The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron

Donald S. Silverberg, Dov Wexler, Miriam Blum, Joseph Z. Tchebiner, David Sheps, Gad Keren, Doron Schwartz, Ron Baruch, Tatyana Yachnin, Meital Shaked, Idit Schwartz, Shoshanna Steinbruch and Adrian Iaina

Department of Nephrology and Cardiology and Congestive Heart Failure Unit, Tel Aviv Medical Center, Tel Aviv, Israel



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. A mild anaemia is often found in patients with congestive heart failure (CHF), but its significance is uncertain. In an open uncontrolled study we investigated the effect of correcting this anaemia [haemoglobin (Hb) 9.5–11.5 g%] with subcutaneous (s.c.) erythropoietin (Epo) and intravenous (i.v.) iron (Fe) in 179 patients, 84 type II diabetics and 95 non-diabetics, with moderate to severe CHF which was resistant to maximally tolerated doses of standard CHF medications.

Methods. Epo, s.c., was given every 1–3 weeks to achieve and maintain the Hb at 12.5 g%. Fe (Fe sucrose-Venofer) was added i.v. as necessary to maintain the Fe stores. Duration of treatment was 11.8+8.2 months.

Results. With the Epo-Fe treatment the Hb increased from 10.41±1.0 to 13.1±1.3 g% in diabetics and from 10.5±1.0 to 12.9±1.2 g% in non-diabetics. Comparing the diabetics and non-diabetics, the New York Heart Association functional class improved by 34.8 and 32.4%, respectively. breathlessness and/or fatigue, as measured by a self-administered Visual Analogue Scale, improved by 69.7 and 67.4%, and the left ventricular ejection fraction improved by 7.4 and 11.5%, respectively. The number of hospitalizations fell by 96.4 and 95.3%, respectively, compared with the pre-treatment period. Although the glomerular filtration rate (GFR) was falling at a rate of ~1 ml/min/month before the study in both groups, neither the mean serum creatinine nor the GFR changed significantly during the study period. The mean dose of Epo needed, measured in IU/week/kg body weight, was similar in the two groups.

Conclusion. The correction of the mild anaemia that was found in diabetics and non-diabetics with resistant CHF and mild to moderate chronic renal failure improved the cardiac function and patient functional status, stabilized the renal function and markedly reduced the need for hospitalization.

Keywords: anaemia; chronic renal failure; diabetes mellitus; erythropoietin; heart failure; iron



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
About half of all patients with congestive heart failure (CHF) have anaemia, as defined by a haemoglobin (Hb) of <12 g% and the prevalence and severity of the anaemia increases with increasing severity of the CHF [1]. The aetiological role of CHF in the production of anaemia has recently been confirmed in experimental studies [2]. Rats in whom CHF was induced by a myocardial infarction had a marked reduction in haematopoiesis, at least partly due to the effects of the cytokine tumour necrosis factor alpha (TNF{alpha}) on the progenitor erythrocytes in the bone marrow [2]. A vicious circle could therefore be set in motion wherein the CHF produces anaemia and the anaemia acts back to further worsen the CHF.

Severe anaemia can cause CHF even in people with normal hearts [3]. However, in people with cardiac disease, both animal and human studies have shown that the damaged heart is much more susceptible to the effects of anaemia than is the normal heart [4]. CHF and/or ischaemia may develop at higher levels of Hb in those with cardiac damage than in normals [4]. Indeed in a recent analysis of a large study of mild to moderate CHF (the SOLVD study [5]) and severe CHF [6] it was found that anaemia was a strong and independent risk factor for mortality in CHF patients. In both uncontrolled [1] and controlled [7] studies, we showed that correction of the anaemia with subcutaneous (s.c.) erythropoetin (Epo) in combination with intravenous (i.v.) iron (Fe) sucrose in patients with CHF resistant to maximal doses of CHF medications can improve their cardiac function [as judged by the left ventricular ejection fraction (LVEF)] and New York Heart Association (NYHA) functional class and also slow down the rate of progression of renal failure. The treatment also reduced hospitalizations and reduced the need for high doses of oral and i.v. diuretics.

