Table 1.
Main features and results of the 21 randomised controlled trials included in the systematic review
| Study (year) | Patients randomised | Medical condition | Clinical inclusion criteria | Intervention drug (dosage) | Comparator drug (dosage) | Time horizon | Efficacy outcome(s) | Safety outcome |
|---|---|---|---|---|---|---|---|---|
| Agarwal et al. (2006) [29]a | 89 | Chronic kidney disease | Hb <12 g/dl; serum ferritin <100 ng/ml and or TSAT <20 % | Intravenous ferric gluconate (250 mg; weekly; 4 weeks) | Oral ferrous sulphate (325 mg; 3 times daily; 6 weeks) | 43 days | Increase in Hb levels (0.4 g/dl in ferric gluconate and 0.2 g/dl in ferrous sulphate) was statistically significant (p <0.01) for intravenous iron only. Compared to ferrous sulphate, ferric gluconate achieved greater improvements in ferritin (232.0 ± 160.8 vs. 55.9 ± 236.2 g/dl) and TSAT (8.3 ± 7.5 vs. 2.9 ± 8.8%, p = 0.007) | Intravenous ferric gluconate: drug-related AEs occurred in 13 out of 44 patients (three of which designated as serious AEs). Hypotension and nausea occurred in six (out of 44) subjects, while vomiting was seen in five and diarrhoea in two. Oral ferrous sulphate: drug-related AEs occurred in nine of 45 patients Constipation was the most frequent effect (four of 45 subjects) followed by dark stools (three patients), nausea (two patients), and diarrhoea (two patients). No serious AEs were seen in this group |
| Bager et al. (2014) [30] | 97 | Non-variceal acute upper gastrointestinal bleeding | Hb <12 g/dl for women and <13 g/dl for men | Intravenous ferric carboxymaltose (1000 mg; single infusion) | Oral ferrous sulphate (100 mg; twice daily; 3 months) or intravenous placebo (saline) | 13 weeks | At week 13, mean Hb (g/dl) in ferric carboxymaltose group was 13.9 (13.4–14.3) vs. 13.5 (12.9–14.1) in oral iron and 11.5 (10.3–12.9) in placebo (p < 0.01) | Re-admission for bleeding was reported in 2.4 % of patients in both the oral and intravenous groups (p = NS). Admission due to cardiovascular symptoms was reported in 4.9, 4.8 and 7.1 % of oral, intravenous and placebo groups, respectively (p = NS) |
| Bailie et al. (2010) [8] | 559 | Iron deficiency anaemia (various conditions) | Hb <12 g/dl; TSAT ≤25 %; serum ferritin <300 ng/ml (CKD and IBD patients) or ≤100 ng/ml (other) | Intravenous ferric carboxymaltose (1000 mg; single infusion) | Intravenous placebo (normal saline, 100–250 ml) | 14 days | Not reported | During the first 24 h of the treatment, at least one TEAE was experienced by 15.0 % of subjects after receiving ferric carboxymaltose and 11.4 % after receiving placebo (p = 0.066). During the 7-day treatment period, at least one TEAE was experienced by 29.3 % of the subjects after receiving ferric carboxymaltose and 19.7 % after receiving placebo (p < 0.001). The most common events in the ferric carboxymaltose group were headache (5.4 %), nausea (3.8 %) and dizziness (1.8 %) |
| Breymann et al. (2008) [9] | 349 | Post-partum anaemia | Hb ≤10.5 g/dl | Intravenous ferric carboxymaltose (1000 mg; up to 3 weekly doses) | Oral ferrous sulphate (100 mg; twice per day; 12 weeks) | 12 weeks | At week 12, Hb levels increased to a mean of 130.4 g/l in ferric carboxymaltose vs. 128.9 g /l in ferrous sulphate (p = NS). Mean ferritin was 161.2 µg/l vs. 43.3 µg/l (p < 0.0001) | Overall, AEs were experienced by 26.0 % in ferric carboxymaltose vs. 22.2 % in ferrous sulphate (p = 0.51). Statistically significant differences (ferric carboxymaltose vs. ferrous sulphate) were seen in gastrointestinal disorders (3.5 vs. 10.3 %; p = 0.015), general disorders and administration site conditions (6.2 vs. 0.0 %; p = 0.003), and musculoskeletal and connective tissue disorders (0.0 vs. 2.6 %; p = 0.039). Constipation was less common in ferric carboxymaltose group (0.4 vs. 6.8 %). Two patients in ferric carboxymaltose group and none in the control group experienced severe AEs (i.e. hypersensitivity). There were no cases of anaphylactic shock/reaction |
