Ferric Carboxymaltose for Anemic Perioperative Populations: A Systematic Literature Review of Randomized Controlled Trials

Figures & data

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart of the study selection process.

Note: Adapted from Page MJ, Moher D, Bossuyt PM, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021;372:n160.³⁷

Table 1 Design and Patient Flow of Included Studies

	Study Description
Study	Perioperative State (Surgery)	Study Group Assignment	Design	Prespecified Blood Transfusion Criteria	Randomized N	Treated N	Withdrawn N
Bisbe et al (2014)^Citation15	Postoperative (orthopedic)	G1: IV FCM 700–1000 mg single dose on postop day 1 G2: Oral ferrous sulfate 100 mg/d from postop day 7 to 30	Single-blinded	3. Hb <70 g/L=3 RBC transfusions independent of symptoms 4. Hb 71–89 g/L=2 RBC transfusions in presence of severe symptoms (HF with NYHA Class ≥III dyspnea, ACS, hemodynamic instability [hypotension, orthostatism], and/or acute or exacerbated chronic respiratory failure)	122 G1: 60 G2: 62	121 G1: 59 G2: 62	G1: 7 (LTFU) G2: 11 (LTFU)
Bernabeu-Wittel et al (2016)^Citation16	Preoperative (orthopedic hip)	G1: EPO 40,000 IU/1 mL EPO SC + IV FCM 1000 mg (2500 mg vials diluted in 250 mL of saline) infused over 20 min G2: 1 mL placebo (saline) SC + IV FCM 1000 mg (2500 mg vials diluted in 250 mL of saline) infused over 20 min G3: 1 mL placebo (saline) SC + IV placebo (250 mL of saline) infused over 20 min	Double-blind	1. Hb <70 g/L=3 RBC transfusions independent of symptoms 2. Hb 71–89 g/L=2 RBC transfusions in presence of severe symptoms (HF with NYHA Class ≥III dyspnea, ACS, hemodynamic instability [hypotension, orthostatism], and/or acute or exacerbated chronic respiratory failure)	303 G1: 100 G2: 103 G3: 100	293 G1: 97 (hip surgery— osteosynthesis, n=66 [68%]; partial arthroplasty, n=27 [28%]; total arthroplasty, n=4 [4%]) G2: 101 (hip surgery—osteosynthesis, n=70 [69%]; partial arthroplasty, n=28 [28%]; total arthroplasty, n=3 [3%]) G3: 97 (hip surgery— osteosynthesis, n=60 [62%]; partial arthroplasty, n=33 [34%]; total arthroplasty, n=4 [4%])	G1: 14 (discontinued intervention, n=6 [not operated, n=3, iron sucrose administration in follow-up period, n=3]); excluded from per protocol analysis,^a n=8) G2: 17 (discontinued intervention, n=6 [not operated, n=2; iron sucrose administration in follow-up period, n=4]); excluded from per protocol analysis,^a n=11) G3: 11 (discontinued intervention, n=4 [not operated, n=3, iron sucrose administration in follow-up period, n=1]); excluded from per protocol analysis, n=7)^a
Froessler et al (2016)^Citation17	Perioperative (abdominal)	G1: Preop―IV FCM single 15 mg/kg injection (maximum: 1000 mg) administered over 15 min Postop―IV FCM 0.5 mg per recorded 1 mL blood loss if blood loss ≥100 mL, given within 2 days of surgery G2: Usual care consisting of no treatment, observation, oral iron recommendations, and ABT; prescription and administration of IV iron allowed	Open (masking not used)	Not reported	72 G1: 40 G2: 32	72 G1: 40 G2: 32	Not reported
Khalafallah et al (2016)^Citation7	Postoperative (orthopedic, abdominal, ENT, plastic, gynecologic, urologic)	G1: IV FCM single 15 mg/kg injection (maximum: 1000 mg) over 15 min G2: No intervention (standard care)	Open-label	Not reported	201 G1: 103 G2: 98	201 G1: 97 G2: 94	G1: 6 (withdrawn from study, n=5; LTFU, n=1) G2: 4 (withdrawn from study, n=2; LTFU, n=2)
