Original Report: Patient-Oriented, Translational Research American
Journal of
Nephrology
Am J Nephrol 2014;39:130–141 DOI: 10.1159/000358336
Received: November 16, 2013 Accepted: December 31, 2013 Published online: February 7, 2014
Efficacy and Safety of Intravenous Iron Therapy for Functional Iron Deficiency Anemia in Hemodialysis Patients: A Meta-Analysis Paweena Susantitaphong a, b, d Fahad Alqahtani c Bertrand L. Jaber a, b a
Kidney and Dialysis Research Laboratory, Division of Nephrology, Department of Medicine, St. Elizabeth’s Medical Center, and b Department of Medicine, Tufts University School of Medicine, Boston, Mass., and c Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, W.Va., USA; d Extracorporeal Multiorgan Support Dialysis Center, Division of Nephrology, Department of Medicine, King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Abstract Background: Studies on benefits of intravenous iron therapy among hemodialysis patients with functional iron deficiency anemia have shown conflicting results. We conducted a meta-analysis to assess the efficacy and safety of intravenous iron in this subset of patients. Methods: We searched MEDLINE (through December 2012), the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for singlearm studies and randomized controlled trials (RCT) that examined the effect of intravenous iron for functional iron deficiency anemia in hemodialysis patients on anemia parameters and markers of oxidative stress and inflammation. Studies of absolute iron deficiency were excluded. Randomeffect model meta-analyses were used to compute changes in outcomes of interest. Results: We identified 34 studies (2,658 patients), representing 24 single-arm studies, and 10 parallel-arm RCT. In the analyses of the study arms, intravenous iron therapy resulted in a significant increase in hemoglobin, serum ferritin, transferrin saturation rate, serum iron, reticulocyte hemoglobin content as well as a significant de-
© 2014 S. Karger AG, Basel 0250–8095/14/0392–0130$39.50/0 E-Mail [email protected] www.karger.com/ajn
crease in the percentage of hypochromic erythrocytes and erythropoietin dose. There were significant increases in plasma malonyldialdehyde level and thiobarbituric acid-reactive substances, and a decrease in neutrophil respiratory burst. The analyses of the RCT revealed less robust net changes in these parameters, and there was no increased risk of adverse events including infections, cardiac events and mortality. Conclusions: Intravenous iron therapy for functional iron deficiency anemia in hemodialysis patients improves anemia parameters but exerts some effects on markers of oxidative stress that are of unclear clinical significance. The longterm safety and efficacy of this treatment strategy requires further study. © 2014 S. Karger AG, Basel
Introduction
Intravenous iron therapy is integral to the management of iron deficiency anemia in hemodialysis patients, and is supported by the US and the European Clinical Practice Guidelines [1, 2]. Iron therapy in hemodialysis patients has This review was presented in part at the 2013 Kidney Week of the American Society of Nephrology, Atlanta, Ga., USA, November 5–10, 2013.
Bertrand L. Jaber, MD, MS St. Elizabeth’s Medical Center 736 Cambridge Street Boston, MA 02135 (USA) E-Mail bertrand.jaber @ steward.org
Downloaded by: Universitätsbibliothek Düsseldorf 134.99.34.168 - 3/10/2014 1:48:09 PM
Key Words Hemodialysis · Functional iron deficiency anemia · Intravenous iron therapy · Oxidative stress · Inflammation, meta-analysis
Methods
traditionally been targeted to maintain the transferrin saturation (TSAT) rate >20% [1, 3] and serum ferritin at 200– 500 ng/ml [1, 3]. Several meta-analyses have demonstrated a superior benefit of intravenous over oral iron therapy in raising the hemoglobin level and decreasing the requirement for erythropoiesis-stimulating agents (ESA) in dialysis patients with absolute iron deficiency anemia as defined by a TSAT rate 500 ng/ml, any erythropoietic response to iron therapy alone is likely to be small, and the safety of this strategy needs to be further studied [17]. To address this important knowledge gap, we conducted a meta-analysis to examine the efficacy and potential risks associated with the use of intravenous iron therapy for the loosely termed ‘functional or relative’ iron deficiency anemia in hemodialysis patients.
