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Detlie TE, Karlsen LN, Jørgensen E, Nanu N, Pollock RF. Evaluating the cost-utility of ferric derisomaltose versus ferric carboxymaltose in patients with inflammatory bowel disease and iron deficiency anaemia in Norway. J Med Econ 2025; 28:291-301. [PMID: 39704663 DOI: 10.1080/13696998.2024.2444833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 12/21/2024]
Abstract
AIMS Iron deficiency anemia (IDA) is among the most common extraintestinal sequelae of inflammatory bowel disease (IBD). Intravenous iron is often the preferred treatment in patients with active inflammation with or without active bleeding, iron malabsorption, or intolerance to oral iron. The aim of the present study was to evaluate the cost-utility of ferric derisomaltose (FDI) versus ferric carboyxymaltose (FCM) in patients with IBD and IDA in Norway. MATERIALS AND METHODS A published patient-level simulation model was used to evaluate the cost-utility of FDI versus FCM in patients with IBD and IDA from a Norwegian national payer perspective. Iron need was modelled based on bivariate distributions of hemoglobin and bodyweight combined with simplified tables of iron need from the FDI and FCM summaries of product characteristics. Patient characteristics and disease-related quality of life data were obtained from the PHOSPHARE-IBD trial. Cost-utility was evaluated in Norwegian Kroner (NOK) over a five-year time horizon. RESULTS Patients required 1.64 fewer infusions of FDI than FCM over five years (5.62 versus 7.26), corresponding to 0.41 fewer infusions per treatment course. The reduction in the number of infusions resulted in cost savings of NOK 5,236 (NOK 35,830 with FDI versus NOK 41,066 with FCM). The need for phosphate testing in patients treated with FCM resulted in further cost savings with FDI (no costs with FDI versus NOK 4,470 with FCM). Total cost savings with FDI were therefore NOK 9,707. FDI also increased quality-adjusted life expectancy by 0.071 quality-adjusted life years (QALYs) driven by reduced incidence of hypophosphatemia and fewer interactions with the healthcare system. CONCLUSIONS FDI resulted in cost savings and improved quality-adjusted life expectancy versus FCM in patients with IDA and IBD in Norway. FDI therefore represents the economically preferable iron formulation in Norwegian patients with IBD and IDA in whom it is indicated.
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Affiliation(s)
- T E Detlie
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
| | - L N Karlsen
- Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway
| | | | - N Nanu
- Covalence Research Ltd, Harpenden, UK
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Detlie TE, Burisch J, Jahnsen J, Bonderup O, Hellström PM, Lindgren S, Frigstad SO. Iron deficiency should not be accepted in patients with inflammatory bowel disease - a Scandinavian expert opinion. Scand J Gastroenterol 2025; 60:430-438. [PMID: 40202208 DOI: 10.1080/00365521.2025.2487907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 03/10/2025] [Accepted: 03/28/2025] [Indexed: 04/10/2025]
Abstract
AIM In this paper, we aim to explain the reason why iron deficiency (ID) is common in patients with inflammatory bowel disease (IBD), how to better apply diagnostic tools to uncover the state of ID as well as how to interpret the results, and not least, how to treat ID in this group of patients. METHODS This article is an expert review and opinion paper on a topic that is too often forgotten in clinical practice. We have not performed a systematic review, but we present the most important research allocated to the topic to substantiate an expert opinion. RESULTS This position paper summarises the pathophysiology of ID and gives recommendations on the monitoring and treatment of ID in IBD. ID with or without concurrent anaemia (IDA) is the most common systemic complication in patients with IBD, related to both disease activity and severity. It has consequences both for health-related quality of life and future course of disease of the IBD patient. Intravenous iron is an efficacious and well tolerated, but still underused, therapy for ID and IDA. Iron deficiency should be treated before symptoms of anaemia appear and quality of life is impacted. However, there is still limited awareness of how to detect and treat ID in clinical practice. Uncertainty regarding which diagnostic tests to use and how to interpret the results may also be responsible for variations in clinical practice. In addition, opinions on how to correct ID and IDA differ, in relation to both clinical efficacy and safety. CONCLUSION The consequences of ID in patients with IBD are significant. Guidelines on diagnosis, treatment and follow-up of ID should be implemented. IDA is a manifestation of severe ID and preventive strategies focusing on efficient treatment of ID regardless of the level of haemoglobin should therefore be explored.
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Affiliation(s)
- Trond Espen Detlie
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
| | - Johan Burisch
- Gastrounit, Medical Division, University Hospital Copenhagen - Amager and Hvidovre Hospital, Hvidovre, Denmark
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, University Hospital Copenhagen - Amager and Hvidovre Hospital, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jørgen Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ole Bonderup
- Department of Gastroenterology, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - Per M Hellström
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Stefan Lindgren
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Department of Gastroenterology, Skane University Hospital Malmö, Lund, Sweden
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3
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Fraser A, Cairnes V, Mikkelsen E, Knellwolf C, Locher R, Andersson M. Understanding and Managing Infusion Reactions and Hypophosphataemia With Intravenous Iron-A Nurses' Consensus Paper. Nurs Open 2025; 12:e70191. [PMID: 40140601 PMCID: PMC11946542 DOI: 10.1002/nop2.70191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 02/03/2025] [Accepted: 03/05/2025] [Indexed: 03/28/2025] Open
Abstract
AIM To provide evidence-based guidance on practical aspects and potential safety concerns (infusion reactions and hypophosphataemia) related to the use of intravenous iron from a nursing perspective. DESIGN A modified Delphi consensus method. METHODS Literature searches were conducted and used to support the development of 16 consensus statements. Six nurses with expertise in the field of gastroenterology and experience with the administration of intravenous iron participated in a modified Delphi process to develop a final set of statements. RESULTS Overall, 16 statements achieved consensus and covered the practicalities of administration, infusion reactions and hypophosphataemia. Patient preparation is a key step in the administration of intravenous iron, but information should be communicated carefully to prevent undue anxiety. Highlighting the nurse's confidence in the management of any reactions may help to reduce anxiety. The patient should be observed during the first 5-10 min of an infusion to allow prompt management of immediate infusion reactions, although severe hypersensitivity reactions are rare. Nurses should be vigilant for symptoms of hypophosphataemia (such as fatigue, weakness and muscle/bone pain), which can develop following treatment with ferric carboxymaltose, saccharated ferric oxide and iron polymaltose. Serum phosphate levels should be measured in patients receiving ferric carboxymaltose who are at risk of low phosphate. IMPACT Infusion reactions and hypophosphataemia with intravenous iron are documented in the literature, but existing publications do not approach these topics from a nursing perspective. This consensus paper highlights the importance of patient preparation, monitoring and prompt management when administering intravenous iron to ensure patient safety. Considering that nurses have a central role in the administration of intravenous iron, the availability of evidence-based guidance is essential for both nurse confidence and patient safety. PATIENT OR PUBLIC CONTRIBUTION No patient or public contribution was involved in the consensus process.
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Affiliation(s)
- Aileen Fraser
- University Hospitals Bristol NHS Foundation TrustBristolUK
| | - Vida Cairnes
- Department of GastroenterologyRoyal Devon University Healthcare NHS Foundation TrustExeterUK
| | - Else Mikkelsen
- Department of GastroenterologyRegional Hospital GødstrupHerningDenmark
| | - Christina Knellwolf
- Center for Neuromuscular Diseases/ALS ClinicKantonsspital St. GallenSt. GallenSwitzerland
| | - Regula Locher
- Center for Gastroenterology and HepatologyZürichSwitzerland
| | - Marie Andersson
- Department of GastroenterologyVästra GötalandsregionenBoråsSweden
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4
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Dutta AK, Chinthala H, George JT, Thomas DM, Joseph Joseph A. Anemia in inflammatory bowel disease-A comprehensive review. Indian J Gastroenterol 2025:10.1007/s12664-024-01735-7. [PMID: 39954228 DOI: 10.1007/s12664-024-01735-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 12/21/2024] [Indexed: 02/17/2025]
Abstract
Anemia is a frequent complication in inflammatory bowel disease (IBD) patients. The etiology is multifactorial, with iron deficiency and anemia of chronic disease being the main reasons. Other causes include vitamin B12 and folate deficiency, hemolytic anemia and medications such as azathioprine and sulfasalazine. Apart from physical symptoms, it is associated with several negative outcomes, including poor quality of life, increased risk of hospital admission, increased risk of surgery and higher treatment costs. Diagnostic evaluation aims to identify the underlying cause and severity to determine the appropriate therapeutic strategy. Investigations include a complete blood count, iron indices, inflammatory markers and vitamin B12 and folate levels. Patients with iron deficiency need adequate replacement therapy to improve hemoglobin and replenish iron stores. Those with moderate to severe anemia and/or active disease need intravenous iron, while mild anemia can be treated with oral iron. Multiple parenteral iron formulations are available which differ in dose and frequency of administration. Traditional oral iron supplements are available in ferrous forms, which, although effective, are associated with gastrointestinal side effects. Newer oral iron formulations have helped reduce these adverse effects but are expensive. Anemia of chronic disease is mainly driven by the effects of inflammatory mediators on iron metabolism and erythropoiesis and treatment requires control of disease activity. Relapse of anemia after therapy is frequent; hence, patients need to be closely followed up for early detection and appropriate management. Significant advances have been made in understanding the pathophysiology of anemia in IBD and better and safer iron formulations are available. However, a significant proportion of IBD patients with anemia go undetected or untreated and there is a need for improved recognition and better management practices. This review discusses various aspects of anemia in IBD and the current approach to diagnosis and management.
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Affiliation(s)
- Amit Kumar Dutta
- Department of Gastroenterology, Christian Medical College Vellore, Ranipet Campus, Vellore, 632 517, India.
| | - Hemanth Chinthala
- Department of Gastroenterology, Christian Medical College Vellore, Ranipet Campus, Vellore, 632 517, India
| | - John Titus George
- Department of Gastroenterology, Christian Medical College Vellore, Ranipet Campus, Vellore, 632 517, India
| | - David Mathew Thomas
- Department of Gastroenterology, Christian Medical College Vellore, Ranipet Campus, Vellore, 632 517, India
| | - Anjilivelil Joseph Joseph
- Department of Gastroenterology, Christian Medical College Vellore, Ranipet Campus, Vellore, 632 517, India
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Kritzinger J, Wyse J, Karaplis A. Severe hypophosphataemia and hypocalcaemia following intravenous ferric derisomaltose and denosumab administration. BMJ Case Rep 2024; 17:e262595. [PMID: 39694647 DOI: 10.1136/bcr-2024-262595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024] Open
Abstract
Serum calcium and phosphorus levels are tightly regulated by the calciotropic hormone parathyroid hormone, fibroblast growth factor 23 and 1,25(OH)2 vitamin D. Commonly prescribed therapies for iron-deficiency anaemia (IDA) such as ferric carboxymaltose and ferric derisomaltose (FDM) have been shown to disrupt phosphorus homeostasis, resulting in hypophosphataemia. Similarly, denosumab use can result in hypocalcaemia due to the inhibition of osteoclastic maturation, activity and survival. Here, we report the development of severe hypophosphataemia and hypocalcaemia in a patient with osteoporosis and IDA following treatment with denosumab and FDM. The patient remained asymptomatic; however, supplementation with calcium, phosphorus and calcitriol replacement was required prior to eventual normalisation of serum levels. Often concomitantly prescribed, little guidance exists regarding electrolyte disturbances following the administration of FDM and denosumab. While hypophosphataemia and hypocalcaemia are relatively uncommon when prescribed individually, synergistic effects likely exist that warrant regular monitoring and occasional supplementation.
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Affiliation(s)
| | - Jonathan Wyse
- Division of Gastroenterology, Department of Medicine, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
| | - Andrew Karaplis
- Division of Endocrinology, Department of Medicine, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
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Kinnera S, Owasoyo O, Rahim HMZ, Rahim A, Sunil KK, Chaudhary P, Rahim U, Awan AA. Recurrent Hypophosphatemia Following a Single Dose of Parenteral Iron Administration. Cureus 2024; 16:e73967. [PMID: 39703298 PMCID: PMC11656189 DOI: 10.7759/cureus.73967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2024] [Indexed: 12/21/2024] Open
Abstract
Although parenteral iron is widely used to treat iron deficiency anemia (IDA), some side effects have been inadequately explored. Hypophosphatemia is becoming a well-documented, yet poorly understood, side effect of parenteral iron infusion, oftentimes causing serious and/or prolonged complications. In this article, we discuss the case of a 33-year-old female with IDA who suffered debilitating physical and mental symptoms of significant recurrent hypophosphatemia following a single standard dose of parenteral iron administration. Despite initial management with repeated parenteral and oral phosphate replacement, the hypophosphatemia, along with its symptoms and sequelae, persisted until active vitamin D supplementation with calcitriol was commenced following a multispecialty team decision. This case highlights the deficiencies in the recognition and management of parenteral iron-induced hypophosphatemia and proposes a requirement for standardization in its management strategies, including the use of vitamin D supplementation.
