J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website https://www.thejh.org

Review

Volume 9, Number 4, December 2020, pages 97-108

The Impact of Preoperative Intravenous Iron Therapy on Perioperative Outcomes in Cardiac Surgery: A Systematic Review

**Table 1.** Study Characteristics
Author (location)	Cladellas et al, 2012 [32] (Spain)	Urena et al, 2017 [34] (Canada)	Johansson et al, 2015 [36] (Denmark)	Padmanabhan et al, 2018 [35] (UK)	Garrido-Martin et al, 2012 [33] (Spain)	Spahn et al, 2019 [37] (Switzerland)
^aWHO criteria (Hb < 13.0 g/dL in men or < 12.0 g/dL in women). ^bIV rhEPO at 500 IU/kg/day every week for 4 weeks and the fifth dose 48 h before VR with each session receiving IV iron sucrose (weight-based dosing). ^cTwo weight-based doses of subcutaneous EPO (0.75 µg/kg darbepoetin alfa). AF: atrial fibrillation; AKI: acute kidney injury; ARF: acute renal failure; CABG: coronary artery bypass grafting; CKMB: creatinine kinase-MB; CPB: cardiopulmonary bypass; CVA: cerebrovascular accident; ECG: electrocardiogram; EPO: erythropoietin; Hb: hemoglobin; HD: hemodialysis; HF: heart failure; IRF: immature reticulocyte fraction; LOS: length of stay; MCV: mean corpuscular volume; MI: myocardial infarction; PO: per os; QOL: quality of life; TAVI: trans-aortic valve implantation; TSAT: transferrin saturation; VR: valve replacement; pre-op: preoperatively; re-op: re-operation; BID: twice a day.
Design	Single center non-blinded non-randomized prospective cohort with historical control	Single center randomized double-blind prospective cohort	Single center randomized double-blind prospective cohort	Single center non-blinded randomized prospective cohort	Single center randomized double-blind prospective cohort	Single center randomized, double-blind prospective cohort
Population	Mean age (years)	72	81	65	74	65	68
Anemia	Yes^a	Yes^a	No^a	Yes^a	No	Yes^a
Surgery type	VR	VR, TAVI	CABG, VR	CABG, VR	CABG, VR	CABG, VR
N	134	100	60	50	210	484
Intervention	IV iron	Iron sucrose	Iron sucrose	Iron isomaltose	Ferric carboxymaltose	Iron sucrose	Ferric carboxymaltose
Dose	200 mg weekly × 5 doses	200 mg weekly × 2 doses	1,000 mg × 1 dose	1,000 - 2,000 mg, 1 - 2 doses	100 mg × 3 doses	1,000 mg × 1 dose
Treatment duration	4 weeks (once per week plus 1 dose 48 h pre-op)	2 weeks (10 days, 1 day)	1 day pre-op	3 - 8 weeks	1 week	1 day pre-op
EPO	Yes^b	Yes^c	No	No	No	Yes
Comparator	Historic observation	Placebo	Placebo	PO Fe fumarate (200 mg) BID	PO iron fumarate (105 mg) or placebo	Placebo
Outcomes	Blood	Hb measured baseline, at the start of surgery, initiation of CPB, every 15 min while on CPB, and at the end of VR	Hb 1 day before and within 24 h of hospital discharge	Hb, ferritin, iron, TSAT, reticulocyte, % anemic	Hb, iron, ferritin, transferrin, C-reactive protein, total iron binding capacity, EPO, achieve > 1.5 g/dL measured at least 3 weeks prior to surgery and again on the day of surgery	Hb, IRF, MCV, ferritin	Hb, reticulocyte, C-reactive protein, calculated RBC loss
Transfusion	Units per patient, number of patients transfused	Units transfused, number of patients transfused within 30 days	Units transfused, number of patients transfused	Units transfused, number of patients transfused	Units/patient, number of patients transfused	Number of units transfused
Safety	Yes	Yes	Yes	Yes	Yes	Yes
Mortality	Yes	Yes (30 day)	Yes	Yes	No	Yes
Other	LOS, HF, CVA, MI, ARF, tamponade, re-op, infection, prolonged ventilation, thrombosis or failure of valve, endocarditis	LOS, peak troponin and CKMB, rates of MI, stroke, AKI, need for HD, and new onset AF	Safety (adverse events, vital signs, ECG, s-phosphate and hematology and biochemistry parameters)	LOS, QOL, AKI, AF, infection	LOS	LOS, infection, CVA, MI, AF, thrombosis, product acquisition costs, duration of mechanical ventilation

