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Clinical Dialysis |
* Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; Department of Medicine, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, New Jersey; The Kidney Institute, Inc., Houston, Texas; Department of Medicine, Harvard Medical School, Boston, Massachusetts; || Satellite Healthcare, Inc., Mountain View, California; and ¶ Clinical Affairs, Watson Laboratories, Inc., Morristown, New Jersey
Address correspondence to: Dr. Daniel W. Coyne, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8129, St. Louis, MO 63110. Phone: 314-362-7211; Fax: 314-747-3743; E-mail: dcoyne{at}im.wustl.edu
Received for publication September 21, 2006. Accepted for publication December 11, 2006.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionConclusionDisclosuresReferences |
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11 g/dl, ferritin 500 to 1200 ng/ml, TSAT 25%, and epoetin dosage 
225 IU/kg per wk or 22,500 IU/wk. Patients with known infections or recent significant blood loss were excluded. Participants (n = 134) were randomly assigned to no iron (control) or to ferric gluconate 125 mg intravenously with eight consecutive hemodialysis sessions (intravenous iron). At randomization, epoetin was increased 25% in both groups; further dosage changes were prohibited. At 6 wk, hemoglobin increased significantly more (P = 0.028) in the intravenous iron group (1.6 ± 1.3 g/dl) than in the control group (1.1 ± 1.4 g/dl). Hemoglobin response occurred faster (P = 0.035) and more patients responded after intravenous iron than in the control group (P = 0.041). Ferritin 800 or >800 ng/ml had no relationship to the magnitude or likelihood of responsiveness to intravenous iron relative to the control group. Similarly, the superiority of intravenous iron compared with no iron was similar whether baseline TSAT was above or below the study median of 19%. Ferritin decreased in control subjects (–174 ± 225 ng/ml) and increased after intravenous iron (173 ± 272 ng/ml; P < 0.001). Intravenous iron resulted in a greater increase in TSAT than in control subjects (7.5 ± 7.4 versus 1.8 ± 5.2%; P < 0.001). Reticulocyte hemoglobin content fell only in control subjects, suggesting worsening iron deficiency. Administration of ferric gluconate (125 mg for eight treatments) is superior to no iron therapy in anemic dialysis patients receiving adequate epoetin dosages and have a ferritin 500 to 1200 ng/ml and TSAT 25%. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionDisclosuresReferences |
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Serum ferritin and transferrin saturation (TSAT) are the standard laboratory tests to evaluate iron stores, and the limits for diagnosis of iron deficiency and adequate iron in healthy adults are fairly well defined. Although these tests are used routinely to guide iron therapy in dialysis patients, studies have shown that ferritin and TSAT cutoffs for diagnosis of iron deficiency must be much higher than that used in the general population (3,4). In addition, studies that have administered intravenous iron to dialysis patients have found ferritin and TSAT repeatedly to be poorly predictive of hemoglobin responsiveness (4–7).
Following the recommendations of the National Kidney Foundation’s 1997 and 2001 Anemia Guidelines to maintain ferritin between 100 and 800 ng/ml, intravenous iron has been administered regularly to most hemodialysis patients, generally as maintenance therapy that is reduced as ferritin approaches 800 ng/ml (1,2). Consequently, the mean ferritin in the US hemodialysis population has been stable between 590 and 630 ng/ml since 2001 (8). The 2006 Anemia Clinical Practice Recommendations (CPR) state that there is insufficient evidence of responsiveness to iron when ferritin is >500 ng/ml, and "routine administration" cannot be recommended, although intravenous iron use should be considered after weighing "ESA [erythropoiesis-stimulating agent] responsiveness, [hemoglobin] and TSAT level, and the patient’s clinical status" (9). Rigidly withholding iron when ferritin is >500 ng/ml on the basis of the new CPR’s opinion-based statement without considering the factors noted above as directed by the recommendation would have significant implications for a large portion of the hemodialysis population, especially if significant numbers of patients with higher ferritin have absolute or functional iron deficiency.
The Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) study is a controlled, multicenter trial that randomly assigned hemodialysis patients to 1 g of ferric gluconate (Ferrlecit; Watson Laboratories, Morristown, NJ) or no iron therapy if they were anemic, had serum ferritin of 500 to 1200 ng/ml, had TSAT 25%, and were receiving adequate epoetin dosages. The trial was designed specifically to determine the response rate to intravenous iron over this broad ferritin range and to determine what upper limit, if any, should be used.
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Materials and Methods |
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Patient Selection
Eligible patients provided informed consent, were at least 18 yr of age, were on hemodialysis for 90 d, were receiving a stable dosage of epoetin 225 IU/kg per wk or 22,500 IU/wk for 2 wk, and received no more than 125 mg/wk intravenous iron during the 4 wk preceding screening/baseline. Other entry criteria were most recent ferritin 500 to 1200 ng/ml, TSAT 25%, and hemoglobin 11.0 g/dl. Exclusion criteria were use of any investigational agent within 30 d, lactating women or women with positive pregnancy tests, known sensitivity to ferric gluconate, planned surgical procedure, evidence of significant blood loss within the previous 6 wk, or hematologic disorders or malignancies. At screening, patients could not have had any active infection that required systemic antibiotics, missed more than three hemodialysis treatments in the previous 8 wk, received a transfusion within 4 wk, or been hospitalized within 2 wk.
Study Design and Procedures
The screening/baseline period (week 0; Figure 1) lasted 1 wk. Any oral and intravenous iron was discontinued during screening. Patients who met all of the entry criteria underwent central laboratory screening to ensure that their hemoglobin, TSAT, and ferritin levels continued to meet the study criteria. Central laboratory screening panel was drawn before the first or second treatment of the week and included complete blood count, reticulocyte count, complete metabolic panel, and complete iron studies. All study samples were analyzed at the central laboratory (Spectra Renal Research, Rockleigh, NJ). Patients were randomly assigned when central laboratory results showed ferritin from 500 to 1200 ng/ml, TSAT 25%, and hemoglobin 11 g/dl, and these results were considered their baseline biochemical values. Patients who failed screening could be rescreened later if they continued to meet all entry criteria at the time of rescreening. Medical, demographic, and renal history, previous intravenous iron and epoetin regimens, Kt/V, and dialysis access were collected only on patients who passed screening and were randomly assigned. Randomly assigned patients could not reenter the study.
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800 or >800 ng/ml, at a 1:1 ratio. Using a computer-generated randomization scheme, within each stratum, patients were centrally randomly assigned 1:1 to either no iron (control group) or 1 g of ferric gluconate (Ferrlecit) administered in eight consecutive 125-mg doses beginning with the first dialysis session of week 1 (intravenous iron group). Patients who missed a dose of iron could receive the dose until the second treatment of week 5. Epoetin dosage was raised by 25% in both groups, and this dosage was maintained for the entire study. Hemoglobin and reticulocyte hemoglobin content (CHr) were obtained weekly before the second dialysis session, and the complete laboratory panel was obtained before the second dialysis session of week 6 or at early termination.
Primary and Secondary Objectives
The study’s predefined primary objective was to compare the difference between treatment groups in change from baseline (CFB) to week 6 in hemoglobin. Secondary efficacy objectives were percentage of responders (defined as hemoglobin increase of 2 g/dl during the study) and time to response. Because both groups received an increase in epoetin dosage, we expected the control group hemoglobin to increase and therefore adopted a stricter definition of a responder than others have in the past (4,5,7). Secondary objectives included a comparison between the two groups in CFB in CHr. For addressing safety concerns, secondary objectives included CFB in TSAT, serum ferritin, and C-reactive protein (CRP).
