Trends in Anemia Management among US Hemodialysis Patients
Joseph A. Coladonato*,
Diane L. Frankenfield,
Donal N. Reddan*,
Preston S. Klassen*,
Lynda A. Szczech*,
Curtis A. Johnson and
William F. Owen, Jr.* for CMS ESRD Clinical Performance Measures Workgroup
*Duke Institute of Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, North Carolina; Office of Clinical Quality and Standards, Centers for Medicare and Medicaid Services, Baltimore, Maryland; University of Wisconsin School of Pharmacy, Madison, Wisconsin.
Correspondence to: Dr. John Stivelman served as guest editor and supervised the review and final disposition of this manuscript.Correspondence to: Dr. Joseph A. Coladonato, Duke Institute of Renal Outcomes Research and Health Policy, Box 3646, Duke University Medical Center, Durham, North Carolina 27710. Phone: 919-668-8008, Fax: 919-668-7128; E-mail joe.coladonato{at}duke.edu
ABSTRACT. This study was undertaken to describe the relationshipbetween hematocrit (Hct) and changes in the prescribed doseof erythropoietin (EPO) as well as selected patient and processcare measures across annual national samples of hemodialysispatients from 1994 to 1998. This study uses the cohorts identifiedin the ESRD Core Indicators Project, random samples of 6181,6241, 6364, 6634, and 7660 patients, stratified by ESRD Networksdrawn for each year from 1994 to 1998. Patient demographic andclinical information was collected from October to Decemberfor each year. Surrogates of iron stores and patterns of ironand EPO administration were profiled from 1996 to 1998. Multivariablestepwise linear regression analyses were performed to adjustfor potential confounding variables and to identify independentvariables associated with Hct and EPO dose. Mean Hct and EPOdose increased each year from 31.1 ± 5.2% to 34.1 ±3.7% and from 58.2 ± 41.8 U/kg to 68.2 ± 55.0U/kg, respectively (P = 0.0001). Increasing Hct was positivelyassociated with male gender, more years on dialysis, older age,higher urea reduction ratio and transferrin saturation, prescriptionof intravenous iron, and lower ferritin and EPO dose in multivariablemodels (all P = 0.0001). Male gender, older age, diabetes, higherHct, and increasing weight, urea reduction ration, and transferrinsaturation were associated with lower EPO doses (all P <0.01). Conversely, intravenous EPO and iron were associatedwith higher prescribed EPO doses (all P = 0.0001). Althoughincreasing Hct is associated with decreasing EPO dose at thepatient level, the increase in Hct seen across years among thecohorts of hemodialysis patients in the United States has beenassociated with increasing doses of EPO at the population level.
Anemia is a frequent complication of chronic kidney disease(CKD) and end-stage renal disease (ESRD), especially for patientsreceiving hemodialysis as renal replacement therapy. Based onMedicare billing data, it is estimated that approximately 95%of Medicare beneficiaries receive recombinant (biosynthetic)human erythropoietin (EPO) as primary treatment for their anemia(1). Since the original availability of EPO for the treatmentof anemia in ESRD, the target hematocrit has increased. Theinitial reimbursed target hematocrit approved by the Food andDrug Administration in August 1989 was 30 to 33% (2); in June1994, the target was raised to 30 to 36% (3). The increase inthe target hematocrit was supported by a structured review ofavailable clinical literature that gave rise to clinical practiceguidelines advocating a hematocrit range from 33 to 36% (4).Because absolute or relative iron deficiency, arising from exhaustionof marrow iron stores and/or the inability to deliver adequateiron stores to support normoblast proliferation and maturation(5–10), are common causes of inefficiency in EPO response,concomitant clinical practice guideline statements have beendeveloped for iron administration (4).
