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Keywords:

  • Adverse events;
  • Intravenous iron;
  • Iron dextran;
  • Iron sucrose;
  • Systematic review

SUMMARY

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION AND CONCLUSIONS
  7. REFERENCES
  8. Appendices

Intravenous iron administration is an effective method of treating iron deficiency anemia, but there have been concerns about adverse side effects, particularly serious events such as anaphylactic reaction. Several different forms of intravenous iron are available, but few studies have attempted to compare the frequency of adverse events.

We carried out a systematic review to assess the frequency of adverse drug events (ADEs) associated with (i) low-molecular-weight intravenous iron dextran and (ii) iron sucrose. We searched several electronic databases; two reviewers screened all studies identified and extracted data. We included 60 studies, but few directly compared adverse events associated with two or more forms of iron, and most were not specifically designed to evaluate adverse events.

In general, with the exception of high-molecular-weight iron dextran (HMWID), serious or life-threatening adverse events appeared rare. Several studies showed lower risks of ADEs on low-molecular-weight iron dextran (LMWID) compared with HMWID, and one large review found a reduced risk on LMWID compared with iron gluconate. Two studies showed little difference between iron sucrose and iron gluconate, and two further studies had similar rates of adverse drug events between iron sucrose and LMWID; however, the sample size for most of these studies was too small to draw firm conclusions. Adequately powered direct comparisons of different forms of intravenous iron are required to assess the safety profiles.


INTRODUCTION

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION AND CONCLUSIONS
  7. REFERENCES
  8. Appendices

Anemia is the leading cause of disability worldwide,1 and many groups of patients need iron supplementation (e.g. patients in renal failure, those with inflammatory bowel disease, and pregnant women among others). Oral iron supplementation is often poorly tolerated due to gastrointestinal side effects.2–4 Other problems with oral iron include poor compliance and lack of efficacy.2,5 Intravenous iron is an alternative for these patients, but there have been concerns about side effects associated with forms of intravenous iron used in the past, particularly high-molecular-weight intravenous iron dextran (HMWID – trade names include Dexferrum and Imferon).4,6–7 New forms of intravenous iron are now available including low-molecular-weight intravenous iron dextran (LMWID – trade names InFed or CosmoFer), iron sucrose or saccharate (Venofer) and iron gluconate (Ferrlicit).

LMWID has a molecular weight of around 90,000 daltons, compared with 265,000 for HMWID. Molecular weight may have an impact on the safety profiles of these products. From selected studies, it has been reported that LMWID dextran offers a safety profile that is very different from the older HMWID complexes.8 LMWID has a significantly lower risk of both serious and nonserious acute adverse drug events (ADEs) compared with HMWID.8 However, few studies have attempted to assess all the evidence on the safety profile of these two products, and there is a need to establish whether LMWID has the same side effect profile as the HMWID previously used, and how the side effects of LMWID compare with other forms of intravenous iron. Further, newer intravenous forms, such as iron sucrose, are now available, and updated summaries of their side effects are also needed. This systematic review aims:

  • 1
    to identify, appraise and summarize studies comparing the side effect profile of LMWID and iron sucrose with each other and with other forms of intravenous iron such as iron gluconate, and HMWID.
  • 2
    to identify, appraise and summarize studies reporting on the side effect profile of LMWID and iron sucrose (i.e. case series of patients receiving iron dextran or iron sucrose, but not comparing safety with other forms of intravenous iron).

METHODS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION AND CONCLUSIONS
  7. REFERENCES
  8. Appendices

Search strategy

The search strategy aimed to identify all relevant studies relating to the use of LMWID complex (trade names InFed or CosmoFer) and iron sucrose (trade name Venofer) compared with each other or with HMWID (trade name Dexferrum or Imferon) or iron gluconate (trade name Ferrlecit) – see Appendix 1.

The electronic databases including MEDLINE, EMBASE, Science Citation Index Expanded/Web of Science and The Cochrane Central Register of Controlled Trials (2004, issue 3) were searched for the period from 1990 to December 2004. The search was not limited to any specific study design, had no language restrictions and was conducted without methodological filters. Specific drug terms (e.g. iron dextran, iron sucrose, CosmoFer, InFed and Venofer) were included.

Inclusion criteria

Randomized controlled trials (RCTs) or other study designs including uncontrolled retrospective/prospective studies were included if they reported on ADEs associated with use of (i) LMWID complex (CosmoFer, InFed), or (ii) iron sucrose or saccharate (Venofer). Case studies with fewer than 10 patients were excluded, as these are too small to obtain reliable data on ADEs.

We identified studies reporting solely on the ADEs associated with LMWID complex, or with iron sucrose. We also identified a small number of comparative studies, comparing the frequency of ADEs on LMWID or iron sucrose with each other or with other forms of intravenous iron (iron gluconate and HMWID).

RESULTS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION AND CONCLUSIONS
  7. REFERENCES
  8. Appendices

Description of studies

Studies comparing different forms of intravenous iron

Ten studies compared ADEs on different forms of intravenous iron (Table 1). Two studies compared iron sucrose (Venofer) with iron gluconate.9,10 One case-crossover study compared LMWID (InFed) with iron sucrose (Venofer).11 One other study compared iron dextran with iron sucrose, but it was unclear whether LMWID or HMWID was used.12 One large ‘chart review’ (a retrospective method of collecting data that involves reviewing medical records) compared LMWID (InFed) with both HMWID (Dexferrum) and iron gluconate (Ferrlecit).13 One study14 compared LMWID (InFed) with iron gluconate (Ferrlecit). Four studies15–18 compared LMWID with HMWID.

Table 1.  Characteristics and nature of ADEs associated with two or more forms of intravenous iron
Study nameIntervention/study design and detailsNonserious ADEsSerious/life-threatening ADEsTotal ADEsInterpretation
  1. 95% CI, 95% confidence intervals; ADEs, adverse drug events; FDA, Food and Drug Administration; HMWID, high-molecular-weight iron dextran; IDA, iron deficiency anemia; IV, intravenous; LMWID, low-molecular-weight iron dextran; OR, Odds Ratio; PD, peritoneal dialysis; rhEPO, recombinant human erythropoietin; RCT, randomized controlled trial; TDI, total dose infusion.

