Economic Evaluation of Ferric Carboxymaltose for the Management of Hemodialysis Patients with Iron Deficiency Anemia in Italy

Patients with chronic kidney disease (CKD) on hemodialysis (HD) are at high risk of developing both iron deficiency and iron deficiency anemia (IDA), with prevalence rates reaching as high as 80%. This is mainly attributed to reduced iron absorption, chronic inflammatory processes and increased blood loss [1, 2].

The availability of adequate iron doses for erythropoiesis is a key factor in allowing a good response to erythropoiesis stimulating agents (ESAs). In cases of absolute or functional iron deficiency, it is necessary to use higher doses of ESAs to obtain a significant erythropoietic response. This is frequent in cases of resistance or hyporesponsiveness [1, 2].

In dialysis patients, the administration of oral iron is frequently ineffective and is often associated with gastrointestinal side effects. Renal failure is associated with upregulation of the iron regulatory peptide hepcidin, which binds to the iron exporter protein ferroportin and thereby reduces iron export from the enterocytes into the plasma, thus limiting dietary uptake. Intravenously administered iron, which bypasses the gastrointestinal tract, leads to faster iron incorporation into bone marrow red blood cells and hemoglobin [3]. The administration of intravenous (IV) iron therefore represents the standard of care for the management of anemia in this patient setting, with a tendency to both increase iron doses and reduce the use of erythropoietin [4, 5]. In this way, both costs and potential risks are optimized, particularly in terms of reduction of major thromboembolic events and related mortality, as shown in several trials [6, 7]. If from one side IV iron overcomes the ineffectiveness of oral formulations, on the other hand, even acute anaphylactoid reactions during iron infusions may happen, although life-threatening in rare cases [8].

Nowadays, data on the use of various IV iron preparations in dialysis are still limited, leading to heterogeneity in administration methods, doses and duration of treatment, with a different impact on the outcomes observed [5].

In Italy, three IV iron formulations are currently available: ferric gluconate (FG, Ferlixit^®—Sanofi-Aventis), iron sucrose (IS, Venofer^®—Vifor Pharma) and ferric carboxymaltose (FCM, Ferinject^®—Vifor Pharma), all formulations having different characteristics. FCM is a new-generation non-dextran-like IV iron, characterized by a high molecular weight and chemical-structural characteristics (external shell of carboxymaltose), allowing the release of iron in a controlled manner, thus permitting high dose infusions in a single administration (up to 1000 mg during a 15 min infusion) [9].

Although the efficacy of the three formulations for the treatment of anemia in patients with CKD has been studied individually by comparing individual preparations with oral supplementation [10‐12], there is still a lack of head-to-head studies among the various IV formulations, particularly in the dialysis population.

Some studies have shown that FCM is well tolerated and effective in correcting hemoglobin (Hb) levels in patients with CKD undergoing dialysis [13, 14].

A recent Dutch study [15] showed that the switch from IS to FCM in HD patients was associated with a significant improvement in iron status and Hb values, unrelated to IV iron dose. Furthermore, weekly doses of ESA decreased after switching to FCM.

The PIVOTAL trial [16], the largest prospective randomized study, recruiting 2171 HD patients, has recently provided important safety results. This study has demonstrated, for the first time, that the use of a liberal, proactive higher dose IS regimen [aimed at targeting higher ferritin and transferrin saturation (TSAT) values] was superior to the use of a low-dose, reactive IS regimen and was associated with a lower risk of major cardiovascular events (acute myocardial infarction, stroke, hospitalization for heart failure or mortality) and did not increase the risk of all-cause mortality. Moreover, a proactive IV iron treatment regimen also allowed the use of lower ESA doses and required fewer transfusions in HD patients [17].

Here we present results of a retrospective real-world study performed in a HD patient cohort aimed at providing further information on the clinical and economic implications that can support hospital decision makers in their choice of treatment of iron deficiency anemia. A comprehensive approach was performed by evaluating the effect of switching from FG to FCM on achievement of adequate Hb values and iron balance from a clinical and pharmacoeconomic point of view.

Anemia is a frequent and early complication of CKD [19]. It contributes to typical CKD symptoms (fatigue, reduced exercise tolerance, dyspnea, cognitive impairment, insomnia) and to disease progression and cardiovascular complications such as left ventricular hypertrophy and left ventricular diastolic dysfunction [20]. Although the etiology of renal anemia is multifactorial, its main cause is a lack of endogenous erythropoietin production, with a consequent reduction in bone marrow erythropoiesis. Treatment of anemia in CKD patients is expensive because of the high cost of erythropoietin. This results in higher direct healthcare costs in patients with CKD and anemia compared with those without anemia [21]. Good iron body stores are needed for the optimal activity of erythropoietin and for curtailing doses. International guidelines recommend the use of the IV administration of iron in HD patients because of the quicker Hb improvement and lower ESA requirement compared with oral iron administration [4]. However, data concerning the use of different parenteral iron preparations are currently still limited in the context of dialysis [5]. Moreover, there is a lack of studies evaluating the economic consequences or cost-effectiveness of different iron IV formulations in this setting. To date, Wong et al. [22] published an economic evaluation aimed at estimating the healthcare costs and benefits of IV iron (iron sucrose and iron polymaltose) compared with oral iron in HD patients receiving ESAs. The study showed that the use of parenteral iron to achieve an Hb target between 9.5 and 12 g/dl was cost-effective compared with oral iron therapy among HD patients with functional iron deficiency. Recently, an Italian study [23] reported that FCM was effective in correcting IDA and was associated with an important reduction in costs related to anemia management compared with ferric gluconate. However, that study was undertaken in non-dialysis CKD.

