Meta-analysis of efficacy and safety of intravenous ferric carboxymaltose (Ferinject) from clinical trial reports and published trial data

Anaemia is common. A 2008 WHO report concentrating on pre-school children and women estimated that worldwide one in four persons is affected by anaemia, with pregnant women and preschool-age children at the greatest risk [1]. High prevalence of anaemia is associated with older age [2], and with acute and chronic conditions, like chronic kidney disease [3].

Blood is expensive. In 2000/2001 the estimated UK NHS cost for an adult transfusion was £635 for red blood cells (RBC), £378 for fresh frozen plasma, £347 for platelets, £834 for cryoprecipitate, with large increases over the preceding decade [4]. The cost of providing red blood cell transfusions to surgical patients in the USA, including major process steps, staff, consumables, and direct and indirect overhead costs amounted to between US$522 and US$1183 [5]. The UK Blood Transfusion Service puts the cost of providing one unit of RBC at about £130 [6], but the total annual cost of provision and transfusion of blood products was put at £898 millions in 2000/1, with an annual increase of about 17% [4].

Despite differences in time and situation, it amounts to an expensive business; it is sensible to avoid these costs and the unnecessary use of blood where possible. There are also potential risks, of incompatibility, infection, and iron overload in patients having recurrent transfusions over long periods.

For iron deficiency anaemia associated with conditions like chronic kidney disease (CKD) the first recourse is to iron supplementation, either oral or parenteral. Anaemia is associated with increased morbidity, and with increased mortality in chronic conditions [7–12], though high Hb levels may be harmful [13, 14]. Anaemia is also associated with huge economic burden [15].

For CKD, for example, iron deficiency is a frequent cause of anaemia, resulting from multiple blood sampling, interventional procedures, gastrointestinal bleeding and poor nutritional intake [3]. The severity of iron deficiency anaemia increases with advancing chronic kidney disease, particularly in patients on haemodialysis [16]. The combination of CKD and a low Hb level occurs in about 100,000 people in the UK [3]. Maintenance of target range Hb levels (11-12 g/dL) in non-dialysis-dependent patients with CKD is associated with positive patient outcomes and improved quality of life and physical function [16]. The complex interrelationships between anaemia and cardiorenal function currently being teased out indicate that we have much to learn [17].

Treatment of iron deficiency anaemia means identifying and treating its cause, and replacing iron may be only part of that [18, 19]. Oral iron is neither suitable nor effective in all patients; oral iron is poorly absorbed, and is not well tolerated because of adverse gastrointestinal effects [20–22]. Intravenous iron preparations were developed to overcome these problems in patients in whom oral iron is poorly tolerated, or more rapid replacement is required, or absorption is compromised. Intravenous iron preparations have included iron as high or low molecular weight iron dextran, iron gluconate, or iron sucrose, and ferric carboxymaltose; differences include the number of administrations required to replenish iron stores. Some, notably iron dextrans with higher molecular weight, have been associated with hypersensitivity reactions that have limited their use [23, 24].

In some conditions, notably CKD, other factors are important, particularly the appropriate balance between stimulation of erythropoiesis and the provision of iron for the manufacture of Hb [3], and the routine use of erythropoiesis-stimulating agents (ESAs) has led to a need for concomitant iron supplementation. Together, ESAs and iron now form the cornerstone of anaemia management in chronic kidney disease. Intravenous iron supplementation is effective in CKD, with acceptable safety; it permits replacement of iron stores for erythropoiesis, and improves the responsive to ESAs, as well as reducing the requirement for costly ESA therapy and transfusions [22, 25–27].

Iron sucrose is typically administered as a slow push injection or a 15- to 30-minute infusion in doses of 100-200 mg, requiring multiple outpatient visits and repeated intravenous access for patients to receive the standard therapeutic course of 1,000 mg elemental iron. Iron dextran can be administered as a single dose, but this requires administration over a period of four to six hours. In addition, iron dextran complexes can cause fatal dextran-induced anaphylactic reactions [3, 28]. Anaphylactic reaction is rare, with estimates for iron dextran products of 0.6% incidence [29].

Ferric carboxymaltose (Ferinject^®) is a novel non-dextran-containing complex of iron that allows for administration of a large replenishment dose (≤1,000 mg of iron) over a short infusion period (15-30 minutes), typically to the amount required for iron repletion. Ferric carboxymaltose is effective in improving Hb concentrations in non-dialysis-dependent patients with CKD [30]. It may be of significant benefit for use in the outpatient department or in a community setting as a result of its rapid and high-dose replacement of depleted iron stores in patients with CKD, as well as in various other adult populations with iron deficiency anaemia [30].

It has been noted that many of the recommendations for intravenous iron treatment are not supported by a high level of evidence [31]. This meta-analysis seeks to address the evidence gap by summarising the available data from clinical trials of ferric carboxymaltose using clinical trial reports and published results. Clinical trial reports frequently contain much more detail than is available in published reports, if only because they are not restricted by word count limits; meta-analyses from clinical trial reports of other drugs have been conducted previously [32–34].

