nature publishing group
EDITORIAL
1889
Intravenous Iron for the Treatment of Iron Deficiency in IBD: the Pendulum Is Swinging Gert Van Assche, MD, PhD1
Abstract: Intravenous (IV) iron therapy has been a major asset in the management of refractory irondeficiency anemia in inflammatory bowel disease (IBD) and other diseases. However, the costeffectiveness of parenteral substitution as the firstline treatment of this condition in IBD has been questioned. A study published by Reinisch et al. in this issue of the journal fails to show non-inferiority of iron isomaltose 1,000, a novel high-dose IV preparation, compared to oral iron sulfate. Am J Gastroenterol 2013; 108:1889–1890; doi:10.1038/ajg.2013.400
Anemia has been called the ‘overlooked villain’ in the management of inflammatory bowel diseases (IBD) (1,2). The truth is that indeed anemia is prevalent globally in most populations of patients with IBD and that it is still not adequately addressed. Anemia has a substantial impact on quality of life as it relates to fatigue and cognitive function. The underlying causes of anemia in IBD are diverse, but unrecognized and maltreated iron deficiency easily beats chronic inflammation, drug-induced bone marrow suppression, or vitamin deficiency as the most common cause of anemia in patients with IBD (2). Treatment of active IBD with powerful anti-inflammatory drugs such as anti-tumor necrosis factor agents, often unveils iron deficiency as a cause of anemia in patients with active IBD and systemic inflammation (3). Here is the good news: iron deficiency can be easily and adequately treated. Anemia and uncorrected iron deficiency are therefore prime candidates to assess quality of care in clinical IBD programs. Iron is administered both parenterally and orally. Tolerance of oral iron is compromised in patients with IBD, notably those with Crohn’s disease (4), particularly as the total amount of iron to replenish the stores often exceeds 1 g. The intestinal iron absorption is tightly regulated by the iron stores and increases when stores are low. Still, only a fraction of ingested iron is absorbed in the duodenum and proximal jejunum, and the abdominal pain and diarrhea observed with oral iron therapy in IBD is most likely secondary to unabsorbed iron
irritating the distal small bowel and colon. For patients with profound iron deficiency or intolerant of oral preparations, six intravenous (IV) iron preparations are available in the United States of America. The high-molecular and low-molecular-weight iron dextans (Dexferrum and Infed) have been used for more than 20 years. Dextrans carry the risk of anaphylactic reactions and require test doses, whereas the smaller molecule IV preparations, Ferric gluconate (Ferlecit and Nulecit) and iron sucrose (Venofer) do not require test doses, but infusion reactions are still possible. More recently Ferumoxytol has been approved by the Food and Drug Administration (FDA) in 2009. This high-dose iron formula does not require a test dose, but it contains dextran derivatives and anaphylactic reactions have been reported (5). In July 2013, the FDA approved iron carboxymaltose (Injectafer), a new high-dose iron preparation, which requires no test dose and is not associated with anaphylactic reactions, although infusion reactions have been reported. In this issue of the American Journal Reinisch et al. (6) report on a multicenter randomized open-label study comparing oral iron to a relatively new IV iron preparation, iron isomaltose 1,000. This compound has not entered the US market. The findings are interesting in many aspects, not in the least because the study failed to demonstrate non-inferiority of IV iron isomaltose compared to oral iron sulfate for achieving the primary end point of change in hemoglobine (Hb) 8 weeks after the start of the trial. Eligible patients in Europe and India were required to have quiescent or mildly active IBD and had a baseline Hb below 12 g/dl with signs of iron deficiency (decreased transferrin saturation). The estimated difference in treatment effect was 0.37 (P = 0.09) g/dl of Hb for the intention to treat and 0.45 (P = 0.04) for the per protocol analysis. The initial Hb levels were comparable and after treatment more than 60% of patients achieved the target increase in Hb level of at least 2 g/dl (exploratory analysis). The secondary end points did not favor any treatment arm, as ferritine levels increased more with IV iron isomaltose and transferrin saturation more with oral iron sulfate. Ten serious adverse events occurred, 8 in the IV iron group, but 9/10 were deemed unrelated to the study drug and no anaphylaxis was observed.
