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Anemia Management for Hemodialysis Patients: Kidney DiseaseOutcomes 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, specificlinical guidelines were developed to optimize the quality of anemia management for patients with chronic kidneyisease. Methods: The Dialysis Outcomes and Practice Patterns Study (DOPPS), an international investigationroviding patient- and facility-level data on hemodialysis practice, was developed to provide information on variousspects of current practices in hemodialysis management, including treatment of renal anemia. Results: Hemoglo-in concentration is strongly associated with both morbidity and mortality in hemodialysis patients. Although some

mprovements can be documented in anemia management practices in the years after the publication of interna-ional guidelines, wide variations in anemia management are still observed among countries. Conclusion: Manyfforts are still needed to allow a greater proportion of patients to reach the recommended hemoglobin concentra-ions. Significantly improved outcomes may therefore be expected by a more widespread reaching of theecommended hemoglobin levels. The results of the DOPPS point to the difficulties in implementing clinicaluidelines in the everyday management of individual patients. In specific circumstances, a well-designed observa-ional study may offer credible information and serve as a basic instrument for monitoring the implementation oflinical guidelines in typical clinical practice. Am J Kidney Dis 44(S2):S27-S33.2004 by the National Kidney Foundation, Inc.

NDEX WORDS: Anemia; hemoglobin; hemodialysis; mortality; erythropoietin; Dialysis Outcomes and Practice

atterns Study (DOPPS); iron.

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N THE LAST few decades, several importantadvances have been made in the treatment of

nd-stage renal disease,1 among these the man-gement of chronic kidney disease (CKD)-elated anemia, which has been associated withatients’ morbidity, mortality, and quality of life,as been well documented.2-6 Anemia is a fre-uent complication of CKD, and its prevalenceas been shown to increase with diminishingenal function, so that a large proportion ofatients reach the need for dialysis in an anemictate.3,7 Nevertheless, the prevalence of anemias reported to be substantial even in patients withildly impaired renal function, which suggests

hat anemia may develop relatively early in theourse of CKD.3,7

The management of renal anemia has beenevolutionized over the last 15 years, after recom-inant human erythropoietin (rHuEpo) was intro-uced in 1989, which replaced blood transfu-ions as the mainstay treatment of thisomplication.8-14 In recent years, specific clini-al guidelines have been developed to optimizehe quality of anemia management secondary toKD. As a result, the National Kidney Founda-

ion’s Kidney Disease Outcomes Quality Initia-ive (K/DOQI) guidelines and the European

enal Association-European Dialysis and Trans-

merican Journal of Kidney Diseases, Vol 44, No 5, Suppl 2 (Nove

lantation Association Best Practice Guidelinesave been published in the United States andurope, respectively.15-17 Complementing thesefforts, the Dialysis Outcomes and Practice Pat-erns Study (DOPPS), a prospective, observa-ional study of nationally representative samples

From the Department of Nephrology and Dialysis, A.anzoni Hospital, Lecco, Italy; University Renal Research

nd Education Association, Ann Arbor, MI; Center of Bloodurification Therapy, Wakayama Medical University,akayama, Japan; Nephrology Service, Hospital Generalniversitario “La Fe,” Valencia, Spain; Centers for Dialy-

is Care, Cleveland, OH; and University Hospital Renalivision, Ghent, Belgium.The Dialysis Outcomes and Practice Patterns Study is

upported by research grants from Amgen and Kirin withoutestrictions on publications. The NKF gratefully acknowl-dges the support of Amgen, founding and principal sponsorf K/DOQI. The publication of this supplement was sup-orted by the DOPPS.Peter B. DeOreo is a member of the DOPPS Advisory

oard. Honoraria are provided by Amgen for speakingngagements.

Address reprint requests to Ronald L. Pisoni, PhD, MS,niversity Renal Research and Education Association, 315. Huron Street, Suite 260, Ann Arbor, MI 48103. E-mail:opps@urrea.org© 2004 by the National Kidney Foundation, Inc.0272-6386/04/4405-0105$30.00/0

doi:10.1053/j.ajkd.2004.08.008

mber), 2004: pp S27-S33 S27

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f randomly selected hemodialysis facilities andatients, was developed to provide informationn current practices in hemodialysis manage-ent, including treatment of renal anemia. By

roviding results from a very large population ofemodialysis patients, the DOPPS has providednsight into how the development of interna-ional guidelines may have helped change theanagement of CKD-related anemia over the

ast several years and, more generally, has re-mphasized the primary role that observationaltudies may play, particularly when designedccording to specific methodological criteria tomprove scientific knowledge.

