A randomized, controlled parallel-group trial on efficacy and safety of iron sucrose (Venofer®) vs iron gluconate (Ferrlecit®) in haemodialysis patients treated with rHuEpo

Markus Kosch, Udo Bahner1, Helga Bettger1, Fritz Matzkies, Markus Teschner1 and Roland M. Schaefer

Department of Internal Medicine D, University of Münster, Germany and 1 KfH-Dialysis Centre, Würzburg, Germany



   Abstract
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 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Background. The objectives of the present trial were to compare the efficacy and safety of two i.v. iron preparations with respect to haemoglobin levels, iron status and recombinant human erythropoetin (rHuEpo) dosage requirements in stable, rHuEpo-treated haemodialysis patients (maintenance phase of iron treatment) over 6 months.

Methods. A total of 59 patients were randomized and assigned to one of two treatment groups and 55 patients were analysed (iron sucrose n=27; iron gluconate n=28). Iron sucrose was administered in a dose of 250 mg iron diluted in 100 ml normal saline given over 60 min once per month, while 62.5 mg iron as iron gluconate was given once per week in a slow push injection (5 min).

Results. Efficacy parameters: Haemoglobin levels could be maintained from baseline to endpoint in both groups. There were, however, more patients in the iron sucrose group than in the iron gluconate group for whom treatment was discontinued because their haemoglobin values exceeded 12.5 g/dl or ferritin values exceeded 1000 ng/ml (five vs two and three vs one patient, respectively). Transferrin saturation and serum ferritin increased significantly in both groups (+255.7 ng/ml with iron sucrose and +278.5 ng/ml with iron gluconate), while rHuEpo dosage did not change significantly throughout the study. Safety parameters: There were a total of 174 infusions of iron sucrose and 720 injections of iron gluconate during the trial; all of them were well tolerated. In particular, we did not observe anaphylactoid reactions or any events suggestive of iron toxicity such as hypotension, dizziness, or nausea.

Conclusions. High doses of iron sucrose (Venofer® at a dose of 250 mg/month) was equally effective in maintaining haemoglobin and equally well tolerated as low doses of iron gluconate (Ferrlecit® at a dose of 62.5 mg once per week) in stable, rHuEpo treated haemodialysis patients.

Keywords: anaemia; haemodialysis; iron gluconate; iron sucrose; recombinant human erythropoietin



   Introduction
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 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
The total body iron content of an adult ranges from 2 to 4 g, approximately two-thirds of this amount is bound in the circulating haemoglobin and one-third is stored in the reticuloendothelial system (liver, spleen and bone marrow). Iron is highly conserved and only about 1 mg is lost each day. As a normal Western diet supplies about 15 mg/24 h, iron deficiency is rare in the absence of blood loss [1]. However, iron stores are frequently low in patients suffering from chronic renal failure. Iron deficiency can be found already in pre-dialysis patients because of a combination of factors, such as decreased iron intake (low protein diet) and reduced gastrointestinal absorption (uraemia per se, phosphate binders). Once patients start haemodialysis therapy, iron deficiency may become even more pronounced because of blood loss by blood remaining in the dialysis tubing and the dialyser, and frequent blood testing [2]. Annual blood loss from dialysis and blood sampling varies, but has been calculated to be approximate 2500 ml in haemodialysis patients. This represents a blood loss of at least 1000 mg of iron per year [3]. In some studies blood losses as high as 6–7 l/year (3000 mg iron) have been reported [4].

With the use of recombinant human erythropoietin (rHuEpo) the demand of iron by the bone marrow is further increased. During the correction phase (i.e. increase of haemoglobin from baseline to target levels) approximately 600 mg of iron will be incorporated into newly formed red blood cells (representing a rise of haemoglobin by 4 g/100 ml) within 2–3 months [5]. During the maintenance phase, the amount of required iron equals the amount of iron lost, which can add up to 1–3 g/year [3,4]. In this clinical situation, oral iron supplementation will often not be sufficient to supply adequate amounts of iron so that the i.v. administration of iron will be necessary in the majority of renal patients. Actually, up to 90% of all haemodialysis patients in Europe have been reported to receive i.v. iron [6].

A number of iron preparations are being used for parenteral iron supplementation in chronic renal failure, such as iron dextran, iron gluconate and iron sucrose.

