The objective of this study was to quantify the incrementalmedical costs that are associated with untreated anemia amongelderly patients with predialysis chronic kidney disease (CKD).An analysis of claims and laboratory data between January 1999and February 2005 was conducted. Inclusion criteria were age65 yr, two or more hemoglobin readings, one or more claims forCKD, and two or more GFR values of <60 ml/min per 1.73 m2(stages 3 to 5 CKD). Patients were excluded when they had canceror lupus, had received organ transplantation, or were treatedfor anemia. An open-cohort design was used to classify patients’observation periods into anemia and nonanemia. Both univariateand multivariate analyses were conducted to compare periodsof anemia and nonanemia for average monthly medical costs; thelatter was adjusted for age, gender, GFR, diabetes, hypertension,liver cirrhosis, coronary artery disease, myocardial infarction,and left ventricular hypertrophy. A subset analysis of patientswith moderate CKD (stage 3) was conducted. A total of 2001 patientswere identified. Untreated anemia was associated with a significantincrease in medical costs, with an unadjusted incremental monthlycost of $1089 (P < 0.0001) and a cost ratio of 1.8:1 relativeto nonanemia. After controlling for covariates, untreated anemiaremained significantly associated with a cost increase (adjustedincremental monthly cost $503; cost ratio 1.4:1; P < 0.0001).Similar significant cost burden was observed in the subset ofpatients with moderate CKD. The retrospective observationaldesign may be more susceptible to bias than a randomized, controlledtrial. This large study, which was based on real-life practicedata, demonstrated that untreated anemia in elderly patientswith predialysis CKD was associated with a significant increasein medical costs.
Chronic kidney disease (CKD) is a significant driver of health-relatedexpenditures. The total spending for the treatment of patientswith ESRD in 2002 was approximately $25.0 billion. Medicareend-stage renal disease program expenditures grew from $5.8billion in 1991 to $17.0 billion by 2002, accounting for nearly7% of the total Medicare budget in 2002. On the basis of theMedicare population, the annual cost was approximately $63,000per dialysis patient in medical costs, patient deductibles,and copayments in 2002 (1).
Anemia in the elderly is a common, widely recognized complicationof CKD and has received increased attention because of its adverseimpact on heart failure and accompanying mortality (2–5).Anemia in patients who have CKD and are 67 yr or older has beenshown to be associated with increased cardiovascular disease,renal replacement therapy, and hospitalization (6). All of theseconditions have a direct impact on medical costs, suggestingthat anemic patients are more likely to have increased utilizationof health care resources.
It has been demonstrated that treatment of anemia with epoetinalfa (7) in predialysis patients with CKD is effective in increasinghemoglobin (Hb) levels, which correlates with significant improvementsin patient-reported quality of life as well as retardation ofrenal disease progression and extended time to dialysis (8–11).Moreover, recent evidence suggests that early intervention withepoetin alfa in anemic patients during the predialysis periodis associated with improved survival in the first year afterthe dialysis and reduced costs of treatment (4). Despite thesebenefits, some of which occur in the future, many predialysispatients with CKD and anemia are not treated, perhaps becauseof concerns about treatment costs. However, the ongoing costsof untreated anemia need to be considered as well.
The economic impact of untreated anemia in the elderly predialysisCKD population has not been documented for a managed care population.Preliminary data suggested that patients with CKD and anemiawere associated with increased direct and indirect medical costsfrom an employer’s perspective; however, this study wasbased on nonelderly workers between 18 and 64 yr of age andwas limited by the small sample size (12,13). Nissenson et al.(14) evaluated the cost of anemia among 4834 adult patientswith CKD from commercially insured and Medicare plans and foundthat anemia accounted for an increase of $28,757 annualizedcost per patient with CKD. However, their study did not differentiatetreated versus untreated anemia and included both pre- and postdialysisCKD populations.
In recent years, anemia overall and, in particular, anemia inthe elderly has gained increasing awareness as a result of theaging population and growing scientific evidence of adverseconsequences of untreated geriatric anemia. The purpose of thisanalysis was to quantify the incremental medical costs thatare associated with untreated anemia in an elderly managed carepopulation with predialysis CKD. Different stages of CKD severityalso were examined for further understanding of the impact ofuntreated anemia on medical costs in patients with CKD.
