Approach

Treatment for IDA includes oral or intravenous iron replacement therapy. Iron replacement therapy should continue after normalisation of haematological parameters to replenish bodily iron stores.

Blood transfusion may be required in patients with symptoms of cardiovascular compromise (e.g., dyspnoea at rest, chest pain, or lightheadedness).

Oral iron replacement therapy

Initial treatment is daily oral iron replacement therapy (e.g., ferrous sulfate, ferrous gluconate, or ferric maltol). Ferrous iron salts have better bioavailability and absorption compared with ferric iron salts.[112]

There is evidence to suggest that oral iron supplementation administered as a single dose on alternate days (e.g., Monday, Wednesday, and Friday) may optimise iron absorption and offer more convenient dosing compared with daily oral iron supplementation.[113][114][115]

Absorption of non-haem iron in plants and dairy requires acid for digestion. Absorption is enhanced by ascorbic acid (vitamin C) and meat, and inhibited by calcium, fibre, tea, coffee, and wine.[23]

Concomitant use of antacids containing sodium bicarbonate or calcium carbonate reduces iron absorption.[116] H2 antagonists impair acid secretion throughout the entire time that the H2 antagonist is active. Drugs and supplements that can interfere with iron absorption when given at the same time as iron supplements include colestyramine, colestipol, neomycin, fluoroquinolone antibiotics, tetracycline antibiotics, calcium, magnesium, manganese, and zinc.

A full blood count and reticulocyte count should be monitored during treatment. The reticulocyte count should peak at 1 to 2 weeks; haemoglobin should show improvement at 3 to 4 weeks (by 20 g/L [2 g/dL]), with normalisation of haemoglobin after 2 to 4 months, and replacement of iron stores after 6 months.[4]

Treatment failure with oral iron

Up to 10% of patients may have gastrointestinal intolerance to oral iron. Alternative options for these patients include switching to a formulation with lower levels of elemental iron, taking a liquid formulation, taking pills with food (although this will decrease absorption), or switching to intravenous iron.

Patients not responding to oral iron, or who are intolerant of oral iron, can be considered for intravenous iron replacement. Results from an analysis of five trials suggest that patients should be transitioned from oral iron to intravenous iron if haemoglobin response with oral iron is <10.0 g/L (<1.0 g/dL) at day 14.[117]

Compared with oral iron, intravenous iron appears to be more effective for the treatment of IDA related to malignancy, inflammatory bowel disease, and possibly heart failure.[118][119][120][121][122][123][124][125]

Supplemental intravenous iron is not beneficial in anaemic critically ill trauma patients; therefore, routine intravenous iron supplementation is not recommended in these patients.[126]

Intravenous iron replacement therapy

Intravenous iron should be considered as a first-line treatment for selected patients with inflammatory bowel disease, including those with active disease or previous intolerance of oral iron.[127]

Weekly low-dose iron in haemodialysis patients (even if iron-replete) may stabilise iron and haemoglobin levels, and allow for erythropoietin dose reduction.[128] One systematic review and meta-analysis found low certainty evidence that intravenous iron, compared with oral iron, increases the number of patients with chronic kidney disease who achieve target haemoglobin, and reduces the requirement for erythropoiesis stimulating agents.[129]

Intravenous iron increases the response to erythropoiesis stimulating agents in patients with cancer and chemotherapy-related anaemia.[125]

Failure to respond to intravenous iron should lead to an investigation for ongoing blood loss and a questioning of the diagnosis. The diagnosis of IDA or recurrent IDA must be followed by an evaluation to determine the underlying cause.[130]

Choice of intravenous iron preparation

Several intravenous iron preparations are available. One preparation has not been found to be more efficacious than the other.[131][132][133][134]

Iron dextran:

  • Only available as a low-molecular-weight preparation.[135]

  • Adverse effects include anaphylaxis, arthralgias, and myalgias.[136][137][138] The risk of adverse effects may be lower with newer intravenous iron preparations compared with iron dextran.[139][140][141][142][143][144]

  • In one study, use of intravenous methylprednisolone before and after total dose infusion of iron dextran decreased the risk of arthralgias and myalgias dramatically.[137]

  • Patients who are intolerant of iron dextran can be considered for treatment with newer intravenous iron preparations.

Iron sucrose:

  • Has a similar safety profile to iron dextran.[145]

  • Retrospective data suggest that initial administration of iron sucrose may be associated with reduced incidence of anaphylaxis compared with iron dextran (1.2 cases per 10,000 first administrations vs. 9.8 cases, respectively)[138]

  • It appears to be safe during pregnancy, and has been shown to be more efficacious than oral iron.[146][147][148][149] In women with postnatal anaemia, iron sucrose may provide a more rapid response than oral iron.[150]

Sodium ferric gluconate complex:

  • Has a superior safety profile compared with iron dextran.[143]

  • Retrospective data suggest that initial administration of ferric gluconate may be associated with reduced incidence of anaphylaxis compared with iron dextran (1.5 cases per 10,000 first administrations vs. 9.8 cases, respectively)[138]

Ferumoxytol:

  • Has a more convenient dosing schedule than iron dextran and iron sucrose.

