Improved Hemoglobin Response with Ferric Carboxymaltose in Patients with Gastrointestinal-Related Iron-Deficiency Anemia Versus Oral Iron

Improved Hemoglobin Response with Ferric Carboxymaltose in Patients with Gastrointestinal-Related... Aims To compare the efficacy and safety of intravenous (IV) ferric carboxymaltose (FCM) versus oral iron and other IV iron therapies in patients with iron-deficiency anemia (IDA) resulting from gastrointestinal (GI) disorders. Methods A pooled analysis of four prospective, randomized, active-controlled trials in patients with IDA was performed. Efficacy measures included change from baseline in hemoglobin (Hb), ferritin, and transferrin saturation (TSAT) and cor - relations of baseline Hb, ferritin, and TSAT to change in Hb. The incidence and type of adverse events were evaluated. Results A total of 191 patients were evaluated. The mean change in Hb from baseline to the maximum value was 0.8 g/dL with oral iron (P = 0.001 vs. FCM), 2.2 g/dL with FCM, 2.0 g/dL with any IV iron (P = 0.391 vs. FCM), and 1.9 g/dL with iron sucrose (P = 0.329 vs. FCM). Patients treated with FCM and iron sucrose had larger increases in Hb. This effect may have been attributed to a lower baseline Hb level. Drug-related adverse events occurred in 11.9, 12, 26.2, and 25% and serious adverse events (SAEs) occurred in 6.9, 4, 9.8, and 12.5% of patients in the FCM, oral iron, other IV iron therapies, and iron sucrose groups, respectively. No SAEs were considered treatment related in the FCM group, compared with two treatment-related SAEs in two patients (6.3%) in the iron sucrose group. Conclusions FCM is an effective therapy in patients with IDA who have GI disorders and has a safety profile comparable to that of other IV iron agents. Keywords Hemoglobin · Inflammatory bowel disease · Ferric carboxymaltose · Iron Introduction frequently caused by iron deficiency [ 2, 3]. Gastrointestinal (GI) diseases are a common cause of both iron deficiency In industrialized and developing countries, anemia is a and anemia. Patients with GI disorders such as inflamma - common and widespread disorder. According to the World tory bowel disease (IBD) are at risk of development of Health Organization, anemia affects approximately 25% iron-deficiency anemia (IDA) due to a combination of fac - of the global population (1.62 billion people) [1] and is tors, including chronic blood loss, inflammatory-mediated impairment of intestinal iron absorption, and the inability to utilize existing iron stores [4–6]. The prevalence of IDA in * Gary R. Lichtenstein IBD has been reported as high as 73.7% [7]. Similarly, celiac grl@uphs.upenn.edu sprue is frequently complicated by the development of IDA, Jane E. Onken which can occur even in the absence of GI symptoms [8]. jane.onken@duke.edu IDA without clinical evidence of intestinal malabsorption is encountered in approximately 50% of adults with subclinical Gastroenterology Division, Hospital of the University of Pennsylvania, University of Pennsylvania School celiac disease [9], while other studies have demonstrated that of Medicine, 7th Floor South, Perelman Center, Room 753, celiac disease is responsible for anemia in 5–6% of cases of 3400 Civic Center Boulevard, Philadelphia, PA 19104-4283, unexplained IDA [8, 10–12]. USA In IBD patients, the initial therapeutic strategy for IDA Department of Medicine, Division of Gastroenterology, Duke should be based on the activity of the disease, the level of University Medical Center, 40 Duke Medicine Circle, Clinic hemoglobin (Hb), and tolerance of the patient to oral iron [5, 2H/2J, Durham, NC 27710, USA Vol.:(0123456789) 1 3 3010 Digestive Diseases and Sciences (2018) 63:3009–3019 13]. In the recent European Crohn’s and Colitis Organisation time to alleviate IDA, potentially consuming substantially (ECCO) guidelines, oral iron may be used in IBD patients more administrative and financial resources [4 ]. with mild anemia whose disease is clinically inactive and Ferumoxytol and ferric carboxymaltose (FCM) are two who have not previously been intolerant to oral iron [13]. newer parenteral iron formulations registered in the USA Oral iron replacement therapy has long been the cornerstone that permit higher single doses to be delivered over shorter of IDA treatment [6]; it is inexpensive, is simple to admin- periods of time. Thus, they require fewer administrations to ister, and is not associated with life-threatening side effects. treat patients with IDA compared with other parenteral irons. Unfortunately, absorption of oral iron is unpredictable in Ferumoxytol was approved for use in the USA in 2009 with patients with active IBD due to the inflammatory inhibition an indication for the treatment of IDA in adults with chronic of absorption as a consequence of the interaction between kidney disease [28]. hepcidin and ferroportin [14]. In a recent study that evalu- FCM is a stable type I polynuclear iron (III)–hydroxide ated whether inflammation as reflected by C-reactive protein carbohydrate complex that prevents the partial release of (CRP) or interleukin 6 at initiation of treatment could predict iron to serum ferritin, allowing the administration of high the response to iron therapy, it was shown that Hb increases doses since this iron is available almost exclusively via retic- in the oral iron group were significantly lower in those with uloendothelial processing [14, 29–31]. In the USA, FCM high CRP levels than in those with low CRP levels. With IV was approved in 2013 and is indicated for the treatment of iron, response was fairly independent of inflammation. This IDA in adults who have intolerance, or have had an inad- further supports the assertion that IV iron can overcome the equate response, to oral iron therapy. It is also indicated hepcidin block and explains why oral iron may not be as for the treatment of IDA in non-dialysis-dependent chronic effective in patients with inflammation [15]. IBD patients kidney disease [32]. This pooled analysis was performed to develop IDA through increased iron loss from ongoing GI assess the safety and efficacy of FCM compared with the bleeding from the inflamed intestinal mucosa as well as safety and efficacy of oral iron therapy and other IV iron from reduced iron absorption within the inflamed mucosa. therapies for IDA secondary to GI disorders. Additionally, in approximately 50% of patients, oral iron ingestion is associated with GI side effects, leading to dis- continuation of therapy, including abdominal pain, nausea, Materials and Methods diarrhea, vomiting, and constipation [16–20]. Although its effect on IBD disease activity is unknown in humans, a num- Study Design ber of animal IBD studies have shown that oral iron can lead to worsening of intestinal inflammation, increased disease This was a post hoc analysis of primary data from four pro- activity, and increased oxidative stress [21]. To date, well- spective, active-controlled trials that evaluated the efficacy controlled trials evaluating the effect of oral iron on IBD and safety of FCM in patients with IDA resulting from a disease activity have not been conducted. broad range of causes [33–35]. The original trial designs Although there are no recent US IBD guidelines for IDA, are summarized in Table  1. The data were re-evaluated ECCO recently published a guideline/consensus paper on by the investigators to identify patients whose principal IDA. Intravenous (IV) iron is recommended as the preferred cause of IDA was underlying GI disorders and to compare route of administration in patients with clinically active IBD, the efficacy and safety of FCM versus those of oral iron previous intolerance to oral iron, and Hb less than 10 g/dL, therapy and other IV iron therapies in patients with these as well as for patients who require erythropoiesis-stimu- disorders. The original study protocols were approved by lating agents. In patients with severe IDA requiring rapid institutional review boards at each center, trials complied replenishment of iron stores, or in patients intolerant of oral with the Declaration of Helsinki, and all patients provided iron therapy, parenteral iron replacement allows rapid, safe, informed consent (NCT00703937 and NCT00704353 [33], effective restoration of iron stores and bypasses the issue of NCT00704028 [34], and NCT00982007 [35]; http://www. poor intestinal absorption [5, 6, 22]. Despite clinical find-clini caltr ials.gov). ings, widespread adoption of IV iron replacement has been slow, in part owing to historical adverse events of anaphy- Patient Selection lactic reactions associated with iron dextran formulations [6, 23, 24]. Newer, dextran-free iron carbohydrate complexes A list of preferred and verbatim terms from the GI section have been developed to avoid the issue of dextran-induced of the patient’s medical history was generated. From these anaphylaxis and allow high-dose IV iron replacement while GI-related terms, conditions considered to be a likely cause minimizing serious safety concerns [6, 25–27]. Although of IDA were determined. Patients were identified and their iron sucrose has been shown to be effective, it has dose- and data pooled if their medical history contained 1 or more of rate-limiting factors that necessitate multiple infusions over the terms. Patients with IDA related to bariatric surgery were 1 3 Digestive Diseases and Sciences (2018) 63:3009–3019 3011 1 3 Table 1 Summary of four randomized controlled trials of ferric carboxymaltose (Injectafer ) versus oral or intravenous iron therapy for the treatment of iron-deficiency anemia [33–35] Study Barish et al. [33] (single-dose study) Barish et al. [33] (multidose study) Hussain