Download Economic appraisal of maintenance parenteral iron administration in

Nephrol Dial Transplant (1996) 11: 319-322
Nephrology
Dialysis
Transplantation
Original Article
Economic appraisal of maintenance parenteral iron administration in
treatment of anaemia in chronic haemodialysis patients
F. Sepandj, K. Jindal, M. West and D. Hirsch
Division of Nephrology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
Abstract
Background. Iron deficiency is common in haemodialysis patients and adequate supplementation by the
oral or parenteral route has been limited by drug sideeffects, absorption, and cost.
Intermittent doses of intravenous iron dextran complex are recommended in patients with inadequate iron
stores despite maximal tolerated oral dose. We conducted a prospective study with economic analysis of
a regular maintenance intravenous iron regimen in this
group of patients.
Methods. Fifty patients comprising one-half of our
haemodialysis population required intravenous iron
treatment, i.e. they failed to achieve an arbitrary goal
serum ferritin 100 ug/1 despite maximal tolerated oral
iron dose. After a loading dose of intravenous iron
dextran complex (IV-FeD) based on Van Wyck's
nomogram (400 + 300 mg) they received a maintenance
dose of 100 mg IV-FeD once every 2 weeks. Initial
goal serum ferritin was set at 100-200 ug/1. If no
increase in haemoglobin was achieved at this level,
transferrin saturation was measured to assess bioavailable iron, and when less than 20%, goal serum ferritin
was increased to 200-300 ug/1. Recombinant human
erythropoietin (rHuEpo) was used where needed to
maintain haemoglobin in the 9.5-10.5 g/1 range only
if ferritin requirements were met.
Results. Mean haemoglobin rose from 87.7 + 12.1 to
100.3 + 13.1 g/1 (P<0.00\, Cl 7.7-17.9) at mean
follow-up of 6 months (range 3-15 months). In patients
on rHuEpo, dose per patient was reduced from
96 + 59 u/kg per week to 63+41 u/kg per week, representing a 35% dose reduction (P<0.05, Cl 1-65). An
annual cost reduction of $3166 CDN was projected;
however, in the first year this is offset by the cost of
the loading dose of IV-FeD required at the beginning
of treatment. No adverse reactions were encountered.
Conclusion. Iron deficiency is very common in our
haemodialysis population, especially in those patients
receiving rHuEpo. A carefully monitored regimen of
maintenance parenteral iron is a safe, effective, and
economically favourable means of iron supplementation in patients with insufficient iron stores on maximum tolerated oral supplements.
Key words: anaemia; ferritin; ferrous sulphate; haemodialysis; intravenous iron dextran complex; recombinant human erythropoietin
Introduction
Iron deficiency is a common accompaniment of
anaemic chronic renal failure patients on haemodialysis. There are many factors which contribute to the
development of an iron deficient state. (1) Blood loss
occurs routinely through the dialysis blood circuit and
blood tests as well as through occult or gross gastrointestinal bleeding [1]. (2) Insufficient input results from
inability to provide adequate amounts through the
restricted renal diet, in addition to a reduction in
absorption related to binding by multiple components
of ingested food and coadministration of other medications such as phosphate binders and histamine H2
blockers, which increase gastric luminal pH [2]. (3)
Accelerated utilization occurs in conjunction with the
use of rHuEpo and the resultant rapid correction of
anaemia; iron deficiency is considered to be the most
common cause of rHuEpo resistance [3-5].
Adequate iron supplementation remains a challenge.
Oral iron preparations are generally quite cheap; however, patient tolerance has been poor and frequently
sufficient stores have been difficult to maintain even
when full oral dose is tolerated. Intermittent intravenous iron dextran complex (IV-FeD) has been advocated and utilized for this purpose [6] but availability,
cost, drug reactions, and iron overload have been
potential limiting factors in its widespread use.
We performed an economic analysis of utilization of
a conservative and closely monitored maintenance
IV-FeD regimen in patients who were either unable to
tolerate oral iron in sufficient doses or alternatively
Correspondence and offprint requests to: F. Sepandj, Suite 306,
Bethune Building, Victoria General Hospital, 1278 Tower Road, were unable to sustain adequate stores despite maximal
tolerated oral dose.
