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J Am Coll Cardiol, 2006; 48:1225-1227, doi:10.1016/j.jacc.2006.07.015
(Published online 25 August 2006). © 2006 by the American College of Cardiology Foundation |
* Department of Clinical Cardiology, The Heart Hospital, London, United Kingdom
Clinical Heart Failure Service, West Middlesex University Hospital, Isleworth, United Kingdom.
Manuscript received April 10, 2006; revised manuscript received July 7, 2006, accepted July 10, 2006.
* Reprint requests and correspondence: Dr. Aidan P. Bolger, Department of Adult Cardiology, The Heart Hospital, 16-18 Westmoreland Street, London W1G 8PH, United Kingdom. (Email: aidan{at}bolgers.org).
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Abstract |
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BACKGROUND: Anemia is common in patients with CHF and is associated with higher morbidity and mortality. The combination of erythropoietin (EPO) and iron increases hemoglobin (Hb) and improves symptoms and exercise capacity in anemic CHF patients. It is not known whether intravenous iron alone is an effective treatment for anemia associated with CHF.
METHODS: Sixteen anemic patients (Hb 
12 g/dl) with stable CHF (age 68.3 ± 11.5 years, 12 men, 9 participants New York Heart Association [NYHA] functional class II and the remainder class III, left ventricular ejection fraction 26 ± 13%) received a maximum of 1 g of iron sucrose by bolus intravenous injections over a 12-day treatment phase in an outpatient setting. Mean follow-up was 92 ± 6 days.
RESULTS: Hemoglobin rose from 11.2 ± 0.7 to 12.6 ± 1.2 g/dl (p = 0.0007), Minnesota Living with Heart Failure (MLHF) score fell (denoting improvement) from 33 ± 19 to 19 ± 14 (p = 0.02), 6-min walk distance increased from 242 ± 78 m to 286 ± 72 m (p = 0.01), and all patients recorded NYHA class II at study end (p < 0.02). Changes in MLHF score and 6-min walk distance related closely to changes in Hb (r = 0.76, p = 0.002; r = 0.56, p = 0.03, respectively). Of all baseline measurements, only iron and transferrin saturation correlated with increases in Hb (r = 0.60, p = 0.02; r = 0.60, p = 0.01, respectively). There were no adverse events relating to drug administration or during follow-up.
CONCLUSIONS: Intravenous iron sucrose, when used without concomitant EPO, is a simple and safe therapy that increases Hb, reduces symptoms, and improves exercise capacity in anemic patients with CHF. Further assessment of its efficacy should be made in a multicenter, randomized, placebo-controlled trial.
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Methods |
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12 g/dl who had been stable on standard heart failure medication for 
6 weeks. Vitamin B12 or folic acid deficiency, hemoglobinopathy, or serum ferritin >400 ng/ml were exclusion criteria. The local research and ethics committee gave study approval. Written, informed consent was obtained from all participants. Study protocol. In an outpatient setting, patients received 200 mg (10 ml) bolus injections of undiluted iron sucrose over 10 min into a peripheral vein on days 1, 3, and 5 of the study. Serum ferritin was measured on day 12 and, if <400 ng/ml, further 200 mg doses were administered on days 15 and 17. Follow-up time was 3 months.
Evaluations. Symptoms were assessed according New York Heart Association (NYHA) functional classification and the Minnesota Living with Heart failure (MLHF) questionnaire. Exercise capacity was quantified using a 6-min walk (6MW) test. Blood samples were taken for determination of hematologic variables, iron indexes, and renal function. All patients were considered for gastrointestinal (GI) endoscopy as investigation into the cause of their anemia.
Statistical analyses. All results are reported as mean values ± SD. Paired and unpaired Student t tests, analysis of variance with Fisher post hoc test, simple linear regression analysis (all Statview 5, SAS Institute Inc., Cary, North Carolina) and McNemar’s test (IFA Services, Amsterdam, the Netherlands) were used as appropriate. The p values <0.05 are referred to as having statistical significance.
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Results |
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Effect of iron sucrose on hematologic parameters. Hemoglobin rose from 11.2 ± 0.7 to 12.6 ± 1.2 g/dl (p = 0.0007) (Fig. 1), serum iron from 9.2 ± 4.4 to 13.7 ± 4.8 µmol/l (p = 0.009), ferritin from 87 ± 113 ng/ml to 217 ± 185 (p = 0.004), and transferrin saturation from 16.0 ± 9.5 to 24.6 ± 8.4% (p = 0.009). Of all baseline measurements, only iron and transferrin saturation correlated with increases in Hb (r = 0.60, p = 0.02; r = 0.60, p = 0.01, respectively). Furthermore, when divided into tertiles according to change in Hb, patients demonstrating the greatest response were those with the lowest baseline iron levels (p = 0.006 vs. the tertile with the lowest response). Although there was no change in serum creatinine or calculated creatinine clearance (Cockcroft-Gault formula), there was a trend toward a fall in cystatin C concentration (1.71 ± 0.52 to 1.50 ± 0.53 mg/l, p = 0.08), suggesting improved glomerular filtration rate.
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Safety and tolerability. Iron sucrose was well tolerated with no instance of local or systemic adverse reactions. During follow-up, no patients were hospitalized, and none died. There were no changes to loop diuretic dose, and there was no statistical difference between baseline and completion body weights.
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Discussion |
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Iron deficiency is present when transferrin saturation is <16% and ferritin <30 ng/ml (6). Seven patients (44%) in this study were iron deficient by these criteria, and they had the greatest response to iron sucrose (increase in Hb 2.1 ± 1.3 g/dl vs. 0.9 ± 1.0 g/dl in the iron replete group, p = 0.06). Iron status is also the leading determinant of EPO responsiveness in patients with chronic renal failure, and concomitant intravenous iron is an essential adjunct in this context. We found no association between GI pathology and iron deficiency or response to iron, suggesting dietary factors or malabsorption may also influence iron status in patients with CHF.
Given that the risk of death in CHF increases with small reductions in Hb (2), modest increases in Hb should confer significant clinical benefits. This is supported by the observations that peak oxygen consumption in CHF correlates with Hb levels (7), and the correction of anemia improves this measure of exercise capacity (4). The mean increase in Hb in this study was 1.4 ± 1.3 g/dl (range: –0.7 to +3.1 g/dl) for a treatment phase of just 5 to 17 days encompassing only 4 or 6 hospital visits. Others have recorded mean increases of 2.6 g/dl (3) and 3.3 g/dl (4) using a combination of EPO and iron in similar CHF groups. Although the EPO/iron combination may result in a greater response than iron alone, there are clearly individuals who have a dramatic hematologic and clinical response to the latter.
The fact that we recorded no adverse events relating to the administration of iron sucrose or during follow-up is consistent with other safety data concerning the use of this drug. After a total of 2,297 injections of iron sucrose in 657 patients with renal failure, Macdougall and Roche (8) reported adverse events in only 2.5%. All were short-lived, and no patient required hospitalization. Furthermore, iron sucrose appears safe in patients with known intolerance of other parenteral iron preparations (9).
Intravenous iron sucrose, without concomitant EPO, is a simple and safe therapy that increases Hb, reduces symptoms, and improves exercise capacity in anemic patients with CHF. Further assessment of its efficacy should be made in multicenter, randomized, placebo-controlled trials.
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