Pii: s0735-1097(01)01248-7

Journal of the American College of Cardiology Vol. 37, No. 7, 2001 2001 by the American College of Cardiology ISSN 0735-1097/01/$20.00 Published by Elsevier Science Inc.
The Effect of Correction of Mild Anemiain Severe, Resistant Congestive Heart FailureUsing Subcutaneous Erythropoietin andIntravenous Iron: A Randomized Controlled StudyDonald S. Silverberg, MD, Dov Wexler, MD, David Sheps, MD, Miriam Blum, MD, Gad Keren, MD,Ron Baruch, MD, Doron Schwartz, MD, Tatyana Yachnin, MD, Shoshana Steinbruch, RN,Itzhak Shapira, MD, Shlomo Laniado, MD, Adrian Iaina, MDTel Aviv, Israel This is a randomized controlled study of anemic patients with severe congestive heart failure(CHF) to assess the effect of correction of the anemia on cardiac and renal function andhospitalization.
Although mild anemia occurs frequently in patients with CHF, there is very little informationabout the effect of correcting it with erythropoietin (EPO) and intravenous iron.
Thirty-two patients with moderate to severe CHF (New York Heart Association [NYHA]class III to IV) who had a left ventricular ejection fraction (LVEF) of ⱕ40% despitemaximally tolerated doses of CHF medications and whose hemoglobin (Hb) levels werepersistently between 10.0 and 11.5 g% were randomized into two groups. Group A (16patients) received subcutaneous EPO and IV iron to increase the level of Hb to at least 12.5g%. In Group B (16 patients) the anemia was not treated. The doses of all the CHFmedications were maintained at the maximally tolerated levels except for oral and intravenous(IV) furosemide, whose doses were increased or decreased according to the clinical need.
Over a mean of 8.2 ⫾ 2.6 months, four patients in Group B and none in Group A died ofCHF-related illnesses. The mean NYHA class improved by 42.1% in A and worsened by11.4% in B. The LVEF increased by 5.5% in A and decreased by 5.4% in B. The serumcreatinine did not change in A and increased by 28.6% in B. The need for oral and IVfurosemide decreased by 51.3% and 91.3% respectively in A and increased by 28.5% and28.0% respectively in B. The number of days spent in hospital compared with the same periodof time before entering the study decreased by 79.0% in A and increased by 57.6% in B.
CONCLUSIONS When anemia in CHF is treated with EPO and IV iron, a marked improvement in cardiac and patient function is seen, associated with less hospitalization and renal impairment and lessneed for diuretics. (J Am Coll Cardiol 2001;37:1775– 80) 2001 by the American Collegeof Cardiology Anemia of any cause is known to be capable of causing consider anemia to be only a rare contributing cause of congestive heart failure (CHF) (1). In patients hospitalized hospitalization for CHF (8,9).
with CHF the mean hemoglobin (Hb) is about 12 g% (2,3), Recently, we performed a study in which the anemia of which is considered the lower limit of normal in adults (4).
severe CHF that was resistant to maximally tolerated doses of Thus, anemia appears to be common in CHF. Recently, in standard medications was corrected with a combination of 142 patients in our special CHF outpatient clinic, we found subcutaneous (sc) erythropoietin (EPO) and intravenous iron that as the CHF worsened, the mean Hb concentration (IV Fe) (5). We have found this combination to be safe, decreased, from 13.7 g% in mild CHF (New York Heart effective and additive in the correction of the anemia of chronic Association [NYHA] class I) to 10.9 g% in severe CHF renal failure (CRF) in both the predialysis period (10) and the (NYHA 4), and the prevalence of a Hb ⬍12 g% increased dialysis period (11). The IV Fe appears to be more effective from 9.1% in patients with NYHA 1 to 79.1% in those with than oral iron (12,13). In our previous study of CHF patients NYHA 4 (5). The Framingham Study has shown that (5), the treatment resulted in improved cardiac function, anemia is an independent risk factor for the production of improved NYHA functional class, increased glomerular filtra- CHF (6). Despite this association of CHF with anemia, its tion rate, a marked reduction in the need for diuretics and a role is not mentioned in the 1999 U.S. guidelines for the 92% reduction in the hospitalization rate compared with a diagnosis and treatment of CHF (7), and many studies similar time period before the intervention.