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Affiliation(s)
- Swaroopa Kinnera
- Acute Medicine, Royal Stoke University Hospital, Stoke-on-Trent, GBR
| | - Oluwaseyi Owasoyo
- Acute Medicine, Royal Stoke University Hospital, Stoke-on-Trent, GBR
| | | | - Asma Rahim
- Acute Medicine, Royal Stoke University Hospital, Stoke-on-Trent, GBR
| | | | - Prabhav Chaudhary
- Acute Medicine, Royal Stoke University Hospital, Stoke-on-Trent, GBR
| | - Uzma Rahim
- Acute Medicine, Royal Stoke University Hospital, Stoke-on-Trent, GBR
| | - Abrar A Awan
- Acute Medicine, Royal Stoke University Hospital, Stoke-on-Trent, GBR
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7
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Martinelli M, Fioretti MT, Aloi M, Alvisi P, Arrigo S, Banzato C, Bramuzzo M, Campanozzi A, Civitelli F, Knafelz D, Lionetti P, Marseglia A, Musto F, Norsa L, Palumbo G, Renzo S, Romano C, Sansotta N, Strisciuglio C, Miele E. Diagnosis and management of anemia in pediatric inflammatory bowel diseases: Clinical practice guidelines on behalf of the SIGENP IBD Working group. Dig Liver Dis 2024; 56:1257-1269. [PMID: 38503658 DOI: 10.1016/j.dld.2024.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 02/22/2024] [Accepted: 02/22/2024] [Indexed: 03/21/2024]
Abstract
Anemia is one of the most frequent extra-intestinal manifestations of inflammatory bowel disease. Insidious onset, variability of symptoms and lack of standardized screening practices may increase the risk of underestimating its burden in children with IBD. Despite its relevance and peculiarity in everyday clinical practice, this topic is only dealt with in a few documents specifically for the pediatric field. The aim of the current guidelines is therefore to provide pediatric gastroenterologists with a practical update to support the clinical and therapeutic management of children with IBD and anemia. A panel of 19 pediatric gastroenterologists and 1 pediatric hematologist with experience in the field of pediatric IBD was agreed by IBD Working group of the Italian Society of Gastroenterology, Hepatology and Nutrition (SIGENP) to produce the present article outlining practical clinical approaches to the pediatric patient with IBD and anemia. The levels of evidence and recommendations have been defined for each part of the statement according to the GRADE system.
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Affiliation(s)
- Massimo Martinelli
- Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II"
| | - Maria Teresa Fioretti
- Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II"
| | - Marina Aloi
- Women's and Children's Health Department, Pediatric Gastroenterology and Hepatology Unit, Sapienza University of Rome, Rome, Italy
| | - Patrizia Alvisi
- Pediatric Gastroenterology Unit, Maggiore Hospital, Bologna, Italy
| | - Serena Arrigo
- Pediatric Gastroenterology and Endoscopy Unit, IRCCS Giannina Gaslini, Genova, Italy
| | - Claudia Banzato
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Pediatric Division, University of Verona, Verona, Italy
| | - Matteo Bramuzzo
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Angelo Campanozzi
- Department of Medical and Surgical Sciences, Section of Pediatrics, University of Foggia, Italy
| | - Fortunata Civitelli
- Department of Gender diseases, Child and Adolescent health, Pediatric unit, Sant' Eugenio Hospital, Rome, Italy
| | - Daniela Knafelz
- Hepatology and Gastroenterology Unit, Bambino Gesù Hospital, Rome, Italy
| | - Paolo Lionetti
- University of Florence-Gastroenterology and Nutrition Unit, Meyer Children's Hospital, IRCCS, Florence
| | - Antonio Marseglia
- Fondazione IRCCS Casa Sollievo della Sofferenza, Division of Pediatrics, San Giovanni Rotondo, Italy
| | - Francesca Musto
- Women's and Children's Health Department, Pediatric Gastroenterology and Hepatology Unit, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Norsa
- Pediatric Department Vittore Buzzi Children's Hospital, University of Milan, Italy
| | - Giuseppe Palumbo
- Department of Haematology, Bambino Gesù Hospital, 00165 Rome, Italy
| | - Sara Renzo
- University of Florence-Gastroenterology and Nutrition Unit, Meyer Children's Hospital, IRCCS, Florence
| | - Claudio Romano
- Pediatric Gastroenterology and Cystic Fibrosis Unit, University of Messina, Messina, Italy
| | - Naire Sansotta
- Paediatric Hepatology Gastroenterology and Transplantation, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialistic Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Erasmo Miele
- Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II".
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8
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Van Doren L, Steinheiser M, Boykin K, Taylor KJ, Menendez M, Auerbach M. Expert consensus guidelines: Intravenous iron uses, formulations, administration, and management of reactions. Am J Hematol 2024; 99:1338-1348. [PMID: 38282557 DOI: 10.1002/ajh.27220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 01/01/2024] [Accepted: 01/08/2024] [Indexed: 01/30/2024]
Abstract
Intravenous iron has become an essential component for the treatment of iron deficiency and iron deficiency anemia. Individuals administering Intravenous iron should have knowledge in intravenous iron administration, including a pre-infusion assessment to evaluate infusion reaction risks, pre- and post-infusion monitoring, identification of and management of infusion reactions, accurate documentation of these reactions, laboratory monitoring and recognition and management of treatment-emergent hypophosphatemia. This comprehensive consensus provides step-by-step guidance and tools for practitioners to promote safe delivery of intravenous iron, recognition, and management of infusion reactions and treatment-emergent hypophosphatemia.
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Affiliation(s)
- Layla Van Doren
- Section of Hematology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | | | - Kristen Boykin
- Florida Cancer Specialists and Research Institute, Florida, USA
| | | | - Monica Menendez
- FEM Iron Infusion Centers by Heme Onc Call, Miami, Florida, USA
| | - Michael Auerbach
- Department of Medicine, Georgetown University School of Medicine, Washington, District of Columbia, USA
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9
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Chauhan A, Lucas S, Garg M. Hypophosphataemia following ferric carboxymaltose and ferric derisomaltose: case closed, but questions remain. Gut 2024; 73:1039. [PMID: 37193585 DOI: 10.1136/gutjnl-2023-330061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 05/08/2023] [Indexed: 05/18/2023]
Affiliation(s)
- Ayushi Chauhan
- Department of Gastroenterology, Northern Health, Melbourne, Victoria, Australia
| | - Sarah Lucas
- Department of Gastroenterology, Northern Health, Melbourne, Victoria, Australia
| | - Mayur Garg
- Department of Gastroenterology, Northern Health, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
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10
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Gordon H, Burisch J, Ellul P, Karmiris K, Katsanos K, Allocca M, Bamias G, Barreiro-de Acosta M, Braithwaite T, Greuter T, Harwood C, Juillerat P, Lobaton T, Müller-Ladner U, Noor N, Pellino G, Savarino E, Schramm C, Soriano A, Michael Stein J, Uzzan M, van Rheenen PF, Vavricka SR, Vecchi M, Zuily S, Kucharzik T. ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease. J Crohns Colitis 2024; 18:1-37. [PMID: 37351850 DOI: 10.1093/ecco-jcc/jjad108] [Citation(s) in RCA: 74] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Indexed: 06/24/2023]
Affiliation(s)
- Hannah Gordon
- Department of Gastroenterology, Barts Health NHS Trust, London, Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, UK
| | - Johan Burisch
- Gastrounit, medical division, Hvidovre Hospital, University of Copenhagen, Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | | | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, Ioannina, Greece
| | - Mariangela Allocca
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Manuel Barreiro-de Acosta
- University Hospital Santiago De Compostela CHUS, Department of Gastroenterology - IBD Unit, Santiago De Compostela, Spain
| | - Tasanee Braithwaite
- School of Immunology and Microbiology, King's College London, The Medical Eye Unit, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK
| | - Thomas Greuter
- Division of Gastroenterology and Hepatology, GZO - Zurich Regional Health Center, Wetzikon, Division of Gastroenterology and Hepatology, University Hospital Lausanne - CHUV, Lausanne, Switzerland; Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Catherine Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London; Department of Dermatology, Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Pascal Juillerat
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland; Crohn and Colitis Center, Gastro-entérologie Beaulieu SA, Lausanne, Switzerland
| | - Triana Lobaton
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent; Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Ulf Müller-Ladner
- Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus Liebig University Giessen, Bad Nauheim, Germany
| | - Nurulamin Noor
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Gianluca Pellino
- Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona UAB, Barcelona, Spain; Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania 'Luigi Vanvitelli', Naples, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Gastroenterology Unit, Azienda Ospedale Università di Padova, Padua, Italy
| | - Christoph Schramm
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alessandra Soriano
- Gastroenterology Division and IBD Center, Internal Medicine Department, Azienda Unità Sanitaria Locale - IRCCS, 42122 Reggio Emilia, Italy
| | - Jürgen Michael Stein
- Interdisciplinary Crohn Colitis Centre Rhein-Main, Frankfurt/Main, Department of Gastroenterology and Clinical Nutrition, DGD Clinics Sachsenhausen, Frankfurt/Main, Germany
| | - Mathieu Uzzan
- Department of Gastroenterology, Hôpital Henri Mondor, APHP, Créteil, France
| | - Patrick F van Rheenen
- Department of Paediatric Gastroenterology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - Maurizio Vecchi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Stephane Zuily
- Vascular Medicine Division and French Referral Center for Rare Auto-Immune Diseases, Université de Lorraine, INSERM, DCAC and CHRU-Nancy, Nancy, France
| | - Torsten Kucharzik
- Department of Gastroenterology, Lüneburg Hospital, University of Münster, Lüneburg, Germany
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11
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Hawke K, Croft A, Lazarus S. Tumor-Induced Osteomalacia in a Patient with Crohn's Disease: A Case Report and Approach to Investigating Hypophosphatemia. Case Rep Gastroenterol 2024; 18:81-89. [PMID: 38410687 PMCID: PMC10896610 DOI: 10.1159/000536136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 01/03/2024] [Indexed: 02/28/2024] Open
Abstract
Introduction Hypophosphatemia occurs commonly in inflammatory bowel disease (IBD) patients and can cause considerable morbidity. The differential diagnoses in IBD include nutritional causes and hypophosphatemia induced by some formulations of intravenous iron infusions. Case Presentation We present the case of a 37-year-old man with active Crohn's disease, presenting with difficulty walking and fractures of the vertebrae and calcaneus. He had long-standing hypophosphatemia. Nutritional causes for hypophosphatemia were considered in the first instance given the presence of chronic diarrhea and vitamin D deficiency; however, there was minimal response to appropriate supplementation with oral phosphorous and vitamin D. Iron infusion-induced hypophosphatemia was then considered, but the nadir phosphate level preceded any iron infusion. Therefore, work-up was undertaken for less common causes. He was ultimately diagnosed with tumor-induced osteomalacia, caused by excess fibroblast growth factor 23 (FGF23) secretion from a phosphaturic mesenchymal tumor about the knee. He had complete resolution of symptoms and biochemical abnormalities following successful resection of the tumor. Conclusion This case illustrates the approach to investigation of hypophosphatemia in IBD patients. If the time course and response to phosphate supplementation are not as expected for nutritional or iron infusion-induced hypophosphatemia, less common causes should be considered.
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Affiliation(s)
- Kate Hawke
- Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Herston, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Anthony Croft
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Department of Gastroenterology, Royal Brisbane and Women's Hospital, Herston, QLD, Australia
| | - Syndia Lazarus
- Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Herston, QLD, Australia
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12
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Seng NWP, Barco JB, Wong MHL, Lim KX, Peh WM, Ng CT, Cushway T, Foo FJ, Koh FHX. Hypophosphatemia related to intravenous iron therapy with ferric carboxymaltose: A case series. Transfus Med 2023; 33:503-508. [PMID: 37263781 DOI: 10.1111/tme.12980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 01/28/2023] [Accepted: 04/13/2023] [Indexed: 06/03/2023]
Abstract
OBJECTIVES This case series would like to highlight hypophosphatemia related to ferric carboxymaltose and its adverse clinical consequences. BACKGROUND Intravenous iron supplementation is a good alternative to oral iron replacement in iron deficiency anaemia due to its ability to correct iron deficit with minimal infusions without incurring the gastrointestinal side effects of oral iron replacement. Ferric carboxymaltose is one common formula for intravenous iron supplementation. However, an increasingly recognised adverse side-effect of intravenous ferric carboxymaltose is hypophosphatemia. There has been increasing reports and studies highlighting hypophosphatemia related to intra-venous iron therapy. Though initially thought to be transient and asymptomatic, recent studies have shown that persistent hypophosphatemia in iron therapy can result in debilitating disease including myopathy, fractures and osteomalacia. METHODS A retrospective analysis of all patients who had ferric carboxymaltose was performed. RESULTS We highlight 3 cases where hyposphatemia affected the clinical outcomes. CONCLUSION With the increased use of IV iron it is important to be aware of the high potential for hypophosphatemia secondary to ferric carboxymaltose.