Statistical Analyses
The primary predefined analysis was based on the intention-to-treat (ITT) analysis, which included participants who received at least one study treatment and had at least one postbaseline hemoglobin level. Lacking any published data on the efficacy of intravenous iron when ferritin is >500 ng/ml, the statistical assumptions (difference in hemoglobin and SD) were based on unpublished clinical data that were collected by the lead investigator of patients who had elevated ferritin levels and did or did not receive 1 g of ferric gluconate. On the basis of statistical power of 90% and type I error of 5%, assuming that the hemoglobin difference between groups would be 0.67 g/dl, and assuming an SD of 1.13 g/dl, 61 patients were required in each treatment group (i.e., a minimum overall total of 122 patients). A predefined confirmatory per-protocol (PP) analysis was performed, which excluded patients who had any serious protocol deviations and received <75% of scheduled epoetin doses or <1000 mg of ferric gluconate (if randomly assigned to intravenous iron). To allow for dropouts and inadvertent iron administration to control patients, we set recruitment within each treatment group, as well as within each stratum, at 75.
Continuous variables were summarized using means and SD or medians and interquartile ranges. Categorical variables were summarized using frequencies and percentages. Differences between the two groups in CFB of continuous variables were analyzed using analysis of covariance (ANCOVA). Within-group CFB was compared with zero using one-sample t test. The Cochran-Mantel-Haenszel test was used to compare response rates in the groups while taking into account the ferritin stratum. Time to response in the groups was compared using the log-rank test. All statistical tests were conducted at 
= 0.05 significance level. All statistical analyses were conducted using SAS 8.2 (SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionDisclosuresReferences |
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Of the 134 patients, 66 were randomly assigned to the control group (38 in lower ferritin stratum, 28 in higher ferritin stratum) and 68 were randomly assigned to the intravenous iron group (39 in lower stratum, 29 in higher stratum; Figure 2). Five patients had no postbaseline hemoglobin levels, leaving 129 patients in the ITT analysis. Two dropouts (one control, one intravenous iron group) were hospitalized after randomization and withdrawn. Three other iron group dropouts were due to one voluntary withdrawal, one major protocol violation, and one by investigator as a result of psychiatric hospitalization. These five dropouts had mean hemoglobin of 9.9 g/dl, ferritin of 726 ng/ml, TSAT of 18.0%, and epoetin dosage of 30,750 IU/wk. Of those who were included in the ITT analysis, 93 met the definition to be included in the PP analysis (control 50; intravenous iron 43).
Baseline demographic and laboratory characteristics are summarized in Table 2. Baseline laboratory tests, including hemoglobin levels, were drawn before the first hemodialysis session of the week in 39 (60%) and 31 (48.4%) patients in the control and intravenous iron groups, respectively. Baseline hemoglobin was similar in both groups whether drawn before the first or the second dialysis session of the week. Baseline hemoglobin levels that were drawn before the first and second sessions were 10.2 ± 0.8 and 10.1 ± 0.6 g/dl, respectively, in the control group, and 10.4 ± 0.6 and 10.3 ± 0.9 g/dl, respectively, in the intravenous iron group. There were no significant differences between groups in any of the characteristics. CRP levels, obtained using the high-sensitivity assay, were significantly elevated, suggesting inflammation in these patients with high ferritin.
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There was no relationship between magnitude of the responsiveness to intravenous iron relative to the control group and ferritin stratum (800 ng/ml stratum, intravenous iron greater by 0.5 g/dl; >800 ng/ml stratum intravenous iron greater by 0.5 g/dl). Similarly, there was no relationship between the magnitude of responsiveness to intravenous iron relative to the control and whether the baseline TSAT was 19% (median baseline TSAT in both groups). The PP analysis yielded similar findings.
Secondary Outcomes
The percentage of responders—those who achieved an increase in hemoglobin 2 g/dl at any point—was 46.9% in the intravenous iron and 29.2% in the control group, a difference that was both clinically and statistically significant (P = 0.041; Table 3). Six patients need to be treated with intravenous iron for one additional patient to be a responder. Similarly, in the PP analysis, 51.2% of the intravenous iron group responded compared with only 24.0% in the control group (P = 0.007). Again, response rates and the superiority of intravenous iron were similar within each ferritin stratum (lower stratum 45.9 versus 29.7%; higher stratum 48.1 versus 28.6%). Patients who received intravenous iron also responded faster (Figure 4), with a median time to response of 6 wk (P = 0.035). To investigate the effect of baseline epoetin dosage on responder rate, we performed an exploratory Cochran-Mantel-Haenszel test while stratifying patients by median baseline epoetin dosage. Baseline epoetin dosage had no effect on response rate (P = 0.145), and intravenous iron continued to be superior to no iron (P = 0.035).