Data Extraction and Quality Assessment The following study characteristics were extracted: country of origin, year of publication, study design, sample size, percentage of men, prevalence of diabetes mellitus, and mean age and duration of dialysis. We extracted data on intravenous iron treatment characteristics including the iron formulation type (iron dextran; iron sucrose, also known as iron saccharate, which is a ferric hydroxide sucrose complex; iron gluconate; iron polymaltose; iron colloid; iron chloride; iron oxide; or ferumoxytol), the dosing strategy (bolus, defined by a large amount of iron administered over a short period of time, vs. maintenance dose) and duration of intervention, and whether the trials were sponsored by manufacturers of intravenous iron preparations. We extracted data on the effect of iron therapy on the following anemia parameters: hemoglobin, hematocrit, serum iron, ferritin, total iron-binding capacity (TIBC), transferrin, TSAT rate, reticulocyte count, reticulocyte hemoglobin content, percentage of hypochromic erythrocytes, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cell distribution width, mean weekly dose of erythropoietin and an overall response rate. When reported, the darbepoetin-α dose was converted to an equivalent erythropoietin-α dose, using a dose conversion ratio of 331 units of erythropoietin-α per 1 μg of darbepoetin-α [19, 20]. When reported, we extracted the response rate to iron therapy, which was variably defined across studies, including a 15% increase in hemoglobin/hematocrit, a 0.5–1.0 g/dl
Iron Therapy for Functional Iron Deficiency in Dialysis
Am J Nephrol 2014;39:130–141 DOI: 10.1159/000358336
Data Sources and Searches We performed a MEDLINE literature search (inception to December 2012) to identify eligible studies, using the Medical Subject Headings search terms ‘iron’, ‘ferrous compounds’, ‘ferric compound’, ‘iron therapy’, ‘parenteral’, ‘intravenous’, ‘oral’, ‘dialysis’ or ‘hemodialysis’. We also searched the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for completed studies, using similar search terms, and reviewed the American Society of Nephrology abstracts (2003–2012 meetings) as well as the bibliographies of retrieved articles.
131
Downloaded by: Universitätsbibliothek Düsseldorf 134.99.34.168 - 3/10/2014 1:48:09 PM
Study Selection We included prospective single-arm studies (with pre- and poststudy evaluations) and crossover and parallel-arm randomized controlled trials (RCT) that examined the effect of intravenous iron preparations in hemodialysis patients with relative or functional iron deficiency on anemia parameters and markers of oxidative stress and inflammation, as well as adverse clinical outcomes. There is no acceptable definition of functional iron deficiency anemia. As a result, for the purpose of our meta-analysis, functional iron deficiency anemia was loosely defined as a serum ferritin level >200 ng/ml with or without a TSAT rate 3 months) duration. Where indicated, the G3Data Graph Analyzer (version 1.5.3) was used to extract data from graphs. Disagreements were resolved through consensus and arbitration by a third author (B.L.J.). The quality of the single-arm studies was assessed using the NewcastleOttawa Scale [21]. The Jadad scale was used to assess the quality of the RCT [22].
Iron Therapy for Functional Iron Deficiency in Dialysis
Am J Nephrol 2014;39:130–141 DOI: 10.1159/000358336
Downloaded by: Universitätsbibliothek Düsseldorf 134.99.34.168 - 3/10/2014 1:48:09 PM
133
2006 2006 2007 2007
2008 2008
2009
Schiesser [48] Warady [49] Bovy [50] Coyne [7]
Coyne [51] Kapoian [8]
Provenzano [53] Bhat* [54] Chinnappa [55] Rath [56] Malovrh [57] Stefánsson [58]
single-arm study parallel-arm RCT (different target) parallel-arm RCT (no iron vs. iron IV) single-arm study single-arm study
parallel-arm RCT (no iron vs. iron IV) Czech parallel-arm RCT Republic (no iron vs. iron IV) Switzerland single-arm study USA single-arm study Belgium single-arm study USA parallel-arm RCT (no iron vs. iron IV) USA single-arm study USA parallel-arm RCT (different IV dose) USA parallel-arm RCT (oral iron vs. iron IV) USA single-arm study UK single-arm study Germany single-arm study Slovenia single-arm study Sweden single-arm study
Germany Czech Republic Israel
Israel
Taiwan Japan
Taiwan The Netherlands Canada prospective cohort Turkey single-arm study
Spain
prospective cohort parallel-arm RCT (different IV dose) prospective cohort prospective cohort parallel-arm RCT (different IV dose) parallel-arm RCT (different IV dose) single-arm study single-arm study
single-arm study single-arm study single-arm study
single-arm study single-arm study
Study design