Findings from the present study show that switching from FG to FCM in adult HD patients with IDA allows a cost reduction per patient/month in the range €14–46, considering the two scenarios of use of biosimilar ESA or originator ESA, respectively. The analysis on the cost per patient at target showed savings in the range of − 36% and − 26% in the two scenarios considered. The cost component of the healthcare personnel had limited impact on the results.

In reference to clinical data, after the switch to FCM, Hb, ferritin and TSAT increased, while transferrin levels decreased, reflecting erythropoiesis that was less restricted by iron deficiency. A similar trend was already observed in a recent study by Hofman et al. [15] after the switch from IS to FCM. During the FG period, the values of ferritin were on average below the recommended threshold of 200 µg/l, while after the switch mean values were in target in 4 out of 6 months. The ferritin levels reported in the first period are likely related to the average lower iron doses per single infusion because of the lower doses allowed with FG (62.5 mg). In this context, FCM could reach much higher doses per single infusion (100 mg), thus inducing higher ferritin levels and a correct maintenance of ferritin and TSAT targets. Our real-life experience is in line with a recent publication by Diebold et al. [24], who demonstrated that after a single infusion of FCM, the ferritin levels increase rapidly and that the curve to baseline could cover 3–4 weeks at least.

The main clinical benefit from switching to FCM was the increase of Hb values, which paralleled an important dose reduction of ESA (− 32% in the present study).

Furthermore, considering similar iron doses over the two periods, FCM was shown to be more effective than FG in restoring iron reserves, probably because of increased bioavailability of elemental iron in FCM compared with FG. Actually, both ferritin and the percentage of patients with TSAT ≥ 20% were always higher during FCM treatment in all the observed periods.

It is also important to highlight the progressive reduction of ERI when FCM was used, confirming lower requirements of ESA and consequently lower mean total cost for drugs (erythropoietin + iron) per patient (from €185 in the pre-switch period to €153 post-switch).

This study has a number of limitations that need to be addressed. It was conducted through a cost-minimization analysis, which basically does not consider differences in effectiveness of the compared treatments. We presented, in addition, a number of clinical parameters that could help highlight the advantages of the use of FCM over FG in HD patients with IDA. Regrettably, the retrospective nature of the study did not allow us to collect data on patients’ quality of life in a prospective way in order to perform a cost-utility analysis, which would have provided a more comprehensive picture of the comparison between FG and FCM in a proper pharmacoeconomic context. For the same reason, we were not able to collect data on patients’ out-of-pocket costs or productivity losses in order to consider the broader societal perspective in our analysis and give insights on the optimal resource allocation supporting an informed public discussion on the burden of the management of dialysis patients with IDA.

Other limitations, apart the small size of the investigated population, include the non-controlled and retrospective nature and being a single-center study. Actually, it was not a trial, but a real-world experience, where unpredictable situations may occur, such as the need to switch from FG to FCM. However, the monthly levels of different parameters assessed (pre- and post-switch) clearly depict the true trend of the investigated parameters. Another limitation relates to the difference in the monthly iron doses between the two periods; although the total 6-month dose was similar for FG and FCM (about 2000 mg), FG doses were progressively halved during the 5 months (from − 6 to − 2) and doubled in the following month (− 1). Anyway, no response was shown at month 0, as Hb values continued to decrease until 9.9 g/dl. This excludes a possible effect of FG in the following month, which on the other hand could be explained by the FCM use.

Moreover, all patients with available follow-up (6 months of use of FG and 6 months of use of FCM) were considered in the study, so we were not able to analyze other possible patients as a control group that in the same 6-month period of FCM use remained on FG.

We assumed that all ESAs were bioequivalent, which means that there were no clinically relevant differences between ESA originators and ESA biosimilars. However, this could not be the case since the biosimilar of epoetin alpha has been reported to have 35% lower activity than the corresponding originator in a real-world setting [25]. Thus, the reduced need for erythropoietin observed in the FCM period could actually underestimate the true savings in erythropoietin units in the scenario of use of ESA biosimilars; indeed, ESA biosimilar consumption should increase by 35% to maintain the same activity level as ESA originators leading to ESA biosimilar expenses of €23,846 and €16,232 for FG and FCM strategies, respectively (see Table 2, scenario with biosimilar ESA, for comparison). Consequently, the total savings considering this scenario with + 35% use of biosimilar ESAs would be €5100 (total cost for FG and FCM strategies of €29,725 and €24,625, respectively) instead of €3126.

A further limitation of our study was the influence by the type of dialysis (HD, hemodiafiltration) on ERI [26]. However, this study includes comparison of multiple data points within one patient for the entire period. Each patient serves as his/her own control, and the dialysis method was maintained during the 12-month observation period.

Based on the results of the current retrospective data, our analyses suggest that FCM compared with FG, considering the same cumulative dose over a 6-month period, improves the control of anemia and is cost-saving in dialysis patients with IDA. The notable improvement in iron parameters by FCM may also have a more general beneficial effect. Nephrologists are mainly focused on the management of anemia and are interested in iron deficiency because these are a compulsory requirement for anemia treatment. However, in several therapeutic areas, especially in congestive heart failure, there is now strong evidence that iron deficiency alone impacts the underlying disease, exercise capacity and quality of life, independently of anemia [9, 27‐29]. This probably applies to HD patients whose congestive heart failure risk is high.

Future studies not limited to the analysis of costs but also considering patients’ quality of life through the assessment of the cost-utility profile of FCM versus FG, possibly performed from the broader societal perspective, may provide further evidence on the sustainability of FCM for the treatment of adult HD patients with IDA.