Intravenous Iron Therapy

Number: 0575

  1. Aetna considers intravenous iron therapy medically necessary for any of the following indications:

    1. For members needing iron supplementation who are unable to tolerate compounds given orally; or
    2. For members who are losing iron (blood) at a rate too rapid for oral intake to compensate for the loss; or 
    3. For members with a disorder of the gastrointestinal tract, such as inflammatory bowel disease (ulcerative colitis and Crohn's disease), in which symptoms may be aggravated by oral iron therapy; or 
    4. For members who are unable to maintain iron balance on treatment with hemodialysis (Note: Venofer, an iron sucrose injection, and Ferrlecit, a sodium ferric gluconate complex in sucrose injection, are indicated for the treatment of iron deficiency anemia (IDA) in members undergoing chronic hemodialysis who are receiving supplemental erythropoietin/epoetin therapy; or 
    5. For members with IDA associated with peritoneal dialysis and non-dialysis-dependent (NDD) chronic kidney disease (Note: Venofer [iron sucrose] and Feraheme [ferumoxytol] are indicated for such use, not Ferrlecit [sodium ferric gluconate]); or 
    6. For members who are donating large amounts of blood for autologous programs; or 
    7. For members who repeatedly fail to heed instructions for oral iron supplementation or are incapable of accepting or following them; or
    8. For members with chemotherapy-induced anemia; or
    9. For members with heart failure and iron deficiency, with or without anemia; or
    10. For members with IDA due to heavy uterine bleeding; or
    11. For members with iron deficiency following gastric bypass surgery and/or subtotal gastric resection and who exhibited decreased absorption of oral iron.
  2. Aetna considers intravenous iron therapy experimental and investigational for all other indications including the following (not an all-inclusive list) because its clinical value for these indications has not been established.

    1. Anemia of pregnancy who do not meet criteria above
    2. Post-partum anemia
    3. Restless legs syndrome
  3. Aetna considers pre-operative intravenous iron therapy experimental and investigational for reduction in need for transfusions from major surgery because the effectiveness of this approach has not been established.

See also CPB 0195 - Erythropoiesis Stimulating Agents


The established indications for intravenous iron therapy were adapted from Wintrobe's Clinical Hematology (1999).  Parenteral iron therapy is as effective but somewhat more dangerous and considerably more expensive than oral therapy.  Nevertheless, failure of oral therapy is to be expected in certain clinical situations.  According to Wintrobe's Clinical Hematology, a history of failure to respond to oral iron, however, is not by itself an indication for parenteral therapy.  The reasons for failure must be analyzed.

The most common use for intravenous iron is in hemodialysis patients.  According to guidelines from the National Kidney Foundation (NKF), a trial of oral iron is acceptable in the hemodialysis patient, but is unlikely to maintain adequate iron balance.  The NKF guidelines state that, to achieve and maintain an hemoglobin level of 11 to 12 g/dL (hematocrit of 33 % to 36 %), most hemodialysis patients will require intravenous iron on a regular basis.  The NKF guideline summary states:

Iron is essential for hemoglobin (Hb) formation, as is erythropoietin (EPO).  Several important issues related to iron deficiency and its management in the patients with chronic kidney disease (CKD), particularly in patients receiving epoetin therapy should be considered:

  1. Iron (blood) losses are high, particularly in the hemodialysis patient.
  2. Oral iron usually can not maintain adequate iron stores, particularly in the hemodialysis patient treated with ESAs.
  3. ESAs, by stimulating erythropoiesis to greater than normal levels, often leads to functional iron deficiency.
  4. Prevention of functional (and absolute) iron deficiency by regular use of intravenous iron (i.e., small doses, weekly, to replace predicted blood losses) improves erythropoiesis.
  5. The serum iron, total iron binding capacity, and serum ferritin are the best indicators of iron available for erythropoiesis and iron stores, but they do not provide absolute criteria for either iron deficiency or iron overload.

    These guidelines suggest that the regular use of small doses of intravenous (IV) iron, particularly in the hemodialysis patient, will prevent iron deficiency and promote better erythropoiesis than can oral iron therapy.

  6. Prior to July 1999, the only IV iron preparation available in the United States was iron dextran.  The doses recommended for iron dextran are detailed in these Guidelines.  Since July 1999, iron gluconate and iron sucrose have become available for IV use in the United States.  Since the amount of iron gluconate per vial differs from that of iron dextran, the Work Group recommends that the substitution of iron gluconate for iron dextran would be 8 doses of 125 mg of iron gluconate (over 8 weeks per quarter), or 8 doses of 62.5 mg of iron gluconate over 8 weeks instead of 10 doses of 50 mg of iron dextran over 10 weeks.  Doses of iron gluconate larger than 125 mg given at one time are not recommended by the manufacturer, whereas iron dextran, although not FDA-approved for doses greater than 100 mg, can be given at one time at doses of 250, 500, and/or 1,000 mg doses, if indicated.  Iron sucrose can be given in doses of 100 mg or less.

  7. Since the amount of iron sucrose per vial differs from that of iron dextran, the Work Group recommends that the substitution of iron sucrose for iron dextran would be 5 doses of 200 mg of iron sucrose (over 4 weeks per quarter), or 5 doses of 200 mg of iron sucrose over 4 weeks instead of 10 doses of 100 mg of iron dextran over 10 weeks.

  8. Venofer, (iron sucrose, USP) can be given in doses of 100 mg undiluted as a slow intravenous injection over 2 to 5 mins, or as an infusion of 100 mg diluted in 100 ml of 0.9 % NaCl or as a 200 mg undiluted as a slow intravenous injection over 2 to 5 mins on 5 different occasions for CKD patients.  There is limited experience with administration of 500 mg of Venofer diluted in a maximum of 250 ml of 0.9 % NaCl over a period of 3.4 to 4 hours on day 1 and 14.  In peritoneal dialysis, administer Venofer in 3 divided doses, given by slow intravenous infusion over a 28-day period: 2 infusions each of 300 mg over 1.5 hours; 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later.  Dilute Venofer in a maximum of 250 ml of 0.9 % NaCl.

Routine supplementation with IV iron usually results in higher hemoglobin and hematocrit values or a decrease in epoetin requirements in patients with anemia and chronic kidney disease.  Morbidity and mortality decrease in epoetin-treated patients with chronic renal failure as the anemia improves.

In a randomized controlled study (n = 120), Madi-Jabera et al (2004) reported that post-operative IV iron supplementation alone or in combination with a single dose of recombinant-human EPO (300 U/kg) is not effective in correcting anemia after cardiac surgery.  A Cochrane review (Dodd et al, 2004) concluded that there is some limited evidence of favorable outcomes for treatment of post-partum anemia with EPO.  Additionally, these authors stated that further high-quality trials assessing the treatment of post-partum anemia with iron supplementation (e.g., IV administration of iron) and blood transfusions are needed.

In a prospective study, Cuenca and associates (2005) examined the effect of pre-operative IV 200 to 300 mg (n = 20) iron sucrose on allogeneic blood transfusion (ABT) requirements and post-operative morbid-mortality in patients undergoing surgery for displaced subcapital hip fracture (DSHF) repair.  A previous series of 57 DSHF patients served as the control group.  All patients were older than 65 years, were operated on the 3rd day after admission to the hospital, by the same medical team, and using the same implant.  Age, gender, American Society of Anesthesiologists classification, surgical procedure, peri-operative hemoglobin, requirements for ABT, post-operative infection, length of hospital stay (LOS) and 30-day mortality rate were examined.  No adverse reactions to the iron administration were observed.  The iron group had a lower transfusion rate (15 % versus 36.8 %), lower transfusion index (0.26 versus 0.77 units per patient), lower 30-day mortality rate (0 versus 19.3 %), shorter LOS (11.9 versus 14.1 days), as well as a trend to a lower post-operative infection rate (15 % versus 33 %).  These researchers concluded that pre-operative parenteral iron administration could be a safe and effective way to reduce the ABT requirements in DSHF patients.  This reduction in the ABT requirements is accompanied by a reduction in the morbid-mortality rate and LOS.  Moreover, the authors noted that a large, randomized, controlled trial to confirm these results is warranted.

In a pilot study, Munoz et al (2006) examined the effect of post-operative administration of 300 mg of IV iron sucrose on ABT requirements in patients undergoing total hip replacement (THR ) (n = 24).  A previous series of 22 THR patients served as the control group.  All patients were operated on by the same surgeon, using the same implant, and a set of clinical data was gathered.  No adverse reactions to iron administration were observed.  The group given iron showed a trend to a lower transfusion rate (46 % versus 73 %; p = 0.067), and lower transfusion index (0.96 versus 1.68 units/patient; p = 0.038).  Moreover, among the non-transfused patients, admission hemoglobin levels were lower in those coming from the iron group than those from the control group (12.7 +/- 0.9 versus 14.0 +/- 1.2 g dL(-1), respectively; p = 0.017).  The authors noted that post-operative parenteral iron administration could be a safe and effective way to reduce ABT requirements in the THR patients.  However, a large, randomized, controlled trial is needed to confirm these results.