Keeler et al (2017)^Citation18	Preoperative (oncological)	G1: IV FCM diluted in 250 mL 0.9% NS over 15 min; dose calculated using body weight and inclusion hemoglobin value. Maximum dose 1000 mg/wk and 2000 mg during trial; second dose ≥7 days after first, if needed G2: Oral ferrous sulphate 200 mg BID continued until surgery (patients advised to take without food and with liquid high in ascorbic acid to maximize enteric absorption)	Open-label	Not reported	116 G1: 55 G2: 61	116 G1: 55 G2: 61	G1: 4 (did not undergo surgical resection) G2: 2 (did not undergo surgical resection)
Kim et al (2017)^Citation19	Preoperative (oncological)	G1: IV FCM 1–2 1000 mg injections for patients <50 kg or 500 mg injections for ≥50 kg over 6–15 min G2: IV saline placebo	Single-blinded	Per guidelines, Hb <7 g/dL	454 G1: 228 G2: 226	445 G1: 222 G2: 223	G1: 5 (did not complete study [LTFU, n=3; withdrew consent after treatment, n=1; physician withdrew patient for surgical complication, n=1]) G2: 10 (did not complete study [withdrew consent after treatment, n=6; LTFU, n=2; eligibility criteria violation recognized after treatment/received blood transfusion before treatment, n=2])
Lee et al (2019)^Citation20	Preoperative (benign uterine diseases)	G1: IV FCM single dose administered over 15 min (maximum: 1000 mg); amount determined based on patient’s body weight (<50 kg, 500 mg iron; ≥50 kg, 1000 mg iron). G2: IV IS single administration over 3 dosing visits per week (maximum: 600 mg iron/week in 200 mg iron doses. Dosage based on calculated iron deficit using the Ganzoni formula	Open-label	Not reported	101 G1: 52 G2: 49	101 G1: 52 G2: 49	G1: 0 G2: 0
Padmanabhan et al (2019)^Citation21	Preoperative (cardiac)	G1: IV FCM diluted in 250 mL of NS administered over 30 min (maximum: 1000 mg dose). A second dose was offered when required. Calculation of dosing regimen as follows: Hb > 100 and weight < 70 kg = 1000 mg; Hb > 100 and weight > 70 kg = 1500 mg; Hb 70–100 and weight < 70 kg = 1500 mg; Hb 70–100 and weight > 70 kg = 2000 mg G2: 200 mg ferrous sulphate PO BID	Open-label	Not reported	50 G1: 26 G2: 24	44 G1: 22 G2: 22	G1: 4 (LTFU) G2: 1 (LTFU)
Park et al (2019)^Citation22	Intraoperative (Unilateral TKA or THA)	G1: IV FCM 1000 mg diluted in 100 mL NS administered over 15 min. G2: IV 100 mL NS placebo	Single-blinded	Hb < 8 g/dL throughout entire perioperative period. If significant hemodynamic instability was observed despite adequate fluid administration or a requirement of an increasing amount of vasopressor was essential, allogenic transfusion of packed RBC was permitted with the Hb ≥ 8 g/dL. In case of transfusion, the subjects received one unit of packed RBC and the Hb level was followed to assess the further administration of additional packed RBC.	69 G1: 32 G2: 34	58 G1: 29 G2: 29	G1: 3 (withdrew consent, n=1, LTFU, n=2) G2: 5 (unnoticed cancer diagnosis, n=1; withdrew consent, n=1; LTFU, n=3)
Richards et al (2020)^Citation23	Preoperative (abdominal)	G1: IV FCM single dose 1000 mg in 100 mL NS administered over 15 min G2: IV 100 mL NS placebo	Double-blinded	Not reported	487 G1: 244 G2: 243	481 G1: 240 G2: 241	G1: 8 (not treated, n=4; withdrew consent, n=4) G2: 6 (not treated, n=2; withdrew consent, n=4)

