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Kidney International, Vol. 57 (2000), pp. 578–589 CLINICAL NEPHROLOGY – EPIDEMIOLOGY – CLINICAL TRIALS Anemia management of adult hemodialysis patients in the U.S.: Results from the 1997 ESRD Core Indicators Project DIANE FRANKENFIELD,CURTIS A. JOHNSON,JAY B. WISH,MICHAEL V. ROCCO,FRANCOIS MADORE, and WILLIAM F. OWEN,JR, for the ESRD CORE INDICATORS WORKGROUP Health Care Financing Administration, Baltimore, Maryland, USA; School of Pharmacy, University of Wisconsin, Madison, Wisconsin, USA; Division of Nephrology, University Hospitals of Cleveland, Cleveland, Ohio, USA; Section of Nephrology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; Centre de Recherche, Ho ˆ pital du Sacre ´-Coeur, Universite ´ de Montreal, Montreal, Quebec, Canada; and Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA of patients with transferrin saturation ,20% and serum ferritin Anemia management of adult hemodialysis patients in the concentration ,800 ng/mL, only 53% were prescribed intrave- U.S.: Results from the 1997 ESRD Core Indicators Project. nous iron. Multivariate linear regression analysis revealed that Background. The Health Care Financing Administration’s serum albumin, urea reduction ratio, age, and transferrin satu- End-Stage Renal Disease (ESRD) Core Indicators Project col- ration were significantly positively associated with hematocrit. lects clinical information on prevalent adult patients receiving in-center hemodialysis (HD) care in the United States to assess Epoetin alfa dose and serum ferritin concentration were sig- the quality of care delivered. Although hematocrit values, nificantly and negatively associated with the hematocrit (P , transferrin saturations, and iron prescription practices have 0.001). improved over the last five years, we sought to determine Conclusion. Although substantial improvements have been whether continued opportunities for improvement of this do- made in anemia management for adult in-center HD patients main of care exist. over the past five years, significant opportunities persist to Methods. A random sample of 7292 adult in-center HD pa- improve iron prescription practices. tients was selected. Dialysis facility staff provided clinical infor- mation for the period of October through December 1996 for 6858 (94%) patients; complete laboratory information was Of the processes of patient care that affect the survival available from 4991 (73%) returned forms. Hematocrit values, transferrin saturations, serum ferritin concentrations, epoetin and hospitalization frequency of end-stage renal disease alfa dosing, and iron prescriptions were abstracted from patient (ESRD) patients, the correction of anemia is particularly medical records to assess anemia management practices. useful for scrutiny. The principal measures of outcome Results. The mean hematocrit for this cohort was 32.6 6 (hematocrit and/or hemoglobin) are routinely collected 3.5%. Seventy-two percent of patients had hematocrit values and are easy to interpret, and interventions are available .30%. Forty-two percent had hematocrit values of 33 to 36%, and 10% were severely anemic (hematocrit ,28%). Ninety- to improve this measure. Multiple data sets have de- four percent of the patients received epoetin alfa intravenously scribed a strong, reproducible statistical association be- (i.v.) and 6% subcutaneously. The mean weekly dose was 202.4 tween odds of death and hemoglobin [1, 2]. Thus, anemia 6 137.2 units/kg. The mean transferrin saturation was 27.4 6 is a predictable and correctable outcome measure for 12.6%; 73% of patients had a mean transferrin saturation $20%. The mean serum ferritin concentration was 386 6 422 ESRD patients that deserves monitoring. The National ng/mL; 79 and 12% of patients had a serum ferritin concentra- Kidney Foundation’s Dialysis Outcomes Quality Initia- tion of .100 and .800 ng/mL, respectively. Nine percent of tive (DOQI) Clinical Practice Guidelines for the Treat- the sample (N 5 434) had a transferrin saturation ,20% and ment of Anemia of Chronic Renal Failure describe clini- serum ferritin concentration ,100 ng/mL. Regardless of the cal performance goals for this process of patient care patient’s transferrin saturation, approximately three fourths of the patients received either oral or i.v. iron, and only approxi- [3]. These guidelines advocate benchmark hematocrit mately one half of the patients received i.v. iron. Of the subset values of 33 to 36%, transferrin saturation $20%, serum ferritin concentrations $100 ng/mL, and more wide- spread use of parenteral iron. Key words: end-stage renal disease, hematocrit, erythropoietin, trans- ferrin, serum ferritin, dialysis, iron. The Health Care Financing Administration’s (HCFA’s) national ESRD Core Indicators Project profiles interme- Received for publication December 22, 1998 diate outcomes for a representative sample of adult and in revised form July 22, 1999 Accepted for publication August 13, 1999 (aged $18 years), in-center hemodialysis (HD), and am- bulatory peritoneal dialysis patients [4]. A principal goal 2000 by the International Society of Nephrology 578

Anemia management of adult hemodialysis patients in the U.S.: Results from the 1997 ESRD Core Indicators Project

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Page 1: Anemia management of adult hemodialysis patients in the U.S.: Results from the 1997 ESRD Core Indicators Project

Kidney International, Vol. 57 (2000), pp. 578–589

CLINICAL NEPHROLOGY – EPIDEMIOLOGY – CLINICAL TRIALS

Anemia management of adult hemodialysis patients in theU.S.: Results from the 1997 ESRD Core Indicators Project

