The role of iron in the management of chemotherapy‐induced anemia in cancer patients receiving erythropoiesis‐stimulating agents

Rahul Mhaskar; Hesborn Wao; Branko Miladinovic; Ambuj Kumar; Benjamin Djulbegovic

doi:10.1002/14651858.CD009624.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: Review authors' judgments about risk of bias in each included study.

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Figure 3

Meta‐regression: total IV iron dose and hematopoietic response

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Figure 4

Meta‐regression: baseline serum ferritin and hematopoietic response.

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Analysis 1.1

Comparison 1 Benefits and harms of iron supplementation, Outcome 1 Hematopoietic response.

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Analysis 1.2

Comparison 1 Benefits and harms of iron supplementation, Outcome 2 RBC transfusion.

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Analysis 1.3

Comparison 1 Benefits and harms of iron supplementation, Outcome 3 Time to hematopoietic response.

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Analysis 1.4

Comparison 1 Benefits and harms of iron supplementation, Outcome 4 Mean change in Hb.

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Analysis 1.5

Comparison 1 Benefits and harms of iron supplementation, Outcome 5 Quality of life.

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Analysis 1.6

Comparison 1 Benefits and harms of iron supplementation, Outcome 6 Thromboembolic events.

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Analysis 1.7

Comparison 1 Benefits and harms of iron supplementation, Outcome 7 Mean change in serum ferritin.

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Analysis 1.8

Comparison 1 Benefits and harms of iron supplementation, Outcome 8 Mean change in TSAT.

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Analysis 2.1

Comparison 2 Subgroup analyses, Outcome 1 Hematopoietic response by type of iron.

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Analysis 2.2

Comparison 2 Subgroup analyses, Outcome 2 Hematopoietic response by route of administration.

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Analysis 2.3

Comparison 2 Subgroup analyses, Outcome 3 Hematopoietic response by type of ESA.

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Analysis 2.4

Comparison 2 Subgroup analyses, Outcome 4 Time to hematopoietic response by route of administration.

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Analysis 2.5

Comparison 2 Subgroup analyses, Outcome 5 Time to hematopoietic response by type of iron.

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Analysis 2.6

Comparison 2 Subgroup analyses, Outcome 6 Time to hematopoietic response by type of ESA.

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Analysis 2.7

Comparison 2 Subgroup analyses, Outcome 7 Mean change in Hb by route of administration.

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Analysis 2.8

Comparison 2 Subgroup analyses, Outcome 8 Mean change in Hb by type of iron.

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Analysis 2.9

Comparison 2 Subgroup analyses, Outcome 9 Mean change in Hb by type of ESA.

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Analysis 2.10

Comparison 2 Subgroup analyses, Outcome 10 Mean change in serum ferritin by route of administration.

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Analysis 2.11

Comparison 2 Subgroup analyses, Outcome 11 Mean change in serum ferritin by type of iron.

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Analysis 2.12

Comparison 2 Subgroup analyses, Outcome 12 Mean change in serum ferritin by type of ESA.

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Analysis 2.13

Comparison 2 Subgroup analyses, Outcome 13 Mean change in TSAT by route of administration.

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Analysis 2.14

Comparison 2 Subgroup analyses, Outcome 14 Mean change in TSAT by type of iron.

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Analysis 2.15

Comparison 2 Subgroup analyses, Outcome 15 Mean change in TSAT by type of ESA.

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Analysis 3.1

Comparison 3 Sensitivity analyses, Outcome 1 Random sequence generation.

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Analysis 3.2

Comparison 3 Sensitivity analyses, Outcome 2 Allocation concealment.

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Analysis 3.3

Comparison 3 Sensitivity analyses, Outcome 3 Blinding.

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Analysis 3.4

Comparison 3 Sensitivity analyses, Outcome 4 Incomplete outcome data.

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Analysis 3.5

Comparison 3 Sensitivity analyses, Outcome 5 Selective reporting.

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Analysis 3.6

Comparison 3 Sensitivity analyses, Outcome 6 Other bias.

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Analysis 3.7

Comparison 3 Sensitivity analyses, Outcome 7 Hematopoietic response by definition(s).

