Iron Supplementation in Upper Non-variceal Gastrointestinal Bleeding

Official title

Intravenous Ferric Carboxymaltose Versus Oral Ferrous Sulfate Replacement in Anaemia Due to Acute Nonvariceal Gastrointestinal Bleeding (FIERCE): Protocol of a Multicentre Randomised Controlled Trial

Overview

Anemia is a frequent complication of gastrointestinal bleeding, affecting 61% of the patients. Currently, anemia caused by gastrointestinal bleeding can be treated with iron supplementation. However, the dose and route of the administration are still a question. The FIERCE clinical trial aims to compare the effect of intravenous iron supplementation and oral iron replacement on mortality, unplanned emergency visits, and hospital readmissions in multimorbid patients with acute nonvariceal gastrointestinal bleeding.

Detailed description

In gastrointestinal bleeding (GIB) iron deficiency anemia (IDA) is a common complication, affecting more than 60% of the patients. There are two pillars of the treatment of acute GIB. First, the bleeding point needs identification and endoscopic treatment. Second, the resulting hypovolemia and anemia require fluid resuscitation, transfusion, and replacement of the lost iron. There are two simple ways to manage IDA after acute GIB. Patients either have intravenous (IV) iron infusions one to six times as part of their hospital treatment or receive three months of oral iron supplementation. There is a gap in current guidelines on which approach clinicians should choose.

Here the investigators plan a multicentric, two-arm, randomized controlled trial, to compare the efficacy of oral and intravenous iron supplementation in multimorbid patients with acute nonvariceal gastrointestinal bleeding. Patients will be randomly allocated in a 1:1 ratio to two groups. Group A will receive one dose of 1000 mg of IV ferric carboxymaltose on the day of randomization, while iron supplementation for group B will be performed with one ferrous sulfate tablet every day (ca. 200-300 mg) for three months. The primary outcome will be the composite outcome of all-cause mortality, unplanned emergency visit, and unplanned hospital readmission within six months after enrollment.

In the first phase, the investigators plan to recruit 15 patients on each arm to assess the proportion of the primary outcome in the two groups. In the second phase, a sample size calculation for the primary outcome will be performed based on the results of the first phase.

Interventions

• Drug Oral iron supplementation
  Ca. 200-300 mg of ferrous sulfate will be administered orally every day for 3 months.
• Drug Intravenous iron supplementation
  One dose of intravenous 1000 mg ferric carboxymaltose will be administered on the day of randomization.

Primary outcome measures

• Composite outcome [Time frame: 3 months]

Secondary outcome measures (12)

• All-cause mortality [Time frame: 1, and 3 months]
• Unplanned emergency visits [Time frame: 1, and 3 months]
• Unplanned hospital admission [Time frame: 1, and 3 months]
• Quality of life using the 36-Item Short-Form Health Survey [Time frame: 1, and 3 months +/- 7 days]
• Quality of life using the EuroQol five-dimensions - 5 levels questionnare [Time frame: 1, and 3 months +/- 7 days]
• Gait speed [Time frame: 1, and 3 months +/- 7 days]
• Six-Minute Walk Test (6MWT) [Time frame: 1, and 3 months +/- 7 days]
• Handgrip strength [Time frame: 1, and 3 months +/- 7 days]
• Normalization of the haemoglobin level [Time frame: 1, and 3 months +/- 7 days]
• Change in Hb level [Time frame: 1, and 3 months +/- 7 days]
• Change in haematocrit [Time frame: 1, and 3 months +/- 7 days]
• Change in serum iron level [Time frame: 1, and 3 months +/- 7 days]

Eligibility criteria

Inclusion criteria

• age ≥ 65 years;
• endoscopically proven acute nonvariceal GIB source;
• 48 hours after the endoscopic diagnosis and/or treatment;
• hemodynamically stable;
• the discharge of the patient is planned;
• hemoglobin level <10 g/dl on the day of randomisation;
• 24 hours after the last transfusion and no need for further transfusion;
• signed informed consent.