In the light of these positive results, a prospective From the Department of Nephrology and Cardiology and Congestive Heart randomized study was undertaken to determine the effects Failure Program, Tel Aviv Medical Center, Weizman 6, Tel Aviv, Israel.
of the correction of anemia in severe symptomatic CHF Manuscript received October 13, 2000; revised manuscript received February 12, 2001, accepted February 19, 2001.
resistant to maximally tolerated CHF medication.
Silverberg et al.
JACC Vol. 37, No. 7, 2001 Correction of Anemia in Heart Failure June 1, 2001:1775– 80 intervention study. A complete blood count, serum creati- Abbreviations and Acronyms
nine, potassium and ferritin and %Fe Sat were performed on CABG ⫽ coronary artery bypass graft every visit. The blood pressure was measured by an elec- ⫽ congestive heart failure tronic device on every visit. The LVEF was measured ⫽ chronic renal failure initially and at four- to six-month intervals by MUGA ⫽ erythropoietin radioisotope ventriculography. This technique measures the %Fe Sat ⫽ percent iron saturationGFR ⫽ glomerular filtration rate amount of blood in the ventricle at the end of systole and at the end of diastole, thus giving a very accurate assessment of the ejection fraction. It has been shown to be an accurate ⫽ international units and reproducible method of measuring the ejection fraction ⫽ left ventricular ejection fraction NYHA ⫽ New York Heart Association Hospital records were reviewed at the end of the inter- ⫽ pulmonary artery vention period to compare the number of days hospitalized during the study with the number of days hospitalized SOLVD ⫽ Studies Of Left Ventricular Dysfunction during a similar period when the patients were treated in theCHF clinic before the initial randomization and entry into MATERIALS AND METHODS the study. Clinic records were reviewed to evaluate the typesand doses of CHF medications used before and during the Patients. Thirty-two patients with CHF were studied.
Before the study, the patients were treated for least six The mean follow-up for patients was 8.2 ⫾ 2.7 months months in the CHF clinic with maximally tolerated doses of (range 5 to 12 months). The study was done with the angiotensin-converting enzyme inhibitors, the beta- approval of the local ethics committee.
blockers bisoprolol or carvedilol, aldospirone, long-acting Statistical analysis. An analysis of variance with repeated
nitrates, digoxin and oral and intravenous (IV) furosemide.
measures (over time) was performed to compare the two In some patients these agents could not be given because of study groups (control vs. treatment) and to assess time trend contraindications and in others they had to be stopped and the interactions between the two factors. A separate because of side effects. Despite this maximal treatment the analysis was carried out for each of the outcome parameters.
patients still had severe CHF (NYHA class ⱖIII), with The Mann-Whitney test was used to compare the change in fatigue and/or shortness of breath on even mild exertion or NYHA class between two groups. All the statistical analysis at rest. All had levels of Hb in the range of 10 to 11.5 g% was performed by SPSS (version 10).
on at least three consecutive visits over a three-week period.
All had a LVEF of ⬍40%. Secondary causes of anemia including hypothyroidism, and folic acid and vitamin B12deficiency were ruled out and there was no clinical evidence The mean age in Group A (EPO and Fe) was 75.3 ⫾ 14.6 of gastrointestinal bleeding.
years and in group B was 72.2 ⫾ 9.9 years. There were 11 The patients were randomized consecutively into two and 12 men in Groups A and B, respectively. Before the groups: Group A, 16 patients, was treated with sc EPO and study the two groups were similar in cardiac function, IV Fe to achieve a target Hb of at least 12.5 g%. Group B, comorbidities, laboratory investigations and medications 16 patients, did not receive the EPO and IV Fe.