DIANE FRANKENFIELD, CURTIS A. JOHNSON, JAY B. WISH, MICHAEL V. ROCCO, FRANCOIS

MADORE, and WILLIAM F. OWEN, JR, for the ESRD CORE INDICATORS WORKGROUP

Health Care Financing Administration, Baltimore, Maryland, USA; School of Pharmacy, University of Wisconsin,Madison, Wisconsin, USA; Division of Nephrology, University Hospitals of Cleveland, Cleveland, Ohio, USA; Sectionof Nephrology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; Centre de Recherche,Hopital du Sacre-Coeur, Universite de Montreal, Montreal, Quebec, Canada; and Renal Division, Brigham and Women’sHospital, Harvard Medical School, Boston, Massachusetts, USA

of patients with transferrin saturation ,20% and serum ferritinAnemia management of adult hemodialysis patients in theconcentration ,800 ng/mL, only 53% were prescribed intrave-U.S.: Results from the 1997 ESRD Core Indicators Project.nous iron. Multivariate linear regression analysis revealed thatBackground. The Health Care Financing Administration’sserum albumin, urea reduction ratio, age, and transferrin satu-End-Stage Renal Disease (ESRD) Core Indicators Project col-ration were significantly positively associated with hematocrit.lects clinical information on prevalent adult patients receiving

in-center hemodialysis (HD) care in the United States to assess Epoetin alfa dose and serum ferritin concentration were sig-the quality of care delivered. Although hematocrit values, nificantly and negatively associated with the hematocrit (P ,transferrin saturations, and iron prescription practices have 0.001).improved over the last five years, we sought to determine Conclusion. Although substantial improvements have beenwhether continued opportunities for improvement of this do- made in anemia management for adult in-center HD patientsmain of care exist. over the past five years, significant opportunities persist to

Methods. A random sample of 7292 adult in-center HD pa- improve iron prescription practices.tients was selected. Dialysis facility staff provided clinical infor-mation for the period of October through December 1996for 6858 (94%) patients; complete laboratory information was

Of the processes of patient care that affect the survivalavailable from 4991 (73%) returned forms. Hematocrit values,transferrin saturations, serum ferritin concentrations, epoetin and hospitalization frequency of end-stage renal diseasealfa dosing, and iron prescriptions were abstracted from patient (ESRD) patients, the correction of anemia is particularlymedical records to assess anemia management practices. useful for scrutiny. The principal measures of outcomeResults. The mean hematocrit for this cohort was 32.6 6

(hematocrit and/or hemoglobin) are routinely collected3.5%. Seventy-two percent of patients had hematocrit valuesand are easy to interpret, and interventions are available.30%. Forty-two percent had hematocrit values of 33 to 36%,

and 10% were severely anemic (hematocrit ,28%). Ninety- to improve this measure. Multiple data sets have de-four percent of the patients received epoetin alfa intravenously scribed a strong, reproducible statistical association be-(i.v.) and 6% subcutaneously. The mean weekly dose was 202.4

tween odds of death and hemoglobin [1, 2]. Thus, anemia6 137.2 units/kg. The mean transferrin saturation was 27.4 6is a predictable and correctable outcome measure for12.6%; 73% of patients had a mean transferrin saturation

$20%. The mean serum ferritin concentration was 386 6 422 ESRD patients that deserves monitoring. The Nationalng/mL; 79 and 12% of patients had a serum ferritin concentra- Kidney Foundation’s Dialysis Outcomes Quality Initia-tion of .100 and .800 ng/mL, respectively. Nine percent of tive (DOQI) Clinical Practice Guidelines for the Treat-the sample (N 5 434) had a transferrin saturation ,20% and

ment of Anemia of Chronic Renal Failure describe clini-serum ferritin concentration ,100 ng/mL. Regardless of thecal performance goals for this process of patient carepatient’s transferrin saturation, approximately three fourths of

the patients received either oral or i.v. iron, and only approxi- [3]. These guidelines advocate benchmark hematocritmately one half of the patients received i.v. iron. Of the subset values of 33 to 36%, transferrin saturation $20%, serum

ferritin concentrations $100 ng/mL, and more wide-spread use of parenteral iron.Key words: end-stage renal disease, hematocrit, erythropoietin, trans-

ferrin, serum ferritin, dialysis, iron. The Health Care Financing Administration’s (HCFA’s)national ESRD Core Indicators Project profiles interme-

Received for publication December 22, 1998diate outcomes for a representative sample of adultand in revised form July 22, 1999

Accepted for publication August 13, 1999 (aged $18 years), in-center hemodialysis (HD), and am-bulatory peritoneal dialysis patients [4]. A principal goal 2000 by the International Society of Nephrology

578

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Frankenfield et al: Anemia management and iron administration 579

of the ESRD Core Indicators Project is to identify cate- were examined using data from the 1997 ESRD CoreIndicators Project.gorical variability in intermediate outcomes of dialysis

care, such as the management and correction of anemiawith recombinant human erythropoietin (epoetin alfa) METHODSand iron. After having identified patterns of variability,

Study design and patient selectionthe goal at the level of the provider of dialysis servicesThe study design and sampling strategy used in theis to facilitate the recognition of opportunities for the

ESRD Core Indicators Project are described in detailimprovement of care [5]. In the case of anemia manage-elsewhere [4, 10]. Briefly, all Medicare-eligible, adultment, this translates into optimizing the hematocrit withESRD patients receiving in-center HD on December 31,epoetin alfa and iron therapy. Using the DOQI Clinical1996, were eligible for inclusion in the sample. A randomPractice Guidelines as clinical performance goals, thesample of patients, stratified by the ESRD Networks,ESRD Core Indicators Project indicates that substantialwas drawn. The sample size (N 5 7292) was estimatedimprovement has occurred in the management of anemiato provide a 95% confidence interval of 65% for ESRDfrom late 1993 to late 1996 [4]. The mean hematocrit forNetwork-specific estimates.adult in-center HD patients increased from 30.5% in

October through December 1993 to 32.7% in OctoberData collection

through December 1996. The proportion of patients withPatient demographic and clinical information weremean hematocrit values .30% increased from 46% in

collected for the months of October to December 1996,late 1993 to 72% in late 1996. The proportion of HDincluding the first monthly recorded hematocrit value,patients with severe anemia, defined as a mean hemato-transferrin saturation, and serum ferritin concentration.crit value ,28%, declined from 23 to 10% over this sameOther abstracted information relating to anemia man-time period. These data are consistent with observationsagement practices included the prescribed weekly epoe-from other databases. For example, the U.S. Renal Datatin alfa dose and route of administration and informationSystem (USRDS) reported in its 1997 Annual Reportregarding the type and route of iron administration.that as of the last quarter of 1995, the mean and medianOther clinical information abstracted from the patients’hematocrit values among epoetin alfa-treated patientscharts included first monthly predialysis and postdialysiswere 31.4 and 32.0%, respectively [6]. From 1993 to 1996,blood urea nitrogen (BUN) concentration and predial-the mean epoetin alfa dose increased from approxi-ysis and postdialysis body weight (kg) to calculate themately 10,500 to 14,350 units per week [7].urea reduction ratio (URR) and single-pool Kt/V (calcu-Despite these improvements in the hematocrit of adultlated using the second-generation formula of Daugirdas