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Safety
Adverse events were typical of the patient population and did not differ significantly between groups (Table 5). Adverse events that occurred in more than 5% of patients were diarrhea (7.6%), hypertension (7.6%), and hypotension (6.1%) in the control group and diarrhea (6.1%) in the intravenous iron group. Diarrhea, dyspepsia, dyspnea, dizziness, chest pain, back pain, and/or increased sweating, which have been reported with all available intravenous iron preparations, occurred in four patients and were thought to be related to the intravenous iron. Thirteen infection episodes in 10 patients occurred in the control arm, and 12 infection episodes occurred in eight patients in the intravenous iron arm. Cardiac adverse events occurred in four patients in each group. Vascular adverse events occurred in 13 and five patients in the control and the intravenous iron groups, respectively. In the control group, 14 serious adverse events (SAE) occurred in nine patients, and 12 SAE occurred in nine patients in the intravenous iron group. One patient died in each group. None of the SAE or deaths was attributed to the study treatment by the investigators. Median (interquartile range) CFB in CRP levels in the control group was 0.0 mg/L (–7.9 to 10.7 mg/L) and in the intravenous iron group was –0.4 mg/L (–10.2 to 6.7 mg/L; P = 0.558).
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Discussion |
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All patients received a 25% increase in their epoetin dosages because this was the standard of care for treatment of anemic hemodialysis patients recommended by the KDOQI guidelines (1). Although a study design without an epoetin dosage increase may have been more desirable, it would have been very difficult to find sites that would agree to participate in the study because a hemoglobin <11 g/dl is a performance outcome measure, and patients and human study committees would have been reluctant to approve such management. The guidelines recommend maintaining TSAT >20%. By including patients with TSAT 25%, we essentially tested whether this cutoff was discriminative. To ensure that only anemic patients who are on adequate dosages of epoetin are studied, we included only patients who were receiving epoetin 225 IU/kg per wk or cumulative dosages 22,500 IU/wk, which exceeded the median dosage in the United States in 2002 of 199.1 IU/kg per wk (11).
The DRIVE study results indicate that 1 g of intravenous ferric gluconate is efficacious in the treatment of anemia in hemodialysis patients who are receiving above-average epoetin dosages and have ferritin 500 ng/ml, and as high as 1200 ng/ml, with concurrent TSAT 25%. Responsiveness to intravenous iron was similar when ferritin was 800 or >800 ng/ml, indicating ferritin alone should not be used to guide iron therapy decisions. KDOQI text suggests consideration of iron when ferritin is >500 ng/ml and TSAT is <20% (9). Similarly, in this study of patients with TSAT 25%, responsiveness to intravenous iron was similar when TSAT was <19 or 19%. Compared with ferritin level (800 or >800 ng/ml) and TSAT level (<19 or 19%), the most effective predictor of improvement in anemia was whether patients received ferric gluconate. This is consistent with previous results that were seen in patients with lower ferritin levels (7). Our results indicate that a significant portion of patients had iron-restricted erythropoiesis as a result of absolute or functional iron deficiency, despite that approximately one third were receiving maintenance iron before screening. Maintenance iron frequently is not given when ferritin is elevated, as was observed in most of our study patients. In this population, withholding iron results in a significant fall in CHr (Figure 5). After an increase in epoetin in anemic patients with high ferritin and low TSAT, a course of intravenous iron is more effective than no iron.
