UNIVERSITÀ DEGLI STUDI DI PISA
Scuola di Specializzazione in Patologia Clinica e Biochimica Clinica
TESI DI SPECIALIZZAZIONE
Intravenous iron administration in iron deficiency anemia: a
multicentre retrospective observational study comparing the
effects of ferric carboxymaltose and sodium ferric gluconate
RELATORE
Dott. Alessandro Mazzoni
CANDIDATA
Dott.ssa Luisa Coluccia
3
I
NDEX
A
BSTRACTp. 4
B
ACKGROUNDp. 6
M
ATERIALS AND METHODSStudy overview
p. 8
Study arms and outcome measures
p. 8
Statistical analysis
p. 9
R
ESULTSBaseline data
p. 10
Iron exposure
p. 11
Primary endpoint
p. 11
Secondary endpoints
p. 13
Adverse events and transfusion need
p. 15
D
ISCUSSIONp. 18
4
ABSTRACT
BACKGROUND. Appropriate therapeutic management of iron deficiency anemia
(IDA) is essential to prevent serious health risks and indiscriminate exposure to allogeneic blood transfusions. Iron therapy is administered intravenously in patients failing to respond to oral iron treatment or needing rapid iron repletion. Several parenteral iron carbohydrate complex formulations are now available, classified as stable, such as ferric carboxymaltose, or labile, such as sodium ferric gluconate, according to the release rate of iron, directly taken up by transferrin and other proteins. The first one preparations allow clinically well-tolerated administration of a single much higher dose of intravenous iron by more rapid infusion than the second one and various therapeutic areas can take advantages of their use, as appropriate therapy for IDA correction.
STUDY DESIGN AND METHODS. In this retrospective study, we considered 346
patients with IDA, eligible for the intravenous treatment. 222 patients (group A) received an average of three intravenous injections of ferric carboxymaltose (500 mg / visit), other 124 patients (group B) received an average of ten infusions of sodium ferric gluconate (62,5 mg / visit). Patients were assessed at first visit and at least after 2, 5 and 7 weeks from the beginning of the treatment. The primary endpoint was the difference in the mean Hb, ferritin and transferrin saturation values detected throughout the whole observation period between the two treatment groups. Drug-related adverse events and transfusion need were also evaluated.
5
RESULTS. Significantly lower baseline levels of Hb, ferritin and transferrin
saturation (TSAT) were detected in group A, than in group B. Nevertheless, we found a faster and greater Hb, ferritin and TSAT increase with ferric carboxymaltose dosing regimen compared with sodium ferric gluconate. Throughout the whole observational period, group A showed a mean Hb level of 11,3 g/dL (95% CI 11,1 – 11,6), a mean ferritin level of 221,1 ng/mL (95% CI 184,4 – 257,7) and a mean TSAT of 20,7% (95% CI 18,9 – 22,5); group B showed a mean Hb level of 10,6 g/dL (95% CI 10,4 – 10,8), a mean ferritin level of 85,4 ng/mL (95% CI 50,9 – 119,9) and a mean TSAT of 14,1% (95% CI 11,8 – 16,4). After drug administration, statistical analysis showed a significant difference between the two groups in terms of mean Hb level (0,74 g/dL, 95% CI 0,42 – 1,06, p<0,0001), mean ferritin level (135,7 ng/mL, 95% CI 85,3 – 186,1, p<0,0001) and mean TSAT (6,6%, 95% CI 3,7 – 9,6, p<0,0001). The occurrence of intravenous iron-related adverse drug effects was very low and the difference among the two groups was not statistically significant (p=0,8). No serious adverse events were witnessed. Patients requiring transfusions after the beginning of the treatment decreased and were 1.4% in group A and 4.8% in group B (p=0,05). Even patients with baseline Hb ≤ 8 g/dL showed a greater increase in Hb concentration in group A compared to group B and a very low proportion of them needed transfusions.
CONCLUSION. The results of this study suggest that ferric carboxymaltose can be
used safely and more effectively than sodium ferric gluconate to rapidly improve and maintain raised Hb concentration and TSAT values after drug withdrawal in patients with iron-restricted erythropoiesis, avoiding their exposure to the potential risks of untreated anemia, unnecessary transfusions or both.