HD patients, opportunities remain for improvement in[11]), delivered HD time at the session the BUN mea-

the management of anemia. In the aforementioned surements were drawn, and first monthly serum albuminHCFA report, the percentage of adult HD patients with concentration [measured by either the bromcresol greena hematocrit of 33 to 36% was only 42% [4]. The USRDS (BCG) or the bromcresol purple (BCP) assay]. Informa-investigators observed that more than 50% of epoetin tion on the relative timing of doses of intravenous ironalfa-treated patients were iron deficient [8, 9]. The and the measurement of the transferrin saturation andUSRDS reported that in 1993, 25% of dialysis patients serum ferritin concentrations was not captured. Valida-received no form of iron supplementation, and only tion of the abstracted data was conducted by Network11.2% received intravenous iron [9]. Arguably, further personnel on a random 5% patient sample by review ofimprovement in anemia management can be achieved the medical charts. No significant differences were foundby improvement in this parameter. This is particularly in the abstraction of the data for any clinical measuresignificant in view of the attenuated effect of epoetin [12].alfa in the absence of optimal iron stores [1, 2] and thelarge Medicare expenditures for this hormone (approxi- Data analysismately $1.5 billion per year) [6]. Regional analysis of Patients with missing laboratory data were excludedthe ESRD Core Indicators data has shown significant from further analysis. Because of the small number ofvariation among ESRD Networks for several anemia- samples processed using the BCP assay, the final datarelated clinical parameters, such as hematocrit values, analysis was restricted to the preponderance of patientstransferrin saturations, serum ferritin concentrations, whose serum albumin concentrations were determinedand patterns of iron administration [4]. Toward identi- by the BCG laboratory method only (83%). The averagefying specific domains of anemia management that may value of each clinical parameter was calculated frombe targets for national quality-improvement initiatives, the values available over the three-month observationpractice patterns for epoetin alfa and iron administration period and was used for subsequent analyses. Simple

descriptive statistical analysis was performed for the ini-among adult, in-center HD patients in the United States

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Frankenfield et al: Anemia management and iron administration580

Table 1. Descriptive characteristics of the study populationtial characterization of anemia management practices.For some analyses, transferrin saturations and serum Characteristic N (%)ferritin concentrations were divided at clinically relevant Total 4991 (100)

Gendercut points. Bivariate analyses, including chi-square, two-Male 2619 (52)tailed Student t-tests, and hierarchical analysis of vari-Female 2372 (48)

ance (ANOVA), were conducted to determine associa- RaceCaucasian 2534 (51)tions between variables. Mean values are presented asAfrican American 1857 (37)the mean 6 sd. A two-tailed P value , 0.01 was consid-Other 600 (12)

ered significant. Linear correlations were performed to Age (yrs)Median 62.0test for associations between mean hematocrit and sev-Meana 59.9615.3eral variables of interest.

Primary diagnosisMultivariate linear regression analysis was performed Diabetes mellitus 1924 (38)

Hypertension 1403 (28)in a stepwise fashion to adjust simultaneously for poten-Glomerulonephritis 669 (13)tial confounding variables and to identify independentOther/unknown 995 (20)

variables associated with hematocrit. Variables entered Years on dialysisMedian 2.2into the regression model included gender, race (Cauca-Meana 3.463.6sian and African American only), age, mean prescribed

Clinical measures (mean)weekly epoetin alfa dose (units/kg predialysis body wt/ URR 67.1%67.3%

Kt/Vb 1.3560.27week), mean transferrin saturation, mean serum ferritinSerum albumin 3.860.39concentration, mean URR, mean serum albumin con-a Mean 6 sdcentration, duration of dialysis (years), predialysis bodyb Kt/V calculated by the Daugirdas II formula [11]

weight (kg), and whether the patient had been prescribedintravenous iron at least once during the three-monthstudy period.

tients (18- to 44-year-old) had significantly lower hema-All data analyses were performed using Epi Info (ver-tocrit values compared with older patients (P , 0.001),sion 6.04) [13] and SPSS for Windows (version 6.1) [14].despite having significantly higher prescribed weeklyepoetin alfa doses (P , 0.001). A significant variation

RESULTS was seen among the ESRD Networks for the percentageThe dialysis facility response rate was 94% (6858 out of patients with hematocrit values $33%, ranging from

of 7292). Complete laboratory information was available 41 to 62% (P , 0.001; Fig. 1). Significant differences infrom 4991 (73%) of the returned forms that formed mean hematocrit, prescribed epoetin alfa doses, meanthe final sample for analysis. There were no significant transferrin saturation values, and mean serum ferritindifferences in patient demographic characteristics in the concentration were noted by category of Kt/V values.group of patients with complete data and the group of Patients with Kt/V ,1.2 had significantly lower meanpatients with incomplete data. The descriptive character- hematocrit, prescribed epoetin alfa doses, transferrin sat-istics of the final patient group are listed in Table 1. The uration values, and serum ferritin concentration com-group was 52% male, 51% Caucasian, and 37% African pared with patients with Kt/V $1.2 (Table 2). LinearAmerican and had a median age of 62 years. Thirty- correlation analysis revealed a positive linear relation-eight percent of the patients had diabetes mellitus as a ship between mean hematocrit and mean Kt/V (r 2 5primary cause of ESRD. 0.01, P , 0.001).

