Safety and Efficacy of Total-Dose Infusion of Low Molecular Weight Iron Dextran for Iron Deficiency Anemia in Patients with Inflammatory Bowel Disease

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1 Dig Dis Sci (2010) 55: DOI /s y ORIGINAL ARTICLE Safety and Efficacy of Total-Dose Infusion of Low Molecular Weight Iron Dextran for Iron Deficiency Anemia in Patients with Inflammatory Bowel Disease Ioannis E. Koutroubakis Pantelis Oustamanolakis Christos Karakoidas Gerassimos J. Mantzaris Elias A. Kouroumalis Received: 7 August 2009 / Accepted: 30 September 2009 / Published online: 16 October 2009 Ó Springer Science+Business Media, LLC 2009 Abstract Background Intravenous iron has been suggested as a safe and effective treatment of anemia complicating inflammatory bowel disease (IBD). Low molecular weight (LMW) iron dextran has the ability to administer the patient s total iron requirement in a single infusion. Aims The aim of this study was to assess the safety and efficacy of the total dose of LMW iron dextran infusion for the treatment of iron deficiency in IBD. Methods Fifty IBD patients (27 female, 35 Crohn s disease, 15 ulcerative colitis) were included in the study. Mean ± standard deviation (SD) hemoglobin and ferritin levels before the infusion were 9.88 ± 1.42 g/dl and 13.9 ± 10.9 ng/ml, respectively. A 25-mg test dose was followed by infusion of the total dose of LMW iron dextran based on the iron deficit. Several clinical and laboratory parameters were measured before and on week 4 after infusion. I. E. Koutroubakis (&) P. Oustamanolakis E. A. Kouroumalis Department of Gastroenterology, University Hospital Heraklion, P.O. Box 1352, Heraklion, Crete, Greece ikoutroub@med.uoc.gr; ktjohn@her.forthnet.gr P. Oustamanolakis pantelis@vodafone.net.gr E. A. Kouroumalis kouroum@med.uoc.gr C. Karakoidas G. J. Mantzaris 1st Department of Gastroenterology, Evangelismos Hospital Athens, Athens, Greece C. Karakoidas ChKarako@otenet.gr G. J. Mantzaris gman195@yahoo.gr Results Four patients (8%) developed adverse reactions during the test infusion and did not receive the total-dose infusion. Only one patient developed an allergic reaction during the total-dose infusion. In the remaining 45 patients, the mean ± SD iron dose that was given was 1,075 ± 269 mg. The mean ± SD elevation of hematocrit and hemoglobin on week 4 was 4.9 ± 1.9% and 1.7 ± 0.8 g/ dl, respectively. Hematopoietic response was observed in 23 of 45 patients (51.1%). Conclusion Total parenteral iron replacement with LMW iron dextran is an easy, safe, and effective alternative method for treating iron deficiency anemia in IBD. Harmless adverse reactions may develop in a minority of patients. Keywords Anemia Crohn s disease Infusions Iron deficiency anemia Ulcerative colitis Introduction Anemia is a common and important complication of inflammatory bowel disease (IBD), associated with a decrease in quality of life and increased rate of hospitalization [1, 2]. The correction of anemia has recently been highlighted as a specific therapeutic goal [3, 4]. Although the cause of anemia in IBD is multifactorial, it is usually due to iron deficiency. Therefore, treatment with iron supplementation is important and it should be initiated when iron deficiency anemia is present. Recent guidelines suggest that iron supplementation should be preferably administered intravenously in IBD, even though many patients will respond to the oral administration of iron [5]. This is because oral iron is limited by poor absorption, intolerance, and induction of