A Cochrane review on treatments for iron-deficiency anemia during pregnancy stated that despite the high incidence and burden of disease associated with this condition, there is a paucity of good quality studies evaluating clinical maternal and neonatal effects of iron administration in pregnant women with anemia.  Daily oral iron therapy improves hematological indices but is associated with gastrointestinal adverse effects.  Intramuscular and IV iron therapy enhances hematological response, compared with oral iron, but there are concerns regarding possible important adverse effects.  The authors noted that large, good quality studies that evaluate clinical outcomes including adverse effects are needed (Reveiz et al, 2007).

Fishbane (2007) stated that iron deficiency has been studied extensively in patients with CKD on hemodialysis.  However, few studies examined iron treatment in the non-dialysis CKD population.  Limited data suggest that iron deficiency is common in patients with CKD with anemia, which can impair the effectiveness of erythropoiesis.  The diagnosis of iron deficiency should entail clinical judgment, with an emphasis on the patient's clinical characteristics because of limited evidence examining the interpretation of iron testing results.  When iron deficiency is diagnosed in non-dialysis patients with CKD, any sources of blood loss must be investigated.  After addressing any blood loss, the preferred route of iron therapy must be ascertained.  To date, no clear advantage has been shown with IV versus oral administration in non-dialysis patients, as shown in the hemodialysis setting.  Thus, oral iron therapy may be a more reasonable option unless oral therapy previously failed.  The author noted that further investigation is needed to support evidence-based guidelines for the treatment of iron deficiency in the non-dialysis CKD population because this population differs from hemodialysis patients in the decreased extent of blood loss.

In an open-label, multi-center study, Henry and colleagues (2007) evaluated the safety and effectiveness of IV sodium ferric gluconate complex (FG), oral ferrous sulfate, or no iron to increase Hb in anemic cancer patients receiving chemotherapy and epoetin alfa.  A total of 187 patients with chemotherapy-induced anemia/CIA (Hb less than 11 g/dL; serum ferritin greater than or equal to 100 ng/ml or transferrin saturation greater than or equal to 15 %) scheduled to receive chemotherapy and epoetin alfa (40,000 U subcutaneously weekly) were randomized to 8 weeks of 125 mg of IV FG weekly, 325 mg of oral ferrous sulfate 3 times daily, or no iron.  The primary outcome was a change in Hb from baseline to endpoint, first whole-blood or red blood cell (RBC) transfusion, or study withdrawal.  A total of 129 patients were evaluable for effectiveness (FG, n = 41; oral iron, n = 44; no iron, n = 44).  Mean increase in Hb was 2.4 g/dL (95 % confidence interval [CI]: 2.1 to 2.7) for FG (p = 0.0092 versus oral iron; p = 0.0044 versus no iron), 1.6 g/dL (95 % CI: 1.1 to 2.1) for oral iron (p = 0.7695 versus no iron), and 1.5 g/dL (95 % CI: 1.1 to 1.9) for no iron.  Hemoglobin response (increase greater than or equal to 2 g/dL) was 73 % for FG (p = 0.0099 versus oral iron; p = 0.0029 versus no iron), 46 % for oral iron (p = 0.6687 versus no iron), and 41 % for no iron.  Intravenous sodium ferric gluconate complex was well-tolerated.  The authors concluded that for cancer patients with CIA receiving epoetin alfa, FG produces a significantly greater increase in Hb and Hb response compared with oral iron or no iron, supporting more aggressive treatment with IV iron supplementation for these patients.

In a randomized, multi-center study, Hedenus and co-workers (2007) assessed if IV iron improves Hb response and permits decreased epoetin dose in anemic (Hb 9 - 11 g/dL), transfusion-independent patients with stainable iron in the bone marrow and lympho-proliferative malignancies not receiving chemotherapy.  Patients (n = 67) were randomized to subcutaneous epoetin beta 30 000 IU once-weekly for 16 weeks with or without concomitant IV iron supplementation.  There was a significantly (p < 0.05) greater increase in mean Hb from week 8 onwards in the iron group and the percentage of patients with Hb increase greater than or equal to 2 g/dL was significantly higher in the iron group (93 %) than in the no-iron group (53 %) (per-protocol population;  p = 0.001).  Higher serum ferritin and transferrin saturation in the iron group indicated that iron availability accounted for the Hb response difference.  The mean weekly patient epoetin dose was significantly lower after 13 weeks of therapy (p = 0.029) and after 15 weeks approximately 10 000 IU (greater than 25 %) lower in the iron group, as was the total epoetin dose (p = 0.051).  The authors concluded that the Hb increase and response rate were significantly greater with the addition of IV iron to epoetin treatment in iron-replete patients and a lower dose of epoetin was required.

Bastit and colleagues (2008) stated that concomitant use of IV iron as a supplement to erythropoiesis-stimulating agents (ESAs) in patients with CIA is controversial.  In a randomized, multi-center study, these investigators assessed safety and effectiveness of darbepoetin alpha given with IV iron versus with local standard practice (oral iron or no iron).  A total of 396 patients with non-myeloid malignancies and Hb less than 11 g/dL received darbepoetin alpha 500 microg with (n = 200) or without (n = 196) IV iron once every 3 weeks (Q3W) for 16 weeks.  The hematopoietic response rate (proportion of patients achieving Hb greater than or equal to 12 g/dL or Hb increase of greater than or equal to 2 g/dL from baseline) was significantly higher in the IV iron group: 86 % versus 73 % in the standard practice group (difference of 13 % [95 % CI: 3 % to 23 %]; p = 0.011).  Fewer RBC transfusions (week 5 to the end of the treatment period) occurred in the IV iron group: 9 % versus 20 % in the standard practice group (difference of -11 % [95 % CI: -18 % to -3 %]; p = 0.005).  Both treatments were well-tolerated with no notable differences in adverse events.  Serious adverse events related to iron occurred in 3 % of patients in the IV iron group and were mostly gastrointestinal in nature.  The authors concluded that addition of IV iron to darbepoetin alpha Q3W in patients with CIA is an important advance in anemia management, allowing more patients to experience the benefit of anemia treatment, with a shorter lag time to response and fewer transfusions.

Pedrazzoli et al (2008) noted that unresponsiveness to ESAs occurring in 30 % to 50 % of patients, is a major limitation to the treatment of CIA.  These researchers prospectively evaluated if IV iron can increase the proportion of patients with CIA who respond to darbepoetin.  A total of 149 patients with lung, gynecological, breast, and colorectal cancers and greater than or equal to 12 weeks of planned chemotherapy were enrolled from 33 institutions.  Patients were required to have Hb less than or equal to 11 g/L and no absolute or functional iron deficiency.  All patients received darbepoetin 150 microg subcutaneously once-weekly for 12 weeks and were randomly assigned to IV FG 125 mg weekly for the first 6 weeks (n = 73) or no iron (n = 76).  Primary end point of the study was the percentage of patients achieving hematopoietic response (Hb greater than or equal to 12 g/dL or greater than or equal to 2 g/dL increase).  Hematopoietic response by intention-to-treat analysis was 76.7 % (95 % CI: 65.4 % to 85.8 %) in the darbepoetin/iron group and 61.8 % (95 % CI: 50.0 % to 72.7 %) in the darbepoetin group (p = 0.0495).  Among patients fulfilling eligibility criteria and having received at least 4 darbepoetin administrations, hematopoietic responses in the darbepoetin/iron group (n = 53) and in the darbepoetin-only group (n = 50) were 92.5 % (95 % CI: 81.8 % to 97.9 %) and 70 % (95 % CI: 55.4 % to 82.1 %), respectively (p = 0.0033).  Increase of Hb during treatment period showed a time profile favoring darbepoetin/iron with statistically significant effect from week 5 on.  The safety profile was comparable in the two arms.  The authors concluded that in patients with CIA and no iron deficiency, IV iron supplementation significantly reduces treatment failures to darbepoetin without additional toxicity.  They stated that based on their findings and those by Henry et al (2007) as well as Hedenus et al (2007), IV iron supplementation should become an integral and routine component of ESA therapy, and should be incorporated into clinical guidelines.

In an editorial that accompanied the studies by Bastit et al as well as Pedrazzoli et al, Auer Bach (2008) stated that IV iron supplementation should be considered a component of the management of anemia of cancer and cancer chemotherapy.  This is in agreement with the observation of Shord et al (2008) who noted that parenteral iron should be administered to patients receiving ESA therapy to improve hematopoietic response.