The mean hematocrit value for the sample for analysis Greater serum albumin concentrations were associ-was 32.6 6 3.5%, which was increased from 30.5 6 3.9% ated with higher hematocrit values across all demo-in 1993 (P , 0.001). Seventy-two percent of patients graphic categories (Tables 2 and 3). Linear correlationhad hematocrit values of .30%. Forty-two percent of analysis revealed a positive linear relationship betweenpatients had hematocrit values of 33 to 36%, and 10% the mean hematocrit and mean serum albumin concen-of patients had a mean hematocrit value of ,28%. Al- tration (r 2 5 0.034, P , 0.001). Stratification by quartilesthough no difference was observed for hematocrit values of serum albumin revealed a similar inverse relationshipbetween men and women, this was at the expense of between serum albumin concentration and epoetin alfaapproximately 20% more epoetin alfa prescribed to dosing. Patients with serum albumin concentrations inwomen (P , 0.001; Table 2). Caucasians had, on average, the lowest and highest quartile were prescribed, on aver-higher hematocrit values than African Americans (P , age, 234.3 units/kg/week and 186.6 units/kg/week of0.01), although each were prescribed the same amount epoetin alfa, respectively (P , 0.01). The mean serumof epoetin alfa. However, the clinical significance of the albumin concentrations of patients in the lowest and

highest quartiles were 3.2 and 4.2 m/dL, respectivelyracial difference in hematocrit was small. Younger pa-

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Frankenfield et al: Anemia management and iron administration 581

Table 2. Mean hematocrit values, prescribed epoetin alfa doses, and iron status by selected patient and clinical care parameters

Serum % of Patients withHematocrit Epoetin dose Transferrin sat % of Patients with ferritin serum ferritin

% units/kg/week % transferrin Sat $20% ng/mL $100 ng/mL

Total 32.6 202.4 27.4 73 385.8 79Gender

Male 32.6 186.8b 27.5 73 365.1b 78Female 32.5 219.5 27.2 72 408.6 80

RaceCaucasian 32.7a 199.2 27.1 72 380.5 78African American 32.4 204.3 27.6 73 395.4 81

Age years18–44 32.1b 222.3b 29.3b 74 353.7a 73b

45–64 32.6 195.5 27.0 72 380.0 80651 32.8 200.1 27.0 72 403.4 81

Primary diagnosisDiabetes mellitus 32.7 192.5b 26.4b 72a 370.6 80Hypertension 32.6 201.8 27.3 72 379.6 80Glomerulonephritis 32.6 208.8 28.8 78 393.6 77Other/unknown 32.6 217.9 28.6 72 418.6 78

Years on dialysis,0.5 31.4a 209.1 24.1b 56b 283.2a 72b

0.5–1 32.7 194.5 27.7 73 325.1 761–2 32.8 193.5 27.0 72 380.6 8121 32.7 206.6 28.1 76 423.3 81

Kt/V quartile,1.2 31.9b 197.5b 26.7a 68b 357.4b 76a

1.2–1.35 32.8 193.5 27.1 73 360.3 781.36–1.5 32.7 199.4 27.4 73 387.8 80.1.5 32.9 218.0 28.4 77 435.2 82

Serum albumin g/dL,3.00 30.2b 260.1b 29.8b 69b 537.2b 873.00–3.49 31.7 241.1 25.9 64 390.7 773.50–3.79 32.6 197.6 27.2 72 385.2 793.80–4.09 33.0 189.9 27.4 75 372.2 794.101 33.1 186.6 28.6 79 377.0 80

Network quartile(by mean hematocrit)

1 (lowest) 32.1b 188.0b 27.6 73 380.2 802 32.4 208.8 27.2 71 386.9 773 32.7 210.1 27.8 73 380.1 804 33.1 201.7 27.1 74 394.2 80a P , 0.01 and b P , 0.001, statistically significant differences between patient characteristic groups

Fig. 1. Percentage of patients with hemato-crit values $33% by ESRD Networks. Sig-nificant difference among Networks, P ,0.001.

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Frankenfield et al: Anemia management and iron administration582

Table 3. Mean hematocrit values by selected patient characteristics, stratified by serum ferritin concentration, transferrin saturation,prescribed weekly epoetin alfa dose, and serum albumin concentration

Mean hematocrit value %

GenderRace

Age group yearsAfrican

Males Females Caucasians Americans 18–44 45–64 651

Total 32.6 32.5 32.7a 32.4 32.1b 32.5 32.8Serum ferritin concentration quartile

1 32.8a 32.3 32.5 32.7 32.3 32.4 32.92 32.8 32.8 33.0 32.5 32.5 32.7 33.03 32.5 32.6 32.6 32.4 31.9 32.5 32.84 (highest) 32.4 32.5 32.7a 32.0 31.6a 32.5 32.6

Transferrin saturation category,20% 31.8 31.9 32.1a 31.5 31.0b 31.6 32.420–25.69% 32.6 32.5 32.6 32.5 32.1 32.6 32.725.75–32.99% 33.0 33.0 32.9 33.0 32.6 32.9 33.233%1 33.3 32.9 33.2 32.8 32.7 33.3 33.2

Weekly epoetin alfa dose (units/kg) quartilec

1 32.6 32.5 32.7 32.4 32.2 32.5 32.82 32.0 32.2 32.2 32.0 31.5a 32.1 32.33 31.5 31.8 31.8 31.4 31.1b 31.4 32.14 (highest) 30.8 30.9 31.1a 30.5 30.3a 30.7 31.3

Serum albumin concentration,3.5 g/dL 31.0 31.4 31.4 30.8 29.9b 31.2 31.6$3.5 g/dL 32.9 32.8 33.0 32.7 32.4b 32.8 33.1a P , 0.01 and b P , 0.001, Statistically significant differences within patient demographic subgroups for each level of the clinical parameterc For the subset of patients with hematocrit ,36%