| Coyne et al. (2003) [27] | 144 (dextran-sensitive) and 2194 (dextran-tolerant) | Haemodialysis | Not reported | Intravenous ferric gluconate (12 mg; single infusion) | Placebo (bacteriostatic saline, 10 ml) | 9 months | Not reported | Among 143 iron dextran-sensitive patients exposed to ferric gluconate, three (2.1 %) had suspected allergic events, including one serious reaction (0.7 %). One patient (0.7 %) had a suspected allergic reaction after placebo. In contrast, among 2194 iron dextran-tolerant patients, ferric gluconate intolerance occurred in seven patients (0.3 %; p = 0.020), including five (0.2 %) who had suspected allergic events (p = 0.010), but none who had serious events (0.0 %; p = 0.061). Two iron dextran-tolerant patients (0.09 %) had allergic-like reactions following placebo |
| Earley et al. (2009) [26] | 18 | Idiopathic restless legs syndrome | Periodic leg movements of sleep (PLMS) >15/h | Intravenous iron sucrose (500 ml; two infusions) | Intravenous placebo (500 ml; two infusions) | 2 weeks | Iron treatment resulted in a small but significant (p = 0.0001) increase in ferritin and a decrease in disease severity | The most commonly reported treatment-related AEs were oedema in either hands or feet (36 %) and nausea or vomiting (36 %), followed by hypotension (18 %), dizziness (18 %) and abdominal pain (9 %). All the reported AEs occurred during treatment and resolved within minutes to hours of completing the infusion. No AEs were reported at 2-week follow-up after the iron treatment |
| Evstatiev et al. (2013) [42] | 256 | Inflammatory bowel disease | Hb ≥12 g/dl in women and ≥13 g/dl in men | Intravenous ferric carboxymaltose (500 mg; single infusion) | Placebo (saline solution; 500 mg) | 8 months | Anaemia recurred in 26.7 % of patients given ferric carboxymaltose vs. 39.4 % given placebo. Time to anaemia recurrence was longer in the ferric carboxymaltose group (p = 0.049). Ferritin and TSAT increased by 30.3 µg/l and 0.6 %, respectively, in ferric carboxymaltose group; the same parameters decreased by 36.1 µg/l and 4.0 %, respectively, in placebo group | AEs were reported in 59.0 % in ferric carboxymaltose group vs. 50.5 % of placebo group, and serious AEs in 6.7 and 8.1 %, respectively. The most common AEs were ulcerative colitis-specific symptoms and nasopharyngitis (7.8 vs. 7.3 %). Gastrointestinal symptoms and flares of ulcerative colitis were somewhat less frequent with ferric carboxymaltose compared with placebo: 20.0 vs 28.3 % (p = 0.17) and 6.7 vs. 12.1 % (p = 0.18), respectively. No anaphylactic reaction was reported and no death occurred |
| Evstatiev et al. (2011) [31] | 485 | Inflammatory bowel disease | Hb = 7–12 g/dl (women) and 7–13 g/dl (men) | Intravenous ferric carboxymaltose (500 or 1000 mg; up to 3 infusions) | Intravenous iron sucrose (200 mg; up to 11 infusions, twice weekly) | 12 weeks | More patients with ferric carboxymaltose than iron sucrose achieved Hb response (65.8 vs. 53.6 %; p = 0.004) or Hb normalisation (72.8 vs. 61.8 %; p = 0.015) | The frequency of treatment-related AEs was comparable between the two groups (p = 0.413). One treatment-related serious AE (i.e. pulmonary embolism) was reported in ferric carboxymaltose group. Skin and subcutaneous tissue disorders such as rash, dermatitis and pruritus were reported in 3.7 % of ferric carboxymaltose patients and 0.8 % of the iron sucrose group (p = 0.063). No true hypersensitivity reactions were reported |
| Favrat et al. (2014) [40] | 294 | Fatigue in premenopausal, non-anaemic women | Serum ferritin <50 µg/l and TSAT <20 %; Hb ≥115 g/l. Piper Fatigue Scale (PFS) score ≥5 | Intravenous ferric carboxymaltose (1000 mg; single infusion) | Intravenous placebo (saline, 1000 mg) | 56 days | Fatigue was reduced in 65.3 % (ferric carboxymaltose) and 52.7 % (placebo) of patients (OR = 1.68; p = 0.03). All ferric carboxymaltose -treated patients (vs. 86 % in placebo group) had haemoglobin levels ≥120 g/l | TEAEs were experienced by 57.2 % of ferric carboxymaltose and 49.0 % of placebo-treated patients (p = 0.16). Five ferric carboxymaltose -treated patients reported severe AEs (in four, the events were considered drug-related) |
