Iron Deficiency in Chronic Heart Failure

Luke Dotson, PharmD

PGY-1 Pharmacy Resident
Learning Objectives:
● Explain the importance of addressing iron deficiency in chronic heart failure.
● Determine if a heart failure patient has an iron deficiency based on pertinent
laboratory information.
● Evaluate different products and administration routes for iron replacement in heart
failure patients.
● Identify eligible CHF patients for the recommended iron replacement therapy based
on the most recent guidelines.
● Develop a treatment plan for eligible heart failure patients with iron deficiency.
Patient Case
Patient Case:
● BW is a 74 year old female with a history of HFrEF, ICD placement, CAD, AFib, HTN, HLD,
anemia, and CKD who presents to The Heart and Vascular Center for scheduled CHF follow-up
appointment.

Current Medications:
amiodarone 200 mg PO daily metolazone 2.5 mg PO daily PRN edema

apixaban 5 mg PO BID metoprolol succinate 50 mg PO daily

aspirin 81 mg PO daily oxybutynin 5 mg PO daily

atorvastatin 40 mg PO QHS pantoprazole 20 mg PO daily

ezetimibe 10 mg PO daily potassium chloride 10 mEq PO daily

ferrous sulfate 325 mg PO BID torsemide 40 mg PO daily

Patient Case:
● BW is a 74 year old female with a history of HFrEF, ICD placement, CAD, AFib, HTN, HLD,
anemia, and CKD who presents to The Heart and Vascular Center for scheduled CHF follow-up
appointment.

Current Medications:
amiodarone 200 mg PO daily metolazone 2.5 mg PO daily PRN edema

apixaban 5 mg PO BID metoprolol succinate 50 mg PO daily

aspirin 81 mg PO daily oxybutynin 5 mg PO daily

atorvastatin 40 mg PO QHS pantoprazole 20 mg PO daily

ezetimibe 10 mg PO daily potassium chloride 10 mEq PO daily

ferrous sulfate 325 mg PO BID torsemide 40 mg PO daily

Patient Case:
● Patient Labs/Tests:
○ LVEF: 30%
○ Weight: 89.3 kg
○ RBC: 3.3 x 10^6/mcL
○ Hgb: 12.1 g/dL
○ MCV: 93.6 fL
○ HCT: 35.5%
○ Ferritin: 644.5 ng/mL (μg/L)
○ TSAT: 28%
○ Potassium: 3.6 mmol/L
○ Scr: 2.1 mg/dL
○ eGFR: 23 mL/min/1.73m2
What is anemia?
Anemia:
● Anemia occurs when you do not have enough red blood cells or when your
red blood cells do not function properly.
○ Hemoglobin less than 13.5 gm/dl in males
○ Hemoglobin less than 12.0 gm/dl in females

Anemia. Hematology.org. American Society of Hematology. Accessed August 14, 2023.

https://www.hematology.org/education/patients/anemia#:~:text=Anemia%20occurs%20when%20you
%20do,American%20Society%20of%20Hematology.
 Types of Anemia:

Anemia: Overview and types: Concise medical knowledge. Lecturio.

https://www.lecturio.com/concepts/anemia-overview/. Published July 4, 2022.
Accessed August 14, 2023.
 Laboratory Marker: Normal Range:

Men: 5-6x106 cells/uL

Red Blood Cells (RBC): Women:
4-5x106 cells/uL
Men: 14-17 mg/dL
Hemoglobin (Hgb): Women: 12-15 mg/dL
Men:
41%-50%
Hematocrit (Hct): 36%-44%
Women:

Mean Corpuscular Volume (MCV): Adults: 80-100mm3

RBC Distribution Width (RDW): Adults: 11.5%-14.5%

Ferritin: (iron stores) Adults: 15-200 ng/mL

Iron: (ready to use, bound to transferrin) Adults: 40-160 mcg/dL

Transferrin: (protein that transports iron) Adults: 200-360 mg/dL

Transferrin Saturation (TSAT): Adults: 20%-50%

Iron Deficiency
 Think - Pair - Share:
● Why might iron deficiency be detrimental in heart failure?
● Should all iron deficiency be treated in heart failure?
● What would you recommend for treating iron deficiency in heart
failure?
Alnuwaysir RIS, Hoes MF, van Veldhuisen DJ, van der Meer P, Grote Beverborg N. Iron
Deficiency in Heart Failure: Mechanisms and Pathophysiology. J Clin Med.
2021;11(1):125. Published 2021 Dec 27. doi:10.3390/jcm11010125
Sindone A, Doehner W, Manito N, et al. Practical Guidance for Diagnosing
and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and
How?. J Clin Med. 2022;11(11):2976. Published 2022 May 25.
doi:10.3390/jcm11112976
Iron Deficiency:

ABSOLUTE VS. FUNCTIONAL

● Inadequate iron stores (ferritin) ● Iron restricted erythropoiesis

● Ferritin ≤15 μg/L (historical) ● Decreased bioavailability and
● Ferritin ≤30 μg/L (proposed) “iron trapping”
● Ferritin <100 μg/L in CHF ● May occur even with normal iron
○ Ferritin is an acute phase stores
reactant, “falsely” ● TSAT ≤20% and elevated/normal
elevated with age, chronic ferritin levels (100 to 300 μg/L in
inflammation
HF)

Shuoyan Ning, Michelle P. Zeller; Management of iron deficiency. Hematology Am Soc Hematol Educ Program 2019;
Published 2019 (1): 315–322. doi: https://doi.org/10.1182/hematology.2019000034
Iron Deficiency in Heart Failure
 40 - 70%
The percentage of CHF patients that have an iron deficiency,
regardless of ejection fraction
Sindone A, Doehner W, Manito N, et al. Practical Guidance for Diagnosing and Treating
Iron Deficiency in Patients with Heart Failure: Why, Who and How?. J Clin Med.
2022;11(11):2976. Published 2022 May 25. doi:10.3390/jcm11112976
What is the cause?
Sindone A, Doehner W, Manito N, et al. Practical Guidance for Diagnosing
and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and
How?. J Clin Med. 2022;11(11):2976. Published 2022 May 25.
doi:10.3390/jcm11112976
Do We Care?
Why We Care:
1. There are overlapping symptoms between CHF and iron deficiency.
2. Iron deficiency independently predicts morbidity and mortality in CHF patients,
regardless of anemia status.
3. Appropriate iron replacement therapy has been shown to improve functional capacity
and prevent recurrent hospitalizations from heart failure.

Sindone A, Doehner W, Manito N, et al. Practical Guidance for Diagnosing

and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and
How?. J Clin Med. 2022;11(11):2976. Published 2022 May 25.
doi:10.3390/jcm11112976
To Treat or Not to Treat?
What Should We Use?
Iron Deficiency Treatment Options - Oral

Active Ingredient Tablet Strength Elemental Iron

Ferrous fumarate 300mg 100mg (33%)

Ferrous sulfate 325mg 65mg (20%)

Ferrous gluconate 300mg 30mg (10%)

Polysaccharide iron
Varies 100%
complex
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure

Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the
American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears
in J Am Coll Cardiol. 2023 Apr 18;81(15):1551]. J Am Coll Cardiol. 2022;79(17):e263-e421. doi:10.1016/j.jacc.2021.12.012
Iron Deficiency Treatment Options - IV
Which One?
 Is there Anemia?
● With anemia:
○ Venofer (iron sucrose)
○ Injectafer (ferric carboxymaltose)
● Without anemia:
○ Injectafer (ferric carboxymaltose)
■ First approved 2013 for iron deficiency anemia
■ Approved June 6, 2023 for iron deficiency (+/- anemia) in Heart Failure

Sindone A, Doehner W, Manito N, et al. Practical Guidance for Diagnosing

and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and
How?. J Clin Med. 2022;11(11):2976. Published 2022 May 25.
doi:10.3390/jcm11112976
 Injectafer (ferric carboxymaltose)
● Nanomedicine
● Colloidal iron (3+) - not in labile form
● Tightly packed, complexed with
carboxymaltose polymer
● Absorbed by macrophages, converted to
labile form
● Replenishes ferritin stores, increases
TSAT
● Benefits in 6-min walk test distance
● Improvement in fatigue score

Injectafer [package insert]. American Regent Inc.

Shirley, New York; 2021
 Injectafer (ferric carboxymaltose)
● Approved for treatment of iron deficiency (+/-
anemia) in HF
● Dextran free - no test dose required
● Minimizes release of labile iron
● Favorable safety and side effect profile
● No dose adjustment for renal/hepatic
dysfunction
● 75% of patients had resolution of iron
deficiency following 2 or less injections

Injectafer [package insert]. American Regent Inc.

Shirley, New York; 2021
Injectafer (ferric carboxymaltose)
Injectafer. Lexi-Drugs. Lexicomp. Wolters Kluwer
Health, Inc. RIverwoods, IL. Available online at
http://lexi.com. Accesses August 14, 2023.
Injectafer. Lexi-Drugs. Lexicomp. Wolters Kluwer
Health, Inc. RIverwoods, IL. Available online at
http://lexi.com. Accesses August 14, 2023.
 Injectafer (ferric carboxymaltose)
● Adverse effects:
○ Well tolerated
○ Hypersensitivity - observe for 30 mins following administration
○ Hypertension - transient
○ Hypophosphatemia
● Monitoring:
○ Hematology and iron
○ Serum phosphate
○ Signs/symptoms of hypersensitivity
○ Signs/symptoms of hypotension

Injectafer [package insert]. American Regent Inc.

