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Conversion From Subcutaneous to Intravenous Erythropoietin in a Hemodialysis Population

From the Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada (Dr Vercaigne, Dr Collins); Manitoba Renal Program, Winnipeg, Manitoba, Canada (Dr Vercaigne); and Departments of Pharmacology and Therapeutics and Internal Medicine, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Dr Penner).

Address for reprints: Lavern M. Vercaigne, PharmD, Office 407 B, Faculty of Pharmacy, University of Manitoba, 50 Sifton Road, Winnipeg, Manitoba, Canada.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The purpose of this study was to compare erythropoietin dosage requirements during subcutaneous versus intravenous administration in a hemodialysis population. Hemodialysis patients receiving subcutaneous epoetin alfa were switched to the intravenous route using a prospective, crossover design. Baseline anemia parameters were measured at months –2, –1, and 0 when patients were receiving subcutaneous dosing and compared to months 4, 5, and 6 after the switch to intravenous dosing. Ninety-eight patients were enrolled into the study with an average age of 54.8 years. Over the course of the study, 34 patients were excluded from analysis, leaving 64 patients with complete hemoglobin and erythropoietin dosing data throughout the subcutaneous and intravenous evaluation periods. In these patients, the dose of erythropoietin increased significantly from the subcutaneous to the intravenous period (7567.7 to 10229.2 IU/wk). The conversion of hemodialysis patients from the subcutaneous to the intravenous route of administration significantly increased epoetin alfa dosage requirements.

Key Words: Erythropoietin • intravenous • dosing • subcutaneoushemo • dialysis

The data presented here are part of an ongoing prospective anemia study in the Sherbrook Hemodialysis Unit, Manitoba Renal Program, Winnipeg, Manitoba, Canada. The purpose of this study was to compare epoetin alfa dosage requirements during SC versus IV administration.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Study Sample/Inclusion Criteria
The study was conducted in adult hemodialysis patients. Specific inclusion criteria included patients who (1) were 18 years and older, (2) received hemodialysis for a minimum of 3 months, (3) provided written informed consent to participate, and (4) received epoetin alfa (Eprex) for at least 3 months by the SC route before the switch was made to IV.

Design
Patients receiving SC epoetin in the hemodialysis unit were all switched to the IV route on February 17, 2003. Figure 1 clearly outlines when data were collected. Baseline parameters were measured at months –2, –1, and 0 when patients were receiving SC dosing. Months 1, 2, and 3 were used to monitor anemia parameters, make dosage changes, and allow epoetin doses and hemoglobin values to stabilize. Months 4, 5, and 6 with IV dosing were compared to months –2, –1, and 0 with SC dosing. All patients provided written informed consent. The study was conducted in accordance with the guidelines proposed in the Declaration of Helsinki and approved by the University of Manitoba Health Research Ethics Board.

View larger version (9K): [in this window] [in a new window]   Figure 1. Data collection.

Data Collection
The parameters of interest included hemoglobin, weekly epoetin dose, monthly IV iron dose, iron saturation (Tsat%), serum ferritin, Kt/V, urea reduction ratio (URR%), serum parathyroid hormone (PTH), chronic disease states, acute bleeding/infection/inflammatory episodes, and use of angiotensin-converting enzyme (ACE) inhibitors. Serum aluminum concentrations are no longer routinely evaluated in our center unless epoetin resistance is present and no other factors are responsible. Therefore, aluminum levels were not included in the monitoring. The main data set included patients with complete hemoglobin and weekly epoetin dosage data in both the SC evaluation period and the IV evaluation period. Analysis of each of the additional parameters used this main data set as the starting point.

Definitions
Hemoglobin. Monthly hemoglobin concentrations were measured from predialysis blood work. Patients were included in the data analysis if they had all Hgb values documented in the SC and IV evaluation periods (ie, 6 complete values). Any patients with missing values during these intervals were excluded from the analysis.

