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James M. Hollands; Edward F. Foote; Alfonso Rodriguez; John Rothschild; Steven Young
Am J Health-Syst Pharm. 2006;63(8):731-734.
Purpose: The safety of high-dose iron sucrose infusion in hospitalized patients with chronic kidney disease was studied.
Methods: A retrospective analysis was conducted at a 478-bed community hospital. A medical informatics search was performed to identify all hospitalized patients who were prescribed i.v. iron sucrose to deliver elemental iron 300 mg every other day for three doses between January and December 2002. Patients were eligible for inclusion in the analysis if they had chronic kidney disease, had an estimated creatinine clearance of <60 mL/min, and were prescribed the above regimen. Information on iron administration, vital signs, hematologic values, and iron indexes was gathered from patients' medical records. Medical record review was also used to identify possible adverse events.
Results: A total of 73 patients met eligibility criteria and received a total of 167 doses of iron sucrose. Twenty adverse events were judged as possibly related to iron sucrose administration and included nausea (n = 8 events), reduced blood pressure (n = 4), vomiting (n = 2), dysgeusia (n = 2), constipation (n = 2), fatigue (n = 1), and anxiety (n = 1). The majority of these adverse events were low in severity, as determined by an objective scale. No severe adverse events occurred. There was no association between infusion rate and the occurrence of potential adverse events (p = 0.44).
Conclusion: Every-other-day i.v. infusion of iron sucrose, to deliver elemental iron 300 mg/dose, was associated with adverse events that were relatively uncommon, minor in severity, and unlikely to require medical intervention.
Anemia is a common complication of kidney disease. Although erythropoietin deficiency is the most important cause of anemia in patients with kidney disease, iron deficiency is common and can complicate treatment by causing a relative resistance to epoetin alfa therapy. I.V. iron is widely used in hemodialysis patients but less so in patients with non-dialysis-dependent chronic kidney disease (NDDCKD). Although oral iron can be used in the latter patients, its use is limited by adverse effects, poor compliance, and the long time period required to replete iron stores.[1]
There are three commercially available i.v. iron products, iron dextran, iron sucrose, and iron ferric gluconate. The use of iron dextran has decreased because of the risk of anaphylaxis. Iron sucrose recently received Food and Drug Administration (FDA)-approved labeling for the treatment of iron deficiency anemia in NDDCKD patients, making it the first of the non-dextran iron supplements to receive such approval. Before this approval, both iron sucrose and iron ferric gluconate were indicated only for the treatment of iron deficiency in dialysis patients. However, these products have been safely used in patients with NDDCKD.[2-4] The most appropriate dose of i.v. iron in NDDCKD has yet to be determined. For hemodialysis patients, 100-125 mg of i.v. iron is given with each hemodialysis session until a total dose is reached, usually 1000 mg. This approach to dosing is very convenient for hemodialysis patients, but, for patients with NDDCKD, this regimen is not realistic, as it would necessitate multiple visits to an infusion clinic or physician's office. Further, the use of i.v. iron has not been studied in hospitalized patients with NDDCKD. This is important because iron deficiency is often diagnosed during hospitalization, but relatively short hospital stays limit the ability to deliver i.v. iron over a long time period.
In a dose-ranging study, Chandler et al.[2] studied high-dose iron therapy in both hemodialysis and NDDCKD dialysis patients and found that 300 mg of elemental iron, as i.v. iron sucrose, could be administered to patients every other month without any adverse events. We theorized that a regimen of iron sucrose that delivered 300 mg of elemental iron i.v. infused over one to two hours every other day for three doses would be a safe strategy for iron supplementation in hospitalized patients with NDDCKD and iron deficiency. The accelerated dosing schedule would allow the delivery of more iron to patients during their hospital stay. We incorporated this into our prescribing practices for our hospitalized patients and performed a retrospective analysis to determine the actual safety of this regimen.
Methods
This retrospective analysis was conducted at Wilkes-Barre General Hospital, a 478-bed community hospital in northeastern Pennsylvania. A medical informatics search was performed to identify all hospitalized patients who were prescribed i.v. iron sucrose to deliver elemental iron 300 mg every other day for three doses between January and December 2002. Iron sucrose containing elemental iron 300 mg was diluted in 100-200 mL of normal saline and infused over one to two hours (infusion rate based on the physician's preference). Patients were eligible for inclusion in the analysis if they had NDDCKD, defined as an estimated creatinine clearance (CLcr) of <60 mL/min, as determined by the Cockcroft-Gault method,[5] and were prescribed the above regimen. To avoid excluding patients who may have had the regimen discontinued because of an adverse event, all patients who received at least one dose of study medication were included in the analysis. Patients were excluded from the analysis if they had an estimated CLcr of ?60 mL/min, had dialysis-dependent CKD, or were prescribed the regimen described but did not receive any doses of the study medication.