2 2328 Dig Dis Sci (2010) 55: oxidative stress at the site of bowel inflammation [1, 3]. Moreover, the intravenous route is faster, easier, better tolerated, and effective, improving patients quality of life to a greater extent than oral iron supplementation. Several studies have shown that intravenous iron sucrose is a safe and effective treatment of anemia complicating IBD [6 10]. However, it has the disadvantage of repeated infusions. Low molecular weight (LMW) iron dextran has a high complex stability and the ability to infuse patients total iron requirements in a single administration (total-dose infusion). The infusion of total-dose intravenous (TDI) iron dextran has been evaluated in iron deficiency anemia [11], as well as in anemia associated with chronic kidney disease [12 15] and pregnancy [16]. The results of these studies showed significant increase of hemoglobin levels after treatment with TDI of LMW iron dextran without significant adverse events. Moreover, Auerbach et al., prospectively comparing three regimens of intravenous iron dextran in hemodialysis patients, found that TDI of iron dextran is safe, convenient, less expensive, and as efficacious as divided-dose infusions [12]. In pediatric IBD patients, TDI iron dextran has been suggested as an effective and safe treatment [17], although two different preparations of both high and low molecular weight iron dextran were used. TDI of LMW iron dextran has not been investigated in anemic adult IBD patients. The aim of this study was to assess the safety and efficacy of TDI of LMW iron dextran for the treatment of iron deficiency anemia in adult patients with IBD. Methods Patients Fifty patients with IBD were investigated at two centers in Greece. All patients had confirmed diagnosis of ulcerative colitis or Crohn s disease according to established criteria [18]. Moreover, they were assessed by their physicians as having refractory anemia to previous treatments. Eligible were patients aged years with anemia and intolerance or no response to oral iron, those with hemoglobin concentrations below 10.0 or 11.0 g/dl for females or males, respectively, or those with active disease and intestinal bleeding. The median age of our patients was 33 years. Thirty-six (72%) of the patients had poor response or intolerance to previous treatment with oral iron. Nine patients (18%) had a history of blood transfusion for the treatment of anemia. The demographic and clinical characteristics of patients included in the study are shown in Table 1. Disease activity in Crohn s disease was evaluated at baseline and at the end of therapy using the Table 1 Patient demographic and clinical parameters Crohn s disease activity index (CDAI) [19] and in ulcerative colitis by the simple clinical colitis activity index (SCCAI) [20]. Patients were excluded from the study if they had untreated vitamin B12 or folate deficiency, other types of anemia, red blood cell transfusion or erythropoietin treatment within 12 weeks before screening, asthma or eczema, acute or chronic infection, clinically evident congestive heart failure or ischemic heart disease, previously diagnosed HIV or HBV infection, and clinical evidence of current malignancy. All patients gave written informed consent for participation in the study; the Ethics Committee of the Medical Faculty of Crete approved the protocol of the study. Administration of the Iron and Measurements UC CD Total Number Male Female Active Inactive Mean disease duration (years) Disease location Proctitis (UC)/ileum (CD) 1 9 Left sided colitis (UC)/colonic (CD) 6 8 Extensive colitis (UC)/ileum? colon (CD) 8 18 Disease behavior (CD) Stenoting 10 Fistulizing 9 Inflammatory 16 Current treatment a Steroids Azathioprine Infliximab Adalimumab Salazopyrin or 5-aminosalicylic acid a Some patients received more than one drug CD Crohn s disease; UC ulcerative colitis All patients received a 25-mg iron dextran test dose (over a period of 15 min) prior to whole-dose infusion. In case of a negative test, the total dose of LMW iron dextran, with a maximum dose of 20 mg/kg, was infused intravenously over 4 6 h. The total dose of iron was calculated according to iron deficit using the Ganzoni s formula [21]: total iron deficit (mg) = [body weight (kg) 9 (target hemoglobin - actual hemoglobin g/dl) ]? 500. A hematopoietic response was defined as an increase in hemoglobin of or above 2.0 g/dl.