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Affiliation(s)
- Nigel Wei-Peng Seng
- Ministry of Health Holdings, Singapore, Singapore
- Sengkang General Hospital, Singapore, Singapore
| | | | | | | | | | | | - Tim Cushway
- The Iron Suites Medical Centre, Singapore, Singapore
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13
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Grino M, Rigaux M, Lagarde AV, Robert V, Papailhau C, Vincentelli MB. [Hypophosphatemia after injectable iron treatments in adults: Comparison between ferric carboxymaltose and iron sucrose]. ANNALES PHARMACEUTIQUES FRANÇAISES 2023; 81:790-800. [PMID: 36963655 DOI: 10.1016/j.pharma.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/13/2023] [Accepted: 03/20/2023] [Indexed: 03/26/2023]
Abstract
Hypophosphatemia is a recognized side effect of treatment of iron deficiency anemias with injectable iron. We analyzed 35 clinical trials that used ferric carboxymaltose (FCM) or iron sucrose (IS). Hypophosphatemia prevalence ranged from 0 to 91.7%. FCM-induced a significant (P<0.001) greater hypophosphatemia prevalence and phosphatemia decrease than IS (52.0% [95% CI: 42.2-61.8%] vs. 7.7% [95% CI: -2.8 to 18.2%] and -1.12mmol/L [95% CI: -1.36 to -0.89mmol/L] vs. -0.13mmol/L [95% CI: -0.59 to 0.32mmol/L]). FCM-induced hypophosphatemia was dose-dependent. The nadir of hypophosphatemia was reached in almost all studies after 7 and 14days. Hypophosphatemia persisted at the end of the study in 53.8% of the reported studies that used FCM and lasted up to 6months. FCM-induced an increase in intact circulating fibroblast growth factor 23 and in renal phosphorus excretion while serum 1-25 dihydroxyvitamin D was decreased. Risk factors for hypophosphatemia after FCM therapy were low basal circulating phosphate or ferritin, low body weight, high glomerular filtration rate, serum parathyroid hormone or hemoglobin and age, whereas renal insufficiency was associated with a lower risk. In conclusion, hypophosphatemia is common after treatment with injectable iron, FCM being associated with a higher risk than IS and with disorders of phosphocalcium metabolism. Monitoring of blood phosphate and 1-25 dihydroxyvitamin D could be considered during FCM therapy.
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Affiliation(s)
- Michel Grino
- Département de recherche clinique, Centre gérontologique départemental de Marseille, 176, avenue de Montolivet, 13012 Marseille, France.
| | - Marine Rigaux
- Pharmacie à usage intérieur, Centre gérontologique départemental de Marseille, 176, avenue de Montolivet, 13012 Marseille, France
| | - Anne-Violette Lagarde
- Pharmacie à usage intérieur, Centre gérontologique départemental de Marseille, 176, avenue de Montolivet, 13012 Marseille, France
| | - Vincent Robert
- Pharmacie à usage intérieur, Centre gérontologique départemental de Marseille, 176, avenue de Montolivet, 13012 Marseille, France
| | - Charlotte Papailhau
- Pharmacie à usage intérieur, Centre gérontologique départemental de Marseille, 176, avenue de Montolivet, 13012 Marseille, France
| | - Marie-Bénédicte Vincentelli
- Pharmacie à usage intérieur, Centre gérontologique départemental de Marseille, 176, avenue de Montolivet, 13012 Marseille, France
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14
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Arboleya L, Braña I, Pardo E, Loredo M, Queiro R. Osteomalacia in Adults: A Practical Insight for Clinicians. J Clin Med 2023; 12:jcm12072714. [PMID: 37048797 PMCID: PMC10094844 DOI: 10.3390/jcm12072714] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/26/2023] [Accepted: 04/01/2023] [Indexed: 04/14/2023] Open
Abstract
The term osteomalacia (OM) refers to a series of processes characterized by altered mineralization of the skeleton, which can be caused by various disorders of mineral metabolism. OM can be genetically determined or occur due to acquired disorders, among which the nutritional origin is particularly relevant, due to its wide epidemiological extension and its nature as a preventable disease. Among the hereditary diseases associated with OM, the most relevant is X-linked hypophosphatemia (XLH), which manifests in childhood, although its consequences persist into adulthood where it can acquire specific clinical characteristics, and, although rare, there are XLH cases that reach the third or fourth decade of life without a diagnosis. Some forms of OM present very subtle initial manifestations which cause both considerable diagnosis and treatment delay. On occasions, the presence of osteopenia and fragility fractures leads to an erroneous diagnosis of osteoporosis, which may imply the prescription of antiresorptive drugs (i.e., bisphosphonates or denosumab) with catastrophic consequences for OM bone. On the other hand, some radiological features of OM can be confused with those of axial spondyloarthritis and lead to erroneous diagnoses. The current prevalence of OM is not known and is very likely that its incidence is much higher than previously thought. Moreover, OM explains part of the therapeutic failures that occur in patients diagnosed with other bone diseases. Therefore, it is essential that clinicians who treat adult skeletal diseases take into account the considerations provided in this practical review when focusing on the diagnosis and treatment of their patients with bone diseases.
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Affiliation(s)
- Luis Arboleya
- Rheumatology Division, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
| | - Ignacio Braña
- Rheumatology Division, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
| | - Estefanía Pardo
- Rheumatology Division, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
| | - Marta Loredo
- Rheumatology Division, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
| | - Rubén Queiro
- Rheumatology Division, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
- ISPA Translational Immunology Division, Biohealth Research Institute of the Principality of Asturias (ISPA), 33011 Oviedo, Spain
- School of Medicine, Oviedo University, 33011 Oviedo, Spain
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15
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Zoller H, Wolf M, Blumenstein I, Primas C, Lindgren S, Thomsen LL, Reinisch W, Iqbal T. Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (PHOSPHARE-IBD): a randomised clinical trial. Gut 2023; 72:644-653. [PMID: 36343979 PMCID: PMC10086283 DOI: 10.1136/gutjnl-2022-327897] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/20/2022] [Indexed: 12/08/2022]
Abstract
OBJECTIVE Intravenous iron-a common treatment for anaemia and iron deficiency due to inflammatory bowel disease (IBD)-can cause hypophosphataemia. This trial compared the incidence of hypophosphataemia after treatment with ferric carboxymaltose (FCM) or ferric derisomaltose (FDI). DESIGN This randomised, double-blind, clinical trial was conducted at 20 outpatient hospital clinics in Europe (Austria, Denmark, Germany, Sweden, UK). Adults with IBD and iron deficiency anaemia (IDA) were randomised 1:1 to receive FCM or FDI at baseline and at Day 35 using identical haemoglobin- and weight-based dosing regimens. The primary outcome was the incidence of hypophosphataemia (serum phosphate <2.0 mg/dL) at any time from baseline to Day 35 in the safety analysis set (all patients who received ≥1 dose of study drug). Markers of mineral and bone homeostasis, and patient-reported fatigue scores, were measured. RESULTS A total of 156 patients were screened; 97 (49 FDI, 48 FCM) were included and treated. Incident hypophosphataemia occurred in 8.3% (4/48) FDI-treated patients and in 51.0% (25/49) FCM-treated patients (adjusted risk difference: -42.8% (95% CI -57.1% to -24.6%) p<0.0001). Both iron formulations corrected IDA. Patient-reported fatigue scores improved in both groups, but more slowly and to a lesser extent with FCM than FDI; slower improvement in fatigue was associated with greater decrease in phosphate concentration. CONCLUSION Despite comparably effective treatment of IDA, FCM caused a significantly higher rate of hypophosphataemia than FDI. Further studies are needed to address the longer-term clinical consequences of hypophosphataemia and to investigate mechanisms underpinning the differential effects of FCM and FDI on patient-reported fatigue.
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Affiliation(s)
- Heinz Zoller
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate Biology, Medical University of Innsbruck, Innsbruck, Austria
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, and Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Irina Blumenstein
- Medical Clinic I, Department of Gastroenterology, Hepatology, and Clinical Nutrition, University Clinic Frankfurt, Frankfurt, Germany
| | - Christian Primas
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Stefan Lindgren
- Department of Gastroenterology and Hepatology, Skåne University Hospital Malmö, Lund University, Lund, Sweden
| | - Lars L Thomsen
- Department of Clinical and Non-Clinical Research, Pharmacosmos A/S, Holbæk, Denmark
| | - Walter Reinisch
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Tariq Iqbal
- Department of Gastroenterology, Queen Elizabeth Hospital Birmingham, Birmingham, UK
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16
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Gold SL, Manning L, Kohler D, Ungaro R, Sands B, Raman M. Micronutrients and Their Role in Inflammatory Bowel Disease: Function, Assessment, Supplementation, and Impact on Clinical Outcomes Including Muscle Health. Inflamm Bowel Dis 2023; 29:487-501. [PMID: 36287025 DOI: 10.1093/ibd/izac223] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Indexed: 12/09/2022]
Affiliation(s)
- Stephanie L Gold
- Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Laura Manning
- Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - David Kohler
- Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA
| | - Ryan Ungaro
- Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bruce Sands
- Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Maitreyi Raman
- Department of Medicine, University of Calgary, Calgary, AB, Canada
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17
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Maas LA, Krishna M, Parian AM. Ironing It All Out: A Comprehensive Review of Iron Deficiency Anemia in Inflammatory Bowel Disease Patients. Dig Dis Sci 2023; 68:357-369. [PMID: 35930123 DOI: 10.1007/s10620-022-07599-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 06/10/2022] [Indexed: 12/09/2022]
Abstract
Iron deficiency anemia affects approximately 45% of patients with inflammatory bowel disease (IBD), negatively impacts the quality of life in this patient population, and significantly burdens our healthcare system. The pathogenesis of iron deficiency in IBD patients is multifactorial, including intestinal bleeding, malabsorption, and inadequate oral intake. Regular screening and diagnosis in these patients are imperative, and often patients have mixed iron deficiency anemia and anemia of chronic disease, especially in those with active inflammation. Iron may be replenished either orally or intravenously. While oral iron is safe, affordable, and easy to administer, patients often suffer from intolerable gastrointestinal side effects, and particularly in IBD patients, oral iron may increase inflammation and contribute to flares. Therefore, although it is substantially underused, intravenous (IV) iron is considered first-line treatment for patients with active disease, severe anemia, oral iron intolerance, and erythropoietin requirements. Several IV iron formulations are available, and iron sucrose and ferric carboxymaltose are the most frequently used and well studied in patients with IBD. However, iron isomaltoside could potentially become a popular choice among providers given its safety, efficacy, and convenience. Overall, screening, diagnosis, and treatment of iron deficiency anemia are important in patients with IBD. Individual patient characteristics, risks, and benefits, and advantages and disadvantages, should be considered when determining the best route and formulation for iron repletion.
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18
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Boots JMM, Quax RAM. High-Dose Intravenous Iron with Either Ferric Carboxymaltose or Ferric Derisomaltose: A Benefit-Risk Assessment. Drug Saf 2022; 45:1019-1036. [PMID: 36068430 PMCID: PMC9492608 DOI: 10.1007/s40264-022-01216-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2022] [Indexed: 11/22/2022]
Abstract
The intravenous iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) offer the possibility of administering a large amount of iron in one infusion. This results in faster correction of anemia and the formulations being better tolerated than oral iron formulations. This triad of logistic advantages, improved patient convenience, and fast correction of anemia explains the fact that intravenous iron formulations nowadays are frequently prescribed worldwide in the treatment of iron deficiency anemia. However, these formulations may result in hypophosphatemia by inducing a strong increase in active fibroblast growth factor-23 (FGF-23), a hormone that stimulates renal phosphate excretion. This effect is much more pronounced with FCM than with FDI, and therefore the risk of developing hypophosphatemia is remarkably higher with FCM than with FDI. Repeated use of FCM may result in severe osteomalacia, which is characterized by bone pain, Looser zones (pseudofractures), and low-trauma fractures. Intravenous iron preparations are also associated with other adverse effects, of which hypersensitivity reactions are the most important and are usually the result of a non-allergic complement activation on nanoparticles of free labile iron-Complement Activation-Related Pseudo-Allergy (CARPA). The risk on these hypersensitivity reactions can be reduced by choosing a slow infusion rate. Severe hypersensitivity reactions were reported in < 1% of prospective trials and the incidence seems comparable between the two formulations. A practical guideline has been developed based on baseline serum phosphate concentrations and predisposing risk factors, derived from published cases and risk factor analyses from trials, in order to establish the safe use of these formulations.
