCT in which the new intervention is compared to conventional therapy in an adequately powered study of groups of patients considered to be similar because they were randomly allocated to either the intervention or control group. In the absence of an RCT proving efficacy of an intervention to improve an outcome, demonstration of an association between achievement of a performance measure and an outcome is subject to the same methodologic problems as in a cohort study demonstrating an association between the risk factor and the outcome. In addition, another limitation, dose-targeting bias, must be considered in observational studies relating achievement of performance measures to outcomes. Dose-targeting bias describes the likelihood that failure to achieve the performance measure is a marker for some other risk factor which is associated with both unresponsiveness to therapy and subsequent adverse outcomes. Dose-targeting bias is a likely explanation for the divergent results of cohort studies which examined the risk of anemia4Foley R.N. Parfrey P.S. Harnett J.D. Kent G.M. Murray D.C. Barre P.E. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease.Am J Kidney Dis. 1996; 28: 53-61Abstract Full Text PDF PubMed Scopus (682) Google Scholar, 5Collins A.J. Influence of target hemoglobin in dialysis patients on morbidity and mortality.Kidney Int (Suppl). 2002; 80: 44-48Crossref PubMed Scopus (76) Google Scholar and of different quantities of dialysis (as measured by Kt/V),6Port F.K. Ashby V.B. Dhingra R.K. Roys E. Wolfe R.A. Dialysis dose and body mass index are strongly associated with survival in hemodialysis patients.J Am Soc Nephrol. 2002; 13: 1061-1066PubMed Google Scholar and subsequent RCTs which examined the effect of anemia therapy7Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1864) Google Scholar, 8Parfrey P.S. Foley R.N. Wittreich B.H. Sullivan D.J. Zagari M.J. Frei D. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease.J Am Soc Nephrol. 2005; 16: 2180-2189Crossref PubMed Scopus (320) Google Scholar, 9Drüeke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1761) Google Scholar, 10Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2249) Google Scholar and of increasing dose of dialysis.11Eknoyan G. Beck G.J. Cheung A.K. et al.Effect of dialysis dose and membrane flux in maintenance dialysis.N Eng J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1560) Google Scholar, 12Greene T. Daugirdas J. Depner T. et al.Association of achieved dialysis dose with mortality in the hemodialysis study: an example of “dose targeting in bias”.J Am Soc Nephrol. 2005; 16: 3371-3380Crossref PubMed Scopus (74) Google Scholar Multiple cohort studies have confirmed that anemia is a cardiac and mortality risk factor,4Foley R.N. Parfrey P.S. Harnett J.D. Kent G.M. Murray D.C. Barre P.E. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease.Am J Kidney Dis. 1996; 28: 53-61Abstract Full Text PDF PubMed Scopus (682) Google Scholar, 5Collins A.J. Influence of target hemoglobin in dialysis patients on morbidity and mortality.Kidney Int (Suppl). 2002; 80: 44-48Crossref PubMed Scopus (76) Google Scholar but multiple RCTs comparing normalization of hemoglobin with erythropoietin to partial correction of anemia failed to demonstrate a clinical benefit, and produced a signal of potential harm in the higher hemoglobin group.7Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1864) Google Scholar, 8Parfrey P.S. Foley R.N. Wittreich B.H. Sullivan D.J. Zagari M.J. Frei D. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease.J Am Soc Nephrol. 2005; 16: 2180-2189Crossref PubMed Scopus (320) Google Scholar, 9Drüeke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1761) Google Scholar, 10Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2249) Google Scholar While the hazard in the high hemoglobin group was opposite to that anticipated from the cohort studies (Fig 1A), the relationships between achieved hemoglobin and primary outcome in both the intervention and control groups were similar to those observed in cohort studies7Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1864) Google Scholar (Fig 1B). It is likely that failure to achieve the higher hemoglobin level in either the intervention or the control group was a marker for some other adverse risk factor unresponsive to anemia therapy. A very similar observation was made in the Hemodialysis (HEMO) Study, an RCT where higher dose of dialysis did not prevent adverse clinical events compared to a lower dose, but higher achieved Kt/V in both intervention and control groups was associated with better clinical outcomes11Eknoyan G. Beck G.J. Cheung A.K. et al.Effect of dialysis dose and membrane flux in maintenance dialysis.N Eng J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1560) Google Scholar, 12Greene T. Daugirdas J. Depner T. et al.Association of achieved dialysis dose with mortality in the hemodialysis study: an example of “dose targeting in bias”.J Am Soc Nephrol. 2005; 16: 3371-3380Crossref PubMed Scopus (74) Google Scholar (Fig 2). Again the latter results from these 2 cohorts were consistent with those reported in previous cohort studies.6Port F.K. Ashby V.B. Dhingra R.K. Roys E. Wolfe R.A. Dialysis dose and body mass index are strongly associated with survival in hemodialysis patients.J Am Soc Nephrol. 2002; 13: 1061-1066PubMed Google Scholar Thus failure to achieve the higher Kt/V in either group was likely associated with some adverse risk factor unresponsive to increasing dialysis dose. What Should Clinicians and Researchers Do?Of the 4 quality indicators studied by Rocco et al,2Rocco M.V. Frankenfield D.L. Hopson S.D. McClellan W.M. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis.Ann Intern Med. 2006; 14: 512-519Crossref Scopus (94) Google Scholar only a higher dialysis dose has RCT evidence to support the expectations that achievement of these targets would be associated with better hard clinical outcomes.13Lowrie E.G. Laird N.M. Parker T.F. Sargent J.A. Effect of the hemodialysis prescription on patient morbidity: report from the National Co-operative Dialysis Study.N Eng J Med. 1981; 305: 1176-1181Crossref PubMed Scopus (602) Google Scholar Thus, a clinical performance measure to achieve Kt/V > 1.2 is justified. One cannot conclude from the Rocco et al analyses that achievement of other clinical performance targets will lead to reduction in mortality and hospitalization. However achievement of some targets should be associated with other clinical benefits. RCTs demonstrate that treatment of anemia to a target hemoglobin value of 11 g/dL (110 g/L) or greater will improve quality of life and limit blood transfusions.14Canadian Erythropoietin Study GroupAssociation between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving hemodialysis.BMJ. 1990; 300: 573-578Crossref PubMed Google Scholar It is likely that preferential use of fistulas rather than grafts should lead to better vascular access outcomes.15Woods J.D. Turenne M.N. Strawderman R.L. et al.Vascular access survival among incident hemodialysis patients in the United States.Am J Kidney Dis. 1997; 30: 50-57Abstract Full Text PDF PubMed Scopus (234) Google Scholar Consequently quality assurance initiatives to achieve these targets can be supported. However, a serum albumin target of 4 g/dL (40g/L) as a clinical performance measure is illusory at present, as it is not currently modifiable.Questions on the efficacy of and target levels for interventions should be answered using RCTs. Effect sizes derived from cohort studies should not be used to influence clinical practice, but to create hypotheses to test in RCTs, except in those situations where the intervention is clearly a dominant strategy as in the provision of dialysis in ESRD, cessation of smoking, or provision of defibrillators in inherited arrhythmogenic right ventricular cardiomyopathy.16Hodgkinson K.A. Parfrey P.S. Bassett A.S. et al.The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cariomyopathy (ARVD5).J Am Coll Cardiol. 2005; 45: 400-408Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar As Rocco et al2Rocco M.V. Frankenfield D.L. Hopson S.D. McClellan W.M. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis.Ann Intern Med. 2006; 14: 512-519Crossref Scopus (94) Google Scholar suggest, the premise that achievement of multiple clinical performance measures will lead to improvement in mortality and hospitalization is testable, but will require an experimental trial which randomly allocates patients to intervention and control groups. Of the 4 quality indicators studied by Rocco et al,2Rocco M.V. Frankenfield D.L. Hopson S.D. McClellan W.M. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis.Ann Intern Med. 2006; 14: 512-519Crossref Scopus (94) Google Scholar only a higher dialysis dose has RCT evidence to support the expectations that achievement of these targets would be associated with better hard clinical outcomes.13Lowrie E.G. Laird N.M. Parker T.F. Sargent J.A. Effect of the hemodialysis prescription on patient morbidity: report from the National Co-operative Dialysis Study.N Eng J Med. 1981; 305: 1176-1181Crossref PubMed Scopus (602) Google Scholar Thus, a clinical performance measure to achieve Kt/V > 1.2 is justified. One cannot conclude from the Rocco et al analyses that achievement of other clinical performance targets will lead to reduction in mortality and hospitalization. However achievement of some targets should be associated with other clinical benefits. RCTs demonstrate that treatment of anemia to a target hemoglobin value of 11 g/dL (110 g/L) or greater will improve quality of life and limit blood transfusions.14Canadian Erythropoietin Study GroupAssociation between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving hemodialysis.BMJ. 1990; 300: 573-578Crossref PubMed Google Scholar It is likely that preferential use of fistulas rather than grafts should lead to better vascular access outcomes.15Woods J.D. Turenne M.N. Strawderman R.L. et al.Vascular access survival among incident hemodialysis patients in the United States.Am J Kidney Dis. 1997; 30: 50-57Abstract Full Text PDF PubMed Scopus (234) Google Scholar Consequently quality assurance initiatives to achieve these targets can be supported. However, a serum albumin target of 4 g/dL (40g/L) as a clinical performance measure is illusory at present, as it is not currently modifiable. Questions on the efficacy of and target levels for interventions should be answered using RCTs. Effect sizes derived from cohort studies should not be used to influence clinical practice, but to create hypotheses to test in RCTs, except in those situations where the intervention is clearly a dominant strategy as in the provision of dialysis in ESRD, cessation of smoking, or provision of defibrillators in inherited arrhythmogenic right ventricular cardiomyopathy.16Hodgkinson K.A. Parfrey P.S. Bassett A.S. et al.The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cariomyopathy (ARVD5).J Am Coll Cardiol. 2005; 45: 400-408Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar As Rocco et al2Rocco M.V. Frankenfield D.L. Hopson S.D. McClellan W.M. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis.Ann Intern Med. 2006; 14: 512-519Crossref Scopus (94) Google Scholar suggest, the premise that achievement of multiple clinical performance measures will lead to improvement in mortality and hospitalization is testable, but will require an experimental trial which randomly allocates patients to intervention and control groups.
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