Iron deficiency anemia (IDA) is a common entity in patients with heart failure with reduced ejection fraction (HFrEF), with almost half of patients having either absolute or functional iron deficiency.1 Many HFrEF patients present with iron deficiency, many with anemia, and many with both.1 The estimated prevalence of anemia varies widely (from 6% to 70%), reflecting the heterogeneity in anemia screening, clinical setting (i.e., hospitalized vs. outpatients), and socioeconomic status of the study populations.2
Anemia is associated with poor clinical outcomes in patients with HFrEF. It is “independently associated with HF disease severity, and iron deficiency appears to be uniquely associated with reduced exercise capacity.”3 Despite the high prevalence and serious consequences of anemia in patients with HF, it often goes unnoticed.4
To shed light on the often-challenging management of this common condition, MPR presented the case of a hypothetical patient to Rachel Bijou, MD, Attending Cardiologist, Columbia University Irving Medical Center, New York, NY. Dr Bijou specializes in advanced heart failure and transplant cardiology.
Ms. W has 30-year history of hypertension, hyperlipidemia and an 8-year history of systolic dysfunction. She has persistent atrial fibrillation (AF) and an AICD for primary prevention. She was hospitalized for congestion following a 5-day river cruise. She seemed to have a good response to therapy with relief of her congestive symptoms; however, she reports persistent weakness and fatigue impacting her quality of life. She finds it taxing to do her errands and feels washed out by the middle of the afternoon. Her appetite is poor; she is eating smaller portions and has lost another 3 lbs. since the hospitalization. A recent colonoscopy was unrevealing. Last year her hemoglobin count was 11.4 g/dL and it is now 9.8. The echocardiogram prior to hospital discharge was notable for an ejection fraction (EF) of 24%.
- Lisinopril 20mg/day
- Carvedilol 25mg BID
- Torsemide 20mg/day
- Spironolactone 12.5mg/day
- Warfarin 4mg/day
- Lipitor 40mg/day
- Omeprazole 20mg/day
- Sodium 138 mEq/L
- Potassium 4.1mEq/L
- BUN 21mg/dL
- Creatinine 1.1mg/dL
- Hemoglobin 9.0gm/dL
- Ferritin 72ng/mL
- Transferrin saturation 17%
What is the etiology of IDA in HFrEF?
There are several mechanisms of iron deficiency in HFrEF. In absolute iron deficiency, iron stores are depleted and mechanisms of iron homeostasis are intact. Bleeding caused by gastrointestinal pathologies, whether overt or occult, is a common cause of absolute iron deficiency.5 Blood loss is frequently attributable to antiplatelet agents and anticoagulants used treat HFrEF comorbidities such as coronary disease and atrial fibrillation. In the case of Ms. W, GI blood loss has been ruled out.
Other nutritional and intestinal factors contribute to iron deficiency. For example, patients with low-output heart failure have anorexia and poor eating habits. Bowel edema affects nutritional absorption and processing. H pylori infection and atrophic gastritis can lead to inadequate iron absorption. Food sources of non-heme iron are best absorbed in a low pH and so the use of proton pump inhibitors can contribute to iron deficiency.5
Advancing heart failure is a state of inflammation notable for high levels of circulating inflammatory cytokines such as TNF-alpha and IL-6. Hepcidin is an iron regulatory peptide from the liver and levels rise in association with states of inflammation. In excess hepcidin inhibits iron absorption, cellular mobilization and transport, promoting further iron deficiency that is functional in nature.5
How is IDA diagnosed in patients with HFrEF?
The presence of fatigue and a change in exercise tolerance may be a sign of worsening CHF due to volume overload, arrhythmias or another systemic process burdening already compromised cardiac function. Seeking to identify a cause, routinely clinicians will screen for infection, anemia or thyroid dysfunction. The most important lab values to screen for iron deficiency anemia are hemoglobin, ferritin, and transferrin saturation.
Regular monitoring of iron parameters should be integrated into the assessment of a patient with heart failure. Definitive testing should measure hemoglobin, ferritin, and transferrin saturation. It is important to note that standard cutoff values of ferritin used to define ID in most medical conditions are not used to diagnose ID in HFrEF. In heart failure, a ferritin level <100 mcg/L or a ferritin value of 100-300 micrograms per liter coupled with transferrin saturation of <20% is accepted as iron deficiency. (Tables 1, 2)
Why do you recommend treating iron deficiency anemia?