Information on iron administration (frequency and rate), vital signs (measured at baseline and before, after, and during the study medication infusion, if available), and demographics was gathered from patients' medical records. Hematologic values (hemoglobin and hematocrit) and iron indexes (iron, total iron-binding capacity, transferrin, transferrin saturation, and ferritin) were also gathered; however, due to multiple confounding variables and the lack of outpatient follow-up, these data could not be assessed. Records were also reviewed to identify potential adverse events.
Appropriate institutional review board approval was obtained. Common Toxicity Criteria, version 2.0, was used to grade the severity of all adverse events.[6] Six adverse events were defined prospectively (reduced blood pressure, defined as a change in systolic blood pressure [SBP] of ?30 mm Hg; hypersensitivity or anaphylaxis; nausea; vomiting; constipation; and dysgeusia). The data collection tool also allowed for the identification of other adverse events during medication record review. Reduced blood pressure was used instead of frank hypotension to ensure that patients who were hypertensive at baseline and subsequently developed relative hypotension after medication administration were not excluded. The Student's t test was used to compare mean blood pressures before and after iron sucrose administration, and chi-square test was used to compare the number of reactions that occurred during each infusion duration. A p value of <0.05 was considered significant.
Results
A total of 100 patients were identified as receiving at least one 300-mg dose of elemental iron i.v. as iron sucrose. Of these patients, 73 had NDDCKD; the remaining 27 patients had a CLcr of ?60 mL/min and were not evaluated in our study.
Characteristics of the study patients are listed in Table 1. Patients were well represented throughout CKD stages 3 through 5. All but 1 of the patients was Caucasian. Only 6 patients were receiving erythropoietin before admission.
A total of 167 doses of iron sucrose were administered to the 73 study patients, of whom 22 (30%) received one dose of elemental iron i.v. as iron sucrose, 15 (21%) received two doses, and 36 (49%) received all three doses. Infusion durations were as follows: 1 hour (57 infusions), 1.5 hours (13 infusions), and 2 hours (66 infusions). The duration was not documented for 31 infusions. Reasons for not administering all three doses of elemental iron i.v. as iron sucrose included discharge or transfer to another institution (n = 22), death (n = 8), nausea (n = 1), and other reasons (n = 6). None of the deaths was attributed to iron sucrose administration. Four patients died as a progression of their underlying disease or admitting diagnosis (e.g., cancer, massive gastrointestinal bleeding). Two patients had their study medication discontinued due to a change in resuscitation status and died shortly thereafter. No deaths occurred during the actual infusion of medication.
During medical record review, 28 possible adverse events were identified, occurring in 22 patients. The most common were nausea (n = 11 events) and reduced blood pressure (n = 6). Other potential adverse events included vomiting (n = 3), dysgeusia (n = 3), constipation (n = 2), anxiety (n = 1), fatigue (n = 1), and rash (n = 1). A maximum of 20 events was judged to be possibly related to iron sucrose administration because they could not be attributed to other causes. These 20 events were nausea (n = 8), reduced blood pressure (n = 4), vomiting (n = 2), dysgeusia (n = 2), constipation (n = 2), fatigue (n = 1), and anxiety (n = 1). The eight other adverse events were either present at baseline or on days when the study medication was not administered and were not attributed to iron sucrose administration. The one patient who developed a rash several hours after receiving the study medication was rechallenged with the study medication at an out-patient clinic with no adverse sequelae. The rate of adverse events did not significantly differ by patient sex.
Reduced blood pressure was the second most common adverse reaction; however, the mean change in blood pressure for all patients was not statistically significant. The mean blood pressure before the start of medication administration was 132/64 mm Hg (mean arterial pressure [MAP], 86). Patients' blood pressure was measured an average of 2.2 hours before infusion. The mean blood pressure after administration was 131/63 (MAP, 86), measured an average of 4.1 hours after the start of the infusion. Of the four patients who did have a reduction of ?30 mm Hg in SBP, only one had an SBP of <100 mm Hg (SBP, 91 mm Hg). This patient developed low blood pressure four hours after study drug administration. No patients required treatment (i.e., fluid or vasoactive agents) for the reduction in blood pressure, and no infusions were stopped as a result of reduced blood pressure.
The majority of adverse events possibly related to iron sucrose therapy were low in severity, as determined by the Common Toxicity Criteria evaluation tool. Of those 20 adverse events, 12 were ranked as least severe (level 1) and the remaining 8 events were considered mild or moderate (level 2). Nausea was the only event that led to drug discontinuation (level 2). No severe events (level 4) occurred.