Our knowledge of iron metabolism is still in a state of rapid development [62–64], but however involved it may turn out, we have to interpret the evidence from completed studies on the basis of the tests used at the time. In the case of the ferric carboxymaltose studies, this meant mainly Hb, serum ferritin, and TSAT. Complications arise when assessing the evidence on anaemia in different conditions and with different causes (chronic kidney disease, uterine or postpartum bleeding, gastrointestinal disease, heart failure), using different comparators (oral iron, IV iron, placebo), and from patients receiving erythropoietin. Moreover, haematological outcomes are reported in different ways, typically average change in value, or response or nonresponse, but with differing definitions of response. Trials also had different regimens for giving IV iron, mainly because of different clinical requirements.

Unfortunately some randomised studies were not blind, and others were non-comparative, which does weaken the strength of the evidence available. Set against this were the relatively large numbers of patients reported on, often concerning appropriate duration, and the consistency of response not only between different trials for similar outcomes, but also between randomised and non-comparative studies. A further strength was the availability of CTRs as well as published articles for a number of trials. CTRs are much more detailed than published reports because they are not constrained by word limits, or limits on tables and figures. Most CTRs, for example, comprised over 100 pages, and at least one over 1,000 pages of details. CTRs have been used for a number of meta-analyses where more insightful examination of clinical trials has been needed. They have been used, for example, in reporting adverse events [33], and determining different outcomes in erectile dysfunction [32] and pain [65].

Comparing IV ferric carboxymaltose with oral iron showed a similar time course for Hb and TSAT, though at each time point results for oral iron were numerically worse. Oral iron had no effect on ferritin. Where response was defined as achievement of target Hb, preset Hb rise, or preset Hb rise together with preset changes in ferritin and/or TSAT, there was a statistically significantly better result for ferric carboxymaltose, with NNTs in the range of 6-7, but as low as 1.5 when clinical success was defined with ferritin changes. The much lower, better, NNT reflected the lack of any effect of oral iron on serum ferritin. However response was defined, the response rate with ferric carboxymaltose was in the range of 70-80% (Table 2).

Ferric carboxymaltose produced significantly greater improvements in mean Hb, ferritin, and TSAT in the five trials that compared them, with an average improvement of about 5 g/L, 163 μg/L, and 5% respectively (Figure 6). These figures were obtained at the end of the trials when the increase in ferritin seen soon after therapy started had declined (Figure 2).

In general, and with large numbers of patients, there was little difference in terms of withdrawals and adverse events, including serious adverse events or hypotension, between ferric carboxymaltose and all comparators or oral iron alone.

There were more deaths in the trial arms using ferric carboxymaltose than with control; they were no more frequent than with placebo or iron sucrose, at between 0.3% and 0.6%, though none occurred with oral iron. In the largest and longest study compared with placebo, death rates were similar in the two groups, and 5 of the 11 deaths with ferric carboxymaltose occurred in that trial [42]. Recent reanalyses of trials of ESAs points to rapid Hb increases as being associated with higher mortality risk [66]. If that finding were replicated with IV iron, with or without use of ESA, it might point to a mechanism where too rapid restoration of iron stores was also associated with an increased mortality risk. The emerging view is that serious adverse events have declined with newer IV iron preparations, such that benefits outweigh any risks [67].

In terms of specific adverse events, ferric carboxymaltose was associated with lower rates of constipation, diarrhoea and nausea or vomiting than oral iron, but injection site reactions were higher compared to other parenteral iron preparations.

It is worth mentioning several points that this analysis was not able to assess. For example, no studies compared ferric carboxymaltose with blood transfusion, and direct comparisons between different IV iron products were limited in number, but clearly of interest. This limited the comparison mainly to that between IV ferric carboxymaltose and oral iron. The rate of decline in Hb after stopping treatment with ferric carboxymaltose or oral iron would have been of interest, particularly in some patient groups. This review goes some way to improving the level of evidence available to support recommendations given for IV iron treatment [38], but is not yet a complete response because of the lack of clinical trials. The review was also limited in being able to obtain useful health economic data except from one recent trial [43] that demonstrated a lower cost for IV ferric carboxymaltose over IV iron sucrose, but with a higher success rate. Recent analyses also show that not treating anaemia in CKD with IV iron or ESAs led to greater mortality and cost [68].

There is substantial evidence that IV ferric carboxymaltose is effective in treating iron deficiency anaemia in many chronic conditions. The review increases the evidence available to support recommendations given for IV iron treatment, but there are limited trial data comparing different IV iron preparations.

RAM - MA DPhil CChem FRSC FRCA DSc - has been involved with systematic reviews and meta-analyses, and method development in pain and other areas

HG - BM BCh DPhil MRCGP - works in secondary care and evidence-based medicine

PR - FRCP FRCPath - has been involved in prospective clinical trials, systematic reviews, meta-analysis and production of clinical guidelines in Haemostasis and Thrombosis.

JA - MRPharms DipClinPharm - specialising in haematology.