In a randomized, controlled clinical trial, Seid and colleagues (2008) assessed the safety, effectiveness, and tolerability of IV ferric carboxymaltose and compared with oral ferrous sulfate in women with post-partum anemia.  A total of 291 women less than 10 days after delivery with Hb 10 g/dL or less were randomized to receive ferric carboxymaltose (n = 143) 1,000 mg or less intravenously over 15 mins or less, repeated weekly to a calculated replacement dose (maximum 2,500 mg) or ferrous sulfate (n = 148) 325 mg orally thrice-daily for 6 weeks.  Ferric carboxymaltose-treated subjects were significantly more likely to: (i) achieve a Hb greater than 12 g/dL in a shorter time period with a sustained Hb greater than 12 g/dL at day 42, (ii) achieve Hb rise 3 g/dL or greater more quickly, and (iii) attain higher serum transferrin saturation and ferritin levels.  Drug-related adverse events occurred less frequently with ferric carboxymaltose.  The authors concluded that IV ferric carboxymaltose was safe and well-tolerated with an efficacy superior to oral ferrous sulfate in the treatment of post-partum iron deficiency anemia.

In an open, randomized controlled trial, Westad et al (2008) analyzed the effect of IV ferrous sucrose compared with oral ferrous sulphate on hematological parameters and quality of life in women with post-partum anemia.  A total of 128 post-partum women with hemorrhagic anemia (Hb between 6.5 g/100 ml and 8.5 g/100 ml) were included in this study.  The intervention group (n = 59) received 600 mg iron sucrose intravenously followed by 200 mg iron sulphate daily from week 5.  The control group (n = 70) were given 200 mg iron sulphate daily.  Randomization and start of treatment occurred within 48 hours of the delivery.  Participants were followed-up at 4, 8 and 12 weeks.  Main outcome measures included Hb, ferritin and quality of life assessed with the Medical Outcomes Study Short Form 36 (SF-36) and the Fatigue Scale.  After 4 weeks, the mean Hb values in both groups were similar (11.9 g/100 ml versus 12.3 g/100 ml, p = 0.89).  The mean serum ferritin value after 4 weeks was significantly higher in the intervention group with 13.7 microg/L versus 4.2 microg/L in the control group (p < 0.001).  At 8 and 12 weeks, the hematological parameters were similar.  The total fatigue score was significantly improved in the intervention group at week 4, 8 and 12, whereas SF-36 scores did not differ.  The authors concluded that women who received 600 mg IV iron sucrose followed by standard oral iron after 4 weeks, replenished their iron stores more rapidly and had a more favorable development of the fatigue score indicating improved quality of life.

Guidelines from the American College of Obstetricians and Gynecologists on anemia of pregnancy (ACOG, 2008) stated that parenteral iron is useful in the rare patient who can not tolerate or will not take modest doses or oral iron.  Patients with malabsorption syndrome and severe idon deficiency anemia may benefit from parenteral therapy.  The guidelines note that anaphylactic reactions have been reported in 1 % of patients receiving parenteral iron dextran.  In comparison with patients who take iron dextran, patients who take ferrous sucrose have fewer allergic reactions (8.7 versus 3.3 allergic events per 1 million doses) and a significantly lower fatality rate (31 versus 0, p < 0.001).  The guidelines cited a randomized controlled clinical study by Bhandal and Russell (2006) comparing oral versus IV iron sucrose for post-partum anemia, finding that women treated with IV iron had higher hemoglobin levels in the short-term (on days 5 and 14) but that by day 40, there was no significant difference in the Hb levels of the two groups.  The ACOG guidelines concluded that, in most circumstances, oral iron preparations are appropriate and sufficient.

Beucher and colleagues (2011) evaluated the effectiveness and the safety of prevention and treatment of iron deficiency anemia during pregnancy.  French and English publications were searched using PubMed and Cochrane library.  Early screening of iron deficiency by systematic examination and blood analysis seemed essential.  Maternal and perinatal complications were correlated to the severity and to the mode of appearance of anemia.  Systematic intakes of iron supplements seemed not to be recommended.  In case of anemia during pregnancy, iron supplementation was not associated with a significant reduction in substantive maternal and neonatal outcomes.  Oral iron supplementation increased blood parameters but exposed to digestive side effects.  Women who received parenteral supplementation were more likely to have better hematological response but also severe potential side effects during pregnancy and in post-partum.  The maternal tolerance of anemia motivated the choice between parenteral supplementation and blood transfusion.  The authors concluded that large and methodologically strong trials are needed to evaluate the effects of iron supplementation on maternal health and pregnancy outcomes.

In a randomized, controlled, observer-blinded trial, Okonko et al (2008) tested the hypothesis that IV iron improves exercise tolerance in anemic and non-anemic patients with symptomatic chronic heart failure (CHF) and iron deficiency.  These investigators randomized 35 patients with CHF (age 64 +/- 13 years, peak oxygen consumption [pVO2] 14.0 +/- 2.7 ml/kg/min) to 16 weeks of IV iron (200 mg weekly until ferritin greater than 500 ng/ml, 200 mg monthly thereafter) or no treatment in a 2:1 ratio.  Ferritin was required to be less than 100 ng/ml or ferritin 100 to 300 ng/ml with transferrin saturation less than 20 %.  Patients were stratified according to Hb levels (less than 12.5 g/dl [anemic group] versus 12.5 to 14.5 g/dl [non-anemic group]).  The observer-blinded primary end point was the change in absolute pVO2.  The difference (95 % CI) in the mean changes from baseline to end of study between the iron and control groups was 273 (151 to 396) ng/ml for ferritin (p < 0.0001), 0.1 (-0.8 to 0.9) g/dl for hemoglobin (p = 0.9), 96 (-12 to 205) ml/min for absolute pVO2 (p = 0.08), 2.2 (0.5 to 4.0) ml/kg/min for pVO2/kg (p = 0.01), 60 (-6 to 126) seconds for treadmill exercise duration (p = 0.08), -0.6 (-0.9 to -0.2) for New York Heart Association (NYHA) functional class (p = 0.007), and 1.7 (0.7 to 2.6) for patient global assessment (p = 0.002).  In anemic patients (n = 18), the difference (95 % CI) was 204 (31 to 378) ml/min for absolute pVO2 (p = 0.02), and 3.9 (1.1 to 6.8) ml/kg/min for pVO2/kg (p = 0.01).  In non-anemic patients, NYHA functional class improved (p = 0.06).  Adverse events were similar.  The authors concluded that IV iron loading improved exercise capacity and symptoms in patients with CHF and evidence of abnormal iron metabolism.  Benefits were more evident in anemic patients.

Anker et al (2009) examined if treatment with IV iron (ferric carboxymaltose) would improve symptoms in patients who had heart failure, reduced left ventricular ejection fraction (LVEF), and iron deficiency, either with or without anemia.  These researchers enrolled 459 patients with CHF of NYHA functional class II or III, a LVEF of 40 % or less (for patients with NYHA class II) or 45 % or less (for NYHA class III), iron deficiency (ferritin level less than 100 microg/L or between 100 and 299 microg/L, if the transferrin saturation was less than 20 %), and a Hb level of 95 to 135 g/L.  Patients were randomly assigned, in a 2:1 ratio, to receive 200 mg of IV iron (ferric carboxymaltose) or saline (placebo).  The primary end points were the self-reported Patient Global Assessment and NYHA functional class, both at week 24.  Secondary end points included the distance walked in 6 minutes and the health-related quality of life.  Among the patients receiving ferric carboxymaltose, 50 % reported being much or moderately improved, as compared with 28 % of patients receiving placebo, according to the Patient Global Assessment (odds ratio for improvement, 2.51; 95 % CI: 1.75 to 3.61).  Among the patients assigned to ferric carboxymaltose, 47 % had an NYHA functional class I or II at week 24, as compared with 30 % of patients assigned to placebo (odds ratio for improvement by one class, 2.40; 95 % CI: 1.55 to 3.71).  Results were similar in patients with anemia and those without anemia.  Significant improvements were seen with ferric carboxymaltose in the distance on the 6-minute walk test and quality-of-life assessments.  The rates of death, adverse events, and serious adverse events were similar in the two study groups.  The authors concluded that treatment with IV ferric carboxymaltose in patients with CHF and iron deficiency, with or without anemia, improves symptoms, functional capacity, and quality of life; the side-effect profile was acceptable.

