IN THE LAST few decades, several important

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1 Anemia Management for Hemodialysis Patients: Kidney Disease Outcomes Quality Initiative (K/DOQI) Guidelines and Dialysis Outcomes and Practice Patterns Study (DOPPS) Findings Francesco Locatelli, MD, Ronald L. Pisoni, PhD, MS, Tadao Akizawa, MD, PhD, José M. Cruz, MD, Peter B. DeOreo, MD, Norbert H. Lameire, MD, and Philip J. Held, PhD Background: After recombinant human erythropoietin was introduced into routine nephrologic practice, specific clinical guidelines were developed to optimize the quality of anemia management for patients with chronic kidney disease. Methods: The Dialysis Outcomes and Practice Patterns Study (DOPPS), an international investigation providing patient- and facility-level data on hemodialysis practice, was developed to provide information on various aspects of current practices in hemodialysis management, including treatment of renal anemia. Results: Hemoglobin concentration is strongly associated with both morbidity and mortality in hemodialysis patients. Although some improvements can be documented in anemia management practices in the years after the publication of international guidelines, wide variations in anemia management are still observed among countries. Conclusion: Many efforts are still needed to allow a greater proportion of patients to reach the recommended hemoglobin concentrations. Significantly improved outcomes may therefore be expected by a more widespread reaching of the recommended hemoglobin levels. The results of the DOPPS point to the difficulties in implementing clinical guidelines in the everyday management of individual patients. In specific circumstances, a well-designed observational study may offer credible information and serve as a basic instrument for monitoring the implementation of clinical guidelines in typical clinical practice. Am J Kidney Dis 44(S2):S27-S by the National Kidney Foundation, Inc. INDEX WORDS: Anemia; hemoglobin; hemodialysis; mortality; erythropoietin; Dialysis Outcomes and Practice Patterns Study (DOPPS); iron. IN THE LAST few decades, several important advances have been made in the treatment of end-stage renal disease, 1 among these the management of chronic kidney disease (CKD)- related anemia, which has been associated with patients morbidity, mortality, and quality of life, has been well documented. 2-6 Anemia is a frequent complication of CKD, and its prevalence has been shown to increase with diminishing renal function, so that a large proportion of patients reach the need for dialysis in an anemic state. 3,7 Nevertheless, the prevalence of anemia is reported to be substantial even in patients with mildly impaired renal function, which suggests that anemia may develop relatively early in the course of CKD. 3,7 The management of renal anemia has been revolutionized over the last 15 years, after recombinant human erythropoietin (rhuepo) was introduced in 1989, which replaced blood transfusions as the mainstay treatment of this complication In recent years, specific clinical guidelines have been developed to optimize the quality of anemia management secondary to CKD. As a result, the National Kidney Foundation s Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines and the European Renal Association-European Dialysis and Transplantation Association Best Practice Guidelines have been published in the United States and Europe, respectively Complementing these efforts, the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective, observational study of nationally representative samples From the Department of Nephrology and Dialysis, A. Manzoni Hospital, Lecco, Italy; University Renal Research and Education Association, Ann Arbor, MI; Center of Blood Purification Therapy, Wakayama Medical University, Wakayama, Japan; Nephrology Service, Hospital General Universitario La Fe, Valencia, Spain; Centers for Dialysis Care, Cleveland, OH; and University Hospital Renal Division, Ghent, Belgium. The Dialysis Outcomes and Practice Patterns Study is supported by research grants from Amgen and Kirin without restrictions on publications. The NKF gratefully acknowledges the support of Amgen, founding and principal sponsor of K/DOQI. The publication of this supplement was supported by the DOPPS. Peter B. DeOreo is a member of the DOPPS Advisory Board. Honoraria are provided by Amgen for speaking engagements. Address reprint requests to Ronald L. Pisoni, PhD, MS, University Renal Research and Education Association, 315 W. Huron Street, Suite 260, Ann Arbor, MI dopps@urrea.org 2004 by the National Kidney Foundation, Inc /04/ $30.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 44, No 5, Suppl 2 (November), 2004: pp S27-S33 S27

