Abstract
Background:
The ACC/AHA heart failure (HF) guidelines include a class IIb recommendation for intravenous (IV) iron replacement in patients with iron deficiency and New York Heart Association class II or III to improve functional status and quality of life. Several studies have addressed the use of IV iron formulations such as ferric carboxymaltose or iron sucrose in HF population; however, few studies focused on sodium ferric gluconate complex (SFGC).
Objectives:
To assess the safety and effectiveness of an IV SFGC administration protocol in patients hospitalized with HF.
Methods:
A retrospective cohort study was conducted. We included patients admitted to the HF service from September 2017 to March 2018. The primary outcome was the frequency of adverse reactions. The secondary outcome was the odds of HF readmissions between the 2 groups (IV SFGC vs. control).
Results:
Of the 123 patients, 70 received IV iron (SFGC group) and 53 did not receive IV iron (control group). Five (7%) patients of the 70 in the SFGC group experienced adverse events, which included hypotension (n = 2, 2.8%), fever (n = 2, 2.8%) and myalgia (n = 2, 2.8%). Nine (12.8%) and 18 (25.7%) were readmitted within 30 days and 6 months respectively. In the control arm, 5 (9.4%) and 14 (26.4%) were admitted within 30 days and 6 months respectively. The odds of HF readmission at 30 days [OR 1.4 (95% CI: 0.45, 4.5)] and at 6 months [OR 0.96 (95% CI: 0.43, 2.2)] were similar in those who did not receive IV iron compared to those who received IV iron.
Conclusions:
Sodium ferric gluconate complex given at an accelerated dosing schedule appears to provide a more efficient means to prescribe IV iron in the inpatient setting and is safe with a low frequency of hypotension, fevers, and myalgias.
Background
Patients with heart failure (HF) and iron deficiency have worse functional outcomes compared with patients with HF without iron deficiency. 1 Correction of iron deficiency in patients with HF has been associated with improved functional capacity and health-related quality of life. 1 The 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure includes a class IIb recommendation for intravenous iron (IV) replacement in patients with New York Heart Association (NYHA) class II and III HF and iron deficiency (defined as ferritin <100 ng/mL or 100-300 ng/mL if transferrin saturation <20%). 1
Evidence suggests that there is a high prevalence of iron deficiency with or without anemia in patients admitted to the hospital for acute decompensated HF regardless of severity. 2 Administration of IV iron in the inpatient setting presents unique challenges related to hospital formulary and length of inpatient hospitalization. 3 Additionally, iron studies are not routinely obtained and/or monitored in inpatient settings. 3 Several studies have focused on iron repletion using IV formulations such as ferric carboxymaltose (FCM) or iron sucrose in the HF population receiving ambulatory care. 4 -8 Few studies, however, have focused on sodium ferric gluconate complex (SFGC). 9,10 The findings from a recent prospective randomized clinical trial (IRON-OUT) suggested that high dose oral iron had marginal effect on iron stores replacement and exercise capacity of enrolled participants. 11 Failure to administer IV iron during hospital admission thus represents a missed opportunity to improve functional status and quality of life in patients with HF. 3
Our institution initiated its IV iron in HF protocol in September 2017. We currently use sodium ferric gluconate complex (SFGC) as the sole IV iron repletion agent in the inpatient setting. Our institution’s protocol recommends administering 250 mg SFGC/100 mL NS over 2 hours once daily for 4 days. This dosing schedule is accelerated compared to the package insert recommendations of 125 mg SFGC/100 mL NS over 1 hour for 8 doses approved by the Food and Drug Administration for treatment of iron deficiency in hemodialysis patients. 12 Also, IV iron when used in previous studies was administered over weeks to months and an equation was used to calculate the iron deficit. A simplified accelerated dosing schedule was chosen to better enable patients to receive a dose of at least 1000 mg prior to discharge.
Studies have examined the safety of higher dose (≥250 mg) in patients receiving dialysis. 13,14 To our knowledge, study by Reed et al 9 is the only one that assessed the safety of SFGC at an increased dose (250 mg IV twice daily) in patients with HF. However, due to the small sample size (13 patients) in Reed and colleagues’ study, we decided to trial a lower dose (250 mg IV once daily) at our institution. The safety and clinical impact of our institution’s accelerated dosing schedule of SFGC has yet to be studied extensively in the HF population. We leverage this research gap by assessing the safety and effectiveness of an IV SFGC administration protocol in hospitalized patients with HF.