Table 1. Study Characteristics

Author (location)

Cladellas et al, 2012 [32] (Spain)

Urena et al, 2017 [34] (Canada)

Johansson et al, 2015 [36] (Denmark)

Padmanabhan et al, 2018 [35] (UK)

Garrido-Martin et al, 2012 [33] (Spain)

Spahn et al, 2019 [37] (Switzerland)

^aWHO criteria (Hb < 13.0 g/dL in men or < 12.0 g/dL in women). ^bIV rhEPO at 500 IU/kg/day every week for 4 weeks and the fifth dose 48 h before VR with each session receiving IV iron sucrose (weight-based dosing). ^cTwo weight-based doses of subcutaneous EPO (0.75 µg/kg darbepoetin alfa). AF: atrial fibrillation; AKI: acute kidney injury; ARF: acute renal failure; CABG: coronary artery bypass grafting; CKMB: creatinine kinase-MB; CPB: cardiopulmonary bypass; CVA: cerebrovascular accident; ECG: electrocardiogram; EPO: erythropoietin; Hb: hemoglobin; HD: hemodialysis; HF: heart failure; IRF: immature reticulocyte fraction; LOS: length of stay; MCV: mean corpuscular volume; MI: myocardial infarction; PO: per os; QOL: quality of life; TAVI: trans-aortic valve implantation; TSAT: transferrin saturation; VR: valve replacement; pre-op: preoperatively; re-op: re-operation; BID: twice a day.

Design

Single center non-blinded non-randomized prospective cohort with historical control

Single center randomized double-blind prospective cohort

Single center non-blinded randomized prospective cohort

Single center randomized double-blind prospective cohort

Single center randomized, double-blind prospective cohort

Population

Mean age (years)

Anemia

Yes^a

No^a

Yes^a

Surgery type

VR, TAVI

CABG, VR

134

100

210

484

Intervention

IV iron

Iron sucrose

Iron isomaltose

Ferric carboxymaltose

Iron sucrose

Ferric carboxymaltose

Dose

200 mg weekly × 5 doses

200 mg weekly × 2 doses

1,000 mg × 1 dose

1,000 - 2,000 mg, 1 - 2 doses

100 mg × 3 doses

1,000 mg × 1 dose

Treatment duration

4 weeks (once per week plus 1 dose 48 h pre-op)

2 weeks (10 days, 1 day)

1 day pre-op

3 - 8 weeks

1 week

1 day pre-op

EPO

Yes^b

Yes^c

Yes

Comparator

Historic observation

Placebo

PO Fe fumarate (200 mg) BID

PO iron fumarate (105 mg) or placebo

Placebo

Outcomes

Blood

Hb measured baseline, at the start of surgery, initiation of CPB, every 15 min while on CPB, and at the end of VR

Hb 1 day before and within 24 h of hospital discharge

Hb, ferritin, iron, TSAT, reticulocyte, % anemic

Hb, iron, ferritin, transferrin, C-reactive protein, total iron binding capacity, EPO, achieve > 1.5 g/dL measured at least 3 weeks prior to surgery and again on the day of surgery

Hb, IRF, MCV, ferritin

Hb, reticulocyte, C-reactive protein, calculated RBC loss

Transfusion

Units per patient, number of patients transfused

Units transfused, number of patients transfused within 30 days

Units transfused, number of patients transfused

Units/patient, number of patients transfused

Number of units transfused

Safety

Yes

Mortality

Yes

Yes (30 day)

Yes

Other

LOS, HF, CVA, MI, ARF, tamponade, re-op, infection, prolonged ventilation, thrombosis or failure of valve, endocarditis

LOS, peak troponin and CKMB, rates of MI, stroke, AKI, need for HD, and new onset AF

Safety (adverse events, vital signs, ECG, s-phosphate and hematology and biochemistry parameters)

LOS, QOL, AKI, AF, infection

LOS

LOS, infection, CVA, MI, AF, thrombosis, product acquisition costs, duration of mechanical ventilation

