Methods

Randomised clinical trial

Participants

Country: Norway

Sample size: 30

Postrandomisation dropout(s): 0 (0%)

Revised sample size: 30

Females: not stated

Mean age: not stated

Inclusion criteria:

• Patients with acute or chronic gastrointestinal bleeding with haemoglobin < 10 g/dL

• Serum iron < 50 mcg/dL

Exclusion criteria:

• Chronic infection

• Renal disease

• Cancer

• Previous gastrectomy

Interventions

Participants were randomly assigned to the following groups:
Group 1: intramuscular iron (n = 10)

Further details: iron sorbitol citric acid complex 100 mg/d until calculated dose was reached
Group 2: oral iron (n = 10)

Further details: ferrous fumarate 300 mg in divided doses
Group 3: control (n = 10)

Further details: no intervention

Outcomes

Outcomes reported were mortality, haemoglobin levels and serious adverse events

Time of measurements: 3 weeks from start of treatment

Notes

Attempts were made to contact study authors in August 2012. They replied in September 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Thirty envelopes were used. In ten were written oral iron, in ten parenteral iron, and in ten no iron. The envelopes were mixed, and one envelope was opened for each patient" (study author replies)

Allocation concealment (selection bias)

Low risk

Quote: "Thirty envelopes were used. In ten were written oral iron, in ten parenteral iron, and in ten no iron. The envelopes were mixed, and one envelope was opened for each patient" (study author replies)

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "The patient and persons who administrated the treatment were informed. The laboratory results were opened at the end of the study" (study author replies)

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "The patient and persons who administrated the treatment were informed. The laboratory results were opened at the end of the study" (study author replies)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: No postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: All important clinical outcomes were reported

Source of funding bias

Low risk

Quote: "Not funded" (study author replies)

Methods

Randomised clinical trial

Participants

Country: multi‐centric (Europe)

Sample size: 158

Postrandomisation dropout(s): 0 (0%)

Revised sample size: 158

Females: not stated

Mean age: not stated

Inclusion criteria:

• Ambulatory patients who had chronic heart failure

• Hb between 9.5 and 13.5 g/dL

• Iron deficiency

Exclusion criteria:

• Uncontrolled hypertension

• Other clinically significant heart disease or inflammation, or clinically significantly impaired liver or renal function

Interventions

Participants were randomly assigned to the following groups:
Group 1: IV iron (n = 110)
Further details: ferric carboxymaltose 200 mg IV weekly until iron repletion was achieved followed by a maintenance 4‐weekly dose
Group 2: control (n = 48)
Further details: normal saline placebo

Outcomes

Outcomes reported were mortality, proportion of patients requiring blood transfusion, haemoglobin levels, quality of life measurements and serious adverse events (in the subgroup of anaemic participants)

Time of measurement: 24 weeks from start of treatment

Notes

Attempts were made to contact the study author in August 2012. They provided additional information

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was performed by IVRS (Interactive Voice Response System), stratified by region in a 2:1 ratio (FCM:placebo). Blocks of 6 (4FCM, 2 placebo) were generated per sites"

Comment: The IVRS utilises a dynamic randomisation system with an adaptive minimisation technique for prespecified stratification variables (study author replies) 

Allocation concealment (selection bias)

Low risk

Quote: "Using a central interactive voice‐response system, we randomly assigned eligible patients, in a 2:1 ratio, to receive either ferric carboxymaltose (provided by Vifor Pharma) or placebo (normal saline)"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Using a central interactive voice‐response system, we randomly assigned eligible patients, in a 2:1 ratio, to receive either ferric carboxymaltose (provided by Vifor Pharma) or placebo (normal saline)"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Using a central interactive voice‐response system, we randomly assigned eligible patients, in a 2:1 ratio, to receive either ferric carboxymaltose (provided by Vifor Pharma) or placebo (normal saline)"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: No anaemic patients were excluded from the trial (study author replies)

Selective reporting (reporting bias)

Low risk

Comment: All important outcomes were reported

Source of funding bias

High risk

Quote: "Sponsored by Vifor Pharma"

Methods

Randomised clinical trial

Participants

Country: multi‐centric (worldwide)

Sample size: 243

Postrandomisation dropout(s): 5 (2.1%)

Revised sample size: 238

Females: 158 (66.4%)

Mean age: 63 years

Inclusion criteria:

• ≥ 18 years of age

• Active non‐myeloid malignancies

• Anemia (screening haemoglobin ≤ 10 g/dL) related to cancer and chemotherapy

• ≥ 8 additional weeks of planned chemotherapy

• Adequate renal and liver function

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

Exclusion criteria:

• Absolute iron deficiency

• Known sensitivity to iron

• History of a haematological disorder that could cause anaemia (other than a non‐myeloid malignancy)

• Unstable or uncontrolled cardiac disease

• History of deep vein thrombosis within 6 months before screening

• RBC transfusions or erythropoietic therapy or myeloablative radiation therapy within 28 days before randomisation and/or screening

Interventions

Participants were randomly assigned to the following groups:
Group 1: IV iron (n = 116)
Further details: IV iron (further details not available) 400 mcg thrice weekly until ferritin level exceeded 1000 ng/mL (and reinstated if ferritin level dropped to 800 ng/mL)
Group 2: control (n = 122)
Further details: no intervention (oral iron was allowed)

Outcomes

Outcomes reported were mortality, blood transfusion requirements, change in Hb and serious adverse events

Time of measurement: end of treatment

Notes

Reason for postrandomisation dropout(s): did not receive drug

Attempts were made to contact study authors in August 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available

Allocation concealment (selection bias)

Low risk

Quote: "A randomization list was created and maintained by an independent randomization group at the study sponsor using permuted blocks"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "The study was blinded to the dose of darbepoetin alfa administered and open‐label for IV iron administration"

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: This information was not available

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: Important outcomes were reported