Shirley, New York; 2021
Who Should Receive IV Iron?
 2021 ESC Guidelines:

Sindone A, Doehner W, Manito N, et al. Practical Guidance for Diagnosing

and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and
How?. J Clin Med. 2022;11(11):2976. Published 2022 May 25.
doi:10.3390/jcm11112976
 2021 ESC Guidelines:

Sindone A, Doehner W, Manito N, et al. Practical Guidance for Diagnosing

and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and
How?. J Clin Med. 2022;11(11):2976. Published 2022 May 25.
doi:10.3390/jcm11112976
Injectafer. Lexi-Drugs. Lexicomp. Wolters Kluwer
Health, Inc. RIverwoods, IL. Available online at
http://lexi.com. Accesses August 14, 2023.
Who Should NOT Receive FCM?
 Contraindications/Precautions
● Hypersensitivity to ferric carboxymaltose
● Hemoglobin >15 g/dL
● Pregnancy - does not cross placenta, fetal risk cannot be ruled out
● Breastfeeding - present in breast milk, infant risk cannot be ruled out

Injectafer [package insert]. American Regent Inc.

Shirley, New York; 2021
 Injectafer Summary:
● FDA approved with or without anemia in CHF
● More expensive than Venofer (5x) - formulary (Category B)
● Dosing based on wt (kg) and hemoglobin
● Administration:
○ Administer as slow IV push (if dose is 750 mg or less)
○ Dilute in NS, administer over 15 mins (if above 750 mg)

Injectafer [package insert]. American Regent Inc.

Shirley, New York; 2021
Patient Case
Patient Case:
● BW is a 74 year old female with a history of HFrEF, ICD placement, CAD, AFib, HTN, HLD,
anemia, and CKD who presents to The Heart and Vascular Center for scheduled CHF follow-up
appointment.

Current Medications:
amiodarone 200 mg PO daily metolazone 2.5 mg PO daily PRN edema

apixaban 5 mg PO BID metoprolol succinate 50 mg PO daily

aspirin 81 mg PO daily oxybutynin 5 mg PO daily

atorvastatin 40 mg PO QHS pantoprazole 20 mg PO daily

ezetimibe 10 mg PO daily potassium chloride 10 mEq PO daily

ferrous sulfate 325 mg PO BID torsemide 40 mg PO daily

Is BW Being Managed Appropriately?
Patient Case:
● Patient Labs/Tests:
○ LVEF: 30%
○ Weight: 89.3 kg
○ Hgb: 12.1 g/dL
○ Ferritin: 644.5 ng/mL
○ TSAT: 28%
What is appropriate?
Takeaways:
● Iron deficiency with or without anemia can be harmful in CHF.
● All CHF patients should be routinely tested for iron deficiency.
● Iron deficiency should be treated based on the algorithm.
● Oral iron supplementation should not be used to correct deficiency in CHF
patients.
● Ferric carboxymaltose is the preferred treatment option for iron deficiency in
eligible HF patients.
■ Inpatient:
● Iron deficiency + hospitalized for acute HF
■ Outpatient
● Iron deficiency + symptoms + LVEF <45%
● Iron deficiency + symptoms + LVEF <50% (if recent HF hospitalization)
Iron Deficiency in Heart Failure
Questions?
QUIZ TIME!
References:
1. Anemia. Hematology.org. American Society of Hematology. Accessed August 14, 2023.
https://www.hematology.org/education/patients/anemia#:~:text=Anemia%20occurs%20when%20you%20do,American%20Society%20of
%20Hematology.
2. Anemia: Overview and types: Concise medical knowledge. Lecturio. https://www.lecturio.com/concepts/anemia-overview/. Published July 4, 2022.
Accessed August 14, 2023.
3. Alnuwaysir RIS, Hoes MF, van Veldhuisen DJ, van der Meer P, Grote Beverborg N. Iron Deficiency in Heart Failure: Mechanisms and
Pathophysiology. J Clin Med. 2021;11(1):125. Published 2021 Dec 27. doi:10.3390/jcm11010125
4. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American
College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears in J Am Coll
Cardiol. 2023 Apr 18;81(15):1551]. J Am Coll Cardiol. 2022;79(17):e263-e421. doi:10.1016/j.jacc.2021.12.012
5. Sindone A, Doehner W, Manito N, et al. Practical Guidance for Diagnosing and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and
How?. J Clin Med. 2022;11(11):2976. Published 2022 May 25. doi:10.3390/jcm11112976
6. Hamano H, Niimura T, Horinouchi Y, et al. Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon
receptor-mediated pathway. Toxicol Lett. 2020;318:86-91. doi:10.1016/j.toxlet.2019.10.016
7. Gafter-Gvili A, Schechter A, Rozen-Zvi B. Iron Deficiency Anemia in Chronic Kidney Disease. Acta Haematol. 2019;142(1):44-50.
doi:10.1159/000496492
8. Al-Naseem A, Sallam A, Choudhury S, Thachil J. Iron deficiency without anaemia: a diagnosis that matters. Clin Med (Lond). 2021;21(2):107-113.
doi:10.7861/clinmed.2020-0582
9. Toblli JE, Angerosa M. Optimizing iron delivery in the management of anemia: patient considerations and the role of ferric carboxymaltose. Drug Des
Devel Ther. 2014;8:2475-2491. doi:10.2147/DDDT.S55499