Note: ^aPatients did not receive intervention, were not operated, or received iron sucrose administration in the follow-up period.

Abbreviations: ABT, allogeneic blood transfusion; ACS, acute coronary syndrome; BID, twice daily; EPO, erythropoietin; FCM, ferric carboxymaltose; G, treatment group; Hb, hemoglobin; HF, heart failure; IV, intravenous; IS, iron sucrose; LTFU, lost to follow-up; NS, normal saline; NYHA, New York Heart Association; PO, by mouth; RBC, red blood cell; SC, subcutaneous; TDD, total daily dose; TID, three times daily; THA, total hip arthroplasty; TKA, total knee arthroplasty.

Table 2 Baseline Patient Characteristics of Included Studies

Author	Age, y, Mean ± SD	Sex, n (%)	Weight, kg, Mean ± SD	ASA Physical Status Classification, n (%)	Preoperative Hb, g/dL, Mean ± SD	Serum Iron, μg/dL, Mean ± SD	Preoperative Serum Ferritin, ng/mL, Mean ± SD	Preoperative TSAT, %, Mean ± SD
Bernabeu-Wittel (2016)^Citation16	G1: 84.6 ± 6.2 G2: 83.4 ± 6.4 G3: 82.3 ± 6.9	G1: 84 (81.5%) (F) G2: 87 (87.0%) (F) G3: 87 (87.0%) (F)	Not reported	G1: III (II–III)^a G2: III (II–III)^a G3: III (II–III)^a	G1: 11.0 ± 0.8 G2: 11.0 ± 0.7 G3: 11.0 ± 0.7	Not reported	G1: 155 ± 170 G2: 137 ± 150 G3: 141 ± 130	Not reported
Keeler (2017)^Citation18	G1: Median (IQR): 73.8 (67.4–78.6) G2: Median (IQR): 74.7 (67.9–80.8)	G1: 35:20 (M:F) G2: 37:24 (M:F)	G1: Mean (95% CI): 79.0 (74.9, 83.2) G2: Mean (95% CI): 72.8 (68.7, 76.9)	G1: I–II, n=30; III–IV, n=25 G2: I–II, n=43; III–IV, n=18	G1: Recruitment: ~10.1; day of surgery: ~11.9 G2: Recruitment: ~10.4; day of surgery: ~11.0	Not reported	Not reported	Not reported
Kim (2017)^Citation19	G1: 60.9 ± 13.7 G2: 61.2 ± 12.6	G1:125 (54.8%) (F) G2:124 (54.9%) (F)	G1: 57.6 ± 9.7 G2: 58.1 ± 9.9	Not reported	G1: 11.6 ± 1.6 G2: 11.8 ± 1.6	G1: 24.6 ± 15.2 G2: 24.0 ± 11.1	G1: 115.9 ± 104.8 G2: 137.1 ± 123.9	G1: 10.8 ± 7.2 G2: 10.5 ± 5.4
Froessler (2016)^Citation17	G1: 64 ± 15 G2: 68 ± 15	G1: 19:21 (M:F) G2: 17:15 (M:F)	G1: 86 ± 27 G2: 88 ± 20	G1: II: 17 (42.5); III: 22 (55); IV: 1 (2.5) G2: II: 17 (53.1); III: 15 (46.9); IV: 0	G1: Randomization: 10.7 ± 1.3 (n=40); admission: 11.5 ± 1.3 (n=36) G2: Randomization: 10.6 ± 1.4 (n=32; P=0.76); admission: 10.7 ± 1.7 (n=29; P=0.12) Difference between randomization and admission: G1: 0.8 ± 0.8 (n=36) G2: 0.1 ± 1.3 (n=29; P=0.010)	Not reported	G1: Randomization, median (IQR): 19 (6–48) G2: Randomization, median (IQR): 37 (11–82)	G1: Randomization, median (IQR): 6 (3–10) G2: Randomization, median (IQR): 9 (7–15)
Bisbe (2014)^Citation15	G1: Mean (range): 72.7 (56–86) G2: Mean (range): 72.8 (40–86)	G1: 47 (78.3%) (F) G2: 50 (80.6%) (F)	G1: 79.6 ± 14.9 G2: 76.2 ± 11.9	G1: ≥III: 12 (20.0) G2: ≥III: 12 (19.4)	G1: 13.6 ± 0.9 G2: 13.6 ± 0.9	G1: 77 ± 22 G2: 74 ± 21	G1: 120 ± 111 G2: 164 ± 95	G1: 20.1 ± 6.6 G2: 20.4 ± 6.7
Khalafallah (2016)^Citation7	G1: Median (IQR): 65 (55–73) G2: Median (IQR): 67 (60–76)	G1: 65 (63%) (F) G2: 50 (51%) (F)	G1: Median (IQR): 82 (70–91) G2: Median (IQR): 81 (69–88)	Not reported	G1: Median (IQR), postop day 1: 10.9 (9.9–12.0) G2: Median (IQR), postop day 1: 10.6 (9.6–11.7)	G1: Preop: 81.6 ± 15.6; postop, day 1: 33.5 ± 21.2; period effect,^† mean difference (95% CI): −48.0 (−54.8 to −41.9) [P<0.0001] G2: Preop: 81.0 ± 21.2; postop, day 1: 33.5 ± 25.1; period effect,^† mean difference (95% CI): −47.4 (−53.9 to −41.0) [P<0.0001]	G1: Postop, day 1, median (IQR): 170 (108–284) G2: Postop, day 1, median (IQR): 243 (134–471)	G1: Postop day 1, median (IQR): 10 (7–15) G2: Postop day 1, median (IQR): 11 (9–15)
Lee (2019)^Citation20	G1: 44.0 ± 5.7 G2: 43.4 ± 5.0	G1: 52 (100%) (F) G2: 49 (100%) (F)	G1: 56.2 ± 6.7 G2: 57.6 ± 9.1	Not reported	G1: 8.4 ± 1.4 G2: 8.4 ± 1.1	Not reported	G1: 58 ± 57 G2: 57 ± 39	G1: 6.1 ± 7.3 G2: 4.8 ± 5.9
Padmanabhan (2019)^Citation21	G1: 73 ± 12 G2: 75 ± 10	G1: 9 (41%) (F) G2: 8 (36%) (F)	G1: 78.9 ± 18.2 G2: 80.5 ± 13.1	Not reported	G1: 11.9 ± 0.89 G2: 113.9 ± 1.11	Not reported	G1: median (IQR) 62.8 (26.2–86.4) G2: median (IQR) 49.7 (19.7–88.8)	Not reported
Parl^Citation22 (2019)	G1: 65.1 ±10.2 G2: 62.0 ± 9.5	G1: 19 (65.5%) (F) G2: 21 (72.4%) (F)	G1: 64.2 ± 9.8 G2: 67.1 ± 11.8	G1: ≥III: 0 G2: ≥III: 0	G1: 12.5 ± 1.3 G2: 13.4 ± 1.1	G1: 92.4 ± 37.0 G2: 101.0 ± 46.5	G1: 90.6 ± 82.5 G2: 87.0 ± 105.2	G1: 29.4 ± 16.3 G2: 33.2 ± 17.2
Richards (2020)^Citation23	G1: Mean (range): 66 (57–72) G2: Mean (range): 65 (50–72)	G1: 125 (51%) (F) G2: 142 (58%) (F)	Not reported	G1: ≥III: 57 (23.4) G2: ≥III: 66 (27.2)	G1: 11.1 ± 1.2 G2: 11.1 ± 1.2	Not reported	All Groups: <100 – 57%	All Groups: <20 – 76%

