Iron supplementation with much less nausea (Polysaccharide and heme forms) – Jan 2016

Oral Iron for Anemia: A Review of the Clinical Effectiveness, Cost-effectiveness and Guidelines

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016 Jan.
CADTH Rapid Response Reports.

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CONTEXT AND POLICY ISSUES

Anemia is a condition in which circulating red blood cells (RBCs) are deficient with regards to quality and/or quantity.1 A generally accepted working definition of anemia in the adult is a hemoglobin level less than the normal mean minus two standard deviations.2
Iron deficiency is the most common cause of anemia. Iron deficiency anemia (IDA) is characterized by small RBCs (microcytic), which are relatively pale (hypochromic) in color relative to normal red cells. It develops in sequence to a reduction in iron stores manifesting as low serum ferritin usually with normal sized RBC in its early stages, and progressing to depleted iron stores when the ferritin level falls below 12 mcg/L.3 Based on data from the 2009 to 2011, a 2012 Statistics Canada report indicated that 4% of Canadians had low serum ferritin while 3% had low hemoglobin anemia.4 Iron deficiency anemia (IDA) is most prevalent among preschool children and women. Approximated 75% of all diagnosed cases of anemia in pregnancy is attributed to iron deficiency.5-7
Iron-deficiency anemia impacts negatively on the affected patients by disturbing the function of body systems such as the

• central nervous system (CNS),
• the immune,
• cardiorespiratory and vascular systems, as well as the
• genital and gastrointestinal tracts.8

The consequence of such disruptions may include

• impaired cognitive function,
• fatigue,
• depression, and
• alterations in cell functions.

Iron-deficiency anemia may also result in

• breathing difficulties,
• palpitations,
• risk of cardiac failure,
• loss of libido,
• menstrual problems,
• anorexia,
• nausea, and
• motility disorders.8

Iron-deficiency anemia is associated with

• maternal mortality,
• prenatal and perinatal infant loss,
• premature births, and
• infants with less than one-half of normal iron reserves.

It is estimated that IDA reduces favorable pregnancy outcomes by 30 to 45%. 3,5
Successful management of iron deficiency anemia requires identification and treatment of the underlying cause(s) of the iron deficiency.7 Treatment options for IDA include dietary measures and administration of iron supplements, with selection driven by the severity of the condition and the ability of the patient to tolerate the intervention.7,9 Patients with mild or moderate IDA are usually treated with oral iron supplements administered as elemental iron at a dose of 3 mg/kg per day, for an average duration of six to eight weeks. Parenteral iron therapy is reserved for patients with severe, persistent anemia who are unresponsive or have proven intolerance to oral supplements. It may also be given to patients with malabsorption or poor compliance to oral iron supplements.9
Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic review s. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts w ithin the time allow ed. Rapid responses should be considered along w ith other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quali ty evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for w hich little information can be found, but w hich may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report.

Oral iron salts such as ferrous fumarate, ferrous gluconate, and ferrous sulfate have been the mainstay of oral iron supplementation because they are inexpensive, effective at restoring iron balance, and have good overall safety and tolerability profile. However, in some patients, absorption of oral iron salts is inadequate, and poor tolerance results in reduced adherence to therapy. Polysaccharide iron complex and heme iron polypeptide products have become available as alternative therapies, offering improved absorption and tolerability profile over the traditional iron salts. However, they are significantly more expensive than iron salts. The aim of this review is to summarize current evidence on the comparative clinical and cost effectiveness of oral and injectable iron supplementation products for IDA.

RESEARCH QUESTIONS

1. What is the clinical effectiveness of oral iron complex products compared with oral iron salts for patients with anemia?
2. What is the clinical effectiveness of oral iron complex products compared with injectable iron supplements for patients with anemia?
3. What is the comparative clinical effectiveness of different oral iron complex products?
4. What is the cost-effectiveness of oral iron complex products for patients with anemia?
5. What are the evidence-based guidelines for the treatment of iron deficiency with oral iron products?

KEY FINDINGS

Among chronic kidney disease (CKD) patients with iron deficiency anemia (IDA), oral heme iron polypeptide (HIP) was comparably effective compared with intravenous (IV) iron preparations or oral ferrous sulfate to improve hemoglobin levels and transferrin saturation. However, both IV iron and oral ferrous sulfate improved serum ferritin levels to a significantly higher level than HIP in CKD patients with IDA. Oral ferrous sulfate is similarly effective to either oral iron polymaltose complex (IPC) or iron-zinc combination preparations to improve hemoglobin levels in children with IDA aged between 6 months and 15 years. Oral ferrous sulfate has comparable efficacy as oral IPC for the treatment of IDA during pregnancy. Although oral IPC was associated with a lower incidence of adverse events compared with ferrous sulfate for the treatment of IDA during pregnancy, both interventions were generally well tolerated with no serious adverse events occurring with either treatment. No studies which compared the clinical or cost effectiveness of different oral iron complex products for patients with anemia were identified.