To encourage and assist in the achievement of the target hematocrit,quality improvement projects focused at dialysis facilitieswere established and executed through individual dialysis unitproviders and nephrologists. On the basis of the results fromseveral national registries and data sets, the hemoglobin/hematocritvalues for hemodialysis patients have increased over the last8 yr (11–15). For example, data from the Centers for Medicareand Medicaid Services (CMS), formerly the Health Care FinancingAdministration, National ESRD Core Indicators/Clinical PerformanceMeasures (CPM) Projects reported an increase in mean hematocritfor their nationally representative sample from 32% in 1995to 34% in 1998 (14). Although improvement in anemia managementhas been achieved, there have been limited analyses of the relationshipbetween the secular increase in hematocrit and changes in thedoses of EPO. Closer examination of this relationship is prudentbecause: (1) current Medicare expenditures for EPO are approximately$1 billion per year (16); (2) reimbursement for injectable drugs,including EPO, parenteral iron, and vitamin D preparations area major revenue source contributing to the profitability ofmost dialysis facilities in the United States (17); (3) theprincipal intravenous route of EPO administration in the UnitedStates (11,12,18) is atypical on a world-wide basis (19) andassociated with less favorable pharmacokinetics (20–23);and (4) the erythropoietic response to EPO is dose-dependent,but the dose-response is variable among ESRD patients (24,25).These background elements prompted us to examine the relationshipbetween the improvement in hematocrit among American ESRD patientsand changes in the dose of EPO.
Patient Selection and Data Collection
The study design, sampling strategy, and reliability testingof measures used in the National ESRD Core Indicators and CPMProjects are described in detail elsewhere (14,26,27). Briefly,all Medicare-eligible, adult ESRD patients receiving in-centerhemodialysis on December 31 of the study year were eligiblefor inclusion in the sample. A new, random sample of patients,stratified by the ESRD Networks, was drawn separately at thebeginning of each calendar year from 1994 to 1998. The samplesize was estimated to provide a 95% confidence interval of ±5% for ESRD Network–specific estimates. Patient demographicand clinical information was collected for the months of Octoberto December for each sample year (1994 to 1998). The demographicand clinical variables used for these analyses included age,gender, race, postdialysis weight, years on dialysis therapy,etiology of ESRD (diabetes mellitus, hypertension, glomerulonephritis,and other/unknown), and ESRD Network in which care was received.For statistical reasons, race was limited to either white orblack due to limited numbers categorized as other racial groups.Treatment variables captured included prescribed EPO dose (U/kgpredialysis body weight per dose), hematocrit, and urea reductionratio (URR, which was calculated from first monthly predialysisand postdialysis blood-urea nitrogen concentration), predialysisand postdialysis body weight, and dialysis session length. From1996 to 1998, additional information was collected on prescribedroute of iron administration (intravenous, oral, both, or none/unknown),prescribed route of EPO administration (intravenous or subcutaneous),transferrin saturation (TSAT), and serum ferritin concentration.An EPO Resistance Index (ERI) was calculated by dividing theaverage prescribed weekly EPO dose by the mean hematocrit forevery individual within each year. A low ERI can arise fromeither a lower weekly dose of EPO and/or a higher achieved hematocrit.
Statistical Analyses
For repeated measures, such as the dose of EPO and the hematocrit,the averages of the values for each patient recorded duringthe 3-mo abstraction period for each year were used for subsequentanalysis. Patients with missing demographic, clinical, or laboratorydata were excluded. Demographic, clinical, and laboratory parameterswere described at baseline for the patient cohorts stratifiedby year. Categorical and continuous variables were comparedamong cohorts using the 2 test and t test, respectively. A two-tailedP < 0.01 was considered significant. Scatter plots were drawnto describe the relationship between hematocrit and EPO dosestratified by year. Average EPO dose and hematocrit were calculatedfor each year and compared across years using ANOVA.
Linear regression was used to estimate the associations betweenhematocrit and clinical and demographic variables in both univariateand multivariable analyses. The fully adjusted, multivariablelinear regression model was built using both forward and backwardstepwise elimination methods. Variables tested for significanceincluded case-mix variables (gender, age, race, years on dialysis,and the presence of diabetes mellitus), mean prescribed EPOdose (U/kg predialysis body weight per dose), clinical variables(postdialysis body weight), and laboratory measurements (transferrinsaturation, serum ferritin concentration, and predialysis andpostdialysis blood-urea nitrogen values to calculate URR). Interactionsbetween EPO dose and variables, such as prescribed route ofEPO administration, prescribed route of iron therapy, TSAT,and serum ferritin concentration, were tested in separate models.Entry and elimination criteria were set at a value of P = 0.01.All P values reported are two-sided, and all confidence intervalsreported are 95% intervals. All data analyses were performedusing SAS version 8.1 (SAS Institute, Inc., Cary, NC).