et al. [34] NCT00704028 Onken et al. [35] NCT00982007 NCT00704353 NCT00703937 a b N 738 (n = 366, FCM; n = 369, SMC) 708 (n = 343, FCM; n = 360, SMC) 160 (n = 82, FCM; n = 78, DEX) 1011 (n = 503, FCM; n = 257, oral iron; n = 251, IVSC) Population Men and women 18–85 years of age Men and women 18–85 years of age Men and women ≥ 18 years of age with Men and women ≥ 18 years of age with with IDA with IDA IDA and history of intolerance to or IDA and history of unsatisfactory unsatisfactory response to oral iron response to oral iron Key inclusion criteria Hb ≤ 12 g/dL and ferritin ≤ 100 ng/mL, Hb ≤ 11 g/dL; ferritin ≤ 100 ng/mL, Hb ≤ 11 g/dL; ferritin ≤ 100 ng/mL, Hb ≤ 11 g/dL; ferritin ≤ 100 ng/mL, or ≤ 300 ng/mL if TSAT ≤ 30% or ≤ 300 ng/mL if TSAT ≤ 30% or ≤ 300 ng/mL if TSAT ≤ 30% or ≤ 300 ng/mL if TSAT ≤ 30% Randomization FCM 15 mg/kg or 750 mg (whichever FCM 15 mg/kg up to a single-dose FCM versus IV iron dextran (doses of FCM 15 mg/kg up to a maximum of was smaller) IV push injection at maximum of 750 mg at 100 mg/min both drugs were calculated by the 750 mg on Days 0 and 7 versus oral 100 mg/min on Day 0 versus SMC on weekly until the calculated iron deficit Ganzoni formula) iron 325 mg TID for 14 days or other Days 0–30 (oral or IV iron prepara- dose had been administered (maxi- FCM 15 mg/kg up to a single-dose IV standard-of-care iron preparation tions) mum total dose: 2250 mg) versus maximum of 750 mg on Days 0, 7, SMC on Days 0–42 (oral or IV iron and 14; IV push injection weekly at preparations) 100 mg/min until the calculated iron All doses were calculated by the Gan- deficit dose had been administered zoni formula (maximum total dose: 2250 mg) IV iron dextran doses on Days 0–42 with a test dose of 25 mg given on Day 0 slowly over 5 min; the remain- der of the dose was administered if no reaction occurred. Doses and infusion times were determined by the investigator until the calculated iron deficit dose had been administered (maximum total dose: 2250 mg) Outcome measures Clinical, laboratory, and safety data Clinical, laboratory, and safety data Incidence of serious TEAEs; change in Mean change from baseline to maximum including adverse events including adverse events Hb, ferritin, and TSAT from baseline observed Hb value at any time between Mean changes from baseline in hemo- Mean changes from baseline in hemo- to the maximum value observed for baseline and Day 35; mean change from globin and ferritin globin, ferritin, and TSAT all patients baseline to maximum ferritin measure- ment any time between baseline and Day 35; mean change from baseline to each scheduled visit for Hb, ferritin, and TSAT levels; serious TEAEs Timing of assessments Clinical, laboratory, and safety data Clinical, laboratory, and safety data Laboratory data were collected at Laboratory data were collected on Days were collected on Days 0, 7, and 30 were collected on Days 0, 7, 14, 28, screening, baseline, and Days 0, 7, 14, 7, 14, and 35; safety data were collected (or end of treatment) and 42 (or end of treatment) 28, and 42; safety data were collected on Days 7, 14, 35, 90, and 120 on Days 0, 7, 14, 28, and 42 DEX iron dextran, Hb hemoglobin, FCM ferric carboxymaltose, IDA iron-deficiency anemia; IVSC intravenous standard-of-care iron therapy, SMC standard medical care (oral or IV iron ther - apy); TEAEs treatment-emergent adverse events, TSAT transferrin saturation Three patients were not treated Five patients were not treated 3012 Digestive Diseases and Sciences (2018) 63:3009–3019 excluded; these data were published in a separate analysis included all randomized patients who received at least one [29]. dose of study drug. Patient demographic data were sum- marized descriptively. The P value for change from base- Assessments line was calculated with a paired t-test, and the P value for the difference between FCM and the other comparators was Efficacy measures included change in Hb, ferritin, and trans- calculated from a one-way analysis of variance. Correlation ferrin saturation (TSAT) from baseline to the maximum of baseline ferritin and TSAT values with change in Hb was value observed for all patients. Change in Hb was stratified calculated by Spearman rank-order correlation. by baseline Hb, ferritin, and TSAT level. The number and percentage of patients reporting treatment-emergent adverse events (TEAEs) were summarized for each treatment group by overall incidence and relationship to study drug using the Results Medical Dictionary for Regulatory Activities (MedDRA) version 10.1. A total of 191 patients (59 males and 132 females) were identified from the four trial datasets as having IDA second- Data Analysis ary to GI disorders. The mean age of patients was 59.3 years, and the mean body mass index was 28.4 kg/m . GI-related All efficacy analyses were performed on the modified conditions contributing to IDA included GI bleeding intent-to-treat (mITT) population. The mITT population (62.8%), inflammatory bowel disease (27.7%), malabsorp- in three of the studies consisted of patients from the safety tion (5.2%), celiac disease (4.7%), and others (6.8%). In all, population who had two baseline Hb values and at least one 101 (52.9%) patients received FCM, 25 (13.1%) received postbaseline Hb assessment [33, 34]. In the fourth study, oral iron (ferrous sulfate), and 61 (31.9%) received any other the mITT population consisted of patients from the safety IV iron comparators, including iron sucrose, 32 patients population who received at least one dose of the randomly (16.8%); iron dextran, 27 patients (14.1%); and ferric glu- assigned study medication and had at least one postbase- conate, two patients (1.0%) (Table 2). Four patients received line Hb assessment [35]. A post hoc subgroup analysis of other comparators and were not included in the analysis changes in Hb, ferritin, and TSAT levels from baseline to because results were confounded by the use of a combination maximum value between baseline and end of study or time of iron therapy and blood transfusions. The mean total doses of intervention was conducted with data from patients with of elemental iron were 1238 mg (FCM), 2703 mg (oral iron), IBD and those without IBD and with GI bleeding. All safety 1086 mg (any other IV iron), and 943 mg (iron sucrose). assessments were performed in the safety population, which Table 2 Demographics and baseline characteristics by comparators FCM (n = 101) Oral iron (n = 25) Any other IV iron Iron sucrose (n = 32) (n = 61) Sex, n (%)  Male 26 (25.7) 8 (32.0) 24 (39.3) 12 (37.5)  Female 75 (74.3) 17 (68.0) 37 (60.7) 20 (62.5) Race, n (%)  Asian 0 0 1 (1.6) 0  Black 11 (10.9) 9 (36.0) 2 (3.3) 2 (6.3)  Caucasian 77 (76.2) 15 (60.0) 55 (90.2) 28 (87.5)  Hispanic 13 (12.9) 1 (4.0) 3 (4.9) 2 (6.3) Mean age (SD), year 59.1 (18.9) 58.0 (13.4) 59.7 (18.3) 55.0 (18.1) Mean weight (SD), kg 73.6 (19.3) 84.4 (19.5) 79.3 (21.4) 80.5 (25.1) Mean BMI (SD), kg/m 27.2 (6.40) 30.5 (7.43) 28.7 (6.58) 28.8 (7.56) Mean baseline Hb (SD), g/dL 9.7 (1.33) 10.6 (0.78) 9.6 (1.24) 9.5 (1.52) Mean baseline ferritin (SD), ng/mL 29.1 (58.5) 39.8 (68.3) 11.4 (11.0) 10.0 (8.69) Mean baseline TSAT (SD), % 11.3 (8.77) 14.6 (10.17) 9.0 (7.08) 8.9 (7.39) BMI body mass index, FCM ferric carboxymaltose, Hb hemoglobin, SD standard deviation, TSAT transferrin saturation Any other IV iron included two ferric gluconate patients, 27 iron dextran patients, and 32 iron sucrose patients 1 3 Digestive Diseases and Sciences (2018) 63:3009–3019 3013 Patients in the FCM group received 1–3 administrations; the [P = 0.001]). FCM also led to significantly (P ≤ 0.001) range in the other IV iron group was 1–20 administrations. greater increases in ferritin than oral iron and the other IV iron therapies in patients with IBD (FCM vs. oral iron: 474.3 Efficacy vs. 12.6 ng/mL [P = 0.001]; FCM vs. other IV therapies: 474.3 vs. 89.0 ng/mL [P < 0.0001]) and those without IBD Hb, ferritin, and TSAT values increased significantly from (FCM vs. oral iron: 540.0 vs. 7.1 ng/mL [P < 0.0001]; FCM baseline to maximum postbaseline values for all treatment vs. other IV therapies: 540.0 vs. 275.5 ng/mL [P < 0.0001]). groups (P = 0.001), with the exception of ferritin values for patients in the oral iron group. Patients treated with Correlation of Baseline Hb, Ferritin, TSAT to Changes in Hb FCM experienced significantly greater mean maximum Hb increases and absolute Hb values compared with patients The more severe a patient’s anemia was at baseline, the treated with oral iron (P = 0.001) (Table  3). Changes in larger the increase in Hb in response to treatment. This cor- Hb were similar with FCM and the other IV iron thera- relation was not observed in patients receiving oral iron pies. Patients in the FCM group had significantly greater therapy (Table 5). Baseline ferritin and TSAT values had a (at least twofold in all comparisons) peak absolute ferritin statistically significant negative correlation with change in values and increases from baseline compared with patients Hb (Spearman correlation coefficient R = − 0.43 [P < 0.001] in the other treatment groups. There were no changes in and R = − 0.55 [P < 0.001], respectively). Lower ferritin ferritin values in the oral iron group. Compared with oral values and lower TSAT values were associated with larger iron therapy and iron sucrose therapy, FCM treatment led to increases in Hb values, as shown in Figs. 1 and 2. statistically significantly greater increases in TSAT values (P = 0.001 and P = 0.002, respectively) and to significantly Safety greater absolute TSAT values. To determine whether responses differed between patients Total incidences in TEAEs were higher in the IV iron with IBD and non-IBD