About 20–40% of all patients with CHF have diabetes [8] and diabetes has been found to a major risk factor for the production of CHF [9]. The prognosis of CHF when associated with diabetes is worse than that of CHF in non-diabetics [10]. One factor that may contribute to this worse prognosis is the presence of anaemia. Recent studies [11,12] have found that anaemia may appear early on in diabetes, even before the onset of chronic renal failure (CRF). This anaemia is associated with blood levels of Epo that are inappropriately low for the level of Hb [11,12]. Thus, the combination of heart disease and premature anaemia in diabetics could partly explain the high prevalence of CHF in diabetes and its severe prognosis.

Based on these observations the present work was undertaken to study the effect of the correction of anaemia on cardiac and renal function in CHF patients with and without diabetes mellitus. These patients had a combination of mild to moderate anaemia, mild to moderate CRF and moderate to severe CHF (NYHA functional class 3 and 4) which was resistant to maximally tolerated medical therapy.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Eighty-four patients with diabetes mellitus type II (NIDDM) with severe resistant CHF and 95 patients with severe resistant CHF without diabetes mellitus were studied. The diagnosis of diabetes was established at least 2 years before the study. All the diabetics were in follow-up in a diabetic clinic and were on diets and all had started therapy with oral hypoglycaemic agents. Twenty-six, however, had been switched to insulin because of poor diabetic control. Before the study, all 179 patients, diabetics and non-diabetics, were being treated by cardiologists for at least 3 months in a special CHF unit in our hospital with maximally tolerated doses of CHF medications—ACE inhibitors, beta-blockers (carvedilol, metropolol or bisoprolol), aldospirone, long acting nitrates, digoxin and oral and i.v. furosemide. In some patients these agents could not be given because of contraindications, and in others they had to be stopped because of side effects (Table 1Go). Despite this treatment the patients still had moderate to severe CHF as judged by NYHA functional classes 3–4. All had levels of Hb in the range of 9.5–11.5 g% on at least three consecutive visits over a 3-week period. Secondary causes of anaemia including hypothyroidism, and folic acid and vitamin B12 deficiency were ruled out and there was no evidence of gastrointestinal bleeding. All these patients were referred to the nephrology clinic for the correction of their anaemia.


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Table 1.  Demographic and clinical characteristics of the 179 diabetic and non-diabetic CHF patients

 

Study protocol
Treatment protocol for the correction of anaemia. All patients received the combination of s.c. Epo and i.v. Fe. The Epo was given once weekly at a starting dose of 4000–5000 IU/week and the dose was increased to up to 10 000 IU/week or decreased to once every 2–3 weeks or discontinued entirely so as to achieve and maintain a target Hb of 12.5 g%. The i.v. Fe (Venofer-Vifor International, Switzerland), a ferric sucrose product, was given in a dose of 200 mg i.v. in 150 ml saline over 60 min every 1–2 weeks until either the serum ferritin reached 500 µg/l, the % Fe saturation (plasma Fe/TIBCx100) reached 40%, or the Hb reached 12.5 g%. The i.v. Fe was then given at longer intervals to maintain these levels.

Medication dose. Except for oral and i.v. furosemide therapy the doses of all other CHF medications, which were used in the maximally tolerated doses before the intervention for at least 3 months, were kept unchanged during the study.

Investigations. Visits were at weekly intervals initially and then at 2–4 week intervals depending on the patient's status. A complete blood count, BUN, serum sodium, potassium, creatinine, ferritin and % Fe saturation were performed on every visit. HbA1c was performed in the diabetics every 3 months. An electronic device measured the blood pressure on every visit. The LVEF was measured by a multiple gated ventricular angiography heart scan initially and at 4–6 month intervals. Hospital records were reviewed to compare the number of hospitalizations during the time the patients were treated for anaemia with the number of hospitalizations during a similar period of time that they were treated in the CHF clinic before the anaemia treatment.