Data Source
Medical and pharmacy claims data from the Integrated HealthCareInformation Services National Managed Care Benchmark Databasebetween January 1999 and February 2005 were used to conductthe analysis. The Integrated HealthCare Information Servicesdatabase included complete medical and pharmacy claims for morethan 30 million managed care patients from more 35 health careplans, covering all census regions of the United States (NewEngland, Middle Atlantic, South Atlantic, East South Central,West South Central, East North Central, West North Central,Mountain, and Pacific). Data elements that were used in thisanalysis included enrollment records, patient demographics,inpatient and outpatient medical claims, pharmacy dispensingclaims, and laboratory results.
The elderly patients who were eligible for inclusion were thosewho were enrolled in managed care senior plans where qualifiedprivate health plans were accepted as a managed care Medicareprovider per the 1982 Tax Equity and Fiscal Responsibility Act(TEFRA). The elderly enrollees in the managed care Medicareplan primarily were community-dwelling or required only short-termnursing home care.
Study Design
A retrospective open-cohort design was used to classify patients’observation periods into untreated anemia versus nonanemia,on the basis of their Hb values. The open-cohort approach wasused to allow a patient’s anemia status to change overtime (Figure 1), mimicking real-life situations.
To be included in our analysis, patients were required to meetall of the following criteria: have continuous health plan coverage,be 65 yr of age on the date of the first Hb reading or serumcreatinine measurement, have one or more claims for CKD (InternationalClassification of Diseases, Ninth Revision [ICD-9] codes 250.4,403 to 404, 585 to 586, and 588), have two or more GFR valuesof <60 ml/min per 1.73 m2, and have two or more Hb readings.
Among patients who were receiving renal dialysis, data werecensored 30 d before the first date of dialysis. Patients wereexcluded from the study when they had received an organ transplant,had received blood transfusions or erythropoietic agents fortreatment of anemia, or had cancer or lupus or had receivedchemotherapy, because they may have become anemic for reasonsother than CKD.
The observation period began from the date of the first Hb readingor on the first day of reaching a GFR of <60 ml/min per 1.73m2, whichever occurred later, until the end of health plan enrollment,30 d before a renal dialysis claim, or the defined study enddate of February 28, 2005, whichever occurred earlier.
Definition of Anemia Status
Patients’ anemia status was defined on the basis of Hbvalues. Hb measurements were identified using the Logical ObservationIdentifiers Names and Codes classification (718-9). Anemia,formulated as a dichotomous variable (yes/no), was defined asHb <11 g/dl, because the National Kidney Foundation KidneyDisease Outcomes Quality Initiative (K/DOQI) guidelines recommendthat Hb levels be maintained between 11 and 12 g/dl for allstages of CKD (15).
Definition of CKD Severity
GFR values were calculated using the Modification of Diet inRenal Disease (MDRD) study abbreviated equation (16), basedon serum creatinine value, age, gender, and ethnicity: GFR =186(SCr)–1.154 x (Age)–0.203 x (0.742 if female)x (1.210 if black), where SCr is serum creatinine value. Becausepatients’ ethnicity variable was not available in thedatabase, this factor was not used in the calculation. For eachpatient, a weighted average GFR value was obtained by scalingthe observation duration of each GFR value:
(1)
where Time is number of days between a GFRassessment and the following determination or the end of observationperiod, whichever occurred first, i is the ith GFR measurementfor the patient, and n is total number of GFR measurements forthe patient.
CKD was defined as an average GFR <60 ml/min per 1.73 m2(stages 3 to 5). Moreover, it has become increasingly importantto understand the impact of anemia in the earlier stages ofCKD. The National Kidney Foundation K/DOQI guidelines expandedthe focus from dialysis to GFR <60 ml/min per 1.73 m2 asa trigger for the ascertainment of anemia (17). To investigatethe economic impact of untreated anemia in patients with moderateCKD, we conducted a subset analysis of patients with stage 3CKD (GFR 30 to <60 ml/ml per 1.73 m2).