causes of GI blood loss, we per- groups (approximately 50–60%) than in the oral iron group formed subgroup analyses of data from these two groups (32.0%; P > 0.05) and were lower for FCM (46.5%) than (Table  4). FCM led to significantly greater increases in for other IV iron groups (55.7% for any other IV com- Hb than oral iron in patients with IBD (1.9 vs. 0.6 g/dL parator, P > 0.05; 59.4% for iron sucrose, P > 0.05). Two [P = 0.028]) as well as in those without IBD (2.1 vs. 0.7 g/dL events of hypophosphatemia were reported in the FCM Table 3 Mean (SD) change in hemoglobin, ferritin, and transferrin saturation from baseline to maximum value between baseline and end of study or time of intervention FCM (n = 101) Oral iron (n = 25) Any other IV iron (n = 61) Iron sucrose (n = 32) Hb, g/dL  Baseline 9.7 (1.33) 10.6 (0.78) 9.6 (1.24) 9.5 (1.52)  Maximum value 11.8 (1.49) 11.4 (1.23) 11.6 (1.44) 11.4 (1.22)  Change to maximum value 2.2 (1.52) 0.8 (1.01) 2.0 (1.24) 1.9 (1.04)  P value* – 0.001 0.391 0.329 Ferritin, ng/mL  Baseline 29.1 (58.52) 39.8 (68.32) 11.4 (11.00) 10.0 (8.69)  Maximum value 567.3 (327.20) 39.8 (42.46) 281.2 (262.89) 167.9 (179.26)  Change to maximum value 538.2 (300.50) 0 (33.13) 269.8 (259.11) 157.9 (173.60)  P value* – 0.001 0.001 0.001 TSAT, %  Baseline 11.3 (8.77) 14.6 (10.17) 9.0 (7.08) 8.9 (7.39)  Maximum value 37.0 (15.38) 24.8 (13.44) 32.7 (19.00) 24.2 (14.29)  Change to maximum value 25.7 (14.34) 10.2 (14.27) 23.6 (17.94) 15.3 (11.56)  P value* – 0.001 0.430 0.002 Iron sucrose is a subgroup of the any other IV iron comparator group FCM ferric carboxymaltose, Hb hemoglobin; IV intravenous, NS, nonsignificant, SD standard deviation, TSAT transferrin saturation *Pvalues refer to the comparison with FCM, from one-way analysis of variance Any other IV iron included ferric gluconate (n = 2), iron dextran (n = 27), and iron sucrose (n = 32) 1 3 3014 Digestive Diseases and Sciences (2018) 63:3009–3019 Table 4 Mean (SD) change in hemoglobin, ferritin, and transferrin tory bowel disease and non-inflammatory bowel disease gastrointesti- saturation from baseline to maximum value between baseline and end nal bleeding of study or time of intervention stratified by patients with inflamma- FCM Oral iron Any other IV iron Iron sucrose IBD (n = 30) Non-IBD IBD (n = 7) Non-IBD IBD (n = 15) Non-IBD IBD (n = 12) Non-IBD GI bleeding GI bleeding GI bleeding GI bleeding (n = 57) (n = 14) (n = 46) (n = 17) Hb, g/dL  Baseline 9.7 (1.3) 9.6 (1.4) 10.5 (0.9) 10.4 (0.9) 9.6 (1.2) 9.5 (1.2) 9.6 (1.3) 9.4 (1.7)  Maximum value 11.6 (1.3) 11.7 (1.6) 11.1 (1.2) 11.2 (1.4) 11.3 (1.3) 11.5 (1.6) 11.5 (1.1) 11.4 (1.3)  Change to maxi- 1.9 (1.5) 2.1 (1.4) 0.6 (0.7) 0.7 (1.0) 1.7 (1.1) 2.0 (1.3) 1.9 (1.1) 2.0 (1.1) mum value  P value* – – 0.028 0.001 0.631 0.811 0.942 0.738 Ferritin, ng/mL  Baseline 26.7 (46.7) 32.5 (68.7) 73.6 (115.0) 53.9 (87.9) 7.4 (4.5) 11.2 (11.1) 6.5 (4.3) 10.6 (5.9)  Maximum value 488.8 (225.8) 559.8 (250.3) 43.4 (39.5) 26.7 (17.7) 96.5 (64.5) 287.3 (247.9) 109.6 (62.9) 235.2 (163.9)  Change to maxi- 474.3 (218.5) 540.0 (247.7) 12.6 (8.2) 7.1 (10.1) 89.0 (62.9) 275.5 (249.5) 102.7 (60.8) 224.2 (165.6) mum value  P value* – – 0.001 <0.0001 <0.0001 <0.0001 <0.0001 0.0004 TSAT, %  Baseline 11.3 (8.8) 11.8 (9.1) 14.7 (10.1) 15.1 (9.8) 7.4 (4.9) 9.1 (7.5) 6.7 (3.9) 10.1 (8.9)  Maximum value 37.8 (17.4) 35.3 (12.8) 29.3 (11.3) 24.7 (14.6) 21.0 (15.6) 33.2 (19.4) 20.0 (9.7) 26.3 (15.2)  Change to maxi- 26.6 (16.1) 23.4 (11.6) 14.6 (14.8) 9.6 (15.7) 13.6 (11.7) 24.1 (19.1) 13.3 (7.2) 16.2 (13.0) mum value  P value* – – 0.082 0.0004 0.009 0.827 0.009 0.032 Iron sucrose is a subgroup of the any other IV iron comparator group FCM ferric carboxymaltose, GI gastrointestinal, Hb hemoglobin, IBD inflammatory bowel disease, IV intravenous; SD standard deviation, TSAT transferrin saturation *P values refer to the comparison with FCM, based on t test Table 5 Mean (SD) change in hemoglobin from baseline to maximum value between baseline and end of study or time of intervention stratified by baseline hemoglobin level FCM Oral iron Any other IV iron Iron sucrose Female Male Female Male Female Male Female Male Patients with mild anemia (hemoglobin 11.0–11.9 g/dL, females; 11.0–12.9 g/dL, males) [36]  n 10 6 6 3 5 1 4 1  Change to maximum value 1.0 (0.7) 1.7 (1.6) 0.6 (0.9) 1.4 (1.3) 0.9 (0.4) 1.0 0.9 (0.4) 1.0  P value* – – 0.336 0.788 0.774 – 0.796 – Patients with moderate anemia (hemoglobin 8.0–10.9 g/dL, females and males) [36]  n 55 19 11 5 29 20 13 8  Change to maximum value 2.2 (1.2) 2.2 (1.7) 0.8 (1.1) 0.6 (0.9) 1.9 (1.1) 2.2 (1.4) 1.9 (0.8) 2.0 (1.0)  P value* – – 0.001 0.061 0.266 > 0.999 0.396 0.763 Patients with severe anemia (hemoglobin < 8.0 g/dL, females and males) [36]  n 9 1 0 0 2 3 2 3  Change to maximum value 3.6 (1.9) 5.9 – – 3.0 (0.7) 3.3 (0.2) 3.0 (0.7) 3.3 (0.2)  P value* – – – – – – – – FCM ferric carboxymaltose, IV intravenous, SD standard deviation *P values refer to the comparison with FCM, from one-way analysis of variance 1 3 Digestive Diseases and Sciences (2018) 63:3009–3019 3015 Fig. 1 Correlation of base- 6.5 Spearman R = −0.43; P<0.001 line ferritin versus change in 6.0 hemoglobin from baseline to 5.5 maximum value between base- 5.0 line and end of study or time of 4.5 intervention in ferric carboxy- 4.0 maltose patients 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 13 10 32 100316 1000 Log Baseline Ferritin (ng/mL) Fig. 2 Correlation of base- 6.5 Spearman R = −0.55; P<0.001 line TSAT versus change in 6.0 hemoglobin from baseline 5.5 to maximum value between 5.0 baseline and end of study or 4.5 time of intervention in ferric 4.0 carboxymaltose patients. TSAT 3.5 transferrin saturation 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 0 5101520253035404550 Log Baseline TSAT (%) group, resolved over the course of the study, and were not As expected for this patient population, GI adverse associated with the development of a serious adverse event events were the most commonly reported drug-related (SAE). The incidences of serious TEAEs were similar TEAEs (Table 7); interestingly, GI adverse events were among the three IV iron groups and were lower with oral more common in the iron sucrose group than with other iron (Table 6). None of the SAEs was considered related therapies. GI disorders, particularly nausea and vomit- to the study drug in patients receiving FCM; however, ing, were less common in patients receiving FCM than two SAEs were considered related to the study drug in in patients receiving other IV iron therapies. Headache, two patients in the iron sucrose group (renal infarct and hypotension, and hypersensitivity were also reported less hypotension). frequently in patients receiving FCM than in patients The incidence of drug-related TEAEs in the safety popu- receiving other IV iron therapies. lation is summarized in Table 7. No hypersensitivity reac- Few patients discontinued therapy because of adverse tions were reported in patients receiving FCM or oral iron events in any of the treatment groups (FCM group, n = 1 but were reported in the other IV iron therapies and iron [1.0%]; oral iron, n = 0; any other IV iron, n = 3 (4.9%); sucrose groups. Drug-related TEAEs occurred in the FCM iron sucrose, n = 1 (3.1%). (11.9%) and oral iron (12.0%) groups at less than half the frequency seen in the other IV iron therapies (26.2%) and iron sucrose (25.0%) groups. 1 3 Change in Hemoglobin (g/dL) from Change in Hemoglobin (g/dL) from Baseline to Highest Value Baseline to Highest Value 3016 Digestive Diseases and Sciences (2018) 63:3009–3019 Table 6 Serious TEAEs TEAE, n (%) FCM (n = 101) Oral iron (n = 25) Any other IV Iron occurring in any treatment iron (n = 61) sucrose group (safety population) (n = 32) Any adverse event 7 (6.9) 1 (4.0) 6 (9.8) 4 (12.5) Gastrointestinal hemorrhage 2 (2) 0 (0) 1 (1.6) 1 (3.1) Anemia 1 (1.0) 0 (0) 0 (0) 0 (0) Iron-deficiency anemia 1 (1.0) 0 (0) 0 (0) 0 (0) Leukocytosis 1 (1.0) 0 (0) 0 (0) 0 (0) Crohn’s disease 1 (1.0) 0 (0) 0 (0) 0 (0) Volvulus 1 (1.0) 0 (0) 0 (0) 0 (0) Death 1 (1.0) 0 (0) 0 (0) 0 (0) Dehydration 1 (1.0) 0 (0) 0 (0) 0 (0) Respiratory distress 1 (1.0) 0 (0) 0 (0) 0 (0) Atrial fibrillation 0 (0) 1 (4.0) 0 (0) 0 (0) Coronary artery disease 0 (0) 0 (0) 1 (1.6) 0 (0) Cellulitis 0 (0) 0 (0) 1 (1.6) 1 (3.1) Cerebrovascular accident 0 (0) 1 (4.0) 0 (0) 0 (0) Transient ischemic attack 0 (0) 0 (0) 1 (1.6) 1 (3.1) Renal infarct 0 (0) 0 (0) 1 (1.6) 1 (3.1) Acute respiratory failure 0 (0) 0 (0) 1 (1.6) 0 (0) Hypotension 0 (0) 0 (0) 1 (1.6) 1 (3.1) IV intravenous, TEAE treatment-emergent adverse event than in patients receiving iron sucrose [4]. In another study, Discussion patients with non-dialysis-dependent chronic kidney disease and IDA were randomly assigned to receive two 750-mg In the present pooled analysis, Hb responses were greater in infusions of FCM in 1 week or iron sucrose 200 mg admin- FCM-treated patients than in patients treated with oral iron istered in up to five infusions in 14 days [41]. Increases and similar to Hb responses in patients treated with iron from baseline to treatment Day 56 for Hb, ferritin, TSAT, sucrose and other IV iron therapies, while requiring fewer and serum iron were superior for patients receiving FCM administrations. Restoration of iron stores (as measured by compared with patients receiving iron sucrose [41]. In the ferritin) and increases in available iron (TSAT) were sig- present study, patients with a lower baseline Hb value who nificantly greater in patients receiving FCM than in those received IV iron therapy had a greater increase in Hb from receiving oral iron and iron sucrose. baseline than did patients with a higher baseline Hb value. Serum