HiFIT Study : Hip Fracture: Iron and Tranexamic Acid

Study Overview
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Brief Summary
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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.

Detailed Description
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Fractures of the upper end of the femur, called commonly Hip fracturesare 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.

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

Conditions
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Hip Fractures Pathologic, Anemia

Intervention / Treatment
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* Drug: Iron Isomaltoside 1000
* Drug: Tranexamic Acid
* Drug: Placebos iron isomaltoside 1000
* Drug: Placebos tranexamic acid


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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iron isomaltoside, tranexamic acid