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Affiliation(s)
- Johannes M M Boots
- Department of Internal Medicine, Maasstad Hospital, Maasstadweg 21, 3079 DZ, Rotterdam, The Netherlands.
| | - Rogier A M Quax
- Department of Internal Medicine, Maasstad Hospital, Maasstadweg 21, 3079 DZ, Rotterdam, The Netherlands
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19
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Schaefer B, Zoller H, Wolf M. Risk Factors for and Effects of Persistent and Severe Hypophosphatemia Following Ferric Carboxymaltose. J Clin Endocrinol Metab 2022; 107:1009-1019. [PMID: 34850000 PMCID: PMC8947794 DOI: 10.1210/clinem/dgab852] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
CONTEXT Hypophosphatemia, osteomalacia, and fractures are complications of certain intravenous iron formulations. OBJECTIVE This study investigated risk factors for incident, severe, and persistent hypophosphatemia, and associated alterations in bone and mineral biomarkers following intravenous iron treatment. METHODS We analyzed data from the PHOSPHARE-IDA randomized clinical trials, comprising 245 patients aged 18 years or older with iron deficiency anemia at 30 outpatient clinics in the United States who received intravenous ferric carboxymaltose (FCM) or ferric derisomaltose (FDI). Outcome measures included serum phosphate, intact fibroblast growth factor-23 (iFGF23), 1,25-dihydroxyvitamin D (1,25(OH)2D), ionized calcium, parathyroid hormone (PTH), and alkaline phosphatase. RESULTS FCM was the only consistent risk factor for incident hypophosphatemia (< 2.0 mg/dL; odds ratio vs FDI: 38.37; 95% CI: 16.62, 88.56; P < 0.001). Only FCM-treated patients developed severe hypophosphatemia (< 1.0 mg/dL; 11.3%; 13/115) or persistent hypophosphatemia (< 2.0 mg/dL at study end; 40.0%; 46/115). More severe hypophosphatemia associated with significantly greater increases in iFGF23, PTH, and alkaline phosphatase, and more severe decreases in 1,25(OH)2D and ionized calcium (all P < 0.05). Patients with persistent vs resolved hypophosphatemia demonstrated significantly greater changes in iFGF23, PTH, 1,25(OH)2D, and N-terminal procollagen-1 peptide levels (all P < 0.01), but alkaline phosphatase increased similarly in both groups. CONCLUSION Treatment with FCM was the only consistent risk factor for hypophosphatemia. Patients who developed severe or persistent hypophosphatemia after FCM treatment manifested more severe derangements in bone and mineral metabolism. Changes in bone biomarkers continued beyond resolution of hypophosphatemia, suggesting ongoing effects on bone that may help explain the association of FCM with osteomalacia and fractures.
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Affiliation(s)
- Benedikt Schaefer
- Christian Doppler Laboratory of Iron and Phosphate Biology at the Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - Heinz Zoller
- Christian Doppler Laboratory of Iron and Phosphate Biology at the Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
- Correspondence: Myles Wolf, MD, MMSc, 2 Genome Court, Room 1009, Durham, NC 27710, USA.
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20
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Spagnuolo R, Abenavoli L, Larussa T, Iannelli C, Pellicano R, Fagoonee S, Doldo P, Luzza F. Safety profile of intravenous iron in inflammatory bowel disease: an up-to-date overview. Minerva Gastroenterol (Torino) 2022; 68:111-118. [PMID: 33267572 DOI: 10.23736/s2724-5985.20.02819-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Up to 30-70% of patients may experience mild and moderate side effects during iron therapy and this is often associated with a poor adherence to therapy. Anemia is frequent in patients with active inflammatory bowel disease (IBD), due to both iron deficiency and chronic inflammation, therefore iron supplementation is frequently needed. Considering that gastrointestinal disorders are the most common side effects with oral iron, in IBD patients intravenous administration must be preferred. Although intravenous iron supplementation remains the most effective therapy of IBD-associated iron deficiency anemia, the perception of risk related to intravenous administration by clinicians could limit this successful strategy. In this narrative review we provided an up to date on the safety of the different iron formulations for intravenous administration, by reporting the most recent studies in IBD patients.
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Affiliation(s)
- Rocco Spagnuolo
- Department of Clinical and Experimental Medicine, "Magna Graecia" University, Catanzaro, Italy
| | - Ludovico Abenavoli
- Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy -
| | - Tiziana Larussa
- Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
| | - Chiara Iannelli
- Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
| | - Rinaldo Pellicano
- Unit of Gastroenterology, Molinette Hospital, Città della Salute e della Scienza, Turin, Italy
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Center, Turin, Italy
| | - Patrizia Doldo
- Department of Clinical and Experimental Medicine, "Magna Graecia" University, Catanzaro, Italy
| | - Francesco Luzza
- Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
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21
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Madero Velázquez L, Muñoz Pérez R, Rodríguez A, Bernal L, Orts B, Sempere L, Gutiérrez Casbas A. Hypophosphatemic osteomalacia, a side effect of iron carboxymaltose administration. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2022; 114:358. [PMID: 35105150 DOI: 10.17235/reed.2022.8621/2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Carboxymaltose iron (Ferinject®) is a formulation for intravenous (iv) administration, used for the treatment of iron deficiency anemia and/or iron deficiency when oral administration of iron is not effective or due to intolerance. Its safety profile is excellent with few, but not nonexistent, side effects. Hypophosphatemia has been described as one of them. It is usually mild, transient and asymptomatic. However, in some cases it may be accompanied by nausea, asthenia, in addition to muscular and neurological symptoms and hematological alterations. It is, therefore, a potentially serious adverse effect whose prevalence is unknown and which requires high clinical suspicion to be detected.
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Affiliation(s)
| | | | | | - Lorena Bernal
- Aparato Digestivo, Hospital General Universitario de Alicante.
| | - Beatriz Orts
- Farmacia, Hospital General Universitario de Alicante.
| | - Laura Sempere
- Aparato Digestivo, Hospital General Universitario de Alicante.
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22
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Auerbach M, Achebe MM, Thomsen LL, Derman RJ. Efficacy and safety of ferric derisomaltose (FDI) compared with iron sucrose (IS) in patients with iron deficiency anemia after bariatric surgery. Obes Surg 2022; 32:810-818. [PMID: 35000068 PMCID: PMC8866325 DOI: 10.1007/s11695-021-05858-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 11/30/2022]
Abstract
Purpose Iron deficiency is common following bariatric surgery, and treatment with intravenous iron is often required. This post hoc analysis of data from two randomized, open-label, multicenter trials evaluated the efficacy and safety of ferric derisomaltose (FDI; formerly iron isomaltoside 1000) versus iron sucrose (IS) over 4 weeks in adults with iron deficiency anemia (IDA) resulting from prior bariatric surgery. Materials and methods Data were pooled for participants who received FDI or IS in the PROVIDE or FERWON-IDA trials for the treatment of IDA post bariatric surgery. Efficacy outcomes included changes in hemoglobin (Hb) and iron parameters; safety outcomes included the incidence of adverse drug reactions (ADRs), serious or severe hypersensitivity reactions (HSRs), and hypophosphatemia. Results The analysis included 159 patients. Mean (standard deviation) cumulative iron doses were 1199 (± 347) mg for FDI and 937 (± 209) mg for IS. Compared with IS, FDI resulted in a faster and more pronounced Hb response, and a higher proportion of responders (Hb level increase ≥ 2 g/dL from baseline) at all time points. The incidence of ADRs was similar with FDI and IS (15.1% and 18.2%, respectively), with no serious ADRs or serious or severe HSRs reported. The incidence of hypophosphatemia was low and similar in both treatment groups, with no cases of severe hypophosphatemia observed. Conclusions In patients with IDA resulting from bariatric surgery, FDI produced a faster and more pronounced Hb response than IS. Both FDI and IS were well tolerated. Graphical abstract ![]()
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Affiliation(s)
- Michael Auerbach
- Department of Medicine, Georgetown University School of Medicine, Washington, DC, USA.
| | - Maureen M Achebe
- Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Lars L Thomsen
- Department of Clinical and Non-Clinical Research, Pharmacosmos A/S, Holbæk, Denmark
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23
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Schaefer B, Tobiasch M, Wagner S, Glodny B, Tilg H, Wolf M, Zoller H. Hypophosphatemia after intravenous iron therapy: Comprehensive review of clinical findings and recommendations for management. Bone 2022; 154:116202. [PMID: 34534708 DOI: 10.1016/j.bone.2021.116202] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/06/2021] [Accepted: 09/10/2021] [Indexed: 12/19/2022]
Abstract
Contemporary intravenous iron formulations allow administration of high doses of elemental iron and enable correction of total iron deficit in one or two infusions. An important but underappreciated complication of certain formulations is hypophosphatemia caused by increased secretion of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). The pathophysiology of FGF23-induced hypophosphatemia due to certain intravenous iron formulations has been recently investigated in prospective clinical trials. To reach the correct diagnosis, clinicians must recognize the typical clinical manifestations of intravenous iron-induced hypophosphatemia and identify a specific pattern of biochemical changes (hyperphosphaturic hypophosphatemia triggered by high FGF23 that causes low 1,25 (OH)2 vitamin D, hypocalcemia and secondary hyperparathyroidism). Physicians and patients should be aware of hypophosphatemia as a common complication of intravenous iron therapy and monitor serum phosphate concentrations in patients receiving repeated doses of specific intravenous iron formulations. Symptoms of hypophosphatemia are associated with severity and duration. Persistent hypophosphatemia can occur with iron therapy and can cause debilitating diseases including myopathy, osteomalacia and fractures. This review summarizes the current understanding of the iron-phosphate axis as well as complications of intravenous iron-induced hypophosphatemia.
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Affiliation(s)
- Benedikt Schaefer
- Medical University of Innsbruck, Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Innsbruck, Austria; Christian Doppler Laboratory on Iron and Phosphate Biology, Austria
| | - Moritz Tobiasch
- University Teaching Hospital of Hall in Tirol, Department of Medicine, Hall, Austria
| | - Sonja Wagner
- Medical University of Innsbruck, Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Innsbruck, Austria; Christian Doppler Laboratory on Iron and Phosphate Biology, Austria
| | - Bernhard Glodny
- Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Medical University of Innsbruck, Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Innsbruck, Austria
| | - Myles Wolf
- Department of Medicine, Division of Nephrology, Duke University, Durham, NC, United States of America
| | - Heinz Zoller
- Medical University of Innsbruck, Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Innsbruck, Austria; Christian Doppler Laboratory on Iron and Phosphate Biology, Austria.
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Muñoz M, Reinisch W. Letter to the Editor Regarding 'Iron Formulations for the Treatment of Iron Deficiency Anemia in Patients with Inflammatory Bowel Disease: A Cost-Effectiveness Analysis in Switzerland'. Adv Ther 2022; 39:811-814. [PMID: 34846707 PMCID: PMC8799545 DOI: 10.1007/s12325-021-02000-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 11/16/2021] [Indexed: 12/15/2022]
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Snook J, Bhala N, Beales ILP, Cannings D, Kightley C, Logan RP, Pritchard DM, Sidhu R, Surgenor S, Thomas W, Verma AM, Goddard AF. British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults. Gut 2021; 70:2030-2051. [PMID: 34497146 PMCID: PMC8515119 DOI: 10.1136/gutjnl-2021-325210] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss.Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel.IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease- with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments.
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Affiliation(s)
- Jonathon Snook
- Gastroenterology, University Hospitals Dorset NHS Foundation Trust, Poole, UK
| | - Neeraj Bhala
- Gastroenterology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust and Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Ian L P Beales
- Gastroenterology, University of East Anglia, Norwich, UK
| | - David Cannings
- Gastroenterology, University Hospitals Dorset NHS Foundation Trust, Poole, UK
| | - Chris Kightley
- Digestive Diseases, Kettering General Hospital NHS Foundation Trust, Kettering, UK
| | | | - D Mark Pritchard
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool and Department of Gastroenterology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Reena Sidhu
- Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Sue Surgenor
- Gastroenterology, University Hospitals Dorset NHS Foundation Trust, Poole, UK
| | - Wayne Thomas
- Haematology, Plymouth Hospitals NHS Foundation Trust, Plymouth, Plymouth, UK
| | - Ajay M Verma
- Digestive Diseases, Kettering General Hospital NHS Foundation Trust, Kettering, UK
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Glaspy JA, Wolf M, Strauss WE. Intravenous Iron-Induced Hypophosphatemia: An Emerging Syndrome. Adv Ther 2021; 38:3531-3549. [PMID: 34053011 PMCID: PMC8279965 DOI: 10.1007/s12325-021-01770-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/30/2021] [Indexed: 12/14/2022]
Abstract
Some, but not all, intravenous iron formulations have been recognized to induce renal phosphate wasting syndrome. Most commonly this has been reported following treatment of iron deficiency anemia (IDA) with ferric carboxymaltose (FCM). A search of PubMed identified relevant randomized controlled trials (RCTs), and case studies evaluating hypophosphatemia (HPP) resulting from intravenous iron treatment. While more recent larger comparative RCTs have confirmed that the majority of patients receiving FCM, especially those with normal renal function, may experience severe HPP, complete documentation is hampered by inconsistent reporting of serum phosphate in such trials. Similarly, while case series and RCTs have documented the persistence of HPP for several weeks or even months, the lack of studies lasting beyond 5–6 weeks has constrained full understanding of the duration of effect. Clinical trials have established that the mechanism involves the bone/metabolic axis with the elevation of intact fibroblast growth factor 23 playing the central role. Reports continue to accumulate of the clinical consequences of severe HPP which are, most commonly, bone abnormalities following repetitive dosing. Case reports and studies, however, have also shown that symptomatic hypophosphatemia can occur after a single FCM dose. The frequency of such events remains unknown, in part due to lack of awareness of hypophosphatemia coupled with the fact that the most common acute symptoms of HPP (fatigue and weakness) are the same for IDA and for many of the chronic diseases that cause IDA. Changes to US and European prescribing information for FCM should raise awareness of the potential for HPP and need to monitor patients at risk for it.