Source of funding bias

Unclear risk

Comment: This information was not available

Methods

Randomised clinical trial

Participants

Country: international multi‐centric trial in Europe

Sample size: 398

Postrandomisation dropout(s): 2 (0.5%)

Revised sample size: 396

Females: 240 (60.6%)

Mean age: 61 years

Inclusion criteria:

• Patients with non‐myeloid malignancy with anaemia (Hb < 11 g/dL)

• At least 18 years of age

• Eastern Cooperative Oncology Group performance status score of 0 to 2

• Adequate renal and liver function

• At least 8 weeks of cytotoxic chemotherapy planned

Exclusion criteria:

• Patients with chronic myeloid leukaemia, acute myeloid or lymphocytic leukaemia, hairy cell leukaemia, Burkitt’s lymphoma or lymphoblastic lymphoma

• History of thromboembolism or primary haematological disorder (other than malignancy) that could cause anaemia

• Iron deficiency (transferrin saturation < 15% and serum ferritin < 10 ng/mL)

• Serum ferritin > 800 ng/mL

• Received an RBC transfusion within 14 days or any ESA within 4 weeks preceding randomisation

Interventions

Participants were randomly assigned to the following groups:
Group 1: iron (n = 200)
Further details: intravenous sodium ferric gluconate or iron sucrose 200 mg every 3 weeks as single dose or 2 doses
Group 2: control (n = 196)
Further details: oral iron or no intervention according to standard practice

Outcomes

Outcomes reported were mortality, blood transfusion requirements, quality of life and serious adverse events

Time of measurements: not stated

Notes

Reason for postrandomisation dropout(s): did not receive darbopoetin

Attempts were made to contact study authors in August 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available

Allocation concealment (selection bias)

Low risk

Quote: "Randomization, assigned using an interactive voice response system, was stratified by tumor type…"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: This information was not available

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: This information was not available

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: Important clinical outcomes were reported

Source of funding bias

Unclear risk

Comment: This information was not available

Methods

Randomised clinical trial

Participants

Country: Brazil

Number randomly assigned: 23

Postrandomisation dropouts: 0 (0%)

Revised sample size: 23

Average age: 66 years

Females: 7 (30.4%)

Inclusion criteria:

• 18 years of age or older

• Clinical diagnosis of heart failure for at least 3 months before study entry

• New York Heart Association (NYHA) functional class II to IV, able to perform ergospirometry

• Documentation of left ventricular eject fraction < 40% within past 6 months

• Adequate baseline therapy for heart failure based on patient's functional class (β‐blockers, ACE inhibitors irrespective of functional class except if contraindications, digoxin, spironolactone if NYHA class III or IV)

• Stable baseline heart failure therapy with same doses of medications and no intent to increase doses for the following 3 months

• Haemoglobin ≤ 12 g/dL and ≥ 9 g/dL

• Transferrin saturation < 20% and ferritin < 500 μg/L

• Ability to provide written informed consent

Exclusion criteria:

• Any clinically overt bleeding: gastrointestinal bleeding, hypermenorrhoea, history of peptic ulcer without evidence of healing or inflammatory intestinal disease

• Uncorrected hypothyroidism

• Other inflammatory, neoplastic or infectious disease

• Serum creatinine > 1.5 mg/dL

• Previous intolerance to oral elemental iron compounds

• Heart failure due to alcoholic cardiomyopathy, current regular drinker of alcoholic beverages or heart failure due to peripartum cardiomyopathy

• Recent admission for decompensated heart failure (past month)

• Recent myocardial revascularisation procedures (past 3 months)

• Recent acute coronary syndrome, stroke or transient ischaemic attack (past 3 months)

• Active or metastatic neoplastic disease with life expectancy of less than 1 year

• Patients on heart transplantation list

• Patients who had participated in any other clinical trial or study within the past month

• Pregnant or lactating women

• Premenopausal women who are not using an effective method of contraception

• Patients using prohibited medications or who have not yet accomplished the washout period

• Patients currently participating in cardiovascular rehabilitation programmes

• Patients with pacemakers, implanted defibrillators or cardiac resynchronisation therapy

Interventions

Participants were randomly assigned to 2 groups:
Group 1: IV iron (n = 10)
Further details: iron sucrose 200 mg intravenously, once a week, in 30 minute infusions, for 5 weeks and placebo of oral presentation, 3 times a day, for 8 weeks
Group 2: oral iron (n = 7)
Further details: ferrous sulphate 200 mg, orally, 3 times a day, for 8 weeks and placebo of IV presentation once a week, for 5 weeks

Group 3: control (n = 6)

Further details: placebo

Outcomes

Outcomes reported were mortality, serious adverse events and haemoglobin

Notes

Time of measurement: 13 weeks from start of treatment
Attempts were made to contact study authors in September 2013. They provided additional replies

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomization system will be based on a computerized table of random numbers and performed in blocks of 3 per participating center"

Allocation concealment (selection bias)

Low risk

Quote: "Each of the 8 participating centers will randomize patients by telephone contact with the randomization center at Hospital de Clınicas de Porto Alegre"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Patients were randomized in a double‐blind method to receive…Each participating center will elect a third‐party blind individual (usually a registered nurse) who will open the allocated medication box, prepare iron sucrose infusions or saline, and administer the preparations to patients using opaque devices. Both patient and attending physicians or nurses will be blind to allocated therapy. Oral medications and oral placebo will be identical in all aspects"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Patients were randomized in a double‐blind method to receive…Each participating center will elect a third‐party blind individual (usually a registered nurse) who will open the allocated medication box, prepare iron sucrose infusions or saline, and administer the preparations to patients using opaque devices. Both patient and attending physicians or nurses will be blind to allocated therapy. Oral medications and oral placebo will be identical in all aspects"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: No postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: Mortality and serious adverse events were reported

Source of funding bias

High risk

Quote: "The sponsors provided the intravenous iron formulation, the placebo formulations for oral and intravenous administration as well as most of the study costs"

