HiFIT Study : Hip Fracture: Iron and Tranexamic Acid (HiFIT)

HiFIT Study: Interest of Intravenous Iron and Tranexamic Acid to Reduce Transfusion in Hip Fracture Patients

Fractures of the upper end of the femur, called commonly "Hip fractures" are very common, with an incidence of approximately 1.6 million cases per year worldwide. This high incidence is anticipated to grow rapidly in the next decades, driven by population aging. Anemia is very frequent on admission for hip fracture, concerning up to 45% of the patients, with a mean hemoglobin level of 12.5±0.2 g/dl. This high prevalence of anemia together with blood losses, secondary to the fracture itself and surgery are responsible for a high rate of blood transfusion (approximately 40-50% of the patients). However, both anemia and blood transfusion are associated with poor outcome, including increased mortality, length of stay, infection rate etc. In addition, blood is a scarce and expensive resource and its use should be limited as much as possible. There is therefore a need to treat this anemia and/or to prevent the decrease in hemoglobin. For this purpose, intravenous iron has been proposed. Some non-randomized, mainly retrospective, studies have shown that perioperative intravenous iron was able to reduce blood transfusion (i.e. the number of patients transfused and the number of units per patient). Another way to reduce blood transfusion would be to reduce perioperative bleeding. Tranexamic acid has proven to be efficient for this purpose both in trauma patients and in elective surgery patients.The interest for perioperative blood management has recently increased thanks to better recognition of the adverse effects of blood transfusion, better understanding of iron metabolism, new intravenous iron drugs and a renewed interest in former medications (i.e. tranexamic acid). HiFIT study therefore propose a 2X2 factorial design for this study in order to answer questions vis-à-vis the interest of iron and tranexamic acid to reduce blood transfusion in hip fracture patients.

Study Overview

• Status: Terminated
• Conditions: Anemia; Hip Fractures Pathologic
• Intervention / Treatment: Drug: Iron Isomaltoside 1000; Drug: Tranexamic Acid; Drug: Placebos tranexamic acid; Drug: Placebos iron isomaltoside 1000

Detailed Description

Fractures of the upper end of the femur, called commonly "Hip fractures"are very common, with an incidence of approximately 1.6 million cases per year worldwide. This high incidence is anticipated to grow rapidly in the next decades, driven by population aging. Anemia is very frequent on admission for hip fracture, concerning up to 45% of the patients, with a mean hemoglobin level of 12.5±0.2 g/dl. This high prevalence of anemia together with blood losses, secondary to the fracture itself and surgery are responsible for a high rate of blood transfusion (approximately 40-50% of the patients). However, both anemia and blood transfusion are associated with poor outcome, including increased mortality, length of stay, infection rate etc. In addition, blood is a scarce and expensive resource and its use should be limited as much as possible. There is therefore a need to treat this anemia and/or to prevent the decrease in hemoglobin. For this purpose, intravenous iron has been proposed. Some non-randomized, mainly retrospective, studies have shown that perioperative intravenous iron was able to reduce blood transfusion (i.e. the number of patients transfused and the number of units per patient). Indeed, a pooled analysis of 5 studies including 1,361 patients suggests that intravenous iron could reduce perioperative transfusion in hip fracture patients. However, there is no definitive data. Another way to reduce blood transfusion would be to reduce perioperative bleeding. Tranexamic acid has proven to be efficient for this purpose both in trauma patients and in elective surgery patients. However, there are only two randomized studies investigating the interest of tranexamic acid in hip fractures, and they are not conclusive probably owing to a lack of power. In addition, use of intravenous tranexamic acid could be limited in this population of frail patients and topical use of tranexamic acid, notably to prevent the intraoperative bleeding, appear to be an accurate and sure alternative.

Although hip fracture is a very frequent pathology, with a high burden of care, few data are available that focus on the management of perioperative anemia in this context. The interest for perioperative blood management has recently increased thanks to better recognition of the adverse effects of blood transfusion, better understanding of iron metabolism, new intravenous iron drugs and a renewed interest in former medications (i.e. tranexamic acid). hiFIT study therefore propose a 2X2 factorial design for this study in order to answer questions vis-à-vis the interest of iron and tranexamic acid to reduce blood transfusion in hip fracture patients.