Temporal Trends in Hematocrit and EPO Dose
The original sample consisted of 7270, 7310, 7292, 7658, and8838 patients in 1994, 1995, 1996, 1997, and 1998, respectively.The original sample was reduced to the a final sample of 6181,6241, 6364, 6634, and 7660 patients in 1994, 1995, 1996, 1997,and 1998, respectively, who had sufficient data on hematocritand EPO dose for analysis. The descriptive characteristics ofeach patient cohort are listed in Table 1. There were no significantdifferences in characteristics among cohorts across years, exceptfor an increase in the percent of patients with diabetes mellitusas the reported cause of ESRD, patients’ weight, and meanURR (P = 0.001). The mean and median hematocrit, prescribeddose of EPO (not adjusted for the prescribed route of administration),and the percentage of patients prescribed subcutaneous EPO hasincreased for each successive year as reported in Table 2 (P< 0.001). From 1994 to 1998, the median hematocrit increasedfrom 31 to 34% (P = 0.0001), whereas the median EPO dose (includingprescribed subcutaneous and intravenous routes of administration)increased from 49 to 54 U/kg from 1994 to 1998 (P = 0.0001).Information on the route of prescribed EPO administration wasnot collected in 1994 and 1995. During 1996, 1997, and 1998,a minority of hemodialysis patients were prescribed subcutaneousEPO (7.7%, 11.2%, and 11.7%, respectively). Although there wasno significant difference in the mean hematocrit by prescribedroute of EPO administration, patients prescribed intravenousEPO received significantly higher doses than those prescribedthe subcutaneous route of administration (67.6 U/kg versus 59.9U/kg, respectively) (P = 0.0001).
Table 2. Mean and median hematocrit (Hct) and prescribed EPO dose per yeara
Interestingly, the proportion of patients reaching the benchmarkhematocrit of 33% appears to increase with each successive year.In 1994, 35.6% had a hematocrit 33%; 42.3% of the patients in1995, 56.4% in 1996, 62.0% in 1997, and 72.7% in 1998. In parallel,the increment in hematocrit was also associated with a secularincrease in prescribed EPO dose. The percent of patients prescribedan EPO dose 58.2 U/kg (mean dose of EPO for referent year 1994)was 35.2% in 1994, 39.6% in 1995, 45.8% in 1996, 42.4% in 1997,and 42% in 1998. To further explore this relationship, the ERIwas calculated for patients from 1994 to 1998 as aggregate andwith patients stratified by quartiles of hematocrit (Table 3).The ERI increased from 1994 to more contemporary years. Whenexamined by hematocrit quartiles within each year, the ERI wassignificantly higher in the lowest quartile, suggesting thatthe increase in EPO dose was disproportionate to the commensurateincrement in hematocrit.
The frequency distribution of patients categorized by hematocritis presented in Figure 1. The increase in the percent of patientsin the higher hematocrit category was accompanied by a paralleldecrease in the patients with more severe anemia. The mean prescribedEPO dose per hematocrit category for each year is shown in Figure 2.The prescribed EPO dose was inversely associated with thehematocrit level, but it tended to reach a plateau at hematocritvalues 33%. Patients with a hematocrit <28% were prescribeda significantly higher mean EPO dose over the 5-yr period comparedwith those with a hematocrit 28% (79.6 U/kg versus 62.3 U/kg,respectively) (P = 0.001). This finding was consistent withineach year. Moreover, the dose of EPO prescribed for each categoryof hematocrit has increased over the period of observation,especially for patients whose hematocrit was <33%.
Figure 2. Mean erythropoietin (EPO) dose by hematocrit for each year.
