Heart failure causes gastrointestinal malabsorption of iron. This makes oral substitution not useful. Taking oral iron supplements has been tested in a large clinical heart failure study (IRONOUT-HF study), but could not demonstrate any added value. Oral iron supplements have the disadvantage of side effects (constipation, black stools, gastrointestinal discomfort), poor compliance, poor absorption and low efficiency. Heart failure also causes gastrointestinal malabsorption of iron. This makes oral substitution not useful in heart failure patients.

Intravenous administration of iron is very efficient. This allows a high dose of iron to be administered directly into the bloodstream in one or two doses. The iron supply is replenished much faster and more efficiently in this way. With older products there was an increased risk of anaphylaxis. With the currently available medicines this risk has become very low.

Available products:

• Iron carboxymaltose ( Injectafer ).
• Iron derisomaltose ( Monoferric ).

• Rapid normalization of iron concentration in the blood and availability of iron to the tissues: bone marrow (red blood cells), heart muscle, skeletal muscles,...

This results in a:

• Better production of hemoglobin and red blood cells. Correction of any anemia. Improvement of oxygen transport to the tissues.
• Improved cell function by, among other things, improved energy production (better production of myoglobin and improved production of ATP in the mitochondria). Improvement of the function of the myocardium and skeletal muscles.
• Improvement of muscle strength, exercise capacity and endurance.
• Slight improvement in renal function, activation of the RAAS system and of the sympathetic system.

Trials in HFrEF and HFmrEF :

• Iron carboxymaltose ( Injectafer ): FAIR-HF, CONFIRM-HF, IRON-CRT, AFFIRM-HF, HEART-FID,...
• Iron derisomaltose ( Monoferric ): IRONMAN.
  
  There are no studies yet with a direct comparison between the different intravenous iron preparations.

Proven effects:

• Short term (FAIR-HF , CONFIRM-HF ): Decrease in dyspnea on exertion. Improvement in exercise capacity and quality of life.
• In CRT non- responders: mild but significant increase in LVEF and improvement in cardiac function.
• After hospitalization for acute heart failure (AFFIRM-HF, IRONMAN): reduction of hospitalizations for heart failure during the first 6 months after hospitalization.
• Longer term (HEART-FID, IRONMAN): Studies show a trend towards reduction of hard endpoints (heart failure hospitalizations and cardiovascular mortality), but these were just not statistically significant. This is attributed, among other things, to the statistical method used, an impact of the COVID pandemic on the studies, the low event rates in the studies, and the inclusion of too many patients with a low ferritin < 100 mg/dl but a high transferrin saturation (TSAT) of > 20 %. These patients probably do not have a true iron deficiency and therefore benefit little from IV iron. Patients with a TSAT > 20% do not appear to benefit significantly from IV iron. If the data from only patients with a TSAT < 20% were examined, there was a significant reduction in heart failure events and cardiovascular mortality.
  
  The greatest benefit is likely to be seen in patients with HFrEF or HFmrEF and reduced transferrin saturation (TSAT) < 20 %.

In HFpEF there is no proven benefit and no reimbursement for intravenous correction of iron deficiency. IV iron may be considered in these patients in certain cases for other indications: see below.

1) Heart failure with reduced LVEF ( HFrEF ).

Refund has been possible in Belgium since 2021 if the following criteria are met:

• NYHA class II-IV.
• Iron deficiency as defined above.
• LVEF ≤ 40%.
• The iron deficiency was investigated for all potentially treatable/reversible causes.

This reimbursement must be requested electronically by a cardiologist.

So far, no reimbursement is possible in the context of HFmrEF and HFpEF.

2) In addition, in Belgium there is also reimbursement for intravenous iron for:

• Hemo - or peritoneal dialysis.
• Vascular malformation.
• Crohn 's disease or ulcerative colitis where one of the following two conditions is met:
  • Hemoglobin level dropped below 10.5 g/dL.
  • Failure of oral iron therapy for at least 2 months but with increased ferritin levels on oral iron therapy but signs of chronic active disease persisting.
• Anemia due to proven and documented iron malabsorption.
• Intolerance to oral iron therapy and persistent anemia (2 determinations with a minimum interval of 1 month show a hemoglobin < 8 g/dl).
• Anemia observed during pregnancy with a confirmed decreased value of hemoglobin below or equal to 9 g/dl, in case of impossibility of peroral correction of this anemia.

3) And also for the treatment of preoperative iron deficiency anemia in patients > 14 years of age undergoing major or complex surgery and who meet all of the following conditions:

• Established risk of blood loss > 500 ml during the procedure or a risk of blood transfusion > 10%.
• The diagnosis of iron deficiency anemia in which the prescribing specialist physician bases himself on too low biological values of hemoglobin, serum ferritin , transferrin saturation and, if necessary, too high biological values of C-reactive protein (CRP):
  • Hb < 13 g/ dL.
  • And serum ferritin < 100 mg/dl and transferrin saturation (TSAT) < 20% or CRP > 5 mg/L.
  • Or serum ferritin > 100 mg/dl and TSAT <20% or CRP > 5 mg/L.
• These biochemical tests for anemia were performed no more than 6 weeks before the planned procedure.

Paravenous administration should be avoided. This may locally cause a long-lasting brown discoloration of the skin.

Little to none.

If side effects do occur, they are usually mild and transient.

• Allergic reaction: rare. Possible symptoms: skin rash (e.g. urticaria), itching, dyspnea, wheezing and/or angioedema of the lips, tongue, throat or entire body. In very rare cases anaphylaxis with hypotension and shock. The risk is higher in patients with known allergies, a history of severe asthma, eczema or other atopic allergy, in patients with immune or inflammatory disorders (e.g. systemic lupus erythematosus, rheumatoid arthritis).
• Headache.
• Dizziness.
• Redness in the face.
• Increased blood pressure.
• Nausea.

Especially with iron carboxymaltose ( Injectafer ) there is an increased risk of hypophosphatemia, especially after more than 1 administration. This can then last for weeks. If more pronounced this can cause symptoms of fatigue, muscle cramps or pains, constipation, nausea, bone pain or osteomalacia (with increased risk of fractures).