Statistical Analyses
Both univariate and multivariate analyses were conducted todetermine the incremental costs of untreated anemia. The outcomemeasures for the analyses were direct medical costs, which consistedof three mutually exclusive components: (1) outpatient services,(2) inpatient services, and (3) pharmacy costs. Average monthlycosts were reported to adjust for different lengths of observationduration by patients.
Descriptive univariate statistics were used to compare periodsof untreated anemia and nonanemia for medical costs. Both incrementalcosts and cost ratios were used to report cost differences.Incremental cost was defined as the average monthly cost ofuntreated anemia periods less the average monthly cost of nonanemiaperiods. Cost ratio was expressed as follows:
(2)
Multivariate analysis was conductedto adjust for potential confounding factors in estimating theincremental costs of untreated anemia. Because of the non-normalityof the health cost outcome variables, which are truncated atzero and positively skewed, a Tobit regression model was usedto estimate the adjusted incremental costs of untreated anemia.Covariates that were used for adjustment in the regression modelswere age, gender, GFR values, hypertension, diabetes, livercirrhosis, coronary artery disease (CAD), myocardial infarction(MI), and left ventricular hypertrophy (LVH). In a further confirmatoryanalysis to determine whether the medical costs increased bydecreasing Hb values, continuous Hb value was inserted insteadof the dichotomous variable for anemia in the regression model.
The null hypothesis of a cost ratio equal to 1 for the untreatedanemia versus nonanemia periods was tested using a t statistic,where the cost of nonanemia periods was fixed using the averagemonthly cost of nonanemia periods. A two-sided error of 0.05was used to declare statistical significance.
Study Population
A total of 2001 patients who had CKD and met all of the entrycriteria formed the study population. Table 1 presents the studypopulation characteristics. Approximately 47% were women; meanage was 76.0 yr; and, on average, patients were observed for2.1 yr. Baseline GFR and Hb values were 40.0 ml/min per 1.73m2 and 12.8 g/dl, respectively. A total of 647 (32%) patientshad an Hb level <11 g/dl at some point during observation.Overall, the total person-years of observation for the anemiaperiod were 529 yr and for the nonanemia period were 3803 yr.
Hypertension was the most prevalent comorbidity (87.9%), followedby diabetes (49.4%), CAD (23.3%), LVH (18.7%), and MI (13.2%).Approximately 60 and 50% of patients had six or more GFR andHb readings during the study period, respectively.
Univariate Analysis
Univariate descriptive statistics are reported in Table 2. Inthe overall CKD population, untreated anemia was associatedwith a significant increase in medical costs, with an unadjustedincremental monthly cost of $1089 ($2529 versus $1439; P <0.0001) and a cost ratio of 1.8:1 (P < 0.0001) relative tononanemia. For the subset of patients with stage 3 CKD, significantcost increases that were associated with anemia also were observed(unadjusted incremental monthly cost $1301; P < 0.0001; costratio 1.9:1; P < 0.0001). The largest driver of medical costdifferences between the untreated anemia and nonanemia groupswas costs that were associated with hospitalizations. Coststhat were related to pharmacy dispensing claims were similarin the untreated anemia periods compared with the nonanemiaperiods.
Table 2. Univariate analysis: Monthly medical costs for untreated anemia periods versus nonanemia periodsa
Multivariate Analysis
After controlling for covariates, the cost impact of untreatedanemia was reduced but remained significant for both the overallCKD population and the patients with stage 3 CKD (adjusted incrementalmonthly cost: overall CKD $503 [P < 0.001]; stage 3 CKD $553[P < 0.001]; Table 3). Of note, the cost burden of anemiawas comparable to other significant comorbidities, such as diabetes,CAD, MI, and LVH (Table 3). Figure 2 indicates that the adjustedcost ratios for untreated anemia periods relative to nonanemiaperiods were 1.4:1 and 1.4:1 for the overall CKD populationand the stage 3 CKD population, respectively. Finally, Table 3reveals that lower Hb and GFR values were associated with highermedical costs, as demonstrated by the negative and statisticallysignificant coefficient on the continuous Hb and GFR variables,respectively.