Notes: ^aN’s were not specified; ^†Estimated in the standard care group (G2) using repeated measures mixed effects linear regression with time from operation as a random factor, adjusted for sex. Outcomes were compared with preoperative sample concentrations: postoperative samples were taken on the first day after the operation.

Abbreviations: ASA, American Society of Anesthesiologists; CI,confidence interval; G, treatment group (as defined in Table 1 in Intervention Groups and Regimen row); IQR, interquartile range; SD, standard deviation; TSAT, transferrin saturation.

Figure 2 Risk of bias summary: authors’ judgment about risk of bias for each item for each of the 6 included studies. The symbol “+” indicates low risk of bias, “?” indicates unclear risk of bias, and “–” indicates high risk of bias.

Figure 3 Risk of bias: authors’ judgment about risk of bias presented as percentages across all 6 included studies.

Table 3 Primary Outcome Measures: Change from Baseline in Hb, Serum Ferritin, and TSAT

Study	Surgery	Surgical Setting	Change from Baseline Hb (g/dL)			Change from Baseline Serum Ferritin (μg/L), Mean (SD)			Change from Baseline TSAT (%), Mean (SD)
			Group 1	Group 2	Group 3	Group 1	Group 2	Group 3	Group 1	Group 2	Group 3
Bisbe et al (2014)^Citation15	Orthopedic	Postop	1.7 (1.2)^a	1.3 (1.0)^a	—	571 (229)^a	60 (88)^a	—	7.2 (−5.2)^a	0.7 (−5)^a	—
Bernabeu-Wittel et al (2016)^Citation16	Hip fracture	Preop	1.38 (0.72)^b	1.53 (0.56)^b	0.88 (0.43)^b	317 (140)^b	288 (110)^b	−4 (−10)^b	—	—	—
Froessler et al (2016)^Citation17	Abdominal	Periop	1.9 (1.4)^c	0.9 (1.4)^c	—	229 (131–498)^d	62 (24–146)^d	—	15 (13–16)^d	5 (0–3)^d	—
Khalafallah (2016)^Citation7	Orthopedic, abdominal, ENT, plastic, gynecologic, urologic	Postop	3.2 (0.16)^e	2.81 (0.18)^e	—	114 (73.2)^e	−133 (−41.1)^e	—	20 (1.1)^e	13.3 (1.4)^e	—
Keeler et al (2017)^Citation18	Colorectal cancer	Preop	1.55 (0.93–2.58)^f	0.50 (−0.13–1.33)^f	—	558 (330–1085)^f	27.5 (17–51.5)^f	—	19 (16–29)^f	9 (5–14)^f	—
Kim et al (2017)^Citation19	Gastrectomy (cancer)	Preop	3.3^g	1.6^g	—	233.3^h	53.4^h	—	35.0^h	19.3^h	—
Lee et al (2019)^Citation20	Benign uterine diseases	Preop	2.2 (0.3)	1.9 (0.2)	—	—	—	—	—	—	—
Padmanabhan et al (2019)^Citation21	Cardiac	Preop	1.3 (0.9)^i	4.4 (0.9)^i	—	313 [228, 496]^j	5.5 [−1.4, 19.4]^j	—	—^k	—^k	—
Park et al (2019)^Citation22	Unilateral TKA or THA	Intraop	0.3 (1.00)^l	−0.8 (0.78)^l	—	1157.5 (412.3)^m	83.8 (52.5)^m	—	8.7 (10.4)^m	−19.5 (−5.2)^m	—
Richards et al (2020)^Citation23	Open abdominal surgery	Preop	4.7 (2.7–6.8)^n; 10.7 (8–13.8)°; 7.3 (3.6–11.1)^p	—	—	—	—	—	—	—	—