In a randomized, controlled trial, Van Wyck and colleagues (2009) assessed the safety and effectiveness of rapid, large-dose IV administration of ferric carboxymaltose compared to oral iron in correcting iron deficiency anemia due to heavy uterine bleeding.  A total of  477 women with anemia, iron deficiency, and heavy uterine bleeding were assigned to receive either IV ferric carboxymaltose (less than or equal to 1,000 mg over 15 mins, repeated weekly to achieve a total calculated replacement dose) or 325 mg of ferrous sulfate (65 mg elemental iron) prescribed orally thrice-daily for 6 weeks.  Compared to those assigned to ferrous sulfate, more patients assigned to ferric carboxymaltose responded with a Hb increase of 2.0 g/dL or more (82 % versus 62 %, 95 % CI for treatment difference: 12.2 to 28.3, p < 0.001), more achieved a 3.0 g/dL or more increase (53 % versus 36 %, p < 0.001), and more achieved correction (Hb greater than or equal to 12 g/dL) of anemia (73 % versus 50 %, p < 0.001).  Patients treated with ferric carboxymaltose compared to those prescribed ferrous sulfate reported greater gains in vitality and physical function and experienced greater improvement in symptoms of fatigue (p < 0.05).  There were no serious adverse drug events.  The authors concluded that in patients with iron deficiency anemia due to heavy uterine bleeding, rapid IV administration of large doses of a new iron agent, ferric carboxymaltose, is more effective than oral iron therapy in correcting anemia, replenishing iron stores, and improving quality of life.

In a randomized, double-blind, placebo-controlled, multi-center study, Grote et al (2009) examined the effect of IV iron sucrose or placebo on symptoms in patients with restless legs syndrome (RLS) and mild-to-moderate iron deficit.  A total of 60 patients with primary RLS (7 males, age of 46 +/-9 years, S-ferritin less than or equal to 45 microg/L) were recruited from a cohort of 231 patients and were randomly assigned in a 12-months double-blind, multi-center study of iron sucrose 1,000 mg (n = 29) or saline (n = 31).  The primary efficacy variable was the RLS severity scale (IRLS) score at week 11.  Median IRLS score decreased from 24 to 7 (week 11) after iron sucrose and from 26 to 17 after placebo (p = 0.123, non-significant for between treatment comparison).  The corresponding scores at week 7 were 12 and 20 in the two groups (p = 0.017).  Drop-out rate because of lack of efficacy at 12 months was 19/31 after placebo and 5/29 patients after iron sucrose (Kaplan-Meier estimate, log-rank test p = 0.0006) suggesting an iron induced superior long-term RLS symptom control.  Iron sucrose was well-tolerated.  This study showed a lack of superiority of iron sucrose at 11 weeks but found evidence that iron sucrose reduced RLS symptoms both in the acute phase (7 weeks) and during long-term follow-up in patients with variable degree of iron deficiency.  The authors concluded that further studies on target patient groups, dosing and dosing intervals are needed before iron sucrose could be considered for treatment of iron deficient patients with RLS.

In a randomized, double-blind, placebo-controlled trial, Earley et al (2009) examined if high-dose (1,000 mg) IV iron sucrose could improve symptoms and change brain iron concentrations in idiopathic RLS.  Primary measures of the clinical status were global rating scale (GRS) and periodic leg movements of sleep (PLMS).  Primary measures of brain iron status were cerebrospinal fluid (CSF) ferritin and magnetic resonance imaging (MRI)-determined iron in the substantia nigra.  At the time of the interim analysis, there were 7 placebo and 11 iron-treated subjects.  At 2 weeks post-treatment, iron treatment resulted in a small but significant increase in CSF ferritin and a decrease in RLS severity (GRS); but did not change PLMS or MRI iron index.  None of the secondary outcomes changed with treatment.  There was no single case of clear treatment benefit in any of the patients.  This interim analysis revealed an effect size that was too small to allow for adequate power to find significant differences with the planned 36-subject enrollment for either the primary objective outcome of PLMS or any of the secondary outcomes.  The study was stopped at this planned break-point given the lack of both adequate power and any indication for clinically significant benefit.  The authors concluded that high-dose IV iron failed to demonstrate the robust changes reported in 3 prior open-label studies.  Differences in iron formulation, dosing regiment, and peripheral iron status may explain some of the discrepancies between this and previous IV iron treatment studies.

Zilberman et al (2010) evaluated the prevalence of RLS in anemic patients with CHF and chronic renal failure (CRF) and evaluated the effect of anemia treatment on RLS.  A total of 38 anemic CHF-CRF patients were treated with subcutaneous EPO and IV iron over 1 year.  They were questioned initially and at 3 months post-treatment about symptoms of RLS according to standard criteria.  They were also contacted by telephone about RLS symptoms 12 months after onset of anemia treatment.  Restless legs syndrome was found in 15 (39.5 %) of the 38 patients.  In 10 (66.7 %) patients it was present at least 6 days a week.  The prevalence of the RLS initially was not related to Hb, to serum iron or % transferrin saturation.  Diabetes and lower serum ferritin were more common in the RLS group (p < 0.05).  After 3 months of treatment, Hb increased from 10.4 +/- 0.8 to 12.3 +/- 1.2 g/dL, but RLS symptoms did not change.  By 12 months, the prevalence and frequency of RLS complaints was similar to what it had been initially.  The authors concluded that RLS is common and often undiagnosed and untreated in anemic CHF-CRF patients.  Unfortunately, successful treatment of anemia with EPO and IV iron did not improve this condition.

In a Cochrane review, Trotti et al (2012) evaluated the effects of iron supplementation (oral or intravenous) for patients with RLS.  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 1995 to April 2011); EMBASE (January 1995 to April 2011); PsycINFO (January 1995 to April 2011); and CINAHL (January 1995 to April 2011).  Corresponding authors of included trials and additional members of the International Restless Legs Syndrome Study Group were contacted to locate additional published or unpublished trials.  Controlled trials comparing any formulation of iron with placebo, other medications, or no treatment in adults diagnosed with RLS according to expert clinical interview or explicit diagnostic criteria.  Two review authors extracted data and at least 2 authors assessed trial quality.  They contacted trial authors for missing data.  A total of 6 studies (192 total subjects) were identified and included in this analysis.  The quality of trials was variable.  The primary outcome was restlessness or uncomfortable leg sensations, which was quantified using the IRLS severity scale in 4 trials and another RLS symptom scale in a 5th trial.  Combining data from the 4 trials using the IRLS severity scale, there was no clear benefit from iron therapy (mean difference in IRLS severity scores of -3.79, 95 % CI: -7.68 to 0.10, p = 0.06).  However, the 5th trial did find iron therapy to be beneficial (median decrease of 3 points in the iron group and no change in the placebo group on a 10-point scale of RLS symptoms, p = 0.01).  Quality of life was improved in the iron group relative to placebo in some studies but not others.  Changes in periodic limb movements were not different between groups (measured in 2 studies).  Objective sleep quality, subjective sleep quality and daytime functioning were not different between treatment groups in the studies that assessed them.  The single study of subjects with end stage renal disease did show a benefit of therapy.  Most trials did not require subjects to have co-morbid iron deficiency and several excluded patients with severe anemia.  The single study that was limited to iron deficient subjects did not show clear benefit of iron supplementation on RLS symptoms.  There was no clear superiority of oral or intravenous delivery of iron.  Iron therapy did not result in significantly more side effects than placebo (risk ratio [RR] 1.39, 95 % CI: 0.85 to 2.27).  The authors concluded that there is insufficient evidence to determine whether iron therapy is beneficial for the treatment of RLS.  They stated that further research to determine whether some or all types of RLS patients may benefit from iron therapy, as well as the best route of iron administration, is needed.

Anemia  Without Chronic Kidney Disease:

In a Cochrane review, Gurusamy and colleagues (2014) evaluated the safety and effectiveness of iron therapies for the treatment of adults with anemia who are not pregnant or lactating and do not have CKD.  These investigators ran the search on July 11, 2013.  They searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE (Ovid SP), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus (EBSCO Host), the Institute for Scientific Information Web of Science (ISI WOS) Scientific Citation Index (SCI)-EXPANDED (1970) and Conference Proceedings Citation Index (CPCI)-Science (1990) and; we also screened reference lists.  An updated search was run on November 24, 2014 but the results have not yet been incorporated into the review.  Two review authors independently selected references for further assessment by going through all titles and abstracts.  Further selection was based on review of full-text articles for selected references.  Two review authors independently extracted study data.  These investigators calculated the RR with 95 % CI for binary outcomes and the mean difference (MD) or the standardized mean difference (SMD) with 95 % CI for continuous outcomes.  They performed meta-analysis when possible, when I(2) was less than or equal to 80 % using a fixed-effect or random-effects model, using Review Manager software.  The range of point estimates for individual studies is presented when I(2) is greater than 80 %.  These researchers included in this systematic review 4,745 participants who were randomly assigned in 21 trials.  Trials were conducted in a wide variety of clinical settings.  Most trials included participants with mild-to-moderate anemia and excluded participants who were allergic to iron therapy.  All trials were at high risk of bias for one or more domains.  They compared both oral iron and parenteral iron versus inactive controls and compared different iron preparations.  The comparison between oral iron and inactive control revealed no evidence of clinical benefit in terms of mortality (RR 1.05, 95 % CI: 0.68 to 1.61; 4 studies, n = 659; very low-quality evidence).  The point estimate of the mean difference in Hb levels in individual studies ranged from 0.3 to 3.1 g/dL higher in the oral iron group than in the inactive control group.  The proportion of participants who required blood transfusion was lower with oral iron than with inactive control (RR 0.74, 95 % CI: 0.55 to 0.99; 3 studies, n = 546; very low-quality evidence).  Evidence was inadequate for determination of the effect of parenteral iron on mortality versus oral iron (RR 1.49, 95 % CI: 0.56 to 3.94; 10 studies, n = 2,141; very low-quality evidence) or inactive control (RR 1.04, 95 % CI: 0.63 to 1.69; 6 studies, n = 1,009; very low-quality evidence).  Hemoglobin levels were higher with parenteral iron than with oral iron (MD -0.50 g/dL, 95 % CI: -0.73 to -0.27; 6 studies, n = 769; very low-quality evidence).  The point estimate of the mean difference in Hb levels in individual studies ranged between 0.3 and 3.0 g/dL higher in the parenteral iron group than in the inactive control group.  Differences in the proportion of participants requiring blood transfusion between parenteral iron and oral iron groups (RR 0.61, 95 % CI: 0.24 to 1.58; 2 studies, n = 371; very low-quality evidence) or between parenteral iron groups and inactive controls (RR 0.84, 95 % CI: 0.66 to 1.06; 8 studies, n = 1,315; very low-quality evidence) were imprecise.  Average blood volume transfused was less in the parenteral iron group than in the oral iron group (MD -0.54 units, 95 % CI: -0.96 to -0.12; very low-quality evidence) based on 1 study involving 44 people.  Differences between therapies in quality of life or in the proportion of participants with serious adverse events were imprecise (very low-quality evidence).  No trials reported severe allergic reactions due to parenteral iron, suggesting that these are rare.  Adverse effects related to oral iron treatment included nausea, diarrhea and constipation; most were mild.  Comparisons of one iron preparation over another for mortality, Hb or serious adverse events were imprecise.  No information was available on quality of life.  Thus, little evidence was found to support the use of one preparation or regimen over another.  Subgroup analyses did not reveal consistent results; therefore these researchers were unable to determine whether iron is useful in specific clinical situations, or whether iron therapy might be useful for people who are receiving erythropoietin.  The authors concluded that (i) very low-quality evidence suggested that oral iron might decrease the proportion of people who require blood transfusion, and no evidence indicated that it decreases mortality; (ii) oral iron might be useful in adults who can tolerate the adverse events, which are usually mild; (iii) very low-quality evidence suggested that intravenous iron resulted in a modest increase in Hb levels compared with oral iron or inactive control without clinical benefit; and (iv) no evidence can be found to show any advantage of one iron preparation or regimen over another.  They stated that additional RCTs with low risk of bias and powered to measure clinically useful outcomes such as mortality, quality of life and blood transfusion requirements are needed.

Iron Deficiency in Individuals Following Bariatric Surgery:

DeFilipp et al (2013) noted that iron deficiency is a major post-operative complication of Roux-en-Y gastric bypass surgery.  Oral replacement can fail to correct the deficiency.  Thus, recourse to parenteral iron administration might be necessary.  These researchers evaluated the safety and effectiveness of a standardized 2-g intravenous iron dextran infusion in the treatment of iron deficiency after Roux-en-Y gastric bypass surgery.  The setting was a university-affiliated community hospital in the United States.  These investigators reviewed the medical records of 23 patients at their institution who had received 2 g of iron dextran intravenously for recalcitrant iron deficiency after Roux-en-Y gastric bypass surgery.  They obtained the demographic data and the complete blood count and serum iron studies obtained before treatment and at outpatient visits after infusion.  Before treatment, all 23 patients were iron deficient (average ferritin 6 ng/ml) and anemic (average hemoglobin 9.4 g/dL).  By 3 months, the average ferritin and hemoglobin had increased to 269 ng/ml and 12.3 g/dL, respectively.  The hemoglobin levels remained stable throughout the follow-up period.  The iron stores were adequately replaced in most patients.  Four patients required a repeat infusion by 1 year, because the ferritin levels had decreased to less than 15 ng/ml.  The probability of remaining in an iron replete state was 84.6 % (95 % confidence interval: 78 to 91.2 %).  One patient required warm compresses for superficial phlebitis.  No other significant adverse events were reported.  The authors concluded that intravenous administration of 2 g of iron dextran corrected the anemia and repleted the iron stores for greater than or equal to 1 year in most patients.  This therapy is safe, tolerable, efficient, and effective.

Malone et al (2013) evaluated their management of Roux-en-Y gastric bypass surgery (RYGB) patients with iron deficiency (ID) and anemia.  Clinic visit records of RYGB patients with ID or anemia from January 1, 2008, to February 1, 2010 were evaluated.  Demographic characteristics, post-surgery iron and anemia indices, and prescribed treatments were recorded.  Three separate definitions for ID and anemia were used (standard textbook, ASBMS, and recent literature).  An intravenous iron protocol was later implemented, and follow-up laboratory values were obtained.  A total of 125 with ID or anemia (89 % female, 86 % Caucasian), mean (SD) age of 44.7 (8.6) years, and body mass index (BMI) of 47.3 (10.8) kg/m(2) at time of RYGB, were included.  Proportion of values meeting criteria for ID or anemia at first follow-up: standard textbook, hemoglobin (Hb, 35 %), transferrin saturation (Tsat, 48 %), ferritin (28 %); ASBMS, ferritin (43 %); recent literature, ferritin (58 %), serum iron (21 %).  At mean follow-up of 45.7 (43) months, oral iron (n = 49) or intravenous iron (n = 4) had been prescribed for 53 (42.4 %) patients, and 32 (25.6 %) patients received multiple blood transfusions.  Nine patients received intravenous iron using the new protocol (400 to 1,400 mg), resulting in increases in Hb (1.8 g/dL; p < 0.05) and ferritin (31.8 ng/ml; p < 0.002).  The authors concluded that iron management was inadequate.  Hematologic values often were deficient for sustained periods.  Initially, few patients received intravenous iron after oral iron failure, many received no iron supplementation, and there was high use of blood transfusions.  Subsequently, administration of intravenous iron was beneficial.

Obinwanne et al (2014) stated that laparoscopic Roux-en-Y gastric bypass (LRYGB) can lead to iron malabsorption through exclusion of the duodenum and proximal jejunum, decreased gastric acidity, and modified diet.  Intravenous (IV) iron is a treatment for severe iron deficiency, but the incidence of iron deficiency and the frequency of treatment with IV iron after LRYGB are largely unknown.  These researchers determined the incidence of iron deficiency and the frequency of IV iron administration after LRYGB.  After obtaining IRB approval, the medical records of patients who underwent LRYGB from September 2001 to December 2011 were retrospectively reviewed.  Inclusion criteria consisted of determination of at least 1 ferritin value after surgery.  Patients were grouped by level of iron deficiency.  Patients with at least 1 ferritin less than 50 ng/ml were considered iron deficient.  Statistical analysis included ANOVA.  There were 959 patients included; 84.9 % were female.  Mean age was 43.8 years, and pre-operative body mass index was 47.4 kg/m(2); 492 (51.3 %) patients were iron deficient.  Of these, 40.9 % were severely iron deficient, with a ferritin less than 30 ng/ml.  Intravenous iron was required by 6.7 % (64 patients).  After IV iron therapy, 53 % (34 patients) had improvement in hemoglobin and ferritin values, and 39 % (25 patients) had improvement in ferritin values only.  The authors concluded that given the incidence of iron deficiency after LRYGB observed in this series, patients should have iron status monitored carefully by all providers and be appropriately referred for treatment.  Female patients should be counseled that there is a 50 % chance they will become iron deficient after LRYGB.

The American Association of Clinical Endocrinologists, the Obesity Society, and the American Society for Metabolic & Bariatric Surgery’s clinical practice guidelines on “The perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient -- 2013 update” (Mechanick et al, 2013) stated that “Intravenous iron infusion (preferably with ferric gluconate or sucrose) may be needed for patients with severe intolerance to oral iron or refractory deficiency due to severe iron malabsorption”.

The University of Rochester Medical Center (2014) states that iron deficiency and anemia are common after a gastric bypass or other weight-loss surgery, especially in women.  In fact, iron deficiency can occur in more than 50 % of women who are pre-menopausal who have this surgery.    For some people, usually women with heavy menstrual periods, supplements aren’t enough.  They may need iron through an IV, blood transfusions, or even surgical revision of the bypass to raise the amount of iron absorbed.

Furthermore, the American Society of Hematology (2014) notes that people who have undergone bariatric procedures, especially gastric bypass operations, are among individuals who are at highest risk for iron-deficiency anemia.  In some cases, one’s doctor may recommend intravenous (IV) iron; IV iron may be necessary to treat iron deficiency in patients who do not absorb iron well in the gastro-intestinal tract, patients with severe iron deficiency or chronic blood loss, patients who are receiving supplemental erythropoietin, a hormone that stimulates blood production, or patients who cannot tolerate oral iron.

