What is the data for use of sodium ferric gluconate IV in patients with HF with preserved ejection fraction? Do you have to confirm patients with HFpEF have iron deficiency anemia?

What is the data for use of sodium ferric gluconate IV in patients with HF with preserved ejection fraction? Do you have to confirm patients with HFpEF have iron deficiency anemia?

Comment by InpharmD Researcher

Available studies suggest that intravenous sodium ferric gluconate is safe and efficient to provide IV iron supplementation to hospitalized patients with advanced heart failure. While the studies did not specifically examine patients with HFpEF, the findings among reduced and preserved heart failure populations indicate that IV sodium ferric gluconate can improve hematologic parameters and exercise capacity in these high-risk heart failure patients. Patients included in these trials typically were required to have anemia of known etiology, and some studies excluded patients of unknown etiology, suggesting that presence of iron deficiency anemia remains a requirement.

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What is the data for use of sodium ferric gluconate IV in patients with HF with preserved ejection fraction? Do you have to confirm patients with HFpEF have iron deficiency anemia?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-4 for your response.

IV Sodium Ferric Gluconate Complex in Patients Hospitalized Due to Acute Decompensated Heart Failure and Iron Deficiency
Design	Retrospective study N= 1,863
Objective	To assess the effect of IV Sodium Ferric Gluconate Complex (SFGC) on readmissions in patients hospitalized due to Acute Decompensated Heart Failure (ADHF) and iron deficiency
Study Groups	IV SFGC (n= 122) Control (n= 718)
Inclusion Criteria	Adults (>18 years) with primary diagnosis of ADHF, NTproBNP >300 pg/ml or >800 pg/ml with atrial fibrillation (AF), hemoglobin 8-13 mg/dL, ferritin <100 mcg/L or ferritin 100-400 mcg/L with transferrin saturation <20%, treatment with IV loop diuretics
Exclusion Criteria	Cardiogenic shock, active bleeding, active malignancy, recent major surgery, recent blood transfusion, hemochromatosis, chronic liver disease, hemolytic anemia, myelodysplastic disorder, chronic lung disease, HIV/AIDS, immunosuppressive therapy, erythropoietin, renal dialysis, or IV iron in the previous 30 days
Methods	Patients were treated with or without IV SFGC on top of standard medical therapy. Median dosage of IV SFGC was 125 mg over 2 days.
Duration	Follow-up: 1 year
Outcome Measures	Primary: Readmission due to ADHF at 30 days, 3 months, and 1 year Secondary: All-cause mortality at 30 days, 3 months, and 1 year
Baseline Characteristics		IV SFGC (n= 122)	Control (n= 718)
	Age, years	71.66	74.85
	Male	59.8%	49.9%
	Ejection fraction	55%	56%
	Comorbidities Ischemic heart disease Atrial fibrillation Diabetes mellitus Chronic kidney disease Hypertension Hyperlipidemia Smoker	45.1% 58.2% 64.8% 52.5% 83.6% 67.2% 35.2%	33.7% 44.4% 64.2% 39.8% 88.7% 67.3% 33.8%
	Lab parameters Hemoglobin, g/dL Mean corpuscular volume, fL Ferritin mcg/L Transferrin saturation Creatinine, mg/dL Brain natriuretic peptide, pg/mL	10.9 84 82 11.3 1.39 611	10.9 84 75 11 1.23 617
	Medications at discharge Beta-blockers Renin-angiotensin system inhibitors Mineralocorticoid receptor antagonists	86.1% 63.9% 41%	85.1% 69.6% 31.5%
	More patients in the iron administered group had AF and ischemic heart disease, while more patients in the control group had chronic kidney disease.
Results	Endpoint	IV SFGC (n= 122)	Control (n= 718)	p-value
	Readmission due to HF, 30 days	6.5%	6.5%	0.99
	Readmission due to HF, 3 months	15.5%	11.5%	0.21
	Readmission due to HF, 1 year	27.9%	24.8%	0.54
	All-cause mortality, 30 days	2.4%	2.5%	0.97
	All-cause mortality, 3 months	7.4%	6.4%	0.69
	All-cause mortality, 1 year	25.4%	25.6%	0.99
Adverse Events	No adverse effects were recorded among patients treated with IV SFGC.
Study Author Conclusions	High risk patients hospitalized with ADHF and treated with IV SFGC showed comparable ADHF readmission rates to those who did not receive iron supplementation.
InpharmD Researcher Critique	The study's retrospective design and unmatched population are limitations. The low median dose of IV SFGC may have impacted the lack of observed benefit. The study also did not account for post-discharge iron treatment, and only included readmissions to the same medical center.