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Summary of findings for the main comparison. Benefits and harms of iron supplementation for chemotherapy‐induced anemia

Benefits and harms of iron supplementation for chemotherapy‐induced anemia
Patient or population: people diagnosed with chemotherapy‐induced anemia Settings: in‐hospital/outpatient Intervention: iron supplementation to erythropoiesis‐stimulating agents or iron alone Comparison: erythropoiesis‐stimulating agents alone
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Benefits and harms of iron supplementation
Overall survival	None of the included studies reported data on overall survival
Hematopoietic response	Study population		RR 1.17 (1.09 to 1.26)	1712 (7 studies, 11 comparisons)	⊕⊕⊕⊕ high
	632 per 1000	740 per 1000 (689 to 796)
	Moderate##
	574 per 1000	672 per 1000 (626 to 723)
Red blood cell transfusion	Study population		RR 0.74 (0.6 to 0.92)	1719 (7 studies, 11 comparisons)	⊕⊕⊕⊝ moderate¹
	195 per 1000	144 per 1000 (117 to 179)
	Moderate##
	167 per 1000	124 per 1000 (100 to 154)
Median time to hematopoietic response	Not applicable#		HR 0.93 (0.67 to 1.28)	1042 (5 studies, 7 comparisons)	⊕⊕⊝⊝ low^1,2
Mean change in hemoglobin (better indicated by higher values)	The mean change in hemoglobin in the intervention groups was 0.48 higher (0.10 higher to 0.86 higher)		MD 0.48 (0.10 to 0.86)	827 (3 studies, 7 comparisons)	⊕⊕⊝⊝ low^1,3
Quality of life (better indicated by higher values)	The mean quality of life in the intervention groups was 0.01 standard deviations higher (0.10 lower to 0.12 higher)		SMD 0.01 (‐0.10 to 0.12)	1124 (3 studies, 4 comparisons)	⊕⊕⊕⊕ high⁴
Thromboembolic events	Study population		RR 0.95 (0.54 to 1.65)	783 (3 studies)	⊕⊕⊕⊝ moderate¹
	62 per 1000	58 per 1000 (33 to 102)
	Moderate##
	62 per 1000	59 per 1000 (33 to 102)
Treatment‐related mortality	Not applicable**		Zero events**	997 (4 studies, 6 comparisons)	⊕⊕⊕⊕ high⁵
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; HR: Hazard ratio; MD: Mean difference;RR: Risk ratio; SMD: Standardized mean difference
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded the quality of evidence by one level due to imprecision (the pooled estimate had wider confidence intervals). ²We noticed substantial heterogeneity among these studies. However, the type of iron used explained the presence of heterogeneity. Nonetheless, we downgraded the quality of evidence by one for the observed inconsistency. ³We noticed substantial heterogeneity among these studies. However, the route of iron administration (oral versus intravenous) and type of iron used explained the presence of heterogeneity. Nonetheless, we downgraded the quality of evidence by one for the observed inconsistency. ⁴We did not observe statistically significant heterogeneity among the included studies for the outcome of quality of life (I² = 0%, P = 0.54). However, it is important to note that quality of life data were reported in four studies (Auerbach 2004a; Bastit 2008; Steensma 2011a; Auerbach 2010) but were extractable from only three studies (Bastit 2008; Steensma 2011a; Auerbach 2010). The studies by Bastit et al, (Bastit 2008), and Auerbach et al, (Auerbach 2010), used the Functional Assessment of Cancer Therapy‐Fatigue scale, while the study by Steensma et al, (Steensma 2011a), used the Functional Assessment of Cancer Therapy‐Anemia scale for assessment of quality of life. Owing to the variation in the scales used, the data from these three studies were converted to the standardized mean difference and then pooled. ⁵Four studies reported data on treatment‐related mortality. **Due to zero events we were not able to conduct meta‐analysis of these data. #Data were available as median and range, and hence were converted to log hazard ratio using the cumulative hazard log‐log transform method. ##The moderate control risk was calculated via GRADEpro software based on clinical experience of the review authors working in the field of hematological disorders.