1. Iron sucrose compared with iron gluconate
Kosch et al. 20019 Munster, GermanyRCT among stable rhEPO-treated hemodialysis patients with two groups:  (1) IV iron sucrose (Venofer) (n = 27)  (2) IV iron gluconate (Ferrlecit) (n = 28)The most common were flu, infections, sinusitis, surgery and pneumonia. Most of the reported ADEs were associated with chronic renal failure, and none considered to be related to the drugsNone16 ADEs on iron sucrose (over 174 infusions) 14 ADEs on iron gluconate (over 740 injections) (Total incidence of 44% regardless of iron preparation)ADEs were similar for both groups.
Bulvik et al. 199710 Department of Haematology, Netanya, IsraelProspective comparative study of 98 IDA patients Group A, n = 57, received Ferrlecit (iron gluconate); Group B, n = 41, received Veneferrum (iron saccharate) 10 infusions, 100 mg over 3 hours.Included nausea, severe diarrhea, metallic taste, moderate hypotension, local phlebitis, severe acute lower back pain, giddiness. No differences between groups.NoneModerate ADEs:  Gluconate 4/57*  Saccharate 3/41 Minor ADEs:  Gluconate 10/57  Saccharate 5/41ADEs were similar for both groups. Abstract. Limited methodological details. Includes one patient who had abnormalities of liver function tests
2. Iron sucrose compared with iron dextran
Moniem and Bhandari 200311 Hull, UKProspective crossover study in 39 stable hemodialysis patients. Received fortnightly 100 mg iron sucrose (Venofer), converted to 100 mg fortnightly iron dextran (CosmoFer) for 6 months, then back to Venofer. Patients received 2111 doses Venofer and 2287 doses CosmoFer, respectively.Minor events included flushing/tingling, diarrhea, vomiting, headache, chest pain.None5/2111 ADEs on Venofer (0.237%, 95% CI 0.077% to 0.55%, 7/2287 ADEs on CosmoFer (0.0031%, 95% CI 0.12% to 0.63%).No reported major clinical events or anaphylaxis. ADEs were similar for both groups.
Prakash et al. 200112 Toronto, CanadaRetrospective analysis of 379 patients attending PD clinics over a 5-year period. 33 received iron dextran, 23 iron saccharate, 5 iron dextran and iron saccharateMinor reactions included skin rash, myalgia, chest pain, abnormal sensation in chestIron dextran: 1/34 had anaphylactic reaction (hypotension, bradycardia, vomiting). Iron saccharate: 1/23 anaphylactic reactionIron dextran: 5/34 (14.7% of patients, 7.4% of injections) had ADE, mostly minor (unclear what form of iron dextran) Iron saccharate: 2/23 (8.7% of patients, 4.3% of injections) had minor ADEsNo deaths, hospitalizations or permanent disabilities. ADEs were similar for both groups.
3. Iron dextran compared with iron gluconate
Chertow et al. 200413 Review of FDA data, USALMWID (InFed) vs. LMWID (Dexferrum) vs. sodium ferric gluconate (Ferrlecit) Retrospective review of FDA data on ADEs (1998–2000). All parenteral iron-related ADEs reported to FDA, Uppsala, Sweden. Total no. of InFed doses administered: 14,919,000 Total no. of Ferrlecit doses: 1,083,000LMWID (InFed):LMWID (InFed):  Anaphylactic reaction   28/14,919,000  Death   9/14,919,000  Respiratory depression   7/14,919,000 Gluconate (Ferrlecit):  Anaphylactic reaction   3/1,083,000  Death   1/1,083,000  Respiratory depression   0/1,083,000Average ADEs reported per patient: InFed 3.1 per patient Ferrlecit 3.6 per patient Dexferrum 3.0 per patient Total major ADEs significantly increased among recipients of Dexferrum (OR 5.5, 95% CI 4.9–6.0) and Ferrlecit (OR 6.2, 95% CI 5.4–7.2) compared with InFed. InFed total ADEs:  598/14,919,000, i.e. 0.004% of infusions experienced ADEs (95% CI = 0.0037% to 0.0043%). Ferrlecit total ADEs:  271/1,083,000, i.e. 0.025% of infusions experienced ADEs (95% CI = 0.022% to 0.028% Dexferrum total ADEs:  1112/5,058,000, i.e. 0.02% (95% CI = 0.021% to 0.023%) Serious ADEs per million doses of 100 mg: InFed  11.6 Ferrlicit  49.6 Dexferrum  57.9Significantly higher rates of life-threatening ADEs observed among Dexferrum compared with InFed
 Allergic reaction:13
 Facial edema:5
 Pruritus:19
 Urticaria:10
Gluconate (Ferrlecit):
 Allergic reaction:7
 Facial edema:1
 Pruritus:10
 Urticaria:5
LMWID (InFed)
 Nausea:21
 Vomiting:9
Gluconate (Ferrlecit):
 Nausea:15
 Vomiting:9
LMWID (InFed):
 Back pain:23
 Chest pain:33
 Tachycardia:10
 Hypotension:35
 Dyspnea:7
 Sweating:9
Gluconate (Ferrlecit):
 Back pain:15
 Chest pain:23
 Tachycardia:2
 Hypotension:23
 Dyspnea:18
 Sweating:5
Fletes et al. 200115 Fresenius Medical Center, USALMWID (InFed) vs. HMWID (Dexferrum) Retrospective study, all clinical variance reports for drug-related ADEs filed at Fresenius Medical Care, North America facilities October 1998–March 1999InFed  55 ADEs from 675,024 infusions Dexferrum  110 ADEsNone55 reported ADEs to InFed out of 675,024 infusions (8.15 × 10−5), i.e. = 0.0081%, 95% CI 0.0061% to 0.0106%8.12-fold increased risk with Dexferrum (95% CI 8.08–8.17).
Peck et al. 199816 Philadelphia, USALMWID (InFed) vs. HMWID (Dexferrum) Prospective study. 28 children with irritable bowel disease and Fe deficiency anemia. 51 infusions were given between 1988 and 1998  InFed 4 ADEs during 44 (9%) infusions Dexferrum 5 ADEs during 7 (74%) infusionsNature and severity of ADEs not reported, available as an abstract only.
McCarthy et al. 200017 Mayo Clinic, USALMWID vs. HMWID Retrospective review June 1992–July 1997. 665 courses of parenteral iron dextran given to 254 patients. 468 of these courses were InFed, the remainder were HMWID. Patients: Male 57% Age > 60 64% Total courses 468Included cutaneous reactions (itching, flushing, hives, rash), gastrointestinal (nausea, diarrhea, abdominal pain, vomiting)NoneADEs per 100 courses 3.2 (i.e. 3.2%, 95% CI 1.8% to 5.2%) Courses with an ADE: 10 (2.1%)Multivariate analysis compared ADEs on InFed HMWID dextran threefold increase in odds of ADE associated with high-molecular-weight ADE (OR = 3.0, 95% CI 1.2–7.2). – After controlling for gender, age, race, prior drug allergy and diabetes.
Case 199818 Jackson MS, USARetrospective review of TDI iron dextran (InFed) and HMWID (Dexferrum) administered to 156 home dialysis patients attending Kidney Care Inc, Jackson, MS, from 1992 to 1996. 142 patients received InFed (422 doses) 14 patients received Dexferrum (76 doses)  InFed 5/142 (i.e. 3.5%, 95% CI 1.2% to 8.0%) patients had any reaction (including itching, urticaria, nausea and vomiting). Dexferrum 4/14 (28.6%, 95% CI 8.4% to 58.1%) of patients had severe reactions including severe back and leg pain, urticaria, and shortness of breath. 
Studies of LMWID

A total of 47 references were identified to which the inclusion criteria were applied. Of these, 19 studies met the inclusion criteria (Table 2), including two RCTs, comparing LMWID with oral iron, placebo, or different methods of delivering intravenous iron. The remaining studies were of observational data (e.g. retrospective case series and reports of ADEs, prospective clinical studies). Seven studies (or eight including Prakash et al.12 where the form of iron dextran is not specified) compared LMWID with HMWID, iron gluconate or iron sucrose and are detailed in Table 1. Eleven studies simply reported ADEs among case series of patient receiving LMWID and are reported in Table 2. All but three of these studies were conducted in the United States (the remainder were performed in the UK or Canada), and many were exclusively of patients experiencing renal failure including patients undergoing hemodialysis (eight studies). Other groups of patients included cancer patients, patients with diabetes, those unable to tolerate or respond to oral iron, home total parenteral nutrition (HPN) patients and a mixture of patients undergoing intravenous iron infusion.

Table 2.  Characteristics and nature of ADEs associated with LMWID
Study nameIntervention/study design and detailsNonserious ADEsSerious/life-threatening ADEsTotal ADEsInterpretation
  1. 95% CI, 95% confidence intervals; ADEs, adverse drug events; EPO, erythropoietin; ESRD, end-stage renal disease; HMWID, high-molecular-weight iron dextran; HPN, home total parenteral nutrition; IBS, inflammatory bowel syndrome; IV, intravenous; LMWID, low-molecular-weight iron dextran; OR, Odds Ratio; RCT, randomized controlled trial; RLS, restless leg syndrome; SC, subcutaneous; TDI, total dose infusion; TSAT, transferring iron saturation percentage.