2 S28 of randomly selected hemodialysis facilities and patients, was developed to provide information on current practices in hemodialysis management, including treatment of renal anemia. By providing results from a very large population of hemodialysis patients, the DOPPS has provided insight into how the development of international guidelines may have helped change the management of CKD-related anemia over the past several years and, more generally, has reemphasized the primary role that observational studies may play, particularly when designed according to specific methodological criteria to improve scientific knowledge. THE IMPORTANCE OF OBSERVATIONAL STUDIES IN THE ERA OF EVIDENCE-BASED MEDICINE Currently, much debate exists over the merit of observational studies versus randomized trials. Although observational studies have been essential for gaining knowledge of the causes and pathogeneses of many diseases, randomized controlled trials should provide the most robust estimate of causal effects. Nevertheless, it is a matter of fact that there are strengths in observational studies and limitations to randomized, controlled trials. In particular, the use of very strict inclusion criteria in randomized, controlled trials can lead to results with limited external validity, thus reducing the ability to generalize them to conditions of everyday clinical practice. Considering that clinical trials are expensive in terms of money and time and thus not always feasible, a more careful and thoughtful approach to implementing and interpreting observational studies is therefore needed. In addition, certain clinical practices cannot be tested against placebos, and their role can be ascertained only in observational studies. Observational studies may also represent an essential means to generate and investigate hypotheses, thus helping investigators to select the interventions that will be more appropriately assessed by clinical trials in a subsequent phase. Moreover, in particular circumstances observational studies may have the chance to attain more or less the same benefits and credibility of randomized trials. 18 Restriction in research topics, such as choosing to analyze only those candidate agents with a high probability of being causal LOCATELLI ET AL factors, may therefore become a methodological requisite of paramount importance. Many improvements in the design and analysis of observational studies have been directed toward appropriate adjustments for potential confounding factors. The importance of measuring confounding variables accurately and precisely is often underappreciated. Another important point is ensuring that covariates are modelled correctly, taking into account their nonlinear associations and interactions. In this context, the DOPPS, a unique observational study in terms of the magnitude of the information prospectively collected from a large, representative sample of hemodialysis patients, and whose analyses have been adjusted for a wide range of case-mix characteristics, represents a striking example of how a well-designed observational study may become a major source of meaningful information aimed at improving clinical practice as well as a randomized, controlled clinical trial. LEVEL OF ANEMIA MANAGEMENT IN HEMODIALYSIS PATIENTS: FINDINGS FROM THE DOPPS Among several practice patterns and outcomes, the DOPPS has evaluated anemia management with rhuepo and intravenous iron preparations, as well as the control of anemia over time, based on data collected from 101 representative dialysis facilities in 5 European countries (France, Germany, Italy, Spain, and the United Kingdom) in 1998 to 2000 (DOPPS I) 19 and from 309 representative dialysis facilities in 12 countries (Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand, Spain, Sweden, the United Kingdom, and United States) from 2002 to 2003 (DOPPS II). 20 As the results from the DOPPS suggest, large variations in anemia management may be observed among the different countries. Indeed, the mean hemoglobin concentrations in prevalent hemodialysis patients varied widely across the studied countries, ranging from 10.1 g/dl to 12.0 g/dl (101 g/l to 120 g/l) (Fig 1). The percentage of patients with a hemoglobin value lower than 11 g/dl (110 g/l) (ie, below the target recommended by both the K/DOQI guidelines and the European Best Practice Guidelines) also ranged widely, from 23% to 77%, depending on the country (Fig 2). 20 Factors such as