609 20 221 60 20
230
20 118
50 23 32 134
20
14
16 7
17
65 197
34 13
149 10
15
157 10 59
23 42
79 43 116
17 18
– – 38.4 174 –
–
– –
– – – 55.8
39
33
49.5 36
–
64.1 –
– –
50.4 48.3
50.5
35.6 – –
59.3 –
73 40.1 –
57 –
PaMean dialysis tients, duration, n months
64.1 60.0 63.7 63.3 63.5
60.2
– 59.8
58.2 13.2 65.0 58.7
72.5
72.0
62.8 70.0
71.2
60.0 59.4
– 49.9
53.9 –
63.9
60.3 57.7 59.0
53.0 60.8
63.0 63.8 58.0
51.0 55.0
58 55 55 65 65
57
– 49
56 70 59 51
–
57
56 43
53
51 61
– 77
42 70
67
54 40 47
35 60
50 28 66
– 56
– – 32 – 40
43
– 38
– – 22 –
–
–
– 29
47
18 14
– –
19 10
–
37 – –
35 –
40 – –
– 11
>200 >200 >200 >200 >200
>200
500 – 1,200 500 – 1,200
>200 >200 >200 500 – 1,200
>200
>200
>200 >200
>200
>200 >200
>200 >200
>200 >200
>200
>200 >200 >200
>200 >200
200 – 600 >200 >200
>200 >200
Mean Men, Diabetes Serum ferriage, % mellitus, tin inclusion years % criterion, ng/ml
NOS = Newcastle-Ottawa Scale; IV = intravenous(ly); NR = not reported. * Scientific abstract.
2010 2010 2010 2011 2011
2006
2003 2003
Chuang [41] Kaneko [42]
Eiselt [47]
2003 2003
Mulay* [39] Cavdar [40]
2005
2002 2002
Chang [37] Kooistra [38]
Michelis [46]
2002
Bolaños [36]
2004 2005
2001 2001 2001
Fishbane [33] Huang [34] Kosch [35]
Riedel [44] Hodkova [45]
2000 2000
2003
USA USA
1997 1998 1999
Michelis [43]
USA Australia UK
1991 1996
Allegra [26] SunderPlassmann [27] Mittman [28] Saltissi [29] Macdougall [30] Agarwal [31] Besarab [32]
USA Taiwan Germany
Italy Austria
Year
First author
Country
Table 1. Characteristics of the studies included in the meta-analysis
Journal of
Nephrology
Am J Nephrol 2014;39:130–141 DOI: 10.1159/000358336
Received: November 16, 2013 Accepted: December 31, 2013 Published online: February 7, 2014
Efficacy and Safety of Intravenous Iron Therapy for Functional Iron Deficiency Anemia in Hemodialysis Patients: A Meta-Analysis Paweena Susantitaphong a, b, d Fahad Alqahtani c Bertrand L. Jaber a, b a
Kidney and Dialysis Research Laboratory, Division of Nephrology, Department of Medicine, St. Elizabeth’s Medical Center, and b Department of Medicine, Tufts University School of Medicine, Boston, Mass., and c Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, W.Va., USA; d Extracorporeal Multiorgan Support Dialysis Center, Division of Nephrology, Department of Medicine, King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Abstract Background: Studies on benefits of intravenous iron therapy among hemodialysis patients with functional iron deficiency anemia have shown conflicting results. We conducted a meta-analysis to assess the efficacy and safety of intravenous iron in this subset of patients. Methods: We searched MEDLINE (through December 2012), the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for singlearm studies and randomized controlled trials (RCT) that examined the effect of intravenous iron for functional iron deficiency anemia in hemodialysis patients on anemia parameters and markers of oxidative stress and inflammation. Studies of absolute iron deficiency were excluded. Randomeffect model meta-analyses were used to compute changes in outcomes of interest. Results: We identified 34 studies (2,658 patients), representing 24 single-arm studies, and 10 parallel-arm RCT. In the analyses of the study arms, intravenous iron therapy resulted in a significant increase in hemoglobin, serum ferritin, transferrin saturation rate, serum iron, reticulocyte hemoglobin content as well as a significant de-
© 2014 S. Karger AG, Basel 0250–8095/14/0392–0130$39.50/0 E-Mail [email protected] www.karger.com/ajn
crease in the percentage of hypochromic erythrocytes and erythropoietin dose. There were significant increases in plasma malonyldialdehyde level and thiobarbituric acid-reactive substances, and a decrease in neutrophil respiratory burst. The analyses of the RCT revealed less robust net changes in these parameters, and there was no increased risk of adverse events including infections, cardiac events and mortality. Conclusions: Intravenous iron therapy for functional iron deficiency anemia in hemodialysis patients improves anemia parameters but exerts some effects on markers of oxidative stress that are of unclear clinical significance. The longterm safety and efficacy of this treatment strategy requires further study. © 2014 S. Karger AG, Basel
Introduction
Intravenous iron therapy is integral to the management of iron deficiency anemia in hemodialysis patients, and is supported by the US and the European Clinical Practice Guidelines [1, 2]. Iron therapy in hemodialysis patients has This review was presented in part at the 2013 Kidney Week of the American Society of Nephrology, Atlanta, Ga., USA, November 5–10, 2013.