Relationships Between EPO Dose, Hematocrit, and Iron Stores
Toward examining the relationship between increasing annualEPO requirements even among patients within the same categoryof hematocrit, surrogates of iron stores and patterns of ironadministration were profiled. Collection of this informationbegan in 1996, in which 8.3% of the patients had TSAT <20%and serum ferritin concentration <100 ng/ml. This proportionwas 5.9% and 8.5% for the years 1997 and 1998, respectively.Figure 3 illustrates the frequency distribution of patientswith a TSAT <20% stratified by hematocrit. At lower hematocritcategories, the percentage of patients with TSAT <20% increasedsignificantly (P = 0.0001). Those patients who had a TSAT <20%had significantly higher EPO doses (P = 0.0001) and lower hematocritvalues (P = 0.0001) (data not shown). Serum ferritin concentrationswere not associated with either hematocrit or EPO dose. Intravenousiron was prescribed to 50.5%, 57.2%, and 59.3% of patients in1996, 1997, and 1998, respectively. There was no significantdifference in the proportion of patients receiving intravenousiron among the different hematocrit categories. Of the subsetof patients with a TSAT <20%, only 47.7%, 55.3%, and 58.8%were prescribed intravenous iron in 1996, 1997, and 1998, respectively.When intravenous iron-prescribing patterns were examined asa function of TSAT and serum ferritin concentration, patientswith a TSAT <20% and ferritin <100 ng/ml were prescribedparenteral iron less often than patients with TSAT 20% and ferritin100 ng/ml (P = 0.001). Moreover, the percent of patients prescribedintravenous iron was inversely proportional to the hematocrit.The patients prescribed intravenous iron were also prescribedsignificantly higher EPO doses (F value, 11.77; P = 0.0006).
Figure 3. The percent of patients with transferrin saturation (TSAT) <20% in each hematocrit category by year.
Other variables historically associated with hematocrit and/orEPO level (18,28,29) were examined for each year of observation.The mean age of patients with hematocrit values <28% wassignificantly lower (P = 0.001) than those in the other hematocritcategories for each year. Female gender was associated withlower hematocrit levels, but higher prescribed EPO doses (Fvalue, 51.98 [P = 0.0001] and F value, 343.25 [P = 0.0001],respectively). In contrast, there was no significant differencein EPO dose by race, but black patients were more likely tohave a modestly lower mean hematocrit than white patients (32.2%versus 32.6%, respectively; P < 0.001).
A bivariate analysis comparing the variables of interest withhematocrit and EPO dose was performed separately for all values(data not shown). Hematocrit was inversely associated with EPOdose (U/kg), black race, and female gender (all P < 0.0001).The mean URR was directly associated with the mean hematocrit(P < 0.0001) and mean EPO dose (U/kg; P < 0.0001). Intravenousiron therapy was associated with higher erythropoietin dosesand hematocrit levels.
Associations with Hematocrit and EPO Dose
Predictors of hematocrit and EPO were assessed separately byusing linear regression in a model that included patterns ofiron and EPO administration for cohort years 1996, 1997, and1998. Seventy-two percent of the patients (14,803 of 20,658)had data relating to the prescribed routes of iron and EPO administrationand were included in the multivariable analysis of hematocritand EPO dose. Male gender, increasing years on dialysis, age,URR, and TSAT, lower serum ferritin values and EPO doses, andprescription of intravenous iron were associated with higherhematocrit values (P = 0.0001) (Table 4). The hematocrit wasnot significantly associated with the prescribed route of EPOadministration. Male gender, diabetes mellitus as the causeof ESRD, increasing age, weight, hematocrit, TSAT, and URR,and prescription of subcutaneous EPO were associated with lowerprescribed EPO doses (P = 0.0001) (Table 5). Prescription ofintravenous iron was associated with higher doses of EPO. Racewas not a significant predictor for either hematocrit or EPOdose.
Table 5. Full linear regression model for predictors of EPO dosea
To further explore the relationship between hematocrit and prescribedEPO doses, multivariable analyses were performed using quartilesof hematocrit rather than treating hematocrit as a continuousvariable. Quartiles of hematocrit were determined for each sampleyear, rather than for all the years in aggregate. This approachwas chosen because processes of care have been modified overyears of observation and to prevent over-representation of patientswith lower hematocrit values from earlier years. The associationsdescribed above remained unchanged; only the lowest 2 quartilesof hematocrit were significantly associated with increasingdoses of EPO (P < 0.0001) (data not shown).
To maximize the cohort years included, the predictors of hematocritand EPO were reexamined in separate models by using linear regressionin a model excluding prescribed routes of iron and EPO administration.Seventy-six percent of the patients (27,540 of 36,066) had adequatedata for inclusion. The direction of the significant parameterestimates for predictors of hematocrit were unchanged, and theF values were not substantially different (P = 0.0001) (datanot shown). Similarly, in a model with EPO dose as the dependentvariable, the direction of the significant parameter estimateswere unchanged and the F values were not substantially different(P = 0.0001) (data not shown). However, the years on dialysiswere positively associated with EPO dose, although the F valuewas small (F value, 8.61; P = 0.003) (data not shown). Diabetesmellitus as the cause of ESRD was not found to be significantin the model without iron and EPO administration. Race was nota significant predictor for either hematocrit or EPO dose.