3 Dig Dis Sci (2010) 55: Clinical assessment, an adverse event check, hematological parameters, and other routine laboratory tests, including serum ferritin, transferrin saturation (TSAT), and C-reactive protein (CRP), were monitored at baseline and on week 4. Statistical Analysis The comparison of laboratory data at baseline and after treatment was made by paired t-tests. The Kolmogorov Smirnov test was used to assess the assumption that data were sampled from populations that follow Gaussian distributions. A level of P \ 0.05 was considered to be statistically significant. Fisher s exact test was used to detect differences between responders and non-responders in terms of possible predictive factors. All analyses were twotailed and conducted using the computer-based statistics software program InStat version 3.0 (GraphPad Software, Inc.). Results The indications for administering intravenous LMW iron dextran instead of oral iron were as follows: poor response (11) and/or intolerance (7) of oral iron supplementation, malabsorption (4), active disease, intestinal bleeding (8), or a combination of these indications (20). In ten cases (20%), premedication with 125 mg intravenous methylprednisolone was given. Our patients received a total iron dose ranging from 800 to 1,600 mg. The laboratory data of all treated patients at baseline and after treatment with LMW iron dextran are shown in Table 2. The mean hemoglobin (Hb) concentrations increased from 9.88 ± 1.42 to ± 1.29 g/dl. All patients showed an increase in the levels of hemoglobin after treatment and the difference between the mean hemoglobin levels at baseline and after treatment was statistically significant (P \ ). However, a Table 2 Patient laboratory data at baseline and after treatment Before treatment After treatment Mean hemoglobin (g/dl) 9.88 ± ± 1.29 Mean corpuscular volume (fl) 74.6 ± ± 8.7 Ferritin (ng/ml) 13.9 ± ± TSAT (%) 11.2 ± ± 11.6 CRP (mg/dl) 1.74 ± ± 1.93 ESR (mm/h) 37.4 ± ± 19.1 TSAT transferrin saturation; CRP C-reactive protein; ESR erythrocyte sedimentation rate hematopoietic response was observed in only 23 of 45 patients (51.1%) on week 4 post-treatment. Treatment resulted in a significant increase in the mean corpuscular volume (MCV) levels (74.6 ± 9.9 at baseline to 79.9 ± 8.7 after treatment, P = 0.008). The mean ferritin levels and the mean TSAT were also significantly increased from 13.9 ± 10.9 ng/ml and 11.2 ± 9.0% at baseline to ± ng/ml and 24.5 ± 11.6%, respectively, at the end of therapy (P \ ). In contrast, no significant changes were seen in the mean CRP and erythrocyte sedimentation rate (ESR) levels at the end of therapy compared with baseline (P = 0.65 and P = 0.09, respectively). Analysis of the baseline characteristics of responders versus non-responders did not reveal any statistically significant differences. However, there was a trend for better response in active disease, in patients with higher CRP levels, and in patients under therapy with infliximab or adalimumab. Four cases (8%) developed adverse reactions, including nausea (3), dyspnea (2), chest pain (1), and tachycardia (1), during administration of the test dose of LMW iron dextran, and they did not receive the total-dose infusion. Only one anaphylactoid reaction (itching and urticaria) occurred during the total-dose infusion in a patient who had a successful test infusion. None of these adverse events were life-threatening, and symptoms were treated symptomatically with anti-histamines or steroids. Two more patients presented mild adverse events after TDI, such as myalgias, arthralgias, and nausea, which were resolved within 72 h after iron infusion. None of the patients who received corticosteroid pre-medication developed any adverse event. Discussion Iron deficiency is the most common cause of anemia in IBD. The causes of iron deficiency are reduced intake, either from dietary deficiency or malabsorption, or increased losses. Chronic intestinal bleeding in IBD may exceed the amount of iron that can be absorbed from the diet, resulting in a negative iron balance [1, 3]. This imbalance is often seen in IBD, leading to anemia. Oral iron treatment of anemia in IBD is limited by poor absorption, intolerance, and the induction of oxidative stress at the site of bowel inflammation [1, 3]. Moreover, there is evidence that oral iron increases the clinical disease activity in IBD. On the other hand, patients with IBD and anemia respond well to intravenous iron therapy, with an increase in hemoglobin levels. Several studies have shown that intravenous iron replacement, especially with iron sucrose, is safe and effective in the treatment of iron-deficient