The glomerular filtration rate (GFR) was calculated from the Cockcroft-Gault formula [13]. The rate of change of the GFR before and during the intervention period was calculated by comparing the change in GFR per month in the year before the anaemia correction with that during the period of correction. Urine protein excretion was determined before the correction of the anaemia study period and at the end of the study from 24 h urine samples.

A Visual Analogue Scale (VAS) was employed that allowed the patients to assess the severity of their fatigue and/or shortness of breath (SOB) at the beginning and at the end of the intervention period. They were shown a 10 cm line with the number zero at one end and the number 10 at the other. The number zero represented normal breathing and strength and the number 10 extreme fatigue and/or SOB. They were asked to mark on the line the degree of fatigue and/or SOB they felt when they started therapy for their anaemia and again at the end of the study period after they had reached and maintained the target Hb of 12.5 g%.

The duration of the study was 11.8+8.2 (range 5–27) months.

Statistical analysis
Mean±standard deviation was calculated. In the intervention study, the significance of the difference between the initial values and those at the end of the study for the individual parameters in the patients was assessed by paired Student's t-test; P<0.05 was considered statistically significant. The correlations between different parameters were calculated. All the statistical analysis was performed by the SPSS program (version 9/Chicago, IL).



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Initial values
The clinical, biochemical and haematological changes of the NIDDM group and non-diabetic group are given in Table 1Go.

Eighty-four (46.9%) of the 179 CHF patients were diabetics. The diabetic patients were, on average, 4 years younger than the non-diabetics and had a higher mean body weight. Although there were more men than women in both groups there were relatively more women in the diabetic group (36.9%) than in the non-diabetic group (24.2%). Of the diabetics, 67.9% had a history of hypercholesterolaemia compared with only 35.8% of the non-diabetics. 91.7% of the diabetics had ischaemic heart disease compared with 77.9% in the non-diabetics and 65.5% of the diabetics had had a coronary artery bypass graft compared with only 26.3% of the non-diabetics. On the other hand only 9.5% of the diabetics had had a percutaneous transluminal coronary angioplasty performed compared with 17.9% of the non-diabetics. The diabetic patients had had more hospitalizations in the time before the study and also had a higher mean 24 h urine protein excretion than the non-diabetic patients. The mean HbA1c levels was elevated in the diabetic group.

The two groups were similar in duration of therapy of the anaemia, age, prevalence of a history of hypertension, initial NYHA functional class, LVEF and the VAS fatigue/SOB index. The percentage of patients taking the various CHF medications was similar (Table 1Go) as were the mean doses of each medication used (not shown). They were also similar in initial Hb, serum Fe, % Fe saturation and serum ferritin and PTH levels, serum creatinine and the rate of change of creatinine clearance in ml/min/month. The mean systolic and diastolic blood pressures were similar in the two groups.

Intervention period (Table 2Go)
The NYHA, LVEF and VAS index improved significantly and equally in both groups. The Hb, serum Fe and ferritin and % Fe saturation all increased significantly and equally in the two groups. The HbA1c level was unchanged with the treatment of the anaemia.


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Table 2.  Results of intervention study

 
The mean serum creatinine and creatinine clearance, as calculated from the Cockcroft-Gault formula, did not change significantly in either group during the study. This was in marked contrast to the rate of fall in creatinine clearance in the period before the study, when the mean rate of fall of creatinine clearance was >1 ml/min/month in both the diabetic and non-diabetic group. There was a marked, significant and equal fall in the number of hospitalizations in both groups compared with an equal period before of time before the study.

