Intravenous Iron Carboxymaltose, Isomaltoside and Oral Iron Sulphate for Postpartum Anemia
Condition: Postpartum Anemia Nos; Iron-deficiency
MeSH terms: Anemia; Anemia, Iron-Deficiency; Iron Deficiencies
Study type: Interventional
Phase: Phase 3

Summary: 
      Anemia affects between 20 and 50 % of women in the postpartum period. It is associated with
      several adverse health consequences, such as impaired physical work capacity, deficits in
      cognitive function and mood, reduced immune function and reduced duration of breastfeeding.
      Postpartum anemia has also been shown to be a major risk factor for postpartum depression and
      to significantly disrupt maternal-infant interactions. Iron deficiency is the principal cause
      of anemia after delivery. Oral iron supplementation with ferrous sulfate has been considered
      the standard of care with blood transfusion reserved for more severe or symptomatic cases. In
      the last decade, two new intravenous iron compounds have been registered for clinical use:
      ferric carboxymaltose (Iroprem®) and iron isomaltoside (Monofer®). No study to date compared
      efficacy of iron carboxymaltose to iron isomaltoside for treatment of postpartum anemia.

      The objective of the study is to compare efficacy of intravenous iron carboxymaltose to
      intravenous iron isomaltoside and oral iron sulphate for treatment of postpartum anemia.
    

Detailed description: 
      RATIONALE Anemia affects between 20 and 50 % of women in the postpartum period. It is
      associated with several adverse health consequences, such as impaired physical work capacity,
      deficits in cognitive function and mood, reduced immune function and reduced duration of
      breastfeeding. Postpartum anemia has also been shown to be a major risk factor for postpartum
      depression and to significantly disrupt maternal-infant interactions.

      Iron deficiency is the principal cause of anemia after delivery. Oral iron supplementation
      with ferrous sulfate has been considered the standard of care with blood transfusion reserved
      for more severe or symptomatic cases. However, efficacy of oral iron is limited by
      gastrointestinal side effects, patient non-adherence as well as prolonged time required to
      treat anemia and replenish body iron stores. Blood transfusion, on the other hand, is
      associated with several hazards, including transfusion of the wrong blood type, infection,
      anaphylaxis and lung injury.

      In last decades, modern formulations of intravenous iron have emerged as safe and effective
      alternatives to oral iron supplementation for iron deficiency anemia management outside
      pregnancy. Several studies have also evaluated efficacy of intravenous iron preparations for
      treatment of postpartum anemia. Westad et al. reported no significant difference in
      hemoglobin levels at 4, 8 and 12 weeks postpartum in women receiving intravenous iron sucrose
      (Venofer®) compared to those receiving oral ferrous sulphate, whereas the total fatigue score
      was significantly improved in the intravenous iron supplementation group at weeks 4, 8 and
      12. In addition, mean serum ferritin value after 4 weeks was significantly higher in the iron
      sucrose group. Several other authors came to similar conclusion, intravenous iron sucrose and
      oral ferrous sulphate were both effective in correcting peripartum anemia, although
      intravenous iron restored stores faster than oral iron.

      In the last decade, two new intravenous iron compounds have been registered for clinical use:
      ferric carboxymaltose (Iroprem®) and iron isomaltoside (Monofer®). These treatments were
      designed to be administered in large doses by rapid intravenous injection. They have been
      demonstrated to be more efficacious than intravenous iron sucrose in patients with
      inflammatory bowel disease and in patients with chronic kidney disease. In the postpartum
      period, ferric carboxymaltose has been compared to oral iron supplements in four randomized
      trials. All reported a faster rise in hemoglobin levels compared to oral ferrous sulphate.
      Pfenninger et al. compared efficacy of intravenous ferric carboxymaltose with iron sucrose
      for the treatment of postpartum anemia in a retrospective cohort study. Both drugs offered
      rapid normalization of hemoglobin levels after delivery with no difference in mean daily
      hemoglobin increase between the groups up to 8 days after treatment. Only one randomized
      study to date compared intravenous ferric carboxylase to intravenous iron sucrose and oral
      ferrous sulphate for treatment of postpartum anemia. Radhod et al. found a significantly
      faster rise in hemoglobin and ferritin levels with ferric carboxylase compared to iron
      sucrose and ferrous sulphate in Indian women presenting with anemia after delivery. This
      study, like most randomized trials on efficacy of various iron treatments, focused solely on
      hematological biomarkers. However, iron deficiency, even without anemia, contributes
      significantly to fatigue experienced by women in the puerperium, and these women may benefit
      from iron supplementation as well. Data on patient reported outcomes associated with
      different iron treatments are, therefore, very much needed. Holm et al. compared the effects
      of single-dose intravenous iron isomaltoside to oral iron supplementation on physical fatigue
      in women after postpartum haemorrhage. They found significant reduction in fatigue within 12
      weeks postpartum in women who received iron isomaltoside. Iron isomaltoside treatment was
      also associated with improved haematological and iron parameters compared to oral ferrous
      sulfate.

      No study to date, however, compared efficacy of iron carboxymaltose to iron isomaltoside for
      treatment of postpartum anemia. The only head-to-head comparison between these two compounds
      merely examined economic aspects of each treatment, showing potential reduction of costs
      associated with the use of iron isomaltoside vs. iron carboxymaltose.

      OBJECTIVE The objective of the study is to compare efficacy of intravenous iron
      carboxymaltose to intravenous iron isomaltoside and oral iron sulphate for treatment of
      postpartum anemia.

      METHODS Single-center, randomized, open-label trial.

      After signed informed consent patients will be allocated randomly in a 1:1:1 fashion into one
      of three groups:

        1. Iron carboxymaltose group. Total dose of intravenous ferric carboxymaltose (Iroprem®)
           needed to correct anemia and replenish iron stores will be calculated using the Ganzoni
           formula modified to include adjustment for baseline iron status: prepregnancy weight in
           kilograms X (15-baseline Hb) X 2.4 + 500. Fifteen is the target Hb in g/dL, 2.4 is a
           unit less conversion constant and 500 is the target iron stores in mg. The maximal dose
           administered in a single day will not exceed 15 mg/kg (current weight) or 1000 mg (for
           participants with body weight > 67 kg). If total calculated dose will exceed 15 mg/kg or
           1000 mg, subsequent doses will be administered weekly until the total calculated dose
           will be reached.

        2. Iron isomaltoside group. Total dose of intravenous iron isomaltoside (Monofer®) needed
           to correct anemia and replenish iron stores will be calculated as described above. The
           maximal dose administered in a single day will not exceed 20 mg/kg (current weight) or
           1500 mg (for participants with body weight > 75 kg). If total calculated dose will
           exceed 20 mg/kg or 1500 mg, subsequent doses will be administered weekly until the total
           calculated dose will be reached.

        3. Iron sulphate group. Participants will receive oral ferrous sulphate (Tardyfer®) 160 mg
           daily for 6 weeks with instruction to take two tablets by mouth once daily 1 hour before
           meal. They will receive no additional iron supplementation.

      The investigators will monitor blood pressure and record adverse events in all patients
      before and after administration of IV iron and ask all patients to report any untoward
      medical event at its onset.
    

Intervention name(s): Iron Carboxymaltose; Iron Isomaltoside; Ferrous sulphate
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Intravenous iron carboxymaltose application; Inravenous iron isomaltoside application; Oral ferrous sulphate application
Intervention MeSH terms: Iron; Iron isomaltoside 1000
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: postpartum anemia; iron deficiency; ferrous sulphate; ferric carboxymaltose; ferric isomaltoside