Because of the association between hematocrit and the morbidityand mortality of ESRD patients (29,30), there have been a seriesof structured quality improvement programs to increase the hematocritin hemodialysis patients (4,18). The most recent and comprehensivecompilation of these recommendations is the Kidney DialysisOutcomes Quality Initiative (KDOQI) of the National Kidney Foundation,Inc. The KDOQI Guidelines recommend a minimum hematocrit of33%, TSAT of 20%, serum ferritin concentration of 100 ng/dl,and that supplemental iron be administered intravenously (4).Moreover, because of favorable pharmacokinetics and possiblydiminished dose and costs (23,31), it has been suggested thatEPO be administered subcutaneously, rather than intravenously.The implementation of these recommendations was greatly strengthenedby the conversion of the original DOQI anemia clinical practiceguideline recommendations into clinical performance measuresby CMS (32). As observed in numerous other large data sets,the hematocrit of prevalent hemodialysis patients has risenin the United States, so that the mean hematocrit is now withinthe recommended range. This increment has been accomplishedby a rightward shift in the frequency distribution of hematocritvalues, rather than an increase in hematocrit for a segmentof the population. Also, as reported from other data sets, weobserved that the overall prescribing of iron and its parenteraladministration has increased. Because of the ability of parenteraliron to enhance the erythropoietic response to EPO (33,34),we posited that EPO doses would have stabilized or perhaps decreasedover this interval. Lastly, although still a minority practicepattern, the percent of patients prescribed EPO subcutaneouslyhas increased. Because of the favorable pharmacokinetics anddosage reductions achieved in several intervention trials, weposited that this trend would also contribute to stabilizationor reduction in EPO doses nationally.
However, the increased hematocrit has occurred in parallel withan increase in EPO dose. The increase in mean EPO dose seemsto be driven by the patients with lower Hct values as supportedby the EPO Resistance Index and the multivariate analyses byquartiles. An interpretation of these findings is that neitheriron nor EPO prescription patterns have been optimized adequatelyto balance the needed increase in EPO to achieve higher hematocritvalues. The inverse relationship between the percent of patientswith a TSAT <20% and the hematocrit supports this conjecture.An alternative and not exclusive interpretation is that patientswho are relatively EPO-sensitive were the ones who first achievedhigher hematocrit values. A greater percentage of the relativelyEPO-resistant subpopulation has been provoked to higher hematocritvalues each year, resulting in a secular increase in EPO dose,too. In other words, as greater numbers of patients are treatedto higher hematocrit values, the heterogeneity of the population’sresponse to EPO is manifest by higher doses each year. Thiscontention is supported by the demonstration of the inverserelationship between EPO dose and hematocrit. The cause of theheterogeneity on EPO responsiveness is unclear and may be aconsequence of other comorbid conditions like overt or covertinflammatory processes (35–37), hyperparathyroidism (38),trace mineral toxicity such as aluminum (39,40), protein-calorieand malnutrition (41), and inadequate hemodialysis (29,42).