• Study Type: Interventional
• Enrollment (Actual): 419
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Angers, France, 49000
    • CHU Angers - DEPARTEMENT D'ANESTHESIE REANIMATION
  • Angers, France, 49000
    • Clinique de L'Anjou- Anesthesie Reanimation
  • Brest, France
    • HIA Clermont-Tonnerre
  • Grenoble, France, 38043
    • Chu Grenoble - Departement D'Anesthesie Reanimation
  • La Roche-sur-Yon, France
    • CHD Vendee
  • Lille, France, 59037
    • CHU Lille
  • Lyon, France, 69002
    • Hospices Civils LYON
  • Lyon, France
    • Ramsay Santé, Clinique de la Sauvegarde
  • Montpellier, France, 34295
    • Chu Montpellier - Departement D'Anesthesie Reanimation
  • Nantes, France, 44093
    • Chu Nantes- Service de Reanimation Chirurgicale
  • Poitiers, France, 86000
    • Chu Poitiers - Service D'Anesthesie Reanimation
  • Rennes, France, 35033
    • Chu Rennes - Service D'Anesthesie Reanimation
  • Villeurbanne, France
    • Medipole

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years,
• Osteoporotic Fractures of the upper end of the femur requiring surgical repair.
• Preoperative hemoglobin between 9.5 and 13 g/dl.
• Patient or relative signed informed consent or inclusion thanks to urgent inclusion procedure

Exclusion Criteria:

• Bone marrow disease or ongoing treatment (such as chemotherapy), which could interfere with bone marrow erythropoiesis,
• Known allergy or counter-indication to iron and/or to tranexamic acid,
• Uncontrolled arterial hypertension,
• Recent iron infusion (within one week),
• Blood transfusion within one week before inclusion or preoperative blood transfusion already scheduled,
• Any patient who cannot be transfused or has refused consent for a blood transfusion,
• Bedridden or very dependent patient (equivalent to GIR 1 or 2 class).
• Non-affiliation to French health care coverage,
• Adult patient protected under the law (guardianship),
• Pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TXA + IIM; The patients randomized to this arm will have iron isomaltoside 1000 and tranexamic acid	Drug: Iron Isomaltoside 1000; Iron Isomaltoside 1000 will be use. Blinding procedure will be put in place for the administration of the treatment; Other Names: monofer; Drug: Tranexamic Acid; Tranexamic acid will be use.; Other Names: exacyl
Experimental: Placebo TXA + IIM; The patients randomized to this arm will have iron isomaltoside 1000 and Placebos tranexamic acid	Drug: Iron Isomaltoside 1000; Iron Isomaltoside 1000 will be use. Blinding procedure will be put in place for the administration of the treatment; Other Names: monofer; Drug: Placebos tranexamic acid; placebo of tranexamic acid correspond to a saline solution.; Other Names: saline serum
Experimental: TXA + Placebo IIM; The patients randomized to this arm will have Placebos iron isomaltoside 1000 and tranexamic acid	Drug: Tranexamic Acid; Tranexamic acid will be use.; Other Names: exacyl; Drug: Placebos iron isomaltoside 1000; placebo of Iron Isomaltoside 1000 correspond to a saline solution. Blinding procedure will be put in place for the administration of this treatment; Other Names: saline serum
Experimental: Placebo TXA + Placebo IIM; The patients randomized to this arm will have Placebos iron isomaltoside 1000 and Placebos tranexamic acid	Drug: Placebos tranexamic acid; placebo of tranexamic acid correspond to a saline solution.; Other Names: saline serum; Drug: Placebos iron isomaltoside 1000; placebo of Iron Isomaltoside 1000 correspond to a saline solution. Blinding procedure will be put in place for the administration of this treatment; Other Names: saline serum