3 ANEMIA MANAGEMENT S29 Fig 1. Mean hemoglobin concentrations among prevalent hemodialysis patients (on dialysis >180 days) and incident dialysis patients (within 7 days of first hemodialytic treatment) in DOPPS II. To convert hemoglobin in g/dl to g/l, multiply by 10. (Data from Pisoni et al. 20 ) female sex, catheter use, and history of cancer or gastrointestinal bleeding were significantly associated with lower hemoglobin levels in prevalent hemodialysis patients. 19,20 Despite the reported differences and large deviations from guidelines observed in some countries, significant improvement has been observed in anemia management in the last few years, given that the overall median hemoglobin of the 5 European DOPPS I countries increased from 10.8 g/dl (108 g/l) in 1998 to 1999 to 11.1 g/dl (111 g/l) in 2000, and the percentage of patients with hemoglobin 11.0 g/dl (110 g/l) increased from 46% to 53% over the same period. 19 The percentage of prevalent hemodialysis patients being prescribed rhuepo has increased as well, given that both the lowest value observed in France and the highest value observed in the United Kingdom increased between 2000 and 2002 to 2003 (from 75% to 83% and from 92% to 94%, respectively). 19,20 Although the majority of prevalent hemodialysis patients receive rhuepo, the same is not true of patients starting hemodialysis. Indeed, only 21% to 65% of incident hemodialysis patients received rhuepo during the pre end stage renal disease period. Correspondingly, their mean hemoglobin concentrations were lower and percentage of patients compliant with the recommendation of the international guidelines was lower at the time of starting hemodialysis, when compared with prevalent dialysis patients (Figs 1 and 2). Furthermore, even if time-trend analyses show that a significant increase in both mean hemoglobin concentration and the percentage of rhuepo use occurs during the first months after beginning hemodialysis, several months are yet required for hemoglobin concentration to rise to the recommended level (Fig 3). 19,20 Considering that anemia is a relatively early complication of CKD, usually arising some years before the need for renal replacement treatment is reached, 3,7 it may therefore be expected that a considerable proportion of patients remain in an anemic state for a prolonged time before the initiation of dialysis. Numerous recent studies have pointed to detrimental pathophysiologic consequences associated with poor anemia control during the early phases of CKD, especially promotion of cardiovascular disease. The percentage of prevalent hemodialysis patients receiving intravenous iron varies greatly

4 S30 LOCATELLI ET AL Fig 2. Percentage of patients with hemoglobin <11 g/dl (<110 g/l) among prevalent hemodialysis patients (on dialysis >180 days) and incident dialysis patients (within 7 days of first hemodialytic treatment) in DOPPS II. (Data from Pisoni et al. 20 ) among DOPPS countries, ranging from 38% to 89%. 19,20 In some countries, a large fraction of patients (31%-38%) have indications for iron deficiency, according to the K/DOQI and European Best Practice Guidelines, namely a transferrin saturation of less than 20%. 20 DOPPS analyses show that transferrin saturation values seem to be unrelated to the administration of intravenous iron, as large proportions of patients continue to have low levels of transferrin saturation, even in countries with high use of intravenous iron. 20 Although additional factors, such as cumulative iron doses, blood losses, and inflammation levels, could be involved in the explanation of these results, they may also suggest that iron supplementation, not just rhuepo administration, is often inadequate in hemodialysis patients. THE CHALLENGE OF IMPLEMENTING CLINICAL GUIDELINES IN MEDICAL PRACTICE Overall, the DOPPS data show that, despite the availability of practice guidelines for the treatment of renal anemia, wide variation in anemia management exists as a gap between what is recommended by the guidelines and what is accomplished in everyday clinical practice. Increasing awareness of the recommendations of international practice guidelines has led, however, to considerable changes in anemia management practices during the last few years and has led to large improvements in the control of anemia for hemodialysis patients. These results, therefore, remind us of the importance of implementing clinical guidelines. Compliance with clinical guidelines is an important indicator of quality and efficacy of patient care. 21 Improvement in patient outcomes can be expected when guidelines are more closely followed. At the same time, their adoption in clinical practice may be mitigated by numerous factors, including clinical expertise, patient preferences, constraints of public health policies, community standards, and budgetary limitations. 22 Nevertheless, whereas large efforts have been made to develop practice guidelines, much has still to be done to encourage implementation of the guidelines. As this is the only way to ensure real improvement in health care outcomes, it is therefore mandatory that more emphasis is placed on implementation strategies, including the development of local implementation support systems, clinical audit programs, and methods of feeding back information concerning current practices.