Notes: Treatment groups are defined in Table 1 in Intervention Groups and Regimen row; ^aValues are increase in mean (SD) from postoperative day 4 to postoperative day 30; ^bValues are increase in mean (SD) from baseline to 60 days postdischarge (change in SD from baseline to 60 days postdischarge); ^cValues are increase in mean (SD) from discharge to postoperative week 4; ^dValues are increase in median (first quartile–third quartile) from randomization to postoperative week 4. ^eValues are increase in mean (SD) from postoperative day 1 to postoperative week 12; ^fValues are increase in median (first quartile–third quartile) from baseline to day of surgery; ^gValues are increase in median from baseline to postoperative week 12; ^hValues are increase in mean from baseline to postoperative week 12; ⁱValues are increase in mean (SD) between enrolment and surgical admission; ^jValues are increase in median (interquartile range) between enrolment and surgical admission; ^kStatistical difference reported in favor of FCM (P=0.001); no data provided; ^lValues are increase in mean (SD) from baseline to postoperative day 30; ^mValues are increase in median (interquartile range) from baseline to postoperative day 5; ⁿValues are increase in mean (95% CI) from baseline to time of surgery; ^oValues are increase in mean (95% CI) from baseline to 8 weeks following intervention; ^pValues are increase in mean (95% CI) from baseline to 6 months following intervention.

Abbreviations: ENT, ear, nose, and throat; FCM, ferric carboxymaltose; Hb, hemoglobin; THA, total hip arthroplasty; TKA, total knee arthroplasty; TSAT, transferrin saturation.

Table 4 Secondary Outcome Measures: ABT, AEs, and Mortality

Study	Surgery	Surgical Setting	Proportion of Patients Receiving an ABT, n/N (%)			Proportion of Patients Experiencing AEs, n/N (%)			Postoperative Mortality, n/N (%)
			Group 1	Group 2	Group 3	Group 1	Group 2	Group 3	Group 1	Group 2	Group 3
Bisbe (2014)^Citation15	Orthopedic	Postop	3/59 (5.1)	2/62 (3.2)	—	20/59 (33.9)	20/62 (32.3)	—	—	—	—
Bernabeu-Wittel (2016)^Citation16	Hip fracture	Preop	53/103 (51.5)	52/100 (52.0)	54/100 (54)	—	—	—	12/103 (11.7)	12/100 (12.0)	10/100 (10.0)
Froessler (2016)^Citation17	Abdominal	Periop	5/40 (12.5)	10/32 (31.3)	—	—	—	—	1/40 (2.5)	0/32 (0)	—
Khalafallah (2016)^Citation7	Orthopedic, abdominal, ENT, plastic, gynecologic, urologic	Postop	1/103 (0.1)	5/98 (5.1)	—	—	—	—	—	—	—
Keeler (2017)^Citation18	Colorectal cancer	Preop	6/55 (10.9)	6/61 (9.8)	—	—	—	—	5/55 (9.1)	4/61 (6.6)	—
Kim (2017)^Citation19	Gastrectomy (cancer)	Preop	3/218 (1.4)	4/219 (1.8)	—	15/222 (6.8)	1/223 (0.4)	—	—	—	—
Lee et al (2019)^Citation20	Benign uterine diseases	Preop	0/52	0/49	—	0/52	0/49	—	0/52	0/49	—
Padmanabhan et al (2019)^Citation21	Cardiac	Preop	16/20 (80)	12/20 (60)	—	0/20	3/20	—	1/20 (5) (unrelated causes)	0/29	—
Park et al (2019)^Citation22	Unilateral TKA or THA	Intraop	2/29 (6.9)	4/29 (12.8)	—	0/29	—	—	—	—	—
Richards et al (2020)^Citation23	Open abdominal surgery	Preop	68/237 (29)	67/237 (28)	—	11/237 (5)	5/237 (2)	—	12/238 (5)	10/236 (4)	—

Note: Treatment groups are defined in Table 1.

Abbreviations: ABT, allogenic blood transfusion; AE, adverse event; ENT, ear, nose, and throat; FCM, ferric carboxymaltose; IV, intravenous; THA, total hip arthroplasty; TKA, total knee arthroplasty.