This study also addresses the question that was posed by the 2006 KDOQI anemia CPR concerning the extent to which iron administration is effective in the setting of "an increase in ferritin level accompanied by a decrease in TSAT [that] suggests inflammation-mediated reticuloendothelial blockade" (9). This study specifically recruited patients who met the criteria for inflammation-mediated reticuloendothelial blockade per the 2006 KDOQI anemia CPR: Increased ferritin, decreased TSAT, decreased hemoglobin, and increased epoetin dosage. Furthermore, the mean CRP at baseline was well above the normal range (<5 mg/L). The DRIVE study results conclusively demonstrate that a course of intravenous iron is effective in overcoming inflammation-mediated reticuloendothelial blockade.
The magnitude of the effect of intravenous iron relative to no iron therapy was 0.5 g/dl at 6 wk, although the responder rate was increased approximately 60% above the rate that was observed in the control group. Our short trial duration and fixed dosage of epoetin did not allow us to assess the persistence of this hemoglobin improvement or any potential epoetin-sparing benefit of iron. After completion of DRIVE, these patients returned to their routine anemia management and entered a 6-wk observational study that assessed the persistence of the higher hemoglobin and any epoetin-sparing effect of intravenous iron. The results of this study will be forthcoming.
Ferritin has been the major laboratory test used to assess iron stores in dialysis patients. Both the 1997 and 2001 National Kidney Foundation’s anemia guidelines proposed maintaining ferritin between 100 and 800 ng/ml via intermittent or maintenance iron administration (1,2). Recently, the 2006 anemia CPR noted that studies that have assessed intravenous iron efficacy in dialysis patients included few patients with ferritin >500 ng/ml and that the normal population has uniformly sufficient iron stores when ferritin exceeds 500 ng/ml (9). The opinion of the anemia workgroup was that there was insufficient evidence to support routine intravenous iron use when ferritin exceeded 500 ng/ml. Our results provide an important piece of that missing evidence.
The belief in the ineffectiveness of intravenous iron in patients with ferritin >500 ng/ml is not recent and has led some to call for withholding intravenous iron when ferritin exceeds 500 ng/ml (4,12–14). This belief is based on several studies that attempted to assess the relationship between ferritin and responsiveness to intravenous iron in dialysis patients. Unfortunately, these studies suffered from many weaknesses, including lack of a control arm and inclusion of few or no patients with pretreatment ferritin >500 ng/ml (4–7,15). It is interesting that most of these studies demonstrated that ferritin was not predictive of intravenous iron responsiveness, a finding echoed in our results. This suggests that use of ferritin in isolation as a clinical marker for withholding iron therapy is misplaced, hence the statement by 2006 KDOQI anemia workgroup that clinical decisions regarding use of iron "should be guided by results of iron status tests taken together with [hemoglobin] levels and ESA [erythropoiesis-stimulating agent] dose" (9). Until now, insufficient published clinical data existed to determine whether a ferritin upper limit of 500 ng/ml or even a higher limit of 800 ng/ml excludes anemic patients who would benefit from receiving intravenous iron therapy or these limits adequately ensure intravenous iron therapy to all iron-deficient patients. Because ferritin is not predictive of iron responsiveness in this study or several studies of dialysis patients with ferritin <500 ng/ml (4,5,7), it should not be used to guide therapy except when low (<300 ng/ml), when it is highly predictive of iron deficiency (4,5,16).
Setting a specific ferritin level beyond which intravenous iron should be withheld is problematic in dialysis patients for several reasons. First, ferritin is an acute-phase reactant, increasing in response to acute and chronic inflammation (17,18). Second, the coefficient of variation of ferritin is high, even among patients who do not receive iron (19). Last, hemodialysis patients have continuing blood and iron losses, and it is reasonable in most patients to replace these ongoing losses (1,2).
A ferritin limit also has been recommended as a result of safety concerns related to use of intravenous iron (12,13). The acute safety of ferric gluconate has been assessed in large, randomized trials (20–23). We found no difference in the incidence of serious or total adverse events between groups. However, our study was neither powered for a safety assessment nor sufficiently long to assess long-term safety. In addition, we found ferric gluconate administration to have no effect on inflammation as measured by CRP. A retrospective review of more than 59,000 US dialysis patients found that intravenous iron administration was associated with improved survival in all patient subgroups, including those with ferritin >500 ng/ml (24).