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Affiliation(s)
- John A Glaspy
- Division of Hematology-Oncology, Department of Medicine, UCLA School of Medicine, Los Angeles, CA, 90095, USA.
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
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Cococcioni L, Pensabene L, El-Khouly S, Chadokufa S, McCartney S, Saliakellis E, Kiparissi F, Borrelli O. Ferric carboxymaltose treatment for iron deficiency anemia in children with inflammatory bowel disease: Efficacy and risk of hypophosphatemia. Dig Liver Dis 2021; 53:830-834. [PMID: 33775573 DOI: 10.1016/j.dld.2021.02.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 01/23/2021] [Accepted: 02/16/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Although intravenous ferric carboxymaltose (FCM) is effective in treating iron deficiency anemia (IDA) in paediatric inflammatory bowel disease (pIBD), no data are available on its post-infusion related risks. AIMS We assessed the efficacy of FCM and the rate of post-infusion hypophosphatemia in a large cohort of children with IBD and IDA. METHODS All children with IBD with IDA treated with FCM over 5-year period were reviewed. Disease activity, biohumoral assessment and treatments were evaluated at baseline, 4-6 and 12 weeks after each infusion. RESULTS 128 patients [median age at first infusion: 13 years] were identified, 81 (63.3%) were <14 years, 10 (7.8%) <6 years. Eighty-three children (64.8%) received one infusion, whilst 45 (35.2%) repeated infusions. A significant increase in Hb (p<0.001), iron (p<0.001) and ferritin (p<0.001) was observed 4-6 and 12 weeks post-infusion. Hb gain was unrelated to disease severity. Low baseline iron was the main predicting factor for repeated infusions (p<0.05). Three patients reported infusion reactions, none <6 years. Twenty-five children had low post-infusion serum phosphate (11 were <14 years, 3 <6 years). Two children developed severe hypophosphatemia. CONCLUSIONS FCM administration is effective for IDA management in pIBD, including children <6 years. Due to the high prevalence of post-infusion hypophosphatemia, serum phosphate monitoring should be mandatory.
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Affiliation(s)
- Lucia Cococcioni
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK; Paediatric Department, "V. Buzzi" Children's Hospital, University of Milan, Milan, Italy
| | - Licia Pensabene
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK; Department of Surgical and Medical Sciences, Pediatric Unit, University of Catanzaro "Magna Graecia", Catanzaro, Italy
| | - Sara El-Khouly
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK
| | - Sibongile Chadokufa
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK
| | - Sara McCartney
- Gastroenterology Department, University College London Hospital, London, UK
| | - Efstratios Saliakellis
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK
| | - Fevronia Kiparissi
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK
| | - Osvaldo Borrelli
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK; Stem Cells and Regenerative Medicine, UCL Institute of Child Health, 30 Guilford Street, London, UK.
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Aksan A, Beales ILP, Baxter G, de Arellano AR, Gavata S, Valentine WJ, Hunt B. Evaluation of the Cost-Effectiveness of Iron Formulations for the Treatment of Iron Deficiency Anaemia in Patients with Inflammatory Bowel Disease in the UK. CLINICOECONOMICS AND OUTCOMES RESEARCH 2021; 13:541-552. [PMID: 34168471 PMCID: PMC8216635 DOI: 10.2147/ceor.s306823] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/06/2021] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION In patients with inflammatory bowel disease (IBD), iron deficiency anaemia (IDA) can impair quality of life and increase healthcare costs. Treatment options for IDA-associated IBD include oral iron and intravenous iron formulations (such as ferric carboxymaltose [FCM], ferric derisomaltose [FD, previously known as iron isomaltoside 1000], and iron sucrose [IS]). The present analysis compared the cost-effectiveness of FCM versus FD, IS, and oral iron sulfate in terms of additional cost per additional responder in the UK setting. METHODS Cost-effectiveness was calculated for FCM versus FD, IS, and oral iron individually in terms of the additional cost per additional responder, defined as haemoglobin normalisation or an increase of ≥2 g/dL in haemoglobin levels, in a model developed in Microsoft Excel. Relative efficacy inputs were taken from a previously published network meta-analysis, since there is currently no single head-to-head trial evidence comparing all therapy options. Costs were calculated in 2020 pounds sterling (GBP) capturing the costs of iron preparations, healthcare professional time, and consumables. RESULTS The analysis suggested that FCM may be the most effective intervention, with 81% of patients achieving a response. Response rates with FD, IS, and oral iron were 74%, 75%, and 69%, respectively. Total costs with FCM, FD, IS, and oral iron were GBP 296, GBP 312, GBP 503, and GBP 56, respectively. FCM was found to be more effective and less costly than both FD and IS, and therefore was considered dominant. Compared with oral iron, FCM was associated with an incremental cost-effectiveness ratio of GBP 2045 per additional responder. CONCLUSIONS FCM is likely to be the least costly and most effective IV iron therapy in the UK setting. Compared with oral iron, healthcare payers must decide whether the superior treatment efficacy of FCM is worth the additional cost.
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Affiliation(s)
- Aysegül Aksan
- Interdisciplinary Crohn Colitis Centre, Rhein-main, Frankfurt/Main, Germany
- Institute of Nutritional Science, Justus-Liebig University, Giessen, Germany
| | - Ian L P Beales
- Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, UK
| | | | | | - Simona Gavata
- Vifor Pharma Group, Market Access, Glattbrugg, Switzerland
| | | | - Barnaby Hunt
- Ossian Health Economics and Communications, Basel, Switzerland
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29
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Blumenstein I, Shanbhag S, Langguth P, Kalra PA, Zoller H, Lim W. Newer formulations of intravenous iron: a review of their chemistry and key safety aspects - hypersensitivity, hypophosphatemia, and cardiovascular safety. Expert Opin Drug Saf 2021; 20:757-769. [PMID: 33993818 DOI: 10.1080/14740338.2021.1912010] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: The newest intravenous (IV) iron products show an improved safety profile over predecessors, allowing for the rapid administration of relatively high doses. Ferric derisomaltose (FDI; also known as iron isomaltoside), ferric carboxymaltose (FCM), and ferumoxytol (FER), are successful treatments for iron deficiency (Europe; FDI and FCM) and iron deficiency anemia (US; FDI, FCM, and FER).Areas covered: This review focusses on the chemistry and structure of FDI, FCM, and FER, and on three key aspects of IV iron safety: (1) hypersensitivity; (2) hypophosphatemia and sequelae; (3) cardiovascular safety.Expert opinion: Although the safety of modern IV iron has improved, immediate infusion reactions and the development of hypophosphatemia must be appreciated and recognized by those who prescribe and administer IV iron. Immediate infusion reactions can occur with any IV iron and are usually mild; severe reactions - particularly anaphylaxis - are extremely rare. The recognition and appropriate management of infusion reactions is an important consideration to the successful administration of IV iron. Severe, persistent, hypophosphatemia is a specific side effect of FCM. No cardiovascular safety signal has been identified for IV iron. Ongoing trials in heart failure will provide additional long-term efficacy and safety data.
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Affiliation(s)
- Irina Blumenstein
- Medical Department 1, Department of Gastroenterology, Hepatology, and Clinical Nutrition, University Clinic Frankfurt, Frankfurt, Germany
| | - Satish Shanbhag
- Department of Hematology/Medical Oncology, Cancer Specialists of North Florida, Fleming Island, FL, USA.,Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MA, USA
| | - Peter Langguth
- Institute of Pharmacy and Biochemistry, Department of Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University, Mainz, Germany
| | - Philip A Kalra
- Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK.,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Heinz Zoller
- Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
| | - Wendy Lim
- Department of Medicine, Division of Hematology and Thromboembolism, St. Joseph's Healthcare Hamilton, McMaster University, Hamilton, ON, Canada
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Detlie TE, Lindstrøm JC, Jahnsen ME, Finnes E, Zoller H, Moum B, Jahnsen J. Hypophosphatemia after high-dose intravenous iron treatment in patients with inflammatory bowel disease: Mechanisms and possible clinical impact. World J Gastroenterol 2021; 27:2039-2053. [PMID: 34007138 PMCID: PMC8108035 DOI: 10.3748/wjg.v27.i17.2039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/19/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND High-dose intravenous iron is an effective treatment option for iron deficiency (ID) or ID anaemia (IDA) in inflammatory bowel disease (IBD). However, treatment with ferric carboxymaltose (FCM) has been associated with the development of hypophosphatemia.
AIM To investigate mechanisms behind the development of hypophosphatemia after intravenous iron treatment, and disclose symptoms and clinical manifestations related to hypophosphatemia short-term.
METHODS A prospective observational study of adult IBD patients with ID or IDA was conducted between February 1, 2017 and July 1, 2018 at two separate university hospitals in the southeast region of Norway. Patients received one dose of 1000 mg of either FCM or ferric derisomaltose (FDI) and were followed for an observation period of at least 7 wk. Blood and urine samples were collected for relevant analyses at baseline, week 2 and at week 6. Clinical symptoms were assessed at the same timepoints using a respiratory function test, a visual analogue scale, and a health-related quality of life questionnaire.
RESULTS A total of 106 patients was available for analysis in this study. The FCM treatment group consisted of 52 patients and hypophosphatemia was present in 72.5% of the patients at week 2, and in 21.6% at week 6. In comparison, the FDI treatment group consisted of 54 patients and 11.3% of the patients had hypophosphatemia at week 2, and 3.7% at week 6. The difference in incidence was highly significant at both week 2 and 6 (P < 0.001 and P < 0.013, respectively). We observed a significantly higher mean concentration of intact fibroblast growth factor 23 (P < 0.001), a significant rise in mean urine fractional excretion of phosphate (P = 0.004), a significant decrease of 1,25-dihydroxyvitamin D (P < 0.001) and of ionised calcium levels (P < 0.012) in the FCM-treated patients compared with patients who received FDI. No clinical symptoms could with certainty be related to hypophosphatemia, since neither the respiratory function test, SF-36 (36-item short form health survey) or the visual analogue scale scores resulted in significant differences between patients who developed hypophosphatemia or not.
CONCLUSION Fibroblast growth factor 23 has a key role in FCM induced hypophosphatemia, probably by inducing loss of phosphate in the urine. Short-term clinical impact of hypophosphatemia was not demonstrated.
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Affiliation(s)
- Trond Espen Detlie
- Department of Gastroenterology, Akershus University Hospital, Lørenskog 1478, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway
| | - Jonas Christoffer Lindstrøm
- Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway
- Health Services Research Unit, Akershus University Hospital, Lørenskog 1478, Norway
| | - Marte Eide Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog 1478, Norway
| | - Elisabeth Finnes
- Division of Medicine, Department of Gastroenterology, Oslo University Hospital Ullevål, Oslo 0424, Norway
| | - Heinz Zoller
- Department of Medicine II, Gastroenterology and Hepatology, Medical University of Innsbruck, Innsbruck A-6020, Austria
| | - Bjørn Moum
- Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway
- Division of Medicine, Department of Gastroenterology, Oslo University Hospital Ullevål, Oslo 0424, Norway
| | - Jørgen Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog 1478, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway
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Wang L, Wu X, Su BSQ, Song R, Zhang JR, Zhu JJ. Enzymatic Biofuel Cell: Opportunities and Intrinsic Challenges in Futuristic Applications. ADVANCED ENERGY AND SUSTAINABILITY RESEARCH 2021. [DOI: 10.1002/aesr.202100031] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Linlin Wang
- State Key Laboratory of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences School of Chemistry and Chemical Engineering Nanjing University Nanjing 210093 China
| | - Xiaoge Wu
- Environment Science and Engineering College Yangzhou University Yangzhou 225009 China
| | - B. S. Qi‐wen Su
- State Key Laboratory of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences School of Chemistry and Chemical Engineering Nanjing University Nanjing 210093 China
| | - Rongbin Song
- State Key Laboratory of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences School of Chemistry and Chemical Engineering Nanjing University Nanjing 210093 China
| | - Jian-Rong Zhang
- State Key Laboratory of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences School of Chemistry and Chemical Engineering Nanjing University Nanjing 210093 China
| | - Jun-Jie Zhu
- State Key Laboratory of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences School of Chemistry and Chemical Engineering Nanjing University Nanjing 210093 China
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Schaefer B, Tobiasch M, Viveiros A, Tilg H, Kennedy NA, Wolf M, Zoller H. Hypophosphataemia after treatment of iron deficiency with intravenous ferric carboxymaltose or iron isomaltoside-a systematic review and meta-analysis. Br J Clin Pharmacol 2021; 87:2256-2273. [PMID: 33188534 PMCID: PMC8247006 DOI: 10.1111/bcp.14643] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/27/2020] [Accepted: 11/03/2020] [Indexed: 12/21/2022] Open
Abstract
AIMS Hypophosphataemia is an increasingly recognized side-effect of ferric carboxymaltose (FCM) and possibly iron isomaltoside/ferric derisomaltose (IIM), which are used to treat iron deficiency. The aim of this study was to determine frequency, severity, duration and risk factors of incident hypophosphataemia after treatment with FCM and IIM. METHODS A systematic literature search for articles indexed in EMBASE, PubMed and Web of Science in years 2005-2020 was carried out using the search terms 'ferric carboxymaltose' OR 'iron isomaltoside'. Prospective clinical trials reporting outcomes on hypophosphataemia rate, mean nadir serum phosphate and/or change in mean serum phosphate from baseline were selected. Hypophosphataemia rate and severity were compared for studies on IIM vs. FCM after stratification for chronic kidney disease. Meta-regression analysis was used to investigate risk factors for hypophosphataemia. RESULTS Across the 42 clinical trials included in the meta-analysis, FCM induced a significantly higher incidence of hypophosphataemia than IIM (47%, 95% CI 36-58% vs. 4%, 95% CI 2-5%), and significantly greater mean decreases in serum phosphate (0.40 vs. 0.06 mmol/L). Hypophosphataemia persisted at the end of the study periods (maximum 3 months) in up to 45% of patients treated with FCM. Meta-regression analysis identified low baseline serum ferritin and transferrin saturation, and normal kidney function as significant predictors of hypophosphataemia. CONCLUSION FCM is associated with a high risk of hypophosphataemia, which does not resolve for at least 3 months in a large proportion of affected patients. More severe iron deficiency and normal kidney function are risk factors for hypophosphataemia.