Methods
This was a retrospective cohort study of HF patients admitted to a 686-bed academic tertiary medical center in Boston, Massachusetts. The institutional review board approved this study and waived informed consent. The electronic medical record (EMR) was used to identify patients admitted to the HF service over a 6-month period (September 2017 to March 2018). Figure 1 outlines the study enrollment procedures.
Study inclusion and exclusion.
Patients were included if they were 18 years or older, had a diagnosis of HF and was admitted to the HF service. Patients were divided into 2 cohorts. The first cohort included patients who received at least one dose of 250 mg IV SFGC while the second cohort did not receive IV iron during hospitalization. We included patients who received at least one dose of IV SFGC because we wanted to assess adverse effects associated with administering high dose (250 mg) of IV SFGC. Patients were excluded if they had a diagnosis of anemia of known etiology, received IV SFGC iron supplementation during the follow up period at our institution, had a left ventricular assist device (LVAD), died during the same admission as the receipt of SFGC or was placed on comfort measures only.
Our institution’s inpatient IV iron replacement eligibility guidelines recommended IV iron in patients who met the following criteria: 1) symptomatic HF with left ventricular ejection fraction (LVEF) < 45%, 2) Hgb ≤ 13.5 g/dL with no immediate need of transfusion, and 3) evidence of absolute/functional iron deficiency: ferritin <100 ng/mL or 100-300 ng/mL if transferrin saturation <20%. The decision to use IV iron (including dose and duration) was at the discretion of the clinical team although the recommendations were outlined in our institutional guidelines.
Demographic characteristics, HF related medication use, IV iron use characteristics (dose, duration and indication), ejection fraction, NYHA functional status at baseline, hemoglobin, iron indices (serum iron, serum ferritin, transferrin saturation), vital signs, readmission and mortality were extracted from the EMR. Home medications and NYHA class were based on admission documentation notes. Similarly, a diagnosis of HF was extracted from the admission notes and discharge summaries. We included both patients with heart failure with preserved ejection fraction (HFpEF) and patients with HF with reduced ejection fraction (HFrEF). The baseline ejection fraction was based on admission echocardiogram within 30 days of admission. Iron indices at baseline were also collected. Transferrin saturation (TSAT) was calculated using the following equation: Serum Iron/Total Iron Binding Capacity x 100. Subjects were deemed iron deficient if their ferritin was <100 ng/mL or between 100-300 ng/mL with a TSAT of <20%. Patients’ blood pressures and temperatures were collected at 3 time points: the closest available point prior to administration of IV iron, within 1 hour after administration of IV iron, and within 4 hours after administration of IV iron.
Outcomes
The primary outcome was the frequency of adverse reactions (hypotension, fever, or myalgia). We chose safety as a primary outcome due to concerns with the safety of IV iron especially when used as an accelerated regimen. We focused on hypotension, fever, and myalgia due to their objective measurability, frequency of occurrence, and likelihood to cause providers to discontinue IV iron administration. Hypotension was defined as an acute change in systolic blood pressure to less than or equal to 90 mmHg during and within 4 hours of IV SFGC administration. Myalgia was determined by reviewing the clinical team’s daily progress notes from the time IV iron was administered until discharge. Patients with documented complaints of myalgia, muscle weakness, soreness or aches on admission were excluded. Fever was defined as a temperature greater than or equal to 100.4° Fahrenheit (°F) during or within 4 hours of SFGC infusion. The secondary outcomes were the odds of HF readmission at 30 days and 6 months. Consistent with prior publication, 4 we chose 30 days and 6 months to assess the impact of IV iron on readmission rates because evidence suggests that benefit of IV iron administration using FCM was evident at 4 weeks and maintained through 6 months. A readmission was associated with HF if documented in the admission note as related to fluid overload, shortness of breath or HF exacerbation.
Statistical Analyses
Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at BIDMC.
15
Descriptive statistics was used to summarize study variables. The median (interquartile range, [IQR]) was used to describe non-parametric continuous variables. Categorical variables were evaluated using chi-square test. Continuous variables were evaluated using T-test for normally distributed data or Mann-Whitney U Test for skewed data. Odds ratios with 95% confidence intervals were generated to examine the association between IV iron administration and HF readmission rate. All analyses were conducted using SPSS v26.0 (IBM Corp, Armonk NY). A
Results
Baseline Characteristics
Of the 158 patients screened, 35 (22%) were excluded (Figure 1). Baseline characteristics were similar between groups. However, those who did not receive SFGC had a higher baseline TSAT, and hemoglobin. Additionally, those who received SFGC had higher use of isosorbide dinitrate/hydralazine for HF (Table 1). A total of 70 patients from the treatment arm and 53 patients in the control arm formed the analytic cohort.