Methods

Randomised clinical trial

Participants

Country: Thailand

Sample size: 44

Postrandomisation dropout(s): 0 (0%)

Revised sample size: 44

Females: 44 (100%)

Mean age: 51 years

Inclusion criteria:

• Patients with ovarian cancer, endometrial cancer or synchronous ovarian and endometrial cancer receiving first‐line platinum‐based chemotherapy after primary surgery

• Haemoglobin level below 10 g/dL

• Aged 20 to 65 years

• Normal liver and kidney function

• No prior radiotherapy, had at least 1 remaining cycle of chemotherapy

Exclusion criteria:

• Patients with iron hypersensitivity

• Risk of iron overload such as chronic renal failure or thalassaemia major

• Progressive disease

• Bone marrow metastasis

• Inability to monitor weekly complete blood counts

Interventions

Participants were randomly assigned to the following groups:
Group 1: IV iron (n = 22)
Further details: iron sucrose 200 mg over 30 minutes intravenous weekly
Group 2: oral iron (n = 22)
Further details: ferrous (preparation not known) 200 mg thrice daily

Outcomes

Outcomes reported were mortality, blood transfusion requirements, quality of life, haemoglobin levels and serious adverse events

Time of measurements: not stated

Notes

Attempts were made to contact study authors in August 2012. They replied promptly

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was done using a random table"

Allocation concealment (selection bias)

Low risk

Quote: "Only the first investigation knew the allocation number"; "We had the other persons enrol the patients. But the first author run the allocation number according to the stratification" (study author replies)

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Patient and drug administrator were not blinded, however the outcome assessors was blinded" (study author replies)

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Patient and drug administrator were not blinded, however the outcome assessors was blinded" (study author replies)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "There were no post‐randomisation drop‐outs" (study author replies)

Selective reporting (reporting bias)

Low risk

Comment: All important clinical outcomes were reported

Source of funding bias

Low risk

Quote: "We did not have source of funding. However, the company (DKSH Limited, Bangkok, Thailand) supported Venofer. But the company did not involve in research protocol and manuscript writing" (study author replies)

Methods

Randomised controlled trial

Participants

Country: UK

Sample size: 18

Postrandomisation dropout(s): not stated

Revised sample size: 18

Females: not stated

Mean age: not stated

Inclusion criteria:

• Patients scheduled to undergo bowel resection for suspected colorectal cancer

Exclusion criteria:

• Younger than 18 years

• Existing (or had been taking) oral iron supplementation within 6 weeks of the day they were approached

• Received a blood transfusion within that same period

• If date of scheduled surgery fell within 15 days of date of recruitment

Interventions

Participants were randomly assigned to the following groups:
Group 1: IV iron (n = 9)
Further details: 300 mg iron sucrose made up to 250 mL with 0.9% saline 2 infusions separated by at least 24 hours completed within a minimum of 14 days before undergoing elective surgery
Group 2: control (n = 9)
Further details: equal volume of normal saline placebo

Outcomes

Outcomes reported were blood transfusion requirements and haemoglobin levels

Time of measurements: blood transfusion requirements postoperatively and haemoglobin levels preoperatively

Notes

This study included anaemic and non‐anaemic participants. Only anaemic participants were included in this review

Attempts were made to contact study authors in August 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Participants were allocated to either the treatment (iron) group or a placebo group, based on a computer‐generated randomization sequence provided by the Research and Development Support Unit"

Allocation concealment (selection bias)

Low risk

Quote: "Allocation codes were sealed in sequentially numbered opaque envelopes which were secured within a locked store room in a dedicated research unit (this was remote from the clinical areas of the hospital where participants were to undergo outpatient, ward and operative treatment). Only after recruitment was an envelope opened by the investigator administering the infusion, following the inscribed strict numerical order and for the relevant subset appropriate to the Hb status of the participant"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Although the investigator administering the infusion was not blinded to the treatment group, this was concealed from the patient by using an opaque sheath to cover the drug giving set. The chief investigator and clinicians involved in perioperative care also remained blinded to the treatment group for the duration of the trial"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The chief investigator and clinicians involved in perioperative care also remained blinded to the treatment group for the duration of the trial"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: 2 postrandomisation dropouts were reported. Whether these participants were anaemic was not clear

Selective reporting (reporting bias)

High risk

Comment: Important clinical outcomes were not reported

Source of funding bias

High risk

Comment: The review authors thank Syner‐Med Pharmaceutical Products Limited for providing Venofer and for funding the blood tests

Methods

Randomised clinical trial

Participants

Country: multi‐centric (Europe)

Sample size: 485

Postrandomisation dropout(s): 2 (0.4%)

Revised sample size: 483

Females: 284 (58.8%)

Mean age: 39 years

Inclusion criteria:

• Patients with iron deficiency anaemia (Hb 7 to 12 g/dL in females and 7 to 13 g/dL in males)

• Mild to moderate inflammatory bowel disease

• Normal levels of vitamin B‐12 and folic acid

• 18 years of age or older

• Females of childbearing potential had to have a negative urine pregnancy test at screening and had to use an acceptable method of birth control during the study and for up to 1 month after the last dose of the study drug

Exclusion criteria:

• Patients with intravenous or oral iron treatment or blood transfusions within 4 weeks before screening

• History of erythropoietin treatment

• Chronic alcohol abuse; chronic liver disease or increase in transaminases more than 3 times above the normal upper range limit

• Presence of portal hypertension with oesophageal varices

• Known hypersensitivity to study drug

• History of acquired iron overload

• Myelodysplastic syndrome

• Pregnancy or lactation

• Known active infection

• Clinically significant overt bleeding

• Active malignancy or chronic renal failure

• Surgery with relevant blood loss (Hb decrease < 2 g/dL) in the 3 months before screening or planned surgery within following 3 months

• Known human immunodeficiency virus; hepatitis B or hepatitis C virus infection

• Significant cardiovascular disease

• Body weight < 35 kg

• Participation in any other interventional study within 1 month before screening 