ferritin levels broadly reflect total body iron stores Similar results were observed when ferritin and TSAT were but should be interpreted with caution in patients with correlated with Hb change from baseline. This may reflect chronic inflammation, since ferritin is an acute-phase reac- the body’s demand to achieve physiologic homeostasis. tant. Iron regulation is closely related to inflammation, with Similar analysis could not be conducted on the oral iron hepcidin and interleukin 6 playing key roles in this regu- group because the number of patients was too small to be latory process [37–39], particularly in the case of Crohn’s conclusive. disease [5, 40]. Nonetheless, absolute values for ferritin The safety results from our pooled analysis suggest and changes from baseline in FCM-treated patients in this that FCM can be safely administered to patients with analysis were nearly fourfold those in iron sucrose-treated GI-related IDAs and represent a favorable safety profile patients, suggesting a more robust replenishment of total compared with that of iron sucrose or other IV therapies body iron stores, necessary for long-term maintenance of Hb in the patient population studied. Our results are con- levels. In contrast, oral iron failed to produce any significant sistent with results from a recently reported systematic improvements in iron stores from baseline. Improvements in review and meta-analysis of FCM studies in patients with TSAT in the FCM-treated patients were also substantially IBD by Aksan and colleagues [42], which also found greater than in the iron sucrose-treated patients. FCM to be well tolerated in this population. Interest- A previous study of patients with IBD receiving FCM ingly, the proportion of patients experiencing FCM- to treat IDA demonstrated improvements in Hb, ferritin, related TEAEs in our analysis (12%) was identical to the and TSAT values that were significantly greater (P ≤ 0.015) 1 3 Digestive Diseases and Sciences (2018) 63:3009–3019 3017 Table 7 Drug-related TEAEs TEAE, n (%) FCM (n = 101) Oral iron (n = 25) Any other IV iron Iron in ≥ 1% of patients in any (n = 61) sucrose treatment group (safety (n = 32) population) Any adverse event 12 (11.9) 3 (12.0) 16 (26.2) 8 (25.0) Diarrhea 2 (2.0) 1 (4.0) 2 (3.3) 1 (3.1) Nausea 2 (2.0) 0 (0) 5 (8.2) 2 (6.3) Arthralgia 2 (2.0) 0 (0) 2 (3.3) 2 (6.3) Headache 1 (1.0) 0 (0) 3 (4.9) 0 (0) Pruritus 1 (1.0) 0 (0) 1 (1.6) 0 (0) Constipation 1 (1.0) 1 (4.0) 0 (0) 0 (0) Vomiting 1 (1.0) 0 (0) 4 (6.6) 4 (12.5) Abdominal discomfort 0 (0) 1 (4.0) 0 (0) 0 (0) Abdominal pain 0 (0) 0 (0) 1 (1.6) 0 (0) Asthenia 0 (0) 0 (0) 1 (1.6) 1 (3.1) Chills 0 (0) 0 (0) 2 (3.3) 2 (6.3) Peripheral edema 0 (0) 0 (0) 1 (1.6) 1 (3.1) Pain 0 (0) 0 (0) 1 (1.6) 1 (3.1) Hypersensitivity 0 (0) 0 (0) 4 (6.6) 2 (6.3) Dizziness 0 (0) 0 (0) 2 (3.3) 1 (3.1) Hypoesthesia 0 (0) 0 (0) 1 (1.6) 1 (3.1) Renal infarct 0 (0) 0 (0) 1 (1.6) 1 (3.1) Cough 0 (0) 0 (0) 1 (1.6) 0 (0) Dyspnea 0 (0) 0 (0) 1 (1.6) 0 (0) Erythema 0 (0) 0 (0) 1 (1.6) 0 (0) Rash 0 (0) 0 (0) 1 (1.6) 0 (0) Hypotension 0 (0) 0 (0) 3 (4.9) 3 (9.4) Thrombophlebitis 0 (0) 0 (0) 1 (1.6) 1 (3.1) IV intravenous, TEAE treatment-emergent adverse event proportion reported by Aksan and colleagues. It should Although this study suggests that FCM may be an be highlighted that the oral iron group may have had appropriate IV iron therapy for the treatment of IDA in GI a lower adverse event profile due to the study design, patients, there were some limitations to consider. As with given that patients included in the study by Onken et al. any retrospective analysis, interpretation of the results is [35] were preselected for lack of a severe reaction (and inherently limited by potential study selection bias and indi- lack of an adequate response) to oral iron. Also, TEAEs rect comparisons in a pooled dataset from open-label studies that were related to oral iron therapy would not have that had different objectives and relatively small patient pop- been counted as adverse events during the treatment ulations. The oral iron treatment group had a higher propor- phase, whereas all treatment-related TEAEs in the FCM tion of black patients than the other groups analyzed and had group were considered new events. No hypersensitiv- a higher mean baseline Hb level compared with the IV iron ity reactions were reported for patients receiving FCM therapy groups. This may have been a result of study design, in this analysis, although they were reported for some as the decision to proceed with oral or IV iron was left to the patients receiving other IV iron therapies (including iron discretion of the investigator. This variation at baseline may sucrose), and were attributed to study drug treatment. have contributed to the fact that the oral iron group experi- In this analysis, high-dose FCM was shown to be effective enced the smallest change from baseline in Hb. Also, two of and well tolerated in the treatment of IDA in the GI setting. the studies in the current analysis used the Ganzoni formula As such, FCM may be an appropriate alternative to more for calculation IV iron doses and the other two did not. It is established parenteral iron therapies, allowing higher doses unclear whether differences in dosing methodologies across with each infusion and therefore fewer infusions to achieve the studies could have affected our results. repletion of iron stores and rapid Hb responses. Use of FCM Further, specific real-world and cost-effectiveness studies may therefore lead to a cost savings, as well as greater con- are required to determine the cost–benefit of IV iron thera- venience for both the patient and the treating physician. pies, as well as the real-world safety and efficacy of FCM 1 3 3018 Digestive Diseases and Sciences (2018) 63:3009–3019 global database on anaemia. In: de Benoist B, McLean E, Egli I, versus IV iron sucrose. The stability of the Hb response and Cogswell M, eds. Geneva: World Health Organization; 2008. clinical outcomes over time were not addressed in the current 2. Miller JL. Iron deficiency anemia: a common and curable disease. analysis. Finally, while use of the Ganzoni formula tradition- Cold Spring Harb Perspect Med. 2013;3:a011866. ally has been considered standard practice for calculation of 3. Kassebaum NJ. The global burden of anemia. Hematol Oncol Clin North Am. 2016;30:247–308. a patient’s total body iron deficit, several investigators have 4. Evstatiev R, Marteau P, Iqbal T, et al. FERGIcor, a randomized reported that the Ganzoni formula underestimates actual iron controlled trial on ferric carboxymaltose for iron deficiency dose requirements in patients with IDA in IBD [4, 14, 43, anemia in inflammatory bowel disease. Gastroenterology. 44]. Currently, no consensus exists on the most appropriate 2011;141:e1–e2. 5. Gomollon F, Gisbert JP. Current management of iron deficiency IV iron dose for patients with IDA; more studies are required anemia in inflammatory bowel diseases: a practical guide. to determine the optimal dosing for this patient population. Drugs. 2013;73:1761–1770. 6. Bayraktar UD, Bayraktar S. Treatment of iron deficiency anemia associated with gastrointestinal tract diseases. World J Gastro- enterol. 2010;16:2720–2725. Conclusions 7. Murawska N, Fabisiak A, Fichna J. Anemia of chronic disease and iron deficiency anemia in inflammatory bowel diseases: FCM is currently indicated in the USA for the treatment of pathophysiology, diagnosis, and treatment. Inflamm Bowel Dis. 2016;22:1198–1208. IDA in adults when oral iron preparations are not tolerated 8. Stein J, Connor S, Virgin G, Ong DE, Pereyra L. Anemia and or are ineffective. This analysis highlights that FCM is effec- iron deficiency in gastrointestinal and liver conditions. World J tive in patients with GI-related IDA and has a safety profile Gastroenterol. 2016;22:7908–7925. comparable to that of other IV iron agents. 9. Bottaro G, Cataldo F, Rotolo N, Spina M, Corazza GR. The clin- ical pattern of subclinical/silent celiac disease: an analysis on 1026 consecutive cases. Am J Gastroenterol. 1999;94:691–696. Acknowledgments The authors thank Aesculapius Consulting, Inc., 10. Corazza GR, Valentini RA, Andreani ML, et al. Subclinical and Peloton Advantage, LLC, for providing editorial support, which coeliac disease is a frequent cause of iron-deficiency anaemia. was funded by Luitpold Pharmaceuticals, Inc., Shirley, NY, in accord- Scand J Gastroenterol. 1995;30:153–156. ance with Good Publication Practice (GPP3) guidelines (http://www. 11. Carroccio A, Iannitto E, Cavataio F, et al. Sideropenic anemia ismpp .org/gpp3). This study was sponsored by Luitpold Pharmaceu- and celiac disease: one study, two points of view. Dig Dis Sci. ticals, Inc. 1998;43:673–678. 12. Howard MR, Turnbull AJ, Morley P, Hollier P, Webb R, Clarke Compliance with ethical standards A. A prospective study of the prevalence of undiagnosed coeliac disease in laboratory defined iron and folate deficiency. J Clin Conflict of interest Gary R. Lichtenstein has served as a consultant Pathol. 2002;55:754–757. to Luitpold Pharmaceuticals, Inc., and Jane E. Onken has served on 13. Dignass AU, Gasche C, Bettenworth D, et al. European con- a Steering Committee and Advisory Board for Luitpold Pharmaceu- sensus on the diagnosis and management of iron deficiency ticals, Inc. and anaemia in inflammatory bowel diseases. J Crohns Colitis.. 2015;9:211–222. Statement of human rights All procedures performed involving human 14. Kulnigg S, Stoinov S, Simanenkov V, et al. 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Improved Hemoglobin Response with Ferric Carboxymaltose in Patients with Gastrointestinal-Related Iron-Deficiency Anemia Versus Oral Iron