| Grote et al. (2009) [41] | 60 | Restless legs syndrome | Serum ferritin <30 µg/l; International Restless Legs Study Group Rating Scale (IRLS) ≥10 | Intravenous iron sucrose (200 mg; 5 infusions in 3 weeks) | Placebo (saline, 1000 mg) | 11 weeks | Median IRLS score decreased from 24 to 7 in iron sucrose group vs. from 26 to 17 in placebo group (p = 0.123, NS). Serum ferritin increased from 20.1 to 118.4 µg/l and Hb from 129.3 to 134.5 g/l in the iron sucrose group; no changes were observed after placebo | In the iron sucrose group the most common AEs were dysaesthesia (7.1 %), taste perversion (4.8 %), headache (9.5 %). In the placebo group they were: headache (11.9 %), nausea and urticaria (4.8 %) |
| Krayenbuehl et al. (2011) [6]a | 90 | Fatigue in premenopausal, non-anaemic women | Serum ferritin ≤50 ng/ml; Hb ≥120 g/l | Intravenous iron sucrose (200 mg; twice weekly for 2 weeks) | Intravenous placebo (saline, four infusions of 200 ml) | 6 weeks | Improvement in fatigue was reported by 65 % of iron-treated and 40 % of placebo-treated patients (p = 0.02). In iron-treated patients, a significant increase in serum ferritin concentration (98 vs. 1 ng/ml; p < 0.001) and TSAT (9 vs. 2 %; p = 0.006) was observed compared to placebo-treated patients | Drug-associated AEs were observed in 21 % of iron-treated patients and in 7 % of placebo-treated patients (p = 0.05) |
| Kulnigg et al. (2008) [32] | 200 | Inflammatory bowel disease | Hb ≤10 g/dl; TSAT <20 % or serum ferritin <100 µg/l | Intravenous ferric carboxymaltose (maximum 1000 mg repeated weekly until deficit was corrected) | Oral ferrous sulphate (100 mg; twice daily; 12 weeks) | 12 weeks | The median Hb improved from 8.7 to 12.3 g/dl (ferric carboxymaltose) vs. from 9.1 to 12.1 g/dl (ferrous sulphate, p = 0.70). Median ferritin increased from 5.0 to 43.5 µg/l (ferric carboxymaltose) vs. from 6.5 to 28.5 µg/l (ferrous sulphate) | Treatment-related AEs occurred in 28.5 % (ferric carboxymaltose) and 22.2 % (ferrous sulphate) of patients, respectively. Most commonly reported (>2 % of patients overall) treatment-related AEs for ferric carboxymaltose and ferrous sulphate respectively were abdominal pain (2.9 vs. 3.2 %), nausea (2.2 vs. 4.8 %), headache (2.9 vs. 1.6 %) and diarrhoea (0.7 vs. 6.3 %) |
| Kulnigg-Dabsch et al. (2013) [33]a | 25 | IBD-related thrombocytosis | Platelet count >450 g/l; Hb >10.5 g/dl (no severe anaemia); TSAT <20 % or ferritin <100 µg/l | Intravenous ferric carboxymaltose (500, mg; once weekly for 3 weeks) | Intravenous Placebo | 6 weeks | Mean platelet counts dropped on ferric carboxymaltose but not on placebo treatment (p = 0.0024). Hb, TSAT and ferritin levels improved in the ferric carboxymaltose but not in the placebo group | Fourteen AEs were reported in nine patients (34.6 %), 11 in ferric carboxymaltose patients and three in the placebo group. Five effects were rated as serious: bowel obstruction, deterioration of ulcerative colitis, systemic inflammatory response syndrome, sepsis-associated heart failure and hospitalization because of fistula |
