Weekly subcutaneous recombinant human erythropoietin corrects anemia of progressive renal failure

Weekly Subcutaneous Recombinant Human Erythropoietin Corrects Anemia of Progressive Renal Failure ANTHONYR. ZAPPACOSTA,M.D., Narberth, Pennsylvania, SUSANT. PERRAS,R.N., M.s.N., c.N.N., Wayne, Pennsylvania, ALISABELL, D.O., Ardmore, Pennsylvania

PURPOSE: The purpose of this study was to analyze data retrospectively from our use of weekly subcutaneous recombinant human erythropoietin (rHuEP0) in predkly& and peritoneal dialysis patienta with anemia PATIENTS

AND

MEI’HODS:

m

amdC

IMdentS

with progressive renal faihue (12 predialysis and seven home peritoneal dialysk) in whom subcutaneous rHuEP0 therapy was begun at, or was reduced to, a weeltly dose were studied retrospectively. Patients were not selected for, nor excluded from, these observations for any other reason. Hematocrit and endogenous creatinine clearance were monitored regularly, and no other new treatment for anemia was given except oral iron. Iron-deficiency anemia was considered improbable because of normal red blood cell mean corpuscular volume Unfortunately, iron parameters were not monitored. RESULTS: The hematocrit increased 4 to 9 percentage points in 4 to 13 weehs in all but two patients who were initially treated with weekly doses, and a hematocrit of 31% was achieved in these patients within 6 to 12 weehs. The mean effective dose to accomplish this was 150 U/kg. All but three patients could be maintained on weekly doses at a hematocrit of 31% or higher. The mean effective dose was 75 U/kg. CONCLUSION: It is concluded that subcutaneous rHuEP0 administered weehly can correct the anemia of predialysis and peritoneal dklysis patients. Weekly dosing is more convenient for patients and may be less costly for Medicare providers.

From The Bryn Mawr Hospital, Bryn Mawr, Pennsylvania. This work was supported by The Bryn Mawr Hospital

M.D., The Bryn Mawr Hospital, Bryn Mawr, Pennsylvania Manuscript submitted March 11, 1991, and accepted

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ntravenous or subcutaneous recombinant human erythropoietin (rHuEP0) safely corrects the anemia of progressive renal failure in both predialysis [1,2] and dialysis patients [3,4]. The half-life for an intravenous dose is approximately 6 to 9 hours [5], and effective therapy for hemodialysis patients is achieved with intravenous doses three times per week with each hemodialysis treatment. After administration of a subcutaneous dose, there is continued absorption for up to at least 70 hours [6], and it has been recommended that home peritoneal dialysis recipients and predialysis patients receive subcutaneous doses three times per week as well [2,4]. Medicare reimbursement has not been available for self-administered rHuEP0, and the inconvenience for home patients to travel to our dialysis unit three times per week prompted us to try administration of rHuEP0 on a weekly basis. We report the correction of anemia with weekly doses of subcutaneous erythropoietin as initial rHuEP0 therapy in predialysis and home peritoneal dialysis patients. In addition, we report the maintenance of a “target” hematocrit with weekly subcutaneous rHuEP0 in patients initially treated with twice or thrice weekly subcutaneous rHuEP0.

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PATIENTSAND METHODS From July 1989 to February 1991, all patients with progressive renal failure who were anemic (12 patients) and all home peritoneal dialysis patients (CAPD) who were anemic (seven patients) started rHuEP0 therapy with subcutaneous Epogen given weekly, once every 2 weeks, or two or three times per week and eventually reduced to once per week. Patients who started hemodialysis before their dose was reduced to weekly were excluded. The observations were retrospective. Eleven patients administered their rHuEP0 and eight received it at our clinic. There was no improvement in creatinine clearance in any of the predialysis patients, and all patients except Patients 4 and 9 became dialysisdependent after 1 to 16 months. It was assumed that the anemia of all patients was due to chronic renal failure, and no other new treatment for anemia was given except oral iron. The mean corpuscular volume of red cells before rHuEP0 was not less than 87 p3, suggesting at least that iron deficiency 1991

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TABLE I Patient Characteristicsand rHuEP0 Dosesin Patients Who Were Initially Treated With and Maintained on Weekly (or Less)rHuEP0

Patient

Sex/Age

1

F/46

:

i;;F

4 6"