The increase in Hb in the first 2 months of Epo treatment was similar in the two groups; 2.0±0.8 g% in the diabetic group and 2.2±1.2 g% in the non-diabetic group. No significant correlations were found between the initial LVEF and NYHA and the response to Epo (i.e. the increase in Hb). In addition the relative improvement in LVEF and NYHA class and quality of life with correction of the anaemia was not correlated with the initial CHF status i.e. the relative degree of benefit was similar independent of initial severity of the CHF. The mean dose of Epo in IU/kg/week required to maintain the Hb at a level of 12.5 g% was also similar. The mean monthly doses of i.v. Fe used for three consecutive 6 month periods were similar in the two groups and were progressively lower as time went on: 254±120, 104±99 and 65±69 mg/month, respectively, in the diabetic group and 275±141, 123±88 and 78±87 mg/month, respectively, in the non-diabetic group.

There were no significant changes in the mean systolic or diastolic blood pressure, PTH levels and urine protein levels in either group. An analysis of the treatment effects on men and women showed no significant differences in erythropoietic response to the Epo-Fe combination (results not shown).

Eighteen of the 179 patients (10.1%) died during the intervention period (Table 3Go). The most common causes of death were: sudden death (seven) followed by infectious complications (five) and cancer (three). Only one patient died from unrelenting CHF. Four of the five infectious deaths occurred in diabetics. The causes of infections were: pneumonia alone (two), pneumonia and urosepsis (one), pneumonia after a hip fracture (one) and empyema and sepsis after valvular surgery.


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Table 3.  Causes of death in the 18 patients who died during the study

 



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The major findings in this study were that, in both diabetics and non-diabetics with severe CHF and mild to moderate CRF, correction of the associated anaemia by the use of s.c. Epo and i.v. Fe was associated with an improvement in the LVEF and cardiac functional status as judged by the improvement in both the NYHA class and in the self-administered VAS fatigue/SOB index. In addition there was a marked slowing of the rate of renal functional deterioration and a marked reduction in re-hospitalization rate in both diabetics and non-diabetics compared with an equal period before the study. The Hb response of the two groups was similar as was the dose of Epo in IU/kg/week. The findings of the present study confirm the results of our previous experience on the effect of correction of anaemia in CHF [1,7]. The prevalence of diabetes in these anaemic-resistant CHF patients was higher than is normally found in CHF [8,9] and may be related to the tendency for anaemia to present early on in diabetes, as mentioned previously [11,12].

Our findings may have considerable relevance to the treatment of CHF since many CHF patients have an Hb level of <12 g% [1], the lower limit of normal being 13 g% in men and 12 g% in women [14]. Yet the role of anaemia in the production of CHF in diabetics and non-diabetics does not appear to be well recognized. It is not mentioned in recent reviews on CHF [15], or in epidemiological surveys on CHF and myocardial damage in diabetes [16].

Our results are consistent with the findings of studies in dialysis patients where treatment of anaemia improves the ejection fraction, reduces heart rate (i.e. ventricular work), prevents ventricular dilation, reduces ventricular hypertrophy and dilation, reduces the chances of developing or getting recurrences of CHF, reduces hospitalization and death and improves exercise tolerance, sleep, cognitive function and quality of life [17].

The striking improvement in self-assessed SOB and fatigue that we assessed by the VAT test is striking. The patients felt a marked improvement in these symptoms, which are the major symptoms of CHF.

The anaemia in CHF may not only be related to CRF with the associated reduction in Epo production produced by the renal damage, but to other factors as well. There may be a loss of Epo in the urine as part of the associated proteinuria [18]. The nephrotic syndrome of any cause can result in excessive loss of Epo, transferrin and Fe in the urine and lead to anaemia [18]. Other causes of anaemia in CHF include Fe deficiency from anorexia and reduced Fe intake, reduced Fe absorption, which is often seen in CRF and use of aspirin, which can cause gastrointestinal bleeding [19]. Elevated levels of cytokines such as TNF{alpha}, which are increased in CHF [2] may also cause anaemia (the so-called anaemia of chronic disease) by reducing Epo production in the kidney, reducing Epo response at the bone marrow and impairing mobilization of Fe stores from the reticuloendothelial system for use in the production of Hb [2,20]. ACE inhibitors, may also be partly responsible for the anaemia since they can reduce Epo production in the kidney and interfere with Epo utilization in the bone marrow [21]. We did not find a difference in the dose of Epo in those receiving these agents and those not receiving them (results not shown).