| Onken et al. (2014) [28] | 2584 | Non-dialysis-dependent CKD | Hb ≤11.5 g/dl; glomerular filtration rate (GFR) <60 ml/min/1.73 m2 | Intravenous ferric carboxymaltose (750 mg; twice weekly) | Intravenous iron sucrose (200 mg; five infusions in 14 days) | 56 days | The mean Hb increase was 1.13 g/dl (ferric carboxymaltose) vs. 0.92 g/dl (iron sucrose; 95 % CI 0.13–0.28). More patients in the ferric carboxymaltose group achieved Hb increase ≥1.0 g/dl (48.6 vs. 41.0 %; 95 % CI 3.6–11.6) | During the study, at least one drug-related TEAE occurred in 298 of 1276 (23.4 %) subjects in ferric carboxymaltose group and 202 of 1285 (15.7 %) subjects in the iron sucrose group. The most common events were nausea (8.6 % in ferric carboxymaltose group vs. 1.6 % in iron sucrose), hypertension (4.6 vs. 2.0 %), flushing (3.0 vs. 0.1 %), dizziness (2.4 vs. 1.2 %) and dysgeusia (2.4 vs. 1.2 %). The majority of drug-related TEAEs were mild or moderate in severity. At least one serious AE was experienced by 202 of 1276 (15.8 %) participants receiving ferric carboxymaltose and 197 of 1285 (15.3 %) participants receiving iron sucrose (p = 0.74), with congestive heart failure being the most commonly reported (2.4 vs. 2.3 %; p = 0.90) |
| Onken et al. (2014) [13] | 507 (A vs. B) 504 (C vs. D) |
Iron deficiency anaemia (various conditions) | Hb ≤11 g/dl; ferritin <100 ng/ml (or <300 ng/ml when TSAT <30 %) | (A) or (C) intravenous ferric carboxymaltose (750 mg; twice weekly) | (B) Oral ferrous sulphate (325 mg; three times a day; 14 days); (D) intravenous iron standard-of-care (IVSC) | 35 days | Mean (±SD) Hb was significantly higher in group A than in group B: 1.57 (±1.19) vs. 0.80 (±0.80) g/dl (p = 0.001). Group C vs. group D: Hb = 2.90 (±1.64) vs. 2.16 (±1.25) g/dl (p = 0.001) | During the treatment phase, at least one drug-related TEAE was experienced by 22.8 % of participants in Group A, 6.3 % in Group B, 25.3 % in Group C, and 26.5 % in Group D. The most common events were hypophosphatemia (Group C 5.5 %; Group A 3.7 %), nausea (Group A 4.1 %; Group D 3.3 %), protocol-defined hypotension (Group D 3.7 %), and constipation (Group B 3.2 %). Serious events were described in eight (3.3 %) patients in group A, 10 (4.0 %) in group B, 17 (6.7 %) in group C, and 16 (6.5 %) in group D. Hypersensitivity events were reported in eight participants: three (0.8 %) were in group A, two (0.8 %) were in group C and six (2.4 %) in group D |
| Quinibi et al. (2011) [34] | 255 | Non-dialysis-dependent CKD | Hb ≤11 g/dl; TSAT ≤25 %; serum ferritin ≤300 ng/ml; glomerular filtration rates ≤45 ml/min/1.73 m2 | Intravenous ferric carboxymaltose (1000 mg; up to two additional doses at two-week intervals) | Oral ferrous sulphate (325 mg; 3 times daily; 56 days) | 56 days | Mean increase in Hb was 0.95 ± 1.12 (ferric carboxymaltose) vs. 0.50 ± 1.23 g/dl (ferrous sulphate; p = 0.005); mean increase in ferritin was 432 ± 189 vs. 18 ±45 ng/ml (p < 0.001); mean increase in TSAT was 13.6 ± 11.9 % vs. 6.1 ± 8.1 % (p < 0.001) | The proportion of subjects who experienced at least one possibly drug-related AE was significantly lower in ferric carboxymaltose group compared with the oral iron group: 2.7 % in ferric carboxymaltose group and 26.2 % in the oral iron group (p = 0.0001). The most commonly AEs the ferric carboxymaltose group were peripheral oedema (6.1 %), hyperkalaemia (4.1 %), urinary tract infection (3.4 %), hypotension (3.4 %), bronchitis, headache and infusion site reaction (2.0 % each). The most commonly experienced AEs in the oral iron group were constipation (17.5 %), nausea (4.9 %), diarrhoea, upper respiratory tract infection (3.9 % each), discoloured faeces and gastrointestinal haemorrhage (2.9 % each). Serious AEs were recorded in 13 (8.8 %) subjects in ferric carboxymaltose group and ten (9.7 %) in the oral iron group |
| Schatz et al. (2013) [35] | 50 | Apheresis-related anaemia | Serum ferritin <100 µg/l; or ferritin <300 µg/l; TSAT <20 % | Intravenous ferric carboxymaltose (500–1000 mg; single infusion) | Intravenous ferric gluconate (62.5 mg; once weekly until deficit was corrected) | 8 weeks | Serum ferritin (mean) at week 8: 117.9 µg/l in ferric gluconate vs. 140.2 µg/l in ferric carboxymaltose (p = 0.4). TSAT: 22 % (ferric gluconate) vs. 26.4 % (ferric carboxymaltose; p = 0.02) | There were no serious AEs in either group, especially no anaphylactic shocks. Six patients per group showed AEs, mainly gastrointestinal distress and flu-like symptoms. All AEs were mild, transient and self-limiting. There were no injection site reactions in either group |