**Table 2.** Evidence Grading With Cochrane Risk of Bias Tool
Author	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Other sources of bias	Quality
Urena et al, 2017 [34]	Low	Low	Low	Low	Low	Unclear	Low	Good
Johansson et al, 2015 [36]	Low	Low	Low	Low	Low	Unclear	Low	Good
Padmanabhan et al, 2018 [35]	Low	Low	High	High	Low	Unclear	High	Poor
Garrido-Martin et al, 2012 [33]	Low	Low	Low	Unclear	High	Unclear	Low	Good
Spahn et al, 2019 [37]	Low	Low	Low	Low	Low	Unclear	Low	Good

Table 2. Evidence Grading With Cochrane Risk of Bias Tool

Author

Random sequence generation

Allocation concealment

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data

Selective reporting

Other sources of bias

Quality

Urena et al, 2017 [34]

Low

Unclear

Low

Good

Johansson et al, 2015 [36]

Low

Unclear

Low

Good

Padmanabhan et al, 2018 [35]

Low

High

Low

Unclear

High

Poor

Garrido-Martin et al, 2012 [33]

Low

Unclear

High

Unclear

Low

Good

Spahn et al, 2019 [37]

Low

Unclear

Low

Good

**Table 3.** Evidence Grading With Newcastle-Ottawa Scale Assessment of Study Quality
Author	Selection	Comparability	Outcome	Total	Quality
Cladellas et al, 2012 [32]	3	1	2	6	Fair

Table 3. Evidence Grading With Newcastle-Ottawa Scale Assessment of Study Quality

Author

Selection

Comparability

Outcome

Total

Quality

Cladellas et al, 2012 [32]

Fair

**Table 4.** Strength of Evidence
Author	Hb	Transfusion rate	Significant AE	QOL	Infections	LOS	Mortality
^aOxford Centre for Evidence-based Medicine’s “Levels of Evidence.” https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/; ^bCincinnati Children’s Hospital Medical Center Evidence Collaboration’s, file:///Users/kellytankard/Downloads/Guideline%20Development%20Manual%20(1).pdf. AE: adverse event; Hb: hemoglobin; QOL: quality of life; LOS: length of stay.
Cladellas et al, 2012 [32]	X	X	X		X	X	X
Urena et al, 2017 [34]	X	X	X		X	X	X
Johansson et al, 2015 [36]	X	X	X		X		X
Padmanabhan et al, 2018 [35]	X	X	X	X	X	X	X
Garrido-Martin et al, 2012 [33]	X	X	X		X
Spahn et al, 2019 [37]	X	X	X		X	X	X
Summary of Level of Evidence^a	(6) 1b	(6) 1b	(6) 1b	(1) 2b	(6) 1b	(4) 1b	(5) 1b
Quality of Body of Evidence^b	Moderate	Moderate	Moderate	Low	Moderate	Moderate	Moderate

Table 4. Strength of Evidence

Author

Transfusion rate

Significant AE

QOL

Infections

LOS

Mortality

^aOxford Centre for Evidence-based Medicine’s “Levels of Evidence.” https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/; ^bCincinnati Children’s Hospital Medical Center Evidence Collaboration’s, file:///Users/kellytankard/Downloads/Guideline%20Development%20Manual%20(1).pdf. AE: adverse event; Hb: hemoglobin; QOL: quality of life; LOS: length of stay.

Cladellas et al, 2012 [32]

Urena et al, 2017 [34]

Johansson et al, 2015 [36]

Padmanabhan et al, 2018 [35]

Garrido-Martin et al, 2012 [33]

Spahn et al, 2019 [37]