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients who received a blood transfusion during their hospital stay following surgery	Proportion of patients who received a blood transfusion during their hospital stay following surgery	From the day of surgery until hospital discharge (or until day 30 if patient is still hospitalized).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients who received a blood transfusion after surgery	Proportion of patients who received a blood transfusion during the month following surgery (including fresh frozen plasma and platelets)	From the day of surgery until Day 3, Day 7 and Day 30 post surgery.
Number of packed red blood cell units transfused per patient, as well as number of fresh frozen plasma and platelets units	Number of packed red blood cell units transfused per patient, as well as number of fresh frozen plasma and platelets units	Till postoperative Day3, first week posteratively,and till hospital discharge (or one month if patients still hospitalised)
Hemoglobin concentration	Hemoglobin concentration	At inclusion and on days 3, 7 (or hospital discharge if it happens first) and 30.
Proportion of patients with anemia (hemoglobin <12 g/dL in women and <13 g/dL in men)	Proportion of patients with anemia (hemoglobin <12 g/dL in women and <13 g/dL in men)	At inclusion and on days 3, 7, hospital discharge (if it happens before Day 30) and 30.
Reticulocytes count	Reticulocytes count	On days 3, 7 (or hospital discharge if it happens first) and 30 post surgery
Perioperative blood loss (estimated according to a formula based on hematocrit variation).	Perioperative blood loss (estimated according to a formula based on hematocrit variation): (HtD0 - HtD3)*TBV + number of RPBC transfused unit x 200 ml. Ht = Haematocrit, TBV = total blood volume (70 mL/kg in men and 65 mL/kg in women)	During surgery
Post operative Iron deficiency rate	Proportion of patients with Iron deficiency (defined as a ferritin < 100 ng/ml or < 300 ng/ml together with transferrin saturation <20%), measurement of ferritin and transferrin saturation	On Day 7 (or hospital discharge if it happens first) and Day 30.
Number of hospitalization days	Number of hospitalization days	On Day 30 and Day 90 following surgery.
Proportion of patients at home	Proportion of patients returned at home (or at their previous place of living)	On Day 30 and Day 90.
Proportion of patients able to walk a distance of ten feet without assistance	Proportion of patients able to walk a distance of ten feet without assistance	On Day 30 and Day 90
Variation of quality of life	Variation of EQ-5D score	From inclusion to Day 30 and Day 90
Variation of perceived quality of life	Variation of perceived quality of life with a single overall item from PQOL scale	From inclusion to Day 7 (or hospital discharge if it happens first) and Day 90.
Variation of IADL test	Variation of IADL test	From inclusion to Day 90.
Death rate from all causes	Death rate from all causes	From inclusion to Day 90
Rate of adverse events including the following clinical complications: Vascular events, Heart failure; Renal failure; Infectious complications; Anaphylactic reaction; Transfusion-related complications	Rate of adverse events including the following clinical complications: Vascular events, Heart failure; Renal failure; Infectious complications; Anaphylactic reaction; Transfusion-related complications	From inclusion to Day 90

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Strength assessed by the Hand Grip Strength test	Maximum strength of the hand and forearm muscles assessed by the Hand Grip Strength test	On day 7 (or hospital discharge if it happens first)
Muscular fatigability assessed by the Hand Grip Strength test	Muscular fatigability between the first attempt and the third attempt of the Hand Grip Strength test (variation of the maximum strength measured at the first and the third atempt)	On day 7 (or hospital discharge if it happens first)
Level of locomotion and balance assessed by the Timed " Up and Go " test.	Level of locomotion and balance assessed by the Timed " Up and Go " test,	On day 7 (or hospital discharge if it happens first)

Collaborators and Investigators

• Sponsor: University Hospital, Angers
• Investigators: Study Director: Sigismond SL Lasocki, PU-PH, UNIVERSITE HOSPITAL, ANGERS

Publications and helpful links

General Publications

• Lasocki S, Bruckert V, Campfort M, Leger M, Rineau E. Restrictive transfusion targets the heart now! Insight from the REALITY study. Anaesth Crit Care Pain Med. 2021 Apr;40(2):100854. doi: 10.1016/j.accpm.2021.100854. Epub 2021 Mar 27. No abstract available.
• Lasocki S, Loupec T, Parot-Schinkel E, Vielle B, Danguy des Deserts M, Roquilly A, Lahlou-Casulli M, Collange V, Desebbe O, Duchalais A, Drugeon B, Bouzat P, Garrigue D, Mounet B, Hamard F, David JS, Leger M, Rineau E; HiFIT Study Group. Study protocol for a multicentre, 2x2 factorial, randomised, controlled trial evaluating the interest of intravenous iron and tranexamic acid to reduce blood transfusion in hip fracture patients (the HiFIT study). BMJ Open. 2021 Jan 17;11(1):e040273. doi: 10.1136/bmjopen-2020-040273.

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2017
• Primary Completion (Actual): September 16, 2021
• Study Completion (Actual): September 16, 2021

Study Registration Dates

• First Submitted: November 21, 2016
• First Submitted That Met QC Criteria: November 21, 2016
• First Posted (Estimate): November 23, 2016

Study Record Updates

• Last Update Posted (Actual): August 2, 2022
• Last Update Submitted That Met QC Criteria: July 28, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: tranexamic acid; iron isomaltoside
• Additional Relevant MeSH Terms: Wounds and Injuries; Leg Injuries; Femoral Fractures; Hip Injuries; Fractures, Bone; Hip Fractures; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Trace Elements; Micronutrients; Antifibrinolytic Agents; Hemostatics; Coagulants; Hematinics; Tranexamic Acid; Iron isomaltoside 1000; Iron; Ferric Compounds
• Other Study ID Numbers: 49RC16_0014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No