FERRIC-HF II Trial of the Effect of Iron Isomaltoside on Skeletal Muscle Energetics in Iron-deficient Patients with Chronic HF

Educational Objectives

After completing the activity, the clinician will be better able to describe trial results showing the effect of intravenous ferric carboxymaltose in patients with heart failure and iron deficiency.

Summary

Interviewer: C. Richard Conti, MD, MACC

Take-home Messages:

• Iron deficiency is seen in about half of patients with chronic heart failure with reduced ejection fraction (HFrEF). It is associated with impaired functional capacity, poor quality of life (QOL), and increased morbidity and mortality, irrespective of the presence of anemia.
• While several therapies have shown disappointing results, treatment with intravenous (IV) ferric carboxymaltose (FCM) has shown promising results in symptomatic patients with HF and iron deficiency.
• However, the benefit of FCM is partly independent of hemoglobin levels, and data on hard clinical endpoints are not yet available. Given that regular administration of IV iron poses logistical challenges and is expensive, more research is necessary to determine the best approach to managing the large number of HF patients with iron deficiency, with or without anemia.

Iron deficiency is common in patients with heart failure (HF), occurring in an estimated 30% to 50% of patients with stable chronic HF; it is also common in patients hospitalized for worsening HF.¹ This iron deficiency can occur without any impact on hemoglobin, yet it remains associated with impaired functional capacity, poor quality of life (QOL), and increased mortality. Plus, the established pathophysiologic mechanisms of progressive HF may be intertwined with increasing myocardial iron scarcity, wherein one begets the other.¹ (Iron deficiency is a continuum that ranges from no iron deficiency and normal hemoglobin levels to iron stores that become depleted, but only at the extremes of iron deficiency is there an impact on hemoglobin levels. In other words, iron-deficiency anemia is the end stage of the process of iron deficiency.)

Studies have not shown a consistent benefit from treating iron deficiency. Investigators conducted a retrospective study to assess the efficacy of oral iron supplementation in iron-deficient patients with chronic heart failure with reduced ejection fraction (HFrEF).² Oral iron supplementation improved markers of iron status over a median of 164 days. However, there was no association between oral iron dosage and degree of improvement in iron markers.

Subsequently, the multicenter, double-blind, randomized controlled trial (RCT) IRONOUT HF (Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure) evaluated inexpensive, readily available oral iron supplementation. After 16 weeks, investigators showed that active therapy had little effect on replacing iron stores and did not improve peak exercise capacity in anemic patients with HFrEF. They also reported no change in natriuretic peptides, peak Vo2, 6-min walk distance, Kansas City Cardiomyopathy Questionnaire score, or ventilator efficiency in patients with HF and iron deficiency.³

Transfusion was originally thought to be promising, but because of the risks of acute hemolytic reactions, infection, acute lung injury, allergic reactions, and lack of evidence to support the value of a liberal transfusion policy in patients with heart disease, the American College of Physicians recommends a restrictive transfusion strategy.

Exogenous erythropoietin is approved for the treatment of anemia as a result of chronic kidney disease or chemotherapy-induced anemia. However, in anemic HF patients, these agents have been a bust, mostly because of safety issues. In one trial, for example, there was no effect of therapy on the primary composite endpoint of death or hospitalization for worsening HF or any of the other endpoints. To the contrary, rates of ischemic stroke and embolic/thrombotic events were significantly increased in those treated with darbepoetin alfa.^4,5

Promise of Intravenous (IV) Administration

In comparison to the oral route, intravenous iron can be administered in larger doses, hence expeditiously correcting the iron deficit. The FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure) trial showed that in the setting of chronic heart failure and iron deficiency, with or without anemia, active therapy improved symptoms, functional capacity, and QOL, compared with placebo.⁶

FAIR-HF evaluated 24-week results; CONFIRM-HF used 52 weeks of follow-up comparing IV FCM to placebo (dosed at baseline and weeks 6, 12, 24, and 36) in symptomatic, iron-deficient HF patients. At 1 year, randomization to active therapy resulted in sustainable improvement in functional capacity, symptoms, and QOL; plus, it seemed to be associated with reduced risk of hospitalization for worsening HF.⁷

Exercise intolerance (dyspnea and fatigue) is a key symptom of HF, and cardiopulmonary exercise testing defines maximum exercise capacity through peak oxygen uptake (peak Vo2).