References:

Borreda I, Zukermann R, Epstein D, Marcusohn E. IV Sodium Ferric Gluconate Complex in Patients Hospitalized Due to Acute Decompensated Heart Failure and Iron Deficiency. J Cardiovasc Pharmacol Ther. 2022;27:10742484211055639. doi:10.1177/10742484211055639

Safety and Effectiveness of an Accelerated Intravenous Iron Administration Protocol in Hospitalized Patients With Heart Failure
Design	Retrospective cohort study N= 123
Objective	To assess the safety and effectiveness of an IV sodium ferric gluconate complex (SFGC) administration protocol in patients hospitalized with HF
Study Groups	IV iron (SFGC group; n= 70) Control (n= 53)
Inclusion Criteria	Patients 18 years or older, diagnosed with HF, admitted to the HF service
Exclusion Criteria	Diagnosis of anemia of known etiology, received IV SFGC during follow-up, had LVAD, died during admission, or placed on comfort measures only
Methods	IV SFGC was administered at 250 mg/100 mL NS over 2 hours once daily for 4 days. Data was collected from electronic medical records (EMR) included demographics, HF medication use, iron indices, and vital signs.
Duration	September 2017 to March 2018 Follow up: 6 months
Outcome Measures	Frequency of adverse reactions (hypotension, fever, myalgia), odds of HF readmissions at 30 days and 6 months
Baseline Characteristics		SFGC (n= 70)	Control (n= 53)
	Age, years	72	73
	Female	43%	38%
	Weight, kg	86.5	85
	Primary admission diagnosis of HF exacerbation	72.9%	86.8%
	Ejection fraction	37%	35%
	NYHA I II III IV	11.4% 21.4% 40% 27.2%	13.2% 22.6% 24.5% 39.7%
Results	Endpoint	SFGC (n= 70)	Control (n= 53)	Odds ratio (95% confidence interval [CI])
	HF readmission within 30 days	9 (12.8%)	5 (9.4%)	1.4 (0.45 to 4.5)
	HF readmission within 6 months	70 (25.7%)	14 (26.4%)	0.96 (0.43 to 2.2)
	Median time to readmission, days	36.5	44	-
Adverse Events	Hypotension (2.8%), fever (2.8%), myalgia (2.8%)
Study Author 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.
InpharmD Researcher Critique	The study supports the safety of accelerated dosing of SFGC in HF patients but is limited by its retrospective design, small sample size, and single-institution setting. The study was not powered to detect differences in clinical outcomes, and the decision to use IV iron was at the discretion of the clinical team, which may introduce bias.

References:

Eche IM, Owen KL, Eche IJ, Patel P, Sabe M. Safety and Effectiveness of an Accelerated Intravenous Iron Administration Protocol in Hospitalized Patients With Heart Failure. J Cardiovasc Pharmacol Ther. 2021;26(4):365-370. doi:10.1177/1074248421989871

Effects of an Accelerated Intravenous Iron Regimen in Hospitalized Patients With Advanced Heart Failure and Iron Deficiency
Design	Prospective, single-arm, open-label study N= 13
Objective	To evaluate the short-term efficacy and safety of an accelerated intravenous iron regimen in hospitalized patients with HF and iron deficiency
Study Groups	Study patients (N= 13)
Inclusion Criteria	Patients with NYHA class III-IV heart failure, anemia (hemoglobin ≤12.0 g/dl), and iron deficiency (ferritin <100 ng/ml, or ferritin 100-300 ng/ml with transferrin saturation <20%)
Exclusion Criteria	Anemia of other known etiology, active bleeding, infection, immunosuppression therapy, renal replacement therapy, pregnancy, or recent iron therapy, erythropoietin-stimulating agents, or blood transfusions
Methods	Patients received sodium ferric gluconate 250 mg in 100 ml of normal saline intravenously over 2 hours twice/day until the iron deficit was corrected or the patient was discharged; no test doses were administered. Monitoring included adverse events and changes in blood pressure and heart rate.
Duration	April 2011 to December 2013 Treatment lasted a mean of 3.4 days with a follow-up of 13.1 days.
Outcome Measures	Change in serum hemoglobin level and serum ferritin level
Baseline Characteristics		Study patients (N= 13)
	Age, years	58.9
	Male	53.8%
	Race Caucasian African American	38.5% 61.5%
	Weight, kg	94.9
	Body mass index, kg/m²	33.9
	NYHA class III IV	53.8% 46.2%
	Ejection fraction, %	20.2
Results	Endpoint	Study patients (N= 13)	95% confidence interval (p-value)
	Hemoglobin level increase, g/dl	1.2	0.45 to 1.9 (p= 0.005)
	Ferritin level increase, ng/ml	364.2	129.7 to 598.7 (p= 0.007)
Adverse Events	Gastrointestinal issues (nausea, constipation, abdominal discomfort), injection site reactions, headache, dyspnea, back pain, leg cramps, bladder discomfort, fatigue, chills
Study Author Conclusions	An accelerated intravenous iron regimen improved hematologic parameters and was well tolerated in hospitalized patients with advanced heart failure. A randomized multicenter trial comparing this regimen with placebo is warranted.
InpharmD Researcher Critique	Limitations include the small sample size, single-arm design, and short follow-up period, which may limit the generalizability of the findings.