Figure 2. Adjusted cost ratio of untreated anemia relative to non-anemia by chronic kidney disease (CKD) severity. Independent variables for adjustments were age, gender, GFR values, hypertension, diabetes, liver cirrhosis, coronary artery disease, myocardial infarction, and left ventricular hypertrophy. *Indicates that the cost ratio was statistically significantly different from 1.0 at P < 0.05.
We conducted this retrospective, open-cohort study to estimatethe incremental costs of untreated anemia in elderly patientswith varying degrees of CKD severity. The analysis was basedon administrative medical and pharmacy claims data coupled withlaboratory results from a period of more than 6 yr from 2001elderly patients who had CKD and were enrolled in managed careMedicare plans. Both univariate and multivariate results consistentlyindicated that untreated anemia was associated with a significantmedical cost increase in elderly patients with CKD, accountingfor an approximately 40% cost increase compared with nonanemia.The largest driver of cost differences between anemia and nonanemiaperiods was costs that were associated with hospitalizations.
The significant cost burden of anemia also was observed in thesubset of patients with stage 3 CKD, those who were characterizedas having a moderate decrease in GFR. This information highlightsthe potential economic importance of early intervention withantianemia therapies. Collins (4) reported that early treatmentwith epoetin alfa in anemic patients during the predialysisperiod was associated with reduced costs of treatment in thefirst year after dialysis. Moreover, from our data, we foundthat the majority (72%) of the patients with CKD were in stage3, suggesting that appropriate anemia management in the earlystage potentially can benefit a large population with CKD. Becauseour findings were robust to CKD severity and were not drivenby the subset of patients with severe CKD disease (stages 4to 5), anemia seemed to incur a significant cost burden acrossthe spectrum of CKD severity, even among those at an earlierstage.
Our study was the first to investigate the cost impact of anemiaamong elderly patients with CKD. Two previous studies evaluatedthe economic costs of anemia in different CKD populations. Modyet al. (12,13) reported that after controlling for confounders,the cost ratios of untreated anemia were approximately 1.6:1for both the direct medical costs and indirect work productivitycosts (e.g., sick leave, short- and long-term disabilities).Their study was based on a relatively small sample size of 176anemic versus 746 nonanemic patients who had CKD and were nonelderlyadults (between 18 and 64 yr of age). In addition, the authorsidentified CKD on the basis of ICD-9 diagnosis codes ratherthan laboratory tests, disallowing them to differentiate CKDseverity on the basis of objective laboratory measures (e.g.,GFR). The identification of anemia on the basis of ICD-9 codesmay have led to an underascertainment of anemia and a systematicselection of symptomatic anemia. Nissenson et al. (14) assessedthe direct medical cost of anemia in an overall adult CKD population(18 yr) regardless of dialysis and found a univariate incrementalannual cost of $28,757 for anemia. It is not surprising thattheir cost figure is approximately two times higher than whatwas found in our study (univariate monthly incremental cost$1089; annual incremental cost $13,068), because their studysample included patients who had severe CKD and were undergoingdialysis and patients who had CKD and were receiving anemiatreatments. Despite differences in study designs and populations,the consistent finding from Mody et al. (12,13), Nissenson etal. (14), and this study was that anemia was associated witha significant medical cost impact in CKD populations.
Our study had the advantages of a large sample size and theavailability of laboratory results data, which enabled the investigationof different degrees of CKD severity and an objective definitionof anemia (based on Hb). The complete claims history allowedfor adjustment of important comorbidities that may otherwiseartificially inflate the cost increase that is attributableto anemia. Our study population was based on relatively healthyseniors who primarily were community dwelling and were locatedthroughout the United States, rendering a high generalizabilityof the study results.