Summary of findings for the main comparison. Benefits and harms of iron supplementation for chemotherapy‐induced anemia

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Table 1. Adverse events

Study ID	Morbidities	Rx group 1 N (%)	Rx group 2 N (%)	Rx group 3 N (%)	Treatment‐related mortality
Auerbach 2004	Participants with any AEs TDI group: delayed arthralgia/myalgia syndrome (2 events, grade 1) or acute hypersensitivity reaction (1 event). The acute hypersensitivity reaction occurred with a test dose (iron dextran as Dexferrum) and precluded further therapy. This event resolved completely with no residual effects. Bolus group: 8% (3/37) of participants experienced the following adverse events: delayed arthralgia/myalgia syndrome (1 event, grade 2), fatigue (1 event), or shortness of breath (1 event). Oral iron group: 2% (1/43) of participants experienced nausea (1 event).	ESAs + TDI iron N = 41	ESAs + bolus iron N = 37	ESAs + oral iron N = 43	Zero events
Auerbach 2004		3 (7)	3 (8)	1 (2)	Zero events
Auerbach 2010	‐	‐	ESAs + IV iron N = 117	ESAs alone N = 121	Zero events
	Participants with any AEs	‐	104 (89)	110 (91)
	Participants with serious AEs	‐	41 (35)	45 (37)
	Participants with treatment‐related AEs	‐	14 (12)	0 (0)
	Participants with serious treatment‐related AEs	‐	3 (3)^a	0 (0)
	Participants with AEs leading to study discontinuation	‐	12 (10)	14 (12)
	Cardiovascular and thromboembolic events	‐	18 (15)	19 (16)
	Embolism/thrombosis	‐	8 (7)	10 (8)
	Arrhythmias	‐	9 (8)	7 (6)
	Congestive heart failure	‐	3 (3)	1 (1)
	Myocardial infarction/artery disorders	‐	2 (2)	2 (2)
	Cerebrovascular accident	‐	1 (1)	0 (0)
	Deaths on study (any reason)^b	‐	8 (7)	13 (11)
Bastit 2008	‐	‐	ESAs + IV iron N = 203	ESAs alone N = 193	Not reported
	No. of participants reporting specific AEs	‐	21 (10)	26 (13)
	Embolism/thrombosis, arterial and venous	‐	12 (6)	12 (6)
	Myocardial infarction, ischemic and coronary artery disease	‐	3 (1)	1 (1)
	Hypertension	‐	2 (1)	5 (3)
	Congestive heart failure	‐	1 (0)	3 (2)
	Cerebrovascular accident	‐	0 (0)	0 (0)
	Deaths on study (any reason)	‐	21 (10)	15 (8)
Beguin 2008	Data are not reported. Authors state that there was no difference in rates of thromboembolic events or other complications among the groups				Not reported
Bellet 2007	A total of 375 participants were enrolled in this phase III RCT. However, the number of participants randomized to each study arm is not reported. Three serious but non‐life‐threatening iron sucrose‐related AEs were observed, including 1 case of significant, transient hypotension in a female weighing 50 kg	‐	IV iron + ESAs	ESAs alone	Not reported
Henry 2007^c,d	‐	‐	ESAs + IV iron N = 63	ESAs + oral iron N = 61	Not reported
	Constipation	‐	2 (3.2)	11 (18)
	Nausea	‐	2 (3.2)	3 (4.9)
	Dyspepsia	‐	1 (1.6)	3 (4.9)
	Asthenia	‐	1 (1.6)	2 (3.3)
	Anorexia	‐	0	2 (3.3)
	Abdominal pain	‐	0	2 (3.3)
	Diarrhea	‐	1 (1.6)	0
	Hypotension	‐	1 (1.6)	0
	Vasodilation	‐	1 (1.6)	0
	Angina pectoris	‐	1 (1.6)	0
	Tremor	‐	1 (1.6)	0
	Pain at injection site	‐	1 (1.6)	0
	Vomiting	‐	0	1 (1.6)
	Back pain	‐	0	1 (1.6)
	Dehydration	‐	0	1 (1.6)
	Dizziness	‐	0	1 (1.6)
	Taste perversion	‐	0	1 (1.6)
	Melena	‐	0	1 (1.6)
	Tinnitus	‐	0	1 (1.6)
Pedrazzoli 2011^e	‐	‐	ESAs + IV iron N = 73	ESAs only N = 76	Zero events
	Participants with AEs	‐	55 (75.3)	49 (64.5)
	Participants with serious AEs	‐	8 (11)	10 (13.2)
	Participants with treatment‐related AEs	‐	7 (9.6)	6 (7.9)
	Vascular/thromboembolic events	‐	3 (4.1)	2 (2.6)
	Fatal AEs: all	‐	4 (5.5)	3 (3.9)
	Fatal AEs: treatment related	‐	0 (0)	0 (0)
Steensma 2011^f	Worst toxicity reported (toxicities were graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events)	ESAs + IV iron N = 164	ESAs + oral iron N = 162	ESAs + placebo N = 163	Zero events
	None	12 (7)	15 (9)	22 (13)
	Mild	28 (17)	40 (25)	33 (20)
	Moderate	35 (21)	35 (22)	33 (20)
	Severe	52 (32)	42 (26)	49 (30)
	Life‐threatening	29 (18)	24 (15)	23 (14)
	Lethal (includes participants who died while on study regardless of causality)	8 (5)	6 (4)	3 (2)
^aEpisodes of transient anaphylactoid reactions occurred in two participants soon after initiating IV iron, but these participants recovered uneventfully without hospitalization; one participant in this group had enlarged uvula, lip swelling, and dyspnea (symptoms resolved). ^bDeaths on study or within 30 days after the last dose of study drug. ^cParticipants may have experienced more than one AE. ^dSix participants discontinued the study due to drug‐related AEs (sodium ferric gluconate complex, N = 2 (one angina, one nausea); oral iron, N = 4 (all gastrointestinal)) ^eSeven participants, four on DA/iron and three on DA only, died during the study or within four weeks after the last administered dose of DA. Deaths were ascribed to disease progression, two cases in each group; and respiratory complications, one in the DA‐only group (infection), two in the DA/iron group (bleeding in one, acute respiratory distress syndrome in one) not related to study drugs administration. ^f7% (95% CI 3% to 12%) of participants in the IV iron arm discontinued study as a result of AEs versus 3% (95% CI 1% to 7%) for oral iron and 5% (95% CI 2% to 9%) for oral placebo. Study authors also stated that no individual AE was significantly more common in the IV iron arm compared with the other arms; instead, the overall difference was a result of small differences in several uncommon AEs, including dyspnea, back pain, and hypotension, which may have been caused by premedication rather than the IV iron product itself. Other AEs associated with IV iron in past studies, including myalgia, arthralgia, abdominal pain, pruritus, rash, nausea, vomiting, or fever, were not more common than with oral placebo or oral iron in this study. AE = adverse event CI = confidence interval DA = darbepoietin ESA = erythropoiesis‐stimulating agent IV = intravenous RCT = randomized controlled trial TDI = total dose infusion