Summary of Level of Evidence^a

(6) 1b

(1) 2b

(6) 1b

(4) 1b

(5) 1b

Quality of Body of Evidence^b

Moderate

Low

Moderate

**Table 5.** Hemoglobin Levels Before and After Preoperative Iron Therapy
Author	Iron	EPO	Hb	Other significant hematologic findings
P < 0.05 between groups; P < 0.05 from baseline; **P < 0.001 between groups; ^aSD not reported. EPO: erythropoietin; Hb: hemoglobin; IV: intravenous; pre-op: preoperatively; POD: postoperative day; post-op: post-operatively; TSAT: transferrin saturation; SD: standard deviation.
Cladellas et al, 2012 [32]	IV	IV	11.2 ± 1	12.6 ± 0.9*	-	-
Historic observation	Historic observation	10.9 ± 0.9	10.9 ± 0.9	-	-
Urena et al, 2017 [34]	IV iron sucrose 200 mg at days 10 and 1	Subcutaneous 0.75 µg/kg	10.7 ± 1.2	10.9 ± 1.2*	9.4 ± 1.6 (discharge)	-	No significant difference between pre-op, post-op, or discharge Hb after intervention
Placebo	Placebo	11.3 ± 1.6	11.1 ± 1.2*	9.9 ± 1.6	-
Johansson et al, 2015 [36]^a	IV	None	14.3	-	10.2 (POD 5)	12.4** (POD 28)	More non-anemic on follow-up
Placebo		14	-	10.5	11.6**
Padmanabhan et al, 2018 [35]	IV	None	8.9	9.8	-	-	Increase in ferritin, decrease in EPO, TSAT
Oral		11.1	12	-	-
Garrido-Martin et al, 2012 [33]	IV	None	14 ± 1.63	12.7 ± 1.64	11.1 ± 1.52 (POD 10)	12.7 ± 1.40 (POD 30)	Higher ferritin
Oral		13.7 ± 1.46	12.6 ± 1.70	11.0 ± 1.28	12.4 ± 1.27
Placebo		14 ± 1.35	12.8 ± 1.29	11.0 ± 1.44	12.3 ± 1.15
Spahn et al, 2019 [37]	IV	Subcutaneous 40,000 units	12.8 ± 1.5	-	9.2*** (POD 5)	9.1*** (POD 7)	Higher reticulocyte count
Placebo		12.9 ± 15	-	8.7***	8.5***

Table 5. Hemoglobin Levels Before and After Preoperative Iron Therapy

Author

Iron

EPO

Other significant hematologic findings

Baseline

Pre-op

Post-op

Follow-up

*P < 0.05 between groups; **P < 0.05 from baseline; ***P < 0.001 between groups; ^aSD not reported. EPO: erythropoietin; Hb: hemoglobin; IV: intravenous; pre-op: preoperatively; POD: postoperative day; post-op: post-operatively; TSAT: transferrin saturation; SD: standard deviation.

Cladellas et al, 2012 [32]

11.2 ± 1

12.6 ± 0.9*

Historic observation

10.9 ± 0.9

Urena et al, 2017 [34]

IV iron sucrose 200 mg at days 10 and 1

Subcutaneous 0.75 µg/kg

10.7 ± 1.2

10.9 ± 1.2*

9.4 ± 1.6 (discharge)

No significant difference between pre-op, post-op, or discharge Hb after intervention

Placebo

11.3 ± 1.6

11.1 ± 1.2*

9.9 ± 1.6

Johansson et al, 2015 [36]^a

None

14.3

10.2 (POD 5)

12.4** (POD 28)

More non-anemic on follow-up

Placebo

10.5

11.6**

Padmanabhan et al, 2018 [35]

None

8.9

9.8

Increase in ferritin, decrease in EPO, TSAT

Oral

11.1

Garrido-Martin et al, 2012 [33]

None

14 ± 1.63

12.7 ± 1.64

11.1 ± 1.52 (POD 10)

12.7 ± 1.40 (POD 30)

Higher ferritin

Oral

13.7 ± 1.46

12.6 ± 1.70

11.0 ± 1.28

12.4 ± 1.27

Placebo

14 ± 1.35

12.8 ± 1.29

11.0 ± 1.44

12.3 ± 1.15

Spahn et al, 2019 [37]

Subcutaneous 40,000 units

12.8 ± 1.5

9.2*** (POD 5)

9.1*** (POD 7)

