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Intravenous Versus Oral Iron Replacement in Patients with a Continuous-Flow Left Ventricular Assist Device

Bode, Lauren E.*; Wesner, Sharon; Katz, Jason N.†,‡; Chien, Christopher V.†,‡; Hollis, Ian*

doi: 10.1097/MAT.0000000000000904
Brief Communication
Free

From the *Department of Pharmacy, University of North Carolina Medical Center

University of North Carolina Medical Center, Chapel Hill, NC

Division of Cardiology, UNC Center for Heart and Vascular Care, Chapel Hill, NC.

Submitted for consideration May 2018; accepted for publication in revised form August 2018.

Disclosures: The authors have no conflicts of interest to report.

Correspondence: Lauren E. Bode, PharmD, BCPS, 261 Mountain View Dr, Colchester, VT 05446. Email: lauren.bode@acphs.edu.

In addition to other complications, heart failure (HF) is strongly associated with iron deficiency. Iron deficiency has been linked to decreased health-related quality of life (HRQoL) and has been suggested as an independent prognostic factor for mortality.1 Furthermore, the use of intravenous iron in patients with HF is associated with reductions in hospitalizations, increases in quality of life, and improvement in functional assessments.2,3 To date, supplementation with oral iron has not shown a similar benefit.4 Iron deficiency remains common after continuous-flow left ventricular assist devices (LVAD) implantation, affecting over half of patients on long-term support.5 Patients with an LVAD and concomitant anemia are more likely to be hospitalized and demonstrate higher mortality rates.6,7 It is currently unknown whether patients with an LVAD experience the same benefits associated with correction of iron deficiency as the general HF population.

In accordance with the ACC/AHA/HFSA 2017 focused update to the 2013 Guideline for the Management of Heart Failure, our institution uses intravenous (IV) iron in HF patients with iron deficiency.8 It has been our practice to prescribe oral iron for patients after LVAD, but more recently, institutional IV iron prescribing guidelines for patients with HF were extended to our LVAD population. Given the novelty of this strategy, we conducted an institutional review board (IRB)-approved, prospective, observational analysis shortly after to compare the efficacy of IV versus oral iron supplementation in correcting iron deficiency in HF patients with durable LVADs.

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Methods

As is established in the general HF population, iron deficiency was defined as ferritin <100 ng/ml or transferrin saturation (Tsat) <20% with ferritin 100–300 ng/ml. Iron-deficient patients were treated off-label with IV iron during an inpatient admission or in the outpatient clinic provided that they had no blood transfusions within the previous 90 days, signs of pump thrombosis (lactate dehydrogenase (LDH) >3 times the upper limit of normal), active bleeding, or infection. Providers engaged in shared decision making with eligible patients regarding treatment with IV or oral iron, with factors such as cost and distance to clinic taken into consideration. Patients who did not receive IV iron were prescribed oral iron. In the inpatient setting, IV ferric gluconate dosed according to the Ganzoni equation was given in increments of 250 mg every 12 hours until total dose was administered.9 In the outpatient clinic, patients were repleted with ferumoxytol 1020 mg IV once administered over 30 minutes.10 Dosing of oral ferrous sulfate was in increments of 325 mg with frequency determined by the prescriber, though prescribing guidance recommended 325 mg daily to maximize absorption. Providers were encouraged to recheck iron parameters during clinic follow-up between 4 and 12 weeks after iron administration.

The primary outcome was the rate of resolution of iron deficiency, defined as no longer meeting criteria for iron deficiency (ferritin ≥100 ng/ml and Tsat ≥20% or ferritin >300 ng/ml). Secondary outcomes included change in ferritin, Tsat%, hemoglobin, and New York Heart Association (NYHA) symptom class (Baseline characteristics Table 1). Changes in HRQoL, as assessed by Kansas City Cardiomyopathy Questionnaire Short Form (KCCQ-12) when available, were compared in stable patients receiving IV iron as an outpatient.