Auerbach et al. 200419 Multicenter RCT, USAMulticenter RCT n = 157 EPO-treated patients with chemotherapy-related anemia No. iron  36 Oral iron 325 mg twice daily   43 Bolus group 100 mg IV 37 TDI group  41 (All patients received iron dextran as InFed)Nausea:  Oral iron group 1/43 Arthralgia-myalgia (delayed reactions)  Grade I   TDI group 2/41  Grade II   Bolus group 1/37 Fatigue  Bolus group 1/37 Shortness of breath  Bolus group 1/37TDI group  Death 1/41 (unrelated to study drug) Oral iron group  Death 1/43 (unrelated to study drug)Total ADEs:  TDI group  3/41  Bolus group  3/37 Total ADEs for InFed therefore 6/78 (i.e. 7.7%, 95% CI = 2.9% to 16.0%). Total ADEs in oral iron group 2.3% (95% CI 0.06% to 12.3%) ADEs did not require discontinuation of therapy.Two patients received Dexferrum during period when InFed unavailable. Unclear whether ADEs were associated with InFed or Dexferrum, therefore ADEs associated with InFed may be overestimated. There was one acute hypersensitivity reaction, but this appears to be for a patient receiving Dexferrum.
Barton et al. 200020 Birmingham, AL, USAUncontrolled observational study of iron-deficient patients with normal renal function: No. 135 Male 26/135 285 infusions of IV iron to these 135 patients.Flushing 3/135 (2%) Nausea   1/135 (1%) Arthralgias, myalgias, bone aches:  10/135 (7%) Weakness, dizziness 3/135 (2%) Cardiac arrhythmia 1/135 (1%) Metallic taste   1/135 (1%) Swollen eyelid  1/135 (1%) Paresthesias  1/135 (1%)NoneMild ADEs: 18/135 (13%, 95% CI 8.1% to 20.3%) 
Earley et al. 200421 John Hopkins School of Medicine, Baltimore, USAProspective case study of 11 patients receiving IV iron dextran 1/11 (reported feeling short of breath after 30 mg of infusion, infusion stopped and patient treated for possible allergic reaction)1/11 patients experienced a major side effect (i.e. 9.1% of patients, 95% CI 2.3% to 41.3%States no other major side effects seen, but minor side effects not reported.
Fishbane et al. 199622 (data also presented in Schaefer 199723) USALMWID – InFed Retrospective review of charts (patients from four hemodialysis patients with ESRD 1993–1995. All patients included) Patients: No.  573 Male  49% Age (year)  48.6 ± 4.2 Diabetes  30%Itching  1.5% Skin flushing  0.3% Nausea  0.5% Dyspepsia  0.5% Chest pain  1.0% Hypotension  0.5% Swelling  0.5% Headache  0.3% Myalgias  0.2% Wheezing or dyspnea 1.5%Anaphylactic reaction  10/573 patients Cardiac arrest  0.2% Serious ADEs (led to hospitalization)  4 (0.7% patients) No. of patients discontinued medication due to ADEs  22 (3.8%)Adverse events: 27 patients had ADEs related to IV iron (i.e. 4.7%, 95% CI 3.1% to 6.8%) Total no. of ADEs = 30 (5.2%). No patient died or developed permanent disability.Only first course of treatment per person included unless patient had a reaction to any course, in which case that course was included. Rates are therefore per person and not per treatment episode. ADEs clearly defined and assessed by two reviewers.
Henry 200124 Pennsylvania Hospital, Philadelphia, USA.Retrospective chart review of patients referred over a 2-year period for administration of EPO prior to elective orthopedic surgery.  3/157 patients (1.9%, 95% CI 0.04% to 5.5%) had any significant, immediate reaction including rash, facial swelling, and chest tightness. All symptoms resolved within 30 minutes.Published as abstract only – limited methodological details
Kaufman et al. 200125 Multicenter, USAPart of a RCT (but not a randomized comparison). Total  208 Epoetin SC  107 Epoetin IV  101 180 patients received 3588 doses of iron dextran 100 mg at 10 consecutive dialysis sessions. Patients with TSAT > 20% and serum ferritin > 100 mg/mL. (InFed)Not reportedNo. of patients with serious ADEs: 2/180 (1.1%, 95% CI 0.13% to 4.0%)2/180 (1.1%, 95% CI 0.13% to 4.0%)Minor ADEs not reported.
Khaodhiar et al. 200226 USARetrospective case study n  55 (treated with HPN, 1994–1999) Patients received InFed: 20 Records of 207 HPN patients from January 1994–December 1999, at the Beth Israel Deaconess Medical Center home nutrition support center.Of the patients receiving TDI: Rash  2/13 Urticaria  1/13 (this patient also had shortness of breath)Of the patients receiving TDI: Chest tightness: 1/13 (this patient also had shortness of breath and infusion discontinued)3/13Reports on ADEs in only a very small sample (n = 13) of patients receiving TDI iron dextran out of 207 patients initially reviewed.
Mamula et al. 200227 Philadelphia, USAInFed Retrospective review of charts of all pediatric patients with IBS at Children’s Hospital of Philadelphia, USA, who received TDI iron (1994–2000) n  70 (Analyzed 34)Rash  1 Shortness of breath  10 Muscle spasm  1 Chills  2 Diaphoresis  1 Hypotension  3 Carpal spasm  1 11 allergic reactions recorded (one during TDI and 10 during test dose). One patient had allergic reactions on two separate occasions. None were life-threatening and none required infusion.Retrospective review – many patients excluded (only 34 of 70 included).
Peebles and Pai 200328 Sunderland, UKSunderland Royal Hospital, renal failure (Hemodialysis unit). Iron-hydroxide dextran (CosmoFer) Retrospective review from January 2002NoneNoneNoneNo adverse effects were observed in > 50 patients (2002–2003) Retrospective review – exact denominator not reported.
Schaefer 200029 New Jersey, USALMWID – ferric hydroxide (InFed) Retrospective review No. unclear Kennedy Dialysis Center, Sewell, New Jersey. January 1997–March 1999 – 207 test doses of InFedAllergic reaction  1/207 Itching  2/207 (one for outpatients maintenance dosing) 3Also used InFed from 1992–1996, three reactions recorded but no denominator reported. No information on severity of allergic reactions reported. Retrospective review
Sloand et al. 200430 University of Rochester Dialysis Unit, USAIron dextran (InFed) vs. placebo (normal saline IV) RCT n  25 (patients with ESRD and RLS at University of Rochester Dialysis Unit). InFed  11 Placebo  14 Male  71%Nausea and vomiting   2/11 (placebo  3/14) Headache  2/11 (placebo  0/14) 10/11 in iron dextran group had some symptoms (91%, 95% CI 59% to 99%) compared with 8/14 in placebo group (57%, 95% CI = 29% to 82%)Very high incidence of ADEs in both placebo and iron dextran arms, and the difference is not statistically significant (Relative risk = 1.59, 95% CI = 0.97 to 2.84). Most appear to be mild.
Studies of iron sucrose

Sixty-seven potentially relevant studies were identified, of these 43 met inclusion criteria. Most of the studies were from Europe (Spain, Italy, Netherlands, Germany, UK, France, Austria, Switzerland, Sweden, Poland), Canada or the United States. Two studies were carried out in Pakistan, and one in South Africa. Patients were mostly undergoing hemodialysis, but other groups included pregnant women, patients with inflammatory bowel disease, patients undergoing hip replacements, children receiving parenteral nutrition, or patients sensitive to iron dextran. There were ten RCTs; one compared iron sucrose with iron gluconate,9 the others compared iron sucrose with oral iron or no iron, or iron sucrose in combination with recombinant human erythropoietin (rhEPO) compared with iron sucrose alone. The other studies were observational in design, and most were very small (under 100 patients receiving iron sucrose). Two studies9,10 compared ADEs on iron sucrose with iron gluconate, and two11,12 with iron dextran. These are reported in Table 1, and the remaining case series of patients on iron sucrose (n = 39) are reported in Table 3.