1
Division of Gastroenterology, University of Leuven and University of Toronto, Leuven, Belgium. Correspondence: Gert Van Assche, MD, PhD, Division of Gastroenterology, University of Leuven and University of Toronto, 49 Herestraat, 3000 Leuven, Belgium. E-mail: [email protected] Received 14 August 2013; accepted 29 October 2013 © 2013 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
INFLAMMATORY BOWEL DISEASE
see related article on page 1877
INFLAMMATORY BOWEL DISEASE
1890
Van Assche
Interestingly, intolerance to oral iron sulfate forced only 3.5% of patients to leave the trial, but patients with known intolerance had been excluded. Negative trials, that fail to achieve their primary end points, can have a real impact on clinical practice, particularly when an active comparator, in this case oral iron, has been used. There has been a shift from oral to IV iron substitution in the management of IBD, especially in Europe where several novel formulations have become available that only require 2 or 3 administrations to deliver the total amount of iron and have not been associated with anaphylactic reactions (7). Iron isomaltose 1,000, assessed in the study by Reinisch et al. (6), and iron carboxymaltose have both earned a place in therapy and replaced iron sucrose and iron dextran formulations in many institutions. Should the pendulum swing back to oral iron, which is undoubtedly cheaper, with the findings in this paper? For patients with a known intolerance or lack of response to oral iron or in whom a fast correction of anemia is needed, IV iron therapy should be the preferred route of administration. For most other patients with IBD and iron deficiency, oral iron preparations should be the first-line therapy. Cost-effectiveness is crucial in this recommendation. The next important question is what was different about this trial compared to others that have shown non-inferiority for high-dose IV iron preparations compared to oral? It is virtually impossible to conclusively answer this question, as there are no comparative trials available between the different high-dose IV iron formulations. The evidence on the comparative efficacy of IV vs. oral iron therapy is not unequivocal, but in general tends to favor IV iron therapy (2). So what is different in this trial? The primary end point was well chosen and comparable to previous trials. The authors suggest that the required IV iron dose may be underestimated by the modified Ganzoni formula, which would favor oral iron in their study (8). Indeed, patients who received in total more than 1 g of iron isomaltose 1,000 almost all increased their Hb by 2 g/dl. Of course, these patients most likely also started with a more profound anemia, as Hb is the main driver of the Ganzoni formula, and were therefore more likely to respond with a 2 g/dl increase. Also, the adapted Ganzoni formula has been used in at least one trial that did show non-inferiority of IV iron carboxymaltose compared to oral iron (9). However, in a follow-up study published in Gastroenterology, iron IV carboxymaltose in a fixed high-dose regimen was also superior to Ganzoni-based dosing of IV iron sucrose (10). Reinisch et al. (6) also speculate that the pharmacodynamics of iron isomaltose 1,000 could be different from other preparations in that the iron is released more slowly and is not as readily available to the bone marrow, but this hypothesis needs to be tested in a controlled trial.