Baseline Characteristics on Admission.
HF = heart failure; NYHA = New York Heart Association; BNP = beta natriuretic peptide; ACEI: angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; SGLT2 = sodium-glucose cotransporter 2 inhibitor.
Values are expressed as medians (IQR) for continuous variables and count (percentages) for categorical variables.
a 65 patients had ferritin and transferrin saturation reported in IV iron group. 13 patients had ferritin and transferrin saturation reported in control group.
b 61 patients had BNP reported in IV iron group, 46 patients had BNP reported in control group.
Iron Administration
The treatment arm received a total of 246 SFGC administrations. All doses administered were 250 mg except for one administration of 125 mg. Each patient received a mean total SFGC dose of 853 mg ± 264 mg. The mean number of doses administered per patient was 3.51 ± 1.164. Forty-six (65.7%) patients received all 4 doses of SFGC while 56 (80%) patients received ≥3 doses. Of the 24 (34.3%) patients who did not complete therapy, 6 received only 1 dose.
Adverse Events
Of the 70 patients who received SFGC, 5 (7.1%) patients developed adverse reactions [fevers, n = 2, 2.8%; hypotension, n = 2, 2.8%; myalgia, n = 2, 2.8%]. All patients who had documented adverse reactions received their full course of 1000 mg of SFGC except for 1 patient who was discharged prior to completion of SFGC therapy. Of the patients with hypotension, this adverse event did not prohibit continuation of therapy. Of the patients who developed fever, 1 patient had both fever and myalgias. The patient experienced fever on days 1 and 2 of therapy and remained afebrile on days 3 and 4. Muscle soreness was documented 1 day after the last dose of SFGC repletion, and the patient complained of leg weakness 8 days after repletion. The second patient developed fever on the first day of IV iron administration, 1 hour after receiving the dose. The patient remained afebrile through subsequent doses of SFGC.
Of note, 38 out of 70 (54%) patients who received IV iron were prescribed antimicrobials during the hospital course. Of those patients, 11 out of 38 (29%) patients had evidence of leukocytosis (white blood cell count >12 k/uL).
Heart Failure Readmission
Within 30 days, 9 out of 70 (12.8%) patients who received IV iron had a HF readmission compared to 5 out of 53 (9.4%) patients in the control group. Within 6 months, 18 out of 70 (25.7%) patients who received IV iron had a HF readmission compared to 14 out of 53 (26.4%) patients in the control group.
The odds of HF readmission at 30 days [OR 1.4 (95% CI 0.45-4.5)] or 6 months [OR 0.96 (95% CI 0.43-2.2)] were similar in those who did not receive IV iron compared to those who received IV iron. The results were the same at 30 days [OR 1.6 (95% CI 0.49-5.2)] or 6 months [OR 1.2 (95% CI 0.53-2.8)] when patients who received <3 doses of IV iron were excluded. The median time to HF readmission was 36.5 days (IQR 10-99) in the IV iron group compared to 44 days (IQR 18.25-74) in the control group.
Discussion
Our investigation focused on assessing the safety and effectiveness of an IV SFGC administration protocol in hospitalized patients with HF. Consistent with prior studies, 4 we found that administration of IV SFGC at 250 mg/day was associated with a low frequency of adverse drug reactions. In the single-arm, open-label study conducted by Reed et al, 9 13 patients received a higher total daily dose (250 mg IV twice a day) of sodium ferric gluconate compared to our study. Overall, patients tolerated this iron repletion schedule well, with gastrointestinal discomfort being the most common side effect. Although we included all patients even if they did not complete the full 4-day SFGC therapy, a high number of patients in our study received at least 3 out of 4 doses of high-dose SFGC. This suggests the feasibility of accelerated dosing of IV iron in hospitalized patients with HF. Of the patients who did not complete the full course of IV iron during their hospitalization, the majority were discharged prior to its completion. From a care delivery standpoint, administration of IV iron during hospitalization is convenient and would potentially alleviate stress for iron-deficient HF patients who would have to consume more health services in the outpatient setting after discharge.