Table 3.  Characteristics and nature of ADEs associated with iron sucrose
Study nameIntervention/study design and detailsNonserious ADEsSerious/life-threatening ADEsTotal ADEsInterpretation
  1. 95% CI, 95% confidence intervals; ABD, autologous blood donation; ADEs, adverse drug events; ANHD, acute concomitant normovolemic hemodilution; CAD, coronary artery disease; CKD, chronic kidney disease; CRF, chronic renal failure; EPO, erythropoietin; ESRD, end-stage renal disease; GI, gastrointestinal; HMWID, high-molecular-weight iron dextran; IBS, inflammatory bowel syndrome; IDA, iron deficiency anemia; IM, intramuscular; IS, iron sucrose; IV, intravenous; LMWID, low-molecular-weight iron dextran; OR, Odds Ratio; PDAB, predeposit of autologous blood; PO, per oral; PRI, progressive renal insufficiency; rhEPO, recombinant human erythropoietin; RCT, randomized controlled trial.

Aaronson and Cornell 200231 USAProspective study of tolerability of IS 24 patients received 500 mg IV iron sucrose over 4 hours. Four patients received 100 mg IV iron sucrose. Tolerability of high-dose IV IS determined in predialysis patients receiving either EPO or darbepoetin.NoneNoneNoneAbstract only – limited methodological details.
Agarwal et al. 200432 Indiana, USARCT (1) IS + placebo (n = 10) (2) IS + N-acetylcysteine (n = 10) Randomized open-label study in patients with CKD by IS given IV 100 mg/5 minutes.Diarrhea  2/202/202/20One patient had sudden death not related to the study drug (underlying CAD) Unclear what the serious ADEs were.
Aggarwal et al. 200233 USAProspective study of 46 patients: 38 patients received two doses each of IV 500 mg IS, eight patients received different no. of infusions In total 46 patients received 97 infusionsMinor ADEs (including emesis, angina, lumbago, mild rash) reported in four patients. These patients were allergic to antibioticsNone4/38Letter only – limited methodological details
Aronoff et al. 200434 Multicenter, USAIron deficient patients given IV IS, 100 mg during hemodialysis sessions. Iron-replete patients given IS, 100 mg, over 5 minutes weekly for 10 weeks. 665 patients included. Multicenter open-label dose-ranging safety studyNo anaphylactic and allergic reactions reported Constipation  3 Vomiting  3 Diarrhea  1 Dry mouth  1 Nausea  2 Hypotension  3 Dermatitis  1 Dizziness  1 Pruritus  2None29 nonserious ADEs reported in 21 patients (per patient incidence of 4.4%, and per exposure incidence of 0.34%). 
Bayoumeu et al. 200235 Nancy, FranceRandom, prospective, open study involving 50 pregnant patients with anemia. IV Group n = 24 PO Group n = 23NoneNoneNone 
Blaustein et al. 200336 New York, USAProspective dose-ranging study IV sucrose 500 mg Infused over 3 hours on two consecutive days (accelerated dosing regimen). n = 107 CKD patientsEpigastric discomfort, nausea, vomiting: 1 patient Abdominal cramps, moderate nausea: 1 patient Possible IS-related mild nausea, diarrhea: 1 patient Sensation of upper body heat: 1 patient Diaphoresis: 1 patientNone10 ADEs were observed in five patients. Of these, seven ADEs in two patients were considered drug-related (nausea, vomiting, diarrhea, and light headedness). 1.8% of patients who had ADEs attributed to IS (95% CI 0.23% to 6.6%). 
Bodemar et al. 200437 University Hospital, Linkoping, SwedenRetrospective analysis of 61 patients with inflammatory bowel disease attending internal medicine clinic over a 3-year period. Iron dose: 1.4 ± 0.5 g.Slight fever and rash: 1 patient (during IV infusion of IS did not reappear in subsequent infusions)None1 
Borawski et al. 200438 Medical University, Bialystok, PolandProspective study of high dose IV sucrose (200 mg daily in 250 mL saline, given over 1-hour median treatment duration 5 days). n = 24 CRF patients Endothelial injury markers studiedNoneNoneNone 
Breymann et al. 200139 Zurich, SwitzerlandRandomized study Group 1: rhEPO plus IV IS (Venofer at 200 mg) n = 20 Group 2: IS (Venofer) alone, same dose and admin route n = 20 Women with gestational iron-deficiency anemiaMetallic taste observed in three patients (unclear which group), ‘feeling warm for a few minutes’ in two patients.None5 
Breymann et al. 200040 Zurich, SwitzerlandRCT with three groups Group 1: rhEPO plus IV IS (Venofer, 200 mg, daily) n = 20 Group 2: placebo plus IV IS n = 20 Group 3: oral iron alone (daily for 4 days beginning 48–72 hours postpartum) n = 20 Postpartum womenMetallic taste in five patients, ‘feeling warm for a few minutes’ in three patients (unclear which group)None8 
Chandler et al. 200141 King’s College, LondonUncontrolled prospective dose-ranging study 335 iron infusions administered in 249 hemodialysis patients and was conducted four phases: 200 mg (over 2 hours) n = 89 500 mg (over 2 hours) n = 22 300 mg (over 2 hours) n = 189 400 mg (over 2 hours) n = 358/22 patients in 500 mg group developed dizziness, hypotension and nausea; and the infusion was abandoned. 2/35 patients in 400 mg group developed hypotension, nausea and lower back pain.  No ADEs observed with the 200- and 300-mg doses. The incidence of ADEs with the 400–500 mg doses given over 2 hours seems to be too high to recommend their routine use.
Charytan et al. 200442 Flushing, NY, USASummary of data from four prospective studies of IV sucrose. 130 hemodialysis patients who are iron dextran and/or sodium ferric gluconate-sensitive IS given 100- or 200-mg dosesSevere diarrhea   1 patient Moderate nausea   1 patient Mild taste disturbances   3 patients Moderate vomiting   1 patient Constipation, dry mouth, skin irritation   1 patient Moderate hypotension   1 patient All above   1 patientNone14 in 8 patients attributed to IS, none of which resulted in discontinuation of therapy. (6.15% of patients experienced ADEs, 95% CI 2.69% to 11.76%). 
Charytan et al. 200243 Multicenter, USARandomized study of 102 predialysis CKD patients treated with EPO Safety data were available on 84 patients: Group 1: oral iron n = 41, for 29 days Group 2: Venofer 200 mg 1/week for 5 weeks n = 43Oral iron: constipation 8, nausea 7, diarrhea 4, (fatigue, hypotension, hypoglycemia, and skin rash 4 events), and other single events Venofer: transient taste disturbances: 4, GI complaints 3, and 5 disparate single eventsNoneOral iron:  Total ADEs 26  Patient with ADEs 17 (41.5%) Venofer:  Total ADEs 22  Patient with ADEs 7 (16.3%)Abstract only – limited methodological details
Charytan et al. 200344 Multicenter, USARCT, open-label, 96 patients with CRF Group 1: oral iron n = 48, 325 mg three times a day Group 2: IV IS (Venofer) 200 mg weekly for 5 weeks n = 48 All patients received epoetin (at least 2000 U weekly through day 43). Extended follow-up continued for an additional 3 months, during which both groups were given IS and/or epoetin.All ADEs related to GI system. Oral iron: 17/48 (35.4%) Venofer: 6/48 (12.5%)None Abstract only – limited methodological details. safety study.
Charytan et al. 200145 Multicenter, USAOpen-label, single arm, prospective, multicenter study in hemodialysis patients undergoing epoetin therapy. Single dosing regimen of 10 doses of 100 mg each, given on consecutive dialysis sessions 76/77 patients completed treatment and were included in the efficacy analysis, all 77 patients were included in the safety analysis.Abdominal pain:   1/77 Diarrhea, nausea:  1/77 Constipation:  1/77 Transient minty taste:  1/77None No patient withdrawals or drug discontinuation caused by drug-related ADEs. Two deaths were not drug-related.
Cuenca et al. 200446 Malaga, SpainProspective pilot study with nonconcurrent control group Group 1: control group of previous series of pertrochanteric hip fracture patients n = 55. Group 2: n = 55, 200–300 mg IV IS, given preoperatively.NoneNoneNone 
Dittrich et al. 200247 Vienna, AustriaFollow-up efficacy study 45 hemodialysis patients were followed over 1 year Low-dose IV iron regimen administered once or twice monthly using 50 mg IV ISSystemic ADEs occurred in 0.5% of 594 applications (including hypotension, nausea, and flush after one application) Local pain at the injection site was reported during two applications (0.3%).None0.5% of applications 
Edwards 200348 Multicenter, USA (5 sites)Observational study Hemodialysis patients, all had end-stage renal disease. Most receiving rhEPO. No inclusion/exclusion criteria applied! Patient numbers not reportedNoneNoneNoneNo methodological details and very limited reporting of side effects: no specific inclusion or exclusion criteria stated
Gasche et al. 200149 Multicenter, AustriaProspective multicenter open-label study Six infusions of IS 200 mg for 4 weeks n = 103 patients with severe IBS-associated anemiaExanthema  1/103 Bitter taste  2/103 Hypotension  1/103NoneFour eventsADEs observed were generally mild and transient