An UpToDate review on “Treatment of the adult with iron deficiency anemia” (Schrier and Auerbach, 2015) states that “For those who have undergone gastric bypass surgery and/or subtotal gastric resection, the limited ability of the remaining stomach to provide acid to protect ferric iron from being converted to an insoluble form, and for facilitating intestinal absorption of ferric as well as ferrous iron, makes intravenous iron an especially good choice.  Some patients, especially those having undergone minimally invasive procedures, such as gastric banding, may tolerate oral iron.  This is less likely in Roux-en-Y or bilio-pancreatic diversion procedures.  However, it is important to remember that all gastric bypass patients have a host of other nutritional perturbations post-operatively, and intravenous iron may simplify care”.

Post-Partum Anemia:

In a randomized, double-blind, parallel-group, placebo-controlled, single-center clinical trial, Perello et al (2014) evaluated the effectiveness of intravenous iron versus placebo added to standard oral iron therapy in the treatment of severe post-partum anemia.  A cohort of 72 women with severe post-partum anemia (6.0 to 8.0 g/dL) treated with oral ferrous sulphate (2 tablets of 525 mg) were included in this study.  Women were randomized to receive either intravenous ferrous sucrose (200 mg/24 hours for 2 consecutive days) or intravenous placebo, in addition to standard iron therapy.  Clinical and laboratory data were obtained at 1, 2, and 6 weeks.  Main outcome measures were Hb and hematocrit at 1, 2, and 6 weeks.  Other hematological and clinical parameters, psychological status, and adverse side effects were also evaluated.  Hemoglobin and hematocrit values were comparable in women receiving intravenous iron or placebo in addition to oral iron therapy at any of the time-points.  At 6 weeks, Hb level (mean ± SD) was 12.2 ± 1.0 versus 12.2 ± 0.9 g/dL, with a mean difference of -0.03 (95 % CI: -0.6 to 0.6), in the placebo and in the intravenous iron groups, respectively.  No differences were found between clinical symptoms of anemia, psychological status, and adverse side effects between groups.  The authors concluded that intravenous iron added to oral iron therapy did not show significant benefits over placebo, neither in Hb rise nor in symptoms or adverse side effects.

Pre-Operative Intravenous Iron Therapy:

Hallet et al (2014) noted that peri-operative anemia is common, yet detrimental, in surgical patients.  However, RBC transfusions (RBCTs) used to treat anemia are associated with significant post-operative risks and worse oncologic outcomes.  Peri-operative iron has been suggested to mitigate peri-operative anemia.  This meta-analysis examined the impact of peri-operative iron compared to no intervention on the need for RBCT in gastro-intestinal (GI) surgery.  These investigators systematically searched Medline, Embase, Web of Science, Cochrane Central, and Scopus to identify relevant randomized controlled trials (RCTs) and non-randomized studies (NRSs).  They excluded studies investigating autologous RBCT or erythropoietin.  Two independent reviewers selected the studies, extracted data, and assessed the risk of bias using the Cochrane tool and Newcastle-Ottawa scale.  Primary outcomes were proportion of patients getting allogeneic RBCT and number of transfused patient.  Secondary outcomes were Hb change, 30-day post-operative morbidity and mortality, length of stay, and oncologic outcomes.  A meta-analysis using random effects models was performed.  From 883 citations, these researchers included 2 RCTs and 2 NRSs (n = 325 patients), all pertaining to colorectal cancer surgery.  Randomized controlled trials were at high risk for bias and under-powered.  One RCT and 1 NRS using pre-operative oral iron reported a decreased proportion of patients needing RBCT.  One RCT on pre-operative intravenous iron and 1 NRS on post-operative PO iron did not observe a difference.  Only 1 study revealed a difference in number of transfused patients.  One RCT reported significantly increased post-intervention Hb.  Among 3 studies reporting length of stay, none observed a difference.  Other secondary outcomes were not reported.  Meta-analysis revealed a trend toward fewer patients requiring RBCT with iron supplementation (RR, 0.66 [0.42, 1.02]), but no benefit on the number of RBCT per patient (weighted mean difference, -0.91 [-1.61, -0.18]).  The authors concluded that although preliminary evidence suggested that it may be a promising strategy, there is insufficient evidence to support the routine use of peri-operative iron to decrease the need for RBCT in colorectal cancer surgery.  They stated that well-designed RCTs focusing on the need for RBCT and including long-term outcomes are needed.

Elhenawy et al (2015) stated that pre-operative anemia is a common and potentially serious hematological problem in elective surgery and increases the risk for peri-operative RBC transfusion.  Transfusion is associated with post-operative morbidity and mortality.  Pre-operative IV iron therapy has been proposed as an intervention to reduce peri-operative transfusion; however, studies are generally small, limited, and inconclusive.  These investigators proposed performing a systematic review and meta-analysis.  They will search MEDLINE, EMBASE, EBM Reviews, Cochrane-controlled trial registry, Scopus, registries of health technology assessment and clinical trials, Web of Science, ProQuest Dissertations and Theses, and conference proceedings in transfusion, hematology, and surgery.  They will contact the study drug manufacturer for unpublished trials.  Titles and abstracts will be identified and assessed by 2 reviewers for potential relevance.  Eligible studies are: randomized or quasi-randomized clinical trials comparing pre-operative administration of IV iron with placebo or standard of care to reduce peri-operative blood transfusion in anemic patients undergoing major surgery.  Screening, data extraction, and quality appraisal will be conducted independently by 2 authors.  Data will be presented in evidence tables and in meta-analytic forest plots.  Primary efficacy outcomes are change in Hb concentration and proportion of patients requiring RBC transfusion.  Secondary outcomes include number of units of blood or blood products transfused peri-operatively, transfusion-related acute lung injury, neurologic complications, adverse events, post-operative infections, cardiopulmonary complications, intensive care unit (ICU) admission/re-admission, length of stay, acute kidney injury, and mortality.  Dichotomous outcomes will be reported as pooled relative risks and 95 % CIs.  Continuous outcomes will be reported using calculated weighted mean differences.  Meta-regression will be performed to evaluate the impact of potential confounding variables on study effect estimates.  The authors concluded that reducing unnecessary RBC transfusions in peri-operative medicine is a clinical priority.  This involves the identification of patients at risk of receiving transfusions along with blood conservation strategies.  Of potential pharmacological blood conservation strategies, IV iron is a compelling intervention to treat preoperative anemia; however, existing data are uncertain.  These researchers proposed performing a systematic review and meta-analysis evaluating the safety and effectiveness of IV iron administration to anemic patients undergoing major surgery to reduce transfusion and peri-operative morbidity and mortality.

Hogan et al (2015) stated that anemia is common in patients with cardiac disease and also in those undergoing cardiac surgery.  There is increasing evidence that pre-operative anemia is associated with increased patient morbidity and mortality following surgery.  These researchers performed a systematic literature review to assess the impact of anemia and IV iron supplementation on outcomes in cardiac surgery.  A total of 16 studies examined pre-operative anemia in detail.  One study examined the role of pre-operative IV iron administration and a further 3, the effect of post-operative iron supplementation on Hb levels and the need for transfusion.  Pre-operative anemia was associated with higher mortality, more post-operative blood transfusions, longer ICU and total hospital stay and also a greater incidence of post-operative cardiovascular events.  In the single study that examined pre-operative IV iron in combination with erythropoietin treatment, there was decreased blood transfusion, shorter hospital stay and an increase in patient survival.  However, this was a small retrospective cohort study, with the observation and treatment groups analyzed over different time periods.  Post-operative administration of IV iron therapy, either alone or in combination with erythropoietin, was not effective in raising Hb levels or reducing red cell concentrate transfusion.  The authors concluded that on the basis of currently available evidence, the effect of peri-operative administration of IV iron to cardiac surgery patients, alone or in combination with erythropoietin, remains unproven.  They stated that well-designed and appropriately powered prospective RCTs are needed to evaluate peri-operative iron supplementation in the context of cardiac surgery.


Dosing of Parentaral Iron Preparations:

Iron dextran preparations contain 50 mg of elemental iron/ml, and are approved for iron deficiency anemia not amenable to oral iron therapy.  High molecular weight (HMW) iron dextran preparations (Dexferrum) are now rarely used because they are associated with a considerably higher incidence of adverse events than are the low molecular weight (LMW) preparations (INFeD).  LMW preparations have a maximum daily dose 100 mg of elemental iron (2 ml).  The recommended dosing in chronic kidney disease is elemental iron 50 to 100 mg once-weekly.  There is no evidence that doses of LMW iron dextran larger than 1,000 mg are clinically useful.  Once transferrin saturation greater than or equal to 20 % or serum ferritin greater than or equal to 100 ng/ml (224.7 pmol/L), IV iron therapy should be continued at lowest dose needed to maintain target hematocrit/hemoglobin levels and iron stores. 