Bertrand L. Jaber, MD, MS St. Elizabeth’s Medical Center 736 Cambridge Street Boston, MA 02135 (USA) E-Mail bertrand.jaber @ steward.org
Downloaded by: Universitätsbibliothek Düsseldorf 134.99.34.168 - 3/10/2014 1:48:09 PM
Key Words Hemodialysis · Functional iron deficiency anemia · Intravenous iron therapy · Oxidative stress · Inflammation, meta-analysis
Methods
traditionally been targeted to maintain the transferrin saturation (TSAT) rate >20% [1, 3] and serum ferritin at 200– 500 ng/ml [1, 3]. Several meta-analyses have demonstrated a superior benefit of intravenous over oral iron therapy in raising the hemoglobin level and decreasing the requirement for erythropoiesis-stimulating agents (ESA) in dialysis patients with absolute iron deficiency anemia as defined by a TSAT rate 500 ng/ml, any erythropoietic response to iron therapy alone is likely to be small, and the safety of this strategy needs to be further studied [17]. To address this important knowledge gap, we conducted a meta-analysis to examine the efficacy and potential risks associated with the use of intravenous iron therapy for the loosely termed ‘functional or relative’ iron deficiency anemia in hemodialysis patients.
Data Extraction and Quality Assessment The following study characteristics were extracted: country of origin, year of publication, study design, sample size, percentage of men, prevalence of diabetes mellitus, and mean age and duration of dialysis. We extracted data on intravenous iron treatment characteristics including the iron formulation type (iron dextran; iron sucrose, also known as iron saccharate, which is a ferric hydroxide sucrose complex; iron gluconate; iron polymaltose; iron colloid; iron chloride; iron oxide; or ferumoxytol), the dosing strategy (bolus, defined by a large amount of iron administered over a short period of time, vs. maintenance dose) and duration of intervention, and whether the trials were sponsored by manufacturers of intravenous iron preparations. We extracted data on the effect of iron therapy on the following anemia parameters: hemoglobin, hematocrit, serum iron, ferritin, total iron-binding capacity (TIBC), transferrin, TSAT rate, reticulocyte count, reticulocyte hemoglobin content, percentage of hypochromic erythrocytes, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cell distribution width, mean weekly dose of erythropoietin and an overall response rate. When reported, the darbepoetin-α dose was converted to an equivalent erythropoietin-α dose, using a dose conversion ratio of 331 units of erythropoietin-α per 1 μg of darbepoetin-α [19, 20]. When reported, we extracted the response rate to iron therapy, which was variably defined across studies, including a 15% increase in hemoglobin/hematocrit, a 0.5–1.0 g/dl
Iron Therapy for Functional Iron Deficiency in Dialysis
Am J Nephrol 2014;39:130–141 DOI: 10.1159/000358336
Data Sources and Searches We performed a MEDLINE literature search (inception to December 2012) to identify eligible studies, using the Medical Subject Headings search terms ‘iron’, ‘ferrous compounds’, ‘ferric compound’, ‘iron therapy’, ‘parenteral’, ‘intravenous’, ‘oral’, ‘dialysis’ or ‘hemodialysis’. We also searched the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for completed studies, using similar search terms, and reviewed the American Society of Nephrology abstracts (2003–2012 meetings) as well as the bibliographies of retrieved articles.
131
Downloaded by: Universitätsbibliothek Düsseldorf 134.99.34.168 - 3/10/2014 1:48:09 PM
Study Selection We included prospective single-arm studies (with pre- and poststudy evaluations) and crossover and parallel-arm randomized controlled trials (RCT) that examined the effect of intravenous iron preparations in hemodialysis patients with relative or functional iron deficiency on anemia parameters and markers of oxidative stress and inflammation, as well as adverse clinical outcomes. There is no acceptable definition of functional iron deficiency anemia. As a result, for the purpose of our meta-analysis, functional iron deficiency anemia was loosely defined as a serum ferritin level >200 ng/ml with or without a TSAT rate 3 months) duration. Where indicated, the G3Data Graph Analyzer (version 1.5.3) was used to extract data from graphs. Disagreements were resolved through consensus and arbitration by a third author (B.L.J.). The quality of the single-arm studies was assessed using the NewcastleOttawa Scale [21]. The Jadad scale was used to assess the quality of the RCT [22].