Weekly epoetin dose. The weekly epoetin dose was recorded for each patient throughout the study. When the switch was made from SC to IV dosing, the same dose and frequency was initially maintained. Dosage and frequency adjustments were made based on monitoring of laboratory results. Patients were included in the data analysis if they had all epoetin doses documented in the SC and IV evaluation periods (ie, 6 complete values). Any patients with missing values during these intervals were excluded from the analysis.

Monthly IV iron dose. The monthly IV iron dose was calculated based on the milligrams of IV iron that were given to the patient per month. For example, if a patient received 100 mg of IV iron every 6 weeks, the monthly dose was recorded as 66.7 mg/month. When patients received bolus doses of 1000 mg over 10 dialysis sessions, the monthly dose was recorded as 1000 mg/month. Patients were included in the analysis if they had all monthly IV iron doses documented in the SC and IV evaluation periods (ie, 6 complete values). Any patients with missing values during these intervals were excluded from this portion of the analysis.

Tsat%/ferritin. Serum Tsat% and ferritin were measured every 3 months. Therefore, in both the SC and IV evaluation periods, 1 Tsat% and 1 ferritin level were measured for each patient per evaluation period.

URR% and Kt/V. The URR% and Kt/V were measured monthly in both the SC and IV evaluation periods. Patients were included in the data analysis if they had all monthly URR% and Kt/V values documented in both periods (ie, 6 complete values). Any patients with missing values during these intervals were excluded from this portion of the analysis.

Parathyroid hormone. Serum PTH values are routinely measured every 6 months in our hemodialysis center. Therefore, for purposes of measuring PTH, we compared 1 value for each patient taken within 6 months before the switch with 1 value per patient taken within 6 months after the switch.

Chronic/acute disease states. We recorded all chronic disease states in our study population to characterize the patient group. Chronic conditions that were previously diagnosed and documented in the patients' charts were recorded (eg, cardiovascular disease, hypertension, diabetes, etc). We also recorded all acute bleeding and infectious and inflammatory episodes to determine if these confounding factors had an effect on hemoglobin changes during the evaluation periods. In general, these were defined as temporary or short-term episodes of bleeding requiring additional monitoring or intervention (eg, gastrointestinal bleed with a drop in Hgb of 10 g/L in 1 month), infections (eg, blood cultures obtained and antibiotics prescribed), or acute inflammatory events (eg, acute episodes of gout).

Angiotensin-converting enzyme inhibitors. We recorded the use of ACE inhibitors during the study periods. To be included in this part of the analysis, the patients' charts must have included documentation that these medications were being taken for at least 2 of the 3 months in each evaluation period. Pill counts were not conducted, which is a limitation of the study methodology.

Statistical Analysis
Descriptive statistics are provided where appropriate. Changes in parameters with a normal distribution (eg, epoetin dosage, HgB, etc) from the SC evaluation period to the IV evaluation period were evaluated using the dependent measures (paired) Student t test.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Demographics
Patient characteristics are shown in Table I. Ninety-eight patients provided written informed consent and were enrolled into the study. During the course of the study, 34 patients were excluded from analysis for reasons outlined in Table II. Therefore, 64 patients had complete hemoglobin and erythropoietin dosing data for the SC and IV evaluation periods; these patients comprise our main study group.

Anemia Management
Results comparing anemia parameters in the SC and IV evaluation periods are shown in Table III. Mean hemoglobin was statistically lower during the IV administration period (reduced by 2.3 g/L, P = .0365). Despite this drop in hemoglobin, epoetin requirements increased significantly from the SC to IV period (7567.7 to 10229.2 IU/wk). Of the patients, 59% had a >20% increase in their epoetin dose, 30% remained at doses ±20% of their baseline, and 11% had a decrease in their dose of >20%. Interestingly, the greatest increases in epoetin dosage were observed in those individuals with the lowest baseline SC doses (Figure 2).

View larger version (13K): [in this window] [in a new window]   Figure 2. Percent increase in epoetin dose from the subcutaneous (SC) to intravenous (IV) evaluation periods, stratified by baseline SC epoetin.