(P , 0.001). There was a significant positive association with the lowest mean hematocrit values also had signifi-cantly lower prescribed doses of epoetin alfa (P , 0.001)between predialysis body weight and serum albumin con-

centrations (r 2 5 0.0065, P , 0.001). Employing stepwise compared with the other quartiles of Networks (Table2). No other statistically significant correlations werelinear regression that used the predialysis body weight

and serum albumin concentration as independent vari- noted.Mean hematocrit values stratified by weekly pre-ables and weekly epoetin alfa dose as the dependent

variable, a stronger association of predialysis body scribed epoetin alfa dose (units/kg), categories of trans-ferrin saturation, serum ferritin concentration, and se-weight compared with serum albumin concentration was

observed (F statistic 415.4 vs. 249.6, respectively). Strati- rum albumin concentration are presented in Table 3.Indifferent of the demographic category, the hematocritfication by quartiles of predialysis body weight revealed

an inverse relationship between body weight and epoetin tended to be lower at higher epoetin alfa doses. Similarly,the hematocrit tended to increase as transferrin satura-alfa dosing. Patients in the lowest quartile of body weight

were prescribed on average 260.6 units/kg of epoetin alfa tion increased from ,20 to 32.9%. Among the subsetof patients with transferrin saturation ,20%, Africanweekly, whereas patients in the highest quartile were

prescribed on average 157.8 units/kg weekly (r 2 5 0.8657, American and younger patients (18 to 44 years) wereagain observed to have lower hematocrit values thanP , 0.01). The mean predialysis weights of the patients

in the lowest and highest quartile were 54.1 and 100.0 Caucasians and older patients (P , 0.01 and P , 0.001,respectively). No clear trends were observed for the in-kg, respectively (P , 0.001).

Ninety-four percent of the patients were prescribed teraction between the serum ferritin concentration, de-mographics, and the hematocrit.epoetin alfa intravenously and 6% subcutaneously. The

mean prescribed weekly epoetin alfa dose was 202.4 6 During the three-month period of observation, 27%of the patients had transferrin saturations ,20%. The137.2 units/kg. Within the subset of patients with hemato-

crit values of ,36%, an inverse relationship existed be- mean transferrin saturation value for all patients in thesample was 27.4% (6 12.6%). The frequency distribu-tween prescribed epoetin alfa doses and hematocrit val-

ues, with smaller doses associated with higher hematocrit tion of transferrin saturations is illustrated in Figure 2.Twenty-one percent of the patients had a serum ferritinvalues (r 2 5 0.044, P , 0.001; Table 3). There was a

significant geographic variation in the mean prescribed concentration of ,100 ng/mL. The mean serum ferritinconcentration for all patients was 386 ng/mL (6 422weekly epoetin alfa doses. Among ESRD Networks, pre-

scribed epoetin alfa doses ranged from 172.8 to 242.0 U/ ng/mL). Seventy-nine percent and 12% of the patientshad a serum ferritin concentration $100 ng/mL andkg/week (P , 0.001). The quartile of ESRD Networks

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Frankenfield et al: Anemia management and iron administration 583

Fig. 2. Frequency distribution profile ofmean transferrin saturation.

Table 4. Categories of iron status for the sample

Patients %

Transferrin saturation $20% 73Transferrin saturation ,20% 27Serum ferritin concentration $100 ng/mL 79Serum ferritin concentration ,100 ng/dL 21Serum ferritin concentration $100–800 ng/mL 68Serum ferritin concentration .800 ng/mL 12Transferrin saturation ,20% and serum ferritin

concentration ,100 ng/mL 9Transferrin saturation ,20% and serum ferritin

concentration $100–800 ng/mL 17Transferrin saturation ,20% and serum ferritin

concentration .800 ng/mL 2

.800 ng/mL, respectively (Table 4). Only 9% of thepatients (N 5 434) had “absolute iron deficiency,” de-fined as a transferrin saturation of ,20% and serum Fig. 3. Bivariate relationship between the mean hematocrit and the

mean transferrin saturation (R2 5 0.0104).ferritin concentration ,100 ng/mL [3, 15, 16]. Becausethe patients in this cohort were not observed for longerthan three months and the erythropoietic response toparenteral iron was not available, it was not possible to mean transferrin saturation yielded an r 2 of only 0.0004accurately distinguish the functional iron deficiency from (not significant). Patients with higher hematocrit valuesinflammation/infectious etiologies of a low transferrin tended to have greater transferrin saturations (r 2 5saturation and normal to elevated serum ferritin concen- 0.0104, P , 0.001). The bivariate relationship betweentration. However, for this report, “relative iron defi- transferrin saturation and hematocrit is illustrated in Fig-ciency” was defined as a transferrin saturation ,20% ure 3. The subset of patients with transferrin saturationand a serum ferritin concentration between 100 and 800 $20% had higher mean hematocrit values comparedng/mL (17% of the patients; Table 4). Most patients fell with patients with transferrin saturation ,20%, that is,into this category. 32.9 vs. 31.8%, respectively (P , 0.001).

Patients with transferrin saturation values ,20% were Patients with a mean hematocrit ,28% had higherprescribed on average 218.2 units/kg of epoetin alfa per serum ferritin concentration than those with a mean he-week compared with patients with transferrin saturation matocrit $28% (P , 0.001). Of patients with a meanvalues $20%, who were prescribed on average 196.4 hematocrit ,28%, 15% had a serum ferritin concentra-U/kg per week (P , 0.001). Linear regression analysis tion .800 ng/mL compared with 13% of those patients

with a mean hematocrit value .36% (not significant;of the mean prescribed weekly epoetin alfa dose versus

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Frankenfield et al: Anemia management and iron administration584

Table 5. Mean transferrin saturation, serum ferritin concentration, higher transferrin saturation values (P , 0.001) com-and categories of transferrin saturation and serum ferritin

pared with patients with serum albumin values $3.0concentration by categories of hematocritg/dL (Table 2). Among the subset of patients with a

Mean transferrin saturation serum ferritin concentration .800 ng/mL, the mean se-All patients 27.4rum albumin concentrations for patients with transferrinHematocrit category

,28% 26.2a saturation ,20% and $20% were 3.65 and 3.75 g/dL,28%–32% 26.1 respectively (P 5 NS).33%–36% 28.4

Although 77% of the patients were prescribed either.36% 30.3Patients with transferrin saturation $20% oral or intravenous iron at least once during the three-

All patients 73% month study period, only 54% of patients were pre-Hematocrit categoryscribed intravenous iron. When the patients were catego-,28% 60%a