:;:z F/71 Ml53

i 9

iy

Diagnosis RN ASVD ASVD Diabetes CGN

Initial rHuEP0 Dose(U)*

7 <20 15 t15 <15

%D %D

4" ; 6" <12 NA

4,000 once/week42/kg

!"5 21 <15 DD DD

!$i

wRt:ihb Hematecritet Approximately31%

10,000once/week 166/kg 10,000once/week 125/kg 10,000once/week 185/kg 10,000once/2 weeks 125/kg 10,000once/week 143/kg 10,000once/week 263/kg 10,000once/lto 2 weeks 87/kg

14

'c"N Diabetes

"F/':: F/81

Creatinine Clearance at Startet rHuEP0 (mUminute)

10,000once/week 87/kg 10,000once/week 175/kg 10,000once/week 147/kg

:

4,000 once/week 58/kg

NA3

DD = dialysis-dependent; CN = chronic nephritis; IN = interstitial nephritis; RN = reflux nephropathy; ASVD = arterioscleroticvascular disease; CGN = crescentic gfomerulonephritis;NA = not achiever *Dose par kg patient weight.

was not a major cause of their anemia. None of the patients had a clinical history suggestive of iron deficiency, and Patients 17 and 19 were transfusion-dependent prior to administration of rHuEP0. Our objective was to raise the hematocrit above a level at which we believed the patients would be at risk for a transfusion should they experience a minor to moderate hemorrhage or serious infection. This “target” hematocrit was 31%; however, we did not reduce the dose when this was achieved because of our uncertainty about the dose response of weekly rHuEP0. No patient received a transfusion after starting rHuEP0 treatment, except Patient 12 (see Comments). Table I shows patient characteristics and rHuEP0 doses in patients who were initially treated with and maintained on weekly (or less) doses. Table II shows patient characteristics and rHuEP0 doses in patients who were initially treated with more than weekly doses and in

whom the dose was reduced to weekly after 3 to 24 weeks.

RESULTS Figure 1 shows the hematocrit response to rHuEP0 in patients described in Table I. In all patients except 8 and 12 (Patient 12 is not shown because she received a transfusion 2 weeks after starting rHuEP0 treatment), a hematocrit of 31% or higher was achieved within 3 to 12 weeks after the the beginning of rHuEP0 administration. Figure 2 shows the hematocrit response to rHuEP0 in patients described in Table II. In all patients except 8, 12, and 14, a hematocrit greater than 31% could be maintained with weekly doses ranging from 4,000 U to 10,000 U. Patients 8 and 12 did not respond to 4,000 U weekly. Patient 12 had a chronic infection of the peritoneal dialysis catheter exit site, and the catheter was removed for this reason within 3 months of initiation of rHuEP0 therapy. Poor re-

TABLE II Patient Characteristicsand rHuEP0 Dosesin Patients Initially Treated With More Than Weekly rHuEP0 and Then Weekly rHuEP0 After 3 to 24 Weeks Creatinine Clearance Patient ii

2

Sex/Age

;2

Ml27 F/32

Diagnosis Lupus TCR TCR Lupus

F/69 :;

19

DD <15

35,26+ I?:

F

A:;

azK%f (mUminute)

CN

K

Maintenance rHuEP0 KU*

4,00O/week 60/kg 4,00O/week 60/kg 4,000/2 weeks 66/kg lO,OOO/week 182/kg 4,000/week48/kg 8,00O/week 52/kg 8,00O/week 58/kg

DD = dialysis-dependent; CN = chronic nephritis; IN = interstitial nephritis; TCR = transplant chronic rejection; NA = not achreved. *Dose per kg patient weight. fclearance before and 1 year after start of rHuEP0 treatment.

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Weeks with Hematocrit>31% Ni

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ERYTHROPOIETIN

CORRECTS

UREMIC

ANEMIA

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Flgure 1. Individual patient hematocrit (HCT) response to subcutaneous rHuEP0 started with a weekly dose, or less frequently. See Table I. Patient number indicated at end of each line.

sponse to rHuEP0 during infection has been reported [7,8]. Patient 8 weighed 95 kg, and it appears that this dose simply was insufficient. Patient 14 had several episodes of pyelonepbritis of the grafted kidney and had chronic rejection as well, and has resumed hemodialysis. Patient 15 was maintained for 55 weeks at a hematocrit above 31% with 4,090 U once every 2 weeks after 16 weeks of 4,000 U per week. As of this writing, his hematocrit has continued to be maintained above 32% with administration of 4,006 U once every 2 weeks for over 71 weeks. Also, Patient 13 has maintained a hematocrit above 31% for more

than 24 weeks. In Patient 1, we reduced the dose of 166 U/kg from weekly with a hematocrit of 38% to once per 2 weeks, but the hematocrit decreased to 33.8% within 3 weeks and rose again to 38% after resumption of the weekly dose.

