Hematocrit Levels and Hospitalization Risks in Hemodialysis Patients

Medicare Patients

All ESRD patients in the United States have been entitled to Medicare coverage since 1972. ESRD patients under the age of 65 yr have a 90-d waiting period before receiving Medicare coverage for in-center hemodialysis. All Medicare rhEPO claims are processed on detailed Uniform Bill forms (UB82/UB92) and require reporting of a hematocrit level prior to the last rhEPO dose of the billing period as a condition for reimbursement. Patients not receiving rhEPO do not have hematocrit levels documented in the Medicare system and are not included in this analysis. Medicare patients with rhEPO claims and with hematocrit levels are the source of data for our hospitalization risk model.

Study Design

We retrospectively evaluated prevalent Medicare hemodialysis patients surviving a 6-mo entry period from July 1 through December 31, 1993. Patient age, gender, race, and renal diagnosis data were obtained from the HCFA 2728 Medical Evidence forms. The 6-mo entry period was selected in order to adequately assign patients within hematocrit groups based on the hematocrit data provided on the rhEPO claims as well as to assess patient severity of disease (see below). The follow-up period was January 1 through December 31, 1994. All patients were on hemodialysis throughout the entry and follow-up periods.

Patient Characteristics

Patient characteristics included age at the beginning of the entry period, gender, race, and renal diagnosis (including diabetic status). Patient comorbidity was obtained from both Part A (1984-1993) and Part B (1991-1993) Medicare claims and profiled as described previously (15). Major medical conditions included atherosclerotic heart disease, congestive heart failure, peripheral vascular disease, cerebrovascular accident/transient ischemic attacks, other cardiac disease (valvular heart disease, arrhythmias, and pacemakers), cancer excluding skin malignancies (except for malignant melanoma), chronic obstructive pulmonary disease, liver disease, gallbladder disease, and gastrointestinal diseases associated with bleeding.

Severity of Disease (Factors Affecting Hematocrit Levels)

Medical conditions associated with blood loss may significantly affect hematocrit levels. Examples of these conditions include vascular access procedures and conditions requiring blood transfusions. Hospitalizations also affect hematocrit levels due to increased blood testing as well as acute medical complications that may create reduced bone marrow responsiveness to rhEPO, which reduces hematocrit levels during the hospitalization (2). These severity of disease measures were assessed for their relationship to the entry period hematocrit level and their predictive value on future hospitalization risks.

Hematocrit Levels

Medicare reimbursement for rhEPO administration requires documentation of the last hematocrit level before the last rhEPO dose given during the billing period. To define a consistent hematocrit level, only those patients with at least four rhEPO claims in the 6-mo entry period were included in the study. At least four rhEPO claims were needed to ensure a minimum of 3 mo of hematocrit data, with a mean of 5.1 mo of the 6-mo entry period. A mean hematocrit was calculated for each patient with subsequent hematocrit groupings of <27% (hemoglobin <9.0 g/dl), 27 to <30% (hemoglobin 9.0 to <10.0 g/dl), 30 to <33% (hemoglobin 10.0 to <11.0 g/dl), 33 to <36% (hemoglobin 11.0 to <12.0 gm/dl), and ≥36% (hemoglobin ≥12.0 g/dl).

Study End Points

Time to first hospitalization and cause-specific hospitalization was assessed, as well as multiple hospitalizations during the follow-up period. Cause-specific hospitalizations were evaluated by partitioning the International Classification of Diseases (ICD-9) codes for principle diagnoses into infectious (all types from all organ systems), cardiovascular, and other groupings. Patients were censored at death, modality change (hemodialysis to peritoneal dialysis or to transplantation), or at the end of the follow-up period.

Statistical Analyses

Explanatory Variables. Explanatory variables included age, race, gender, comorbidity, prior ESRD time, number of vascular access procedures, number of blood transfusions, and entry period hospital length of stay in days. Hematocrit groupings were evaluated after adjustments for the prior variables. χ² was used to compare the differences in hospitalizations by hematocrit group in the univariate analysis.

Cox and Andersen-Gill Regression. The time from January 1, 1994 to the first hospitalization was used in the Cox proportional hazards model to assess the relative risk (16). An Andersen-Gill multiple event model (17), a modification of the Cox regression, was used to evaluate outpatient time between each hospitalization event as a risk ratio. By using multiple hospitalizations, the number of events is increased three- to fourfold, compared to single hospitalizations. All models were stratified by diabetic status to address the proportional hazards assumption (18). Patient outcomes during the follow-up period were adjusted for prior ESRD time, since patients with shorter time on ESRD have higher death rates compared to patients with longer time on dialysis (19). Comparison of results with and without severity of disease were evaluated to address the potential interaction between sicker patients and lower hematocrit levels. The reference patients were male and white, with no comorbidity, no access procedures or blood transfusions, and no hospitalizations during the entry period. The reference hematocrit group was 30 to <33%. All probability values were two-tailed.

Sensitivity Study. A sensitivity analysis was performed to assess the robustness of the results with respect to the number of patients in the 33 to <36% hematocrit group. We randomly selected samples of 50, 40, 30, 20, and 10% of the patients, using the last two digits of the Social Security number (20,21), rerunning the Cox regression model for each sample to determine the point at which significance of the findings is lost.

