Chronic kidney disease (CKD) is a significant driver of health-related expenditures. The total spending for the treatment of patients with ESRD in 2002 was approximately $25.0 billion. Medicare end-stage renal disease program expenditures grew from $5.8 billion in 1991 to $17.0 billion by 2002, accounting for nearly 7% of the total Medicare budget in 2002. On the basis of the Medicare population, the annual cost was approximately $63,000 per dialysis patient in medical costs, patient deductibles, and copayments in 2002 (1).
Anemia in the elderly is a common, widely recognized complication of CKD and has received increased attention because of its adverse impact on heart failure and accompanying mortality (2–5). Anemia in patients who have CKD and are 67 yr or older has been shown to be associated with increased cardiovascular disease, renal replacement therapy, and hospitalization (6). All of these conditions have a direct impact on medical costs, suggesting that anemic patients are more likely to have increased utilization of health care resources.
It has been demonstrated that treatment of anemia with epoetin alfa (7) in predialysis patients with CKD is effective in increasing hemoglobin (Hb) levels, which correlates with significant improvements in patient-reported quality of life as well as retardation of renal disease progression and extended time to dialysis (8–11). Moreover, recent evidence suggests that early intervention with epoetin alfa in anemic patients during the predialysis period is associated with improved survival in the first year after the dialysis and reduced costs of treatment (4). Despite these benefits, some of which occur in the future, many predialysis patients with CKD and anemia are not treated, perhaps because of concerns about treatment costs. However, the ongoing costs of untreated anemia need to be considered as well.
The economic impact of untreated anemia in the elderly predialysis CKD population has not been documented for a managed care population. Preliminary data suggested that patients with CKD and anemia were associated with increased direct and indirect medical costs from an employer’s perspective; however, this study was based on nonelderly workers between 18 and 64 yr of age and was limited by the small sample size (12,13). Nissenson et al. (14) evaluated the cost of anemia among 4834 adult patients with CKD from commercially insured and Medicare plans and found that anemia accounted for an increase of $28,757 annualized cost per patient with CKD. However, their study did not differentiate treated versus untreated anemia and included both pre- and postdialysis CKD populations.
In recent years, anemia overall and, in particular, anemia in the elderly has gained increasing awareness as a result of the aging population and growing scientific evidence of adverse consequences of untreated geriatric anemia. The purpose of this analysis was to quantify the incremental medical costs that are associated with untreated anemia in an elderly managed care population with predialysis CKD. Different stages of CKD severity also were examined for further understanding of the impact of untreated anemia on medical costs in patients with CKD.
Materials and Methods
Data Source
Medical and pharmacy claims data from the Integrated HealthCare Information Services National Managed Care Benchmark Database between January 1999 and February 2005 were used to conduct the analysis. The Integrated HealthCare Information Services database included complete medical and pharmacy claims for more than 30 million managed care patients from more 35 health care plans, covering all census regions of the United States (New England, 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 this analysis included enrollment records, patient demographics, inpatient and outpatient medical claims, pharmacy dispensing claims, and laboratory results.
The elderly patients who were eligible for inclusion were those who were enrolled in managed care senior plans where qualified private health plans were accepted as a managed care Medicare provider per the 1982 Tax Equity and Fiscal Responsibility Act (TEFRA). The elderly enrollees in the managed care Medicare plan primarily were community-dwelling or required only short-term nursing 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 was used to allow a patient’s anemia status to change over time (Figure 1), mimicking real-life situations.
To be included in our analysis, patients were required to meet all of the following criteria: have continuous health plan coverage, be ≥65 yr of age on the date of the first Hb reading or serum creatinine measurement, have one or more claims for CKD (International Classification of Diseases, Ninth Revision [ICD-9] codes 250.4, 403 to 404, 585 to 586, and 588), have two or more GFR values of <60 ml/min per 1.73 m2, and have two or more Hb readings.
Among patients who were receiving renal dialysis, data were censored 30 d before the first date of dialysis. Patients were excluded from the study when they had received an organ transplant, had received blood transfusions or erythropoietic agents for treatment of anemia, or had cancer or lupus or had received chemotherapy, because they may have become anemic for reasons other than CKD.