Ferric gluconate complex (Ferrlecit) contains 12.5 mg/ml elemental iron, and is approved for hemodialysis patients with iron deficiency anemia on epoetin alfa therapy.  Ferric gluconate is approved for a maximum single dose of 125 mg, although published evidence suggests that a dose of 250 mg is well-tolerated.  The adult dose 125 mg IV at or during dialysis session, and most patients require cumulative dose greater than or equal to 1,000 mg over 8 sessions.  Once transferrin saturation greater than or equal to 20 % and serum ferritin level greater than or equal to 100 ng/ml achieved, ferric gluconate should be continued at the lowest dose needed to maintain hemoglobulin/hematocrit levels (for example, 25 to 100 mg elemental iron weekly for 10 weeks). 

Iron sucrose (Venofer, iron saccharate) contains 20 mg/ml elemental iron, and approved for iron deficiency anemia in non-dialysis-dependent chronic kidney disease patients (receiving or not receiving erythropoietin), and chronic kidney disease patients on dialysis (hemodialysis or peritoneal dialysis) and receiving erythropoietin.  Iron sucrose has been approved as a single infusion of up to 500 mg, administered over 4 hours.  Recommended dosing in hemodialysis patients is 100 mg (undiluted over 2 to 5 minutes or diluted in saline over 15 minutes) per consecutive dialysis session.  Recommended dosing in peritoneal dialysis patients is 300 mg over 1.5 hours, then 300 mg over 1.5 hours 14 days later, then 400 mg over 2.5 hours 14 days later.  Recommended dosing in non-dialysis patients is 5 doses of 200 mg over 2 to 5 minutes each over 14-day period.  Most patients require minimum cumulative dose of 1,000 mg of elemental iron given over 10 dialysis sessions

Ferumoxytol (Feraheme) has 30 mg/ml elemental iron, and is approved for iron deficiency anemia in adults with chronic kidney disease.  Ferumoxytol is approved for a 510 mg injection in patients with chronic kidney disease, although ferumoxytol has been shown to be safe and efficacious as a 1,020 mg infusion.  The initial dose is 510 mg, with an additional 510 mg dose 3 to 8 days after the initial dose. The 2-dose course may be repeated.

The reported experience with Feraheme has been in iron deficiency anemia in persons with CKD; the reported experience with the use of Feraheme for iron deficiency anemia in persons without CKD is relatively limited.  A recent report on Feraheme by the Canadian Agency for Drugs and Technologies in Health (CADTH, 2013) concluded that limited evidence from studies with methodological issues suggested that ferumoxytol seems to have comparable efficacy compared with other available IV iron preparations, but that Feraheme has higher adverse events compared with other available IV iron preparations.  No evidence-based guidelines for the use of Feraheme were identified.  There are also limited data on the cost-effectiveness of Feraheme with other IV iron preparations.  Recently, the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA, 2014) issued a warning that new data on serious hypersensitivity reactions following ferumoxytol administration are currently being reviewed by the European Medicines Agency.

CPT Codes / HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB:
96365 - 96368 Intravenous infusion administration
96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96374 - 96379 Intravenous push administration
HCPCS codes covered if selection criteria are met:
J1439 Injection, ferric carboxymaltose, 1 mg
J1750 Injection, iron dextran, 50 mg
J1756 Injection, iron sucrose, 1 mg
J2916 Injection, sodium ferric gluconate complex in sucrose injection, 12.5 mg
Q0138 Injection, Ferumoxytol, for treatment of iron deficiency anemia, 1mg (non-ESRD use) [Feraheme] [for iron deficiency anemia with chronic kidney disease]
Q0139 Injection, Ferumoxytol, for treatment of iron deficiency anemia, 1mg (for ESRD on dialysis) [Feraheme] [for iron deficiency anemia in chronic kidney disease]
Other HCPCS codes related to the CPB:
J0885 Injection, epoetin alfa, (for non-ESRD use), 1,000 units
J0886 Injection, epoetin alfa, 1000 units (for ESRD on dialysis)
J0887 Injection, epoetin beta, 1 microgram, (for ESRD on dialysis)
J0888 Injection, epoetin beta, 1 microgram, (for non-ESRD use)
Q4081 Injection, epoetin alfa, 100 units (for ESRD on dialysis)
ICD-9 codes covered if selection criteria are met (not all-inclusive):
275.0 Disorders of iron metabolism
280.0 - 280.9 Iron deficiency anemias
285.0 Sideroblastic anemia
285.8 Other specified anemias [chemotherapy-induced anemia]
425.4 Other primary cardiomyopathies (e.g., congestive, constrictive, familial, hypertrophic, idiopathic, non-obstructive, obstructive, restrictive)
428.0 - 428.9 Heart failure
555.0 - 555.9 Regional enteritis [Crohn'sdisease]
556.0 - 556.9 Ulcerative colitis
585.1 - 585.9 Chronic kidney disease (CKD)
626.2 Excessive or frequent menstruation
626.3 Pubertal menorrhagia
627.0 Premenopausal menorrhagia
627.1 Postmenopausal bleeding
E933.1 Antineoplastic and immunosuppressive drugs causing adverse effects in therapeutic use [chemotherapy-induced anemia]
V15.81 Noncompliance with medical treatment
V45.11 - V45.12 Renal dialysis status
V45.86 Bariatric surgery status
V59.01 Donors, blood, whole blood
V59.09 Donors, blood, other
ICD-9 codes not covered for indications listed in the CPB:
333.94 Restless legs syndrome
648.20 - 648.24 Anemia of mother, complicating pregnancy, childbirth, or the puerperium, unspecified as to episode of care
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015:
Other CPT codes related to the CPB:
96365 - 96368 Intravenous infusion administration
96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96374 - 96379 Intravenous push administration
HCPCS codes covered if selection criteria are met:
J1439 Injection, ferric carboxymaltose, 1 mg
J1750 Injection, iron dextran, 50 mg
J1756 Injection, iron sucrose, 1 mg
J2916 Injection, sodium ferric gluconate complex in sucrose injection, 12.5 mg
Q0138 Injection, Ferumoxytol, for treatment of iron deficiency anemia, 1mg (non-ESRD use) [Feraheme] [for iron deficiency anemia with chronic kidney disease]
Q0139 Injection, Ferumoxytol, for treatment of iron deficiency anemia, 1mg (for ESRD on dialysis) [Feraheme] [for iron deficiency anemia in chronic kidney disease]
Other HCPCS codes related to the CPB:
J0885 Injection, epoetin alfa, (for non-ESRD use), 1,000 units
J0886 Injection, epoetin alfa, 1000 units (for ESRD on dialysis)
J0887 Injection, epoetin beta, 1 microgram, (for ESRD on dialysis)
J0888 Injection, epoetin beta, 1 microgram, (for non-ESRD use)
Q4081 Injection, epoetin alfa, 100 units (for ESRD on dialysis)
ICD-10 codes covered if selection criteria are met (not all-inclusive):
D50.0 - D50.9 Iron deficiency anemias
D64.0 - D64.3 Sideroblastic anemia
D64.81 Anemia due to antineoplastic chemotherapy
E83.10 - E83.19 Disorders of iron metabolism
I42.0, I42.2
I42.5, I42.8
Other cardiomyopathies (e.g., congestive, constrictive, familial, hypertrophic, idiopathic, non-obstructive, obstructive, restrictive)
I50.1 - I50.9 Heart failure
K50.00 - K50.919 Crohn's disease [regional enteritis]
K51.00 - K51.919 Ulcerative colitis
N18.1 - N18.9 Chronic kidney disease (CKD)
N92.0 - N92.1 Excessive and frequent menstruation
N92.2 Excessive menstruation at puberty
N92.4 Excessive bleeding in the premenopausal period
N95.0 Postmenopausal bleeding
T45.1x5+ Adverse effect of antineoplastic and immunosuppressive drugs [chemotherapy-induced anemia]
Z52.000 - Z52.098 Blood donor
Z91.11 - Z91.19 Patient's noncompliance with medical treatment and regimen
Z98.84 Bariatric surgery status
Z99.2 Dependence on renal dialysis
ICD-10 codes not covered for indications listed in the CPB::
G25.81 Restless legs syndrome
O99.011 - O99.019 Anemia complicating pregnancy