The American Journal of GASTROENTEROLOGY
Even if this study does not end the discussion on the best modalities of iron therapy in IBD, it urges us to reflect on our practice. First, the cost-effectiveness of oral iron therapy as the first-line treatment in IBD has been reinforced. Second, fixed dose IV iron therapy is more practical for health professionals than calculating the Ganzoni formula and may be more efficacious. Finally, although it was not addressed in this study, the recurrence of iron deficiency should be closely monitored in patients with IBD. Frequent relapse was found in a recent trial, even after high-dose IV iron substitution (11). Probably, many out patients with IBD who report symptom-control, have ongoing mucosal ulcers and bleed obscurely. Ferritin and transferrin saturation levels should be considered at follow-up blood tests in patients with IBD. CONFLICT OF INTEREST
Guarantor of the article: Gert Van Assche, MD, PhD. Financial support: No financial support or writing assistance was obtained. Potential competing interests: The author has received honoraria from Vifor Pharma. REFERENCES 1. Gasche C. Anemia in IBD: the overlooked villain. Inflamm Bowel Dis 2000;6:142–50. 2. Gasche C, Berstad A, Befrits R et al. Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. Inflamm Bowel Dis 2007;13:1545–53. 3. Katsanos K, Cavalier E, Ferrante M et al. Intravenous iron therapy restores functional iron deficiency induced by infliximab. J Crohns Colitis 2007;1:97–105. 4. Schröder O, Mickisch O, Seidler U et al. Intravenous iron sucrose versus oral iron supplementation for the treatment of iron deficiency anemia in patients with inflammatory bowel disease—a randomized, controlled, open-label, multicenter study. Am J Gastroenterol 2005;100:2503–9. 5. Krikorian S, Shafai G, Shamim K. Managing iron deficiency anemia of CKD with IV iron. US Pharm 2013;8:22–6. 6. Reinisch W, Staun M, Tandon RK. A randomized, open label, non inferiority study of iron isomaltose 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PRO-CEED). Am J Gastroenterol 2013;108:1877–88 (this issue). 7. Vavricka SR, Schoepfer AM, Safroneeva E et al. A shift from oral to intravenous iron supplementation therapy is observed over time in a large Swiss cohort of patients with inflammatory bowel disease. Inflamm Bowel Dis 2013;19:840–6. 8. Ganzoni AM. Intravenous iron-dextran: therapeutic and experimental possibilities. Schweiz Med Wochenschr 1970;100:301–3. 9. Kulnigg S, Stoinov S, Simanenkov V et al. A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial. Am J Gastroenterol 2008;103:1182–92. 10. Evstatiev R, Marteau P, Iqbal T et al. FERGI Study Group. FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease. Gastroenterology 2011;141:846–53. e1-2. 11. Evstatiev R, Alexeeva O, Bokemeyer B et al. FERGI Study Group. Ferric carboxymaltose prevents recurrence of anemia in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11:269–77.
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VOLUME 108 DECEMBER 2013 www.amjgastro.com
EDITORIAL
1889
Intravenous Iron for the Treatment of Iron Deficiency in IBD: the Pendulum Is Swinging Gert Van Assche, MD, PhD1
Abstract: Intravenous (IV) iron therapy has been a major asset in the management of refractory irondeficiency anemia in inflammatory bowel disease (IBD) and other diseases. However, the costeffectiveness of parenteral substitution as the firstline treatment of this condition in IBD has been questioned. A study published by Reinisch et al. in this issue of the journal fails to show non-inferiority of iron isomaltose 1,000, a novel high-dose IV preparation, compared to oral iron sulfate. Am J Gastroenterol 2013; 108:1889–1890; doi:10.1038/ajg.2013.400
Anemia has been called the ‘overlooked villain’ in the management of inflammatory bowel diseases (IBD) (1,2). The truth is that indeed anemia is prevalent globally in most populations of patients with IBD and that it is still not adequately addressed. Anemia has a substantial impact on quality of life as it relates to fatigue and cognitive function. The underlying causes of anemia in IBD are diverse, but unrecognized and maltreated iron deficiency easily beats chronic inflammation, drug-induced bone marrow suppression, or vitamin deficiency as the most common cause of anemia in patients with IBD (2). Treatment of active IBD with powerful anti-inflammatory drugs such as anti-tumor necrosis factor agents, often unveils iron deficiency as a cause of anemia in patients with active IBD and systemic inflammation (3). Here is the good news: iron deficiency can be easily and adequately treated. Anemia and uncorrected iron deficiency are therefore prime candidates to assess quality of care in clinical IBD programs. Iron is administered both parenterally and orally. Tolerance of oral iron is compromised in patients with IBD, notably those with Crohn’s disease (4), particularly as the total amount of iron to replenish the stores often exceeds 1 g. The intestinal iron absorption is tightly regulated by the iron stores and increases when stores are low. Still, only a fraction of ingested iron is absorbed in the duodenum and proximal jejunum, and the abdominal pain and diarrhea observed with oral iron therapy in IBD is most likely secondary to unabsorbed iron