Table 5 Secondary Endpoint Outcomes: Hospital Length of Stay and QOL

Study	Surgery	Surgical Setting	Length of Hospital Stay, d			Instrument	Validated QOL Measure
			Group 1	Group 2	Group 3		Group 1	Group 2	Group 3
Bisbe (2014)^Citation15	Orthopedic	Postop	7.9 (1.7)^a	7.6 (0.9)^a	—	EQ-5D Barthel questionnaire	Total EQ-5D increase: 0.6 (0.9)^b Barthel increase: 92.6 (6.2)^b	Total EQ-5D increase: 0.6 (0.17)^b Barthel increase: 93.0 (8)^b	—
Bernabeu-Wittel (2016)^Citation16	Hip fracture	Preop	7 (5–10)^c	8 (6–11)^c	8 (6–10)^c	SF-36v2	Physical decrease: 4.4 (14)^d Mental decrease: 2.7 (20)^d	Physical decrease: 7.4 (11)^d Mental decrease: 1.2 (13)^d	Physical: 4.5 (15)^d Mental: −2 (20)^d
Froessler (2016)^Citation17	Abdominal surgery	Periop	6 (1, 19)^e	9 (1, 23)^e	—	SF-36	SF-26 decrease (pre-post): 8 (18)^f	Decrease (preop to postop): 6 (17)^f	—
Khalafallah (2016)^Citation7	Orthopedic, abdominal, ENT, plastic, gynecologic, urologic	Postop	7.8 (10.3)^a	11.6 (15.6)^a	—	SF-36	SF-36 increase: 13.4^g Physical increase: 13.4^g Mental increase: 13.3^g	SF-36 increase: 9.1^g Physical increase: 7.9^g Mental increase: 9.9^g	—
Keeler (2017)^Citation18	Colorectal cancer	Preop	6 (5–10)^c	6 (4–9)^c	—	—	—	—	—
Kim (2017)^Citation19	Gastrectomy (cancer)	Preop	10.7 (7.9)^a	10.9 (13.8)^a	—	EORTC QLQ-C30v3 QLQ-STO22	Fatigue (week 3): 30.0 (26.8, 33.1)^h Dyspnea (week 12): 9.5 (7.2, 11.8)^h	Fatigue (week 3): 34.6 (31.3, 37.9)^h Dyspnea (week 12) 14.2 (11.3, 17.1)^h	—
Lee et al (2019)^Citation20	Benign uterine diseases	Preop	—	—	—	SF-12	PCS (visit 3 vs visit 1): 3.7 ± 10.0 MCS (visit 3 vs visit 1): 4.5 ± 8.0	PCS (visit 3 vs visit 1): 2.3 ± 8.0 MCS (visit 3 vs visit 1): 1.6 ± 6.5	—
Padmanabhan et al (2019)^Citation21	Cardiac	Preop	7 (6–12)^c	9 (6–14))^c	—	EQ-5D SF-36	—	—	—
Park et al (2019)^Citation22	Unilateral TKA or THA	Intraop	—	—	—	—	—	—	—
Richards et al (2020)^Citation23	Open abdominal surgery	Preop	9 (7–14)^c	9 (5–14)^c	—	EQ-5D-5L MFI	EQ-5D-5L Utility score: 10-day: 0.80 (0.20); 8-week: 0.79 (0.20); 6-month: 0.82 (0.22) EQ-5D-5L Health score: 10-day: 70.6 (20.5); 8-week: 70.7 (19.4); 6-month: 75.0 (18.4) MFI: 10-day: 53.2 (18.4); 8-week: 52.9 (17.1); 6-month: 48.8 (18.9)	EQ-5D-5L Utility score: 10-day: 0.81 (0.21); 8-week: 0.77 (0.21); 6-month: 0.82 (0.21) EQ-5D-5L Health score: 10-day: 73.8 (19.6); 8-week: 71.1 (19.5); 6-month: 76.2 (19.2) MFI: 10-day: 50.5 (18.9); 8-week: 53.9 (17.7); 6-month: 47.4 (19.1)	—

Notes: Treatment groups are defined in Table 1; ^aValues are mean (standard deviation); ^bValues are the mean (standard deviation) increase from before surgery to postoperative day 30; ^cValues are median (first quartile–third quartile); ^dValues are mean (standard deviation) decrease from baseline to 60 days postdischarge; ^eValues are median (minimum, maximum); ^fValues are mean (standard deviation) increase from presurgery/intervention to postoperative week 4; ^gValues are the increase from postoperative day 1 to postoperative week 12; ^hValues are mean (95% confidence interval).

Abbreviations: ED-5Q, EuroQol 5-dimension quality of life scale; EORTC, European Organization for Research and Treatment of Cancer; FCM, ferric carboxymaltose; IV, intravenous; MCS, mental health composite scores; MFI, Multidimensional Fatigue Inventory; PCS, physical health composite scores; QLQ-C30v3, Quality of Life Questionnaire-Core 30 version 3; QLQ-STO22, Quality of Life Questionnaire-Stomach; QOL, quality of life; SF-12, Short Form-12 Health Survey; SF-36, 36-Item Short Form Survey; THA, total hip arthroplasty; TKA, total knee arthroplasty.