Patient Characteristics

The 1993 study cohort contained 71,717 patients, with a mean age of 60.2 yr, 49% white, 41% black, 52% female, and 31% diabetic, from the primary renal diagnosis. This was comparable to the United States in-center hemodialysis population at a mean age 59.0 yr, 55% white, 39% black, 49% female, and 33% diabetic (see Tables C4 and C5 of the 1997 USRDS Annual Data Report) (22). The study cohort represented 78% of the patients surviving the 6-mo entry period and are more completely described in our mortality study of the same population (23).

Comorbidity, Disease Severity, and Hematocrit Group in the Entry Period

We analyzed the relationship between the number of preexisting comorbid conditions, the hematocrit level during the entry period, and the total hospital days for diabetic and nondiabetic patients (Table 1). Overall, diabetic patients had 62% more hospital days during the entry period compared with nondiabetic patients. There was a consistent pattern of increased hospital days in the entry period as the number of comorbid conditions increased and the hematocrit decreased.

Hospitalizations in the Follow-Up Period

The relationship between hematocrit level and future hospitalization days per patient year is shown in Figure 1. The rapid falloff in patients at the higher levels is consistent with the restrictive Medicare reimbursement policies for patients with hematocrits >36%. The future hospital days per patient year monotonically decreases as the hematocrits rise to 36%. Hematocrits >36% were associated with more variable hospital days per patient year. The hospital days by hematocrit group is shown in Table 2. There was a steady decrease in admission rates and hospital days as patient hematocrits rose to the 33 to <36% range.

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Figure 1.

Follow-up total hospital days per patient year and patient distribution by hematocrit level (unadjusted).

All-Cause Hospitalization Risk

We analyzed the adjusted risk of all-cause hospitalization in the follow-up period using the Cox proportional hazards model for the first hospitalization and the Andersen-Gill multiple event model for multiple hospitalizations (Tables 3 and 4). These analyses were performed with and without adjustments for severity of disease measures, which included blood transfusions, vascular access procedures, and total hospital days during the entry period. Compared with the baseline group of 30 to <33%, patients with hematocrit levels <30% had a 14 to 30% increased risk of future hospitalization without adjusting for disease severity, and a 7 to 18% increased risk with that adjustment. Patients with hematocrit levels in the 33 to <36% range had the lowest risk of future hospitalizations, at 0.93 and 0.88 (p = 0.0001), both with and without adjustment for disease severity, respectively. The severity of disease adjustment changed the magnitude, but not the direction, of the risks, except in the hematocrit group of ≥36. The latter variable results, both with and without severity of disease measures, may reflect the low sample size of 687 patients.

The impact of disease severity on future hospitalization risk was highly significant (Table 4). Each unit of blood transfused in the entry period was associated with a future hospitalization risk of 1.05. A similar but smaller risk (1.03) was noted for each vascular access procedure performed during the entry period. When assessing the future risk of hospitalization, the impact of prior hospital days during the entry period was the largest among all of the factors adjusted for in the model. Therefore, prior hospital days are strong predictors of future risk of hospitalization.

Risk for Cause-Specific First Hospitalization

Cause-specific hospitalizations are shown in Table 5. Cardiovascular hospitalizations consisted of congestive heart failure, fluid overload, and cardiomyopathy (38%); ischemic heart disease (20%); circulatory system disorders (17%); cerebrovascular disease (11%); and other (14%). The infectious hospitalizations consisted of respiratory infection (37%), bacteremia/septicemia/viremia (20%), vascular access (18%), and other (25%). The differential effects relative to the specific hospitalization categories appear to be reflected in most of the risk factors. For example, females appear to have an 11% higher risk of infectious hospitalization as their male counterparts. Blacks and other minorities appear to have a lower hospitalization risk for all-cause, cardiac, and infectious hospitalization compared with whites. Individual comorbidity risks appear to have different associations based on the type of hospitalization. Atherosclerotic heart disease was associated with a 1.49 risk (95% confidence interval [CI], 1.43 to 1.56) for cardiovascular hospitalizations but only a 1.07 risk (95% CI, 1.02 to 1.13) for infectious hospitalizations. Chronic obstructive pulmonary disease was associated with a 1.48 risk of infectious hospitalization (95% CI, 1.41 to 1.56) compared to cardiovascular at 1.25 (95% CI, 1.19 to 1.31). Peripheral vascular disease was associated with an infectious risk of 1.31 (95% CI, 1.24 to 1.37) compared to cardiovascular at 1.18 (95% CI, 1.13 to 1.23). Congestive heart failure had a high cardiovascular hospitalization risk at 1.62, and infectious hospitalization risk was also high at 1.44.

The cause-specific risk by hematocrit group also shows a differential pattern. Patients in the <27% hematocrit group had a 1.32 cardiovascular (95% CI, 1.25 to 1.41) and a 1.57 infectious (95% CI, 1.47 to 1.68) hospitalization risk compared to the reference group of 30 to <33%. Patients in the hematocrit group 33 to <36% had the lowest all-cause, cardiovascular, and infectious hospitalization risk.

Sensitivity Analysis

Using the Cox regression model, we performed a sensitivity analysis on the risk of first hospitalization to determine the sample size required to detect the impact of the hematocrit group 33 to <36%. Figure 2 shows that at least 3000 to 4000 patients were required to detect the lower risk of hospitalization when severity of disease was included, whereas approximately 2000 patients were needed if disease severity was excluded.

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Figure 2.

The impact of sample size on the mortality risk in the 33 to <36% hematocrit group, both with and without adjustment for severity of disease (number of access procedures, blood transfusions, and hospital length of stay), defined in the entry period.