6
Background
Several burgeoning data, including analysis of benchmark studies (1-2), suggest that there is a sleeping giant of undertreated patients with an unsafe condition of iron deficiency anemia (IDA) (3), for which intravenous iron supplementation should be warranted. Eligibility criteria for this therapy are: oral iron non-compliance / intolerance or ineffectiveness (4); severe IDA in pregnancy (beyond the first trimester) (5-6) and postpartum (7-8); excessive bleeding (9-10); surgeries that decrease iron absorption (gastrectomy, duodenal bypass) (11); gastrointestinal tract disorders (active inflammatory bowel diseases; H. pylori colonization; impaired gastric acid secretion; coeliac disease) (12-16); erythropoietic-stimulating agents (ESA) therapy in chronic kidney disease (CKD) (17-18) and in cancer (19-21);
CKD (irrespective of ESA) (22); genetic iron refractory IDA (IRIDA) (23); unaccepted blood transfusions for religious issues; a clinical need for a rapid iron supply, closely related to functional capacity, e.g. in the perioperative setting (24); and acute event-related anaemia (AERA), in critical illness and tissue damage for the changes in iron metabolism induced by inflammatory effect (25).
For all these clinical and surgical settings, different formulations of parenteral iron are now available, consisting of a mineral core of iron oxohydroxide, surrounded by a carbohydrate shell, that determine their pharmacological and biological differences. Following injection, stable complexes, with high molecular weight and structural homogeneity, such as ferric carboxymaltose (FCM) (molecular mass of 150,000 Daltons), slowly deliver iron to transferrin, only via macrophages
7
endocytosis and consequent controlled export (26). These preparations permit rapid and larger dose (up to 1000 mg / visit) infusions to be administered over short therapeutic course (27).
In less stable preparations, such as sodium ferric gluconate (SFG) (molecular mass of 37,500 Daltons), instead, iron is rapidly released from carbohydrate complex and only if they are given slowly in small doses (up to 62,5 - 125 mg / visit ) is the iron taken up, at first, via endocytosis by the macrophages and not directly by transferrin. If transferrin was quickly fully saturated, there would be large amounts of toxic non-transferrin bound iron in the serum, responsible for lipid peroxidation, reactive oxygen species formation (28) and, as a consequence, systemic side effects (29). The typical therapeutic course of such labile preparations requires up to 5 injections and so administration
times are markedly longer (30) than for stable complexes.
The primary objective of this study was to evaluate the efficacy and safety of two different forms of parenteral iron, FCM compared with SFG, in patients with confirmed IDA of various etiologies.
8
Materials and methods
Study overview
In order to evaluate the effects of the two intravenous iron preparations, we performed a retrospective observational study, analyzing 346 patients consecutively admitted at 3 different centers for intravenous iron support between January 2009 and December 2015.
Study arms and outcome measures
Subjects who received FCM, administered in an average of three infusions of 500 mg, were allocated to the first arm (Group A); subjects who received SFG, administered in an average of ten infusions of 62,5 mg, were allocated to the second arm (Group B).
All patients assigned to group A and B were clustered depending on various etiologies of IDA (pregnancy, postpartum,
heavy uterine bleeding, gastrointestinal disorders, chronic heart failure, hematological disease, chronic disease or unexplained) and baseline hemoglobin (Hb) (≤8; 8,1-10; >10 g/dL).
Laboratory tests, showing hematopoietic response and iron repletion, were obtained at the beginning of iron therapy and 2, 5 and 7 weeks later.
The primary endpoint was the difference in the mean Hb, ferritin and transferrin saturation (TSAT) values detected throughout the whole observation period from baseline to Day 49 between the two treatment groups.
Other secondary endpoints included for each group, mean changes in Hb, ferritin and TSAT from baseline to Day 14, 35 and 49; the difference in the percentage of patients achieving an increase in Hb value of at least 1 g/dL any time between baseline and Day 14; the highest Hb value observed any time from baseline to Day
9
35 and 49; mean change from baseline to the highest observed Hb value from baseline to Day 14 and 49, and proportion of patients requiring transfusion, in the cluster of patients with Hb≤8 g/dL, allocated to both treatment groups.
Treatment-emergent adverse events and transfusion requirements in both groups, throughout the whole observation period of 7 weeks from the initiation of therapy, were also analyzed.
Statistical analysis
Variables with normal distribution are expressed as mean and SD, while categorical data as frequency and percentage. Between groups, comparisons of data were performed by t-test for unpaired data or the Mann-Whitney U-test for continuous variables, and by the chi-square test for categorical variables. The independent relationship between the two forms of parenteral iron (FCM and
SFG) and laboratory parameters over time (dependent variable) was investigated by a multiple linear mixed model and data were expressed as regression coefficient, 95% confidence interval and p value. The significance level was set at p≤0,05.
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Results
Baseline data
A total of 346 patients, affected by IDA, were allocated to the two different groups: 222 supported with FCM to group A, and 124 supported with SFG to group B.