Table 1. Adverse events

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Comparison 1. Benefits and harms of iron supplementation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hematopoietic response Show forest plot	11	1712	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]

2 RBC transfusion Show forest plot	11	1719	Risk Ratio (IV, Random, 95% CI)	0.74 [0.60, 0.92]

3 Time to hematopoietic response Show forest plot	7	1042	Hazard Ratio (Random, 95% CI)	0.93 [0.67, 1.28]

4 Mean change in Hb Show forest plot	7	827	Mean Difference (Random, 95% CI)	0.48 [0.10, 0.86]

5 Quality of life Show forest plot	4	1124	Std. Mean Difference (Random, 95% CI)	0.01 [‐0.10, 0.12]

6 Thromboembolic events Show forest plot	3	783	Risk Ratio (IV, Random, 95% CI)	0.95 [0.54, 1.65]

7 Mean change in serum ferritin Show forest plot	6	1010	Mean Difference (Random, 95% CI)	253.02 [84.30, 421.73]

8 Mean change in TSAT Show forest plot	5	908	Mean Difference (Random, 95% CI)	4.96 [0.94, 8.99]

Comparison 1. Benefits and harms of iron supplementation

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Comparison 2. Subgroup analyses

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hematopoietic response by type of iron Show forest plot	11	1712	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]

1.1 Dextran	3	340	Risk Ratio (IV, Random, 95% CI)	1.76 [1.01, 3.09]
1.2 Gluconate	4	879	Risk Ratio (IV, Random, 95% CI)	1.17 [1.08, 1.27]
1.3 Sucrose	1	102	Risk Ratio (IV, Random, 95% CI)	1.14 [0.97, 1.33]
1.4 Sulfate	3	391	Risk Ratio (IV, Random, 95% CI)	1.04 [0.87, 1.24]
2 Hematopoietic response by route of administration Show forest plot	11	1712	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]