THE IMPORTANCE OF OBSERVATIONALSTUDIES IN THE ERA OF

EVIDENCE-BASED MEDICINE

Currently, much debate exists over the meritf observational studies versus randomized tri-ls. Although observational studies have beenssential for gaining knowledge of the causesnd pathogeneses of many diseases, randomizedontrolled trials should provide the most robuststimate of causal effects. Nevertheless, it is aatter of fact that there are strengths in observa-

ional studies and limitations to randomized,ontrolled trials. In particular, the use of verytrict inclusion criteria in randomized, controlledrials can lead to results with limited externalalidity, thus reducing the ability to generalizehem to conditions of everyday clinical practice.onsidering that clinical trials are expensive in

erms of money and time and thus not alwayseasible, a more careful and thoughtful approacho implementing and interpreting observationaltudies is therefore needed. In addition, certainlinical practices cannot be tested against place-os, and their role can be ascertained only inbservational studies.Observational studies may also represent an

ssential means to generate and investigate hy-otheses, thus helping investigators to select thenterventions that will be more appropriatelyssessed by clinical trials in a subsequent phase.oreover, in particular circumstances observa-

ional studies may have the chance to attain morer less the same benefits and credibility of ran-omized trials.18 Restriction in research topics,uch as choosing to analyze only those candidate

gents with a high probability of being causal i

actors, may therefore become a methodologicalequisite of paramount importance. Many im-rovements in the design and analysis of observa-ional studies have been directed toward appropri-te adjustments for potential confounding factors.he importance of measuring confounding vari-bles accurately and precisely is often underap-reciated.Another important point is ensuring that covari-

tes are modelled correctly, taking into accountheir nonlinear associations and interactions. Inhis context, the DOPPS, a unique observationaltudy in terms of the magnitude of the informa-ion prospectively collected from a large, repre-entative sample of hemodialysis patients, andhose analyses have been adjusted for a wide

ange of case-mix characteristics, represents atriking example of how a well-designed observa-ional study may become a major source ofeaningful information aimed at improving clini-

al practice as well as a randomized, controlledlinical trial.

LEVEL OF ANEMIA MANAGEMENT INHEMODIALYSIS PATIENTS: FINDINGS FROM

THE DOPPS

Among several practice patterns and out-omes, the DOPPS has evaluated anemia manage-ent with rHuEPO and intravenous iron prepara-

ions, as well as the control of anemia over time,ased on data collected from 101 representativeialysis facilities in 5 European countries (France,ermany, Italy, Spain, and the United Kingdom)

n 1998 to 2000 (DOPPS I)19 and from 309epresentative dialysis facilities in 12 countriesAustralia, Belgium, Canada, France, Germany,taly, Japan, New Zealand, Spain, Sweden, thenited Kingdom, and United States) from 2002

o 2003 (DOPPS II).20 As the results from theOPPS suggest, large variations in anemia man-

gement may be observed among the differentountries. Indeed, the mean hemoglobin concen-rations in prevalent hemodialysis patients variedidely across the studied countries, ranging from0.1 g/dL to 12.0 g/dL (101 g/L to 120 g/L) (Fig). The percentage of patients with a hemoglobinalue lower than 11 g/dL (110 g/L) (ie, below thearget recommended by both the K/DOQI guide-ines and the European Best Practice Guidelines)lso ranged widely, from 23% to 77%, depend-

ng on the country (Fig 2).20 Factors such as

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ANEMIA MANAGEMENT S29

emale sex, catheter use, and history of cancer orastrointestinal bleeding were significantly asso-iated with lower hemoglobin levels in prevalentemodialysis patients.19,20

Despite the reported differences and large de-iations from guidelines observed in some coun-ries, significant improvement has been observedn anemia management in the last few years,iven that the overall median hemoglobin of theEuropean DOPPS I countries increased from