Halifax, NS B3H 2Y9, Canada.
© 1996 European Dialysis and Transplant Association-European Renal Association
320
Subjects and methods
Patient selection
Stable patients undergoing haemodialysis for at least 4
months were screened. They received thrice-weekly dialysis,
3.5-4.5 h each session, using standard 36 mEq bicarbonate
dialysate and 1.3-2.1 m2 surface area cellulose acetate membranes, and goal urea reduction of at least 60%. Baseline
measurements of serum ferritin, haemoglobin, and rHuEpo
dose were obtained and subsequently followed (haemoglobin
and rHuEpo dose monthly, serum ferritin every 3 months).
Intact parathyroid hormone levels were measured routinely
every 6 months; however, patients receiving vitamin D3
treatment had levels followed every 3 months. Aluminium
studies were not done routinely and were performed only if
clinical suspicion was present. Those patients who had a
serum ferritin level less than 100 ug/1 who had not tolerated
oral iron or had not been able to achieve this level despite
maximal tolerated oral dose were started on IV-FeD. Patients
with known hypersensitivity to iron, active or ongoing overt
source of bleeding, severe acute illness within the previous 2
months, chronic active inflammatory conditions, history of
solid tumours or haematological malignancies, or other
unrelated documented causes for anaemia were excluded. In
the event of transplantation, severe acute illness, or death
patients were removed from the study and their last results
before such events were used for the analysis only if they
had received IV-FeD for at least 3 months.
Patients with renal bone disease of any variety were not
excluded and continued to receive appropriate treatment
such as vitamin D3 or parathyroidectomy for hyperparathyroidism or aluminium chelation therapy for aluminium overload when indicated.
Iron preparations
Oral iron. Generic ferrous sulphate was administered as a
single 900-mg dose taken on an empty stomach at bedtime
or before breakfast along with vitamin C for maximal
absorption, or divided into three 300-mg doses 1-2 h before
meals on an empty stomach if the single large dose was not
tolerated [7]. Upon initiation of IV-FeD treatment, oral iron
was stopped.
Intravenous iron. Iron dextran preparations are not available for general use in Canada. Permission for use was
obtained from Health Protection Branch, Ottawa, Ontario,
Canada. Two different iron preparations were utilized. All
patients initially received INFED purchased from Schein
Pharmaceutical (USA) and were later switched to INFUFER
produced by Sabex Pharmaceutical (Canada) when this
product became available. Both preparations are supplied in
100-mg vials (50 mg/ml, 2 ml/vial).
Patients initially received a test dose of IV-FeD followed
by a loading dose and a regular maintenance dose. The test
dose was administered by adding 100 mg of IV-FeD to a
250 ml bag of normal saline and infused slowly via the
venous drip chamber utilizing an infusion pump starting at
5 ml/h and increasing by 5 ml/h every 5 min for 30 min and
if no reactions were encountered during this time, the rest
was infused over 2 h. Determination of total loading dose
was based on Van Wyck's nomogram [4]. The calculated
amount was given over the next several dialysis treatments
by adding 100 mg IV-FeD to 100 ml normal saline bag and
infused over 30 min. Maintenance dose was initially given as
100 mg in 100 ml normal saline infused over 30 min once
every 2 weeks, based on an estimated assessment of iron loss
F. Sepandj et al.
in dialysis patients of 2.5 g/year corresponding to approximately 6 ml/day blood loss from all sources [1,8].
The goal of iron supplementation was to obtain an arbitrary
serum ferritin level in the 100-200 ug/1 range. Only if there
was no change in haemoglobin at this level of serum ferritin
were transferrin saturation studies carried out to assess
bioavailability, and if transferrin saturation was less than
20%, the maintenance dose was given more frequently
(q 7-10 days) to achieve serum ferritin in the 200-300 ug/1
range. Serum ferritin levels greater than 300 ug/1 under any
circumstances resulted in temporary discontinuation or reduction of frequency of dose administration to allow ferritin
levels to return to the previously determined goal range.
rHuEpo
Eprex was purchased from Ortho-Biotech Pharmaceuticals
(Canada) supplied in 4000-unit vials. Patients were given
rHuEpo subcutaneously in 4000-unit doses as frequently as
necessary to achieve haemoglobin in the 95-105 g/1 range,
and dose adjustment was carried out when needed to maintain haemoglobin within this range. Patients required a
minimum serum ferritin > 100 ug/1 before initiation of
rHuEpo treatment.