(Tables 1, 2 and 3), except for IV furosemide (Table 3), Treatment protocol for correction of anemia. All patients
which was higher in the treatment group. The mean NYHA in Group A received the combination of sc EPO and IV Fe.
class of Group A before the study was 3.8 ⫾ 0.4 and was The EPO was given once a week at a starting dose of 4,000 3.5 ⫾ 0.5 in Group B. The contributing factors to CHF in international units (IU) per week sc and the dose was Groups A and B, respectively, are seen in Table 1 and were increased to two or three times a week or decreased to once similar. The main contributing factors to CHF were con- every few weeks as necessary to achieve and maintain a sidered to be ischemic heart disease (IHD) in 11 and 10 target Hb of 12.5 g%. The IV Fe (Venofer-Vifor Interna- patients respectively, hypertension in two and two patients, tional, Switzerland), a ferric sucrose product, was given in a valvular heart disease in two and two patients, and idio- dose of 200 mg IV in 150 ml saline over 60 min every two pathic cardiomyopathy in one and two patients, respectively.
weeks until the serum ferritin reached 400 ␮g/l or the %Fe A significant change after treatment was observed in the saturation (%Fe Sat is serum iron/total iron binding capac- two groups in the following parameters: IV furosemide, days ity ⫻ 100) reached 40% or the Hb reached 12.5g%. The IV in hospital, Hb, ejection fraction, serum creatinine and Fe was then given at longer intervals as needed to maintain serum ferritin. In addition, the interaction between the these levels.
study group and time trend was significant in all measure- Investigations. Visits to the clinic were at two- to three-
ments except for blood pressure and %Fe Sat. This inter- week intervals depending on the patient's status. This was action indicates that the change over time was significantly the same frequency of visits to the CHF clinic as before the different in the two groups. For example, before treatment JACC Vol. 37, No. 7, 2001 Silverberg et al.
June 1, 2001:1775– 80 Correction of Anemia in Heart Failure Table 1. Medical Conditions and Contributing Factors to after onset of the study. She was hospitalized for 21 days in Congestive Heart Failure in the 16 Patients Treated for the the seven months before randomization and for 28 days Anemia and in the 16 Controls during the seven months after randomization.
Case 2: A 62-year-old man with a longstanding history of hypertension complicated by IHD, coronary artery bypass graft (CABG) and atrial fibrillation had persistent NYHA 4 Ischemic heart disease CHF and a PA pressure of 35 mm Hg, and died from pneumonia and septic shock eight months after onset of the study. He was hospitalized for seven days in the eight months before randomization and for 21 days during the Chronic renal failure eight months after randomization.
Mitral regurgitation Case 3: A 74-year-old man with IHD, CABG, chronic Atrial fibrillation Rheumatic heart disease obstructive pulmonary disease, a history of heavy smoking and diabetes had persistent NYHA 4 CHF and a PA pressure of 28 mm Hg, and died of pulmonary edema and Peripheral vascular disease cardiogenic shock nine months after onset of the study. He CABG ⫽ coronary artery bypass graft.
was hospitalized for 14 days in the nine months beforerandomization and for 41 days during the nine months after the level of oral furosemide was higher in the control group (136.2 mg/day) compared with the treatment group Case 4: A 74-year-old man with a history of IHD, (132.2 mg/day). After treatment, while the dose of oral CABG, diabetes, dyslipidemia, hypertension and atrial furosemide of the treated patients was reduced to fibrillation, had persistent NYHA 4 CHF and a PA 64.4 mg/day the dose of the nontreated patients was pressure of 30 mm Hg, and died of pneumonia and septic increased to 175 mg/day.
shock six months after onset of the study. He was hospi- The same results of improvement in the treated group talized for five days in the six months before randomization and deterioration in the control group are expressed in the and for 16 days during the nine months after randomiza- following parameters: IV furosemide, days in hospital, Hb, ejection fraction and serum creatinine.