Table 6 Quality of Evidence (GRADE) Assessment

Outcome	Studies	Risk of Bias	Inconsistency	Indirectness	Imprecision	Publication Bias	Other Considerations	Quality of Evidence
Absolute or relative change in hemoglobin concentration
Rationale	10/10	8/10 RCTs inadequately blinded outcome assessments; 8/10 RCTs inadequately blinded participants and personnel. The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results.	Positive effect demonstrated in 10/10 RCTs. Both clinical and methodologic heterogeneity are high. Therefore, some inconsistency exists.	Secondary endpoint in 6/10 studies (primary in 4/10) and therefore may not be powered appropriately. The intervention was given preop. in 7/10 studies, postop. in 3/10, and intraop. in 1/10. Difficult to make direct comparisons because of difference in comparators and populations.	1 study terminated early; no CIs reported for 6/10 studies; wide CI/IQR for 5/10 studies. Insufficient sample sizes (<400 total) in 8/10 studies.	Undetected	There are potentially many subgroups in this analysis (eg, type of surgery, severity of condition, age) that may have affected findings that cannot be considered because of small sample sizes.	We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of the effect. There generally appears to be a consistent effect with low risk of AEs. Most articles report positive outlook on use in future similar patient populations. Patients appear neutral to positive.
Absolute or relative change in iron stores (serum ferritin)
Rationale	8/10 (Not Lee or Richards)	7/8 RCTs inadequately blinded outcome assessments; 7/8 RCTs inadequately blinded participants and personnel. The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results.	Positive effect demonstrated in 8/8 RCTs. Both clinical and methodologic heterogeneity are high. Direction appears consistent but variation appears large and therefore inconsistent.	Secondary endpoint in 6/8 studies (primary in 1 study) and therefore not sufficiently powered. Difficult to make direct comparisons because of differences in comparators and populations.	1 study terminated early; no CI reported for 4/8; wide CI/IQR range for 4/4 studies. Insufficient sample sizes (<400 total) in 8/8 studies.	Undetected	Selective reporting in 2/8 studies (TSAT/ferritin endpoint not prespecified).	We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of the effect
Absolute or relative change in iron stores (TSAT)
Rationale	6/10 (Not Lee,Bernabeau-Wittlel, Padmanabhan, or Richards)	5/6 RCTs inadequately blinded outcome assessments; 6/6 RCTs inadequately blinded participants and personnel. The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results	Positive effect demonstrated in 6/6 RCTs. Both clinical and methodologic heterogeneity are high. Direction appears consistent but variation appears large and therefore inconsistent.	Secondary endpoint in 5/6 studies (primary in 1 study) and therefore not sufficiently powered. Difficult to make direct comparisons because of difference in comparators and populations	1 study terminated early; no confidence interval reported for 3/6; wide CI/IQR for 3/3 studies. Insufficient sample sizes in each study (<400 total).	Undetected	Selective reporting in 2/6 studies (TSAT/ferritin endpoint not prespecified).	We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of the effect.
Proportion of participants who received a perioperative ABT
Rationale	10/10	5/10 RCTs inadequately blinded outcome assessments; 7/10 RCTs inadequately blinded participants; 6/10 inadequately blinded personnel. The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results.	Positive effect reported in 2/10 studies (no difference in 8/10 studies). Consistency in findings may be an artifact of the disease severity/age/complexity of the surgery. Large variations in degree to which outcome is affected.	Primary endpoint in 4/10; percentage of blood transfusions secondary endpoint in 3/10; number of transfused blood units primary endpoint (1/10); reported as an absolute number in 8/10. Difference in populations and intervention schedules may have influenced outcome.	1 study terminated early; no CI reported for 6/10; wide CI/IQR for 3/6. Uncertain if there was a large enough sample size despite a large enough number of events to calculate a precise effect estimate. Several studies had only 1 participant with the outcome of interest.	Undetected	N/A	We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of the effect. The studies in this review looked at populations who had a large range of bleed/transfusion risk perioperatively. Need to assess ABT risk and adequately power the studies to detect sufficient number of events. Event may be too rare in some cases.
Proportion of participants who experienced adverse events
Rationale	6/10 (Not Bernabeu-Wittel, Froessler, Khalafallah, Keeler,)	5/6 RCTs inadequately blinded outcome assessments; 5/6 RCTs inadequately blinded participants and personnel. The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results.	No SAE (4/6); no significant difference in safety reported for 4/6 studies.	Prespecified secondary endpoint (3/6). Safety was not assessed similarly within or between. Studies also had different comparators.	1 study terminated early. Not clear how safety was assessed.	Undetected	N/A	We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of the effect. Lack of evidence, high inconsistency in reporting, high indirectness, and high imprecision.
Postoperative mortality
Rationale	Directly reported in 6/10 studies; indirectly in 4/10 as apparently no deaths occurred during follow-up.	8/10 RCTs inadequately blinded outcome assessments; 8/10 RCTs inadequately blinded participants and personnel. The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results.	Results were not consistent; may be an artifact of severity of disease in population under study.	Not a surrogate outcome; prespecified secondary endpoint (2/6); primary endpoint composite (1/6) all-cause (2/6); 30-day (1/6). Death is dichotomous; however, the assumption in 4/10 studies is that no one had died.	Insufficient number of events to make a conclusion. Not a primary outcome in 9/10 studies, so likely underpowered to observe the true effect.	Undetected	N/A	We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of the effect.
Length of hospital stay
Rationale	8/10 (Not Lee or Parks)	4/10 RCTs inadequately blinded outcome assessments; 5/8 RCTs inadequately blinded participants and personnel. The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results.	Both clinical and methodologic heterogeneity are high. Heterogeneity among healthcare systems may also have influenced this outcome. Inconsistent results.	Not a surrogate outcome; prespecified secondary endpoint in 4/10 studies.	Wide CIs present in most studies.	Undetected	N/A	We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of the effect.
Any validated measure of quality of life
Rationale	7/10 (Not Padmanabhan, Keeler, or Parks)	6/7 RCTs inadequately blinded outcome assessments; 5/7 RCTs inadequately blinded participants and personnel. The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results.	Both clinical and methodologic heterogeneity are high. Results reported inconsistently owing to different instruments. No difference of effect is consistent.	Surrogate marker; outcome not assessed similarly within and among studies, yielding very indirect comparisons.	Wide CIs present in most studies. Extreme imprecision present. Concentrated on certain subscores in some studies.	Undetected.	Selective reporting was present for this outcome in a few studies.	We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of the effect.