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Medicine & Public Health; Gastroenterology; Hepatology; Oncology; Transplant Surgery; Biochemistry, general
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Abstract

Aims To compare the efficacy and safety of intravenous (IV) ferric carboxymaltose (FCM) versus oral iron and other IV iron therapies in patients with iron-deficiency anemia (IDA) resulting from gastrointestinal (GI) disorders. Methods A pooled analysis of four prospective, randomized, active-controlled trials in patients with IDA was performed. Efficacy measures included change from baseline in hemoglobin (Hb), ferritin, and transferrin saturation (TSAT) and cor - relations of baseline Hb, ferritin, and TSAT to change in Hb. The incidence and type of adverse events were evaluated. Results A total of 191 patients were evaluated. The mean change in Hb from baseline to the maximum value was 0.8 g/dL with oral iron (P = 0.001 vs. FCM), 2.2 g/dL with FCM, 2.0 g/dL with any IV iron (P = 0.391 vs. FCM), and 1.9 g/dL with iron sucrose (P = 0.329 vs. FCM). Patients treated with FCM and iron sucrose had larger increases in Hb. This effect may have been attributed to a lower baseline Hb level. Drug-related adverse events occurred in 11.9, 12, 26.2, and 25% and serious adverse events (SAEs) occurred in 6.9, 4, 9.8, and 12.5% of patients in the FCM, oral iron, other IV iron therapies, and iron sucrose groups, respectively. No SAEs were considered treatment related in the FCM group, compared with two treatment-related SAEs in two patients (6.3%) in the iron sucrose group. Conclusions FCM is an effective therapy in patients with IDA who have GI disorders and has a safety profile comparable to that of other IV iron agents. Keywords Hemoglobin · Inflammatory bowel disease · Ferric carboxymaltose · Iron Introduction frequently caused by iron deficiency [ 2, 3]. Gastrointestinal (GI) diseases are a common cause of both iron deficiency In industrialized and developing countries, anemia is a and anemia. Patients with GI disorders such as inflamma - common and widespread disorder. According to the World tory bowel disease (IBD) are at risk of development of Health Organization, anemia affects approximately 25% iron-deficiency anemia (IDA) due to a combination of fac - of the global population (1.62 billion people) [1] and is tors, including chronic blood loss, inflammatory-mediated impairment of intestinal iron absorption, and the inability to utilize existing iron stores [4–6]. The prevalence of IDA in * Gary R. Lichtenstein IBD has been reported as high as 73.7% [7]. Similarly, celiac grl@uphs.upenn.edu sprue is frequently complicated by the development of IDA, Jane E. Onken which can occur even in the absence of GI symptoms [8]. jane.onken@duke.edu IDA without clinical evidence of intestinal malabsorption is encountered in approximately 50% of adults with subclinical Gastroenterology Division, Hospital of the University of Pennsylvania, University of Pennsylvania School celiac disease [9], while other studies have demonstrated that of Medicine, 7th Floor South, Perelman Center, Room 753, celiac disease is responsible for anemia in 5–6% of cases of 3400 Civic Center Boulevard, Philadelphia, PA 19104-4283, unexplained IDA [8, 10–12]. USA In IBD patients, the initial therapeutic strategy for IDA Department of Medicine, Division of Gastroenterology, Duke should be based on the activity of the disease, the level of University Medical Center, 40 Duke Medicine Circle, Clinic hemoglobin (Hb), and tolerance of the patient to oral iron [5, 2H/2J, Durham, NC 27710, USA Vol.:(0123456789) 1 3 3010 Digestive Diseases and Sciences (2018) 63:3009–3019 13]. In the recent European Crohn’s and Colitis Organisation time to alleviate IDA, potentially consuming substantially (ECCO) guidelines, oral iron may be used in IBD patients more administrative and financial resources [4 ]. with mild anemia whose disease is clinically inactive and Ferumoxytol and ferric carboxymaltose (FCM) are two who have not previously been intolerant to oral iron [13]. newer parenteral iron formulations registered in the USA Oral iron replacement therapy has long been the cornerstone that permit higher single doses to be delivered over shorter of IDA treatment [6]; it is inexpensive, is simple to admin- periods of time. Thus, they require fewer administrations to ister, and is not associated with life-threatening side effects. treat patients with IDA compared with other parenteral irons. Unfortunately, absorption of oral iron is unpredictable in Ferumoxytol was approved for use in the USA in 2009 with patients with active IBD due to the inflammatory inhibition an indication for the treatment of IDA in adults with chronic of absorption as a consequence of the interaction between kidney disease [28]. hepcidin and ferroportin [14]. In a recent study that evalu- FCM is a stable type I polynuclear iron (III)–hydroxide ated whether inflammation as reflected by C-reactive protein carbohydrate complex that prevents the partial release of (CRP) or interleukin 6 at initiation of treatment could predict iron to serum ferritin, allowing the administration of high the response to iron therapy, it was shown that Hb increases doses since this iron is available almost exclusively via retic- in the oral iron group were significantly lower in those with uloendothelial processing [14, 29–31]. In the USA, FCM high CRP levels than in those with low CRP levels. With IV was approved in 2013 and is indicated for the treatment of iron, response was fairly independent of inflammation. This IDA in adults who have intolerance, or have had an inad- further supports the assertion that IV iron can overcome the equate response, to oral iron therapy. It is also indicated hepcidin block and explains why oral iron may not be as for the treatment of IDA in non-dialysis-dependent chronic effective in patients with inflammation [15]. IBD patients kidney disease [32]. This pooled analysis was performed to develop IDA through increased iron loss from ongoing GI assess the safety and efficacy of FCM compared with the bleeding from the inflamed intestinal mucosa as well as safety and efficacy of oral iron therapy and other IV iron from reduced iron absorption within the inflamed mucosa. therapies for IDA secondary to GI disorders. Additionally, in approximately 50% of patients, oral iron ingestion is associated with GI side effects, leading to dis- continuation of therapy, including abdominal pain, nausea, Materials and Methods diarrhea, vomiting, and constipation [16–20]. Although its effect on IBD disease activity is unknown in humans, a num- Study Design ber of animal IBD studies have shown that oral iron can lead to worsening of intestinal inflammation, increased disease This was a post hoc analysis of primary data from four pro- activity, and increased oxidative stress [21]. To date, well- spective, active-controlled trials that evaluated the efficacy controlled trials evaluating the effect of oral iron on IBD and safety of FCM in patients with IDA resulting from a disease activity have not been conducted. broad range of causes [33–35]. The original trial designs Although there are no recent US IBD guidelines for IDA, are summarized in Table  1. The data were re-evaluated ECCO recently published a guideline/consensus paper on by the investigators to identify patients whose principal IDA. Intravenous (IV) iron is recommended as the preferred cause of IDA was underlying GI disorders and to compare route of administration in patients with clinically active IBD, the efficacy and safety of FCM versus those of oral iron previous intolerance to oral iron, and Hb less than 10 g/dL, therapy and other IV iron therapies in patients with these as well as for patients who require erythropoiesis-stimu- disorders. The original study protocols were approved by lating agents. In patients with severe IDA requiring rapid institutional review boards at each center, trials complied replenishment of iron stores, or in patients intolerant of oral with the Declaration of Helsinki, and all patients provided iron therapy, parenteral iron replacement allows rapid, safe, informed consent (NCT00703937 and NCT00704353 [33], effective restoration of iron stores and bypasses the issue of NCT00704028 [34], and NCT00982007 [35]; http://www. poor intestinal absorption [5, 6, 22]. Despite clinical find-clini caltr ials.gov). ings, widespread adoption of IV iron replacement has been slow, in part owing to historical adverse events of anaphy- Patient Selection lactic reactions associated with iron dextran formulations [6, 23, 24]. Newer, dextran-free iron carbohydrate complexes A list of preferred and verbatim terms from the GI section have been developed to avoid the issue of dextran-induced of the patient’s medical history was generated. From these anaphylaxis and allow high-dose IV iron replacement while GI-related terms, conditions considered to be a likely cause minimizing serious safety concerns [6, 25–27]. Although of IDA were determined. Patients were identified and their iron sucrose has been shown to be effective, it has dose- and data pooled if their medical history contained 1 or more of rate-limiting factors that necessitate multiple infusions over the terms. Patients with IDA related to bariatric surgery were 1 3 Digestive Diseases and Sciences (2018) 63:3009–3019 3011 1 3 Table 1 Summary of four randomized controlled trials of ferric carboxymaltose (Injectafer ) versus oral or intravenous iron therapy for the treatment of iron-deficiency anemia [33–35] Study Barish et al. [33] (single-dose study) Barish et al. [33] (multidose