Higher reticulocyte count

Placebo

12.9 ± 15

8.7***

8.5***

**Table 6.** Association of Iron Therapy With Transfusion Rate
Author	Intervention	Transfusion
P < 0.05 between groups; *P < 0.001 between groups. Hb: hemoglobin; IV: intravenous; IM: intramuscular; NR: not reported; EPO: Epogen; SC: subcutaneous; ICU: intensive care unit.
Cladellas et al, 2012 [32]	IV iron + IV EPO	Hb < 7 g/dL	50/75 (67)	NR
Historic observation	55/59 (93)**	NR
Urena et al, 2017 [34]	IV iron + IM EPO	Hb < 7 g/dL, Hb 7 - 8 g/dL if symptomatic	13/48 (27)	1
Placebo	13/52 (27)	2
Johansson et al, 2015 [36]	IV	NR	8/30 (27)	1
Placebo	11/30 (37)	2
Padmanabhan et al, 2018 [35]	IV	NR	16/20 (80)	1.5
Oral	12/20 (60)	2
Garrido-Martin et al, 2012 [33]	IV	Hb < 8 g/dL in coronary patients, Hb < 7 g/dL in valve surgery patients	20/54 (37)	0
Oral	27/53 (51)	1
Placebo	26/50 (50)	0.5
Spahn et al, 2019 [37]	IV + SC EPO	Hb < 7 - 8 g/dL intraoperative and ICU, Hb < 8 g/dL on wards	108/243 (44)	0
Placebo	127/241 (53)*	1

Table 6. Association of Iron Therapy With Transfusion Rate

Author

Intervention

Transfusion

Transfusion trigger

Transfusion rate, n/N (%)

Median number of units transfused

*P < 0.05 between groups; **P < 0.001 between groups. Hb: hemoglobin; IV: intravenous; IM: intramuscular; NR: not reported; EPO: Epogen; SC: subcutaneous; ICU: intensive care unit.

Cladellas et al, 2012 [32]

IV iron + IV EPO

Hb < 7 g/dL

50/75 (67)

Historic observation

55/59 (93)**

Urena et al, 2017 [34]

IV iron + IM EPO

Hb < 7 g/dL, Hb 7 - 8 g/dL if symptomatic

13/48 (27)

Placebo

13/52 (27)

Johansson et al, 2015 [36]

8/30 (27)

Placebo

11/30 (37)

Padmanabhan et al, 2018 [35]

16/20 (80)

1.5

Oral

12/20 (60)

Garrido-Martin et al, 2012 [33]

Hb < 8 g/dL in coronary patients, Hb < 7 g/dL in valve surgery patients

20/54 (37)

Oral

27/53 (51)

Placebo

26/50 (50)

0.5

Spahn et al, 2019 [37]

IV + SC EPO

Hb < 7 - 8 g/dL intraoperative and ICU, Hb < 8 g/dL on wards

108/243 (44)

Placebo

127/241 (53)*

**Table 7.** Other Outcomes
Author	Surgery	Significant AE^a	QOL	Infections	LOS, median (IQR)	Mortality
^aAs defined by study. AE: adverse event; CABG: coronary artery bypass grafting; diff: difference; IQR: interquartile range; LOS: length of stay; NR: not reported; QOL: quality of life; TAVI: trans-aortic valve implantation; VR: valve replacement.
Cladellas et al, 2012 [32]	VR	None	NR	Decreased: 8% vs. 24%, P = 0.01	Shorter: 10 days (8 - 14) vs. 15 days (10 - 27), P < 0.01	Decrease: 9% vs. 23%, P = 0.04
Urena et al, 2017 [34]	VR (TAVI)	No diff	NR	No diff	No diff	No diff
Johansson et al, 2015 [36]	CABG, VR	No diff	NR	No diff	NR	No diff
Padmanabhan et al, 2018 [35]	CABG, VR	None	No diff	No diff	No diff	No diff
Garrido-Martin et al, 2012 [33]	CABG, VR	None	NR	Not increased	NR	NR
Spahn et al, 2019 [37]	CABG, VR	No diff	NR	No diff	No diff	No diff

Table 7. Other Outcomes

Author

Surgery

Significant AE^a

QOL

Infections

LOS, median (IQR)

Mortality

^aAs defined by study. AE: adverse event; CABG: coronary artery bypass grafting; diff: difference; IQR: interquartile range; LOS: length of stay; NR: not reported; QOL: quality of life; TAVI: trans-aortic valve implantation; VR: valve replacement.

Cladellas et al, 2012 [32]

None

Decreased: 8% vs. 24%, P = 0.01

Shorter: 10 days (8 - 14) vs. 15 days (10 - 27), P < 0.01

Decrease: 9% vs. 23%, P = 0.04

Urena et al, 2017 [34]

VR (TAVI)

No diff

Johansson et al, 2015 [36]

CABG, VR

No diff

Padmanabhan et al, 2018 [35]

CABG, VR

None

No diff

Garrido-Martin et al, 2012 [33]

CABG, VR

None

Not increased

Spahn et al, 2019 [37]

CABG, VR

No diff