Abbreviations: AE, adverse event; CI, confidence interval; IQR, interquartile range; RCT, randomized clinical trial; SAE, serious adverse event; TSAT, transferrin saturation.

Page MJ, Moher D, Bossuyt PM, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021;372:n160. doi:10.1136/bmj.n71

 Google Scholar

Bisbe E, Molto L, Arroyo R, Muniesa JM, Tejero M. Randomized trial comparing ferric carboxymaltose vs oral ferrous glycine sulphate for postoperative anaemia after total knee arthroplasty. Br J Anaesth. 2014;113(3):402–409. doi:10.1093/bja/aeu092

 Web of Science ®Google Scholar

Bernabeu-Wittel M, Romero M, Ollero-Baturone M, et al. Ferric carboxymaltose with or without erythropoietin in anemic patients with hip fracture: a randomized clinical trial. Transfusion. 2016;56(9):2199–2211. doi:10.1111/trf.13624

 Web of Science ®Google Scholar

Froessler B, Palm P, Weber I, Hodyl NA, Singh R, Murphy EM. The important role for intravenous iron in perioperative patient blood management in major abdominal surgery: a randomized controlled trial. Ann Surg. 2016;264(1):41–46. doi:10.1097/SLA.0000000000001646

 PubMed Web of Science ®Google Scholar

Khalafallah AA, Yan C, Al-Badri R, et al. Intravenous ferric carboxymaltose versus standard care in the management of postoperative anaemia: a prospective, open-label, randomised controlled trial. Lancet Haematol. 2016;3(9):e415–425. doi:10.1016/S2352-3026(16)30078-3

 Web of Science ®Google Scholar

Keeler BD, Simpson JA, Ng O, Padmanabhan H, Brookes MJ, Acheson AG. Randomized clinical trial of preoperative oral versus intravenous iron in anaemic patients with colorectal cancer. Br J Surg. 2017;104(3):214–221. doi:10.1002/bjs.10328

 PubMed Web of Science ®Google Scholar

Kim YW, Bae JM, Park YK, et al. Effect of intravenous ferric carboxymaltose on hemoglobin response among patients with acute isovolemic anemia following gastrectomy: the FAIRY randomized clinical trial. JAMA. 2017;317(20):2097–2104. doi:10.1001/jama.2017.5703

 PubMed Web of Science ®Google Scholar

Lee S, Ryu KJ, Lee ES, Lee KH, Lee JJ, Kim T. Comparative efficacy and safety of intravenous ferric carboxymaltose and iron sucrose for the treatment of preoperative anemia in patients with menorrhagia: an open-label, multicenter, randomized study. J Obstet Gynaecol Res. 2019;45(4):858–864. doi:10.1111/jog.13893

 Web of Science ®Google Scholar

Padmanabhan H, Siau K, Nevill AM, et al. Intravenous iron does not effectively correct preoperative anaemia in cardiac surgery: a pilot randomized controlled trial. Interact Cardiovasc Thorac Surg. 2019;28(3):447–454. doi:10.1093/icvts/ivy226

 Web of Science ®Google Scholar

Park HS, Kim TY, Kim HJ, Ro YJ, Jang HY, Koh WU. The effect of intraoperative ferric carboxymaltose in joint arthroplasty patients: a randomized trial. J Clin Med. 2019;8(10):1674. doi:10.3390/jcm8101674

 Web of Science ®Google Scholar

Richards T, Baikady RR, Clevenger B, et al. Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial [published online ahead of print, 2020 Sep 4]. Lancet. 2020;396(10259):1353–1361. doi:10.1016/S0140-6736(20)31539-7

 Web of Science ®Google Scholar