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Affiliation(s)
- Benedikt Schaefer
- Department of Medicine I, Gastroenterology, Hepatology and EndocrinologyMedical University of InnsbruckInnsbruckAustria
- Christian Doppler Laboratory of Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
| | - Moritz Tobiasch
- Department of MedicineUniversity Teaching Hospital of Hall in TirolHallAustria
| | - André Viveiros
- Department of Medicine I, Gastroenterology, Hepatology and EndocrinologyMedical University of InnsbruckInnsbruckAustria
- Christian Doppler Laboratory of Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
| | - Herbert Tilg
- Department of Medicine I, Gastroenterology, Hepatology and EndocrinologyMedical University of InnsbruckInnsbruckAustria
| | - Nicholas A. Kennedy
- IBD PharmacogeneticsUniversity of ExeterExeterUK
- Gastrointestinal UnitWestern General HospitalEdinburghUK
| | - Myles Wolf
- Department of Medicine, Division of Nephrology, and Duke Clinical Research InstituteDuke University School of MedicineDurhamNCUSA
| | - Heinz Zoller
- Department of Medicine I, Gastroenterology, Hepatology and EndocrinologyMedical University of InnsbruckInnsbruckAustria
- Christian Doppler Laboratory of Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
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Lecoq AL, Dong C, Carbonnel F, Becquemont L. [Hypophosphatemia following the administration of intravenous iron formulations: A case report and literature review]. Therapie 2021; 76:705-714. [PMID: 33962799 DOI: 10.1016/j.therap.2021.04.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/23/2021] [Accepted: 04/13/2021] [Indexed: 12/21/2022]
Abstract
Iron deficiency and iron-deficiency anemia are common medical conditions. Management of the etiology and iron supplementation are both necessary to treat this condition. Use of intravenous iron preparations is increasing due to its advantages over oral iron. Indeed, the total dose required can be provided in a single infusion, and it is more effective and increases hemoglobin levels more quickly than oral iron. Hypophosphatemia, sometimes severe, following intravenous iron administration, has been described in literature these past years, in particular with ferric carboxymaltose. We report here a case of severe hypophosphatemia with ferric carboxymaltose and carry out a literature review to determine the incidence of hypophosphatemia and to precise its clinical presentation, its pathophysiological mechanisms and its treatment. We found that hypophosphatemia is frequent with ferric carboxymaltose. Most of the time, there are no clinical manifestations, but cases of symptomatic osteomalacia have been described. Duration of hypophosphatemia is variable, from a few weeks to several months in case of prolonged administration. Hypophosphatemia owing to renal phosphate wasting is caused by an increase in intact fibroblast growth factor 23 (FGF-23) levels. However, the mechanism of ferric carboxymaltose- induced increase in intact FGF-23 is still unknown.
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Affiliation(s)
- Anne-Lise Lecoq
- Assistance publique-Hôpitaux de Paris (AP-HP), hôpital Bicêtre, Centre de Recherche Clinique AP-HP, université Paris-Saclay, 78, rue du Général-Leclerc, 94270 Le Kremlin-Bicêtre, France.
| | - Catherine Dong
- Service de Gastro-Entérologie, Assistance publique-Hôpitaux de Paris (AP-HP), hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - Franck Carbonnel
- Service de Gastro-Entérologie, Assistance publique-Hôpitaux de Paris (AP-HP), hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - Laurent Becquemont
- Assistance publique-Hôpitaux de Paris (AP-HP), hôpital Bicêtre, Centre de Recherche Clinique AP-HP, université Paris-Saclay, 78, rue du Général-Leclerc, 94270 Le Kremlin-Bicêtre, France
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Kassianides X, Bhandari S. Hypophosphataemia, fibroblast growth factor 23 and third-generation intravenous iron compounds: a narrative review. Drugs Context 2021; 10:dic-2020-11-3. [PMID: 33519940 PMCID: PMC7819638 DOI: 10.7573/dic.2020-11-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/08/2020] [Indexed: 02/06/2023] Open
Abstract
Third-generation intravenous (i.v.) iron preparations are safe and efficacious and are increasingly used in the treatment of iron-deficiency anaemia. Hypophosphataemia is emerging as an established side-effect following the administration of certain compounds. Symptoms of hypophosphataemia can be masked by their similarity to those of iron-deficiency anaemia and both acute and chronic hypophosphataemia can be detrimental. Hypophosphataemia appears to be linked to imbalances in the metabolism of the phosphatonin fibroblast growth factor 23. In this narrative review, we discuss the possible pathophysiology behind this phenomenon, the studies comparing third-generation i.v. iron compounds, and the potential implications of the changes in fibroblast growth factor 23 and hypophosphataemia. We also present an algorithm of how to approach such patients requiring i.v. iron in anticipation of hypophosphataemia and how the impact related to it can be minimized.
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Affiliation(s)
- Xenophon Kassianides
- Department of Academic Renal Research, Hull University Teaching Hospitals NHS Trust, 2nd Floor Alderson House, Hull Royal Infirmary, Anlaby Road, Kingston upon Hull, UK
| | - Sunil Bhandari
- Department of Academic Renal Research, Hull University Teaching Hospitals NHS Trust, 2nd Floor Alderson House, Hull Royal Infirmary, Anlaby Road, Kingston upon Hull, UK
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McKenna MJ, Crowley RK, Twomey PJ, Kilbane MT. Renal Phosphate Handling: Independent Effects of Circulating FGF23, PTH, and Calcium. JBMR Plus 2021; 5:e10437. [PMID: 33615106 PMCID: PMC7872336 DOI: 10.1002/jbm4.10437] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 11/13/2020] [Indexed: 12/25/2022] Open
Abstract
Excess fibroblast growth factor 23 (FGF23), excess PTH, and an increase in extracellular calcium cause hypophosphatemia by lowering the maximum renal phosphate reabsorption threshold (TmP/GFR). We recently reported two cases of X-linked hypophosphatemia (XLH) with severe tertiary hyperparathyroidism who had normalization of TmP/GFR upon being rendered hypoparathyroid following total parathyroidectomy, despite marked excess in both C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23). We explored the effects of FGF23, PTH, and calcium on TmP/GFR in a cross-sectional study (n = 74) across a spectrum of clinical cases with abnormalities in TmP/GFR, PTH, and FGF23. This comprised three groups: FGF23-dependent hypophosphatemia (n = 27), hypoparathyroidism (HOPT; n = 17), and chronic kidney disease (n = 30). Measurements included TmP/GFR, cFGF23, PTH, ionized calcium, vitamin D metabolites, and bone turnover markers. The combined effect of cFGF23, PTH, and ionized calcium on TmP/GFR was modeled using hierarchical multiple regression and was probed by moderation analysis with PROCESS. Modeling analysis showed independent effects on TmP/GFR by cFGF23, PTH, and ionized calcium in conjunction with a weak but significant effect of the interaction term for PTH and FGF23; probing showed that the effect was most prominent during PTH deficiency. Teriparatide 20 μg daily was self-administered for 28 days by one case of X-linked hypophosphatemia with hypoparathyroidism (XLH-HOPT) to assess the response of TmP/GFR, cFGF23, iFGF23, nephrogenous cyclic adenosine monophosphate (NcAMP), vitamin D metabolites, and bone turnover markers. After 28 days, TmP/GFR was lowered from 1.10 mmol/L to 0.48 mmol/L; this was accompanied by increases in NcAMP, ionized calcium, and bone turnover markers. In conclusion, the effect of FGF23 excess on TmP/GFR is altered by PTH such that the effect is ameliorated by hypoparathyroidism and the effect is augmented by hyperparathyroidism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Malachi J McKenna
- UCD School of MedicineUniversity College DublinDublinIreland
- Department of Clinical ChemistrySt. Vincent's University HospitalDublinIreland
- Department of EndocrinologySt. Vincent's University HospitalDublinIreland
| | - Rachel K Crowley
- UCD School of MedicineUniversity College DublinDublinIreland
- Department of Clinical ChemistrySt. Vincent's University HospitalDublinIreland
- Department of EndocrinologySt. Vincent's University HospitalDublinIreland
| | - Patrick J Twomey
- UCD School of MedicineUniversity College DublinDublinIreland
- Department of Clinical ChemistrySt. Vincent's University HospitalDublinIreland
| | - Mark T Kilbane
- UCD School of MedicineUniversity College DublinDublinIreland
- Department of Clinical ChemistrySt. Vincent's University HospitalDublinIreland
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Pasricha SR, Gilbertson M, Indran T, Bennett A, van Dam M, Coughlin E, Dev A, Chunilal S, Opat S. Safety of rapid injection of undiluted ferric carboxymaltose to patients with iron-deficiency anaemia: a Phase II single-arm study. Intern Med J 2021; 51:1304-1311. [PMID: 33462917 DOI: 10.1111/imj.15195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 07/13/2020] [Accepted: 12/30/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND Ferric carboxymaltose is increasingly utilised to treat iron deficiency and is usually diluted in saline and administered as an intravenous infusion over 15 min. Although this is highly convenient compared with older formulations, we hypothesised the drug could be administered, safely given as a rapid bolus injection. AIMS To define the risk of serious adverse events following administration of an undiluted, rapid, high-dose ferric carboxymaltose injection. Secondary aims included all other adverse events, as well as longitudinal effects on haemoglobin, iron stores, phosphate and hepcidin. METHODS In a single-arm, Phase II study in 121 patients with iron-deficiency anaemia, we administered up to 1000 mg of ferric carboxymaltose as a rapid undiluted bolus injection, and recorded adverse events and collected blood samples over the first hour, and again at 2 and 4 weeks post-treatment. RESULTS No patient experienced a serious adverse event. Flushing during the injection was common, as was a transient headache in the subsequent weeks. One patient experienced Grade 3 chest tightness, necessitating emergency department assessment but not admission or treatment. Treatment produced an average 12.3 g/L improvement in haemoglobin within 2 weeks, but commonly caused reductions in serum phosphate (although none of these was clinically symptomatic). Parenteral iron caused elevations in hepcidin sustained to 4 weeks post-injection. Patients stated they would be prepared to receive the treatment again. CONCLUSION Rapid injection of undiluted ferric carboxymaltose is well tolerated and could provide an approach to treat patients in the ambulatory setting.