  • Ferumoxytol has similar efficacy and safety compared with iron sucrose and ferric carboxymaltose.[132][133][151]

  • Retrospective data suggest that initial administration of ferumoxytol may be associated with increased incidence of anaphylaxis (4 cases per 10,000 first administrations) compared with iron sucrose (1.2 cases) or ferric carboxymaltose (0.8 cases), respectively.[138]

  • Ferumoxytol is safe to use in patients with chronic kidney disease, but if haemodialysis is required, it should be given >1 hour after haemodialysis when blood pressure has stabilised.[152]

Ferric carboxymaltose:

  • Superior safety and efficacy compared with oral iron.[134][153] Retrospective data suggest low risk for anaphylaxis (0.8 cases per 10,000 first administrations).[138]

  • Ferric carboxymaltose is better tolerated and more effective than other intravenous iron preparations at treating IDA in patients with inflammatory bowel disease.[154]

  • Its use in systolic heart failure patients with iron deficiency may reduce recurrent cardiovascular hospitalisations.[155] In one randomised placebo-controlled study of patients with iron deficiency and persistently reduced left ventricular ejection fraction, treatment with ferric carboxymaltose resulted in improved cardiac function.[156]

  • In women with postnatal anaemia, use of ferric carboxymaltose may restore haemoglobin and ferritin levels faster than other intravenous iron preparations.[157]

Ferric derisomaltose:

  • Can be given as a single infusion; therefore, dosing is more convenient than other preparations.

  • Superior efficacy and faster acting than iron sucrose, with a similar safety profile.[158][159]

  • In one study, the likelihood of hypersensitivity reactions was 3.4 times higher with ferric derisomaltose compared with ferric carboxymaltose.[160]

Adverse effects of intravenous iron

Use of intravenous iron is associated with anaphylaxis, which can be life threatening.[143][161] One retrospective cohort study reported the following anaphylaxis incidence rates per 10,000 first administrations:[138]

  • 9.8 cases for iron dextran

  • 4.0 cases for ferumoxytol

  • 1.5 cases for ferric gluconate

  • 1.2 cases for iron sucrose, and

  • 0.8 cases for ferric carboxymaltose.

A test dose can be carried out, although this is not recommended in some countries as allergic reactions may still occur in patients who have not reacted to a test dose.[162]

Intravenous iron should be administered in settings where appropriately trained staff and resuscitation facilities are available to manage allergic reactions.[161] Patients should be closely monitored for signs of allergy during and after every administration.[161] Infection- and cardiovascular-related adverse events have also been reported with intravenous iron.[163][164]

Ferric carboxymaltose and ferric derisomaltose are both associated with transient hypophosphataemia; it is significantly more common with the former.[165][166] Muscle fatigue and osteomalacia have been reported in patients treated with ferric carboxymaltose.[167][168]

Red cell transfusion

Patients with symptoms of cardiovascular compromise (e.g., dyspnoea at rest, chest pain, or lightheadedness) can be given red cell transfusions, but caution should be used to avoid replacing red cells too quickly (which may lead to volume overload).[96] Red cell transfusion provides the patient with only approximately 250 mg of elemental iron per unit (enough to raise the haemoglobin by 1 gram) and so further iron replacement is required even after blood transfusion. Intravenous iron replacement in patients with heart failure and iron deficiency (with or without anaemia) has been shown to improve symptoms, functional capacity, and quality of life.[141]

Serious hazards of transfusion include infectious disease transmission, acute and delayed transfusion reactions, post-transfusion purpura, transfusion-associated graft-versus-host disease, and transfusion-related acute lung injury.[169]

Transfusion is not indicated in patients with cardiac compromise who are asymptomatic at rest and on exertion. Rest and treatment of anaemia are advised.

Pregnancy and postpartum

Initial treatment is daily supplementation with ferrous iron salts.[61] In women with twin pregnancy and IDA, doubling the dose of iron may provide benefit without causing gastrointestinal adverse effects.[170] Intravenous iron may be considered in pregnancy during the second or third trimester if the patient is unresponsive to, or intolerant of, oral iron, but it should be avoided in the first trimester.[61][171]

Women diagnosed with IDA postnatallly who are haemodynamically stable should be offered daily oral iron supplementation. In women with severe postnatal anaemia, adding intravenous iron (e.g., iron sucrose) to oral iron does not provide additional benefits compared with oral iron alone.[172] Guidelines advise considering the use of intravenous iron postpartum for women who have previously been intolerant of, or unresponsive to, oral iron, and/or when symptoms of anaemia require prompt management.[61]

Patients undergoing surgery

Major, non-urgent surgery should be deferred to allow for the treatment of IDA.[71] Treatment with oral iron should be started as soon as possible.

Intravenous iron may be considered before or after surgery when patients have IDA and:[173]

  • are unable to tolerate, absorb, or adhere to oral iron

  • have functional iron deficiency (are unable to mobilise stored iron quickly or effectively enough to support erythropoiesis)

  • the predicted interval between diagnosis of anaemia and surgery is too short for oral iron to be effective.

The target haemoglobin preoperatively is 130 g/dL (13 g/dL) for males and females.[71] One randomised controlled trial found that a single dose of ferric carboxymaltose, administered to patients with anaemia 10 to 42 days before elective major abdominal surgery, did not reduce the need for transfusion compared with placebo.[174] One prospective randomised trial compared treatment of postoperative IDA using ferric carboxymaltose with standard care. Patients treated with ferric carboxymaltose had significantly higher haemoglobin concentration and decreased transfusion requirements at 4 weeks.[175]

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