Gasche et al. 199750 Multicenter, AustriaDouble blind RCT with a subsequent open-label phase in patients with Crohn disease anemia All patients received IV iron saccharate for 16 weeks. Blinded phase: first 8 weeks, patients were randomly assigned to receive EPO n = 20 or placebo n = 20. Open-label phase: second 8 weeks, EPO dose was increased in nonresponders who had received EPO and EPO therapy initiated in nonresponders who had received placebo.Local burning at the injection site:  3/40 Bitter taste  2/40 Transient fever  2/40 Transient hypotension  2/40NoneSix different ADEs observed in 14 patients.Limited methodological details. Unclear whether truly randomized.
Gombotz et al. 200051 Graz, AustriaProspective randomized study of 60 preoperative female patients (for primary hip replacement) Group 1: EPO, n = 20 Group 2: ANHD, n = 20 Group 3: PDAB, n = 20 Groups 1 and 2 received rhEPO and iron saccharate 100 mg on day 14, and on day 7 before surgery, if needed. Group 3 received oral ironNoneNoneNone 
Hollands 200352 USARetrospective study to evaluate safety and efficacy of 300 mg IV IS. n = 73 CKD patients Review of medical records of all 73 CKD patients who received IS at least once in 2002.Rash  1 Nausea  11 Vomiting  3 Dysgusia  3 (loss of taste) Constipation  2 Hypotension  11 Anxiety  1 Fatigue  1None33 eventsAbstract only, limited details. Some patients experienced these ADEs prior to IS so causality was difficult to determine.
Hussain et al. 199853 Karachi, PakistanProspective study with two groups of hemodialysis patients treated with EPO Group 1: received IV iron saccharate post dialysis (100 mg twice weekly) n = 10 Group 2: oral ferrous sulfate given 200 mg three times daily n = 10 Both groups received rhEPONoneNoneNoneUnclear how patients were assigned to the two groups; small sample size. Methods for identifying and recording ADEs not clear
Kooistra et al. 200254 Utrecht, NetherlandsProspective study 10 stable hemodialysis patients on rhEPO received 100 mg iron saccharate (Venofer) in 60 minutes (protocol 1) and 1 week later 100 mg in 6 minutes (protocol 2).Allergic reactions  0/10 Metallic taste  1/10 Hypotensive episodes  0/10NoneOne patientSmall sample size
Macdougall et al. 199955 London, UKProspective complete case series of hemodialysis patients for 1 year (n = 116). Received weekly IV bolus of 100 mg iron sucrose.No reactions recorded, although two patients complained of a transient metallic taste. Total of 4564 injections given over 1 yearNone0–2/4564 
Michaud et al. 200256 Lille, FranceProspective 2-year study of children receiving parenteral nutrition, with iron deficiency anemic, poor tolerance or unresponsive to oral supplementation. 22 children aged 5 months to 17 years received 100 mg iron sucrose (Venofer) in 0.9% saline. Each received a test dose of 25 mg first.Transient exanthema and mild hypotension: 1/22None11 adverse reaction to test dose (stopped dose).
Perewusnyk et al. 200257 Zurich, SwitzerlandRetrospective review of cases from 1992 to 2000. 500 patients received 2500 amouples, each containing 100 mg iron.Rash  4/500 Flush  3/500Not clearly statedSide effects were 1.5% relative to total number of patients (95% CI 0.0623% to 3.0%) and 0.36% relative to number of ampoules.All side effects on first day of treatment.
Rohling et al. 200058 Zurich, SwitzerlandProspective study comparing (1) oral iron sulfate (n = 6) and (2) IV iron sucrose (Venofer). 200 mg in 250 mL NaCl IV over 20 minutes twice a week (n = 6). Preoperative adults with normal hemoglobin and iron due for elective surgery involving potential blood loss over 500 mL. All patients also received rhEPOOral: 2/6 None in IV iron groupNoneNone (with IV iron)Unclear how patients were assigned to the two groups; small sample size.
Silverberg et al. 199959 IsraelUnclear – retrospective review of 541 patients. 123 predialysis patients received 200 mg IV iron; 360 hemodialysis patients received 100 mg IV iron twice monthly; 200 mg to 58 PD patients weekly.Not clearly statedNoneNot clearly statedNo anaphylactic reactions in over 20,000 infusions over a 4-year period
Stark et al. 200260 Petah Tikva, IsraelRetrospective review of 136 patients with IDA of different etiology. Retrospective review of patients treated with IV iron sucrose (Venofer) infusions of 100–200 mg in 100–200 mL saline over 15–20 minutes, two to three times a week. Mean no. infusion 10.5 ± 4.2/patient. Total n. infusions 2317.1/136 moderately severe rash 1/136 headache and dizziness.None28 (20.6%, 95% CI 14.13% to 28.36%) of patients reported 32 ADEs (1.4% of infusions); in most cases only during first infusionAbstract only – limited methodological details
Stoves et al. 200161 Leeds, UKRCT among 45 anemia patients with PRI, not yet on dialysis comparing (1) oral iron (ferrous sulfate 200 mg three times a day) n = 23 (2) IV iron sucrose (Venofer) 300 mg monthly, n = 22. Patients followed for average 5.2 months; mean of 0.91 (95% CI 0.84 to 0.98) infusion of iron sucrose per patient per month.IV iron: 3/22 possible allergic reactions (including urticarial rash, abdominal pain, arthralgia, myalgia, nausea, headache, paresthesia and loss of consciousness) Oral iron: 1/23 (severe constipation)None3/22All possible ADEs in women with low body mass. Oral iron discontinued in 1/23 patients
Sunder-Plassman and Horl 199662 Vienna, AustriaDosing study with four regimens of IV iron saccharate (Ferrivenin) 10, 20, 40 and 100 mg (n = 18 regular hemodialysis patients with renal failureNoneNoneNoneNo clearly described methods for identifying and recording ADEs, although primary aim was to carry out a safety study.
Sunder-Plassman and Horl 199563 Vienna, AustriaProspective case series of ESRD patients receiving 100-mg iron saccharate (64 chronically uremic patients undergoing regular hemodialysis).3/64 chest pain, loin pain or bronchospasm  Symptoms only observed when 100-mg IV iron saccharate injected in under 5 minutes; not observed with slow injection or dose reduction.
Surico et al. 200264 Bari, ItalyProspective study in children comparing (1) IV iron saccharate (2-hour infusion in saline, average dose 28 mg/kg, over average 6.5 days, n = 19) (2) IM iron injection (n = 14)IV group: 1/19 (mild systemic reaction), withdrawnNone1/19Not clear how children were assigned to each group.
Van Wyck et al. 200065 USProspective study of 23 patients sensitive to iron dextran; 223 doses in total. Patients received 100-mg IV iron sucrose (Venofer) in 10 consecutive dialysis treatment sessions. Two groups: (1) with mild reactions to iron dextran; received 100 mg IV iron sucrose by IV push over 5 minutes (2) with severe reactions to iron dextran; received same dose or IUV 100 mg in 0.9% NaCl over 15–30 minutes.Four patients developed pruritus, in one patient thought related to IV iron sucrose, one patient developed metallic tasteNo serious ADEs, episodes of anaphylaxis, patient withdrawals or drug discontinuation.Three ADEs possibly related to IV iron sucrose observed in two patients; these were mild.Primary outcome was safety; reports clearly methods for identifying and recording ADEs.
Vychytil and Haag-Weber 199966 Location unclearCase series of peritoneal dialysis patients treated with 100 or 200 mg of iron saccharate monthly for 6 months, n = 17Not clearly describedNoneSide effects occurred in 0.9% after application of 100 mg and 5.9% after infection of 200 mg iron saccharateNo methodological details and very limited reporting of side effects; most of article reviews other studies and details found only in abstract
Wali et al. 200267 Karachi, PakistanProspective quasi-randomized study n = 60, pregnant women, gestation age 12–24 weeks, with iron-deficiency anemia. IV iron sucrose 500 mg = 15 IV iron sucrose 200 mg = 20 IM iron sorbitol = 25IV group: 1/35 with moderate abdominal pain, 2/35 with shivering and weakness, 3/35 with phlebitis IM group: 5/25 dropped out due to intolerance (mostly pain at injection site)None Limited methodological details; unclear whether truly randomized
Weisbach et al. 199968 Nuremberg, GermanyRCT in adult patients schedules for ABD before major orthopedic or cardiovascular surgery. n = 90 Oral iron: 30 IV iron sucrose: 30 No iron: 30IV group: general discomfort and dizziness: 1/30, small itching erythema (1/30) Oral group: constipation and diarrhea (7/30), abdominal pain (1/30), itching erythema (1/30) Two patients removed from both oral iron and IV iron group due to mild ADEs.NoneTwo patients withdrew from both groupsLimited methodological details regarding how patients were randomized/allocation concealed. 90 of 123 patients completed study.