irritating the distal small bowel and colon. For patients with profound iron deficiency or intolerant of oral preparations, six intravenous (IV) iron preparations are available in the United States of America. The high-molecular and low-molecular-weight iron dextans (Dexferrum and Infed) have been used for more than 20 years. Dextrans carry the risk of anaphylactic reactions and require test doses, whereas the smaller molecule IV preparations, Ferric gluconate (Ferlecit and Nulecit) and iron sucrose (Venofer) do not require test doses, but infusion reactions are still possible. More recently Ferumoxytol has been approved by the Food and Drug Administration (FDA) in 2009. This high-dose iron formula does not require a test dose, but it contains dextran derivatives and anaphylactic reactions have been reported (5). In July 2013, the FDA approved iron carboxymaltose (Injectafer), a new high-dose iron preparation, which requires no test dose and is not associated with anaphylactic reactions, although infusion reactions have been reported. In this issue of the American Journal Reinisch et al. (6) report on a multicenter randomized open-label study comparing oral iron to a relatively new IV iron preparation, iron isomaltose 1,000. This compound has not entered the US market. The findings are interesting in many aspects, not in the least because the study failed to demonstrate non-inferiority of IV iron isomaltose compared to oral iron sulfate for achieving the primary end point of change in hemoglobine (Hb) 8 weeks after the start of the trial. Eligible patients in Europe and India were required to have quiescent or mildly active IBD and had a baseline Hb below 12 g/dl with signs of iron deficiency (decreased transferrin saturation). The estimated difference in treatment effect was 0.37 (P = 0.09) g/dl of Hb for the intention to treat and 0.45 (P = 0.04) for the per protocol analysis. The initial Hb levels were comparable and after treatment more than 60% of patients achieved the target increase in Hb level of at least 2 g/dl (exploratory analysis). The secondary end points did not favor any treatment arm, as ferritine levels increased more with IV iron isomaltose and transferrin saturation more with oral iron sulfate. Ten serious adverse events occurred, 8 in the IV iron group, but 9/10 were deemed unrelated to the study drug and no anaphylaxis was observed.
1
Division of Gastroenterology, University of Leuven and University of Toronto, Leuven, Belgium. Correspondence: Gert Van Assche, MD, PhD, Division of Gastroenterology, University of Leuven and University of Toronto, 49 Herestraat, 3000 Leuven, Belgium. E-mail: [email protected] Received 14 August 2013; accepted 29 October 2013 © 2013 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
INFLAMMATORY BOWEL DISEASE
see related article on page 1877
INFLAMMATORY BOWEL DISEASE
1890
Van Assche
Interestingly, intolerance to oral iron sulfate forced only 3.5% of patients to leave the trial, but patients with known intolerance had been excluded. Negative trials, that fail to achieve their primary end points, can have a real impact on clinical practice, particularly when an active comparator, in this case oral iron, has been used. There has been a shift from oral to IV iron substitution in the management of IBD, especially in Europe where several novel formulations have become available that only require 2 or 3 administrations to deliver the total amount of iron and have not been associated with anaphylactic reactions (7). Iron isomaltose 1,000, assessed in the study by Reinisch et al. (6), and iron carboxymaltose have both earned a place in therapy and replaced iron sucrose and iron dextran formulations in many institutions. Should the pendulum swing back to oral iron, which is undoubtedly cheaper, with the findings in this paper? For patients with a known intolerance or lack of response to oral iron or in whom a fast correction of anemia is needed, IV iron therapy should be the preferred route of administration. For most other patients with IBD and iron deficiency, oral iron preparations should be the first-line therapy. Cost-effectiveness is crucial in this recommendation. The next important question is what was different about this trial compared to others that have shown non-inferiority for high-dose IV iron preparations compared to oral? It is virtually impossible to conclusively answer this question, as there are no comparative trials available between the different high-dose IV iron formulations. The evidence on the comparative efficacy of IV vs. oral iron therapy is not unequivocal, but in general tends to favor IV iron therapy (2). So what is different in this trial? The primary end point was well chosen and comparable to previous trials. The authors suggest that the required IV iron dose may be underestimated by the modified Ganzoni formula, which would favor oral iron in their study (8). Indeed, patients who received in total more than 1 g of iron isomaltose 1,000 almost all increased their Hb by 2 g/dl. Of course, these patients most likely also started with a more profound anemia, as Hb is the main driver of the Ganzoni formula, and were therefore more likely to respond with a 2 g/dl increase. Also, the adapted Ganzoni formula has been used in at least one trial that did show non-inferiority of IV iron carboxymaltose compared to oral iron (9). However, in a follow-up study published in Gastroenterology, iron IV carboxymaltose in a fixed high-dose regimen was also superior to Ganzoni-based dosing of IV iron sucrose (10). Reinisch et al. (6) also speculate that the pharmacodynamics of iron isomaltose 1,000 could be different from other preparations in that the iron is released more slowly and is not as readily available to the bone marrow, but this hypothesis needs to be tested in a controlled trial.