2.1 Intravenous iron	8	1321	Risk Ratio (IV, Random, 95% CI)	1.20 [1.10, 1.31]
2.2 Oral iron	3	391	Risk Ratio (IV, Random, 95% CI)	1.04 [0.87, 1.24]
3 Hematopoietic response by type of ESA Show forest plot	11	1712	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]

3.1 epoetin	5	337	Risk Ratio (IV, Random, 95% CI)	1.53 [1.05, 2.22]
3.2 darbepoetin	6	1375	Risk Ratio (IV, Random, 95% CI)	1.16 [1.09, 1.24]
4 Time to hematopoietic response by route of administration Show forest plot	7		Hazard Ratio (Random, 95% CI)	0.93 [0.67, 1.28]

4.1 Intravenous iron	6		Hazard Ratio (Random, 95% CI)	0.88 [0.60, 1.29]
4.2 Oral iron	1		Hazard Ratio (Random, 95% CI)	1.24 [0.99, 1.56]
5 Time to hematopoietic response by type of iron Show forest plot	7		Hazard Ratio (Random, 95% CI)	0.93 [0.67, 1.28]

5.1 Dextran	3		Hazard Ratio (Random, 95% CI)	0.95 [0.36, 2.52]
5.2 Gluconate	2		Hazard Ratio (Random, 95% CI)	0.78 [0.65, 0.94]
5.3 Sucrose	1		Hazard Ratio (Random, 95% CI)	1.15 [0.60, 2.21]
5.4 Sulfate	1		Hazard Ratio (Random, 95% CI)	1.24 [0.99, 1.56]
6 Time to hematopoietic response by type of ESA Show forest plot	7		Hazard Ratio (Random, 95% CI)	0.93 [0.67, 1.28]

6.1 epoetin	4		Hazard Ratio (Random, 95% CI)	1.00 [0.58, 1.72]
6.2 darbepoetin	3		Hazard Ratio (Random, 95% CI)	0.81 [0.67, 0.96]
7 Mean change in Hb by route of administration Show forest plot	7		Mean Difference (Random, 95% CI)	0.48 [0.10, 0.86]

7.1 Intravenous iron	4		Mean Difference (Random, 95% CI)	0.84 [0.21, 1.46]
7.2 Oral iron	3		Mean Difference (Random, 95% CI)	0.07 [‐0.19, 0.34]
8 Mean change in Hb by type of iron Show forest plot	7		Mean Difference (Random, 95% CI)	0.48 [0.10, 0.86]

8.1 Dextran	2		Mean Difference (Random, 95% CI)	1.55 [0.62, 2.47]
8.2 Gluconate	2		Mean Difference (Random, 95% CI)	0.54 [‐0.15, 1.22]
8.3 Sucrose	0		Mean Difference (Random, 95% CI)	0.0 [0.0, 0.0]
8.4 Sulfate	3		Mean Difference (Random, 95% CI)	0.07 [‐0.19, 0.34]
9 Mean change in Hb by type of ESA Show forest plot	7		Mean Difference (Random, 95% CI)	0.48 [0.10, 0.86]

9.1 epoetin	5		Mean Difference (Random, 95% CI)	0.77 [0.25, 1.29]
9.2 darbepoetin	2		Mean Difference (Random, 95% CI)	0.10 [‐0.13, 0.33]
10 Mean change in serum ferritin by route of administration Show forest plot	6		Mean Difference (Random, 95% CI)	253.02 [84.30, 421.73]

10.1 Intravenous iron	4		Mean Difference (Random, 95% CI)	362.15 [219.69, 504.61]
10.2 Oral iron	2		Mean Difference (Random, 95% CI)	72.18 [‐6.59, 150.95]
11 Mean change in serum ferritin by type of iron Show forest plot	6		Mean Difference (Random, 95% CI)	253.02 [84.30, 421.73]

11.1 Dextran	1		Mean Difference (Random, 95% CI)	489.1 [344.28, 633.92]
11.2 Gluconate	2		Mean Difference (Random, 95% CI)	420.02 [336.23, 503.81]
11.3 Sucrose	1		Mean Difference (Random, 95% CI)	86.0 [‐125.67, 297.67]
11.4 Sulfate	2		Mean Difference (Random, 95% CI)	72.18 [‐6.59, 150.95]
12 Mean change in serum ferritin by type of ESA Show forest plot	6		Mean Difference (Random, 95% CI)	253.02 [84.30, 421.73]