Iron dextran has been available in the US and the UK for more than 30 years. At the present time, iron dextran is primarily sold in the US and is not used in continental Europe or the UK. The major drawback of iron dextran is its relatively high rate of life-threatening and fatal anaphylactic reactions. There have been several reviews to assess the risk of serious reactions to iron dextran. Hamstra et al. retrospectively examined the experience of 481 patients who received a total of 2099 i.v. doses of 250 or 500 mg of iron as iron dextran [7]. There were three life-threatening (0.6%) and 12 non-life-threatening (2.6%) immediate systemic reactions. Thus, approximately 20% of allergic reactions were life-threatening. Woodman et al. [8] reported a rate of anaphylaxis of 1.8% among 1260 patients given iron dextran. Conducting a retrospective chart review in haemodialysis patients, Fishbane et al. [9] identified 10 mild anaphylactoid reactions (1.7%) and four serious events (0.7%). Anaphylaxis after iron dextran is thought to be associated with the high-molecular weight of dextran complexes, which are known to be potent antigens even when not complexed to iron [10]. Moreover, dextran is thought to be immunogenic, even to patients that have not been treated with dextran previously, because of cross-reactivity of dextran to native antibodies formed to polysaccharides produced by intestinal organisms [10].

Only limited data exist on safety and efficacy of both iron gluconate and iron sucrose. There is one report of Pascual et al. [11] describing three out of 60 patients with self-limiting hypotension, and flushing in three patients who had received iron gluconate i.v. at doses of 125 mg. Nissenson and co-workers [12] treated 88 haemodialysis patients with 125 mg of iron gluconate and there were three patients who were withdrawn from the trial because of rash, nausea, and chest pain with pruritus. However, there was no clear-cut link to the administration of iron gluconate, nor was there a dose effect. In terms of iron sucrose, there is one long-term study published by Silverberg et al. [13] describing a total of 64 haemodialysis patients on iron sucrose for 12 months. There were no adverse effects throughout this trial and the target haematocrit of 33% had been reached without or with very low doses of rhEpo. In a more recent publication Van Wyck et al. [14] reported on 23 haemodialysis patients suffering from intolerance to iron dextran. These were switched to i.v. iron sucrose for 10 consecutive dialysis treatments (total dose 1000 mg). No test dose was given. A total of 223 doses of iron sucrose were administered and there were no serious adverse events. Taken together, data concerning safety and efficacy are still sparse despite the fact that both iron compounds have been used for many years.

Therefore, we conducted a prospective, open, randomized controlled trial on iron supplementation in stable haemodialysis patients on rHuEpo (maintenance phase of iron treatment). This was to compare efficacy and safety of two i.v. iron preparations (high doses of iron sucrose (Venofer®) 250 mg iron once a month versus low doses of iron gluconate (Ferrlecit®) 62.5 mg iron once a week), with respect to maintenance of stable haemoglobin concentrations, iron status and rHuEpo dosage requirements over a treatment period of 6 months.



   Material and methods
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 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Patients
Our study conforms with the principles outlined in the declaration of Helsinki and was performed in accordance with protocols approved by the local ethics committee at the University of Münster. All patients gave written informed consent to the study protocol.

A total of 59 patients were enrolled into the trial. However, four patients were lost in the period between enrollment and randomization, or after randomization before the first study medication was given (consent withdrawn n=2, clincal event n=1, lost to follow up n=1). Thus, data of 55 patients were analysed (mean age 59±15 years, 26 male and 29 female) in an intention-to-treat analysis. Patients were considered eligible according to the following criteria: regular haemodialysis for at least 3 months; rHuEpo therapy for at least 4 months; haemoglobin concentration between 9 and 12 g/dl; serum ferritin between 100 and 600 µg/l; absence of infection, malignancy or surgery; normal serum vitamin B12 and folic acid concentrations; exclusion of chronic inflammatory disease; and no blood transfusions in the last 3 months. All patients were treated with anti-anaemic preparations (including iron preparations and rHuEpo) prior to their enrollment in this study. However, after enrollment (4 weeks before baseline laboratory values for analysis were taken and treatment started) iron preparations were stopped until application of study medication started.

Iron treatment
Patients were randomly assigned to one of the following treatment groups. In the iron sucrose (Venofer®) group (n=27), 250 mg Fe(III) diluted in 100 ml 0.9% saline was infused within 60 min during haemodialysis once per month [15]. In the iron gluconate (Ferrlecit®) group (n=28), 62.5 mg Fe(III) was given over 5 min during haemodialysis once per week. Treatment according to protocol was performed for 6 months, iron supplementation was stopped when haemoglobin values exceeded 12.5 g/dl or ferritin values increased above 1000 µg/l to avoid iron overload and toxicity.