0.8 g/dL (108 g/L) in 1998 to 1999 to 11.1 g/dL111 g/L) in 2000, and the percentage of patientsith hemoglobin �11.0 g/dL (110 g/L) increased

rom 46% to 53% over the same period.19

The percentage of prevalent hemodialysis pa-ients being prescribed rHuEpo has increased asell, given that both the lowest value observed

n France and the highest value observed in thenited Kingdom increased between 2000 and002 to 2003 (from 75% to 83% and from 92%o 94%, respectively).19,20 Although the majorityf prevalent hemodialysis patients receiveHuEpo, the same is not true of patients startingemodialysis. Indeed, only 21% to 65% of inci-ent hemodialysis patients received rHuEpo dur-

Fig 1. Mean hemoglobin concentrations among prncident dialysis patients (within 7 days of first hemodio g/L, multiply by 10. (Data from Pisoni et al.20)

ng the pre–end stage renal disease period. t

orrespondingly, their mean hemoglobin concen-rations were lower and percentage of patientsompliant with the recommendation of the inter-ational guidelines was lower at the time oftarting hemodialysis, when compared withrevalent dialysis patients (Figs 1 and 2). Further-ore, even if time-trend analyses show that a

ignificant increase in both mean hemoglobinoncentration and the percentage of rHuEpo useccurs during the first months after beginningemodialysis, several months are yet requiredor hemoglobin concentration to rise to the rec-mmended level (Fig 3).19,20 Considering thatnemia is a relatively early complication of CKD,sually arising some years before the need forenal replacement treatment is reached,3,7 it mayherefore be expected that a considerable propor-ion of patients remain in an anemic state for arolonged time before the initiation of dialysis.umerous recent studies have pointed to detri-ental pathophysiologic consequences associ-

ted with poor anemia control during the earlyhases of CKD, especially promotion of cardio-ascular disease.The percentage of prevalent hemodialysis pa-

t hemodialysis patients (on dialysis >180 days) andreatment) in DOPPS II. To convert hemoglobin in g/dL

evalen

ients receiving intravenous iron varies greatly

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mong DOPPS countries, ranging from 38% to9%.19,20 In some countries, a large fraction ofatients (31%-38%) have indications for ironeficiency, according to the K/DOQI and Euro-ean Best Practice Guidelines, namely a trans-errin saturation of less than 20%.20 DOPPSnalyses show that transferrin saturation valueseem to be unrelated to the administration ofntravenous iron, as large proportions of patientsontinue to have low levels of transferrin satura-ion, even in countries with high use of intrave-ous iron.20 Although additional factors, such asumulative iron doses, blood losses, and inflam-ation levels, could be involved in the explana-

ion of these results, they may also suggest thatron supplementation, not just rHuEpo adminis-ration, is often inadequate in hemodialysis pa-ients.

THE CHALLENGE OF IMPLEMENTINGCLINICAL GUIDELINES IN MEDICAL PRACTICE

Overall, the DOPPS data show that, despitehe availability of practice guidelines for thereatment of renal anemia, wide variation innemia management exists as a gap betweenhat is recommended by the guidelines and what

s accomplished in everyday clinical practice.

Fig 2. Percentage of patients with hemoglobin <11ialysis >180 days) and incident dialysis patients (withrom Pisoni et al.20)

ncreasing awareness of the recommendations of p

nternational practice guidelines has led, how-ver, to considerable changes in anemia manage-ent practices during the last few years and has

ed to large improvements in the control ofnemia for hemodialysis patients. These results,herefore, remind us of the importance of imple-enting clinical guidelines. Compliance with

linical guidelines is an important indicator ofuality and efficacy of patient care.21 Improve-ent in patient outcomes can be expected when

uidelines are more closely followed. At theame time, their adoption in clinical practice maye mitigated by numerous factors, including clini-al expertise, patient preferences, constraints ofublic health policies, community standards, andudgetary limitations.22

