Effect of Intravenous Ferrous Sucrose on Exercise Capacity in Chronic Heart Failure - FERRIC-HF

Description:

The goal of this trial was to evaluate the effect of intravenous (IV) iron in addition to optimal conventional therapy on exercise and functional capacity in patients with New York Heart Association (NYHA) class II or III chronic heart failure and iron deficiency.

Hypothesis:

Iron repletion would improve exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency.

Study Design

Study Design:

Patients Screened: N/A
Patients Enrolled: 35
NYHA Class: II or III
Mean Follow Up: 18 weeks
Mean Patient Age: 63.4 years
Female: 28
Mean Ejection Fraction: 29.7%

Patient Populations:

Evidence of systolic heart failure, with ejection fraction <45% by echocardiography or magnetic resonance imaging within 6 months; NYHA class II or III symptoms of heart failure; exercise limitation (pVO2/kg ≤18 ml/kg/min); age ≥21 years; hemoglobin <12.5 (anemic subgroup) or 12.5-14.5 (nonanemic subgroup); ferritin <100 µg/L, use of optimal conventional heart failure medications for at least 4 weeks prior to recruitment and without dose changes for at least 2 weeks; resting blood pressure ≤160/100 mm Hg; normal red cell folate; and vitamin B12

Exclusions:

Use of erythropoietin, iron (oral or IV), or blood transfusion within the previous 30 days; history of acquired iron overload; personal or family history of hemochromatosis; history of allergic disorders; hypersensitivity to parenteral iron preparations; active infection; bleeding; malignancy; hemolytic anemia; presence of any condition precluding exercise testing such as decompensated heart failure; significant musculoskeletal disease; unstable angina; obstructive cardiomyopathy; severe uncorrected valvular heart disease; uncontrolled brady- or tachyarrhythmias; concurrent immunosuppressive or renal replacement therapy; or chronic liver disease (defined as alanine aminotransferase >3 times normal)

Primary Endpoints:

Change in absolute pVO2 in ml/min from baseline to week 18

Secondary Endpoints:

• Change in peak pVO2/kg (week 18)
• Change in absolute exercise duration (week 18)
• Change in NYHA class (weeks 8, 18)
• Change in subjective measures of well-being: patient global assessment, MLHFQ score, fatigue score (weeks 8, 18)

Drug/Procedures Used:

Patients with NYHA class II or III heart failure (ejection fraction <45%) with low exercise tolerance and low iron stores were randomized in a 2:1 ratio to receive 16 weeks of IV iron sucrose or to the control group (either normal saline or no intervention). Iron was given weekly (therapeutic phase) unless ferritin was ≥500 ng/ml, and then at weeks 4, 8, 12, and 16 (maintenance phase). A test infusion was performed before the first treatment.

Concomitant Medications:

Optimal heart failure medications, including diuretics (71%), angiotensin-converting enzyme inhibitors (74%), angiotension-receptor blockers (20%), beta-blockers (89%), spironolactone (49%), and digoxin (23%)

Principal Findings:

A total of 35 patients were randomized in this trial, 24 to the IV iron arm, and 11 to the control arm. Baseline characteristics between the two arms were similar. About 74% of all patients studied had ischemic cardiomyopathy. The mean ejection fraction was 29.4%. At least 73% of patients in both arms were on afterload-reducing therapy; all patients in the control arm, and 83% in the iron arm were on beta-blocking agents.

In all patients receiving IV iron, there was a trend toward an improvement in exercise tolerance at 18 weeks, as measured by absolute peak oxygen consumption (pVO2) (treatment effect [TE] = 96 ml/min, 95% confidence interval [CI] -12 to 205; p = 0.08). Patients with anemia demonstrated a significant increase in pVO2 at 18 weeks (TE = 204 ml/min, 95% CI 31-378; p = 0.02). Such an effect was not noted in nonanemic patients (TE = -17 ml/min, 95% CI -110 to 76; p = 0.71).

The peak pVO2/kg was significantly better in the iron arm compared with the control arm (TE = 2.2 ml/kg/min, 95% CI 0.5- to 4.0; p = 0.01). This was again true for anemic patients only. Iron had no impact on the absolute exercise duration (TE = 60 seconds, 95% CI -6 to 126; p = 0.08) or percent change in exercise duration from baseline (TE = 17%, 95% CI -3 to 36; p = 0.09). This was true for both subgroups as well. In addition, patients treated with iron had a significant improvement in NYHA functional class at 18 weeks (p = 0.007). This was true for anemic patients only. Subjective estimates of patient well-being, such as patient global assessment, fatigue score, and Minnesota Living with Heart Failure (MLHFQ) score, were significantly better in the iron arm at 18 weeks, compared with the control arm.

IV iron significantly improved serum indices of iron metabolism in all patients, with significant improvements noted in serum ferritin (p < 0.0001) and transferrin saturation (p = 0.001), but not hemoglobin (p = 0.87). No episodes of symptomatic hypotension or anaphylactic reactions occurred with IV iron. Iron did not significantly alter renal and liver function tests.

Interpretation:

Given that this was a very small trial, with only 35 patients enrolled, the investigators were underpowered to demonstrate a significant difference in their main outcome: change in absolute pVO2 at 18 weeks in both anemic and nonanemic patients. However, they were able to demonstrate that in anemic patients with symptomatic chronic systolic heart failure and documented iron deficiency, treatment with IV iron improves maximal exercise capacity, as quantified by absolute pVO2 and peak pVO2/kg, as well as NYHA functional class and patient well-being. These benefits seem to be independent of elevations in serum hemoglobin concentrations.

Despite it being a small study, these findings are interesting, and warrant further investigation, especially in patients with chronic symptomatic heart failure and iron deficiency anemia. The investigators documented an absolute increase of 30% in the pVO2/kg in this subgroup, which compares favorably with other interventions in heart failure patients, such as cardiac resynchronization therapy. If borne out by other larger studies, IV iron repletion could be a simple yet effective way of improving functional capacity and symptoms in heart failure patients with iron deficiency. Further studies will also need to address whether this benefit is noted with oral iron repletion as well.

References:

Okonko DO, Grzeslo A, Witkowski T, et al. 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, observed-blinded trial. J Am Coll Cardiol 2008;51:103-12.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Implantable Devices, Lipid Metabolism, Statins, Acute Heart Failure, Chronic Heart Failure, Echocardiography/Ultrasound, Magnetic Resonance Imaging

Keywords: Iron, Exercise Tolerance, Minnesota, Hypotension, Blood Pressure, Vitamin B 12, Heart Failure, Systolic, Magnetic Resonance Imaging, Ferric Compounds, Cardiac Resynchronization Therapy, Liver Function Tests, Ferritins, Hemoglobins, Transferrins, Oxygen Consumption, Folic Acid, Research Personnel, Cardiomyopathies, Confidence Intervals, Anemia, Iron-Deficiency, Echocardiography


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