When patients were converted from the SC to IV route, the dose and frequency of epoetin administration were initially maintained with no empiric changes. However, by the end of the IV evaluation period, 52% of patients were receiving epoetin more frequently than at the time of the route conversion. Dosage frequencies at the time of the switch and at the end of the IV evaluation period are shown in Table IV.

Iron saturation, monthly dose of IV iron, albumin, predialysis urea, and PTH were not statistically or clinically different between the 2 periods. Although the Kt/V and URR% were statistically different (P < .05) between the evaluation periods, the differences were minimal (eg, a Kt/V difference from 1.61 up to 1.67, URR difference from 75.9% to 77.4%) and are unlikely to be clinically significant.

Ferritin increased significantly from the SC to the IV evaluation periods. In both periods, the mean ferritin was well above the lower recommended limit of 100 µg/mL and below the upper recommended limit of 800 µg/mL. An elevated ferritin plasma concentration in the IV evaluation period could be indicative of more infectious or inflammatory events. Table V demonstrates that there were more infectious episodes in the IV evaluation period. Bleeding episodes were less common in the IV evaluation period, and acute episodes of inflammation were similar in both.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Several studies have documented a decrease in erythropoietin dosage requirements when switching from the IV to the SC route of administration.^3-10 A metaanalysis of 27 studies with parallel or crossover designs demonstrated a decrease of approximately 30%.¹¹ The results of this current study show that conversion in the opposite direction, from the SC to the IV route, results in a significant increase in epoetin dosage requirements. These results are in contrast to 3 studies reporting no significant dosage changes when switching from the SC to IV routes (range, 0%-3% increase).^12-14 All 3 studies have small sample sizes (<25 patients/study) and may not have had sufficient power to detect a significant difference.

On a much larger scale (n = 10 803), the European Survey on Anemia Management (ESAM) demonstrated that there was a small and nonsignificant difference in epoetin dosing requirements between the SC and IV routes of administration. Participants receiving IV epoetin in the maintenance phase (n = 5490) had a mean ± SD dose of 113.5 ± 86.2 U/kg/wk. Participants receiving SC epoetin in the maintenance phase (n = 5313) had a mean ± SD dose of 104.7 ± 79.6 U/kg/wk. Hemoglobin values were similar at 108 and 109 g/L, respectively.¹⁵

In contrast, the End Stage Renal Disease Core Indicators Project (ESRD-CIP) survey done in the United States indicated that hemodialysis patients had greater epoetin dosage requirements when receiving IV dosing compared to SC dosing.¹⁶ Analysis of the survey results controlled for hematocrit, iron status, serum albumin, patient characteristics, duration of dialysis, and postdialysis weight. Participants receiving IV epoetin had a mean dose of 193.6 U/kg/wk compared to those receiving SC with a mean dose of 167.4 U/kg/wk (mean difference of 26 IU/kg/wk).¹⁶ Our results using a prospective, controlled, crossover design over a 9-month period add support to these survey results, indicating a significant increase in dosing requirements when changing from the SC to the IV route. Our results are also consistent with the largest single study by Kaufman et al¹⁷ investigating differences in dosage requirements between the IV and SC routes. This randomized, prospective, parallel study in 208 hemodialysis patients reported an average ± SD epoetin dose in the SC group of 7397 ± 6139 compared to 10 068 ± 6334 U/wk for the IV group (P = .002). These results are very consistent with this study's crossover design in 64 patients, all converted from SC to IV, with a mean ± SD epoetin SC dose of 7567.71 ± 6712.46 compared to a mean ± SD epoetin IV dose of 10 229.2 ± 8181.3 U/wk.

The increase in dosage requirements in our study was unlikely due to a minority of outliers. In fact, most patients in the study had at least a 20% increased dosage requirement when switching from the SC to IV route (59% of patients had >20% increase in their epoetin dose, 30% of patients remained at doses ±20% of their baseline, and 11% of patients had a decrease in their dose of >20%). There were 2 patients who had a greater than 10 000-IU/wk increase from the SC to the IV evaluation period, which was balanced by 1 patient who had a >10 000-IU/wk decrease from the SC to IV period.