Nevertheless, whereas large efforts have beenade to develop practice guidelines, much has

till to be done to encourage implementation ofhe guidelines. As this is the only way to ensureeal improvement in health care outcomes, it isherefore mandatory that more emphasis is placedn implementation strategies, including the devel-pment of local implementation support sys-ems, clinical audit programs, and methods ofeeding back information concerning current

<110 g/L) among prevalent hemodialysis patients (onays of first hemodialytic treatment) in DOPPS II. (Data

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ANEMIA-CONTROLLED OUTCOMES

Another important contribution of the DOPPSs the finding of a strong association betweenigher hemoglobin concentrations and improvedealth outcomes.19,20 This confirms the recom-endations of clinical guidelines. Lower hemo-

lobin is associated with significantly higheratient morbidity (as measured by hospitaliza-ion) and mortality at least for hemodialysisatients. Indeed, before the publication of theOPPS results, only a few studies had examinedith detailed adjustment for associated comor-idities whether adherence to guidelines for he-oglobin in clinical practice really was associ-

ted with better clinical outcomes. Studies havehown considerable differences in the extent ofn impact of anemia control and outcomes23 orven their failure in improving patient outcomeshen applied in prospective, multimember, and

andomized trials.24

Although the results of these studies haveeen somewhat disappointing, the results mayave been conditioned by some points of weak-ess in the studies themselves, not least the facthat many of them were performed on selectedopulations of patients, thus precluding the gen-ralizability of their results.25 The DOPPS has

Fig 3. Time trend in rHuEpo use and mean hemoglonvert hemoglobin in g/dL to g/L, multiply by 10. Reprniversity Press, © 2003 European Renal Association—

roperly overcome this limitation, and its analy- r

es have been performed on very large popula-ions of hemodialysis patients, using adjustmentsor a large number of patient case-mix character-stics. This is particularly important for anemiaanagement, given the substantial differences

oted by the DOPPS across countries. Suchifferences include causes of end-stage renalisease, comorbidities, hospitalization rates, vas-ular access use, and other hemodialysis prac-ices, which may affect anemia and its manage-ent practices.26,27 In this context, the DOPPS

howed that higher hemoglobin concentrationsre associated with better outcomes in hemodialy-is patients, independent of potentially confound-ng factors, with the adjusted risk for mortalitynd hospitalization, respectively, 4% to 5% and% to 6% lower for every 1 g/dL (10 g/L) higheremoglobin concentration (Fig 4).19,20 Althoughhe DOPPS results, being observational, cannotrove causality, they do provide additional evi-ence that supports the validity of the practiceuidelines for managing CKD-related anemia.ccording to a recent analysis of the DOPPSata that assumes causality, it has been estimatedhat treating all patients in the United States withemoglobin below 11 g/dL (110 g/L) to bringhem within the recommended levels, would

oncentration by time since starting hemodialysis. Torom Locatelli et al,19 with the permission of the Oxfordean Dialysis and Transplant Association.

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esult in 23,910 life years potentially gained over

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5-year period.28 These results suggest that aignificant trend toward improved outcomes inemodialysis patients may be expected by wide-pread implementation of these guidelines.

CONCLUSIONS

The international results shown by the DOPPSn the management of anemia secondary to CKDn hemodialysis patients indicate that, althoughome improvements have occurred in anemiaanagement practices since the publication of

nternational guidelines, significant variations inractice are still observed among countries, andany efforts are still needed for the greater

roportion of patients to reach the target hemoglo-in concentrations recommended by clinical prac-ice guidelines. The challenge is important toesolve because the results of the DOPPS clearlyhow that hemoglobin concentration is stronglyssociated with the risk of hospitalization andeath in hemodialysis patients. Significantly im-

Fig 4. Relationship between patient hemoglobin conzation in DOPPS I. To convert hemoglobin in g/dL to germission from the National Kidney Foundation.

roved outcomes may be expected by a more 1

idespread achievement of the recommendedemoglobin levels. Collecting data from a large,epresentative population of hemodialysis pa-ients from different countries, analyzing it, anddjusting for numerous patient case-mix charac-eristics, has allowed the DOPPS to show how anbservational study, if performed under specificethodological circumstances, may become

ighly informative and credible, while also prov-ng to be a basic instrument for monitoring themplementation of clinical guidelines in every-ay clinical practice.

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