COMMENTS It is possible to correct the anemia of chronic renal failure in predialysis and peritoneal dialysis patients with subcutaneous rHuEP0 therapy that is initiated with weekly doses. The time to increase the hematocrit 4 to 9 percentage points was 4 to 13

Figure 2. Individual patient hematocrit (HCT) response to subcutaneous rHuEP0 started at a twice or thrice weekly dose (solid line) and maintained at a weekly, or less, dose (broken line). See Table II. The weekly dose is indicated when it was changed. Patient number indicated at end of each line. September

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weeks, which is similar to the response rate of thrice weekly intravenous doses [9]. The mean effective weekly dose to achieve a hematocrit of 31% within 6 to 12 weeks was 150 U/kg (range, 87 to 263 U/kg). The dose given by Watson et al [2] was 300 to 450 U/kg subcutaneously per week in three separate doses. Patients 4 and 7 responded within 6 to 12 weeks to 10,000 U once per 10 to 14 days. It is also possible to maintain a “target” hematocrit with weekly rHuEP0. The mean effective maintenance dose for ah patients (including those in whom the dose was initiahy weekly and then was reduced) was 75 U/kg (range, 48 to 182 U/kg). In Patient 15, we were able to reduce the frequency of doees to once per 2 weeks and maintain the hematocrit at 31% or higher for 55 weeks, during which time the endogenous creatinine clearance decreased from 35 to 26 ml/minute. Our observations support the subcutaneous use of rHuEP0 for predialysis and peritoneal dialysis patients, in a schedule that begins with weekly doses. In some patients, a “target” hematocrit can be maintained with one dose every 2 weeks. During the study period, reimbursement for rHuEP0 was made according to the regulations published in the Health Care Financing Administration Provider Reimbursement Manual, publication 15-27. This provided for an add-on amount to the dialysis treatment of $40.00 per dose under 10,000 U. For any dose greater than 10,000 U, an additional $30.00 was paid. Consistent with Medicare reimbursement, 80% of the designated amount was paid and the remaining 20% was paid by private insurance. Under these rules, smaller, more frequent doses were reimbursed at a higher percentage of cost. This has changed as of January 1,1991, and

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weekly doses wiIl be more affordable to dialysis providers. As of January 1, 1991, the regulations concerning rHuEP0 were changed, and the use of this agent will now be reimbursed at the rate of $11.00 per 1,000 U, rounded to the nearest 100 U, with no maximum payment established [lo]. This reimbursement change wiIl not punish providers for administering higher doses of rHuEP0 less frequently. In addition, as of July 1,1991, Medicare coverage for rHuEP0 is provided for self-administration of the drug.

REFERENCES 1. Eschbach JW. Kelly MR. Haley NR, Abels RI, Adamson JW. Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med 1989; 321: 158-62. 2. Watson AJ. Gimenez LF. Cotton S. Walser M, Spivak JL. Treatment of the anemia of chronic renal failure with subcutaneous recombinant human erythropoietin. Am J Med 1990; 89: 432-5. 3. Eschbach JW. Egrie JC. Downing MR. Browne JK. Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. N Engl J Med 1987; 316: 73-8. 4. Bommer J, Ritz E. Weinreich T. Bommer G, Zibgler T. Subcutaneous erythropoietin. Lancet 1988; 2: 406. 5. Lim US, DeGowin RL, Zaval D. et a/. Recombinant human erythropoietin treatment in pre-dialysis patients. Ann Intern Med 1989; 110: 108-14. 6. Boelaret JR, Schurgers ML, Matthys EG. et al. Comparative pharmacokinetits of recombinant erythropoietin administered by the intravenous, subcutaneous and intraperitoneal routes, in continuous ambulatory peritoneal dialysis (CAPD) patients. Peritoneal Dialysis Bulletin 1989; 9: 95-8. 7. Stockenhuber F. Kurz RW. Geissler K, eta/. Recombinant human erythropoietin activates a broad spectrum of progenitor cells. Kidney Int 1990; 37: 150-6. 8. Kuhn K, Nonnast-Daniel B. Grutzmacher B, et al. Analysis of initial resistance of erythropoietin to treatment with recombinant human erythropoietin. Contrib Nephrol 1988; 66: 94-103. 9. Eschbach JW, Abdulhadi MH. Browne JK. eta/. Recombinant human erythropoietin in anemia patients with end-stage renal disease. Ann Intern Med 1989; 111: 992-1000. 10. ESRD Provisionsof Budget Reconciliation Bill FY 1991. Contemporary Dialysis and Nephrology 1991; 12: 8-20.

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