28%–32% 69% rized into those with a transferrin saturation $20% and33%–36% 78%

,20% (73 and 27% of the sample, respectively), the.36% 79%

results were almost identical across categories (Table 6).Serum ferritin concentration ng/mLAll patients 386 Among the subset of patients with transferrin saturationsHematocrit category

,20%, only 78% were prescribed either oral or intrave-,28% 471a

nous iron at least once during the three months. Only28%–32% 37633%–36% 375 54% of these patients were prescribed intravenous iron..36% 393 Two hundred and ninety-eight (22%) of the 1363 pa-Patients with serum ferritin concentration $100 ng/mL

tients with transferrin saturations ,20% were not pre-All patients 79%Hematocrit category scribed iron by any route of administration. Among the

,28% 80% subset of patients with transferrin saturations $20%,28%–32% 78%only 77% were prescribed either oral or intravenous iron33%–36% 80%

.36% 77% at least once during the three months. Fifty-four percentPatients with serum ferritin concentration .800 ng/mL of this subset were prescribed intravenous iron, and 23%All patients 12%

were not prescribed iron by any route of administration.Hematocrit category,28% 15% Two hundred and seventy-two (26%) of the 1037 pa-28%–32% 11% tients with serum ferritin concentrations ,100 ng/mL33%–36% 11%

were not prescribed iron by any route of administration..36% 13%Analysis of the subgroup of patients with a mean hema-a Significant differences among hematocrit categories within groups, P , 0.001tocrit ,36% revealed similar patterns of iron prescrip-tion.

Of the 9% of the patient sample with absolute irondeficiency (transferrin saturation ,20% and a serum

Table 5). The mean hematocrit for patients with a trans-ferritin concentration ,100 ng/mL), only 38% were pre-

ferrin saturation ,20% and serum ferritin concentration scribed intravenous iron. Chi-square analysis of all the.800 ng/mL was 31.6%, not significantly different from patients and of the subset of patients with transferrinthe group with absolute iron deficiency (31.9%). Fifty- saturations ,20% revealed no significant difference inone percent of patients in this sample for analysis had the percentage of patients prescribed intravenous iron bytransferrin saturation $20% and a serum ferritin concen- categories of hematocrit. The percentage of patients pre-tration between 100 and 800 ng/mL. The mean hemato- scribed intravenous iron varied significantly by ESRDcrit for this subset was 32.9%, significantly higher than Network, ranging from 40 to 68% (P , 0.001). Similarly,the mean hematocrit values for the other two subsets there was significant variability by ESRD Network in(P , 0.001). Figure 4 displays the association between the percentage of patients with a transferrin saturationquartile of prescribed weekly epoetin alfa dose and mean ,20% and a serum ferritin concentration ,100 ng/mLhematocrit, by category of transferrin saturation. There that were prescribed intravenous iron (16 to 92%,was a consistent inverse relationship between prescribed P , 0.001).weekly epoetin alfa dose and hematocrit value, with The results of the multivariate linear regression analy-higher hematocrit values as transferrin saturation in- sis evaluating the association between several patientcreased for all quartiles of weekly epoetin alfa doses. As characteristics and laboratory clinical parameters withthe transferrin saturation increased, the effect of epoetin hematocrit are summarized in Table 7. The overall r 2 ofalfa on hematocrit status was attenuated. the final model was 0.101, indicating that approximately

Patients with serum albumin values ,3.0 g/dL had 10% of the variability in hematocrit values was ac-significantly lower mean hematocrit values (P , 0.001), counted for by the variables that remained in the model.

Patient gender, race, and weight did not remain in thehigher serum ferritin concentrations (P , 0.001), and

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Frankenfield et al: Anemia management and iron administration 585

Fig. 4. Relationship between the mean he-matocrit and quartiles of weekly epoetin alfadoses by transferrin saturation category. Sig-nificant differences among mean values byepoetin dose quartile, P , 0.01.

Table 6. Patterns of iron administration by categories of transferrin saturation and serum ferritin concentration

All patientsTransferrin saturation ,20% Transferrin saturation $20%

Percent of patients Percent of patientsOral iron 40b Oral iron 35Intravenous iron 38b Intravenous iron 42Both 16a Both 12Neither 22 Neither 23

Serum ferritin concentration ,100 ng/mL Serum ferritin concentration .800 ng/mLPercent of patients Percent of patients

Oral iron 47b Oral iron 29Intravenous iron 29b Intravenous iron 43Both 10 Both 14Neither 26 Neither 27

Patients with hematocrit ,36%Transferrin saturation ,20% Transferrin saturation $20%

Percent of patients Percent of patientsOral iron 41b Oral iron 35Intravenous iron 38b Intravenous iron 42Both 16 Both 13Neither 22 Neither 23

Serum ferritin concentration ,100 ng/mL Serum ferritin concentration .800 ng/mLPercent of patients Percent of patients

Oral iron 48b Oral iron 30Intravenous iron 28b Intravenous iron 43Both 11 Both 14Neither 26 Neither 27a Statistically significant differences between iron stores groups, P , 0.01b Statistically significant differences between iron stores groups, P , 0.001

final model nor did years on dialysis or the prescription tion, and age were all positively associated with hemato-of intravenous iron. In this model, each decade of in- crit (P , 0.001).creasing age was associated with an increase in hemato-crit of 0.23%. In this model, weekly prescribed epoetin

DISCUSSIONalfa dose and serum ferritin concentration were inverselyStrategies for optimal anemia management have beenassociated with hematocrit (P , 0.001), whereas the

URR, serum albumin concentration, transferrin satura- reported in the DOQI Clinical Practice Clinical Guide-

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Frankenfield et al: Anemia management and iron administration586

Table 7. Variables associated with hematocrit by multivariate linear regression analysisa

RegressionVariable F statistic coefficient se of coefficient

Epoetin alfa dose (1000 units/kg/week) 188 24.4 0.37Albumin g/dL 162 1.45 0.127URR % 130 4.91 0.690Age decade 108 0.23 0.03Transferrin saturation % 94 0.028 0.004Serum ferritin ng/mL 82 26.02 3 104 0.00012

