Effects of β-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome

Article Outline

• Abstract
• Materials and methods
  • Inclusion criteria
  • Exclusion criteria
  • Study protocol
  • Initial 4-month study
  • Follow-up study at 1 year
  • Laboratory data
  • Echocardiographic evaluation
  • Statistical analysis
• Results
• Discussion
• Study limitations
• Conclusions
• References
• Copyright

Background

Although anemia is frequently found in congestive heart failure (CHF), little is known about the effect of its correction with erythropoietin (EPO) on cardiac structure and function.

Objectives

The present study examines in patients with advanced CHF, chronic renal insufficiency, and anemia the effects of β-EPO on left ventricular (LV) systolic diameter and volume (LVSD and LVSV), LV diastolic diameter and volume (LVDD and LVDV), LV mass, LV ejection fraction (LVEF), pulmonary artery pressure (PAP), and B-type natriuretic peptide (BNP) levels.

Methods

Fifty-one consecutive subjects affected with advanced CHF and anemia were studied. We performed a randomized double-blind controlled study of correction of anemia with subcutaneous EPO for 4 months (group A, 26 patients) using saline as the placebo in the control group (group B, 25 patients). We then maintained the EPO treatment in the treated group for another 8 months. Both groups received oral iron throughout the total 12-month period. Echocardiographic evaluation, BNP levels, and hematological parameters are reported at 4 and 12 months.

Results

The patients in group A during the double-blind phase (4 months) demonstrated an increase in LVEF and mild reduction in LVSD and LVSV with respect to baseline and to group B with no differences in PAP, LVDD, and LVDV. Over the 12-month period, the hemoglobin increased from 10.40.6 to 12.4 ± 0.8 g/dL (P < .01) in group A but did not change in group B. Compared with group B, group A had lower LVDD, LVSD, LVDV, LVSV, LV mass, PAP, and BNP and higher LVEF. The serum creatinine and creatinine clearance remained unchanged in the 2 groups.

Conclusions

In anemic patients with CHF, correction of anemia with EPO and oral iron over 1 year lead to an improvement in LV systolic function, LV remodeling, BNP levels, and PAP compared with a control group in which only oral iron was used.

Although survival of congestive heart failure (CHF) has improved over the last decades, it is still unacceptably poor. Anemia has been found to occur very frequently in patients with CHF and has been found to be an independent risk factor for severity of CHF including mortality, morbidity, and hospitalization.¹, ², ³ It is therefore possible that anemia could be contributing to poor survival in CHF. The Framingham Study⁴ showed that anemia is also an independent risk factor for the production of CHF. Despite this association between CHF and anemia, its role was not mentioned in US CHF treatment guidelines.⁵

However, it is still uncertain whether anemia is actually a causal factor in worsening CHF or merely an innocent bystander, a marker of other causes such as inflammation, hemodilution, or renal failure.¹, ², ³ It was demonstrated in one study that as CHF worsened, the mean hemoglobin (Hb) concentration decreased, from 13.7 g/dL in mild CHF (New York Heart Association [NYHA] I) to 10.9 g/dL in severe CHF (NYHA IV), and the prevalence of Hb <12 g/dL increased from 9.1% in patients with NYHA I to 79.1% in those with NYHA IV.⁶

Up to recently, the published studies on correction with erythropoietin (EPO) or darbepoetin⁷ or IV iron alone⁸ have been either uncontrolled,⁶, ⁸, ⁹ case-controlled,¹⁰ randomized controlled but without a placebo group,¹¹ or placebo-controlled but single-blind.¹² Two double-blind randomized placebo-controlled studies using either EPO or darbepoetin in CHF have recently been published.¹³, ¹⁴ In one of these,¹³ we reported on a double-blind placebo-controlled study using EPO and oral iron versus oral iron alone in 38 anemic patients with CHF. We showed favorable effects on NYHA, B-type natriuretic peptide (BNP), oxygen utilization during maximal exercise, exercise endurance and distance walked, serum creatinine and creatinine clearance (CrCl), and hospitalization over a 4-month double-blind and a further 8-month non–placebo-controlled period. However, the effects of this treatment on echocardiographically measured morphological or functional changes in the heart were not reported. The cardiorenal anemia syndrome is characterized by CHF, chronic renal insufficiency (CRI), and anemia.² In the present study, we investigated, in patients with this combination, the effect of β-EPO therapy and oral iron on left ventricular (LV) dimensions and function, pulmonary artery pressure (PAP), and BNP in a larger number of patients (including the patients in the original study) during a 1-year period, a 4-month double-blinded period, and a further 8-month unblinded follow-up, where the EPO and iron were maintained in the study group and the oral iron maintained in the controlled group.