References:

Reed BN, Blair EA, Thudium EM, et al. Effects of an accelerated intravenous iron regimen in hospitalized patients with advanced heart failure and iron deficiency. Pharmacotherapy. 2015;35(1):64-71. doi:10.1002/phar.1525

IV Sodium Ferric Gluconate Complex in Patients With Iron Deficiency Hospitalized due to Acute Heart Failure— Investigator Initiated, Randomized Controlled Trial
Design	Prospective, single-blind, investigator-initiated, randomized controlled trial N= 34
Objective	To evaluate the efficacy of IV sodium ferric gluconate complex (SFGC) in improving exercise capacity in patients with acute heart failure and iron deficiency
Study Groups	Treatment (n= 19) Control (n= 16)
Inclusion Criteria	Hemoglobin levels of 8-14 mg/dL, ferritin levels <100 ng/mL or ferritin 100-300 ng/mL with transferrin saturation <20%, NT-proBNP level >300 pg/mL (or >800 pg/mL with atrial fibrillation), treatment with IV loop diuretics
Exclusion Criteria	Inability to perform the 6-minute walk test, cardiogenic shock, recent blood transfusion or IV iron, myelodysplastic disorder, chronic lung disease, renal dialysis, immunosuppressive therapy
Methods	Patients received 125 mg of IV SFGC per day for 3-5 days. Follow-up included 6-minute walk tests at 12 and 24 weeks post-discharge.
Duration	Treatment: 3 to 5 days Follow-up: 6 months
Outcome Measures	Primary: Change in 6-minute walk test (6MWT) distance at 3 and 6 months Secondary: Change in NYHA class, all-cause mortality, hospitalizations due to heart failure
Baseline Characteristics		Treatment (n= 18)	Control (n= 16)
	Age, years	70	74.5
	Male	66.7%	68.8%
	Ejection fraction	30%	40%
	NYHA, score	3	3
	LVEF >50%	4 (22.2%)	4 (25%)
	Comorbidities Ischemic heart disease Atrial fibrillation Diabetes mellitus Chronic kidney disease Hypertension Hyperlipidemia Smoker	72.2% 55.6% 31.1% 66.7% 94.4% 88.9% 11.1%	43.8% 31.3% 75.0% 75.0% 93.8% 87.5% 25.0%
Results	Endpoint	Treatment (n= 19)	Control (n= 15)	p-value
Results	Clinical outcomes NYHA improved ≥ 1 at 3 months NYHA improved ≥ 1 at 6 months 6MWT change at 3 mo, meters 6MWT change at 6 mo, meters Readmission due to HF, 3 months Readmission due to HF, 6 months All-cause mortality, 6 months	14 (77.8%) 10 (55.6%) 21.6 (-44.3 to 77.1) -5.0 (-28.0 to 94.8) 3 (16.67%) 4 (22.2%) 3 (16.7%)	11 (68.8%) 7 (43.8%) 24.1 (-15 to 108) 46 (-12.2 to 92.7) 1 (6.25%) 3 (18.8%) 0	0.55 0.49 0.65 0.77 0.68 0.86 0.27
Adverse Events	No adverse events related to IV SFGC were reported. Hospitalizations and mortality events were not related to the study drug.
Study Author Conclusions	IV SFGC-treated patients had comparable 6-minute walk test results at 3 and 6 months despite more severe heart failure with higher baseline NT-proBNP levels.
InpharmD Researcher Critique	Limitations include a small sample size, early termination due to COVID-19, and lack of long-term follow-up data.

References:

Marcusohn E, Borreda I, Hellman Y, et al. IV Sodium Ferric Gluconate Complex in Patients With Iron Deficiency Hospitalized due to Acute Heart Failure-Investigator Initiated, Randomized Controlled Trial. J Cardiovasc Pharmacol. 2022;80(2):194-196. Published 2022 Aug 1. doi:10.1097/FJC.0000000000001287