Iron Therapy for Functional Iron Deficiency in Dialysis
Am J Nephrol 2014;39:130–141 DOI: 10.1159/000358336
Downloaded by: Universitätsbibliothek Düsseldorf 134.99.34.168 - 3/10/2014 1:48:09 PM
133
2006 2006 2007 2007
2008 2008
2009
Schiesser [48] Warady [49] Bovy [50] Coyne [7]
Coyne [51] Kapoian [8]
Provenzano [53] Bhat* [54] Chinnappa [55] Rath [56] Malovrh [57] Stefánsson [58]
single-arm study parallel-arm RCT (different target) parallel-arm RCT (no iron vs. iron IV) single-arm study single-arm study
parallel-arm RCT (no iron vs. iron IV) Czech parallel-arm RCT Republic (no iron vs. iron IV) Switzerland single-arm study USA single-arm study Belgium single-arm study USA parallel-arm RCT (no iron vs. iron IV) USA single-arm study USA parallel-arm RCT (different IV dose) USA parallel-arm RCT (oral iron vs. iron IV) USA single-arm study UK single-arm study Germany single-arm study Slovenia single-arm study Sweden single-arm study
Germany Czech Republic Israel
Israel
Taiwan Japan
Taiwan The Netherlands Canada prospective cohort Turkey single-arm study
Spain
prospective cohort parallel-arm RCT (different IV dose) prospective cohort prospective cohort parallel-arm RCT (different IV dose) parallel-arm RCT (different IV dose) single-arm study single-arm study
single-arm study single-arm study single-arm study
single-arm study single-arm study
Study design
609 20 221 60 20
230
20 118
50 23 32 134
20
14
16 7
17
65 197
34 13
149 10
15
157 10 59
23 42
79 43 116
17 18
– – 38.4 174 –
–
– –
– – – 55.8
39
33
49.5 36
–
64.1 –
– –
50.4 48.3
50.5
35.6 – –
59.3 –
73 40.1 –
57 –
PaMean dialysis tients, duration, n months
64.1 60.0 63.7 63.3 63.5
60.2
– 59.8
58.2 13.2 65.0 58.7
72.5
72.0
62.8 70.0
71.2
60.0 59.4
– 49.9
53.9 –
63.9
60.3 57.7 59.0
53.0 60.8
63.0 63.8 58.0
51.0 55.0
58 55 55 65 65
57
– 49
56 70 59 51
–
57
56 43
53
51 61
– 77
42 70
67
54 40 47
35 60
50 28 66
– 56
– – 32 – 40
43
– 38
– – 22 –
–
–
– 29
47
18 14
– –
19 10
–
37 – –
35 –
40 – –
– 11
>200 >200 >200 >200 >200
>200
500 – 1,200 500 – 1,200
>200 >200 >200 500 – 1,200
>200
>200
>200 >200
>200
>200 >200
>200 >200
>200 >200
>200
>200 >200 >200
>200 >200
200 – 600 >200 >200
>200 >200
Mean Men, Diabetes Serum ferriage, % mellitus, tin inclusion years % criterion, ng/ml
NOS = Newcastle-Ottawa Scale; IV = intravenous(ly); NR = not reported. * Scientific abstract.
2010 2010 2010 2011 2011
2006
2003 2003
Chuang [41] Kaneko [42]
Eiselt [47]
2003 2003
Mulay* [39] Cavdar [40]
2005
2002 2002
Chang [37] Kooistra [38]
Michelis [46]
2002
Bolaños [36]
2004 2005
2001 2001 2001
Fishbane [33] Huang [34] Kosch [35]
Riedel [44] Hodkova [45]
2000 2000
2003
USA USA
1997 1998 1999
Michelis [43]
USA Australia UK
1991 1996
Allegra [26] SunderPlassmann [27] Mittman [28] Saltissi [29] Macdougall [30] Agarwal [31] Besarab [32]
USA Taiwan Germany
Italy Austria
Year
First author
Country
Table 1. Characteristics of the studies included in the meta-analysis