Reporting of adverse events

Reporting of adverse events was not consistent and the level of reporting varied across the studies. Some studies reported on all adverse effects whereas others reported treatment-emergent adverse events, which were new events that began after the first dose of active treatment or events that worsened during therapy. These generally include allergic (e.g. flushing, pruritus, urticaria, rash), gastrointestinal (e.g. nausea and vomiting, diarrhea), systemic (e.g. arthralgias, back pain, headache, fever, tachycardia, hypotension), respiratory (e.g. wheezing or dyspnea) and serious or life-threatening adverse events (e.g. death, cardiac arrest, myocardial infarction, anaphylactic reactions, anaphylactic shock and those that led to hospitalization or discontinuation of treatment). Some studies reported ‘mild’ or total ADEs whereas others were restricted to major or serious ADEs, which limits comparability between studies.

We have provided details of these adverse events along with relevant study information in a series of tables; Table 1 describes results from comparative studies, comparing at least two forms of intravenous iron. Table 2 details studies of LMWID and Table 3 iron sucrose.

Quality assessment

Overall, the methodological quality of the included studies was variable, and some were poor. Most of the studies were retrospective analyses of patient or adverse event databases. In many cases the databases were not designed specifically for assessing the incidence of ADEs and therefore important information was missing – in particular most studies reported the number of ADEs per episode of intravenous iron dextran treatment rather than per patient treated. This may underestimate the incidence of ADEs (as most patients will have received several episodes of treatment). Selection bias is also possible – those studies which reported and published data on ADEs associated with iron dextran or iron sucrose may have atypical groups of patients (e.g. referral centers and teaching hospitals). Few studies directly compared ADEs associated with iron dextran with other forms of intravenous iron and even those that did may have selection biases (as it is unclear how decisions were made to prescribe one or other form of intravenous iron). A few studies used both HMWID and LMWID (InFed and Dexferrum) and did not separate results by type of iron dextran, which renders their results uninterpretable.

None of the studies reported sample size calculations, which may be an indication of insufficient power. Small sample sizes and possibly selected populations mean it is difficult to estimate with confidence or precision the incidence of side effects associated with LMWID in different patient groups.

Data analysis

We present the results narratively in Tables 1–3. Where feasible and where the denominator was > 50, we calculated the percentage experiencing any ADE and 95% confidence intervals (CI) for this percentage.

We have not carried out any statistical pooling (meta-analysis) of adverse events across studies. As the studies are so heterogenous in terms of design, patient groups, definitions and methods of assessing adverse events, it would be inappropriate to combine estimates of the incidence of adverse events across studies. It may be possible in future analyses to combine studies by obtaining individual patient data – and hence carry out more detailed data checking and quality assessment, applying consistent inclusion criteria to ensure more robust conclusions.

Comparison of ADEs on different forms of intravenous iron

Five studies consistently found much lower risks of ADEs on LMWID compared with HMWID.13,15–18

Two studies compared ADEs on LMWID with iron gluconate (Ferrlecit). One of these found no difference in ADEs, but only four patients received iron gluconate.14 One large review for the Food and Drug Administration (FDA)13 found a much higher rate of ADEs for patients receiving iron gluconate (Ferrlecit) compared with LMWID (InFed) (Odds Ratio 6.2, 95% CI 5.4–7.2). This finding needs to be replicated in other studies.

Two studies compared iron sucrose (Venofer) with iron gluconate (Ferrlicit).9,10 Neither found any major ADEs, or any difference in ADEs between the two forms of intravenous iron, but the sample size was small in both cases (only 98 and 57 patients respectively).

Two studies compared iron sucrose with iron dextran,11,12 but only one specified the form of iron dextran used (LMWID – in Moniem and Bhandari11). Moniem compared the two forms of intravenous iron in a case-crossover design. There were no major ADEs including anaphylaxis, and no difference in ADEs between the two arms; however, only 39 patients were enrolled in this study. Prakash et al.12 noted one case of anaphylaxis in each group and slightly more mild ADEs in patients administered iron dextran compared with iron sucrose. However, this difference was not statistically significant, the sample size was small, and the type of iron dextran unclear.