Interventions

Participants were randomly assigned to the following groups:
Group 1: preparation 1 (n = 244)
Further details: IV ferric carboxymaltose in single dose (repeated twice if necessary)
Group 2: preparation 2 (n = 239)
Further details: IV iron sucrose twice weekly up to 11 infusions

Outcomes

Outcomes reported were serious adverse events and haemoglobin levels
Time of measurement: 12 weeks from start of treatment

Notes

Reason for postrandomisation dropout(s): did not receive treatment

Attempts were made to contact study authors in August 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomized 1:1 to each of the treatment arms according to a predefined, computer‐generated list and stratified by gender and disease (CD/UC) as provided via sequentially numbered randomization envelopes by data management, PAREXEL International GmbH"

Allocation concealment (selection bias)

Low risk

Quote: "Patients were randomized 1:1 to each of the treatment arms according to a predefined, computer‐generated list and stratified by gender and disease (CD/UC) as provided via sequentially numbered randomization envelopes by data management, PAREXEL International GmbH"

Comment: Allocation concealment probably achieved

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Both participants and physicians were aware of which treatment was being administered"

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Both participants and physicians were aware of which treatment was being administered"

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Postrandomisation dropouts were reported

Selective reporting (reporting bias)

High risk

Comment: Important outcomes were not reported

Source of funding bias

High risk

Quote: "The authors thank all investigators at all study sites (see Appendix), the support in funding and conducting the study (Barbara von Eisenhart Rothe, responsible Medical Director; Janne Harjunpää, statistical analysis; Vifor Pharma, Switzerland), and medical writing support (Walter Fürst; SFL Regulatory Affairs & Scientific Communication, Switzerland)"

Methods

Randomised clinical trial

Participants

Country: Sweden

Sample size: 67

Postrandomisation dropout(s): 0 (0%)

Revised sample size: 67

Females: 42 (62.7%)

Mean age: 76 years

Inclusion criteria:

• Adults with a diagnosis of clinically stable lymphoproliferative malignancy (indolent non‐Hodgkin’s lymphoma (NHL), chronic lymphocytic leukaemia (CLL) or multiple myeloma (MM)) not requiring chemotherapy or blood transfusions

• Hb level of 9 to 11 g/dL (measured on 2 occasions within 1 month and an interval of at least 2 weeks)

• Demonstration of stainable iron in a bone marrow aspirate within 1 month before inclusion

Exclusion criteria:

• Patients with anaemia attributable to factors other than cancer (such as vitamin B₁₂ or folate deficiency, haemolysis or active inflammatory or infectious disease)

• Serum ferritin > 800 mg/L 

• Serum creatinine > 175 mmol/L

• Serum bilirubin > 40 mmol/L

• Eastern Cooperative Oncology Group performance status of > 2

• Prior antitumour therapy within 8 weeks before randomisation or expected within 16 weeks following inclusion

• Prior epoetin treatment within 12 weeks of enrolment

• Iron therapy within the previous 4 weeks

• Uncontrolled hypertension or cardiac disease

• Neurological or psychiatric disorders

• Pregnancy 

Interventions

Participants were randomly assigned to the following groups:
Group 1: IV iron (n = 33)
Further details: intravenous iron sucrose 100 mg per week for 6 weeks followed by 100 mg every alternative week for 8 weeks
Group 2: control (n = 34)
Further details: no intervention

Outcomes

Outcomes reported were mortality, blood transfusion requirements and haemoglobin levels

Time of measurements: end of treatment

Notes

Attempts were made to contact study authors in August 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A central randomization procedure was used (fax formular) and patients received numbers in a consecutive order according to a predetermined scheme and randomly allocated to either receive IV iron or no iron" (study author replies)

Allocation concealment (selection bias)

Low risk

Quote: "A central randomization procedure was used (fax formular) and patients received numbers in a consecutive order according to a predetermined scheme and randomly allocated to either receive IV iron or no iron" (study author replies)

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "This was a prospective, open‐label, randomized, multicenter study"

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "This was a prospective, open‐label, randomized, multicenter study"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: No postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: All important clinical outcomes were reported

Source of funding bias

High risk

Comment: This work was supported by grants from Roche AB, Sweden, and the Research and Development Centre, Sundsvall Hospital, Sundsvall, Sweden

Methods

Randomised clinical trial

Participants

Country: Australia

Number randomly assigned: 605

Postrandomisation dropouts: 0 (0%)

Revised sample size: 605

Average age: not stated

Females: not stated

Inclusion criteria:

• Gastrointestinal patients with iron deficiency anaemia who cannot take oral iron

Interventions

Participants were randomly assigned to 2 groups:
Group 1: IV iron (n = 406)
Further details: ferrumoxytol 510 mg 2 doses 3 to 8 days apart
Group 2: IV iron (n = 199)
Further details: iron sucrose 200 mg 5 infusions over 14 days

Outcomes

Outcomes reported were mortality and serious adverse events

Notes

Time of measurement: 5 weeks after start of treatment
Attempts were made to contact study authors in September 2013. They provided additional information

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomization scheme and codes were computer‐generated" (study author replies)

Allocation concealment (selection bias)

Low risk

Quote: "An interactive voice response system (IVRS) was used to assign unique randomization numbers for each subject. This is a telephone based system that was accessible at all times. Randomization numbers were not reused for any use" (study author replies)

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Open‐label"

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Open‐label"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: No postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: Mortality and morbidity were reported

Source of funding bias

High risk

Comment: sponsored by AMAG Pharmaceuticals Inc

Methods

Randomised clinical trial

Participants

Country: Canada

Sample size: 26

Postrandomisation dropout(s): 5 (19.2%)

Revised sample size: 21

Females: 5 (23.8%)

Mean age: 62 years

Inclusion criteria:

• Adult patients (> 18 years old) undergoing open‐heart surgery, total hip arthroplasty or spinal fusion with Hb between 7 and 9 g/dL on the morning of the first postoperative day (POD‐1)

Exclusion criteria:

• Preoperative anaemia (Hb < 12 g/dL in women and < 14 g/dL in men)

• Preoperative autologous blood donation

• IV iron or erythropoietin therapy

• Active infection

• Pregnancy or lactation

• Major co‐morbidities (previous history of stroke, transient ischaemic attacks or seizures; significant respiratory disease (FEV₁ < 50% predicted), renal disease (creatinine > 200 micromol/L)

• Liver disease (hepatitis, cirrhosis)

• Uncontrolled hypertension (systolic > 180, diastolic > 100 mmHg)

• Any haematological disease (e.g. thromboembolic events, haemoglobinopathy, coagulopathy, haemolytic disease)

• Patients with ongoing haemorrhage

• Evidence of organ dysfunction on POD‐1

Interventions

Participants were randomly assigned to the following groups:
Group 1: iron (n = 11)
Further details: iron sucrose 200 mg IV on 1st, 2nd and 3rd postoperative days for a total of 600 mg
Group 2: control (n = 10)
Further details: normal saline placebo
Another group in which erythropoietin was added to iron was excluded from analysis

Outcomes

Outcomes reported were blood transfusion requirements and haemoglobin levels

Time of measurements: 42nd postoperative day

Notes

Study authors used arbitrary weights to adjust haemoglobin levels based on transfusion
Reason for postrandomisation dropout(s): 4 withdrew, so the primary outcome could not be measured. In one, the primary outcome could not be measured

Attempts were made to contact study authors in August 2012. They replied promptly

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "In each stratum, patients were randomized in randomly permuted blocks of three patients according to a computer‐generated table of random numbers"

Allocation concealment (selection bias)

Low risk

Quote: "The assignments were placed into opaque sequentially numbered envelopes with pharmacy"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "For all three groups the IV solution was draped with an opaque cover and the IV tubing was covered with a translucent tape. Patients in the vontrol group and the iron group received SC and IV injections of normal saline"
Comment: Subcutaneous placebo was for blinding different groups to the combination treatment of iron and erythropoietin

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "For all three groups the IV solution was draped with an opaque cover and the IV tubing was covered with a translucent tape. Patients in the vontrol group and the iron group received SC and IV injections of normal saline"
Comment: Subcutaneous placebo was for blinding different groups to the combination treatment of iron and erythropoietin

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: All important clinical outcomes were reported

Source of funding bias

High risk

Quote: "K. Karkouti is supported in part by the Canadian Institutes of Health Research and the Canadian Blood Services. T.M. Yau is supported in part by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Ontario. K. Karkouti and S.A. McCluskey have received research funding and speakers’ fees from Ortho Biotech"

Methods

Randomised clinical trial

Participants

Country: UK

Sample size: 20

Postrandomisation dropout(s): not stated

Revised sample size: 20

Females: 9 (45%)

Mean age: not stated

Inclusion criteria:

• Patients undergoing surgery for colorectal cancer

(only anaemic patients were included in this review)

Interventions

Participants were randomly assigned to the following groups:C
Group 1: oral iron (n = 6)
Further details: 200 mg oral ferrous sulphate until surgery
Group 2: control (n = 14)
Further details: no intervention

Outcomes

Outcome reported was blood transfusion requirements
Time of measurement: perioperative

Notes

Attempts were made to contact study authors in August 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available

Allocation concealment (selection bias)

Low risk

Quote: "patients were randomised (by telephone to a distant centre) to…"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "It was not possible to use a placebo and blind the patient, as oral iron alters stool colour"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The clinical team (surgeons, nurses, anaesthetists) were blinded to treatment allocation. The collection of data was performed by a research fellow not involved in the direct
care of the patient, and gathered from the clinical notes"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: This information was not available

Selective reporting (reporting bias)

High risk

Comment: Important outcomes were not reported

Source of funding bias

Unclear risk

Comment: This information was not available

Methods

Randomised clinical trial

Participants

Country: Sweden

Sample size: 91

Postrandomisation dropout(s): not stated

Revised sample size: 91

Females: 63 (69.2%)

Mean age: 42 years

Inclusion criteria:

• Patients with inflammatory bowel disease with iron deficiency anaemia (haemoglobin (Hb) concentration < 11.5 g/dL with serum ferritin concentrations ≤ 30 mcg/dL and iron deficiency based on iron, transferrin and ferritin)

• Age between 18 and 85 years

Exclusion criteria:

• Active relapsing stage of inflammatory bowel disease

• Pregnant

• Clinically significant haematological disease other than iron‐deficiency anaemia or any other clinically significant disease/dysfunction that in the opinion of the investigator disqualified them from this study

• Symptomatic intestinal strictures

• Treated with oral or parenteral iron during previous month

• Serum creatinine levels > 250 mmol/L

• Deficiencies in cobalamin and/or folic acid

• Contraindications for administration of iron sucrose or ferrous sulphate

• If there were plans for significant surgery during the study period

Interventions

Participants were randomly assigned to the following groups:
Group 1: IV iron (n = 45)
Further details: iron sucrose 200 mg once a week or twice a week for 20 weeks to reach the cumulative dose
Group 2: oral iron (n = 46)
Further details: ferrous sulphate 200 mg twice a day for 20 weeks

Outcomes

Outcomes reported were haemoglobin levels and serious adverse events

Time of measurements: end of treatment

Notes

Attempts were made to contact study authors in August 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were allocated to any of the treatments over the Internet, by applying the minimization method to ensure a balance within the patient factors age, B‐Hb and S‐ferritin"

Allocation concealment (selection bias)

Low risk

Quote: "Patients were allocated to any of the treatments over the Internet, by applying the minimization method to ensure a balance within the patient factors age, B‐Hb and S‐ferritin"
Comment: In the absence of blinding, this may lead to bias