The American Journal of GASTROENTEROLOGY
Even if this study does not end the discussion on the best modalities of iron therapy in IBD, it urges us to reflect on our practice. First, the cost-effectiveness of oral iron therapy as the first-line treatment in IBD has been reinforced. Second, fixed dose IV iron therapy is more practical for health professionals than calculating the Ganzoni formula and may be more efficacious. Finally, although it was not addressed in this study, the recurrence of iron deficiency should be closely monitored in patients with IBD. Frequent relapse was found in a recent trial, even after high-dose IV iron substitution (11). Probably, many out patients with IBD who report symptom-control, have ongoing mucosal ulcers and bleed obscurely. Ferritin and transferrin saturation levels should be considered at follow-up blood tests in patients with IBD. CONFLICT OF INTEREST
Guarantor of the article: Gert Van Assche, MD, PhD. Financial support: No financial support or writing assistance was obtained. Potential competing interests: The author has received honoraria from Vifor Pharma. REFERENCES 1. Gasche C. Anemia in IBD: the overlooked villain. Inflamm Bowel Dis 2000;6:142–50. 2. Gasche C, Berstad A, Befrits R et al. Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. Inflamm Bowel Dis 2007;13:1545–53. 3. Katsanos K, Cavalier E, Ferrante M et al. Intravenous iron therapy restores functional iron deficiency induced by infliximab. J Crohns Colitis 2007;1:97–105. 4. Schröder O, Mickisch O, Seidler U et al. Intravenous iron sucrose versus oral iron supplementation for the treatment of iron deficiency anemia in patients with inflammatory bowel disease—a randomized, controlled, open-label, multicenter study. Am J Gastroenterol 2005;100:2503–9. 5. Krikorian S, Shafai G, Shamim K. Managing iron deficiency anemia of CKD with IV iron. US Pharm 2013;8:22–6. 6. Reinisch W, Staun M, Tandon RK. A randomized, open label, non inferiority study of iron isomaltose 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PRO-CEED). Am J Gastroenterol 2013;108:1877–88 (this issue). 7. Vavricka SR, Schoepfer AM, Safroneeva E et al. A shift from oral to intravenous iron supplementation therapy is observed over time in a large Swiss cohort of patients with inflammatory bowel disease. Inflamm Bowel Dis 2013;19:840–6. 8. Ganzoni AM. Intravenous iron-dextran: therapeutic and experimental possibilities. Schweiz Med Wochenschr 1970;100:301–3. 9. Kulnigg S, Stoinov S, Simanenkov V et al. A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial. Am J Gastroenterol 2008;103:1182–92. 10. Evstatiev R, Marteau P, Iqbal T et al. FERGI Study Group. FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease. Gastroenterology 2011;141:846–53. e1-2. 11. Evstatiev R, Alexeeva O, Bokemeyer B et al. FERGI Study Group. Ferric carboxymaltose prevents recurrence of anemia in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11:269–77.
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VOLUME 108 DECEMBER 2013 www.amjgastro.com