All P values are ,0.001.aVariables included in the model: patient gender, race (Caucasian and African American only), age, mean prescribed weekly epoetin alfa dose (units/kg pre-

dialysis body wt), mean transferrin saturation, mean serum ferritin concentration, mean URR, mean serum albumin concentration, duration of dialysis (years), pre-dialysis body weight (kg), and whether the patient had been prescribed intravenous iron at least once during the three month study period.

lines for the Treatment of Anemia of Chronic Renal powerful predictor than in other analyses [1, 17], perhapsbecause of more variability of dose in our sample. An-Failure [3]. These guidelines advocate target hematocrit

values of 33 to 36%, transferrin saturation $20%, serum other possibility is that previous investigators includedother normalizing variables (that is, creatinine and anionferritin concentrations $100 ng/mL, and more wide-

spread use of intravenous iron. Data from the ESRD gap [1]) in their model. Serum albumin was the predictormost positively associated with increasing hematocrit,Core Indicators Project and the USRDS demonstrate

continual improvement in the hematocrit of American followed by URR, age, and transferrin saturation. Theinclusion of laboratory surrogates of nutrition like creati-HD patients since the availability of epoetin alfa [4, 6,

8]. However, this increment in hematocrit has occurred nine and anion gap, along with URR in the model, woulddiminish some of the predictive power of URR. Ourin the setting of an approximately 120% increase in epoe-

tin alfa doses from 1990 to 1996 [7]. The finding of an findings are consistent with those of other investigators,who have reported a similar association of serum albu-inverse relationship between the epoetin alfa dose and

hematocrit has been observed in other data sets and min and age with hematocrit [1]. In this analysis, thetransferrin saturation, a measure of iron availability tomay, in part, reflect physician prescribing patterns in the

setting of a hematocrit-linked ceiling for epoetin alfa the marrow for hemoglobin synthesis [15, 16], was simi-larly observed to predict hematocrit, as has been re-reimbursement and differential hormone responsive-

ness [1]. ported by others [1].In addition to the aforementioned statistical link be-This analysis, derived from a nationally representative

patient database, identifies an important area for im- tween laboratory surrogates of iron stores and hemato-crit, previous intervention studies have demonstrated theprovement, and a complimentary strategy for affecting

it that is within the domain of the dialysis care team, that impact of iron deficiency on anemia correction in theabsence and presence of epoetin alfa [1, 19–22]. Foris, correction of iron deficiency. Twenty-eight percent of

the prevalent patients did not achieve a mean hematocrit some ESRD patients, partial anemia correction has beenobserved with vigorous repletion of iron alone, that is,of 30%. Only 42% of the patients had mean hematocrit

values within the target range of 33 to 36%, as recom- in the absence of epoetin alfa [1, 22]. Supporting thisinterpretation is the observation that patients with highermended by the DOQI Clinical Practice Guidelines for

the Treatment of Anemia of Chronic Renal Failure [3]. hematocrit values had greater transferrin saturations.This study demonstrates that indifferent of the categoryPreviously reported demographic trends and statistical

linkages to hematocrit [1, 3, 17, 18] were noted in the of epoetin alfa dose, higher percentages of transferrinsaturation were associated with higher hematocrit val-current database, strengthening the validity of the obser-

vations reported herein. ues. For patients receiving the largest doses of epoetinalfa, increasing the transferrin saturation had the sameFactors other than iron therapy may be manipulated

to potentially improve the hematocrit, and thus should effect on the hematocrit as was observed with lowerepoetin alfa doses in the setting of adequate iron reple-similarly be included in continuous quality-improvement

initiatives for anemia. An example is the dose of HD. tion. As anticipated, the percentage of patients withtransferrin saturation $20% increased with greater he-It was striking that patients with inadequate delivered

doses of HD (Kt/V ,1.2) also had significantly lower matocrit values, and patients with transferrin saturation,20% tended to receive higher doses of epoetin alfa.hematocrits and prescribed epoetin alfa doses and iron

parameters. The concordance of these findings suggests Although iron management for American dialysis pa-tients has improved [8], it is still not optimal. Becausea possible need in care that crosses multiple domains of

service. The dialysis dose was observed to be a more of substantial ongoing iron losses associated with the

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Frankenfield et al: Anemia management and iron administration 587

provision of HD, most HD patients cannot have their hematocrits as men, but at the expense of higher epoetinalfa doses; and (d) nondiabetics have equivalent hemato-iron needs met by oral iron alone [1, 23–25]. However,

during the 90-day period of observation, approximately crits as diabetics, but require more epoetin alfa. Thestatistical associations between race, gender, and hema-25% of this nationally representative base of patients

received no iron supplements. Even among the 27% of tocrit are unsurprising in that similar patterns have beenobserved in healthy populations [1, 31, 32]. However,patients with overt iron deficiency, defined as a trans-

ferrin saturation ,20%, approximately one fourth of for the Core Indicators’ ESRD patients, there were nogender differences in iron stores like in healthy persons.these received no iron supplements. If parenteral iron

replacement is viewed as a best clinical intervention for Therefore, relative epoetin unresponsiveness amongwomen secondary to iron deficiency seems not to accountiron deficiency [3], approximately 50% of the patients

were not treated by this strategy. In that a similar pattern for this difference. The direct relationship between in-creasing age and hematocrit may be a reflection of theof iron replacement was observed for patients with trans-

ferrin saturations $20%, it appears that laboratory sur- discrepancy between prescribed and delivered epoetinalfa doses. The data analysis provided herein is based onrogates of iron stores were not a principal determinant of

when or how to intervene with iron replacement therapy. prescribed doses. Because epoetin alfa is administered aspart of the HD treatment, it is subject to the limitationsThis practice pattern is surprising in view of the routine

availability of parenteral iron, a supportive reimburse- of HD compliance. If patients miss HD sessions, theydo not receive their epoetin alfa. In that younger patientsment mechanism for parenteral iron, a facile means of

intradialytic administration [25, 26] and a low incidence miss dialysis sessions more often than older patients [33],the latter would be expected to have higher hematocritof significant acute side-effects [27]. Concern for long-

term toxicity has been raised by a recent retrospective values. Alternatively, age-associated differences in bloodpressure may have affected epoetin alfa dosing. The rela-analysis using HCFA billing data that suggested a delete-

rious correlation between putative dosing schedules for tively reduced dose of epoetin alfa needed by diabeticsis a novel finding. Patients with diabetes mellitus haveintravenous iron dextran and mortality, especially sec-

ondary to infectious events (abstracts; Collins et al, J often been excluded from intervention trials, and thus,the basis for this counter-intuitive finding is unexplained.Am Soc Nephrol 8:190A, 1997, and Collins et al, J Am