The EFFECT-HF (Effect of Ferric Carboxymaltose on Exercise Capacity in Patients with Chronic Heart Failure and Iron Deficiency) trial investigators decided to specifically concentrate their analysis on peak VO2, given that it is an important predictor of prognosis in HF and is objective, reproducible, and used to evaluate cardiac transplantation and whether a patient is a candidate for a left ventricular assist device. Even a modest increase in peak Vo2 has been associated with more favorable outcomes in HF patients.

EFFECT-HF investigators enrolled symptomatic HF patients with iron deficiency with or without anemia.⁸ Iron deficiency was defined as serum ferritin < 100 μg/L or between 100 to 300 μg/L if transferrin saturation was < 20%. All patients had symptomatic heart failure and left ventricular EF ≤ 45%.

In the open-label study, patients with stable HFrEF with reduced exercise capacity and iron deficiency received either IV injections of FCM on day 0, week 6, and week 12 (mean treatment dose: 1,204 mg) or usual care for 24 weeks. Iron supplementation with IV FCM significantly increased serum ferritin and transferrin saturation. For the primary endpoint, active therapy was associated with significantly improved peak Vo2 at 24 weeks after treatment with IV FCM, compared to standard care (p = 0.02).

New York Heart Association (NYHA) functional class was not significantly different between groups at baseline. After 6, 12, and 24 weeks, patients on FCM had improved their NYHA functional class significantly, compared with patients in the control group (at all time points, p < 0.05, with a p value of 0.04 at 24 weeks.)

Patients typically reported feeling better within a day or 2 of initiating therapy. In the next 4 to 8 weeks, there was improvement in QOL and 6-min walk distance. So, we have both subjective and objective evidence of improvement with FCM.

A systematic review with meta-analysis including 5 RCTs showed a robust reduction in hospitalizations for HF (odds ratio: 0.28; p < 0.0001) in patients receiving IV iron compared with placebo.⁹ However, these results were mainly driven by the FCM trials.

Where does that leave the targeting of iron deficiency in HF? In a review paper published in early 2018 in JACC: Heart Failure, the authors concluded that anemia in patients with HF is still relevant, even though the therapies studied thus far have largely been disappointing.¹⁰ Yes, IV iron therapy looks promising for iron-deficiency anemia, but its benefit is partly independent of hemoglobin levels, and data on hard clinical endpoints are not yet available. And, of course, regular administration of IV iron poses logistical challenges and is expensive.

Thus, there is still work to be done to determine how best to manage HF patients with iron deficiency.

Readings

1. Rocha BML, Cunha GJL, Menezes Falcão LF. The burden of iron deficiency in heart failure: therapeutic approach. J Am Coll Cardiol 2018;71:782-93. www.onlinejacc.org/content/71/7/782.full

2. Niehaus ED, Malhotra R, Cocca-Spofford D, Semigran M, Lewis GD. Repletion of iron stores with the use of oral iron supplementation in patients with systolic heart failure. J Card Fail 2015;21:694-7.

3. Lewis GD, Malhotra R, Hernandez AF, et al. 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;317:1958-66.

4. Swedberg K, Young JB, Anand IS, et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med 2013;368:1210-9.

5. Bello NA, Lewis EF, Desai AS, et al. Increased risk of stroke with darbepoetin alfa in anaemic heart failure patients with diabetes and chronic kidney disease. Eur J Heart Fail 2015;17:1201-7.

6. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436-48.

7. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al.; CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015;36:657-68.

8. van Veldhuisen DJ, Ponikowski P, van der Meer P, et al.; EFFECT-HF Investigators. Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency. Circulation 2017;136:1374-83.

9. Jankowska EA, Tkaczyszyn M, Suchocki T, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail 2016;18:786-95.

10. Grote Beverborg N, van Veldhuisen DJ, van der Meer P. Anemia in heart failure: still relevant? JACC Heart Fail 2018;6:201-8. http://heartfailure.onlinejacc.org/content/6/3/201

Disclosures

Darlington Obinnaya Okonko, MBBS, PhD
Pharmacosmos A/S (G,B); Vifor Pharma Management Ltd (B)

Interviewer: C. Richard Conti, MD, MACC
This author has nothing to disclose.

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

AC500715

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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