The observation period began from the date of the first Hb reading or on the first day of reaching a GFR of <60 ml/min per 1.73 m2, whichever occurred later, until the end of health plan enrollment, 30 d before a renal dialysis claim, or the defined study end date of February 28, 2005, whichever occurred earlier.
Definition of Anemia Status
Patients’ anemia status was defined on the basis of Hb values. Hb measurements were identified using the Logical Observation Identifiers Names and Codes classification (718-9). Anemia, formulated as a dichotomous variable (yes/no), was defined as Hb <11 g/dl, because the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines recommend that Hb levels be maintained between 11 and 12 g/dl for all stages of CKD (15).
Definition of CKD Severity
GFR values were calculated using the Modification of Diet in Renal Disease (MDRD) study abbreviated equation (16), based on serum creatinine value, age, gender, and ethnicity: GFR = 186(SCr)−1.154 × (Age)−0.203 × (0.742 if female) × (1.210 if black), where SCr is serum creatinine value. Because patients’ ethnicity variable was not available in the database, this factor was not used in the calculation. For each patient, a weighted average GFR value was obtained by scaling the observation duration of each GFR value:
;)
where Time is number of days between a GFR assessment and the following determination or the end of observation period, whichever occurred first, i is the ith GFR measurement for the patient, and n is total number of GFR measurements for the patient.
CKD was defined as an average GFR <60 ml/min per 1.73 m2 (stages 3 to 5). Moreover, it has become increasingly important to understand the impact of anemia in the earlier stages of CKD. The National Kidney Foundation K/DOQI guidelines expanded the focus from dialysis to GFR <60 ml/min per 1.73 m2 as a trigger for the ascertainment of anemia (17). To investigate the economic impact of untreated anemia in patients with moderate CKD, we conducted a subset analysis of patients with stage 3 CKD (GFR 30 to <60 ml/ml per 1.73 m2).
Statistical Analyses
Both univariate and multivariate analyses were conducted to determine the incremental costs of untreated anemia. The outcome measures for the analyses were direct medical costs, which consisted of three mutually exclusive components: (1) outpatient services, (2) inpatient services, and (3) pharmacy costs. Average monthly costs were reported to adjust for different lengths of observation duration by patients.
Descriptive univariate statistics were used to compare periods of untreated anemia and nonanemia for medical costs. Both incremental costs and cost ratios were used to report cost differences. Incremental cost was defined as the average monthly cost of untreated anemia periods less the average monthly cost of nonanemia periods. Cost ratio was expressed as follows:
Multivariate analysis was conducted to adjust for potential confounding factors in estimating the incremental costs of untreated anemia. Because of the non-normality of the health cost outcome variables, which are truncated at zero and positively skewed, a Tobit regression model was used to estimate the adjusted incremental costs of untreated anemia. Covariates that were used for adjustment in the regression models were age, gender, GFR values, hypertension, diabetes, liver cirrhosis, coronary artery disease (CAD), myocardial infarction (MI), and left ventricular hypertrophy (LVH). In a further confirmatory analysis to determine whether the medical costs increased by decreasing Hb values, continuous Hb value was inserted instead of the dichotomous variable for anemia in the regression model.
The null hypothesis of a cost ratio equal to 1 for the untreated anemia versus nonanemia periods was tested using a t statistic, where the cost of nonanemia periods was fixed using the average monthly cost of nonanemia periods. A two-sided α error of 0.05 was used to declare statistical significance.
Results
Study Population
A total of 2001 patients who had CKD and met all of the entry criteria formed the study population. Table 1 presents the study population characteristics. Approximately 47% were women; mean age was 76.0 yr; and, on average, patients were observed for 2.1 yr. Baseline GFR and Hb values were 40.0 ml/min per 1.73 m2 and 12.8 g/dl, respectively. A total of 647 (32%) patients had an Hb level <11 g/dl at some point during observation. Overall, the total person-years of observation for the anemia period were 529 yr and for the nonanemia period were 3803 yr.