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Affiliation(s)
- Sant-Rayn Pasricha
- Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.,Diagnostic and Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Department of Medical Biology, and Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Michael Gilbertson
- Department of Haematology, Monash Health, Melbourne, Victoria, Australia
| | - Tishya Indran
- Department of Haematology, Monash Health, Melbourne, Victoria, Australia
| | - Ashwini Bennett
- Department of Haematology, Monash Health, Melbourne, Victoria, Australia
| | - Matthew van Dam
- Department of Haematology, Monash Health, Melbourne, Victoria, Australia
| | - Elizabeth Coughlin
- Department of Haematology, Monash Health, Melbourne, Victoria, Australia
| | - Anouk Dev
- Department of Gastroenterology, Monash Health, Melbourne, Victoria, Australia.,Department of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Sanjeev Chunilal
- Department of Haematology, Monash Health, Melbourne, Victoria, Australia
| | - Stephen Opat
- Department of Haematology, Monash Health, Melbourne, Victoria, Australia
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Pollock RF, Muduma G. An Economic Analysis of Ferric Derisomaltose versus Ferric Carboxymaltose in the Treatment of Iron Deficiency Anemia in Patients with Inflammatory Bowel Disease in Norway, Sweden, and Finland. CLINICOECONOMICS AND OUTCOMES RESEARCH 2021; 13:9-18. [PMID: 33442276 PMCID: PMC7800446 DOI: 10.2147/ceor.s284959] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 11/25/2020] [Indexed: 12/29/2022] Open
Abstract
Background and Aims Iron deficiency anemia (IDA) is a common sequela of inflammatory bowel disease (IBD), arising from the combined effects of gastrointestinal blood loss and reduced iron absorption. Given this, intravenous (IV) iron should be considered as the first-line treatment in patients with clinically active IBD. The present study evaluated the budget impact of administering IV iron with ferric derisomaltose (FDI) versus ferric carboxymaltose (FCM) in patients with IDA and IBD in Norway, Sweden, and Finland. Methods A cohort level model of iron need was developed using a bivariate distribution of hemoglobin and bodyweight based on observational data from a multi-country Scandinavian study of patients with IDA and IBD. The base case analysis was conducted over 5 years in patients with IDA with mean bodyweight of 75.4 kg (SD 17.5 kg) and hemoglobin levels of 10.77 g/dL (SD 1.43 g/dL). Infusion costs were modeled using diagnosis-related groups. Sensitivity analyses were performed around different patient characteristics, care settings, and retreatment frequencies, and probabilistic sensitivity analyses were conducted. Results Using FDI required 1.25 infusions to correct the mean iron deficit, compared with 1.64 infusions with FCM. In Norway, the per-patient cost of iron replenishment over 5 years was estimated to be NOK20,767 with FCM versus NOK15,799 with FDI, reflecting a cost saving of NOK4,968 or 23.9%. In Finland, costs were projected to decrease from EUR3075 with FCM to EUR2339 with FDI, reflecting a cost saving of EUR736 per patient. In Sweden, costs decreased from SEK27,760 with FCM to SEK21,119 with FDI. Conclusion Using FDI in place of FCM resulted in a substantial reduction in the number of infusions required to correct iron deficits in patients with IDA and IBD. The reduction in infusions was accompanied by substantial cost savings relative to FCM over 5 years across all three Nordic countries evaluated.
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Affiliation(s)
- Richard F Pollock
- Health Economics and Outcomes Research, Covalence Research Ltd, London, UK
| | - Gorden Muduma
- International Market Access, Pharmacosmos A/S, Holbæk, Denmark
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Aksan A, Schoepfer A, Juillerat P, Vavricka S, Bettencourt M, Ramirez de Arellano A, Gavata S, Morin N, Valentine WJ, Hunt B. Iron Formulations for the Treatment of Iron Deficiency Anemia in Patients with Inflammatory Bowel Disease: A Cost-Effectiveness Analysis in Switzerland. Adv Ther 2021; 38:660-677. [PMID: 33216324 PMCID: PMC7854431 DOI: 10.1007/s12325-020-01553-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 10/24/2020] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD) and can result in reduced quality of life and increased healthcare costs. IDA is treated with iron supplementation, either with oral iron therapy (OI) or intravenous iron formulations, including ferric carboxymaltose (FCM), iron isomaltoside 1000 (IIM), and iron sucrose (IS). This analysis compared the cost-effectiveness of FCM versus IIM, IS, and OI in terms of additional cost per additional responder in Switzerland. METHODS A health economic model was developed to assess the additional cost per additional responder, defined as normalization or an increase of at least 2 g/dL in hemoglobin levels, for FCM versus IIM, IS, and OI. To date, no single head-to-head trial comparing all therapies is available, and therefore relative efficacy data were taken from a published network meta-analysis. Costs of treatment were calculated in 2020 Swiss francs (CHF) using a microcosting approach, and included the costs of iron, healthcare professional time, and consumables. Costs are also presented in euros (EUR) based on an exchange rate of CHF 1 = EUR 0.94. RESULTS Response rates with FCM, IIM, IS, and OI were 81%, 74%, 75%, and 69%, respectively, with FCM projected to be the most effective treatment. FCM was associated with cost savings of CHF 24 (EUR 23) versus IIM and of CHF 147 (EUR 138) versus IS, and increased costs by CHF 345 (EUR 324) versus OI. Therefore FCM was considered dominant versus both IIM and IS, improving clinical outcomes with cost savings. FCM was associated with an incremental cost-effectiveness ratio of CHF 2970 (EUR 2792) per additional responder versus OI. CONCLUSIONS FCM was projected to be the most cost-effective intravenous iron therapy in Switzerland, increasing the number of responders and leading to cost savings for healthcare payers.
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Kassianides X, Bodington R, Bhandari S. An evaluation of ferric derisomaltose as a treatment for anemia. Expert Rev Hematol 2020; 14:7-29. [PMID: 33317356 DOI: 10.1080/17474086.2021.1858406] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Introduction: Originally approved in Europe in 2009, ferric derisomaltose is the most recently authorized intravenous iron compound in the United States of America (2020). Ferric derisomaltose given as a rapid high-dose infusion can allow complete iron repletion in a single dose and it is now widely used in the treatment of iron deficiency. Areas covered: The chemistry, pharmacodynamics and pharmacokinetics of ferric derisomaltose are reviewed. Results from phase II, III and IV trials regarding efficacy and safety are presented. Mechanisms behind minor infusion reactions, hypersensitivity and hypophosphatemia are discussed. The economic impact of ferric derisomaltose use is presented. Data pertaining to the use of ferric derisomaltose in iron deficiency anemia, chronic kidney disease, inflammatory bowel disease, chronic heart failure, perioperative care and other patient groups are comprehensively covered. Expert opinion: Ferric derisomaltose is an effective intravenous iron formulation with a good safety profile, providing rapid, cost-effective iron repletion. Ferric derisomaltose releases low quantities of labile iron relative to older compounds. Anaphylaxis is extremely rare, and 'Fishbane' reactions are uncommon. Hypophosphatemia following ferric derisomaltose administration is infrequent in comparison to other intravenous irons such as ferric carboxymaltose. The scope of ferric derisomaltose use is growing with increasing research in these areas.
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Affiliation(s)
- Xenophon Kassianides
- Academic Renal Department, Hull University Teaching Hospitals NHS Trust and Hull York Medical School , Hull, UK
| | - Richard Bodington
- Academic Renal Department, Hull University Teaching Hospitals NHS Trust and Hull York Medical School , Hull, UK
| | - Sunil Bhandari
- Academic Renal Department, Hull University Teaching Hospitals NHS Trust and Hull York Medical School , Hull, UK
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40
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Frazier R, Hodakowski A, Cai X, Lee J, Zakarija A, Stein B, David V, Wolf M, Isakova T, Mehta R. Effects of ferric carboxymaltose on markers of mineral and bone metabolism: A single-center prospective observational study of women with iron deficiency. Bone 2020; 141:115559. [PMID: 32730929 PMCID: PMC7680361 DOI: 10.1016/j.bone.2020.115559] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 06/03/2020] [Accepted: 07/07/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Two weekly infusions of ferric carboxymaltose (FCM) are commonly prescribed for treatment of iron-deficiency anemia. However, administration of FCM increases intact levels of fibroblast growth factor 23 (FGF23), which causes hypophosphatemia due to renal phosphate wasting, calcitriol deficiency and secondary hyperparathyroidism. The adverse effects of FCM on mineral metabolism and bone health emerged from case reports and secondary analyses of trials. Data on these safety signals with FCM in clinical practice are limited because markers of mineral and bone metabolism are not routinely checked. METHODS To obtain real-world experience with effects of FCM on mineral and bone metabolism, we conducted a prospective observational study of 16 women who were managed at a single-center hematology clinic for iron-deficiency anemia. From October 2016 to February 2018, all participants received two weekly infusions of FCM at a hematology infusion clinic. We hypothesized that FCM would decrease phosphate, increase intact FGF23 (iFGF23), and decrease c-terminal FGF23 (cFGF23). Secondary outcomes were changes in hemoglobin, iron indices, urine fractional excretion of phosphate (FePi), parathyroid hormone (PTH), calcitriol, calcium, osteocalcin, and bone-specific alkaline phosphatase (BAP). FCM was administered at weeks zero and one, and we measured laboratory values at weeks zero, one, two, and five of the study. We used linear mixed models to analyze the significance of the changes in laboratory values over time. RESULTS After two FCM infusions, nearly all (14 of 16) participants developed hypophosphatemia. iFGF23 increased, cFGF23 decreased, and phosphate decreased significantly from week zero to week two (iFGF23 increased by +134.0% [40.6, 305.8], p < 0.001; cFGF23 decreased by -516.3% [-1332.7, -142.7], p = 0.002; phosphate decreased by -49.8 ± 15.4%, p < 0.001). There was also a significant increase in FePi, PTH, and BAP and a significant decrease in calcitriol and calcium from week zero to week two. There was no significant change in osteocalcin during this time period. iFGF23, but not PTH, was independently associated with decreased phosphate. iFGF23 was also significantly associated with decrease in calcitriol from week zero to week two. Elevation in BAP suggests disordered bone mineralization in response to FCM therapy. CONCLUSION In this prospective observational study of women with iron deficiency anemia, two FCM infusions significantly altered markers of bone mineralization and mineral metabolism. The results suggest that FCM should be used cautiously in the treatment of iron-deficiency anemia.
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Affiliation(s)
- Rebecca Frazier
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Jesse Brown Veterans Administration Medical Center, Chicago, IL 60612, USA.
| | - Alexander Hodakowski
- Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Xuan Cai
- Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Jungwha Lee
- Division of Biostatistics, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Anaadriana Zakarija
- Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Brady Stein
- Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Valentin David
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC 27701, USA
| | - Tamara Isakova
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Rupal Mehta
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Jesse Brown Veterans Administration Medical Center, Chicago, IL 60612, USA
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Rosano G, Schiefke I, Göhring UM, Fabien V, Bonassi S, Stein J. A Pooled Analysis of Serum Phosphate Measurements and Potential Hypophosphataemia Events in 45 Interventional Trials with Ferric Carboxymaltose. J Clin Med 2020; 9:3587. [PMID: 33172157 PMCID: PMC7694774 DOI: 10.3390/jcm9113587] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 12/20/2022] Open
Abstract
Ferric carboxymaltose (FCM) has been shown to achieve rapid replenishment of iron stores and correction of anaemia in various populations with iron deficiency. A decrease in serum phosphate (PO43-) levels, which in most cases is asymptomatic, has been reported with IV iron preparations. Hypophosphataemia (HP) is a known adverse drug reaction with FCM. This post hoc pooled analysis investigates the frequency, duration, risk factors, and clinical signs of HP as reported in interventional clinical trials with FCM. Pooled data from subjects enrolled across 45 clinical trials in different therapy areas were included. A three-step adjudication process was utilised to identify adverse events of HP. Stratified analyses by therapy group and stepwise logistic regression analysis were used to identify predictors of HP. This pooled analysis confirms that FCM is associated with increased rates of serum PO43- lowering, but mean serum PO43- values were seen to recover at Week 4 and further recover at Week 8. Among all subjects receiving FCM therapy (n = 6879), 41.4% (n = 2847) reached a PO43- nadir value <2.5 mg/dL at any point on study and 0.7% (n = 49) reached a nadir <1 mg/dL. Although gastroenterology and women's health subjects were identified to be at higher risk, occurrence of severe HP (<1 mg/dL [0.3 mmol/L]) following FCM administration was not observed to be common among subjects in these studies. Furthermore, there was no correlation between laboratory serum PO43- values and the occurrence of reported adverse events related to low PO43- levels.