12.1 epoetin	2		Mean Difference (Random, 95% CI)	260.88 [‐89.56, 611.32]
12.2 darbepoetin	4		Mean Difference (Random, 95% CI)	248.35 [26.24, 470.45]
13 Mean change in TSAT by route of administration Show forest plot	5		Mean Difference (Random, 95% CI)	4.96 [0.94, 8.99]

13.1 Intravenous iron	3		Mean Difference (Random, 95% CI)	5.07 [‐1.74, 11.87]
13.2 Oral iron	2		Mean Difference (Random, 95% CI)	5.90 [‐0.67, 12.46]
14 Mean change in TSAT by type of iron Show forest plot	5		Mean Difference (Random, 95% CI)	4.96 [0.94, 8.99]

14.1 Dextran	1		Mean Difference (Random, 95% CI)	7.1 [1.11, 13.09]
14.2 Gluconate	2		Mean Difference (Random, 95% CI)	4.78 [‐6.65, 16.22]
14.3 Sucrose	0		Mean Difference (Random, 95% CI)	0.0 [0.0, 0.0]
14.4 Sulfate	2		Mean Difference (Random, 95% CI)	5.90 [‐0.67, 12.46]
15 Mean change in TSAT by type of ESA Show forest plot	5		Mean Difference (Random, 95% CI)	4.96 [0.94, 8.99]

15.1 epoetin	2		Mean Difference (Random, 95% CI)	11.40 [4.17, 18.64]
15.2 darbepoetin	3		Mean Difference (Random, 95% CI)	3.01 [‐0.73, 6.75]

Comparison 2. Subgroup analyses

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Comparison 3. Sensitivity analyses

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Random sequence generation Show forest plot	11	1712	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]

1.1 Adequate (low risk)	4	830	Risk Ratio (IV, Random, 95% CI)	1.13 [1.02, 1.26]
1.2 Inadequate (high/unclear risk)	7	882	Risk Ratio (IV, Random, 95% CI)	1.23 [1.09, 1.39]
2 Allocation concealment Show forest plot	11	1711	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]

2.1 Adequate (low risk)	11	1711	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]
2.2 Inadequate (high/unclear risk)	0	0	Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Blinding Show forest plot	11	1712	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]

3.1 Adequate (low risk)	1	102	Risk Ratio (IV, Random, 95% CI)	1.14 [0.97, 1.33]
3.2 Inadequate (high/unclear risk)	10	1610	Risk Ratio (IV, Random, 95% CI)	1.18 [1.08, 1.29]
4 Incomplete outcome data Show forest plot	11	1712	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]

4.1 Adequate (low risk)	8	1430	Risk Ratio (IV, Random, 95% CI)	1.18 [1.07, 1.30]
4.2 Inadequate (high/unclear risk)	3	282	Risk Ratio (IV, Random, 95% CI)	1.15 [1.00, 1.33]
5 Selective reporting Show forest plot	11	1712	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]

5.1 Adequate (low risk)	11	1712	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]
5.2 Inadequate (high/unclear risk)	0	0	Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 Other bias Show forest plot	11	1711	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]

6.1 Adequate (low risk)	9	1371	Risk Ratio (IV, Random, 95% CI)	1.16 [1.05, 1.28]
6.2 Inadequate (high/unclear risk)	2	340	Risk Ratio (IV, Random, 95% CI)	1.21 [1.07, 1.38]
7 Hematopoietic response by definition(s) Show forest plot	11	1712	Risk Ratio (IV, Random, 95% CI)	1.17 [1.09, 1.26]

7.1 Hematopoietic response	8	1430	Risk Ratio (IV, Random, 95% CI)	1.18 [1.07, 1.30]
7.2 Hematologic response	2	180	Risk Ratio (IV, Random, 95% CI)	1.24 [0.80, 1.94]
7.3 Patients reaching Hb > 13 g/dL	1	102	Risk Ratio (IV, Random, 95% CI)	1.14 [0.97, 1.33]

Comparison 3. Sensitivity analyses

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