Hypertension was the most prevalent comorbidity (87.9%), followed by diabetes (49.4%), CAD (23.3%), LVH (18.7%), and MI (13.2%). Approximately 60 and 50% of patients had six or more GFR and Hb readings during the study period, respectively.
Univariate Analysis
Univariate descriptive statistics are reported in Table 2. In the overall CKD population, untreated anemia was associated with a significant increase in medical costs, with an unadjusted incremental monthly cost of $1089 ($2529 versus $1439; P < 0.0001) and a cost ratio of 1.8:1 (P < 0.0001) relative to nonanemia. For the subset of patients with stage 3 CKD, significant cost increases that were associated with anemia also were observed (unadjusted incremental monthly cost $1301; P < 0.0001; cost ratio 1.9:1; P < 0.0001). The largest driver of medical cost differences between the untreated anemia and nonanemia groups was costs that were associated with hospitalizations. Costs that were related to pharmacy dispensing claims were similar in the untreated anemia periods compared with the nonanemia periods.
Multivariate Analysis
After controlling for covariates, the cost impact of untreated anemia was reduced but remained significant for both the overall CKD population and the patients with stage 3 CKD (adjusted incremental monthly cost: overall CKD $503 [P < 0.001]; stage 3 CKD $553 [P < 0.001]; Table 3). Of note, the cost burden of anemia was comparable to other significant comorbidities, such as diabetes, CAD, MI, and LVH (Table 3). Figure 2 indicates that the adjusted cost ratios for untreated anemia periods relative to nonanemia periods were 1.4:1 and 1.4:1 for the overall CKD population and the stage 3 CKD population, respectively. Finally, Table 3 reveals that lower Hb and GFR values were associated with higher medical costs, as demonstrated by the negative and statistically significant coefficient on the continuous Hb and GFR variables, respectively.
Discussion
We conducted this retrospective, open-cohort study to estimate the incremental costs of untreated anemia in elderly patients with varying degrees of CKD severity. The analysis was based on administrative medical and pharmacy claims data coupled with laboratory results from a period of more than 6 yr from 2001 elderly patients who had CKD and were enrolled in managed care Medicare plans. Both univariate and multivariate results consistently indicated that untreated anemia was associated with a significant medical cost increase in elderly patients with CKD, accounting for an approximately 40% cost increase compared with nonanemia. The largest driver of cost differences between anemia and nonanemia periods was costs that were associated with hospitalizations.
The significant cost burden of anemia also was observed in the subset of patients with stage 3 CKD, those who were characterized as having a moderate decrease in GFR. This information highlights the potential economic importance of early intervention with antianemia therapies. Collins (4) reported that early treatment with epoetin alfa in anemic patients during the predialysis period was associated with reduced costs of treatment in the first year after dialysis. Moreover, from our data, we found that the majority (72%) of the patients with CKD were in stage 3, suggesting that appropriate anemia management in the early stage potentially can benefit a large population with CKD. Because our findings were robust to CKD severity and were not driven by the subset of patients with severe CKD disease (stages 4 to 5), anemia seemed to incur a significant cost burden across the spectrum of CKD severity, even among those at an earlier stage.
Our study was the first to investigate the cost impact of anemia among elderly patients with CKD. Two previous studies evaluated the economic costs of anemia in different CKD populations. Mody et al. (12,13) reported that after controlling for confounders, the cost ratios of untreated anemia were approximately 1.6:1 for both the direct medical costs and indirect work productivity costs (e.g., sick leave, short- and long-term disabilities). Their study was based on a relatively small sample size of 176 anemic versus 746 nonanemic patients who had CKD and were nonelderly adults (between 18 and 64 yr of age). In addition, the authors identified CKD on the basis of ICD-9 diagnosis codes rather than laboratory tests, disallowing them to differentiate CKD severity on the basis of objective laboratory measures (e.g., GFR). The identification of anemia on the basis of ICD-9 codes may have led to an underascertainment of anemia and a systematic selection of symptomatic anemia. Nissenson et al. (14) assessed the direct medical cost of anemia in an overall adult CKD population (≥18 yr) regardless of dialysis and found a univariate incremental annual cost of $28,757 for anemia. It is not surprising that their cost figure is approximately two times higher than what was found in our study (univariate monthly incremental cost $1089; annual incremental cost $13,068), because their study sample included patients who had severe CKD and were undergoing dialysis and patients who had CKD and were receiving anemia treatments. Despite differences in study designs and populations, the consistent finding from Mody et al. (12,13), Nissenson et al. (14), and this study was that anemia was associated with a significant medical cost impact in CKD populations.