In the recently published AFFIRM-AHF trial, 16 the first dose of FCM was administered shortly before discharge in a high-risk population of patients with stabilized acute HF. Subsequent doses were administered at follow-up. Study findings showed that HF hospitalization was reduced with FCM treatment compared with placebo. Similarly, in the CONFIRM-HF trial, 5 FCM showed significant reduction in the risk of hospitalizations for worsening HF. In contrast, in the FAIR-HF trial, 4 there was no difference in the proportion of patients hospitalized for worsening HF. In our study, administration of SFGC did not appear to significantly impact HF readmission rate at 30 days and 6 months. However, this study was not powered to detect these differences. At baseline, lower TSAT and hemoglobin levels were observed in the IV iron group compared to the control group. As iron deficiency and anemia are known to be associated with worse outcomes in HF, 1 it is plausible that the risk of re-hospitalization in the IV iron group was higher at baseline compared to the control group. Despite this, the hospitalization rates were similar in both the IV iron and control group which may suggest that IV iron repletion was impactful. Additionally, higher doses of IV iron were given over several weeks in previous trials and not all potential confounding variables that may impact the readmission rates were controlled for.
Compared to the fixed accelerated dosing used in our study, previous studies 4,5 used a formula to estimate the total amount to IV iron required for each patient with doses administered over weeks to months. The mean dose of ferric carboxymaltose (FCM) administered in the CONFIRM-HF and AFFIRM-AHF trials, 5,16 were 1500 mg and 1350 mg respectively over the 1-year study period compared to 853 mg over a 4- day period in this study. In the FAIR-HF study, 4 patients received a median of 6 FCM injections (200 mg each) during the weekly correction phase which was followed by a monthly maintenance phase over the 6-month study period. The appropriate dose for use in inpatient administration of IV iron remains unclear.
Interestingly, more than half of the patients who received IV iron in our study also received antimicrobials during the index hospitalization. While infection was not a contraindication to IV iron administration per our institutional guidelines, there are plausible biological mechanisms that IV iron may promote microbial growth and disrupt the body’s immune response, thus increasing the risk for infection. 17 However, evidence linking IV iron with increased infection risk is limited. Future studies however should examine worsening outcomes in the setting of concomitant infection and IV iron use in hospitalized HF patients.
When compared to previous studies, 4,5 this study supports existing knowledge that accelerated dosing of SFGC in patients with HF is safe but importantly underscores the need for larger prospective studies. Although unlikely to have a significant impact on overall outcome, the effect of using alternative IV iron formulations warrant further investigation.
Limitations
This retrospective cohort study has several limitations. Our study was limited to a single institution and thus, we heavily relied on the accuracy of providers’ EMR documentation. Adverse events such as myalgia may not have been documented if it were not closely associated with SFGC administration. We did not collect information on the frequency of hypophosphatemia. Since hypophosphatemia may explain myalgias, it would have been beneficial to know the frequency in our study. Additionally, hypophosphatemia is particularly common with newer IV iron preparations such as FCM while its incidence is less known with SFGC.
Our guidelines also recommended assessment of ferritin and TSAT prior to IV iron administration, but these laboratory studies were not consistently obtained in patients with HF. The decision to use IV iron was at the discretion of the clinical team and thus, few patients received IV iron despite not meeting the threshold for iron deficiency. Our sample size was small and the study was not powered to determine a difference in adverse events and clinical outcomes. Readmission rates were only captured per EMR documentation. NYHA class documentation on admission was inconsistent; therefore, it was not a reliable indicator of improvement in functional status.
Conclusion
Sodium ferric gluconate complex given at an accelerated dosing schedule appears to provide a more efficient means to prescribe IV iron in the inpatient setting and is safe with a low frequency of hypotension, fevers, and myalgias. Although readmission for HF is complex with likely multifactorial etiologies, larger studies to assess the clinical impact of inpatient administration of SFGC on functional capacity and readmission rates remain important.
Footnotes
Acknowledgments
We thank Lynne Sylvia, PharmD, for her expertise and thoughtful review of this manuscript.
Author Contributions
Ifeoma Mary Eche, Kathryn Owen, Parth Patel, and Marwa Sabe conceived and designed the study. Ifeoma Mary Eche, Kathryn Owen, and Parth Patel were involved in data acquisition. Ifeoma Mary Eche, Kathryn Owen, Ijeoma Julie Eche, and Marwa Sabe analyzed the data. Ifeoma Mary Eche and Kathryn Owen prepared the manuscript. Ijeoma Julie Eche, Parth Patel, and Marwa Sabe reviewed the manuscript. Ifeoma Mary Eche, Kathryn Owen, Ijeoma Julie Eche, Parth Patel, and Marwa Sabe approved the manuscript.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