The NYHA class was 3.8 ⫾ 0.4 before treatment and 2.2 ⫾ 0.7 after treatment in Group A and 3.5 ⫾ 0.7 beforetreatment and 3.9 ⫾ 0.3 after treatment in Group B. The Main findings. The main finding of the present study is
improvement in NYHA class was significantly higher (p ⬍ that the correction of even mild anemia in patients with 0.0001) in the treatment group compared with the control symptoms of very severe CHF despite being on maximally group (Table 4).
tolerated drug therapy resulted in a significant improvement There were no deaths in Group A and four deaths in in their cardiac function and NYHA functional class. There was also a large reduction in the number of days of Case 1: A 71-year-old woman with severe mitral insuf- hospitalization compared with a similar period before the ficiency and severe pulmonary hypertension (a pulmonary intervention. Furthermore, all this was achieved despite a artery [PA] pressure of 75 mm Hg) had persistent NYHA marked reduction in the dose of oral and IV furosemide.
4 CHF and died during mitral valve surgery seven months In the group in whom the anemia was not treated, four Table 2. Number and Percentage of Cases Taking Each Medication and the Doses used in mg/day in the Treatment and Control Groups During the Study Dose, mg/d
Dose, mg/d
Angiotensin II receptor blockers The dose of these medications was not changed during the study.
ACE ⫽ angiotensin-converting enzyme.
Silverberg et al.
JACC Vol. 37, No. 7, 2001 Correction of Anemia in Heart Failure June 1, 2001:1775– 80 Table 3. The Effect of Correction of Anemia by Intravenous Iron and Erythropoietin Therapy on Various Parameters in 16 Patientsin the Treatment (A) and 16 in the Control (B) Group Time Group
IV furosemide mg/wk Oral furosemide mg/d Ejection fraction Serum creatine mg% Serum ferritin, ␮g/l Diastolic BP, mm Hg Systolic BP, mm Hg p values are given for analysis of variance with repeated measures and for independent t tests for comparison of baseline levels between the two groups.
BP ⫽ blood pressure; Fe Sat ⫽ iron saturation; Hb ⫽ hemoglobin; IV ⫽ intravenous; NS ⫽ not stated; Std Dev. ⫽ standard deviation.
patients died during the study. In all four cases the CHF rehospitalization than was hypertension, IHD or the pres- was unremitting and contributed to the deaths. In addition, ence of a previous CABG. A recent analysis of the Studies for the group as a whole, the LVEF, the NYHA class and Of Left Ventricular Dysfunction (SOLVD) (16) showed the renal function worsened. There was also need for that the level of hematocrit (Hct) was an independent risk increased oral and IV furosemide as well as increased factor for mortality. During a mean follow-up of 33 months the mortality was 22%, 27% and 34% for those with a Hct Study limitations. The major limitations of this study are
of ⬎40, 35 to 40 and ⬍35 respectively. The striking the smallness of the sample size and the fact that random- response of our patients to correction of mild anemia ization and treatment were not done in a blinded fashion.
suggests that the failing heart may be very susceptible to Nevertheless, the two groups were almost identical in anemia. It has, in fact, been found in both animal (17) and cardiac, renal and anemia status; in the types and doses of human studies (17–19) that the damaged heart is more medication they were taking before and during the inter- vulnerable to anemia and/or ischemia than is the normal vention and in the number of hospitalization days before the heart. These stimuli may result in a more marked reduction intervention. Although the results of this study, like those of in cardiac function than occurs in the normal heart and may our previous uncontrolled study (5), suggest that anemia explain why, in our study, the patients were so resistant to may play an important role in the mortality and morbidity of high doses of CHF medications and responded so well CHF, a far larger double-blinded controlled study should be when the anemia was treated.
carried out to verify our findings.