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Affiliation(s)
- Giuseppe Rosano
- Department of Medical Sciences, IRCCS San Raffaele Pisana, 00166 Rome, Italy
| | - Ingolf Schiefke
- Department of Gastroenterology, Hepatology, Diabetology and Endocrinology, Klinikum St. Georg, 04129 Leipzig, Germany;
| | | | | | - Stefano Bonassi
- Department of Human Sciences and Quality of Life Promotion, San Raffaele University, 00166 Rome, Italy;
- Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, 00166 Rome, Italy
| | - Jürgen Stein
- Department of Gastroenterology and Clinical Nutrition, DGD Clinics Sachsenhausen, 60594 Frankfurt am Main, Germany;
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Fragkos KC, Sehgal V, Rogers J, Arulrajan S, Pavanerathan P, Barragry J, Sebepos‐Rogers GM, Mehta SJ, Di Caro S, Rahman F. Hypophosphataemia after intravenous iron therapy with ferric carboxymaltose—Real world experience from a tertiary centre in the UK. ACTA ACUST UNITED AC 2020. [DOI: 10.1002/ygh2.415] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
| | - Vinay Sehgal
- University College London Hospitals NHS Foundation TrustGI Services London UK
| | - Jennifer Rogers
- University College London Hospitals NHS Foundation TrustGI Services London UK
| | | | | | - John Barragry
- University College London Hospitals NHS Foundation TrustGI Services London UK
| | | | - Shameer J. Mehta
- University College London Hospitals NHS Foundation TrustGI Services London UK
| | - Simona Di Caro
- University College London Hospitals NHS Foundation TrustGI Services London UK
| | - Farooq Rahman
- University College London Hospitals NHS Foundation TrustGI Services London UK
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43
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Bellos I, Frountzas M, Pergialiotis V. Comparative Risk of Hypophosphatemia Following the Administration of Intravenous Iron Formulations: A Network Meta-Analysis. Transfus Med Rev 2020; 34:188-194. [PMID: 32819760 DOI: 10.1016/j.tmrv.2020.07.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/13/2020] [Accepted: 07/16/2020] [Indexed: 02/04/2023]
Abstract
Intravenous iron therapy is increasingly used in patients with iron deficiency anemia, although concerns of hypophosphatemia have been recently raised. The aim of this study was to evaluate different intravenous iron formulations for the risk of hypophosphatemia. Medline, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, Clinicaltrials.gov, and Google Scholar databases were systematically searched to 20 March 2020. All randomized controlled trials reporting the incidence of hypophosphatemia among adult patients treated with any intravenous iron preparation were included. Pool estimates were obtained by applying an arm-based Bayesian network meta-analysis model. Eight randomized controlled trials were included, comprising 5989 patients. Ferric carboxymaltose was associated with significantly higher incidence of hypophosphatemia compared to iron isomaltoside (risk ratio [RR]: 7.90, 95% confidence interval [CI]: 2.10-28.0), iron sucrose (RR: 9.40, 95% CI: 2.30-33.0), iron dextran (RR: 6.60, 95% CI: 1.91-220.0), and ferumoxytol (RR: 24.0, 95% CI: 2.50-220.0). Therefore, ferric carboxymaltose ranked as the worst treatment presenting the highest surface under the cumulative ranking curve (99.1%). No significant differences were estimated for the comparisons among iron isomaltoside, iron sucrose, iron dextran, and ferumoxytol. In conclusion, it is suggested that the occurrence of hypophosphatemia is common after the administration of intravenous ferric carboxymaltose. Further research is needed in large-scale randomized controlled trials to determine the risk of symptomatic and persistent hypophosphatemia as well as to elucidate the exact pathophysiology of the observed association.
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Affiliation(s)
- Ioannis Bellos
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Greece.
| | - Maximos Frountzas
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Greece
| | - Vasilios Pergialiotis
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Greece
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44
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Fang W, Kenny R, Rizvi QUA, McMahon LP, Garg M. Hypophosphataemia after ferric carboxymaltose is unrelated to symptoms, intestinal inflammation or vitamin D status. BMC Gastroenterol 2020; 20:183. [PMID: 32522150 PMCID: PMC7288415 DOI: 10.1186/s12876-020-01298-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 05/06/2020] [Indexed: 12/21/2022] Open
Abstract
Background Intravenous iron replacement is recommended for iron-deficient patients with inflammatory bowel disease (IBD), but may be associated with hypophosphataemia, predisposing to osteomalacia and fractures. This study aimed to evaluate the incidence and risk factors for hypophosphataemia following intravenous ferric carboxymaltose (FCM) in patients with IBD. Methods This prospective observational study of patients with and without IBD evaluated serum phosphate for 28 days following intravenous FCM, and assessed associations with symptoms, markers of inflammation and vitamin D status. Results Twenty-four patients with IBD (11 with Crohn’s disease [CD], 13 with ulcerative colitis [UC], mean age 45 years [range 19–90], 7 female), and 20 patients without IBD (mean age 56 [22–88] y, 11 female), were included. Overall, serum phosphate declined by a mean of 36% at Day 7, with a mean fall of 42% (SD 19%) at some time point over 28 days (p < 0.001). Twenty-four of 44 (55%) patients developed moderate to severe hypophosphataemia (serum phosphate < 0.6 mmol/L). No differences between patients with and without IBD were seen, but patients with CD had greater decline in phosphate than those with UC. There was no association between hypophosphataemia and symptomatic adverse events, faecal calprotectin, C-reactive protein, albumin, platelet count, 25(OH) vitamin D, or 1,25(di-OH) vitamin D. Serum phosphate < 1.05 mmol/L on Day 2 predicted susceptibility to moderate-severe hypophosphataemia (OR 7.0). Conclusions Hypophosphataemia following FCM is common, unrelated to symptomatic adverse events, baseline intestinal or systemic inflammation, or vitamin D status.
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Affiliation(s)
- Wendy Fang
- Department of Gastroenterology, Northern Health, 185 Cooper St, Epping, Victoria, 3076, Australia
| | - Rachel Kenny
- Eastern Health Clinical School, Monash University, 5 Arnold St, Box Hill, Victoria, 3128, Australia
| | - Qurat-Ul-Ain Rizvi
- Department of Gastroenterology, Northern Health, 185 Cooper St, Epping, Victoria, 3076, Australia
| | - Lawrence P McMahon
- Eastern Health Clinical School, Monash University, 5 Arnold St, Box Hill, Victoria, 3128, Australia.,Department of Nephrology, Eastern Health, 8 Arnold St, Box Hill, Victoria, 3128, Australia.,Department of Renal Medicine, Box Hill Hospital, Level 3W, Building B, 8 Arnold St, Box Hill, Victoria, 3128, Australia
| | - Mayur Garg
- Department of Gastroenterology, Northern Health, 185 Cooper St, Epping, Victoria, 3076, Australia. .,Eastern Health Clinical School, Monash University, 5 Arnold St, Box Hill, Victoria, 3128, Australia. .,Department of Gastroenterology, Northern Health, Epping, Victoria, Australia. .,Department of Gastroenterology and Hepatology, Royal Melbourne Hospital, Parkville, Victoria, Australia. .,Department of Gastroenterology and Hepatology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
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Achebe M, DeLoughery TG. Clinical data for intravenous iron - debunking the hype around hypersensitivity. Transfusion 2020; 60:1154-1159. [PMID: 32479668 PMCID: PMC7384172 DOI: 10.1111/trf.15837] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 02/13/2020] [Accepted: 02/26/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Reluctance to use intravenous (IV) iron for the treatment of iron deficiency continues due to a perceived high risk of severe hypersensitivity reactions (HSRs). Additionally, it has been hypothesized that 'dextran-derived' IV iron products (e.g., ferumoxytol [FER] and ferric derisomaltose/iron isomaltoside 1000 [FDI]) have a higher risk of severe HSRs than 'non-dextran-derived' products (e.g., ferric carboxymaltose [FCM] and iron sucrose [IS]). In the present analysis, HSR data from head-to-head randomized controlled trials (RCTs) with IV iron products were evaluated to determine if differences in safety signals are present among these IV iron formulations. STUDY DESIGN AND METHODS Reported serious or moderate-to-severe HSR incidence data from five RCTs (FIRM; FERWON-NEPHRO/-IDA; PHOSPHARE-IDA04/-IDA05) were used to calculate risk differences with 95% confidence intervals (CIs) for FER, FCM, FDI, and IS. The rates and risk differences for these HSRs were compared. RESULTS The analysis included data for 5247 patients: FER (n = 997), FCM (n = 1117), FDI (n = 2133) and IS (n = 1000). Overall rates of serious or moderate to severe HSRs were low (0.2%-1.7%). The risk differences (95% CIs) showed small differences between the IV iron formulations: FER versus FCM, -0.1 (-0.8 to 0.6); FDI versus IS, 0.1 (-0.3 to 0.5); FDI versus FCM, -0.9 (-3.7 to 1.9). CONCLUSION RCT evidence confirms a low risk of serious or moderate to severe HSRs with newer IV iron formulations and no significant differences among existing commercially available products. Thus, RCT data show that the supposed classification of dextran-derived versus non-dextran-derived IV iron products has no clinical relevance.
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Affiliation(s)
- Maureen Achebe
- Brigham and Women's HospitalDana Farber Cancer Institute, Harvard Medical SchoolBostonMassachusetts
| | - Thomas G. DeLoughery
- Department of Hematology and Medical Oncology, Knight Cancer CenterOregon Health Sciences UniversityPortlandOregon
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Kearns J, Jacob SG. Real-world evaluation of an intravenous iron service for the treatment of iron deficiency in patients with gastroenterological disorders. Frontline Gastroenterol 2020; 12:265-271. [PMID: 34249310 PMCID: PMC8231433 DOI: 10.1136/flgastro-2020-101406] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 04/03/2020] [Accepted: 04/08/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND In gastroenterological disorders, iron deficiency (ID) is often treated with intravenous iron. This real-world study assessed the effectiveness and safety of iron isomaltoside (IIM), a high-dose intravenous iron, for the treatment of ID in patients with gastroenterological disorders, as part of a service evaluation and improvement process. METHODS Medical records of 117 patients with gastroenterological disorders, who received IIM, were examined retrospectively. Study outcomes included dose of IIM (estimated iron need versus actual dose received), number of appointments required to deliver the dose and changes in haemoglobin (Hb) and ferritin at ~1 month and ~6 months post-treatment. Safety was assessed through adverse drug reactions (ADRs). RESULTS Overall, 76.1% of patients received their estimated iron need; 23.9% were underdosed. The mean (SD) iron dose was 1317 (409.7) mg; 62.4% of patients received their dose in one appointment. From baseline, mean (SD) Hb increased by 20.9 (15.4) g/L at 1 month post-treatment (p<0.0001) and by 22.0 (17.9) g/L at 6 months post-treatment (p<0.0001). Mean (SD) baseline ferritin was 26.6 (37.8) μg/L, which increased to 234.6 (142.9) μg/L at 1 month post-treatment (p<0.0001), and remained increased at 6 months post-treatment (122.8 (99.2) μg/L; p<0.0001). A substantial proportion of patients were non-anaemic at 1 month (57.5%) and 6 months (61.8%) post-treatment. At both post-treatment timepoints, the proportion of non-anaemic patients was higher in those receiving their total iron need versus those who were underdosed. No serious ADRs were reported. CONCLUSION IIM was efficacious and well tolerated in patients with gastroenterological disorders. This real-world study highlights the importance of administering the full iron need to maximise treatment response.
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Wolf M, Rubin J, Achebe M, Econs MJ, Peacock M, Imel EA, Thomsen LL, Carpenter TO, Weber T, Brandenburg V, Zoller H. Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia: Two Randomized Clinical Trials. JAMA 2020; 323:432-443. [PMID: 32016310 PMCID: PMC7042864 DOI: 10.1001/jama.2019.22450] [Citation(s) in RCA: 174] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 12/23/2019] [Indexed: 12/14/2022]
Abstract
Importance Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23-mediated hypophosphatemia. Objective To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose. Design, Setting, and Participants Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B. Interventions Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7. Main Outcomes and Measures The primary end point was the incidence of hypophosphatemia (serum phosphate level <2.0 mg/dL) between baseline and day 35. Results In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, -67.0% {95% CI, -77.4% to -51.5%}], P < .001; trial B: 8.1% vs 73.7% [adjusted rate difference, -65.8% {95% CI, -76.6% to -49.8%}], P < .001). Beyond hypophosphatemia and increased parathyroid hormone, the most common adverse drug reactions (No./total No.) were nausea (iron isomaltoside: 1/125; ferric carboxymaltose: 8/117) and headache (iron isomaltoside: 4/125; ferric carboxymaltose: 5/117). Conclusions and Relevance In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference. Trial Registration ClinicalTrials.gov Identifiers: NCT03238911 and NCT03237065.
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Affiliation(s)
- Myles Wolf
- Duke Clinical Research Institute, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Janet Rubin
- Division of Endocrinology, Department of Medicine, University of North Carolina at Chapel Hill
| | | | - Michael J. Econs
- Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis
| | - Munro Peacock
- Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis
| | - Erik A. Imel
- Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis
| | - Lars L. Thomsen
- Department of Clinical and Non-clinical Research, Pharmacosmos A/S, Holbæk, Denmark
| | - Thomas O. Carpenter
- Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, Connecticut
| | - Thomas Weber
- Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | | | - Heinz Zoller
- Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria
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Musgrove J, Wolf M. Editorial: awareness and prevention of intravenous iron-induced hypophosphataemia. Aliment Pharmacol Ther 2019; 50:609-610. [PMID: 31414533 DOI: 10.1111/apt.15437] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- John Musgrove
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.,Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
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50
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Detlie TE, Jahnsen J. Editorial: awareness and prevention of intravenous iron-induced hypophosphataemia. Authors' reply. Aliment Pharmacol Ther 2019; 50:610-611. [PMID: 31414537 DOI: 10.1111/apt.15443] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Trond Espen Detlie
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jørgen Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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