Soc Nephrol 9:205A, 1998). However, these findings have The lower hematocrit values for patients relatively newto HD may reflect: (a) late patient referral to nephrolo-not been validated in other data sets [28, 29]. Therefore,

iron administration is a domain of care that is readily gists, resulting in an inability to start epoetin alfa in atimely fashion prior to the initiation of chronic dialysiswithin the dialysis team’s control [30].

Because clinical practice in 1996 did not include wide- therapy [34]; (b) epoetin alfa resistance secondary touremia [35]; (c) a high prevalence of comorbid conditionsspread use of weekly or monthly maintenance intrave-

nous iron therapy, it is possible that the three-month that impact epoetin alfa responsiveness, such as vascularsurgeries, and/or limit its administration, such as inade-study period did not capture iron use in some patients

dosed less frequently. The Core Indicators data set does quately controlled hypertension; and/or (d) continuedactivity of the original disease that resulted in ESRD,not collect information on the timing of intravenous iron

administration with respect to the measurement of trans- such as systemic lupus erythematosus and hemolytic–uremic syndrome.ferrin saturations. However, the bias invoked by this

data limitation would favor higher transferrin satura- Not all HD patients will respond to iron replacementtherapy alone [22, 30, 36]. The multivariate analysis de-tions, thus strengthening our contention that continued

improvement is possible in iron management. scribed that approximately 90% of the variability in thehematocrit was accounted for by factors not included inHowever, this data set also illustrates that some com-

ponents of anemia correction may be more difficult for the model. Variables not included in the multivariatemodel that may impact the hematocrit are the presencethe dialysis care team to identify and thus control. For

example, this national data set did not identify regional of severe hyperparathyroidism [37, 38], aluminum intoxi-cation [39, 40], folate and vitamin B12 deficiencies [41],differences in measures of iron availability that corre-

lated with the geographic variability in hematocrit. This and particularly, comorbid conditions associated withblood loss, such as vascular access surgery and gastroin-negative correlation suggests that the other elements that

affect hematocrit may be defined by geographic regions. testinal bleeding.Recent reports have noted that laboratory surrogatesFurther investigation of this and other associations is

needed using data sets with more extensive elements. of an acute inflammatory state, such as the C-reactiveprotein (CRP), are also powerful statistical predictorsOther examples of inadequately understood associations

are that: (a) African Americans have lower hematocrits of the response to epoetin alfa [18]. Patients with higherlevels of CRP had lower hematocrit and albumin valuesthan Caucasians; (b) younger patients have lower hema-

tocrits than older patients; (c) women have equivalent and higher serum ferritin concentrations. Therefore, the

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Frankenfield et al: Anemia management and iron administration588

hematocrit and albumin may behave as negative acute- suggested values, and the data presented herein suggestthat many patients would benefit from even higher trans-phase reactants. In this analysis, patients with serum

albumin values ,3.0 g/dL had significantly lower mean ferrin saturation values. Third, monitoring for iron defi-hematocrit values, higher serum ferritin concentrations, ciency is not difficult, and corrective strategies are readilyand lower transferrin saturation values compared with available. Finally, substantial systematic cost savings maypatients with serum albumin values $3.0 g/dL. These be effected through improved anemia correction and itsfindings indicate that a subset of ESRD patients may beneficial effect on patient morbidity and mortality, andhave an inflammatory disorder or functional iron defi- by enhancing the effectiveness of epoetin alfa with ironciency that compromises their response to epoetin [15, (abstract; Collins et al, J Am Soc Nephrol 18:190A, 1997)16]. Functional iron deficiency or inflammation was the [1–3, 42, 43]. Furthermore, as demonstrated by the analy-predominant disorder, rather than absolute iron defi- sis presented herein, national patterns of anemia correc-ciency. For many ESRD patients, epoetin alfa-stimulated tion, with attention to provision of adequate dialysiserythropoiesis provokes iron utilization at a rate that and serum albumin levels, can and should be routinelyexceeds iron delivery. Many of these patients will have tracked as local and regional CQI strategies are imple-an erythropoietic response to parenteral iron therapy mented.(defined as either an increase in hematocrit and/or adecrease in epoetin dose) [3, 30]. This intervention may ACKNOWLEDGMENTSfacilitate the segregation of patients who are inflamed/ The authors wish to express their appreciation to the professionalinfected from those with functional iron deficiency. and volunteer staff of the 18 ESRD Network organizations and the

dialysis care teams in the more than 2000 participating hemodialysisTherefore, iron supplementation should not be withheldfacilities in the United States. Without their support of the Nationalin the setting of normal or moderately elevated serumESRD Core Indicators Project, this study would not have been possible.

ferritin levels alone (300 to 800 ng/mL) and a low trans- The views expressed in this manuscript are those of the authors, anddo not necessarily reflect official policy of the Health Care Financingferrin saturation [3, 15, 29, 32]. However, greater eleva-Administration.tions in the serum ferritin concentration should herald

a cessation of iron therapy. In addition, because the Reprint requests to Dr. Diane L. Frankenfield, Health Care FinancingAdministration, Office of Clinical Standards and Quality, 7500 Securityserum ferritin concentration is also increased in inflam-Boulevard, Mailstop S3-02-01, Baltimore, Maryland 21244, USA.matory situations, the observed inverse relationship withE-mail: [email protected]

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