study) Hussain et al. [34] NCT00704028 Onken et al. [35] NCT00982007 NCT00704353 NCT00703937 a b N 738 (n = 366, FCM; n = 369, SMC) 708 (n = 343, FCM; n = 360, SMC) 160 (n = 82, FCM; n = 78, DEX) 1011 (n = 503, FCM; n = 257, oral iron; n = 251, IVSC) Population Men and women 18–85 years of age Men and women 18–85 years of age Men and women ≥ 18 years of age with Men and women ≥ 18 years of age with with IDA with IDA IDA and history of intolerance to or IDA and history of unsatisfactory unsatisfactory response to oral iron response to oral iron Key inclusion criteria Hb ≤ 12 g/dL and ferritin ≤ 100 ng/mL, Hb ≤ 11 g/dL; ferritin ≤ 100 ng/mL, Hb ≤ 11 g/dL; ferritin ≤ 100 ng/mL, Hb ≤ 11 g/dL; ferritin ≤ 100 ng/mL, or ≤ 300 ng/mL if TSAT ≤ 30% or ≤ 300 ng/mL if TSAT ≤ 30% or ≤ 300 ng/mL if TSAT ≤ 30% or ≤ 300 ng/mL if TSAT ≤ 30% Randomization FCM 15 mg/kg or 750 mg (whichever FCM 15 mg/kg up to a single-dose FCM versus IV iron dextran (doses of FCM 15 mg/kg up to a maximum of was smaller) IV push injection at maximum of 750 mg at 100 mg/min both drugs were calculated by the 750 mg on Days 0 and 7 versus oral 100 mg/min on Day 0 versus SMC on weekly until the calculated iron deficit Ganzoni formula) iron 325 mg TID for 14 days or other Days 0–30 (oral or IV iron prepara- dose had been administered (maxi- FCM 15 mg/kg up to a single-dose IV standard-of-care iron preparation tions) mum total dose: 2250 mg) versus maximum of 750 mg on Days 0, 7, SMC on Days 0–42 (oral or IV iron and 14; IV push injection weekly at preparations) 100 mg/min until the calculated iron All doses were calculated by the Gan- deficit dose had been administered zoni formula (maximum total dose: 2250 mg) IV iron dextran doses on Days 0–42 with a test dose of 25 mg given on Day 0 slowly over 5 min; the remain- der of the dose was administered if no reaction occurred. Doses and infusion times were determined by the investigator until the calculated iron deficit dose had been administered (maximum total dose: 2250 mg) Outcome measures Clinical, laboratory, and safety data Clinical, laboratory, and safety data Incidence of serious TEAEs; change in Mean change from baseline to maximum including adverse events including adverse events Hb, ferritin, and TSAT from baseline observed Hb value at any time between Mean changes from baseline in hemo- Mean changes from baseline in hemo- to the maximum value observed for baseline and Day 35; mean change from globin and ferritin globin, ferritin, and TSAT all patients baseline to maximum ferritin measure- ment any time between baseline and Day 35; mean change from baseline to each scheduled visit for Hb, ferritin, and TSAT levels; serious TEAEs Timing of assessments Clinical, laboratory, and safety data Clinical, laboratory, and safety data Laboratory data were collected at Laboratory data were collected on Days were collected on Days 0, 7, and 30 were collected on Days 0, 7, 14, 28, screening, baseline, and Days 0, 7, 14, 7, 14, and 35; safety data were collected (or end of treatment) and 42 (or end of treatment) 28, and 42; safety data were collected on Days 7, 14, 35, 90, and 120 on Days 0, 7, 14, 28, and 42 DEX iron dextran, Hb hemoglobin, FCM ferric carboxymaltose, IDA iron-deficiency anemia; IVSC intravenous standard-of-care iron therapy, SMC standard medical care (oral or IV iron ther - apy); TEAEs treatment-emergent adverse events, TSAT transferrin saturation Three patients were not treated Five patients were not treated 3012 Digestive Diseases and Sciences (2018) 63:3009–3019 excluded; these data were published in a separate analysis included all randomized patients who received at least one [29]. dose of study drug. Patient demographic data were sum- marized descriptively. The P value for change from base- Assessments line was calculated with a paired t-test, and the P value for the difference between FCM and the other comparators was Efficacy measures included change in Hb, ferritin, and trans- calculated from a one-way analysis of variance. Correlation ferrin saturation (TSAT) from baseline to the maximum of baseline ferritin and TSAT values with change in Hb was value observed for all patients. Change in Hb was stratified calculated by Spearman rank-order correlation. by baseline Hb, ferritin, and TSAT level. The number and percentage of patients reporting treatment-emergent adverse events (TEAEs) were summarized for each treatment group by overall incidence and relationship to study drug using the Results Medical Dictionary for Regulatory Activities (MedDRA) version 10.1. A total of 191 patients (59 males and 132 females) were identified from the four trial datasets as having IDA second- Data Analysis ary to GI disorders. The mean age of patients was 59.3 years, and the mean body mass index was 28.4 kg/m . GI-related All efficacy analyses were performed on the modified conditions contributing to IDA included GI bleeding intent-to-treat (mITT) population. The mITT population (62.8%), inflammatory bowel disease (27.7%), malabsorp- in three of the studies consisted of patients from the safety tion (5.2%), celiac disease (4.7%), and others (6.8%). In all, population who had two baseline Hb values and at least one 101 (52.9%) patients received FCM, 25 (13.1%) received postbaseline Hb assessment [33, 34]. In the fourth study, oral iron (ferrous sulfate), and 61 (31.9%) received any other the mITT population consisted of patients from the safety IV iron comparators, including iron sucrose, 32 patients population who received at least one dose of the randomly (16.8%); iron dextran, 27 patients (14.1%); and ferric glu- assigned study medication and had at least one postbase- conate, two patients (1.0%) (Table 2). Four patients received line Hb assessment [35]. A post hoc subgroup analysis of other comparators and were not included in the analysis changes in Hb, ferritin, and TSAT levels from baseline to because results were confounded by the use of a combination maximum value between baseline and end of study or time of iron therapy and blood transfusions. The mean total doses of intervention was conducted with data from patients with of elemental iron were 1238 mg (FCM), 2703 mg (oral iron), IBD and those without IBD and with GI bleeding. All safety 1086 mg (any other IV iron), and 943 mg (iron sucrose). assessments were performed in the safety population, which Table 2 Demographics and baseline characteristics by comparators FCM (n = 101) Oral iron (n = 25) Any other IV iron Iron sucrose (n = 32) (n = 61) Sex, n (%)  Male 26 (25.7) 8 (32.0) 24 (39.3) 12 (37.5)  Female 75 (74.3) 17 (68.0) 37 (60.7) 20 (62.5) Race, n (%)  Asian 0 0 1 (1.6) 0  Black 11 (10.9) 9 (36.0) 2 (3.3) 2 (6.3)  Caucasian 77 (76.2) 15 (60.0) 55 (90.2) 28 (87.5)  Hispanic 13 (12.9) 1 (4.0) 3 (4.9) 2 (6.3) Mean age (SD), year 59.1 (18.9) 58.0 (13.4) 59.7 (18.3) 55.0 (18.1) Mean weight (SD), kg 73.6 (19.3) 84.4 (19.5) 79.3 (21.4) 80.5 (25.1) Mean BMI (SD), kg/m 27.2 (6.40) 30.5 (7.43) 28.7 (6.58) 28.8 (7.56) Mean baseline Hb (SD), g/dL 9.7 (1.33) 10.6 (0.78) 9.6 (1.24) 9.5 (1.52) Mean baseline ferritin (SD), ng/mL 29.1 (58.5) 39.8 (68.3) 11.4 (11.0) 10.0 (8.69) Mean baseline TSAT (SD), % 11.3 (8.77) 14.6 (10.17) 9.0 (7.08) 8.9 (7.39) BMI body mass index, FCM ferric carboxymaltose, Hb hemoglobin, SD standard deviation, TSAT transferrin saturation Any other IV iron included two ferric gluconate patients, 27 iron dextran patients, and 32 iron sucrose patients 1 3 Digestive Diseases and Sciences (2018) 63:3009–3019 3013 Patients in the FCM group received 1–3 administrations; the [P = 0.001]). FCM also led to significantly (P ≤ 0.001) range in the other IV iron group was 1–20 administrations. greater increases in ferritin than oral iron and the other IV iron therapies in patients with IBD (FCM vs. oral iron: 474.3 Efficacy vs. 12.6 ng/mL [P = 0.001]; FCM vs. other IV therapies: 474.3 vs. 89.0 ng/mL [P < 0.0001]) and those without IBD Hb, ferritin, and TSAT values increased significantly from (FCM vs. oral iron: 540.0 vs. 7.1 ng/mL [P < 0.0001]; FCM baseline to maximum postbaseline values for all treatment vs. other IV therapies: 540.0 vs. 275.5 ng/mL [P < 0.0001]). groups (P = 0.001), with the exception of ferritin values for patients in the oral iron group. Patients treated with Correlation of Baseline Hb, Ferritin, TSAT to Changes in Hb FCM experienced significantly greater mean maximum Hb increases and absolute Hb values compared with patients The more severe a patient’s anemia was at baseline, the treated with oral iron (P = 0.001) (Table  3). Changes in larger the increase in Hb in response to treatment. This cor- Hb were similar with FCM and the other IV iron thera- relation was not observed in patients receiving oral iron pies. Patients in the FCM group had significantly greater therapy (Table 5). Baseline ferritin and TSAT values had a (at least twofold in all comparisons) peak absolute ferritin statistically significant negative correlation with change in values and increases from baseline compared with patients Hb (Spearman correlation coefficient R = − 0.43 [P < 0.001] in the other treatment groups. There were no changes in and R = − 0.55 [P < 0.001], respectively). Lower ferritin ferritin values in the oral iron group. Compared with oral values and lower TSAT values were associated with larger iron therapy and iron sucrose therapy, FCM treatment led to increases in Hb values, as shown in Figs. 1 and 2. statistically significantly greater increases in TSAT values (P = 0.001 and P = 0.002, respectively) and to significantly Safety greater absolute TSAT values. To determine whether responses differed between patients Total incidences in TEAEs were higher in the IV iron with IBD and