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Venofer is a dark‐brown, non‐transparent, aqueous solution to be administered intravenously. There is no placebo solution available"
Comment: Participants and healthcare providers not blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: Although the trial states that observer blinding was performed, further details were not available

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: This information was not available

Selective reporting (reporting bias)

High risk

Comment: Important clinical outcomes were not reported

Source of funding bias

High risk

Comment: The study was supported by Renapharma AB, Uppsala, Sweden

Methods

Randomised clinical trial

Participants

Country: Italy

Sample size: 148

Postrandomisation dropout(s): 0 (0%)

Revised sample size: 148

Females: 59 (39.9%)

Mean age: 68 years

Inclusion criteria:

• Patients with advanced cancer with Hb level ≤ 10 g/dL

• 18 years of age or older

• Eastern Cooperative Oncology Group performance status (ECOG PS) score ≤ 2

• No previous treatment

• Receiving first‐line chemotherapy while on study

• Serum ferritin level ≥ 100 ng/mL but ≤ 800 mg/dL and/or transferrin saturation > 15%

• Life expectancy ≥ 6 months

• Adequate renal and hepatic function

Exclusion criteria:

• Patients with anaemia attributable to factors other than cancer and chemotherapy (e.g. B₁₂ or folate deficiency, haemolysis, gastrointestinal bleeding, myelodysplastic syndrome, bone marrow metastases)

• Prior transfusion, ESA or IV iron therapy within 4 weeks of enrolment

• Allergy or intolerance to iron and/or rHuEPO, active infection

• Absolute iron deficiency

• Pregnancy, breastfeeding, inadequate birth control measures

• History of seizure disorders

• Active cardiac disease, thromboembolic disease and uncontrolled hypertension

Interventions

Participants were randomly assigned to the following groups:
Group 1: IV iron (n = 73)
Further details: 125 mg of ferric gluconate IV once weekly
Group 2: oral iron (n = 75)
Further details: 200 mg of lactoferrin daily

Outcomes

Outcomes reported were haemoglobin levels

Time of measurements: end of treatment

Notes

Attempts were made to contact study authors in August 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomized using a computer‐generated list of random numbers elaborated by an external data manager" (study author replies)

Allocation concealment (selection bias)

Low risk

Quote: "The allocation concealment incorporates the involvement of an external data manager, not a physician involved in patient management, who assigned the randomization sequence in order to protect the randomization sequence until allocation" (study author replies)

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "This was an open‐label, randomized, controlled, prospective study comparing the efficacy and safety of rHuEPO combined with oral lactoferrin (Lattoglobina; Grunenthal‐ Formenti, Milan, Italy) or IV iron supplementation in advanced cancer patients with anemia undergoing chemotherapy"

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "This was an open‐label, randomized, controlled, prospective study comparing the efficacy and safety of rHuEPO combined with oral lactoferrin (Lattoglobina; Grunenthal‐ Formenti, Milan, Italy) or IV iron supplementation in advanced cancer patients with anemia undergoing chemotherapy"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: No postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: All important clinical outcomes were reported

Source of funding bias

Low risk

Quote: "This work was supported by the Associazione Sarda per la ricerca nell’Oncologia Ginecologica‐ONLUS"; "No funding has been received from the drug manufacturer. The study was not sponsored nor funded by any manufacturers" (study author replies)

Methods

Randomised clinical trial

Participants

Country: Lebanon

Sample size: 80

Postrandomisation dropout(s): 0 (0%)

Revised sample size: 80

Females: not stated

Mean age: not stated

Inclusion criteria:

• 120 American Society of Anesthesiologists (ASA) II or III patients, who underwent elective cardiac surgery using cardiopulmonary bypass and in whom postpump haemoglobin ranged between 7 and 10 g/dL

Exclusion criteria:

• Transfusion of allogeneic blood intraoperatively

• Unstable haemodynamic status after surgery

• Ejection fraction < 40%

• Preoperative anaemia of any cause such as renal failure, hypothermic bypass

• Contraindications for parenteral iron such as rheumatoid arthritis, history of allergic reactions to iron, haemosiderosis and liver disease

Interventions

Participants were randomly assigned to the following groups:
Group 1: iron (n = 40)
Further details: iron sucrose IV 200 mg/d starting on day 1 to reach total iron deficit
Group 2: control (n = 40)
Further details: placebo.
Another group in which iron was used in combination with erythropoietin was excluded

Outcomes

Outcomes reported were mortality, blood transfusion requirements and haemoglobin levels

Time of measurements: 30 days from start of treatment

Notes

Attempts were made to contact study authors in August 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available

Allocation concealment (selection bias)

Low risk

Quote: "Drug manipulation and assignment were handled by the central pharmacy to assure double blinding"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: Although a placebo was used, further details of placebo such as colour were not available

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: This information was not available

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: No postrandomisation dropouts for the main clinical outcomes were reported

Selective reporting (reporting bias)

Low risk

Comment: Important clinical outcomes were reported

Source of funding bias

Unclear risk

Comment: This information was not available

Methods

Randomised clinical trial

Participants

Country: UK

Number randomly assigned: 300

Postrandomisation dropouts: 0 (0%)

Revised sample size: 300

Average age: 82 years

Females: 245 (81.7%)

Inclusion criteria:

• Postoperative haemoglobin level < 110 g/L within 5 days after hip fracture surgery

Exclusion criteria:

• Patient unwilling to give written informed consent or for whom the relative or next of kin was unavailable or declined to give assent

• Postoperative haemoglobin level ≥ 110 g/L

• Multiple trauma (defined as more than 2 other fractures or any other fracture requiring surgery other than simple manipulation)

• Patient unable to take oral iron medication because of adverse effects

• Patient taking iron therapy at time of admission

• Haemoglobin level < 110 g/L at time of admission

• Patient unable to attend routine follow‐up at hip fracture clinic

• Age < 60 years

Interventions

Participants were randomly assigned to 2 groups
Group 1: oral iron (n = 150)
Further details: ferrous sulphate 200 mg twice daily orally for 28 days