Baseline characteristics of these patients are listed in Table 1. Statistically significant differences were detected in laboratory data between the two groups, group A exhibiting lower mean values for Hb, ferritin and TSAT than group B.
Table 1. Demographic characteristics*
Group A: FCM (n=222) Group B: SFG (n=124) p value Age (years) 58.4±17.7 55.8±18.4 0.29 Sex Female Male 171 (77.0) 51 (23.0) 98 (79.0) 26 (21.0) 0.67 Etiology of IDA
Pregnancy, post-partum, HUB Gastrointestinal disorders Chronic disease Chronic heart failure Hematological disease Unexplained 69 (32.4) 70 (32.9) 35 (16.4) 4 (1.9) 6 (2.8) 29 (13.1) 23 (18.5) 31 (25.0) 22 (17.7) 1 (0.8) 10 (8.1) 37 (29.8) <0.0001 Baseline Hb (g/dL) 8.7±1.2 9.4±1.4 <0.0001 Hb category (g/dL) ≤8 8.1-10 >10 66 (30.4) 124 (57.1) 27 (12.4) 26 (21.0) 55 (44.4) 43 (34.7) <0.0001 Baseline ferritin (ng/mL) 11.1±29.3 14.2±26.6 0.0003 Baseline TSAT (%) 4.5±3.5 6.2±5.2 0.0006 Previous ABT requirement 14 (6.3) 25 (20.2) <0.0001 Previous iron therapy 96 (43.2) 56 (45.2) 0.7303 Active bleeding 41 (18.6) 28 (22.6) 0.37 *Data are expressed as means ± SD or as number (%)
ABT=allogeneic blood transfusion; FCM=ferric carboxymaltose; HUB=heavy uterine bleeding; IDA=iron deficiency anemia; SFG=sodium ferric gluconate; TSAT=transferrin saturation.
11
Iron exposure
Although the Ganzoni formula (31) is the best way to calculate patient’s total body iron deficit and to fully replete the iron stores, in clinical practice we utilized approved product labels (13), stating specific dosing regimens, to estimate intravenous iron needs.
The mean cumulative dose of intravenous iron received from subjects was significantly higher in group A than group B: 1439,4 (±536,9) mg versus 632,4 (±344) mg (p<0,0001); while the proportion of patients treated with iron therapy before baseline was similar between groups: 43,2% in group A and 45,2% in group B (p=0,7303).
Primary endpoint
Group A was associated with a faster and greater increase in Hb, ferritin and TSAT level than group B, and the difference between the two groups reached the
maximum from baseline to Day 28 (Figure 1) for Hb level (2,47 g/dL; 95% CI 1,68-3,27); to Day 7 (Figure 2) for ferritin level (322,4 ng/ml; 95% CI 187,7-457,2) and to Day 14 (Figure 3) for TSAT value (21,9%; 95% CI 13,5-30,4).
Mean difference in mean Hb, ferritin and TSAT values detected throughout the whole observation period between Group A and Group B was statistically significant and respectively: 0,74 g/dL (95% CI 0,42 -1,06), p<0,0001; 135,7 ng/mL (95% CI 85,3-186,1), p<0,0001; and 6,6% (95% CI 3,7 -9,6), p<0,0001; being mean Hb, ferritin and TSAT value observed in this period higher in group A than group B: respectively 11,3 g/dL (95% CI 11,1 - 11,6), 221,1 ng/ml (95% CI 184,4 - 257,7) and 20,7% (95% CI 18,9 - 22,5) versus 10,6 g/dL (95% CI 10,4 - 10,8), 85,4 ng/mL (95% CI 50,9 - 119,9) and 14,1% (95% CI 11,8 - 16,4).
12
Figure 1. Effects of ferric carboxymaltose (Group A, red line) and sodium ferric gluconate
(Group B, blue line) on hemoglobin levels throughout the observation period of the study.
Figure 2. Effects of ferric carboxymaltose (Group A, red line) and sodium ferric gluconate
(Group B, blue line) on ferritin levels throughout the observation period of the study.
Hemoglobin (g/dL)
13
Figure 3. Effects of ferric carboxymaltose (Group A, red line) and sodium ferric gluconate
(Group B, blue line) on transferrin saturation throughout the observation period of the study.
Secondary endpoints
Mean increase in Hb, ferritin, and TSAT from baseline to highest value by Day 14 was significantly greater in group A than group B: respectively, 2 (±1,2) g/dL versus 1,1(±0,9) g/dL, p=0,0057; 253,4 (±165,5) ng/ml versus 49,3 (±46,8) ng/ml, p=0,019 and 22,8 (±20,6)% versus 2,5 (±3,3)%, p=0,0398 (Table 2).