Statistical analysis
Each patient was used as his/her own prospective control.
Haemoglobin, serum ferritin, and rHuEpo dose recorded at
the onset and termination of study period were compared.
For hypothesis testing of the statistical significance of an
observed difference between the mean values of the study
groups a paired t test was performed. A two-sided P value
of less than 0.05 was considered statistically significant and
confidence intervals were subsequently determined accordingly and reported. Mean values were reported + one standard deviation.
Economic analysis
IV-FeD administration cost calculation included the drug
itself, i.v. saline bag, i.v. line, and syringe. There was no
additional nursing cost, since IV-FeD, when needed, was
considered to be part of the patient's routine care and
administered by the attending nurse during the dialysis
session. Erythropoietin administration cost calculations
included the cost of the drug and one syringe. The cost of
oral iron consisted only of the cost of ferrous sulphate
tablets, since all patients were receiving vitamin C routinely.
The individual costs are summarized in Table 1. The exact
cost over the 6-month mean follow-up period was calculated
and projected over a 12-month period to estimate the
annual cost.
Table 1. Drug administration cost
1. INFED (per dose)
2. Epo (per dose)
3. FeSO 4 (per dose)
'All prices in Canadian dollars.
Drug
Line
i.v. saline
Syringe
Drug
Syringe
Drug
S20.99*CDN
0.90
0.92
0.03
S57.00
0.03
S0.05
Maintenance parenteral iron
321
Results
A
Table 2. Patient characteristics
Age (years)
Sex
Weight (kg)
Diabetes mellitus
Glomerulonephritis
Polycystic disease
Tubulointerstitial disease
Hypertensive nephropathy/ischaemic renal disease
Miscellaneous
55+16
38 M/12 F
72+18
5
12
5
8
14
6
1,0.
™
J
105
100
1
*•
1
x
I
as
B
350
300
1
250
1
c
200
150'
<o
u_
100
rriti
Fifty patients comprising slightly over one-half of our
haemodialysis population ultimately required intravenous iron treatment. The patient characteristics are
summarized in Table 2. Twenty-four patients (48%)
had gastrointestinal intolerance and 26 (52%) did not
achieve our goal serum ferritin (greater than 100 ug/1)
despite full prescribed oral iron dose. The male: female
ratio was 3.2:1. At the time of this analysis, patients
on maintenance IV-FeD had received such treatment
for a mean duration of 6 months (range 3-15 months).
At the onset of the study, 18 patients were receiving
vitamin D3 treatment and five more patients received
this treatment during the study period. Two patients
required parathyroidectomy. Only one patient received
aluminium chelation therapy over the study period;
however, she also had severe hyperparathyroidism
requiring vitamin D3 treatment.
Mean haemoglobin before initiation of treatment
with intravenous iron was 87.7 + 12.1 g/1. This value
rose to 100.3+ 13.6 g/1, indicating a mean rise of
12.8 g/1 (i>< 0.001, 95% Cl 7.7-17.9). This is illustrated
in Figure 1A. The baseline haemoglobin was similar in
patients receiving treatment for hyperparathyroidism
compared to others (87.4 + 14.2 g/1 vs 87.9 +10.0 g/1)
and there was no statistically significant difference in
the extent of rise in haemoglobin (13.1 +13.0 g/1 vs
12.5 +13.6 g/1).
Mean serum ferritin rose from its baseline
36 + 20 ug/1 to 217 + 127 ug/1 as illustrated in Figure 1B
(P< 0.001, 95% Cl 142-220).