Group 2: control (n = 150)
Further details: no intervention

Outcomes

Outcomes reported were mortality, serious adverse events and haemoglobin levels
Time of measurement: mortality 1 year; adverse events and haemoglobin levels 6 weeks after hospital discharge

Notes

Attempts were made to contact study authors in November 2012. They replied promptly

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The envelopes for this study were prepared by me, sealed, mixed up and then numbered" (study author replies)

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was accomplished by opening a sealed opaque numbered envelope for each patient" 

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Potential weaknesses of the study include the lack of a placebo"

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Also, there was no blinding of the outcome assessors for the present study"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: No postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: All important outcomes were reported

Source of funding bias

Low risk

Quote: "There was no external funding for this study" (study author replies)

Methods

Randomised controlled trial

Participants

Country: USA

Sample size: 200

Postrandomisation dropout(s): 0 (0%)

Revised sample size: 200

Females: 103 (51.5%)

Mean age: 57 years

Inclusion criteria:

• Admitted to the general surgical, burn or neurosurgical intensive care unit (ICU)

• Age ≥ 18 years

• Hb < 13 g/dL

• < 72 hours from hospital admission

• Current tolerance of enteral medications

• Expected ICU length of stay ≥ 5 days

Exclusion criteria:

• Active bleeding

• Chronic inflammatory conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis)

• End‐stage renal disease (dialysis‐dependent)

• Haematological disorders (e.g. thalassaemia, sickle cell disease, myelodysplasia)

• Macrocytic anaemia

• Current use of erythropoietin

• Pregnancy

• Prohibition of RBC transfusions

• Moribund state in which death was imminent

• Enrolment in any other clinical trial

Interventions

Participants were randomly assigned to the following groups:
Group 1: oral iron (n = 97)
Further details: enteral iron sulphate 325 mg thrice daily for 6 weeks or until discharge
Group 2: control (n = 103)
Further details: placebo

Outcomes

Outcomes reported were blood transfusion requirements
Time of measurement: end of treatment

Notes

Attempts were made to contact study authors in August 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was accomplished by the investigational pharmacy (SB) using a block pattern stratified by ICU type"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "All involved parties with the exception of the investigational pharmacist were blinded to the identity of the study drug, including patients and their families, those administering the intervention, and those assessing the outcomes..."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "All involved parties with the exception of the investigational pharmacist were blinded to the identity of the study drug, including patients and their families, those administering the intervention, and those assessing the outcomes..."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: No postrandomisation dropouts were reported

Selective reporting (reporting bias)

High risk

Comment: Important outcomes were not reported

Source of funding bias

Unclear risk

Comment: This information was not available

Methods

Randomised controlled trial

Participants

Country: USA

Sample size: 502

Postrandomisation dropout(s): 12 (2.4%)

Revised sample size: 490

Females: 320 (65.3%)

Mean age: 64 years

Inclusion criteria:

• 18 years of age or older

• Receiving chemotherapy for a non‐myeloid neoplasm

• Hb < 11.0 g/dL

• Ferritin > 20 ng/mL

• Transferrin saturation < 60%

• Zubrod performance score better than 2

Exclusion criteria:

• Patients with history of thromboembolism within 1 year of enrolment

• Genetic haemochromatosis

• Recent surgery

• Anaemia caused by myelodysplastic syndrome, nutritional deficiency or a non‐neoplastic haematologic disorder such as thalassaemia

• Received an ESA within 3 months or red cell transfusion within 14 days

Interventions

Participants were randomly assigned to the following groups:
Group 1: IV iron (n = 164)

Further details: sodium ferric gluconate complex in sucrose IV 187.5 mg over 90 minutes once every 3 weeks for 5 doses
Group 2: oral iron (n = 163)

Further details: ferrous sulphate oral 325 mg once daily
Group 3: control (n = 163)

Further details: oral placebo 

Outcomes

Outcomes reported were mortality, blood transfusion requirements, quality of life and serious adverse events

Time of measurements: 16 weeks from start of treatment

Notes

Reason for postrandomisation dropout(s): did not have haemoglobin measurements

Attempts were made to contact study authors in August 2012. They replied promptly

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "It was computer generated" (study author replies)

Allocation concealment (selection bias)

Low risk

Quote: "Random assignment was done by calling the central randomization center by telephone"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Patients and investigators were blinded to assignment of oral iron or oral placebo, but, for practical reasons, assignment to IV iron versus an oral product was not blinded"

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Patients and investigators were blinded to assignment of oral iron or oral placebo, but, for practical reasons, assignment to IV iron versus an oral product was not blinded"

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: Important clinical outcomes were reported

Source of funding bias

Unclear risk

Quote: "Supported in part by Public Health Service Grant No. CA‐124477 and grant from Amgen (Thousand Oaks, CA) to the Mayo Clinic Cancer Research Consortium"

Methods

Randomised controlled trial

Participants

Country: UK

Number randomly assigned: 72

Postrandomisation dropouts: not stated

Revised sample size: 72

Average age: 70 years

Females: 30 (41.7%)

Inclusion criteria:

• Anaemic patients (8 to 12 g/dL for men and 8 to 11 g/dL for women) at 5 to 7 days postoperatively after primary hip or knee arthroplasty

Exclusion criteria:

• Preoperative level of haemoglobin < 12 g/dL for men and < 11 g/dL for women

• Not able to give informed consent

• Were to be followed up elsewhere

• Had rheumatoid arthritis

• Were taking ciprofloxacin, tetracyclines, antacids or bisphosphonates

• Already taking iron salts or vitamin supplements, which might include iron

Interventions

Participants were randomly assigned to 2 groups:
Group 1: oral iron (n = 35)

Further details: ferrous sulphate 200 mg thrice daily orally for 6 weeks after surgery
Group 2: control (n = 37)
Further details: gelatine placebo