Interestingly, while disappeared at Day 35 (Table 3), such statistically significant differences between the FCM group and the SFG group, were confirmed at Day 49, when the average of Hb, ferritin and TSAT improvement from baseline was respectively 3,8 (±1,7) g/dL versus 1,2 (±1,3) g/dL, p<0,0001; 124,7 (±124,4) ng/ml versus 55,8 (±83,5) ng/ml,
14
p=0,0351 and 16,3 (±7,6) % versus 2,2 (±1,3) %, p=0,0009 (Table 4). Of note, at the end of the observational period, in
SFG group TSAT level returned close to baseline, while in FCM group TSAT remained stable, over 16%.
Table 2. Mean increase from baseline ferritin, Hb and TSAT to Day 14*
Group A Group B p value Ferritin (ng/mL) 253.4 ± 165.5 49.3 ± 46.8 0.019 Hb (g/dL) 2.0 ± 1.2 1.1 ± 0.9 0.0057 TSAT (%) 22.8 ± 20.6 2.5 ± 3.3 0.0398 *Data are expressed as mean ± SD. Hb=haemoglobin; TSAT=transferrin saturation.
Table 3. Mean increase from baseline ferritin, Hb and TSAT to Day 35*
Group A Group B p value Ferritin (ng/mL) 115.2 ± 97.9 49.5 ± 45.4 0.4939 Hb (g/dL) 2.2 ± 2.3 1.8 ± 1.8 0.5269 TSAT (%) 14.9 ± 9.5 11.9 ± 11.8 1 *Data are expressed as mean ± SD. Hb=haemoglobin; TSAT=transferrin saturation.
Table 4. Mean increase from baseline ferritin, Hb and TSAT to Day 49*
Group A Group B p value Ferritin (ng/mL) 124.7 ± 124.4 55.8 ± 83.5 0.0351 Hb (g/dL) 3.8 ± 1.7 1.2 ± 1.3 < 0.0001 TSAT (%) 16.3 ± 7.6 2.2 ± 1.3 0.0009 *Data are expressed as mean ± SD. Hb=hemoglobin; TSAT=transferrin saturation.
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The proportion of patients who achieved an increase in Hb level of at least 1 g/dL from baseline to Day 14 was significantly greater in group A than group B: 82,1% (95% CI 66,9 - 91,2) versus 45% (95% CI 25,3 - 66,4), p=0,005.
Likewise, the highest Hb value reached from baseline to Day 35 was significantly greater in group A than group B: 11 (±1,4) g/dL versus 10,6 (±1,4) g/dL, p= 0,015; such as the highest Hb value recorded from baseline to Day 49: 11,5 (±1,7) g/dL versus 10,9 (±1,3) g/dL, p=0,0006.
In the subgroup of 92 patients with Hb level ≤8 g/dL (66 supported with FCM and 26 with SFG), we found a mean increase in Hb from baseline to Day 14 that did not significantly differ, between group A and group B: 2,4 (±1,4) g/dL versus 1,4 (±0,8) g/dL, p=0,1837. The difference between the groups became statistically significant to Day 49, when mean increase in Hb level from baseline
was 4,6 (±2,1) g/dL in the FCM group versus 2,7 (±0,8) g/dL in the SFG group (p=0,0041).
In both subgroups of severely anemic subjects, we found a very low proportion of patients requiring transfusion after the beginning of parenteral iron therapy: 3,03% in group A and 3,85% in group B (p=1). Fisher exact test was used for statistical analysis and the lack of a statistically significant difference between the two subgroups may be due to sample size that didn’t provide the power to detect a treatment difference.
Adverse events and transfusion need
There weren’t any serious adverse events in both groups and there wasn’t a statistically significant difference in the proportion of patients who experienced a possibly drug-related side effect: 5.4 % in group A versus 7.2 % in group B, p=0,0821. The most common adverse
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events in the group A were mild hypersensitivity reactions, reversible even without therapy (2,3%) and dizziness (1,8%); conversely, the most common
adverse events in the group B were nausea/vomit (1,6%), and epigastric pain (1,6%) (Table 5).
Table 5. Adverse events*
Adverse event Group A Group B Headache 0 (0.0) 1 (0.8) Dizziness 4 (1.8) 0 (0.0) Nausea/vomit 1 (0.5) 2 (1.6) Epigastric pain 0 (0.0) 2 (1.6) Back pain 0 (0.0) 1 (0.8) Mild hypersensitivity reactions 5 (2.3) 1 (0.8) Abdominal pain 0 (0.0) 1 (0.8) Dysphagia 1 (0.5) 0 (0.0) *Data are expressed as number (%).