Efficacy and safety parameters
Blood was drawn 4 weeks after the last application of iron sucrose and 1 week after the last application of iron gluconate. Serum ferritin and transferrin were measured by turbimetry, serum iron was analysed photometrically with ferrozin as a chromogen, using a Hitachi 917 autoanalyser (Boehringer, Mannheim, Germany). The transferrin saturation was calculated as follows: transferrin saturation in %=serum Fe in µg/dl/serum transferrin in mg/dlx70.9. Quantitative red cell analysis and measurement of the percentage of hypochromic red cells was performed by flow cytometry using a Technicon H*3 haematology analyser (Bayer Diagnostics, Tarrytown, NY, USA). AST and ALT as well as C-reactive protein were measured according to standard procedures.

Safety was assessed by recording all adverse events based on close monitoring of patients during the trial and on spontaneous reports by patients. Additionally, specific questions for symptoms being typical of iron toxicity such as hypotension, dizziness, or nausea as well as for symptoms suggestive of anaphylactoid reactions were asked after each iron administration. Other safety variables were haematologic and clinical chemistry laboratory parameters.

Statistics
For data analyses SAS® for Windows (Cary, USA) was used. Variables were presented as means±SD. Statistical comparison between the two treatment groups was done by one-way analysis of variance (ANOVA) or two-sided t-test with Bonferroni's correction. Data were analysed on an intention-to-treat basis. P-values <0.05 were considered statistically significant.



   Results
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 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Efficacy
Primary efficacy parameters
There were no significant differences in haemoglobin, transferrin saturation, ferritin values, percentage of hypochromic red blood cells and rHuEpo dose requirements between the two treatment groups at baseline or after 6 months of treatment.

The treatment was discontinued for more patients in the iron sucrose group than in the iron gluconate group, because their haemoglobin values exceeded 12.5 g/dl or ferritin values exceeded 1000 ng/ml. In the iron sucrose group, eight patients were discontinued (five patients because of Hb >12.5 g/dl, three patients because ferritin values exceeded 1000 ng/ml); in the iron gluconate group, three patients were discontinued (two because of Hb increase >12.5 g/dl, one patient because of ferritin values exceeded 1000 ng/ml). Ferritin values and transferrin saturation increased significantly in both treatment groups from baseline to the end of the trial (P<0.05, Table 1Go). The time course of ferritin concentrations over the 6 months of treatment is shown in Figure 1Go.


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Table 1. Change of iron and blood parameters in treatment groups

 


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Fig. 1. Time course of ferritin values during treatment with iron sucrose (Venofer®) or iron gluconate (Ferrlecit®). Ferritin concentrations are given as absolute values in ng/ml. Beside baseline values the data for each month of the observation period is given.

 
There was no statistically significant difference in the mean decrease of hypochromic red blood cells between the treatment groups (iron gluconate -5.6%; iron sucrose -2.0%) from baseline to after 6 months of treatment. Within the iron gluconate group there was a higher mean decrease which was, however, due to the circumstance that this group started out at a higher value of 10.8% compared with the iron sucrose group with a value of 6.3%, which does not indicate a difference in efficacy between the two i.v. iron treatments.

Moreover, there was no difference in the relation between individual serum ferritin concentrations and percentage or change in hypochromic red cells.

Patients treated with iron sucrose showed a slight but insignificant decrease of rHuEpo requirements from 86±54 to 80±44 U/kg/week compared with 86±53 to 86±60 U/kg/week in the patients treated with iron gluconate. The total dose of iron administered was 43 400 mg in the iron sucrose group and 45 000 mg in the iron gluconate group.

Secondary efficacy parameters
Significant differences between treatment groups were observed in the mean change of platelet values and the incidence rate of abnormal high values for leukocytes.

The mean change in platelets for the iron sucrose group was 28 500/ml from 223 800/ml at baseline (Table 1Go). In the iron gluconate group the mean change in platelets was -1000/ml from 227 600/ml at baseline. The difference in change of platelet levels was significant between the treatment groups (P<0.05).

Abnormal high values for leukocytes were observed only in the iron gluconate group. The incidence rates of high laboratory abnormalities for leukocytes were 6/26 (23%) in the iron gluconate group compared with 0/22 (0%) in the iron sucrose group (P<0.05).