Exclusion criteria

• known hypersensitivity to iron products (mild side effects excluded);
• previous diagnosis of iron overload \[e.g., transferrin receptor saturation (TSAT) >50%, ferritin> 160 for women ng/ml, ferritin >270 ng/ml for men) or disorders of iron utilisation;
• pregnancy or breast feeding;
• diagnosis of iron malabsorption (at discretion of the attending clinician; e.g., severe inflammatory bowel disease, active celiac disease);
• chronic end stage diseases (chronic heart failure-New York Heart Association Classification class 4, chronic kidney disease (eGFR <30 mL/min/1.73 m2) with or without dialysis, liver cirrhosis with Child Pugh C score, chronic kidney disease with dialysis, chronic obstructive pulmonary disease stage 4, chronic inflammatory disease, malignancies, AIDS);
• active malignancies;
• liver cirrhosis with known varices at high risk of bleeding - endoscopic features of high risk of variceal bleeding or liver stiffness measured by transient elastography >20 kiloPascal and platelet count <150 × 10\^9 cells/L;
• gastrointestinal tract malignancies with high risk of gastrointestinal bleeding;
• high risk of poor compliance or no fixed abode;
• myelo- or lymphoproliferative diseases;
• anemia not attributable to iron deficiency (sideroblastic anaemia, aplastic anaemia, haemolytic anaemia, thalassaemia, B12 vitamin or folic acid deficiency or combination of these with IDA);
• primary coagulation disorders (e.g. Glanzmann thrombasthenia, Von Willebrand disease, Haemophylia A, Haemophylia B);
• the patient will be transferred to another institute after discharge (e.g. hospital, senior care center);
• Eastern Cooperative Oncology Group (ECOG) Performance Status >2.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Hungary · 1 center

• Institute for Translational Medicine, University of Pécs — Pécs

Publications

• McNutt MK, Bradford M, Drazen JM, Hanson B, Howard B, Jamieson KH, Kiermer V, Marcus E, Pope BK, Schekman R, Swaminathan S, Stang PJ, Verma IM. Transparency in authors' contributions and responsibilities to promote integrity in scientific publication. Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):2557-2560. doi: 10.1073/pnas.1715374115. Epub 2018 Feb 27. PMID 29487213
• McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B. Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993-2005. Public Health Nutr. 2009 Apr;12(4):444-54. doi: 10.1017/S1368980008002401. Epub 2008 May 23. PMID 18498676
• Ferrer-Barcelo L, Sanchis Artero L, Sempere Garcia-Arguelles J, Canelles Gamir P, P Gisbert J, Ferrer-Arranz LM, Monzo Gallego A, Plana Campos L, Huguet Malaves JM, Lujan Sanchis M, Ruiz Sanchez L, Barcelo Cerda S, Medina Chulia E. Randomised clinical trial: intravenous vs oral iron for the treatment of anaemia after acute gastrointestinal bleeding. Aliment Pharmacol Ther. 2019 Aug;50(3):258-268. PMID 31197861
• Bager P, Dahlerup JF. Randomised clinical trial: oral vs. intravenous iron after upper gastrointestinal haemorrhage--a placebo-controlled study. Aliment Pharmacol Ther. 2014 Jan;39(2):176-87. doi: 10.1111/apt.12556. Epub 2013 Nov 19. PMID 24251969
• Tolkien Z, Stecher L, Mander AP, Pereira DI, Powell JJ. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One. 2015 Feb 20;10(2):e0117383. doi: 10.1371/journal.pone.0117383. eCollection 2015. PMID 25700159
• Sultan P, Bampoe S, Shah R, Guo N, Estes J, Stave C, Goodnough LT, Halpern S, Butwick AJ. Oral vs intravenous iron therapy for postpartum anemia: a systematic review and meta-analysis. Am J Obstet Gynecol. 2019 Jul;221(1):19-29.e3. doi: 10.1016/j.ajog.2018.12.016. Epub 2018 Dec 19. PMID 30578747
• Cotter J, Baldaia C, Ferreira M, Macedo G, Pedroto I. Diagnosis and treatment of iron-deficiency anemia in gastrointestinal bleeding: A systematic review. World J Gastroenterol. 2020 Dec 7;26(45):7242-7257. doi: 10.3748/wjg.v26.i45.7242. PMID 33362380
• Teutsch B, Vancsa S, Farkas N, Szakacs Z, Vorhendi N, Boros E, Szabo I, Hagendorn R, Alizadeh H, Hegyi P, Eross B. Intravenous ferric carboxymaltose versus oral ferrous sulfate replacement in elderly patients after acute non-variceal gastrointestinal bleeding (FIERCE): protocol of a multicentre, open-label, randomised controlled trial. BMJ Open. 2023 Mar 14;13(3):e063554. doi: 10.1136/bmjopen-2022 PMID 36918236

Identifiers

NCT: NCT05060731 · 46395-5/2021/EÜIG

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