METHODS

Literature Search Methods
A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, Canadian and major international health technology agencies, as well as a focused Internet search. Filters were applied to specific questions to limit the retrieval to health technology assessments, systematic reviews, randomized controlled trials, economic studies, and guidelines. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1,2010 and November 30, 2015.
Rapid Response reports are organized so that the evidence for each research question is presented separately.
Selection Criteria and Methods
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Table 1: Selection Criteria
Exclusion Criteria
Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to January 1, 2010. Review articles not based upon a systematic literature search, studies which broadly described the intervention or comparator as oral iron without specifying the kind (salts or complexes), and primary studies included in a systematic review already selected to be included in this report were also excluded. Guidelines which targeted populations in specific geographical locations and thus present uncertainty about generalizability, and guidelines which were based on expert opinion without evidentiary support were excluded.

Critical Appraisal of Individual Studies
The included systematic review was critically appraised using AMSTAR10 while the randomized controlled trials (RCTs) were critically appraised using the Downs and Black checklist for measuring quality of studies,11 and the guideline was assessed with the AGREE II instrument.12 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described narratively. The strengths and limitations of the individual studies are summarized in Appendix 3.

SUMMARY OF EVIDENCE

Quantity of Research Available
A total of 362 citations were identified in the literature search. Following screening of titles and abstracts, 340 citations were excluded and 22 potentially relevant reports from the electronic search were retrieved for full-text review. Five potentially relevant publications were retrieved from the grey literature search. Of the 27 potentially relevant papers, 23 publications were excluded for various reasons, while four publications met the inclusion criteria and were included in this report. Appendix 1 describes the PRISMA flowchart of the study selection.
Additional references of potential interest that did not meet the selection criteria are provided in Appendix 5.
Summary of Study Characteristics
A summary of individual study characteristics is provided in Appendix 2.
Study Design
One systematic review,13 two randomized controlled trials (RCTs),5,14 and one clinical guideline15 met the inclusion criteria of this review. The systematic review was published in 2015 and included three primary active-control studies published between 2003 and 2013. One of the primary studies was had a single-blind design while two were open-label RCTs. One of the selected RCTs14 for this review was a single-setting study published in 2015 and the other was a multicenter RCT5 published in 2011. Both RCTs5,14 had an open-label design. The clinical guideline was published in 2013.
Country of Origin
The systematic review13 was performed by authors from the United States of America (USA) with primary studies conducted in Australia, Canada, and the USA. One of the RCTs was conducted in Turkey,14 while the other was conducted at multiple centers in Argentina and Colombia.5 The clinical guideline15 was produced by the American College of Obstetricians and Gynecologists (ACOG) in the USA.
Patient Population
The systematic review involved 161 chronic kidney disease (CKP) patients with iron deficiency anemia, made up of 40 participants from one primary RCT who were not using dialysis, 59 patients on hemodialysis from another primary study, and 62 patients from a third primary study who used peritoneal dialysis. Among patients who were not on any dialysis, baseline hemoglobin and ferritin levels ranged from 108.5 g/dL to110.5 g/dL and 67 pg/L to 71 pg/L, respectively, while transferrin saturation was 17% for all treatment groups. The systematic review did not report similar iron indices for its two other primary studies.
One of the selected RCTs14 for this review included 60 children with iron deficiency anemia ranging in age from 6 months to fifteen years old. At baseline, the treatment groups had mean hemoglobin levels between 8.6 ± 1.0 g/dL and 9.6 ± 0.5 g/dL, and mean corpuscular volume (MCV) between 60.2 ± 7.5 fL and 63.9 ± 6.6 fL. Transferrin saturation (TSAT) was between 4.0% and 5.0% while serum ferritin levels were between 8.8 ng/mL and 20.0 ng/mL. The other RCT5 included 80 pregnant women (16 years or older) with gestational age between 18 and 26 weeks who had been diagnosed with iron deficiency anemia. At baseline, they had hemoglobin level < 10.5 g/dL, mean corpuscular volume (MCV) < 80 fL, and serum ferritin level < 15 ng/mL.
The targeted patient group of the clinical guideline was pregnant women with IDA.
Interventions and Comparators
For the systematic review,13 one of the primary studies compared oral HIP complex (11 mg three times daily) with IV iron sucrose (200mg monthly) for 6 months. Another primary study compared two different doses of oral HIP (21 mg daily and 36 mg daily) with IV iron (administered per site protocol), while the third primary study compared oral HIP (12 mg twice daily) with oral ferrous sulfate (105 mg elemental iron twice daily). The duration of treatment was 6 months for each of the primary studies. All the patients in the three primary studies of the systematic review were on concomitant treatment with erythropoiesis stimulating agents (ESA) while being treated with the study drugs.
One selected RCT14 for this review randomized patients to one of ferrous sulfate, IPC, or iron- zinc combination product (elemental iron to zinc ratio 40:15 mg), all administered orally for eight weeks. A therapeutic dose of 6 mg/kg daily for eight weeks was set for iron, followed by a maintenance dose of 2 mg/kg daily for the next eight weeks. However, results for the eight weeks treatment phase was the focus of the study. Another included RCT5 assigned patients to oral treatment with 100 mg iron twice daily for 90 days using IPC or ferrous sulfate.
The IDA interventions in the clinical guidelines referred to oral and IV iron supplementation as well as pack cells or blood transfusion. To answer the specific questions of this review, pack cells or blood transfusion have not been included subsequent discussions.
Outcomes
Change from baseline in hemoglobin levels was the most common efficacy outcome measure of interest, reported by the systematic review13 and the two RCTs.5,14 Serum ferritin levels and TSAT were outcome measures in the systematic review,13 and one RCT5 which also reported on serum iron levels and hematocrit. The systematic review13 also reported on changes in ESA dosing and sensitivity index following iron supplementation therapy. The ESA sensitivity index was derived by dividing the total weekly dose by the hemoglobin level.