The above policy is based on the following references:
    1. National Kidney Foundation (NKF). NKF-DOQI clinical practice guidelines for the treatment of anemia of chronic renal failure. Am J Kidney Dis. 1997;30(4 Suppl 3):S192-S240.
    2. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis. 1995;26:41-46.
    3. National Kidney Foundation (NKF). NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2000. New York, NY: NKF; 2000. Available at: Accessed June 18, 2001.
    4. National Heritage Insurance Company (NHIC). Intravenous iron therapy. Local Medical Review Policy. NHIC Medicare Part B. Marysville, CA: NHIC; December 1, 2000. Available at: Accessed June 18, 2001.
    5. Veritus Medicare. Intravenous iron therapy. Local Medical Review Policy. Provider Notice 00-100. Camp Hill, PA: Veritus Medicare; December 12, 2000. Available at: Accessed June 18, 2001.
    6. Fishbane S, Wagner J. Sodium ferric gluconate complex in the treatment of iron deficiency for patients on dialysis. Am J Kidney Dis. 2001;37(5):879-883.
    7. Reveiz L, Gyte GML, Cuervo LG. Treatments for iron deficiency anaemia in pregnancy. Cochrane Database Syst Rev. 2007;(2):CD003094.
    8. Foret JP. Diagnosing and treating anemia and iron deficiency in hemodialysis patients. Nephrol Nurs J. 2002;29(3):292-296.
    9. Silverberg DS, Blum M, Agbaria Z, et al. Intravenous iron for the treatment of predialysis anemia. Kidney Int Suppl. 1999;69:S79-S85.
    10. Kosch M, Bahner U, Bettger H, et al. A randomized, controlled parallel-group trial on efficacy and safety of iron sucrose (Venofer) vs iron gluconate (Ferrlecit) in haemodialysis patients treated with rHuEpo. Nephrol Dial Transplant. 2001;16(6):1239-1244.
    11. Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anemia in inflammatory bowel disease: A systematic review of the literature. Am J Med. 2004;116 Suppl 7A:44S-49S.
    12. Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol. 2004;76(1):74-78.
    13. Madi-Jebara SN, Sleilaty GS, Achouh PE, et al. Postoperative intravenous iron used alone or in combination with low-dose erythropoietin is not effective for correction of anemia after cardiac surgery. J Cardiothorac Vasc Anesth. 2004;18(1):59-63.
    14. Dodd J, Dare MR, Middleton P. Treatment for women with postpartum iron deficiency anaemia. Cochrane Database Syst Rev. 2004;(4):CD004222.
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    16. Munoz M, Naveira E, Seara J, et al. Role of parenteral iron in transfusion requirements after total hip replacement. A pilot study. Transfus Med. 2006;16(2):137-142.
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    18. Fishbane S. Iron management in nondialysis-dependent CKD. Am J Kidney Dis. 2007;49(6):736-743.
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    20. Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12(2):231-242.
    21. Hedenus M, Birgegård G, Näsman P, et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: A randomized multicenter study. Leukemia. 2007;21(4):627-632.
    22. Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol. 2008;26(10):1611-1618.
    23. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha. J Clin Oncol. 2008;26(10):1619-1625.
    24. Auerbach M. Should intravenous iron be the standard of care in oncology? J Clin Oncol. 2008;26(10):1579-1581.
    25. Shord SS, Hamilton JM Jr, Cuellar S. Parenteral iron with erythropoiesis-stimulating agents for chemotherapy-induced anemia. J Oncol Pharm Pract. 2008;14(1):5-22.
    26. Seid MH, Derman RJ, Baker JB, et al. Ferric carboxymaltose injection in the treatment of postpartum iron deficiency anemia: A randomized controlled clinical trial. Am J Obstet Gynecol. 2008;199(4):435.e1-e7.
    27. Westad S, Backe B, Salvesen KA, et al. A 12-week randomised study comparing intravenous iron sucrose versus oral ferrous sulphate for treatment of postpartum anemia. Acta Obstet Gynecol Scand. 2008;87(9):916-923.
    28. American College of Obstetricians and Gynecologists (ACOG). Anemia in pregnancy. ACOG Practice Bulletin No. 95. Washington, DC: ACOG; July 2005.
    29. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: A randomized, controlled, observer-blinded trial. J Am Coll Cardiol. 2008;51(2):103-112.
    30. Anker SD, Comin Colet J, Filippatos G, et al; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436-2448.
    31. Van Wyck DB, Mangione A, Morrison J, et al. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: A randomized, controlled trial. Transfusion. 2009;49(12):2719-2728.
    32. Lyseng-Williamson KA, Keating GM. Ferric carboxymaltose: A review of its use in iron-deficiency anaemia. Drugs. 2009;69(6):739-756
    33. Gomollón F, Gisbert JP. Anemia and inflammatory bowel diseases. World J Gastroenterol. 2009;15(37):4659-4665.
    34. Muñoz M, Gómez-Ramírez S, García-Erce JA. Intravenous iron in inflammatory bowel disease. World J Gastroenterol. 2009;15(37):4666-4674.
    35. Dangsuwan P, Manchana T. Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy. Gynecol Oncol. 2010;116(3):522-525.
    36. Grote L, Leissner L, Hedner J, Ulfberg J. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord. 2009;24(10):1445-1452.
    37. Earley CJ, Horská A, Mohamed MA, et al. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Med. 2009;10(2):206-211.
    38. Zilberman M, Silverberg DS, Schwartz D, Oksenberg A. Restless legs syndrome (RLS) in anemic patients with congestive heart failure and chronic renal failure: Lack of effect of anemia treatment. Int J Cardiol. 2010;143(2):205-207.
    39. Lu M, Cohen MH, Rieves D, Pazdur R. FDA report: Ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. Am J Hematol. 2010;85(5):315-319.
    40. Silverberg DS, Blum M, Agbaria Z, et al. The effect of i.v. iron alone or in combination with low-dose erythropoietin in the rapid correction of anemia of chronic renal failure in the predialysis period. Clin Nephrol. 2001;55(3):212-219.
    41. Mircescu G, Garneata L, Capusa C, Ursea N. Intravenous iron supplementation for the treatment of anaemia in pre-dialyzed chronic renal failure patients. Nephrol Dial Transplant. 2006;21(1):120-124.
    42. Macdougall IC, Roche A. Administration of intravenous iron sucrose as a 2-minute push to CKD patients: A prospective evaluation of 2,297 injections. Am J Kidney Dis. 2005;46(2):283-289.
    43. Beucher G, Grossetti E, Simonet T, et al. Iron deficiency anemia and pregnancy. Prevention and treatment. J Gynecol Obstet Biol Reprod (Paris). 2011;40(3):185-200.
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    45. Avni T, Leibovici L, Gafter-Gvili A. Iron supplementation for the treatment of chronic heart failure and iron deficiency: Systematic review and meta-analysis. Eur J Heart Fail. 2012;14(4):423-429.
    46. Lee TW, Kolber MR, Fedorak RN, van Zanten SV. Iron replacement therapy in inflammatory bowel disease patients with iron deficiency anemia: A systematic review and meta-analysis. J Crohns Colitis. 2012;6(3):267-275.
    47. Trotti LM, Bhadriraju S, Becker LA. Iron for restless legs syndrome. Cochrane Database Syst Rev. 2012;5:CD007834.
    48. Gafter-Gvili A, Rozen-Zvi B, Vidal L, et al. Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia - systematic review and meta-analysis of randomised controlled trials. Acta Oncol. 2013;52(1):18-29.
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    50. American Reagent, Inc. DexFerrum Iron Dextran Injection. Prescribing Information. NDA 40-024/S-022. IN0234. MG #7721. Shirley, NY: American Reagent; August 2008.
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    52. American Reagent, Inc. Venofer Iron Sucrose Injection. Prescribing Information.  IN2340. MG #15727. Shirley, NY: American Reagent; June 2011.
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    54. CADTH. Ferumoxytol versus other intravenous iron therapies for anemia: a review of the clinical and cost-effectiveness and guidelines. Ottawa: Canadian Agency for Drugs and Technologies in Health (CADTH). Rapid Response - Summary with Critical Appraisal. 2013.
    55. MHRA. Ferumoxytol: Serious hypersensitivity reactions --reminder of precautions to take before and during administration. Drug Safety Update. 2014;7(11):A2.
    56. Hornyak M, Scholz H, Kohnen R, et al. What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications. Sleep Med Rev. 2014;18(2):153-164.
    57. Gurusamy KS, Nagendran M, Broadhurst JF, et al. Iron therapy in anaemic adults without chronic kidney disease. Cochrane Database Syst Rev. 2014;12:CD010640.
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    59. DeFilipp Z, Lister J, Gagne D, et al. Intravenous iron replacement for persistent iron deficiency anemia after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2013;9(1):129-132.
    60. Malone M, Alger-Mayer S, Lindstrom J, Bailie GR. Management of iron deficiency and anemia after Roux-en-Y gastric bypass surgery: An observational study. Surg Obes Relat Dis. 2013;9(6):969-974.
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    65. Elhenawy AM, Meyer SR, Bagshaw SM, et al. Role of preoperative intravenous iron therapy to correct anemia before major surgery: Study protocol for systematic review and meta-analysis. Syst Rev. 2015;4(1):29.
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