This study had several limitations. First, claims data haveinherent limitations, such as inaccuracies in billing diagnoses,costs, and missing data on laboratory results. Second, becausethe patients’ ethnicity was not available in our database,GFR values for black patients were underestimated by a smallincrement because of the omission of this factor for the calculation.The measurement errors of the GFR values affected the subsetof black patients estimated at approximately 10% of the totalpopulation (18). Third, the study evaluated only the directmedical costs. Information to determine the indirect costs ofuntreated anemia, such as work productivity loss and reducedquality of life, was not available. Fourth, the observationaldesign was susceptible to various biases. We recognize thata randomized trial may be the ideal way of addressing this question;however, a randomized trial that focuses on economic end pointsseldom is undertaken because economic behaviors can be influencedin a controlled setting. In the absence of such randomized trials,well-designed observational studies with appropriate statisticaltechniques that adjusted for confounding provided valuable informationwith real-life scenarios and high generalizability. In thisanalysis, we tried to identify the cost increase that was associatedwith anemia by comparing the costs in the anemia group withthe costs in a reference, nonanemia group. However, becauseanemia is related to the underlying kidney conditions, it ispossible that some of the cost increase from anemia may havebeen attributable to the renal condition. In our multivariateanalysis, we controlled for this impact by inserting the GFRvalues in the regression model. Also, detection bias was a possibility.Because laboratory results and diagnoses were not collectedat prespecified intervals as in randomized, clinical trials,false-negative results of CKD and anemia could have occurredin patients who did not seek care (especially those who didnot have symptomatic manifestations). Finally, our databaseexcluded information from long-term nursing home care. For thisreason, the impact of untreated anemia may be underestimated.Despite these limitations, this research has several advantagesover existing studies, including the important advantage ofrelying on real-world data, a relatively large sample size,availability of laboratory results to allow CKD staging classifications,and multivariate adjustments to control for confounders.
Previous research has demonstrated the detrimental health effects(e.g., diminished quality of life, increased prevalence of cardiovasculardiseases, accelerated renal disease progression) (19–23)of anemia in the elderly. This study showed an adverse economicimpact of untreated anemia in elderly patients who have CKDand are not receiving dialysis. The cost impact remained significantfor the subset of patients with moderate CKD. Therefore, earlyidentification and assessment of anemia in predialysis patientswith CKD is important, because timely intervention may be desirablefor this population. Correction of anemia may reduce the utilizationof health care resources and also may improve patient and clinicaloutcomes. Further studies to evaluate the cost-effectivenessof erythropoietic treatment in anemic patients with CKD arewarranted.
Despite limitations that are associated with a retrospective,observational design, this large study demonstrated that untreatedanemia in elderly patients with predialysis CKD was associatedwith a significant increase in medical costs. The cost burdenof untreated anemia remained significant after adjustment forimportant comorbidities that otherwise may contribute to thecost increase. Similar findings were observed for the subsetof patients with moderate CKD.
Acknowledgments
This research was supported by Ortho Biotech Clinical Affairs,LLC. P.L., M.S.D. and S.B. are employees of Analysis Group,which has received research grants from Ortho Biotech ClinicalAffairs, LLC. B.B. and S.H.M. are employees of Ortho BiotechClinical Affairs, LLC.
Parts of this work were presented as a poster at the 2005 AmericanSociety of Nephrology Annual Renal Week; November 8 through13; Philadelphia, PA.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
Introduction
65 yr, two or more hemoglobin readings, one or more claims for CKD, and two or more GFR values of <60 ml/min per 1.73 m2 (stages 3 to 5 CKD). Patients were excluded when they had cancer or lupus, had received organ transplantation, or were treated for anemia. An open-cohort design was used to classify patients’ observation periods into anemia and nonanemia. Both univariate and multivariate analyses were conducted to compare periods of anemia and nonanemia for average monthly medical costs; the latter was adjusted for age, gender, GFR, diabetes, hypertension, liver cirrhosis, coronary artery disease, myocardial infarction, and left ventricular hypertrophy. A subset analysis of patients with moderate CKD (stage 3) was conducted. A total of 2001 patients were identified. Untreated anemia was associated with a significant increase in medical costs, with an unadjusted incremental monthly cost of $1089 (P < 0.0001) and a cost ratio of 1.8:1 relative to nonanemia. After controlling for covariates, untreated anemia remained significantly associated with a cost increase (adjusted incremental monthly cost $503; cost ratio 1.4:1; P < 0.0001). Similar significant cost burden was observed in the subset of patients with moderate CKD. The retrospective observational design may be more susceptible to bias than a randomized, controlled trial. This large study, which was based on real-life practice data, demonstrated that untreated anemia in elderly patients with predialysis CKD was associated with a significant increase in medical costs. 
error of 0.05 was used to declare statistical significance. 