There were no significant differences between treatment groups or between baseline and endpoint values in mean corpuscular volume, C-reactive protein, AST or ALT (Table 1Go).

Safety
The total incidence of all adverse events over the 6 months of the trial regardless of relation to iron treatment was 44%. The most common findings were flu syndrome, infections, sinusitis, surgery, and pneumonia (Table 2Go). Most of the reported adverse events are known to be commonly associated with chronic renal failure disease. None of the reported adverse events were considered to be drug related by the attending physician. There were no deaths during the observation period. Seven patients were prematurely withdrawn due to serious adverse events, three patients in the iron sucrose group (peripheral gangrene, angina pectoris and surgery), and four patients in the iron gluconate group (shunt infection, fever and leucocytosis, pneumonia and surgery). The frequency of adverse events as well as the intensity of symptoms recorded was comparable for both study groups. There were a total of 174 infusions of iron sucrose and 720 injections of iron gluconate during the trial. In particular, there were no anaphylactic reactions nor were there any events suggestive of iron toxicity such as hypotension, flushing, dizziness, or nausea.


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Table 2. Adverse events observed during the study (all classified ‘not drug related’)

 



   Discussion
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 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
In haemodialysis patients, oral iron is poorly absorbed and a number of well-controlled, randomized studies showed oral iron to be incapable of maintaining a well-balanced iron status in the long-term [1619]. However, the optimum regimen for i.v. iron is not clear and various protocols are used throughout Europe. To date, only sparse data exist on controlled comparisons of the efficacy and safety of different i.v. iron preparations.

In the present open, prospective, randomized and controlled study, we compared the effect of 6-month of treatment with either iron sucrose or iron gluconate on haemoglobin levels (maintenance), rHuEpo dosage requirements, ferritin concentration, transferrin saturation and percentage of hypochromic red blood cells in stable haemodialysis patients on rHuEpo (maintenance phase of iron treatment). The dosage of iron was 250 mg/month in both groups, achieved either by a monthly infusion of 250 mg iron as iron sucrose or by a weekly administration of 62.5 mg iron as iron gluconate.

We did not observe a significant difference in one of these primary efficacy parameters between treatment groups at baseline or after 6 months of treatment. As all patients enrolled in this study were previously treated with anti-anaemic preparations (including iron preparations and rHuEpo) and the study was conducted in the maintenance phase of iron treatment, significant changes of the primary efficacy parameters (haemoglobin levels, iron status and rHuEpo dosage requirements) were not expected. There were, however, more patients in the iron sucrose group than in the iron gluconate group for whom treatment was discontinued because their haemoglobin values exceeded 12.5 g/dl or ferritin values exceeded 1000 ng/ml.

In both treatment groups, we could observe substantial increases in the mean serum ferritin concentration and the transferrin saturation, showing a comparable improvement in iron status. Therefore, the i.v. iron treatment with iron sucrose in higher doses of 250 mg iron once per month was as effective in maintaining and even increasing serum ferritin levels as iron gluconate given in low doses of 62.5 mg iron once a week. However, there was no significant difference between both treatment groups in the mean increase of these two efficacy parameters. Furthermore, hypochromic red blood cells decreased to a similar degree in both groups indicating higher iron utilization by the bone marrow.

Based on the currently available literature, the European Dialysis and Transplantation Association (EDTA) published recently guidelines for cut-off values and therapy targets for i.v. iron therapy [20]. For serum ferritin concentrations a minimal concentration of >100 mg/l and an optimal range between 200 and 500 mg/l is recommended. Following the EDTA-guidelines serum ferritin concentrations should not be kept >800 mg/l during long-term iron supplementation, as otherwise deposition of iron outside the reticulo-endothelial system may occur. Moreover, concerning markers of iron-deficient erythropoesis a minimal therapy target <10% hypochromic erythrocytes and as optimal range a percentage of hypochromic erythrocytes <2.5% is recommended [20]. Thus, according to these therapy targets, in our study with both i.v. iron administration regimens ferritin concentrations and percentages of hypochromic erythrocytes well within the therapeutic target range were achieved.

There is an increasing body of evidence that regular i.v. iron supplementation enhances the haematopoetic response to rHuEpo and, hence, reduces the rHuEpo dosage requirements [20,21]. We did not observe a significant change in rHuEpo requirements after therapy or a significant difference between treatment groups. However, there was a trend to lower rHuEpo doses during therapy in the iron sucrose group compared with the iron gluconate group despite the fact that all patients were treated with anti-anaemic preparations (including iron preparations and rHuEpo) prior to their enrolment into this study and the limited size of the study population.