The proportion of patients receiving transfusions before starting intravenous therapy was significantly higher in group B than group A (20,2% versus 6,3%, p<0,0001), such us after the beginning of treatment, when subjects requiring
transfusion decreased and were 4,8% in group B versus 1,4% in group A (p=0,05) (Table 6), with 19 packed red blood cells (PRBC) units transfused in group B versus 6 in group A.
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Table 6. Transfusion need before and after intravenous iron injection*
Group A Group B P value Patients transfused before iron injection 14 (6.3) 25 (20.2) < 0.0001 Patients transfused after iron injection 3 (1.4) 6 (4.8) 0.05 *Data are expressed as number (%).
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Discussion
Our aim was to compare the effects of two forms of parenteral iron in patients with iron-restricted erythropoiesis.
We analyzed patients with every type of iron deficiency (ID): absolute ID, functional ID (for following treatment with ESA), and ID associated with chronic disease (ACD/IDA).
The ACD/IDA diagnosis wasn’t always straightforward, because of the lack of a widely available assay for determination of hepcidin-25 isoform (32), that, best of all, reflects iron need for erythropoiesis (33-34), without being an invasive method, like bone marrow aspiration stained with Prussian blue.
Subjects labeled “unexplained”, unresponsive to oral iron therapy, mostly “baby boomers” with a negative gastrointestinal workup, represented a sharp proportion in both groups of our
study and, after hematologic evaluation, were examined by serology for H. pylori IgG, celiac disease, serum gastrin and antiparietal/intrinsic factor antibodies, even if their noncompliance, for frequent side effects and multiple daily doses concerning to oral iron therapy (35), often affected this refractoriness.
In clinical practice, FCM stands out by the rate at which a maximum single dose can be infused safely, with fewer visits need, facilitating a rapid haematological response and iron replacement.
Our findings show that this newer formulation produces significantly greater and faster increases in Hb, ferritin and TSAT levels than SFG, maintaining raised their values even after drug withdrawal (Figure 1, 2, 3).
The low rate of adverse events of FCM was comparable to that of SFG, and supports the evidence that these preparations are safe (36), provided that
19
published European Medicines Agency’s Committee for Medicinal Products for Human Use advice (37) is followed. Infusion reactions (itching, flushing, dizziness, nausea), described in our patients and common with newer formulations (38), usually did not require any therapy and resolved without residua (39-40). Misinterpretation of the clinical nature of these mild reactions, deemed as serious adverse events and treated over-aggressively, often with vasopressors and antihistamines, fueled the historical perception of peril attributed to the intravenous iron, that novel comprehensive reviews reply (22,36). Furthermore, in terms of safety, our experience confirmes that intravenous iron administration, by readily increasing hematopoietic response rate, decreases allogeneic blood transfusion need, being proportion of subjects requiring transfusion, even among severely anemic
patients, lower in the FCM group than SFG group.
Properly administered, FCM, with an estimated incidence of serious adverse events of <1:200.000, is much safer than allogeneic blood transfusion (41), associated with events responsible for major morbidity in 1:21.413 components issued (according to the Serious Hazards of Transfusion 2012 data) (42).
In respect to infectious complications, transfusion of even a single PRBC unit may limit the immune response, induce inflammatory mediators (43) and delivers on average 200 mg of Heme Fe, which has growth-promoting effect on microorganisms (44), in contrast to commercial intravenous iron complex, that has been demonstrated in various surgical settings not to increase infection rate (45-46).
Additionally, FCM, although its higher acquisition cost than SFG, may be
20
considered a less expensive alternative (47-48). Factors to be taken into consideration include the lower frequency of infusion need and the resulting advantages both for the patient, with lower working days lost, and for the health system, with lower overhead costs: both direct (e.g., medical and nursing staff, infusion material, laboratory tests , with materials needed for sampling) and indirect (e.g., utilities, property and nonprofessional personnel), being the second ones the highest proportion of the total cost of the treatment.
Nowadays, the central purpose of health care organizations, including transfusion medicine services, is to maintain the greatest benefit for patients at lower overall cost, and for patients with iron deficiency, without hemodynamic instability, it means to actively treat underlying disease and replete iron stores for erythropoiesis, with oral and/or
intravenous iron supplementation, without adopting transfusion as front line therapy if clinically unnecessary (49).
In conclusion, our data suggest that, in appropriately selected individuals needing replenishment of iron stores, administration of FCM is an accurate approach, as safe and more effective than SFG, rapidly increasing medullary response and iron store, maintaining raised Hb and TSAT values even after drug withdrawal and decreasing transfusion need, with costs and complications related.
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