| Seid et al. (2008) [36]a | 289 | Post-partum anaemia | Hb ≤10 g/dl | Intravenous ferric carboxymaltose (1000 mg; weekly for a maximum of 2500 mg) | Oral ferrous sulphate (325 mg; 3 times daily; 6 weeks) | 6 weeks | Ferric carboxymaltose -treated patients were significantly more likely to achieve Hb >12 g/dl (91 vs. 67 %; p < 0.0001) in a shorter time period (14 vs. 27 days; p < 0.0002) and attain higher TSAT (36 vs. 28 %) and ferritin (647 vs. 12 ng/ml) levels (p < 0.0001) | Patients reporting one or more drug-related AEs were lower in ferric carboxymaltose (10.6 %) than in oral ferrous sulphate (21.8 %) group. Urticaria (2 %) was the only AE occurring in ≥2 % of the ferric carboxymaltose -treated patients. Four (2.8 %) subjects in ferric carboxymaltose group and four (2.7 %) subjects in the oral iron group experienced at least one serious AE, none of which was considered to be related to study medication or led to premature discontinuation |
| Toblli et al. (2007) [37] | 40 | Chronic heart failure and chronic renal failure | Hb ≤12.5 g/dl; TSAT <20 %; ferritin <100 ng/ml; creatinine clearance <90 ml/min; left ventricular ejection fraction ≤35 % | Intravenous iron sucrose (200 mg weekly; 5 weeks) | Placebo (saline solution, 200 mg) | 6 months | The treatment group showed better haematological values: mean (±SD) Hb was 11.8 (±0.7) vs. 9.8 (±0.6) g/dl in placebo; mean ferritin: 240.4 (±55.6) ng/ml vs. 78.9 (±30.1); TSAT (%): 0.25 (±0.04 %) vs. 0.20 (±0.01) | Therapy with iron sucrose was well tolerated in all patients, and there were no side effects reported in the two groups throughout the study |
| Van Wyck et al. (2009) [39]a | 477 | Uterine bleeding | Hb ≤11 g/dl; serum ferritin ≤100 ng/ml; TSAT ≤25 % | Intravenous ferric carboxymaltose (maximum 1000 mg repeated weekly to achieve a total replacement dose) | Oral ferrous sulphate (325 mg; 3 times daily; 6 weeks) | 6 weeks | Compared to ferrous sulphate, more patients assigned to ferric carboxymaltose achieved correction (Hb ≥12 g/dl) of anaemia (73 % vs. 50 %; p < 0.001) and experienced greater improvement in symptoms of fatigue (p < 0.05) | No hypotensive or serious drug-related AEs were reported in either treatment group. There were no deaths. Patients assigned to oral iron therapy were more likely to experience drug-related gastrointestinal complaints, particularly constipation (14.2 vs. 3.0 %), diarrhoea (4.4 vs. 1.7 %), nausea (11.9 vs. 3.5 %), and vomiting (3.1 vs. 0.4 %). Patients assigned to intravenous iron therapy were more likely to report transient fatigue (2.2 vs. 0 %), headache (6.5 vs. 4.4 %), dizziness (2.2 vs. 0.4 %), dysgeusia (2.6 vs. 0.9 %), and rash (2.2 vs. 0 %) |
| Van Wyck et al. (2007) [38]a | 352 | Post-partum anaemia | Hb ≤10 g/dl | Intravenous ferric carboxymaltose (maximum 1000 mg repeated weekly to achieve a total replacement dose) | Oral ferrous sulphate (325 mg; 3 times daily; 6 weeks) | 6 weeks | Patients assigned to intravenous ferric carboxymaltose compared with those assigned to oral iron were more likely to achieve Hb >12 g/dl (90.5 vs. 68.6 %; p < 0.001) | No serious drug-related AEs occurred in either treatment group. Patients assigned to oral iron therapy were more likely to report gastrointestinal complaints, particularly constipation (11.2 vs. 3.4 %; p = 0.07), diarrhoea (3.9 vs. 0 %; p = 0.015) and nausea (7.3 vs. 1.1 %; p = 0.006) in comparison to ferric carboxymaltose. Patients assigned to intravenous ferric carboxymaltose were more likely to experience skin disorders (5.2 vs. 2.2 %; p = 0.164), principally mild pruritus and rash that usually resolved within 15 min from infusion |
AE adverse event, CKD chronic kidney disease, Hb haemoglobin, HS hydroxide sucrose, IBD inflammatory bowel disease, TEAEs treatment-emergent adverse events, TSAT transferrin saturation
aIndicates the studies included in the network meta-analysis