Summary of Critical Appraisal

The systematic review13 was based on studies selected from a systematic search of electronic databases, supplemented by an evaluation of the bibliography of the relevant articles for additional studies. Three primary studies were included in the systematic review,13 and the criteria for study selection and data extraction were not described. Moreover, one of the three primary studies was not fully randomized because patients from a study site who were supposed to receive intravenous iron were given supplementation with HIP because they did not have a reimbursement plan for the intravenous product. Furthermore, the studies were not assessed for methodological quality or publication bias, and a list of excluded studies was not provided. Therefore, the systematic review is limited by the small number of primary studies, a high potential for selection bias, and inability to assess the robustness of its findings since its primary studies were not graded for quality. In addition, information about patient characteristics and the settings of the included studies was not well reported, making it difficult to assess the generalizability of the study findings to Canadian settings and context. The authors declared no conflict of interest and they received no funding for the study.13
The two RCTs5,14 described their study objectives, interventions of interest, and main outcomes to be measured clearly. In addition, both studies5,14 defined their inclusion and exclusion criteria, and provided relevant patient characteristics. In each study, 5,14 participants were randomly assigned to their respective treatments, and baseline characteristics were similar across treatment groups. Both RCTs5,14 had small sample sizes, and since none of them performed a sample size and power calculation, it is uncertain whether any of them was sufficiently powered to detect relevant differences in outcomes between treatment groups. One RCT14 had a high drop-out rate (25%). The distribution of drop-outs across the treatment groups was not reported and there was no information about how missing data was treated. In the other RCT,5 a total of four (0.5%) participants discontinued prematurely, two from each treatment group. Missing data was treated using the last observation carried forward (LOCF) approach. One rCt14 provided no information about blinding or concealment of treatment assignment, while the other RCT5 was an exploratory, open-label study. However, this design and reporting limitations are unlikely to influence the reported efficacy outcomes since they were objectively determined. However, adverse events outcomes are susceptible to bias in open-label studies. The generalizability of the findings of the two RCTs5,16 to Canadian settings is unknown since both were conducted in foreign countries, with little or no information about the settings of the study. Researchers in one of the RCTs5 received funding and travel grants from a pharmaceutical company which also funded the study. It is unknown whether this apparent conflict of interest biased the study and the reporting of its findings. Authors of the other RCT14 declared no conflict of interest, and received no funding for the study.
The guideline15 had well-described objectives, targeted professional users, and population to whom it was meant to apply. Evidence was collected through systematic manual and electronic searches of relevant databases. The quality and strength of evidence was reported using a clearly described rating scheme. The recommendations were based on expert consensus, with the strength of each recommendation appropriately linked to the supporting evidence. Drafts of the guideline were validated by two internal clinical review panels composed of practicing obstetrician-gynecologists, generalists and sub-specialists, while the final guidelines were reviewed and approved by the American College of Obstetricians and Gynecologists (ACOG) Executive Board.