5 ANEMIA MANAGEMENT S31 Fig 3. Time trend in rhuepo use and mean hemoglobin concentration by time since starting hemodialysis. To convert hemoglobin in g/dl to g/l, multiply by 10. Reprinted from Locatelli et al, 19 with the permission of the Oxford University Press, 2003 European Renal Association European Dialysis and Transplant Association. ANEMIA-CONTROLLED OUTCOMES Another important contribution of the DOPPS is the finding of a strong association between higher hemoglobin concentrations and improved health outcomes. 19,20 This confirms the recommendations of clinical guidelines. Lower hemoglobin is associated with significantly higher patient morbidity (as measured by hospitalization) and mortality at least for hemodialysis patients. Indeed, before the publication of the DOPPS results, only a few studies had examined with detailed adjustment for associated comorbidities whether adherence to guidelines for hemoglobin in clinical practice really was associated with better clinical outcomes. Studies have shown considerable differences in the extent of an impact of anemia control and outcomes 23 or even their failure in improving patient outcomes when applied in prospective, multimember, and randomized trials. 24 Although the results of these studies have been somewhat disappointing, the results may have been conditioned by some points of weakness in the studies themselves, not least the fact that many of them were performed on selected populations of patients, thus precluding the generalizability of their results. 25 The DOPPS has properly overcome this limitation, and its analyses have been performed on very large populations of hemodialysis patients, using adjustments for a large number of patient case-mix characteristics. This is particularly important for anemia management, given the substantial differences noted by the DOPPS across countries. Such differences include causes of end-stage renal disease, comorbidities, hospitalization rates, vascular access use, and other hemodialysis practices, which may affect anemia and its management practices. 26,27 In this context, the DOPPS showed that higher hemoglobin concentrations are associated with better outcomes in hemodialysis patients, independent of potentially confounding factors, with the adjusted risk for mortality and hospitalization, respectively, 4% to 5% and 5% to 6% lower for every 1 g/dl (10 g/l) higher hemoglobin concentration (Fig 4). 19,20 Although the DOPPS results, being observational, cannot prove causality, they do provide additional evidence that supports the validity of the practice guidelines for managing CKD-related anemia. According to a recent analysis of the DOPPS data that assumes causality, it has been estimated that treating all patients in the United States with hemoglobin below 11 g/dl (110 g/l) to bring them within the recommended levels, would result in 23,910 life years potentially gained over

6 S32 LOCATELLI ET AL Fig 4. Relationship between patient hemoglobin concentration and adjusted relative risks of death and hospitalization in DOPPS I. To convert hemoglobin in g/dl to g/l, multiply by 10. Reprinted from Pisoni et al, , with permission from the National Kidney Foundation. a 5-year period. 28 These results suggest that a significant trend toward improved outcomes in hemodialysis patients may be expected by widespread implementation of these guidelines. CONCLUSIONS The international results shown by the DOPPS in the management of anemia secondary to CKD in hemodialysis patients indicate that, although some improvements have occurred in anemia management practices since the publication of international guidelines, significant variations in practice are still observed among countries, and many efforts are still needed for the greater proportion of patients to reach the target hemoglobin concentrations recommended by clinical practice guidelines. The challenge is important to resolve because the results of the DOPPS clearly show that hemoglobin concentration is strongly associated with the risk of hospitalization and death in hemodialysis patients. Significantly improved outcomes may be expected by a more widespread achievement of the recommended hemoglobin levels. Collecting data from a large, representative population of hemodialysis patients from different countries, analyzing it, and adjusting for numerous patient case-mix characteristics, has allowed the DOPPS to show how an observational study, if performed under specific methodological circumstances, may become highly informative and credible, while also proving to be a basic instrument for monitoring the implementation of clinical guidelines in everyday clinical practice. REFERENCES 1. Port FK, Orzol SM, Held PJ, et al: Trends in treatment and survival for hemodialysis patients in the United States. Am J Kidney Dis 32:S34-S38, 1998 (suppl 4) 2. Locatelli F, Conte F, Marcelli D: The impact of hematocrit levels and erythropoietin treatment on overall and cardiovascular mortality and morbidity The experience of the Lombardy Dialysis Registry. Nephrol Dial Transplant 13: , 1998

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