Our findings about the importance of anemia in CHF are Anemia as a risk factor for hospitalization and death in
not surprising when one considers that, in dialysis patients, CHF. Our results are consistent with a recent analysis of
anemia has been shown to be associated with an increased 91,316 patients hospitalized with CHF (15). Anemia wasfound to be a stronger predictor of the need for early prevalence and incidence of CHF (20) and that correctionof anemia in these patients is associated with improvedcardiac function (21,22), less mortality (23,24) and fewer Table 4. Changes from Baseline to Final New York HeartAssociation (NYHA) Class hospitalizations (23,25).
Effect of improvement of CHF on CRF. Congestive
Initial minus final
NYHA class
heart failure can cause progressive renal failure (26,27).
Renal ischemia is found very early on in patients with cardiac dysfunction (28,29), and chronic ischemia may causeprogression of renal failure (30). Indeed, the development of The improvement in NYHA class was statistically higher (p ⬍ 0.0001) in thetreatment group compared with control.
CHF in patients with essential hypertension has been found JACC Vol. 37, No. 7, 2001 Silverberg et al.
June 1, 2001:1775– 80 Correction of Anemia in Heart Failure to be one of the most powerful predictors of the eventual The combination of IV Fe and EPO. The use of IV Fe
development of end-stage renal disease (31). Patients who along with EPO has been found to have an additive effect, develop CHF after a myocardial infarction experience a fall increasing the Hb even more than would occur with EPO in the glomerular filtration rate (GFR) of about 1 ml/min/ alone while at the same time allowing the dose of EPO to month if the CHF is not treated (32).
be reduced (10 –13). The lower dose of EPO will be In another recent analysis of the SOLVD study, treating cost-saving and also reduce the chances of hypertension the CHF with both angiotensin-converting enzyme inhib- developing (43). We used iron sucrose (Venofer) as our IV itors and beta-blockers resulted in better preservation of the Fe medication because, in our experience, it is extremely renal function than did angiotensin-converting enzyme well tolerated (10,11) and has not been associated with any inhibitors alone (26), suggesting that the more aggressive serious side effects in more than 1,200 patients over six the treatment of the CHF, the better the renal function is preserved. In the present study, as in our previous one (5), Implications of treatment of anemia in CHF. The cor-
we found that the deterioration of GFR was prevented with rection of anemia is not a substitute for the well- successful treatment of the CHF, including correction of documented effective therapy of CHF but seems to be an the anemia, whereas the renal function worsened when the important, if not vital, addition to the therapy. It is CHF remained severe. All these findings suggest that early surprising, therefore, that judging from the literature on detection and treatment of CHF and systolic and/or dia- CHF, such an obvious treatment for improving CHF is so stolic dysfunction from whatever cause could prevent the rarely considered. We believe that correction of the anemia deterioration not only of the cardiac function but of the will have an important role to play in the amelioration of renal function as well. This finding has very broad implica- cardiorenal insufficiency, and that this improvement will tions in the prevention of CRF, because most patients with have significant economic implications as well.
advanced CRF have either clinical evidence of CHF or atleast some degree of systolic dysfunction (33). Systolic and/or diastolic dysfunction can occur early on in many The authors thank Rina Issaky, Miriam Epstein, Hava conditions, such as essential hypertension (34), renal disease Ehrenfeld and Hava Rapaport for their secretarial assis- of any cause (35,36) or IHD, especially after a myocardial infarction (37). The early detection and adequate treatmentof this cardiac dysfunction, including correction of the Reprint requests and correspondence: Dr. D. S. Silverberg,
anemia, could prevent this cardiorenal insufficiency. To Department of Nephrology, Tel Aviv Medical Center, Weizman detect cardiac dysfunction early on, one would need at least 6, Tel Aviv, 64239, Israel.
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