Our study had the advantages of a large sample size and the availability of laboratory results data, which enabled the investigation of different degrees of CKD severity and an objective definition of anemia (based on Hb). The complete claims history allowed for adjustment of important comorbidities that may otherwise artificially inflate the cost increase that is attributable to anemia. Our study population was based on relatively healthy seniors who primarily were community dwelling and were located throughout the United States, rendering a high generalizability of the study results.
This study had several limitations. First, claims data have inherent limitations, such as inaccuracies in billing diagnoses, costs, and missing data on laboratory results. Second, because the patients’ ethnicity was not available in our database, GFR values for black patients were underestimated by a small increment because of the omission of this factor for the calculation. The measurement errors of the GFR values affected the subset of black patients estimated at approximately 10% of the total population (18). Third, the study evaluated only the direct medical costs. Information to determine the indirect costs of untreated anemia, such as work productivity loss and reduced quality of life, was not available. Fourth, the observational design was susceptible to various biases. We recognize that a randomized trial may be the ideal way of addressing this question; however, a randomized trial that focuses on economic end points seldom is undertaken because economic behaviors can be influenced in a controlled setting. In the absence of such randomized trials, well-designed observational studies with appropriate statistical techniques that adjusted for confounding provided valuable information with real-life scenarios and high generalizability. In this analysis, we tried to identify the cost increase that was associated with anemia by comparing the costs in the anemia group with the costs in a reference, nonanemia group. However, because anemia is related to the underlying kidney conditions, it is possible that some of the cost increase from anemia may have been attributable to the renal condition. In our multivariate analysis, we controlled for this impact by inserting the GFR values in the regression model. Also, detection bias was a possibility. Because laboratory results and diagnoses were not collected at prespecified intervals as in randomized, clinical trials, false-negative results of CKD and anemia could have occurred in patients who did not seek care (especially those who did not have symptomatic manifestations). Finally, our database excluded information from long-term nursing home care. For this reason, the impact of untreated anemia may be underestimated. Despite these limitations, this research has several advantages over existing studies, including the important advantage of relying 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 cardiovascular diseases, accelerated renal disease progression) (19–23) of anemia in the elderly. This study showed an adverse economic impact of untreated anemia in elderly patients who have CKD and are not receiving dialysis. The cost impact remained significant for the subset of patients with moderate CKD. Therefore, early identification and assessment of anemia in predialysis patients with CKD is important, because timely intervention may be desirable for this population. Correction of anemia may reduce the utilization of health care resources and also may improve patient and clinical outcomes. Further studies to evaluate the cost-effectiveness of erythropoietic treatment in anemic patients with CKD are warranted.
Conclusion
Despite limitations that are associated with a retrospective, observational design, this large study demonstrated that untreated anemia in elderly patients with predialysis CKD was associated with a significant increase in medical costs. The cost burden of untreated anemia remained significant after adjustment for important comorbidities that otherwise may contribute to the cost increase. Similar findings were observed for the subset of patients with moderate CKD.
Figure 1: Study design scheme.
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.
Table 1: Patient characteristicsa
Table 2: Univariate analysis: Monthly medical costs for untreated anemia periods versus nonanemia periodsa
Table 3: Multivariate analysis: Incremental monthly medical costs associated with untreated anemia periodsa
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 Clinical Affairs, LLC. B.B. and S.H.M. are employees of Ortho Biotech Clinical Affairs, LLC.
Parts of this work were presented as a poster at the 2005 American Society of Nephrology Annual Renal Week; November 8 through 13; Philadelphia, PA.
Published online ahead of print. Publication date available at www.jasn.org.
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