Therapies for treating iron deficiency anaemia in Crohn's disease and ulcerative colitis

What is the aim of this review?

The aim of this Cochrane Review was to find out whether treatments in people with Crohn's disease and ulcerative colitis can improve iron deficiency anaemia.

We analysed data from 11 studies to answer this question.

Key messages

Iron in the form of ferric carboxymaltose given intravenously is probably better than iron sucrose given intravenously in improving iron deficiency anaemia, although people improved taking both treatments.

Oral iron in the form of ferric maltol may be better than placebo (dummy treatment).

It is unclear whether any of the other treatments considered are better than each other, however, there is limited evidence due to low numbers of studies and issues due to low quality of the reporting of the research studies.

What was studied in the review?

People with both ulcerative colitis and Crohn's disease both commonly suffer with low iron levels that in turn lowers their haemoglobin (blood) levels (this is called anaemia). This can lead to a number of symptoms, including tiredness and pain.

Several treatments exist to treat iron deficiency anaemia, consisting of delivering extra iron either orally or intravenously (through a vein). An additional treatment, erythropoietin, was also studied which stimulates the body to produce more blood itself.

Currently, no consensus has been reached amongst physicians as to which treatment is better.

What are the main results of the review?

We searched for randomised controlled trials (RCTs; clinical studies where people are randomly put into one of two or more treatment groups) comparing any treatment with another or dummy treatment. We found 11 RCTs looking at 1670 participants. The trials looked at adult participants, with none considering children.

1) Intravenous iron in the form of ferric carboxymaltose probably leads to more people having an improvement in iron deficiency anaemia than intravenous iron sucrose (one extra person would improve for every 9 treated and five out of 10 people would improve with either therapy).

2) Oral iron as ferric maltol may lead to more people having resolution of iron deficiency than dummy treatment.

3) It is unclear whether there is any difference between any of the other treatments studied for treating iron deficiency anaemia.

4) It is unclear whether any therapy leads to a difference in adverse events (minor or serious) when compared to any other therapy.

Conclusion

Iron delivered via a vein as ferric carboxymaltose probably improves anaemia in more people that iron sucrose via a vein, although both groups of people improved. Oral iron as ferric maltol may improve more patients than dummy treatment. No conclusions can be drawn on other treatments due to lack of evidence and quality issues with the studies that were found. Further research is needed, particularly to investigate whether iron delivered through a vein is better than iron delivered orally and also how much treating anaemia in people with IBD makes a difference in terms of the symptoms they may experience.

How up-to-date is this review?

This review is up-to-date as of November 2019.

Authors' conclusions: 

Intravenous ferric carboxymaltose probably leads to more people having resolution of IDA (iron deficiency anaemia) than intravenous iron sucrose. Oral ferric maltol may lead to more people having resolution of IDA than placebo.

We are unable to draw conclusions on which of the other treatments is most effective in IDA with IBD (inflammatory bowel disease) due to low numbers of studies in each comparison area and clinical heterogeneity within the studies. Therefore, there are no other conclusions regarding the treatments that can be made and certainty of all findings are low or very low. Overall, intravenous iron delivery probably leads to greater response in patients compared with oral iron, with a NNTB (number needed to treat) of 11.

Whilst no serious adverse events were specifically elicited with any of the treatments studied, the numbers of reported events were low and the certainty of these findings very low for all comparisons, so no conclusions can be drawn. There may be more withdrawals due to such events when oral is compared with intravenous iron delivery.

Other outcomes were poorly reported and once again no conclusions can be made as to the impact of IDA on any of these outcomes.

Given the widespread use of many of these treatments in practice and the only guideline that exists recommending the use of intravenous iron in favour of oral iron, research to investigate this key issue is clearly needed. Considering the current ongoing trials identified in this review, these are more focussed on the impact in specific patient groups (young people) or on other symptoms (such as fatigue). Therefore, there is a need for studies to be performed to fill this evidence gap.