non-IBD causes of GI blood loss, we per- groups (approximately 50–60%) than in the oral iron group formed subgroup analyses of data from these two groups (32.0%; P > 0.05) and were lower for FCM (46.5%) than (Table  4). FCM led to significantly greater increases in for other IV iron groups (55.7% for any other IV com- Hb than oral iron in patients with IBD (1.9 vs. 0.6 g/dL parator, P > 0.05; 59.4% for iron sucrose, P > 0.05). Two [P = 0.028]) as well as in those without IBD (2.1 vs. 0.7 g/dL events of hypophosphatemia were reported in the FCM Table 3 Mean (SD) change in hemoglobin, ferritin, and transferrin saturation from baseline to maximum value between baseline and end of study or time of intervention FCM (n = 101) Oral iron (n = 25) Any other IV iron (n = 61) Iron sucrose (n = 32) Hb, g/dL  Baseline 9.7 (1.33) 10.6 (0.78) 9.6 (1.24) 9.5 (1.52)  Maximum value 11.8 (1.49) 11.4 (1.23) 11.6 (1.44) 11.4 (1.22)  Change to maximum value 2.2 (1.52) 0.8 (1.01) 2.0 (1.24) 1.9 (1.04)  P value* – 0.001 0.391 0.329 Ferritin, ng/mL  Baseline 29.1 (58.52) 39.8 (68.32) 11.4 (11.00) 10.0 (8.69)  Maximum value 567.3 (327.20) 39.8 (42.46) 281.2 (262.89) 167.9 (179.26)  Change to maximum value 538.2 (300.50) 0 (33.13) 269.8 (259.11) 157.9 (173.60)  P value* – 0.001 0.001 0.001 TSAT, %  Baseline 11.3 (8.77) 14.6 (10.17) 9.0 (7.08) 8.9 (7.39)  Maximum value 37.0 (15.38) 24.8 (13.44) 32.7 (19.00) 24.2 (14.29)  Change to maximum value 25.7 (14.34) 10.2 (14.27) 23.6 (17.94) 15.3 (11.56)  P value* – 0.001 0.430 0.002 Iron sucrose is a subgroup of the any other IV iron comparator group FCM ferric carboxymaltose, Hb hemoglobin; IV intravenous, NS, nonsignificant, SD standard deviation, TSAT transferrin saturation *Pvalues refer to the comparison with FCM, from one-way analysis of variance Any other IV iron included ferric gluconate (n = 2), iron dextran (n = 27), and iron sucrose (n = 32) 1 3 3014 Digestive Diseases and Sciences (2018) 63:3009–3019 Table 4 Mean (SD) change in hemoglobin, ferritin, and transferrin tory bowel disease and non-inflammatory bowel disease gastrointesti- saturation from baseline to maximum value between baseline and end nal bleeding of study or time of intervention stratified by patients with inflamma- FCM Oral iron Any other IV iron Iron sucrose IBD (n = 30) Non-IBD IBD (n = 7) Non-IBD IBD (n = 15) Non-IBD IBD (n = 12) Non-IBD GI bleeding GI bleeding GI bleeding GI bleeding (n = 57) (n = 14) (n = 46) (n = 17) Hb, g/dL  Baseline 9.7 (1.3) 9.6 (1.4) 10.5 (0.9) 10.4 (0.9) 9.6 (1.2) 9.5 (1.2) 9.6 (1.3) 9.4 (1.7)  Maximum value 11.6 (1.3) 11.7 (1.6) 11.1 (1.2) 11.2 (1.4) 11.3 (1.3) 11.5 (1.6) 11.5 (1.1) 11.4 (1.3)  Change to maxi- 1.9 (1.5) 2.1 (1.4) 0.6 (0.7) 0.7 (1.0) 1.7 (1.1) 2.0 (1.3) 1.9 (1.1) 2.0 (1.1) mum value  P value* – – 0.028 0.001 0.631 0.811 0.942 0.738 Ferritin, ng/mL  Baseline 26.7 (46.7) 32.5 (68.7) 73.6 (115.0) 53.9 (87.9) 7.4 (4.5) 11.2 (11.1) 6.5 (4.3) 10.6 (5.9)  Maximum value 488.8 (225.8) 559.8 (250.3) 43.4 (39.5) 26.7 (17.7) 96.5 (64.5) 287.3 (247.9) 109.6 (62.9) 235.2 (163.9)  Change to maxi- 474.3 (218.5) 540.0 (247.7) 12.6 (8.2) 7.1 (10.1) 89.0 (62.9) 275.5 (249.5) 102.7 (60.8) 224.2 (165.6) mum value  P value* – – 0.001 <0.0001 <0.0001 <0.0001 <0.0001 0.0004 TSAT, %  Baseline 11.3 (8.8) 11.8 (9.1) 14.7 (10.1) 15.1 (9.8) 7.4 (4.9) 9.1 (7.5) 6.7 (3.9) 10.1 (8.9)  Maximum value 37.8 (17.4) 35.3 (12.8) 29.3 (11.3) 24.7 (14.6) 21.0 (15.6) 33.2 (19.4) 20.0 (9.7) 26.3 (15.2)  Change to maxi- 26.6 (16.1) 23.4 (11.6) 14.6 (14.8) 9.6 (15.7) 13.6 (11.7) 24.1 (19.1) 13.3 (7.2) 16.2 (13.0) mum value  P value* – – 0.082 0.0004 0.009 0.827 0.009 0.032 Iron sucrose is a subgroup of the any other IV iron comparator group FCM ferric carboxymaltose, GI gastrointestinal, Hb hemoglobin, IBD inflammatory bowel disease, IV intravenous; SD standard deviation, TSAT transferrin saturation *P values refer to the comparison with FCM, based on t test Table 5 Mean (SD) change in hemoglobin from baseline to maximum value between baseline and end of study or time of intervention stratified by baseline hemoglobin level FCM Oral iron Any other IV iron Iron sucrose Female Male Female Male Female Male Female Male Patients with mild anemia (hemoglobin 11.0–11.9 g/dL, females; 11.0–12.9 g/dL, males) [36]  n 10 6 6 3 5 1 4 1  Change to maximum value 1.0 (0.7) 1.7 (1.6) 0.6 (0.9) 1.4 (1.3) 0.9 (0.4) 1.0 0.9 (0.4) 1.0  P value* – – 0.336 0.788 0.774 – 0.796 – Patients with moderate anemia (hemoglobin 8.0–10.9 g/dL, females and males) [36]  n 55 19 11 5 29 20 13 8  Change to maximum value 2.2 (1.2) 2.2 (1.7) 0.8 (1.1) 0.6 (0.9) 1.9 (1.1) 2.2 (1.4) 1.9 (0.8) 2.0 (1.0)  P value* – – 0.001 0.061 0.266 > 0.999 0.396 0.763 Patients with severe anemia (hemoglobin < 8.0 g/dL, females and males) [36]  n 9 1 0 0 2 3 2 3  Change to maximum value 3.6 (1.9) 5.9 – – 3.0 (0.7) 3.3 (0.2) 3.0 (0.7) 3.3 (0.2)  P value* – – – – – – – – FCM ferric carboxymaltose, IV intravenous, SD standard deviation *P values refer to the comparison with FCM, from one-way analysis of variance 1 3 Digestive Diseases and Sciences (2018) 63:3009–3019 3015 Fig. 1 Correlation of base- 6.5 Spearman R = −0.43; P<0.001 line ferritin versus change in 6.0 hemoglobin from baseline to 5.5 maximum value between base- 5.0 line and end of study or time of 4.5 intervention in ferric carboxy- 4.0 maltose patients 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 13 10 32 100316 1000 Log Baseline Ferritin (ng/mL) Fig. 2 Correlation of base- 6.5 Spearman R = −0.55; P<0.001 line TSAT versus change in 6.0 hemoglobin from baseline 5.5 to maximum value between 5.0 baseline and end of study or 4.5 time of intervention in ferric 4.0 carboxymaltose patients. TSAT 3.5 transferrin saturation 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 0 5101520253035404550 Log Baseline TSAT (%) group, resolved over the course of the study, and were not As expected for this patient population, GI adverse associated with the development of a serious adverse event events were the most commonly reported drug-related (SAE). The incidences of serious TEAEs were similar TEAEs (Table 7); interestingly, GI adverse events were among the three IV iron groups and were lower with oral more common in the iron sucrose group than with other iron (Table 6). None of the SAEs was considered related therapies. GI disorders, particularly nausea and vomit- to the study drug in patients receiving FCM; however, ing, were less common in patients receiving FCM than two SAEs were considered related to the study drug in in patients receiving other IV iron therapies. Headache, two patients in the iron sucrose group (renal infarct and hypotension, and hypersensitivity were also reported less hypotension). frequently in patients receiving FCM than in patients The incidence of drug-related TEAEs in the safety popu- receiving other IV iron therapies. lation is summarized in Table 7. No hypersensitivity reac- Few patients discontinued therapy because of adverse tions were reported in patients receiving FCM or oral iron events in any of the treatment groups (FCM group, n = 1 but were reported in the other IV iron therapies and iron [1.0%]; oral iron, n = 0; any other IV iron, n = 3 (4.9%); sucrose groups. Drug-related TEAEs occurred in the FCM iron sucrose, n = 1 (3.1%). (11.9%) and oral iron (12.0%) groups at less than half the frequency seen in the other IV iron therapies (26.2%) and iron sucrose (25.0%) groups. 1 3 Change in Hemoglobin (g/dL) from Change in Hemoglobin (g/dL) from Baseline to Highest Value Baseline to Highest Value 3016 Digestive Diseases and Sciences (2018) 63:3009–3019 Table 6 Serious TEAEs TEAE, n (%) FCM (n = 101) Oral iron (n = 25) Any other IV Iron occurring in any treatment iron (n = 61) sucrose group (safety population) (n = 32) Any adverse event 7 (6.9) 1 (4.0) 6 (9.8) 4 (12.5) Gastrointestinal hemorrhage 2 (2) 0 (0) 1 (1.6) 1 (3.1) Anemia 1 (1.0) 0 (0) 0 (0) 0 (0) Iron-deficiency anemia 1 (1.0) 0 (0) 0 (0) 0 (0) Leukocytosis 1 (1.0) 0 (0) 0 (0) 0 (0) Crohn’s disease 1 (1.0) 0 (0) 0 (0) 0 (0) Volvulus 1 (1.0) 0 (0) 0 (0) 0 (0) Death 1 (1.0) 0 (0) 0 (0) 0 (0) Dehydration 1 (1.0) 0 (0) 0 (0) 0 (0) Respiratory distress 1 (1.0) 0 (0) 0 (0) 0 (0) Atrial fibrillation 0 (0) 1 (4.0) 0 (0) 0 (0) Coronary artery disease 0 (0) 0 (0) 1 (1.6) 0 (0) Cellulitis 0 (0) 0 (0) 1 (1.6) 1 (3.1) Cerebrovascular accident 0 (0) 1 (4.0) 0 (0) 0 (0) Transient ischemic attack 0 (0) 0 (0) 1 (1.6) 1 (3.1) Renal infarct 0 (0) 0 (0) 1 (1.6) 1 (3.1) Acute respiratory failure 0 (0) 0 (0) 1 (1.6) 0 (0) Hypotension 0 (0) 0 (0) 1 (1.6) 1 (3.1) IV intravenous, TEAE treatment-emergent adverse event than in patients receiving iron sucrose [4]. In another study, Discussion patients with non-dialysis-dependent chronic kidney disease and IDA were randomly assigned to receive two 750-mg In the present pooled analysis, Hb responses were greater in infusions of FCM in 1 week or iron sucrose 200 mg admin- FCM-treated patients than in patients treated with oral iron istered in up to five infusions in 14 days [41]. Increases and similar to Hb responses in patients treated with iron from baseline to treatment Day 56 for Hb, ferritin, TSAT, sucrose and other IV iron therapies, while requiring fewer and serum iron were superior for patients receiving FCM administrations. Restoration of iron stores (as measured by compared with patients receiving iron sucrose [41]. In the ferritin) and increases in available iron (TSAT) were sig- present study, patients with a lower baseline Hb value who nificantly greater in patients receiving FCM than in those received IV iron therapy had a greater increase in Hb from receiving oral iron and iron sucrose. baseline than did patients with a higher baseline