At the onset of IV-FeD treatment, 19 patients (38%)
were on rHuEpo. At 6 months, this number was
reduced to 17 (34%) and in further eight patients a
reduction in rHuEpo dose was achieved. Overall, 10
patients (52%) had a downward adjustment in their
rHuEpo dose by at least 4000 units per week. In
patients on rHuEpo, mean weekly dose was reduced
from 96 + 59 u/kg/week to 63 + 41 u/kg/week representing a 35% overall dose reduction as illustrated in
Figure 1C (P<0.05, Cl 1-65).
Mean IV-FeD loading dose was 400 ± 300 mg and
majority of patients required a maintenance dose of
100 mg every second week. During the follow-up
period we did not encounter any anaphylactic reactions
and no patients reported any adverse symptoms during infusion or in the interdialytic period. Only nine
patients had serum ferritin levels greater than 300 ug/1,
115
SO
I
^ ^ ^ ^ ^ ^ ^ |
0
Fig. 1. Study results. Haemoglobin (A), serum ferritin (B), and
weekly Epo dose (C) pre [D] and post [•] treatment with maintenance intravenous iron. Mean values are shown +SD.
requiring a reduction in maintenance dose, and no
patient's ferritin level exceeded 500 ug/1.
Estimated savings on Epo administration was projected at $30120 and for oral iron at $2738 CDN.
Estimated cost of IV-FeD administration was $29 692.
This represents an annual projected cost reduction of
$3016 CDN ($63 CDN per patient).
Initial cost of IV-FeD loading was approximately
$3426 CDN. This will offset the above-mentioned cost
reduction during the first year only and would not
apply to the subsequent years.
Discussion
Iron deficiency is an extremely common problem facing nephrologists caring for chronic haemodialysis
patients. Our study demonstrated that over one-half
of our haemodialysis patient population were unable
to maintain adequate iron stores despite our concerted
efforts in aggressive oral supplementation. This group
included a large number of patients who had developed
iron deficiency while receiving rHuEpo, mostly related
to increased utilization, a phenomenon previously
described by other investigators [3,4,10]. Of these
patients, approximately one-half had gastrointestinal
322
intolerance whereas the other half did not achieve
appropriate ferritin levels despite the maximal prescribed dose. Adequacy of iron absorption in uraemic
patients has been a matter of controversy [8]; however,
concomitant use of commonly prescribed medications
such as histamine H2 blockers and phosphate binders
are well documented to interfere with optimal absorption of oral iron by increasing gastric pH [2]. With a
medication such as oral iron, which has significant
gastrointestinal side-effects, issue of compliance can be
a significant one [9]; this cannot be assessed reliably
by serum ferritin measurements in haemodialysis
patients with ongoing iron losses.
Many nephrologists have used intermittent doses of
intravenous iron when indicated [6]. Gokal et al.
reported use of similar maintenance doses of intravenous iron (100 mg every 2 weeks) for all patients regardless of their iron status; however, used in this manner
a significant number of patients developed iron overload with organ deposition [8]. More recent studies of
IV-FeD use in iron-deficient haemodialysis patients
have shown improvement in haemoglobin as well as
some reduction in erythropoietin dosage [10,11]. We
utilized a conservative regimen of maintenance intravenous iron treatment in patients who had not achieved
adequate serum ferritin levels at their maximum tolerated dose of oral iron. We used 100 mg every second
week, which is based on an estimated annual iron loss
of approximately 2.6 g from all sources of blood loss
in our patients, mainly related to haemodialysis and
occult gastrointestinal sources.
Our goal levels for serum ferritin were chosen somewhat arbitrarily, based on current available literature
[3,4,6]. Patients are thought to be in a state of absolute
iron deficiency if serum ferritin < 30 ug/1 and/or transferrin saturation <16%. Relative iron deficiency is
suggested when serum ferritin < 100 ug/1 and/or transferrin saturation < 20%. Accordingly we elected serum
ferritin range 100-200 ug/1 as our initial goal, representing a state of iron store repletion, and if no response
was observed at this range we increased this goal to
200-300 ug/1 range if transferrin saturation was less
than 20%, suggesting low iron bioavailability. Based
on these levels, our patients were mostly in the relative
rather than absolute iron deficiency range (mean ferritin 38 ug/1) where usually oral iron is recommended
and prescribed.