Adverse events associated with LMWID

Over 2000 patients appear to have received LMWID in studies (the exact number is not certain as some studies report only the number of infusions, rather than the number of patients). However, the study by Chertow et al.13 reviewed an estimated 14.9 million doses of LMWID administered over the 2-year period 1998–2000 – presumably a far larger number of patients.

The frequency of reporting of any ADE associated with LMWID varied greatly between the studies, from about 0.004% to 91%. This range may reflect clinical heterogeneity (different patient groups), chance (as sample sizes were often small), and different definitions of an ADE. In particular, some studies may not have reported ‘milder’ ADEs comprehensively. It may also reflect publication bias – it is plausible that retrospective case series of patients may be more likely to be published if they report a high incidence of ADEs. For this reason, studies with larger sample sizes are likely to provide less biased estimates (as studies with larger sample sizes are more likely to be published regardless of their results).

In larger studies where the denominator was infusions rather than patients, ADEs appeared to be less common (although the range of estimates was still vast – from approximately 0.004%, 95% CI 0.0037% to 0.0043% to 20.5%, 95% CI 9.3% to 36.5%). In studies where ADEs were reported per patient they were more common, as would be expected (ranging from approximately none to 91%, 95% CI 59% to 99%), Sloand’s RCT30 found the highest incidence, but this was in a small study of dialysis patients, ADEs appeared mild and were also very common in the placebo arm of the study), suggesting that they may not necessarily be due to the medication.

There were relatively few serious or life-threatening ADEs. Eight of the 19 studies reported that serious ADEs had occurred (although some others did not state clearly whether ADEs were mild or serious). Auerbach et al.’s19 RCT reported one death among 78 patients (but this was unrelated to intravenous iron, in the opinion of the author). Chertow’s large review for the FDA found a low incidence of death, respiratory depression and anaphylactic reaction (nine deaths, seven instances of respiratory depression and 28 anaphylactic reactions in 14.9 million infusions).13 Eichbaum et al.14 reported one serious ADE (anaphylactic shock and cardiovascular collapse) among 39 patients receiving InFed, Kaufman et al.25 reported two serious ADEs among 180 patients; and Fishbane et al.22 reported four serious ADEs (which led to hospitalization) among 573 patients. Khaodhiar et al.26 reported one of 13 patients to have chest tightness, Earley et al.21 reported one allergic reaction requiring discontinuation of treatment in a case series of 11 patients, Prakash et al.12 reported one anaphylactic reaction, but the form of iron dextran used was not clear.

Adverse events associated with iron sucrose

The included studies report on over 4000 patients who have received intravenous iron sucrose. As with intravenous iron dextran there is a huge range in reporting of adverse events, most probably due to difference in classifying and recording ADEs between studies. Many of the studies were small and the primary or secondary outcome was not incidence of ADEs.

Many studies (n = 12) reported no ADEs at all, and there were few reports of life-threatening or serious ADEs. Most of the reported ADEs appeared to be mild, including skin rash, myalgia, abnormal or metallic taste, headaches or dizziness, abdominal including nausea and vomiting. Although Chandler et al.41 reported that infusion was abandoned in eight patients (suffering from dizziness, hypotension and nausea), this was a dose ranging study, and treatment had to be stopped only among those patients receiving the highest doses (400 or 500 mg, 22 of 249 patients). No ADEs were reported in those receiving lower doses (200 or 300 mg, n = 279). Agarwal et al.32 reported a sudden death (not directly attributed to the study drug) and two serious/life-threatening ADEs among 20 patients (but the nature of the serious events is unclear). Charytan et al.45 reported two deaths in an open-label study in hemodialysis patients, again stating that these were not drug related. Prakash et al.12 also reported one serious ADE (anaphylactic reaction) among 23 patients receiving iron saccharate. There have been suggestions that concomitant treatment with rhEPO and iron sucrose may reduce adverse events; however, only two studies compared treatment with iron sucrose and rhEPO with iron sucrose alone.39,40 Both these studies identified only few mild ADEs and did not clearly state which treatment group was associated with these ADEs.

The yellow card database in the UK reported two deaths and 53 ADEs associated with iron sucrose, but both deaths were in patients with serious underlying conditions (exacerbation of asthma, and epidermal necrolysis).69 Also this UK system is passive, voluntary, and does not include causality assessment. Hence the denominator (and incidence) cannot be estimated, and likelihood that the ADE was related to the drug is unclear. A similar analysis for LMWID could not be undertaken as the reports for all iron dextran (high and low molecular weight) products are collated in one report.

DISCUSSION AND CONCLUSIONS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION AND CONCLUSIONS
  7. REFERENCES
  8. Appendices

Relatively few studies have compared the safety profiles of different forms of intravenous iron. Several studies showed considerably lower risks of ADEs on LMWID compared with HMWID, and one13 a low risk compared with Ferrlecit (iron gluconate), but this requires confirmation in future studies. Two studies showed little difference between iron sucrose and iron gluconate, and two further studies had similar ADE rates between iron sucrose and iron dextran; however, the sample size for most of these studies was small. Adequately powered, head-to-head, preferably prospective comparisons of different forms of intravenous iron are needed. This may entail multicenter studies, due to the large sample sizes required. For example, to show a statistically significant difference for an increase in a serious side effect from 1% to 2% (between two different forms of intravenous iron) with 90% power, 3300 patients would be needed in both of the intravenous iron groups (i.e. a total of 6600 patients). Although prospective studies are ideal, retrospective analysis is a relevant tool to identify risk factors for rare events such as serious adverse events with intravenous iron therapy. As the authors in the Chertow article state in the last lines of the introduction: ‘Since parenteral iron-related ADEs are rare, population based cohort analyses are necessary to provide valid estimates of safety.’13

Clear definitions of what constitutes an ‘adverse event’ need to be established, and two or more independent clinicians should apply these definitions to each patient included in the study. Further methodological details are also needed to assess quality, e.g. how patients were selected from retrospective case records, how many researchers carried out this selection process, precise definitions of ADEs, and whether they were ‘serious’ ADEs requiring hospitalization or life-threatening. They should report rates of ADEs per patient rather than per infusion and include complete case series of patients. As in Chertow’s study, ADE rates should be adjusted for the dose of iron infused, as typically total dose infusion of iron dextran leads to higher doses than the smaller doses administered of iron gluconate or iron sucrose.

The relatively few studies available suggest that serious or life-threatening ADEs are rare on LMWID (InFed). Studies consistently found much lower risks of ADEs on LMWID compared with HMWID. A minority of studies (8 of 19) have reported serious ADEs among over 18 patients including nine deaths, anaphylactic shock, cardiovascular collapse, and ADEs requiring hospitalization or discontinuation of treatment. These ADEs need to be considered in the context of the administration of 14.9 million doses in tens of thousands of patients encompassed in the Chertow review of the FDA database.