The long-term safety of iron at all ferritin target values remains untested by randomized trials. In addition, improvements in hemoglobin from iron and/or epoetin therapy are a surrogate for patient outcomes. This is highlighted by the direct harm that was observed with hemoglobin targets >13 g/dl in randomized trials of epoetin therapy that targeted a higher versus lower hemoglobin target (25,26).
Another potential concern of intravenous iron administration is iron overload and its attendant organ damage. Studies of patients with organ damage from hereditary hemochromatosis showed dramatically higher ferritin than that observed in our study or the general dialysis population (27,28). In addition, it is estimated that >20 g of excess iron is necessary to result in organ damage from hemochromatosis (29–31), an amount that few dialysis patients receive in their lifetime, even before accounting for ongoing iron losses. The increase in ferritin and TSAT that we observed after 1 g of iron is inconsistent with any serious concerns for iron overload.
The control group demonstrated a significant increase in hemoglobin. This may be due to the 25% increase in epoetin dosages at randomization, although no randomized, controlled trials have assessed this. The increase in hemoglobin also may reflect resolution of an inflammatory state, improved iron mobilization, or hemoglobin cycling. Last, baseline hemoglobin could be obtained before the first dialysis treatment of the week, when values are lower as a result of greater fluid gains, whereas in-study hemoglobin levels were obtained midweek, potentially enhancing the treatment effect of both arms.
The control group also demonstrated that withholding iron for 6 wk results in significant declines in ferritin and CHr, consistent with continued iron loss and worsening iron-restricted erythropoiesis. However, TSAT increased slightly. This may reflect resolution of inflammation in some patients (32) or be due to mobilization of iron from stores induced by the 25% increase in epoetin dosage. Although this mobilization was sufficient to increase the TSAT slightly, it was not sufficient to provide enough iron to maintain the CHr. CHr is not known to be affected by inflammation as TSAT is; therefore, its significant fall in the control group is consistent with worsening iron deficiency. In contrast, administration of 1 g of ferric gluconate maintained CHr, consistent with providing sufficient iron for erythropoiesis. Because the purpose of continued intravenous iron therapy is to replace ongoing iron losses, administration of low-dosage iron in these patients would be reasonable.
This study assessed the effectiveness of intravenous iron in patients who had ferritin of 500 to 1200 ng/ml and simultaneous TSAT 25% and remained anemic despite receiving adequate epoetin dosages; its results cannot be extrapolated to patients with higher ferritin and TSAT >25%. The KDOQI Anemia guidelines recommend maintaining TSAT >20%, a cutoff that has been reported to be approximately 80% sensitive for identifying iron deficiency (4). Our use of a TSAT 25% as an entry criterion effectively tested this recommendation, and we found that responsiveness to intravenous iron was similar in patients with TSAT above and below the median of 19%. This suggests that a TSAT lower limit of 20% may be too low, but further studies are needed in a less select population than we examined here. Patients with TSAT >25% may not have iron-restricted erythropoiesis, and further study is needed in this population also.
Another limitation of our trial is that no changes in epoetin dosages were allowed once patients received the initial 25% increase, whereas in clinical practice, epoetin dosages are adjusted frequently in response to changes in hemoglobin. However, this restriction allowed for assessment of the effect of intravenous iron without the confounding impact of epoetin dosage adjustments. In addition, an entry hemoglobin 11 g/dl was chosen to limit the likelihood that a marked increase in hemoglobin during the study would necessitate epoetin dosage reductions. It remains to be seen whether patients with >11 g/dl hemoglobin and lower epoetin dosages would respond similarly to intravenous iron.
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Conclusion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionDisclosuresReferences |
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500 ng/ml and TSAT 25% and are receiving adequate epoetin. Hemoglobin increases faster and higher after intravenous iron treatment than no iron therapy. Administration of intravenous iron in this patient population overcomes functional iron deficiency/inflammation-mediated reticuloendothelial blockade. Withholding intravenous iron in these patients can result in worsening of iron-restricted erythropoiesis. |
Disclosures |
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Acknowledgments |
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Footnotes |
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