Outcomes

Outcomes reported were haemoglobin levels
Time of measurement: end of treatment

Notes

Attempts were made to contact study authors in November 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Those patients who entered into the study were randomly assigned by the hospital pharmacy into two groups using computer generated random numbers" 

Allocation concealment (selection bias)

Low risk

Quote: "Those patients who entered into the study were randomly assigned by the hospital pharmacy into two groups using computer generated random numbers"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "One group received ferrous sulphate in 200 mg capsules and the second (37 patients) were given a gelatine placebo. Both groups were prescribed their capsules three times daily for six weeks after discharge from hospital. Both patients and investigators were blind to the treatment allocated until the end of the trial"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "One group received ferrous sulphate in 200 mg capsules and the second (37 patients) were given a gelatine placebo. Both groups were prescribed their capsules three times daily for six weeks after discharge from hospital. Both patients and investigators were blind to the treatment allocated until the end of the trial"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: This information was not available

Selective reporting (reporting bias)

Low risk

Comment: All important outcomes were reported

Source of funding bias

Low risk

Quote: "No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article"

Methods

Randomised controlled trial

Participants

Country: worldwide

Number randomly assigned: 812

Postrandomisation dropouts: 4 (0.5%)

Revised sample size: 808

Average age: 45 years

Females: 720 (89.1%)

Inclusion criteria:

• 18 years of age or older with a history of iron deficiency anaemia, defined as haemoglobin (Hgb) level < 10.0 g/dL and transferrin saturation (TSAT) < 20%

• History of unsatisfactory oral iron therapy or those in whom oral iron could not be used

Exclusion criteria:

• History of allergy to iron

• Hb level ≤ 7.0 g/dL

• Serum ferritin > 600 ng/mL

• Known causes of anaemia other than iron deficiency

• Active infection

• Haematological malignancies

• On dialysis or had estimated glomerular filtration rate < 30 mL/min/1.73 m²

• Pregnant, intended to become pregnant or were breastfeeding

• Patients who received another investigational agent or IV iron therapy within 4 weeks of screening, or who had received oral iron therapy or blood transfusion within 2 weeks before screening

Interventions

Participants were randomly assigned to 2 groups
Group 1: IV iron (n = 608)
Further details: ferumoxytol 510 mg IV weekly for 5 weeks
Group 2: control (n = 200)
Further details: placebo

Outcomes

Outcomes reported were mortality, morbidity, quality of life and haemoglobin levels

Notes

Time of measurement: 5 weeks after start of treatment
Attempts were made to contact study authors in September 2013
Reasons for postrandomisation dropouts: adverse event (1); protocol violation (1); withdrew consent (2)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available

Allocation concealment (selection bias)

Low risk

Quote: "Patients were randomized using an Interactive Voice Randomization System"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Blinding was accomplished by having both ferumoxytol and normal saline administered in a shrouded manner by a unblinded Test Article Administrator, while both study participants and all other study staff including the investigator were blinded to what was administered"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Blinding was accomplished by having both ferumoxytol and normal saline administered in a shrouded manner by a unblinded Test Article Administrator, while both study participants and all other study staff including the investigator were blinded to what was administered"

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: Mortality and morbidity were reported

Source of funding bias

Unclear risk

Quote: "All data were analyzed by representatives of the clinical and biostatistical groups of AMAG Pharmaceuticals"

Methods

Randomised clinical trial

Participants

Country: USA, Mexico

Sample size: 477

Postrandomisation dropout(s): 24 (5%)

Revised sample size: 453

Females: 453 (100%)

Mean age: 39 years

Inclusion criteria:

• Patients with anaemia, defined as haemoglobin ≤ 11.0 g/dL

• 18 years of age or older

• Heavy uterine bleeding

• Use of adequate birth control

• Serum transferrin saturation ≤ 25%, and serum ferritin level ≤ 100 ng/mL

Exclusion criteria:

• Red blood cell (RBC) transfusion or parenteral iron administration within prior 8 weeks or anticipated need for blood transfusion during study

• Existing disorders of erythropoiesis

• Haemochromatosis

• Initiation of hormonal therapy potentially affecting uterine bleeding during 8 weeks before study entry

• Use of erythropoiesis‐stimulating agents within prior 12 weeks

• Postmenopausal patients without endometrial biopsy within prior 6 months

• Malignancy

• Endometrial hyperplasia with atypia

• Alcohol or drug abuse

• Myelosuppressive therapy

• Evidence of chronic viral infection (hepatitis B surface antigen, hepatitis C virus antibody or human immunodeficiency virus)

• Serum transaminase level > 1.5 times upper limit of normal

• Serum creatinine level > 2.0 mg/dL

Interventions

Participants were randomly assigned to the following groups:
Group 1: IV iron (n = 228)
Further details: ferric carboxymaltose 500 mg IV on study day 0, 7, 14 (as needed) to obtain calculated dose
Group 2: oral iron (n = 225)
Further details: ferrous sulphate 325 mg 3 times daily for 42 days

Outcomes

Outcomes reported were mortality, quality of life, haemoglobin levels and serious adverse events

Time of measurements: 6 weeks from start of treatment

Notes

Reason for postrandomisation dropout(s): did not complete study or haemoglobin levels were not available

Attempts were made to contact study authors in August 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomization sequence for the VIT02/03 studies were generated by using Proc Plan in SAS Version 8 by the CRO we used for these trials"

Allocation concealment (selection bias)

Low risk

Quote: "Treatment group and subject number were assigned by blocked randomization using an interactive voice response system"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "This was an open‐label, Phase 3, randomized, active control clinical trial with two parallel treatment groups"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "This was an open‐label, Phase 3, randomized, active control clinical trial with two parallel treatment groups"

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: All important clinical outcomes were reported

Source of funding bias

Unclear risk

Quote: "Support for this study was provided by American Regent, Inc., the human drug division of Luitpold Pharmaceuticals, Shirley, NY"