Very few studies (4 of 43) report any serious ADEs on iron sucrose, and the number of serious ADEs is very small. In one of these studies, serious ADEs (requiring stopping treatment) were observed only when using high doses of 400 and 500 mg of iron sucrose (compared with the currently recommended 100 mg in up to 100 mL),70 and in one other the author stated that two deaths observed were not drug related.42 Thus only two studies report three ADEs definitely related to the drug (one anaphylactic shock and two other serious ADEs, not described), although yellow card data from the UK suggest other serious ADEs may have occurred.69 Most of the reported ADEs on iron sucrose in other studies may be considered mild to moderate. Several other reviews have reached similar conclusions7,71–74 although they also point out that clinical trials of iron sucrose may have enrolled too few patients to detect rare events.6

Serious adverse events appear rare with either LMWID or iron sucrose, and intravenous iron preparations may have many benefits in patients with severe iron deficiency. However, as most of the larger studies were not comparative, (simply analyzing case series of iron dextran or iron sucrose patients,) it is difficult to state conclusively whether any one form is safer than another. The lack of information on denominators from some studies even make it difficult to assess the incidence of serious ADEs reported in case studies of different forms. Large case reviews of iron sucrose and iron gluconate should be carried out as soon as possible to facilitate comparisons of the incidence of all and serious ADEs for intravenous iron formulations in current use. Use of the WHO Uppsala Monitoring Center dataset should also be explored to compare reports of ADEs on different intravenous iron compounds.75

REFERENCES

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION AND CONCLUSIONS
  7. REFERENCES
  8. Appendices
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Appendices

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION AND CONCLUSIONS
  7. REFERENCES
  8. Appendices

APPENDIX 1 SEARCH STRATEGIES FOR STUDIES

Table 4. 
Search for studies (low-molecular-weight iron dextran): summary
DatabaseYearsSearch strategyNumber of hits retrieved
MEDLINE1990–2004((Iron adj2 dextran) or InFed or CosmoFer).af. limited to human 243
EMBASE1990–2004((Iron adj2 dextran) or InFed or CosmoFer).af. limited to human 423
Science Citation Index Expanded/Web of Science1990–2004Iron dextran or InFed or CosmoFer 445
The Cochrane Central Register of Controlled Trials (CENTRAL)2004 (3)((Iron next dextran) or InFed or CosmoFer)  82
 Total references identified1193
Search for studies (iron sucrose): summary
DatabaseYearsSearch strategyNumber of hits retrieved
MEDLINE1990–2004((Iron adj2 Sucrose) or Venofer).af. limited to human 92
EMBASE1990–2004((Iron adj2 Sucrose) or Venofer).af. limited to human164
Science Citation Index Expanded/Web of Science1990–2004Iron Sucrose or Venofer100
The Cochrane Central Register of Controlled Trials (CENTRAL)2004 (3)((Iron next sucrose) or Venofer) 21
 Total references identified377

APPENDIX 2 DETAILS OF REFERENCES EXCLUDED FROM THE REVIEW

ReferencesReason for exclusion
Anuradha S, Singh NP, Agarwal SK. Total dose infusion iron dextran therapy in predialysis chronic renal failure patients. Ren Fail 2002; 24: 307–13.High-molecular-weight iron dextran? (Unclear)
Auerbach M, Winchester J, Wahab A, et al. A randomized trial of three iron dextran infusion methods for anemia in EPO-treated dialysis patients. Am J Kidney Dis 1998; 31: 81–6.First 5 patients received Imferon. Unable to separate out results
Bailie GR, Handa JJ, Tang L, Low CL, Eisele G. Minimal removal of iron-dextran by conventional haemodialysis. An in vivo study. Clin Drug Investig 1997; 14: 12–15.Adverse events not reported
Bastani B, Mounce L. Lack of allergic reaction to ferrlecit in a patient with a history of severe pruritic reaction with INFeD. Nephron 2001; 89: 237–8. [Letter]Case report
Besarab A, Amin N, Ahsan M, et al. Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients. J Am Soc Nephrol 2000; 11: 530–8.Adverse events not reported
Bhowmik D, Modi G, Ray D, et al. Total dose iron infusion: safety and efficacy in predialysis patients. Ren Fail 2000; 22: 39–43.Imferon
Coyne DW, Adkinson NF, Nissenson AR, et al. Sodium ferric gluconate complex in hemodialysis patients. II. Adverse reactions in iron dextran-sensitive and dextran-tolerant patients. Kidney Int 2003; 63: 217–24.Ferric gluconate only
Cuervo LG, Mahomed K. Treatments for iron deficiency anaemia in pregnancy. Cochrane Database Syst Rev 2001; CD003094.Review
Faich G, Strobos J. Sodium ferric gluconate complex in sucrose: safer intravenous iron therapy than iron dextrans. Am J Kidney Dis 1999; 33: 464–70.Ferric gluconate
Feldman HI, Santanna J, Wensheng GUO, et al. Iron administration and clinical outcomes in hemodialysis patients. J Am Soc Nephrol 2002; 13: 734–44.Probably high-molecular-weight iron dextran due to time period of study
Fishbane S. Review of issues relating to iron and infection. Am J Kidney Dis 1999; 34(4 Suppl. 2): S47–52.Review
Geisser P, Baer M, Schaub E. Structure/histotoxicity relationship of parenteral iron preparations. Arzneimittelforschung 1992; 42: 1439–52.Animal study
Hatton RC, Portales IT, Finlay A, Ross EA. Removal of iron dextran by hemodialysis: an in vitro study. Am J Kidney Dis 1995; 26: 327–30.In vitro study
Lapointe M. Iron supplementation in the intensive care unit: when, how much, and by what route? Crit Care 2004; 8(Suppl. 2): S37–41.Not a study
Kalantar-Zadeh K, McAllister CJ, Lehn RS, Liu E, Kopple JD. A low serum iron level is a predictor of poor outcome in hemodialysis patients. Am J Kidney Dis 2004; 43: 671–84.No data on ADEs
Kane RC. Intravenous iron replacement with sodium ferric gluconate complex in sucrose for iron deficiency anemia in adults. Curr Ther Res 2003; 64: 263–7.Ferric gluconate only
Michael B, Coyne DW, Fishbane S, et al. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int 2002; 61: 1830–9.Unable to separate out results for low-molecular-weight iron dextran
Nissenson AR, Charytan C. Controversies in iron management. Kidney Int 2003; 64(Suppl. 87): S64–71.Review
Roe DJ, Harford AM, Zager PG, et al. Iron utilization after iron dextran administration for iron deficiency in patients with dialysis-associated anemia: a prospective analysis and comparison of two agents. Am J Kidney Dis 1996; 28: 855–60.No data on ADEs
Sengoelge G, Rainer V, Kletzmayr J, et al. Dose-dependent effect of parenteral iron therapy on bleomycin-detectable iron in immune apheresis patients. Kidney Int 2004; 66: 295–302.Iron sucrose only
Sharma JB, Jain S, Mallika V, et al. A prospective partially randomized study of pregnancy outcomes and hematologic responses to oral and intramuscular iron treatment in moderately anemic pregnant women. Am J Clin Nutr 2004; 79: 116–22.Imferon
Sloand JA, Shelly MA, Erenstone AL, et al. Safety and efficacy of total dose iron dextran administration in patients on home renal replacement therapies. Perit Dial Int 1998; 18: 522–7.Unable to separate out results for InFed from those for Imferon (high-molecular-weight iron dextran)
Solomons NW, Schumann K. Intramuscular administration of iron dextran is inappropriate for treatment of moderate pregnancy anemia, both in intervention research on underprivileged women and in routine prenatal care provided by public health services. [Comment]. Am J Clin Nutr 2004; 79: 1–3.Editorial
Van Wyck D, Anderson J, Johnson K. Labile iron in parenteral iron formulations: a quantitative and comparative study. Nephrol Dial Transplant 2004; 19: 561–5.Animal study
Zager RA, Johnson AC, Hanson SY. Parenteral iron nephrotoxicity: potential mechanisms and consequences. Kidney Int 2004; 66: 144–56.Animal study