4 2330 Dig Dis Sci (2010) 55: anemia in IBD [6 10]. However, treatment with iron sucrose has the disadvantage of the need for repeated infusions, as single doses should not exceed 300 mg/infusion. Therefore, strategies with higher doses of intravenous iron administration have been suggested. New intravenous iron formulations such as ferric carboxymaltose, which can be administered as single doses up to 1,000 mg iron per week, have shown high safety and efficacy in IBD-associated anemia [22, 23], but it has not been approved by the Food and Drug Administration (FDA) and it is not available commercially in our country yet. Moreover, ferumoxytol, which is a novel, semisynthetic, carbohydratecoated, super paramagnetic iron oxide nanoparticle that is administered IV rapidly as an injection of 510 mg, has been suggested in the treatment of anemia or chronic kidney disease [24]. This study was designed to evaluate the safety and efficacy of the total dose of LMW iron dextran infusion for the treatment of iron deficiency in IBD. LMW iron dextran has the ability to infuse the patient s total iron requirement in a single administration (total-dose infusion) and has been proven as a safe and effective treatment of iron deficiency [11 17]. Since TDI is simpler and more convenient for the patients, we tried to assess its efficacy in IBD patients with refractory anemia. We found that total parenteral iron replacement with LMW iron dextran is a safe and effective therapy without significant adverse effects. Moreover, it increased significantly the hemoglobin concentrations and improved the measured hematological parameters (MCV, TSAT, and serum ferritin) in these patients. Regarding the hematopoietic response, we found that 51.1% of the patients were responders after one month. The adverse events of LMW iron dextran are immediate anaphylactoid reactions, such as malaise, itching, urticaria, sweating, myalgia, arthralgia and febrile episodes, and delayed reactions, such as lymphadenopathy, myalgia, arthralgia, backache, headache, fevers, nausea, vomiting, dizziness, and diaphoresis, which usually resolve within 72 h after iron infusion. Serious adverse events and lifethreatening anaphylactic reactions are rare with LMW iron dextran (\1 in 200,000) [25, 26]. In our study, 8% of the patients had a positive test and did not receive a total-dose infusion. Although it has been suggested that some of the mild reactions do not recur with rechallenge [26], and it is likely that these four patients could have tolerated the IV iron, a conservative decision was made during the contact of the study in order to avoid the total dose in these cases. One patient also had allergic reaction during the total-dose infusion which was not life-threatening, and the symptoms were treated symptomatically. Moreover, two patients (4%) had delayed reactions which were resolved within 72 h after iron infusion. The prevalence of hypersensitivity reactions in our study was rather higher than that reported in patients with anemia without IBD [11 16], but it is similar to that reported in 9% of pediatric IBD patients [17]. It could be suggested that this difference may be attributed to the known higher rate of immune-mediated drug reactions in inflammatory than in non-inflammatory diseases and the high prevalence of allergy in IBD patients [27, 28]. Another point is that only 20% of our patients received pre-medication with methylprednisolone but, considering the total-dose infusion of LMW iron dextran, maybe pre-medication should be included as routine clinical practice [26]. Our study has some obvious limitations, such as the rather short follow up period and the absence of a control group treated with oral iron. However, the majority of the patients had already experienced intolerance and/or ineffectiveness of oral iron replacement therapy, and it was considered unethical to include an arm in the study with this treatment. In conclusion, our results suggest that the total dose of LMW iron dextran infusion may be useful in treating IBDassociated anemia. This approach is effective and has the additional advantage of being simple, easy to accept, and more convenient for the patients. A minority of patients (about 10%) develop an allergic reaction to the test dose and is excluded from further treatment. Based on these data and the available data on accelerated regimens of high-dose intravenous iron sucrose [10, 29 31], anemia in IBD patients could be treated either with high-dose infusions of iron sucrose in about three sessions or with a single dose of LMW iron dextran. Further randomized studies comparing the available regimens of intravenous iron in IBD patients with anemia should be conducted. References 1. Gasche C, Lomer MCE, Cavill I, Weiss G. Iron, anaemia, and inflammatory bowel diseases. Gut. 2004;53: Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anemia in inflammatory bowel disease: a systematic review of the literature. Am J Med. 2004;116(Suppl 7A):44S 49S. 3. Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn s disease. Aliment Pharmacol Ther. 2006;24: Tsiolakidou G, Koutroubakis IE. Stimulating erythropoiesis in inflammatory bowel disease associated anemia. 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