The mean dose of Epo used was ~5000–6000 IU/week. This relatively low dose is probably due to the fact that we administered Venofer (iron sucrose) regularly. This acts in an additive fashion with the Epo to increase the Hb [19].

The 1-year mortality rate in the CHF patients in our study, 10.1%, is far less than the 30–50% 1-year mortality often seen in severe CHF in an older population [22]. It is possible that the high mortality of CHF patients in the community could be partially related to the uncontrolled anaemia, since anaemia is an independent risk factor or mortality in CHF [5,6]. Similarly one reason for the continuing high rate of re-hospitalization in CHF may be that the associated anaemia has not been treated. Anaemia has been found to be a significant predictor of the need for re-hospitalization in both CHF [23] and CRF [24] and, as shown above, treatment of anaemia in CHF reduces markedly the need for hospitalization. Although treatment with Epo may cost a few thousand dollars a year per patient this is probably far less costly than the multiple hospitalizations, which characterize the course of severe CHF patients in whom the anaemia is not treated. Reducing these hospitalizations would therefore substantially reduce health costs in these severely ill anaemic CHF patients while simultaneously greatly improving their quality of life.

With the correction of anaemia there was also a significant slowing in the rate of fall in GFR in both diabetics and non-diabetics. The stabilization of GFR with the correction of anaemia is probably due, at least in part, to the improvement in cardiac function which occurred with correction of the anaemia with the associated increase in renal blood flow [3] and reduction in renal hypoxia. Renal hypoxia itself may contribute to the progression of renal failure [25]. Correction of anaemia in CRF has also been associated with an improvement in renal function in some studies [26]. Our study suggests that the deterioration in renal function that occurs in diabetes may be at least partially due to the associated uncontrolled anaemia and CHF and not just to progressive diabetic nephropathy.

The mean LVEF was relatively high (35%) compared with the severity of the CHF as judged by the NYHA functional class [3,9]. This is because of the fact that while many patients with severe CHF have systolic dysfunction with a low LVEF, almost an equal number have diastolic dysfunction in which the LVEF may be normal or even elevated even in the face of severe CHF.

The lack of correlation between the initial severity of CHF and the relative degree of improvement in these parameters with correction of the anaemia suggests that correction of the anaemia can cause improvement at all levels of CHF. Clearly, however, the earlier the anaemia is treated the greater the chance of preserving or improving cardiac and renal function.

A major limitation of this study is that it was not a randomized controlled study. The patients clearly received more attention and were being better followed than previously, since they were now seeing a nephrologist in addition to their cardiologist. Nevertheless, the doses of CHF medication except for furosemide were unchanged and the improvement in NYHA class, self-assessed SOB and/or fatigue and the objective improvements in ejection fraction and rate of change in creatinine clearance do suggest that the treatment of anaemia had a profound (and equal) effect on both diabetics and non-diabetics. Clearly, randomized double-blind controlled studies of anaemia correction with Epo and i.v. Fe in CHF are indicated.

We have called this close association between cardiac failure, renal failure and anaemia the cardio renal anaemia syndrome. It is our impression that only by adequate control of all three of these elements, including early diagnosis, referral and aggressive therapy of both the CHF and the anaemia, can one prevent or slow down the progression of both the CHF and the CRF. Clearly the treatment also includes adequate control of diabetes and hypertension. All this will require the close cooperation of nephrologists, diabetologists, cardiologists, general internists and family physicians. The substantial benefits that the patient will enjoy in terms of reduced hospitalization and improved quality of life would seem to make it worth the effort.



   Notes
 
Correspondence and offprint requests to: Donald S. Silverberg, Department of Nephrology and Cardiology and Congestive Heart Failure Unit, Tel Aviv Medical Center, Weizman 6, Tel Aviv 64239, Israel. Email: donald{at}netvision.net.il Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 4. 4.02
Accepted in revised form: 30. 8.02