Read the full abstract...
Background: 

Inflammatory bowel disease affects approximately seven million people globally. Iron deficiency anaemia can occur as a common systemic manifestation, with a prevalence of up to 90%, which can significantly affect quality of life, both during periods of active disease or in remission. It is important that iron deficiency anaemia is treated effectively and not be assumed to be a normal finding of inflammatory bowel disease. The various routes of iron administration, doses and preparations present varying advantages and disadvantages, and a significant proportion of people experience adverse effects with current therapies. Currently, no consensus has been reached amongst physicians as to which treatment path is most beneficial.

Objectives: 

The primary objective was to evaluate the efficacy and safety of the interventions for the treatment of iron deficiency anaemia in people with inflammatory bowel disease.

Search strategy: 

We searched CENTRAL, MEDLINE, Embase, and two other databases on 21st November 2019. We also contacted experts in the field and searched references of trials for any additional trials.

Selection criteria: 

Randomised controlled trials investigating the effectiveness and safety of iron administration interventions compared to other iron administration interventions or placebo in the treatment of iron deficiency anaemia in inflammatory bowel disease. We considered both adults and children, with studies reporting outcomes of clinical, endoscopic, histologic or surgical remission as defined by study authors.

Data collection and analysis: 

Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using the GRADE methodology.

Main results: 

We included 11 studies (1670 randomised participants) that met the inclusion criteria. The studies compared intravenous iron sucrose vs oral iron sulphate (2 studies); oral iron sulphate vs oral iron hydroxide polymaltose complex (1 study); oral iron fumarate vs intravenous iron sucrose (1 study); intravenous ferric carboxymaltose vs intravenous iron sucrose (1 study); erythropoietin injection + intravenous iron sucrose vs intravenous iron sucrose + injection placebo (1 study); oral ferric maltol vs oral placebo (1 study); oral ferric maltol vs intravenous ferric carboxymaltose (1 study); intravenous ferric carboxymaltose vs oral iron sulphate (1 study); intravenous iron isomaltoside vs oral iron sulphate (1 study); erythropoietin injection vs oral placebo (1 study).

All studies compared participants with CD and UC together, as well as considering a range of disease activity states. The primary outcome of number of responders, when defined, was stated to be an increase in haemoglobin of 20 g/L in all but two studies in which an increase in 10g/L was used.

In one study comparing intravenous ferric carboxymaltose and intravenous iron sucrose, moderate-certainty evidence was found that intravenous ferric carboxymaltose was probably superior to intravenous iron sucrose, although there were responders in both groups (150/244 versus 118/239, RR 1.25, 95% CI 1.06 to 1.46, number needed to treat for an additional beneficial outcome (NNTB) = 9).

In one study comparing oral ferric maltol to placebo, there was low-certainty evidence of superiority of the iron (36/64 versus 0/64, RR 73.00, 95% CI 4.58 to 1164.36).

There were no other direct comparisons that found any difference in the primary outcomes, although certainty was low and very low for all outcomes, due to imprecision from sparse data and risk of bias varying between moderate and high risk.

The reporting of secondary outcomes was inconsistent. The most common was the occurrence of serious adverse events or those requiring withdrawal of therapy. In no comparisons was there a difference seen between any of the intervention agents being studied, although the certainty was very low for all comparisons made, due to risk of bias and significant imprecision due to the low numbers of events.

Time to remission, histological and biochemical outcomes were sparsely reported in the studies. None of the other secondary outcomes were reported in any of the studies.

An analysis of all intravenous iron preparations to all oral iron preparations showed that intravenous administration may lead to more responders (368/554 versus 205/373, RR 1.17, 95% CI 1.05 to 1.31, NNTB = 11, low-certainty due to risk of bias and inconsistency). Withdrawals due to adverse events may be greater in oral iron preparations vs intravenous (15/554 versus 31/373, RR 0.39, 95% CI 0.20 to 0.74, low-certainty due to risk of bias, inconsistency and imprecision).

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