Treating IDA in HFrEF is an evidence-based recommendation.3,6 In addition to improving hemoglobin, ferritin and transferrin saturation, iron therapy is associated with clinical endpoints such as improved exercise capacity, New York Heart Association Class and quality of life as measured by questionnaires such as the Kansas City Cardiomyopathy Questionnaire (KCCQ).
Do you favor oral or intravenous supplementation; are there guidelines for therapy?
Although oral iron supplementation is accessible and inexpensive, the efficacy of oral therapy for HFrEF is not established. The heightened activity of cytokines raises levels of hepcidin leading to reduced iron absorption. Iron is associated with intestinal side effects leading to non-compliance with therapy. Oral iron absorption is impaired by certain foods and medications and the presence of bowel edema. Most importantly, there is no clinical evidence of oral iron benefit in heart failure patients. In the placebo controlled IRONOUT-HF trial,7 oral iron polysaccharide supplementation did not improve exercise capacity. In contrast, there are several many placebo-controlled trials demonstrating efficacy of IV iron supplementation.8,9
IV iron therapy is the evidenced-based recommendation to replenish iron store in in patients with heart failure.3,6 (Table 3) Short-term therapy results in improvement in exercise capacity, and increase in hemoglobin and other iron markers. Data illustrating improvement in morbidity or mortality is not yet available and for this reason the recent ACC/AHA/HSFA update on heart failure management recommend IV iron replacement with a IIb indication.3
What agents should be used to replete iron?
Iron sucrose is labeled for use in iron deficiency anemia associated with chronic kidney disease. Recommended dosing is for non-dialysis-dependent patient is 200mg administered on five different occasions within a 14-day period (total cumulative dose: 1000mg in 14-day period); may repeat treatment if clinically indicated. Dosage has also been administered as two infusions of 500mg on day 1 and day 14 (limited experience).
IV ferric carboxymaltose (IV FCM) is indicated to treat IDA in a setting of intolerance to oral iron or unsatisfactory response to oral iron. The dose for individuals >50kg is 750mg on day 1 and a repeat dose after at least 7 days (maximum: 1500mg per course).
For the largest and most recent placebo-controlled HF trials, IV FCM is the agent of choice; the dose is based upon weight and hemoglobin. The most common dosing intervals is 6 weeks for 2-4 doses. Serious adverse side effects have not been observed in these short-term studies and there is no data on the safety of long-term therapy.
In the past, iron dextran, a high molecular weight product, was frequently used as a supplement; it was associated with allergic and sometimes anaphylactic reactions and is not recommended.10
It is also important to note that erythropoietin-stimulating agents are not recommended for patients with HF and anemia, as these agents are sometimes prothrombotic and have shown limited clinical efficacy in heart failure.
- Ebner N, von Haehling S. Iron Deficiency in Heart Failure: A Practical Guide. Nutrients. 2013;5(9):3730-3739.
- Goodnough LT, Comin-Colet J, Leal-Noval S, et al. Management of anemia in patients with congestive heart failure. Am. J. Hematol. 2017;92:88–93.
- Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017 Aug 8;136(6):e137-e161.
- Kocyigit D, Gurses KM. Iron deficiency and its treatment in heart failure: indications and effect on prognosis. ESC. 2016;14(30):
- Kaitha S, Bashir M, Ali T. Iron deficiency anemia in inflammatory bowel disease. World J Gastrointest Pathophysiol. 2015;6(3):62-72.
- Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016 Aug;18(8):891-975.
- Lewis GD, Malhotra R, Hernandez AF. Effect of Oral Iron Repletion on Exercise Capacity in Patients with Heart Failure with Reduced Ejection Fraction and Iron Deficiency: the IRONOUT HF Randomized Clinical Trial. JAMA. 2017;317(19):1958-1966.
- Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36:357-368.
- Kapoor M, Schleinitz MD, Gemignani A, et al. Outcomes of patients with chronic heart failure and iron deficiency treated with intravenous iron: a metaanalysis. Cardiovasc Hematol Disord Drug Targets. 2013;14:35-44.
- Wang C, Graham DJ, Kane RC, et al. Comparative risk of anaphylactic reactions associated with intravenous iron products. JAMA. 2015;314(19):2062-2068.
This article originally appeared on MPR