Hb value. Serum ferritin levels broadly reflect total body iron stores Similar results were observed when ferritin and TSAT were but should be interpreted with caution in patients with correlated with Hb change from baseline. This may reflect chronic inflammation, since ferritin is an acute-phase reac- the body’s demand to achieve physiologic homeostasis. tant. Iron regulation is closely related to inflammation, with Similar analysis could not be conducted on the oral iron hepcidin and interleukin 6 playing key roles in this regu- group because the number of patients was too small to be latory process [37–39], particularly in the case of Crohn’s conclusive. disease [5, 40]. Nonetheless, absolute values for ferritin The safety results from our pooled analysis suggest and changes from baseline in FCM-treated patients in this that FCM can be safely administered to patients with analysis were nearly fourfold those in iron sucrose-treated GI-related IDAs and represent a favorable safety profile patients, suggesting a more robust replenishment of total compared with that of iron sucrose or other IV therapies body iron stores, necessary for long-term maintenance of Hb in the patient population studied. Our results are con- levels. In contrast, oral iron failed to produce any significant sistent with results from a recently reported systematic improvements in iron stores from baseline. Improvements in review and meta-analysis of FCM studies in patients with TSAT in the FCM-treated patients were also substantially IBD by Aksan and colleagues [42], which also found greater than in the iron sucrose-treated patients. FCM to be well tolerated in this population. Interest- A previous study of patients with IBD receiving FCM ingly, the proportion of patients experiencing FCM- to treat IDA demonstrated improvements in Hb, ferritin, related TEAEs in our analysis (12%) was identical to the and TSAT values that were significantly greater (P ≤ 0.015) 1 3 Digestive Diseases and Sciences (2018) 63:3009–3019 3017 Table 7 Drug-related TEAEs TEAE, n (%) FCM (n = 101) Oral iron (n = 25) Any other IV iron Iron in ≥ 1% of patients in any (n = 61) sucrose treatment group (safety (n = 32) population) Any adverse event 12 (11.9) 3 (12.0) 16 (26.2) 8 (25.0) Diarrhea 2 (2.0) 1 (4.0) 2 (3.3) 1 (3.1) Nausea 2 (2.0) 0 (0) 5 (8.2) 2 (6.3) Arthralgia 2 (2.0) 0 (0) 2 (3.3) 2 (6.3) Headache 1 (1.0) 0 (0) 3 (4.9) 0 (0) Pruritus 1 (1.0) 0 (0) 1 (1.6) 0 (0) Constipation 1 (1.0) 1 (4.0) 0 (0) 0 (0) Vomiting 1 (1.0) 0 (0) 4 (6.6) 4 (12.5) Abdominal discomfort 0 (0) 1 (4.0) 0 (0) 0 (0) Abdominal pain 0 (0) 0 (0) 1 (1.6) 0 (0) Asthenia 0 (0) 0 (0) 1 (1.6) 1 (3.1) Chills 0 (0) 0 (0) 2 (3.3) 2 (6.3) Peripheral edema 0 (0) 0 (0) 1 (1.6) 1 (3.1) Pain 0 (0) 0 (0) 1 (1.6) 1 (3.1) Hypersensitivity 0 (0) 0 (0) 4 (6.6) 2 (6.3) Dizziness 0 (0) 0 (0) 2 (3.3) 1 (3.1) Hypoesthesia 0 (0) 0 (0) 1 (1.6) 1 (3.1) Renal infarct 0 (0) 0 (0) 1 (1.6) 1 (3.1) Cough 0 (0) 0 (0) 1 (1.6) 0 (0) Dyspnea 0 (0) 0 (0) 1 (1.6) 0 (0) Erythema 0 (0) 0 (0) 1 (1.6) 0 (0) Rash 0 (0) 0 (0) 1 (1.6) 0 (0) Hypotension 0 (0) 0 (0) 3 (4.9) 3 (9.4) Thrombophlebitis 0 (0) 0 (0) 1 (1.6) 1 (3.1) IV intravenous, TEAE treatment-emergent adverse event proportion reported by Aksan and colleagues. It should Although this study suggests that FCM may be an be highlighted that the oral iron group may have had appropriate IV iron therapy for the treatment of IDA in GI a lower adverse event profile due to the study design, patients, there were some limitations to consider. As with given that patients included in the study by Onken et al. any retrospective analysis, interpretation of the results is [35] were preselected for lack of a severe reaction (and inherently limited by potential study selection bias and indi- lack of an adequate response) to oral iron. Also, TEAEs rect comparisons in a pooled dataset from open-label studies that were related to oral iron therapy would not have that had different objectives and relatively small patient pop- been counted as adverse events during the treatment ulations. The oral iron treatment group had a higher propor- phase, whereas all treatment-related TEAEs in the FCM tion of black patients than the other groups analyzed and had group were considered new events. No hypersensitiv- a higher mean baseline Hb level compared with the IV iron ity reactions were reported for patients receiving FCM therapy groups. This may have been a result of study design, in this analysis, although they were reported for some as the decision to proceed with oral or IV iron was left to the patients receiving other IV iron therapies (including iron discretion of the investigator. This variation at baseline may sucrose), and were attributed to study drug treatment. have contributed to the fact that the oral iron group experi- In this analysis, high-dose FCM was shown to be effective enced the smallest change from baseline in Hb. Also, two of and well tolerated in the treatment of IDA in the GI setting. the studies in the current analysis used the Ganzoni formula As such, FCM may be an appropriate alternative to more for calculation IV iron doses and the other two did not. It is established parenteral iron therapies, allowing higher doses unclear whether differences in dosing methodologies across with each infusion and therefore fewer infusions to achieve the studies could have affected our results. repletion of iron stores and rapid Hb responses. Use of FCM Further, specific real-world and cost-effectiveness studies may therefore lead to a cost savings, as well as greater con- are required to determine the cost–benefit of IV iron thera- venience for both the patient and the treating physician. pies, as well as the real-world safety and efficacy of FCM 1 3 3018 Digestive Diseases and Sciences (2018) 63:3009–3019 global database on anaemia. In: de Benoist B, McLean E, Egli I, versus IV iron sucrose. The stability of the Hb response and Cogswell M, eds. Geneva: World Health Organization; 2008. clinical outcomes over time were not addressed in the current 2. Miller JL. Iron deficiency anemia: a common and curable disease. analysis. Finally, while use of the Ganzoni formula tradition- Cold Spring Harb Perspect Med. 2013;3:a011866. ally has been considered standard practice for calculation of 3. Kassebaum NJ. The global burden of anemia. Hematol Oncol Clin North Am. 2016;30:247–308. a patient’s total body iron deficit, several investigators have 4. Evstatiev R, Marteau P, Iqbal T, et al. FERGIcor, a randomized reported that the Ganzoni formula underestimates actual iron controlled trial on ferric carboxymaltose for iron deficiency dose requirements in patients with IDA in IBD [4, 14, 43, anemia in inflammatory bowel disease. Gastroenterology. 44]. Currently, no consensus exists on the most appropriate 2011;141:e1–e2. 5. Gomollon F, Gisbert JP. Current management of iron deficiency IV iron dose for patients with IDA; more studies are required anemia in inflammatory bowel diseases: a practical guide. to determine the optimal dosing for this patient population. Drugs. 2013;73:1761–1770. 6. Bayraktar UD, Bayraktar S. Treatment of iron deficiency anemia associated with gastrointestinal tract diseases. World J Gastro- enterol. 2010;16:2720–2725. Conclusions 7. Murawska N, Fabisiak A, Fichna J. Anemia of chronic disease and iron deficiency anemia in inflammatory bowel diseases: FCM is currently indicated in the USA for the treatment of pathophysiology, diagnosis, and treatment. Inflamm Bowel Dis. 2016;22:1198–1208. IDA in adults when oral iron preparations are not tolerated 8. Stein J, Connor S, Virgin G, Ong DE, Pereyra L. Anemia and or are ineffective. This analysis highlights that FCM is effec- iron deficiency in gastrointestinal and liver conditions. World J tive in patients with GI-related IDA and has a safety profile Gastroenterol. 2016;22:7908–7925. comparable to that of other IV iron agents. 9. Bottaro G, Cataldo F, Rotolo N, Spina M, Corazza GR. The clin- ical pattern of subclinical/silent celiac disease: an analysis on 1026 consecutive cases. Am J Gastroenterol. 1999;94:691–696. Acknowledgments The authors thank Aesculapius Consulting, Inc., 10. Corazza GR, Valentini RA, Andreani ML, et al. Subclinical and Peloton Advantage, LLC, for providing editorial support, which coeliac disease is a frequent cause of iron-deficiency anaemia. was funded by Luitpold Pharmaceuticals, Inc., Shirley, NY, in accord- Scand J Gastroenterol. 1995;30:153–156. ance with Good Publication Practice (GPP3) guidelines (http://www. 11. Carroccio A, Iannitto E, Cavataio F, et al. Sideropenic anemia ismpp .org/gpp3). This study was sponsored by Luitpold Pharmaceu- and celiac disease: one study, two points of view. Dig Dis Sci. ticals, Inc. 1998;43:673–678. 12. Howard MR, Turnbull AJ, Morley P, Hollier P, Webb R, Clarke Compliance with ethical standards A. A prospective study of the prevalence of undiagnosed coeliac disease in laboratory defined iron and folate deficiency. J Clin Conflict of interest Gary R. Lichtenstein has served as a consultant Pathol. 2002;55:754–757. to Luitpold Pharmaceuticals, Inc., and Jane E. Onken has served on 13. Dignass AU, Gasche C, Bettenworth D, et al. European con- a Steering Committee and Advisory Board for Luitpold Pharmaceu- sensus on the diagnosis and management of iron deficiency ticals, Inc. and anaemia in inflammatory bowel diseases. J Crohns Colitis.. 2015;9:211–222. Statement of human rights All procedures performed involving human 14. Kulnigg S, Stoinov S, Simanenkov V, et al. 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Digestive Diseases and SciencesSpringer Journals

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