The current data set does not permit an examination of all theserelationships. However, the full multivariable analysis illustratesseveral anticipated and unanticipated hypothesis-generatingfindings. Because the hematocrit is a clinical end-point thatdepends on EPO administration as a process of care, a separateanalysis was performed of measures associated with EPO dose.Other models evaluating factors predicting EPO dose and hematocrithave included albumin (18,29). We deliberately excluded albuminin our model as low serum albumin has a strong and consistentassociation with higher EPO doses. Such a notable impact maymask more subtle relationships of interests. Patient-specificvariables, such as age, weight, gender, and race (only in themodel for hematocrit), were associated with hematocrit and EPOdose. Some of the demographic differences may be reflectiveof disparities in frequency of drug dosing secondary to patientadherence to their dialysis treatment schedule, because thedialysis unit is the venue where EPO is administered. For example,younger patients miss dialysis more often than older patients(43) and would therefore be prone to miss their EPO doses morefrequently. The association of increased years on dialysis (vintage)with higher hematocrit values has been observed by other investigatorsusing different data sets (44,45). This relationship may bea consequence of patient-specific variables, such as bettercompliance and subsequent fewer missed EPO injections, and/orsurvival bias giving rise to a patient subgroup with fewer EPO-resistantcomorbid conditions. Patient weight is a surprising findingin view of the adjustment for EPO dose by weight and may reflectan interaction between patients’ nutritional state andEPO responsiveness (41). Care processes, such as prescribedEPO dose, the prescribed route of EPO and iron administration,and laboratory surrogates of marrow iron stores, demonstratedassociations in the anticipated manner. The finding of reproduciblylower TSAT for those patients with the lowest hematocrit continuesto identify a group for whom care processes may be enhanced.Moreover, the availability of non-dextran iron preparationsin the United States that have lower occurrence of major sideeffects should facilitate improving parenteral iron managementfurther (46). Small solute clearance from a single hemodialysissession was quantified by the URR. The current analysis confirmsprevious reports describing a statistical association betweenhemodialysis dose, hematocrit, and EPO dose (29,42,47). Theserelationships may reflect direct or indirect benefits of bettersolute clearance, such as enhanced removal of putative solubleerythropoietic inhibitors (48,49) and/or improved nutritionand substrate availability for erythropoiesis (41,42). Alternatively,improved anemia correction with increased dialysis doses maybe reflective of diligence to other components of patient carethat could improve EPO responsiveness, diminish blood losses,and/or enhance erythrocyte survival. For example, patients receivinghigher hemodialysis doses may also be more prone to being treatedwith high-flux, biocompatible dialyzers (50), less likely touse catheters for vascular access (so more reliable blood flowrates, lower thrombosis rates, fewer systemic infections) (51,52),or be aggressively monitored and treated for hyperparathyroidism(38).
The external validity of these findings is high because of thenational sampling strategy and the large number of subjects.However, this analysis shares the usual limitations associatedwith observational analyses, including indication bias thatis likely for some elements, such as the administration of parenteraliron and subcutaneous EPO. Similarly, some relationships arelikely reflective of care processes that are not within thecontrol of the providers; the inverse relationship between EPOdose and hematocrit may be driven by reimbursement constraintsas well as biologic variability. The 3-mo study period may notcapture iron use in some patients dosed less frequently or justbefore the collection period. Nor do the Core Indicators/ClinicalPerformance Measures data sets collect information on the timingof intravenous iron administration with respect to the measurementof transferrin saturations. Moreover, the absence of administereddosing of iron makes the interpretation of parenteral iron influencemore difficult.
On the basis of the findings herein, hematocrit values haveincreased at the expense of greater EPO doses. Although a minorityof the apparently EPO-resistant patients identified were irondeficient, which may attenuate their response to EPO, most patientswith higher hematocrit values and prescribed EPO doses werenot iron deficient. Population-based differences in EPO dose-responseseem to drive the increment in EPO as the achieved hematocritrises among the hemodialysis population. Using these data, weposit that to achieve still higher hematocrit values, as hasbeen advocated by some (53–56), disproportionately greaterEPO dose is likely, unless alternative routes of administrationare used (23,31) or different patterns of iron administrationare demonstrated to be safe, effective, and can be implemented(33,34). Alternatively, understanding more about how other factorsnot collected in this data set may influence hematocrit andEPO response, such as markers for inflammation, hyperparathyroidism,trace mineral toxicity, and protein-calorie malnutrition, mayoffer other interventions to achieve target hematocrit valueswithout a concomitant increase in EPO dose.
Acknowledgments
Dr. Coladonato is partially supported by a National ResearchService Award T32 HS0079–03 from the Agency of HealthcareResearch and Quality. Dr. Szczech’s work is supportedby grant DK02724–01A1 from the National Institutes ofHealth.
Footnotes
The views expressed in this manuscript are those of the authorsand do not necessarily reflect official policy of the Centersfor Medicare and Medicaid Services.
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Received for publication July 27, 2001.
Accepted for publication December 17, 2001.
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Abstract
Introduction
2 test and t test, respectively. A two-tailed P < 0.01 was considered significant. Scatter plots were drawn to describe the relationship between hematocrit and EPO dose stratified by year. Average EPO dose and hematocrit were calculated for each year and compared across years using ANOVA. 
33% appears to increase with each successive year. In 1994, 35.6% had a hematocrit 
