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CLINICAL RESEARCH: CLINICAL TRIAL

Effect of Intravenous Iron Sucrose on Exercise Tolerance in Anemic and Nonanemic Patients With Symptomatic Chronic Heart Failure and Iron Deficiency

FERRIC-HF: A Randomized, Controlled, Observer-Blinded Trial

Darlington O. Okonko, BSc, MRCP^{_*,2,3,4,5,_*}, Agnieszka Grzeslo, MD^,4, Tomasz Witkowski, MD, Amit K.J. Mandal, MRCP, Robert M. Slater, MBBS, Michael Roughton, MSc^_*, Gabor Foldes, MD, PhD^_*, Thomas Thum, MD^_*,, Jacek Majda, MD, Waldemar Banasiak, MD, PhD, Constantinos G. Missouris, MD, Philip A. Poole-Wilson, MD, FMedSci^_*,2,5,7, Stefan D. Anker, MD, PhD^_*,||,1,2,6 and Piotr Ponikowski, MD, PhD^,1,2,6

^_* Clinical Cardiology, NHLI, Imperial College London, London, United Kingdom
Cardiac Department, Military Hospital, Wroclaw, Poland
Department of Cardiology, Wexham Park Hospital, Slough, United Kingdom
Department of Cardiology, Julius-Maximilians University, Würzburg, Germany
^|| Division of Applied Cachexia Research, Department of Cardiology, Charité Campus Virchow-Klinikum, Berlin, Germany.

Manuscript received November 9, 2006; revised manuscript received August 14, 2007, accepted September 11, 2007.

^_* Reprint requests and correspondence: Dr. Darlington O. Okonko, Clinical Cardiology, NHLI, Dovehouse Street, London SW3 6LY, United Kingdom. (Email: d.okonko{at}imperial.ac.uk).

Objectives: We tested the hypothesis that intravenous iron improves exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure (CHF) and iron deficiency.

Background: Anemia is common in heart failure. Iron metabolism is disturbed, and administration of iron might improve both symptoms and exercise tolerance.

Methods: We randomized 35 patients with CHF (age 64 ± 13 years, peak oxygen consumption [pVO ₂] 14.0 ± 2.7 ml/kg/min) to 16 weeks of intravenous iron (200 mg weekly until ferritin >500 ng/ml, 200 mg monthly thereafter) or no treatment in a 2:1 ratio. Ferritin was required to be <100 ng/ml or ferritin 100 to 300 ng/ml with transferrin saturation <20%. Patients were stratified according to hemoglobin levels (<12.5 g/dl [anemic group] vs. 12.5 to 14.5 g/dl [nonanemic group]). The observer-blinded primary end point was the change in absolute pVO ₂.

Results: The difference (95% confidence interval [CI]) in the mean changes from baseline to end of study between the iron and control groups was 273 (151 to 396) ng/ml for ferritin (p < 0.0001), 0.1 (–0.8 to 0.9) g/dl for hemoglobin (p = 0.9), 96 (–12 to 205) ml/min for absolute pVO ₂ (p = 0.08), 2.2 (0.5 to 4.0) ml/kg/min for pVO ₂/kg (p = 0.01), 60 (–6 to 126) s for treadmill exercise duration (p = 0.08), –0.6 (–0.9 to –0.2) for New York Heart Association (NYHA) functional class (p = 0.007), and 1.7 (0.7 to 2.6) for patient global assessment (p = 0.002). In anemic patients (n = 18), the difference (95% CI) was 204 (31 to 378) ml/min for absolute pVO ₂ (p = 0.02), and 3.9 (1.1 to 6.8) ml/kg/min for pVO₂/kg (p = 0.01). In nonanemic patients, NYHA functional class improved (p = 0.06). Adverse events were similar.

Conclusions: Intravenous iron loading improved exercise capacity and symptoms in patients with CHF and evidence of abnormal iron metabolism. Benefits were more evident in anemic patients. (Effect of Intravenous Ferrous Sucrose on Exercise Capacity in Chronic Heart Failure; http://www.clinicaltrials.gov/ct/show/NCT00125996; NCT00125996 [ClinicalTrials.gov] )

Abbreviations and Acronyms   CHF = chronic heart failure   Hb = hemoglobin   IV = intravenous   NYHA = New York Heart Association   TSAT = transferrin saturation   pVO 2 = peak oxygen consumption

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