However, some quality measures such as the criteria for selection of evidence and the procedure for updating the guideline,15 which are determinants of rigor of development, were not available for assessment. Moreover, the guideline did not provide advice on how the iron supplementation should be executed. The place in therapy of the various formulations (oral and parenteral) for iron supplementation to treat IDA was not discussed. In addition, there was no information about the comparative effectiveness of the traditional interventions and the newer oral iron complexes and iron polypeptide products, and issues about facilitators or barriers to their application were not discussed. These limitations must be interpreted with consideration to the fact that only a summary form of the guideline was available for this review and a full version could not be retrieved. Thus, whether the full-version document responds adequately to these limitations is unknown.

Summary of Findings

The following is a summary of findings from one systematic reviews13 two RCTs5,14 and a clinical guideline15 included in this review. Appendix 4 provides further details of findings of the individual studies.
What is the clinical effectiveness and of oral iron complex products compared with oral iron salts for patients with anemia?
One systematic review13 compared the clinical efficacy of oral heme iron polypeptide (HIP) with oral ferrous sulfate in patients with chronic kidney disease with iron deficiency anemia (IDA) and reported that the treatments had comparable efficacies with regards to improvement from baseline in hemoglobin levels and transferrin saturation, as well as the mean dosage and sensitivity index of darbepoetin, an erythropoiesis stimulating agent (ESA). However, improvements in serum ferritin levels were significantly higher (P = 0.01) with oral ferrous sulfate compared with oral HIP (292mcg/L versus 124 mcg/L; P = 0.003, respectively). The incidence of adverse events was similar for both interventions.
One RCT16 comparing the efficacy of oral forms of ferrous sulfate, iron polymaltose complex (IPC) and an iron-zinc combination product for IDA in children found that the three treatments had comparable effectiveness to improve hemoglobin levels after 8 weeks of treatment. Another RCT5 found that after six months of treatment, oral IPC had, at least, a comparable efficacy as ferrous sulfate for the treatment of IDA in pregnant women. While there were no significant differences in the increase from baseline in hemoglobin levels and transferrin saturation at 90 days between the two interventions, the increases in hematocrit and serum ferritin levels were significantly higher among patients treated with oral IPC compared with those treated with ferrous sulfate (6.62 ± 2.04% versus 5.81 ± 2.4%, P = 0.07; and 64 ± 40 ng/mL versus 41 ± 28 ng/mL, P = 0.004, respectively). Although adverse events occurred significantly more frequently in the ferrous sulfate group, no serious adverse events occurred in either treatment group. The most commonly reported adverse events were nausea, vomiting and constipation.5

What is the clinical effectiveness of oral iron complex products compared with injectable iron supplements for patients with anemia?

One systematic review13 compared the effectiveness of oral HIP with that of IV iron to treat IDA in chronic kidney disease patients and reported that the treatments had comparable efficacies to improve hemoglobin levels and transferrin saturation from baseline. However, after six months of treatment, mean serum ferritin levels increased from 676 mcg/L at baseline to 723 mcg/L among patients treated with IV iron, while the mean serum ferritin levels decreased from 552 mcg/L at baseline to 446 mcg/L among patients treated with oral HIP. The difference was statistically significant (P = 0.01). Comparisons of the effect of HIP versus IV iron on ESA dosage in the participants produced inconclusive results. The reported incidence of adverse events was similar for the two interventions.

What is the comparative clinical effectiveness of different oral iron complex products?

The literature search for this review did not find any studies which compared the clinical effectiveness of different oral iron complex products for patients with anemia

What is the cost-effectiveness of oral iron complex products for patients with anemia?

The literature search for this review did not find any studies which compared the cost- effectiveness of oral iron complex products for patients with anemia

What are the evidence-based guidelines for the treatment of iron deficiency with oral iron products?

The literature search found one summary guideline15 for the treatment of IDA in pregnancy. While the document recommended iron supplementation for IDA in pregnancy (Grade C recommendation, based on consensus and expert opinion), it did not provide details of which formulations (oral or IV) should be used for IDA at different stages of pregnancy.
Limitations
The systematic review13 reported outcomes on an individual primary study basis without pooling results. Thus the benefit of effect estimate derived from appropriate combination of findings from multiple studies was not available from this systematic review.13 Furthermore, the quality of the primary studies included in the systematic was not assessed and there is reason to suspect that each of them had some undesirable quality issues. For example, there was no indication that any of primary studies was powered to detect relevant differences between treatment groups. Moreover, one of the three primary studies was not fully randomized because patients from a study site who were supposed to receive intravenous iron were given supplementation with HIP because they did not have a reimbursement plan for the intravenous product, and oral HIP was compared with suboptimal intravenous iron dose in another primary study. Furthermore, the study population of one primary study included iron-replete patients who do not fit the population of interest (patients with IDA) for this review.
The two RCTs5,14 selected for this review have limitations of small sample sizes and uncertainty about adequate power to detect relevant differences between treatment groups. In addition, both were conducted in foreign countries and their findings may not be generalizable to Canadian settings.
The guideline15 lacks details about comparative advantages of the various iron supplementation interventions, and it is narrow in scope, targeting only pregnant women.

CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING

One systematic review13 comprising three RCTs of uncertain quality found that among chronic kidney disease (CKD) patients with iron deficiency anemia (IDA), treatment with oral heme iron polypeptide (HIP) improved hemoglobin level and transferrin saturation to a similar level as treatment with oral ferrous sulfate or intravenous iron. Furthermore, both oral ferrous sulfate and intravenous iron improved serum ferritin to a significantly higher level than oral HIP in CKD patients with IDA. A randomized controlled study16 found that the effectiveness of oral iron polymaltose complex (IPC) to treat IDA in children was not significantly different from that of oral ferrous sulfate or oral iron-zinc combination preparation. Another RCT5 reported that the effectiveness of oral IPC to IDA during pregnancy was comparable to that of oral ferrous sulfate, although the frequency of adverse events was lower with IPC than with ferrous sulfate. The most commonly reported adverse events were nausea, vomiting and constipation, none of which was graded as severe.5
Overall, oral HIP and oral IPC preparations did not appear to confer superior efficacy benefit over traditional oral iron salt or intravenous iron supplementation for the treatment of iron deficiency anemia. Although one RCT5 reported that oral IPC had a superior safety profile compared to ferrous sulfate for the treatment of iron-deficiency anemia during pregnancy, both interventions were well tolerated by the patients, with no serious adverse events occurring in either treatment group.

REFERENCES

1. National Institute of Research Health (NIHR). Ferumoxytol for iron deficiency anaemia in adults with chronic kidney disease. Birmingham, England: National Horizon Scanning Centre (NIHR); 2011.
2. Price EA, Schrier SL. Anemia in the older adult. 2015 [cited 2015 Dec 22]. In: UpToDate [Internet]. Waltham (MA): UpToDate. http://www.uptodate.com [subscription required].
3. Breymann C, Bian XM, Blanco-Capito LR, Chong C, Mahmud G, Rehman R. Expert recommendations for the diagnosis and treatment of iron-deficiency anemia during pregnancy and the postpartum period in the Asia-Pacific region. J Perinat Med. 2011 Mar;39(2):113-21.
4. Cooper M, Green-Finestone L, Lowell H, Levesque J, Robinson S. Iron sufficiency of Canadians [Internet]. Ottawa (ON): Statistics Canada; 2012. Report No.: 82-003x [cited 2015 Dec 22]. Available from: http://www.statcan.gc.ca/pub/82-003- x/2012004/article/11742-eng.htm
5. Ortiz R, Toblli JE, Romero JD, Monterrosa B, Frer C, Macagno E, et al. Efficacy and safety of oral iron(III) polymaltose complex versus ferrous sulfate in pregnant women with iron-deficiency anemia: a multicenter, randomized, controlled study. J Matern Fetal Neonatal Med. 2011 Nov;24(11):1347-52.
6. National Institute of Research Health (NIHR). Ferumoxytol (Feraheme) for iron deficient anaemia not associated with chronic kidney disease: first or second line [Internet]. Birmingham, England: National Horizon Scanning Centre (NIHR); 2012.
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14. Ozsurekci Y, Unal S, Cetin M, Gumruk F. Comparison of ferrous sulfate, polymaltose complex and iron-zinc in iron deficiency anemia. Minerva Pediatr. 2015 Jul 22.
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17. Nagaraju SP, Cohn A, Akbari A, Davis JL, Zimmerman DL. Heme iron polypeptide for the treatment of iron deficiency anemia in non-dialysis chronic kidney disease patients: a randomized controlled trial. BMC Nephrol [Internet]. 2013 [cited 2015 Dec 1];14:64. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606612
18. Barraclough KA, Brown F, Hawley CM, Leary D, Noble E, Campbell SB, et al. A randomized controlled trial of oral heme iron polypeptide versus oral iron supplementation for the treatment of anaemia in peritoneal dialysis patients: HEMATOCRIT trial. Nephrol Dial Transplant [Internet]. 2012 Nov [cited 2015 Dec 1];27(11 ):4146-53. Available from: http://ndt.oxfordiournals.org/content/27/11/4146.full.pdf+html
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APPENDIX 1-5 in PDF