There was no association between infusion rate and the occurrence of potential adverse events (p = 0.44). Of the 20 adverse events apparently associated with iron sucrose, 6 occurred with the 1-hour infusions, 1 occurred with the 1.5-hour infusions, 3 occurred with the 2-hour infusions, and 10 occurred with infusions whose duration was not recorded.
Discussion
Iron repletion is a very common and necessary therapy for patients with NDDCKD. Oral iron supplementation is frequently not tolerated and sometimes inadequate to replete the body's iron stores. The maximum recommended dose of elemental iron i.v. as iron sucrose per infusion is one that would deliver 200 mg of elemental iron.[7] This would necessitate five infusions to achieve the goal of 1 g of iron. If doses higher than 200 mg are proven equally safe and effective, the time and economic burden of multiple infusions would be greatly reduced.
In our study, 300 mg of iron as iron sucrose administered every other day for three doses appeared to be well tolerated. Of the 167 infusions administered, only 20 adverse events (12.0%) occurred that were not present at baseline or on nontreatment days and could possibly be attributed to iron sucrose administration. However, because of the retrospective nature of the trial, causality could not be determined. The vast majority of the 20 adverse events were minor and did not require treatment. In only one patient was the study drug discontinued due to an adverse event (nausea). In no patients did the reduced blood pressure result in symptoms or discontinuation of therapy. The adverse-event rates seen in this trial are similar to those listed in the medication's package insert.[7]
In addition to the study conducted by Chandler et al.,[2] other clinicians have reported their experiences with high-dose iron sucrose. In a trial comparing oral iron to i.v. iron, 48 patients who received i.v. iron sucrose to deliver elemental iron 200 mg weekly for five doses had improved hematologic values and iron indexes and relatively few adverse effects.[8] Gastrointestinal disturbance was the most common adverse event, and no patients developed infusion-related hypotension. Schwenk and Blaustein[9] reported safely treating anemia in two patients with NDDCKD by administering elemental iron 500 mg i.v. as iron sucrose over 2 to 4 hours. No adverse events were seen. Similarly, Blaustein and colleagues[10] studied i.v. iron sucrose to deliver elemental iron 500 mg over 3.5 hours on two consecutive days in 107 CKD patients. The regimen was well tolerated and efficacious in restoring iron stores. Although other authors have reported the use of high-dose iron sucrose,[11-14] many of their studies used dialysis-dependent CKD patients, and the results probably cannot be extrapolated to patients with residual renal function.
It is important to note that iron administration can have implications other than the adverse events readily defined by this study. It has been postulated that iron overload can promote cardiovascular disease[15] and have a deleterious effect on immune status.[16] Although patients' iron stores were repleted with the regimen we described, the possibility of undetected reactions exists, and the retrospective nature of our study prevents us from detecting many of these long-term adverse events.
This study was limited by its retrospective nature. Documentation was sometimes inadequate. If an adverse event was not mentioned in nursing or physician notes, we assumed that the patient did not have an adverse event. In addition, because many of the patients in our study were not in the hospital's intensive care unit, their blood pressure was not always monitored immediately before and after the infusion. Sometimes blood pressure was measured several hours before and after the infusion. Although we evaluated "reduced blood pressure" instead of "hypotension" to ensure that all adverse events were identified, we may have overestimated the effect of iron sucrose on blood pressure. We defined reduced blood pressure as a 30 mm Hg or greater drop in SBP. It was not possible to take into account the other medications that the patients were on that could have affected their blood pressures. Also, the study investigators determined if an adverse event occurred, as well as potential causality, which could introduce investigator bias into the study. Because of the retrospective nature of our study, causality of adverse events could not be fully assessed.
Although our data suggest that this method of iron administration is safe, a potential drawback of this approach is that the cost of the drug will likely not be covered in a capitated hospital admission. Further study is needed to determine if the cost of the drug would offset potential reductions in health care costs over time, such as for reduced hospital admissions.
The results of our study support those of previous studies, indicating that high-dose iron therapy may be safe for certain patient populations. Our study also suggests that our regimen of i.v. iron therapy may be a safe and convenient way to manage iron deficiency in hospitalized CKD patients. A larger randomized controlled trial is needed to fully establish the maximally tolerated dose and rate of i.v. iron sucrose.
Conclusion
Every-other-day i.v. infusion of iron sucrose, to deliver elemental iron 300 mg/dose, was associated with adverse events that were relatively uncommon, minor in severity, and unlikely to require medical intervention.