The observed increase in platelets in the iron sucrose group is not directly related to the iron treatment and there is no known scientific reason why platelet levels should change due to iron treatment. The statistically significant differences in platelets observed between the two treatment groups imply a normalization of the platelet values in the iron sucrose group.

Recent findings by Collins et al. suggested that frequent administration of low doses of i.v. iron was associated with a higher risk of all-cause and infectious deaths [25]. In a more extended analysis, the same authors observed a 20% increased infectious mortality with high-dose, high frequency administration [26]. In the present study, abnormal high values of leukocytes were only observed in the iron gluconate group, not in the iron sucrose group. Although no significant increase in the C-reactive protein and no increased infectious morbidity could be observed in the iron gluconate group, an association between the frequent low dosing and the risk for infections cannot be ruled out. To further explore this possibility, additional investigations would be necessary.

Adverse events occurred with similar frequency in the two treatment groups in our study; however, none of the reported adverse events were drug related. We did not observe any iron-associated adverse events like anaphylactoid reactions or hypotensive episodes. There was also no difference in the number of patients withdrawn from the study because of adverse events in both groups.

True anaphylactic reactions, that are a rare but potentially fatal complication with administration of iron dextran due to pre-formed anti-dextran antibodies [7,9], are generally not observed in therapy with iron sucrose or iron gluconate [1214]. However, as a limitation of our study it has to be considered that the number of patients enrolled was clearly too small to draw conclusions on the incidence of possibly extremely rare anaphylactic complications with either of the two study medications. Large-scale multi-centre studies are needed to clarify this issue. Another adverse reaction that has been reported after administration of iron gluconate is upper loin and abdominal pain [11]. However, we did not observe such a reaction in the 720 injections of iron gluconate during the trial.

Generally, all i.v. iron therapies can be followed by a vasoactive reaction, especially with larger doses administered rapidly [2224]. This reaction is not allergic in origin, but relates to the administration of free iron itself and appears to be of clinical relevance especially when larger doses of iron gluconate are injected [11]. Zanen and co-workers showed transferrin saturation rates higher than 100% (binding of iron to other plasma proteins) after application of 62.5 mg iron gluconate [23]. After administration of iron sucrose such an excess of free iron has not been observed, probably because of the higher stability of the iron(III)-hydroxide–sucrose complex [22]. This has led to the recommendation of a maximal single dose of 500 mg iron sucrose and 62.5 mg iron gluconate [20]. However, data are equivocal and in patients with rather low levels of transferrin (<100 mg/dl) a significant ‘oversaturation’ of transferrin has been demonstrated also after application of 100 mg iron sucrose [22]. Moreover, in a recent American study, i.v. administration of iron gluconate in a single dose of 62.5 and 125 mg was compared and comparable tolerability was reported [12].

In our study, the administration of 250 mg of iron sucrose was equally well tolerated as the injection of 62.5 mg iron gluconate in stable, rHuEpo-treated haemodilysis patients when given as a slow infusion over 60 min. The application of a single higher dose of iron sucrose is more convenient in the clinical setting, especially in patients on peritoneal dialysis or in pre-dialysis patients, who have neither ready vascular access for regular boluses nor are foreseen to have closely scheduled hospital visits. Additionally, recent findings showed that frequent dosing of low doses of intravenous iron was associated with a higher risk of all-cause and infectious deaths [25]. However, the available data allow no clear recommendation for dosage schedules in intravenous iron therapy yet.

We conclude that iron sucrose at a higher dose of 250 mg iron once per month is equally effective and well tolerated as iron gluconate at a lower dose of 62.5 mg iron once weekly in stable haemodialysis patients in the maintenance phase of iron therapy when given over a period of 6 months. Therefore, iron sucrose has an advantage in practicability because of i.v. administration of higher doses at once without impairment of good tolerability. Consequently, more frequent visits to the clinic for iron treatment may be avoided.



   Notes
 
Correspondence and offprint requests to: Prof. Dr med. Roland M. Schaefer, Medizinische Poliklinik, Albert-Schweitzer-Str. 33, D-48129 Münster, Germany. Back



   References
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 

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Received for publication: 17.10.00
Revision received 5. 1.01.