Table 1

Table 1

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Results

Of 108 patients eligible for inclusion, the iron status of 82 patients was evaluated between June 2017 and February 2018. Of those, 67 (62%) were iron deficient, and 31 patients were treated with iron products and had complete follow-up with iron-specific laboratory data. Ten patients received IV iron, and 21 received oral iron. The median IV iron dose was 1037 mg, and the median time to follow-up iron studies was 42 days (interquartile range [IQR]: 33–64 days) after IV iron administration. Of the patients receiving oral iron, 43% were prescribed ferrous sulfate 325 mg once daily and 48% twice daily. Median time to follow-up iron studies while receiving oral iron therapy was 237 days (IQR: 81–436 days).

Resolution of iron deficiency occurred in 40% of patients receiving IV iron vs. 0% receiving oral iron (Fisher exact test, p = 0.008). Additionally, the median increase in ferritin in the IV group was 165.2 vs. 8.65 ng/ml in the oral group (Wilcoxon rank-sum test, p = 0.0006). Changes in Tsat% (+5.5 vs. +6.0; p = 1.0) and hemoglobin (+2.2 vs. +1.8 g/dl; p = 0.386) were not different. Decreases in serum creatinine were greater (−0.1 vs. −0.02 mg/dl; p = 0.024) in the IV iron group. Changes in total bilirubin (−0.15 vs. −0.2 mg/dl; p = 0.97) were not different. There was no significant difference in NYHA symptom class. Five patients who received IV iron had paired KCCQ-12 data with a median increase of 9.38 (p = 0.075) after treatment. One patient had a vasovagal episode during infusion of ferric gluconate that prevented administration of the complete dose (patient 6 in Table 2).

Table 2

Table 2

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Discussion

This is the first study to describe the results of IV iron supplementation in patients with a durable LVAD, demonstrating it to be significantly more effective than oral supplementation in correcting iron deficiency in this population. Importantly, our results also indicate that oral iron supplementation in durable LVAD patients is ineffective, a finding that aligns with that seen in the general HF population. Although the decrease in serum creatinine after IV iron was statistically significant, this finding requires additional study before interpretation. Additionally, although sample size may have precluded statistical significance in KCCQ-12 change, the qualitative improvement in HRQoL merits additional investigation.

Limitations of this study include its small, single-center cohort, as well as possible variability in iron parameters based on clinical setting. Additionally, patients received only one-time repletion of IV iron, potentially underestimating the full effect of IV iron if multiple doses were given. Regardless, our study adopted current best practices for the diagnosis and treatment of iron deficiency associated with HF, and we propose that IV iron replacement is a safe and reasonably effective method for correction of iron deficiency in LVAD patients. Given the significant burden of ongoing iron deficiency anemia after LVAD and its association with poor outcomes, as well as the previously published efficacy of IV iron in the general HF population, additional research is clearly warranted.

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References

1. Rocha BML, Cunha GJL, Menezes Falcão LF. The burden of iron deficiency in heart failure: therapeutic approach. J Am Coll Cardiol 2018.71: 782–793.
2. 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: 657–668.
3. 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: 1374–1383.
4. Lewis GD, Malhotra R, Hernandez AF, et al. NHLBI Heart Failure Clinical Research Network: 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: 1958–1966.
5. Amione-Guerra J, Cruz-Solbes AS, Bhimaraj A, et al. Anemia after continuous-flow left ventricular assist device implantation: Characteristics and implications. Int J Artif Organs 2017.40: 481–488.
6. Jennings DL, Wagner JL, To L, et al. Epidemiology and outcomes associated with anemia during long-term support with continuous-flow left ventricular assist devices. J Card Fail 2014.20: 387–391.
7. Vrtovec B, Radovancevic R, Delgado RM, et al. Significance of anaemia in patients with advanced heart failure receiving long-term mechanical circulatory support. Eur J Heart Fail 2009.11: 1000–1004.
8. 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. J Card Fail 2017.23: 628–651.
9. 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: 64–71.
10. Auerbach M, Strauss W, Auerbach S, Rineer S, Bahrain H. Safety and efficacy of total dose infusion of 1,020 mg of ferumoxytol administered over 15 min. Am J Hematol 2013.88: 944–947.
Keywords:

left ventricular assist device; iron deficiency; intravenous iron; oral iron; heart failure

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