The largest increases in erythropoietin dosage requirements to maintain a similar hemoglobin in the IV evaluation period occurred in patients with the lowest starting SC doses at baseline (see Figure 2). Patients with baseline SC doses <5000 IU/wk had increased requirements of up to 59%, whereas patients already on >20 000 IU/wk had requirements that only increased by 14.6%. Patients with elevated epoetin dosage requirements (those on >20 000 IU/wk in the SC period) are arguably less sensitive to the effects of erythropoietin; thus, switching the administration routes from SC to IV may have little effect on this underlying decreased sensitivity. In contrast, patients receiving lower doses (<5000 IU/wk in the SC administration period) may potentially be more responsive to the changes in half-life associated with SC versus IV administration.

During the conversion from the SC to IV route, the dose and frequency of epoetin administration were initially maintained. However, as dosage requirements began to increase as the study progressed with IV dosing, the frequency of administration was increased. This was done to account for a shorter half-life of epoetin when given by the IV route. Giving smaller doses more frequently (eg, 5000 IU IV twice weekly) should have a greater effect than giving larger doses less often (10 000 IU IV once each week).¹⁸ Although there is some evidence for using epoetin once weekly during subcutaneous administration, once-weekly intravenous administration is less appropriate.¹⁸ As 44% of patients in our study had an increased dosing frequency, the observed increase in epoetin dosage is unlikely due to giving larger IV doses at longer intervals.

Confounding factors that could potentially explain our results were investigated. There were no clinically or statistically significant changes in Tsat%, monthly IV iron dose, serum albumin, predialysis urea, or serum PTH between the evaluation periods. There were statistically significant differences in Kt/V and URR%, as well as ferritin. The changes in Kt/V and URR%, although statistically significant, were small and of questionable clinical significance (less than 4% difference between the SC and IV evaluation periods). In fact, the Kt/V and URR% were slightly better in the IV evaluation period, which would not contribute to a higher epoetin requirement.

Ferritin was greater in the IV evaluation period. Although the mean ferritin in both periods was considered to be acceptable (>100 µg/mL and <800 µg/mL), an elevated ferritin in the IV evaluation period may indicate more inflammatory or infectious processes occurring.¹⁹ In our study, there were 6 more infectious episodes in the IV evaluation period. A decreased response to erythropoietin (and hence increased dosing requirements) cannot be ruled out. Other investigators have observed increased epoetin dosage requirements in patients with elevated ferritin levels as part of the acute phase response, but quantitating the increase in dosage requirement per infectious episode is not well described.²⁰ It is unlikely that the difference in the number of infectious episodes in the IV evaluation period of our study would solely account for the increase in dosage requirements.

Another proposed explanation for an increased dose when switching from SC to IV is the administration of IV epoetin into the venous drip chamber of the Fresenius delivery system. A previous report suggested that significant trapping of epoetin occurs if the medication is injected into the venous drip chamber.²¹ The policy at the Sherbrook dialysis unit is to inject medications into the venous port of the dialysis tubing. As we did not specifically document the administration location for each patient enrolled, we cannot be absolutely sure that every patient received the epoetin in this fashion.

In conclusion, the conversion of hemodialysis patients from the SC to the IV route of administration significantly increased epoetin dosage requirements in our population.

	ACKNOWLEDGEMENTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
We would like to acknowledge Cali Orsulak, BSc (Pharm), for her extensive input during the implementation of the study and conversion of patients between the SC and IV routes. We acknowledge the exceptional research nurses who played a pivotal role in conducting the study: Janine Kemp, Sherri Pocket, Brad Whiteside, and Lori Berard. Our thanks are also extended to the Sherbrook dialysis nurses and ward clerks for their support with this study.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

1. Manitoba Renal Program. Health Sciences Centre, Winnipeg, Manitoba, Canada, 2003.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Vercaigne, L. M. Articles by Penner, S. B. Search for Related Content PubMed PubMed Citation Articles by Vercaigne, L. M. Articles by Penner, S. B. Social Bookmarking                   What's this?