This regimen resulted in a predictable rise in serum
ferritin with very few patients exceeding our upper
limits for serum ferritin and no patient exceeded
500 ug/1 level, above which difficulties with iron overload have been reported. In association with adequate
iron supplementation in this manner, there was a
clinically and statistically significant rise in haemoglobin and decrease in rHuEpo requirements in this
patient population, including those receiving treatment
for hyperparathyroidism.
The main message of our study is that maintenance
intravenous iron supplementation in this subset of
patients does not add extra cost to an already expensive
process; on the contrary it can actually save money.
F. Sepandj et al.
The above rise in haemoglobin with its associated
clinical benefits were gained at no extra cost during
the first year and this practice would result in some
savings in the subsequent years when loading dose is
no longer required. We must add that we have not
taken into consideration quality of patient life assessment and possible economic benefits of such improvement, nor did we take into consideration the possible
reduced morbidity and hospital admissions and related
cost savings, if they are similar to those described with
rHuEpo-associated rises in haemoglobin [12-14]. We
did not measure transferrin saturations routinely, and
this test was used only for specific situation described
previously; we did not include the cost savings associated with this practice.
We therefore feel quite strongly that a regimen of
maintenance intravenous iron treatment in the subset
of haemodialysis patients in whom oral supplementation has failed is a safe, effective, and economically
favourable means of iron supplementation when carefully and closely monitored.
References
1. Eschbach JW, Cook JD, Scribner BH et al. Iron balance in
haemodialysis patients. Arch Intern Med 1977; 87: 710-713
2. Forth W, Rummel W. Iron absorption. Physio! Rev 1973;
53: 724-729
3. Van Wyck DB. Iron management during recombinant human
erythropoietin therapy. Am J Kidney Dis 1989; 14 2 [Suppl
1]: 9—13
4. Van Wyck DB, Stivelman JC, Ruiz J et al. Iron status in patients
receiving erythropoietin for dialysis associated anaemia. Kidney
Int 1989; 35: 712-716
5. MacDougall AC, Hutton RD, Cavill I, Coles GA, Williams JD.
Poor response to treatment of renal anaemia with erythropoietin
corrected by iron given intravenously. Br Med J 1989; 299:
157-158
6. Van Wyck DB. Iron dextran in chronic renal failure. Semin Dial
1991; 4,2: 112-114
7. Eschbach JW, Cook JD, Finch CA. Iron absorption in chronic
renal disease. Clin Sci 1970; 38: 191-196
8. Gokal R, Millard PR, Weatherall DJ et al. Iron metabolism in
hemodialysis patients: a study of the management of iron therapy
and overload. Q J Med 1979; 48: 369-391
9. Bonnar J, Goldberg A, Smith JA. Do pregnant women take
their own iron? Lancet 1969; 1: 457-458
10. Schaefer RM, Schaefer L. Management of iron substitution
during rHuEpo therapy in chronic renal failure patients.
Erythropoiesis 1992; 3: 71-75
11. Sunder-Plassmann G, Hoed WH. Iron metabolism and iron
substitution during erythropoietin therapy. Clin Invest (in press)
12. Stevens ME, Summerfield GP, Hall AA et al. Cost benefits of
low dose subcutaneous erythropoietin in patients with anaemia
of end stage renal disease. Br Med J 1992; 304: 474-477
13. Canadian Erythropoietin Study Group. Association between
recombinant human erythropoietin and quality of life and
exercise capacity of patients receiving haemodialysis. Br Med J
1990; 300: 573-578
14. Sheingold S, Churchill D, Murihead N, et al. The impact of
recombinant human erythropoietin on medical care costs for
hemodialysis patients in Canada. Soc Sci Med 1992; 34: 9:
983-991
Received for publication: 30.1.95
Accepted in revised form: 4.9.95
Editor's note
Please see also the Consensus Statement by Horl (pp. 246-250 in
this issue).