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Materials and methods 

Inclusion criteria 

We studied consecutively 51 patients with a history of moderate or severe CHF (NYHA III or IV) with systolic dysfunction (left ventricular ejection fraction [LVEF] <40%), mild to moderate renal insufficiency with creatinine levels between 1.5 and 3 mg/dL and with CrCl between 60 and 30 mL/min, and moderate anemia (Hb levels <11.5 g/dL). Before the study, the subjects were treated for at least 6 months with maximally tolerated doses of angiotensin-converting enzyme inhibitors, β-blockers, aldosterone, digoxin, and oral or intravenous furosemide. All patients recruited underwent gastroscopic examination to exclude bleeding as a cause of the anemia. Although this was negative, fecal occult blood tests were positive; colonoscopy was also carried out.

Exclusion criteria 

Patients with isolated diastolic dysfunction, valvular disease, recent myocardial infarction (within 12 weeks), severe hypertension, and gastrointestinal bleeding were excluded. Secondary causes of anemia including hypothyroidism, folic acid, and vitamin B₁₂ deficiency were also excluded.

Study protocol 

Fifty-six consecutive patients who were seen in our cardiac division with previous diagnosis of CHF mild renal insufficiency and anemia and stable conditions were randomized in a double-blind fashion into 2 groups with a 1:1 ratio to receive either β-EPO (Recormon, Hoffmann LaRoche, Basel, Switzerland) or placebo treatment coming from our department and from the nephrology department of our hospital.

Initial 4-month study 

Group A, consisting of 26 patients, was treated with subcutaneous β-EPO twice weekly and oral iron as a ferrous gluconate 300-mg tablet daily. Group B, consisting of 25 patients, received oral iron alone and subcutaneous saline injections twice weekly. The EPO and saline injections were similar, and it was impossible to know which syringes the patients received. The physicians were unaware which syringes they used. The dose of β-EPO was 6000 IU. The EPO or placebo was given twice weekly for 4 months. Checkups at the clinic were given at 2- to 3-week intervals depending on the patient's clinical status. This was the same frequency of checkups as that before the study. All patients had been in a stable condition for at least 6 months before the study. Blood pressure was measured using the oscillometric method on every visit.

Follow-up study at 1 year 

The patients who received EPO and oral iron initially for the 4-month period (group A) were maintained on these medications for an additional 8 months to maintain a target Hb of between 12.0 and 12.5 g/dL. Those who had been in the placebo group (group B) during the initial 4-month period had the placebo injections stopped, but the oral iron was maintained for the next 8 months of follow-up. Both groups were reevaluated at 12 months.

Primary end points included evaluation of LV dimensions and systolic function between treatment groups during double-blind (4 months) and open label periods (12 months). Laboratory data assessment included hematological parameters, renal functional parameters, and BNP levels between treatment groups at the start, at 4 months, and at the end of the study period. Secondary end points included monitoring cardiac events (sudden death, hospitalization, myocardial infarction), body weight, and blood pressure changes; edema development; and NYHA class modifications.

Laboratory data 

A complete blood count Hb, hematocrit (Hct), red blood cell (RBC) count and red cell indices, and serum creatinine, sodium, and potassium were performed at 4 and 12 months. Creatinine clearance was estimated from the serum creatinine values using the Cockroft-Gault formula.¹⁵ Blood samples for BNP were taken in EDTA tubes to which 250 μL of aprotinin had been added to inhibit breakdown of the hormone. All samples were stored at 2°C to 6°C and centrifuged within 3 hours at 2000 turns for 20 minutes. Plasma and serum were obtained and stored at −20°C, and all samples were measured within 1 month after sampling. B-type natriuretic peptide concentrations were determined using a solid-phase sandwich immunoradiometric assay with a coefficient variability of less than 10% in the range 3 to 100 ng/L. The detection limit of the assay was 3 ng/L (Shionora BNP, Schering). The mean follow-up for patients was 12.4 ± 2.5 months (range 11-14 months). The study was performed with the approval of the local ethics committee, and all patients gave their informed written consent.

Echocardiographic evaluation 

Echocardiography was performed using a Hewlett-Packard Sonos 5500 echocardiograph (Hewlett-Packard Instruments, Andover, MA). Left ventricular ejection fraction was qualitatively assessed in the 2- and 4-chamber views following recommendations of the American Society of Echocardiography.¹⁶, ¹⁷ Only patients with moderate to severe systolic dysfunction (LVEF < 40%) were included into the study. Pulmonary systolic artery pressure was measured using the Doppler method at the tricuspid level.¹⁸ The echocardiographic readers were blinded to the subject study assignment and their laboratory data.

Statistical analysis 

The data (expressed as mean ± SD) were obtained for each of the treatment groups at each time point. Repeated measures analysis of variance calculation was performed between 4 and 12 months. Effects were evaluated using the general linear model and mixed model procedures with factors termed Subject Group and Time. In this model, the slope was measured by the effect of Time, within analyses, the slope was tested by testing Time. Particular interest was devoted to the interaction between Group and Time by performing between-group comparison of changes. The data were analyzed for statistically significant differences by analysis of variance/analysis of covariance test for unpaired data and by linear correlation using the SPSS 11.5 for Windows (SPSS Inc, Chicago, IL). The significant level was set at P < .05. Results were considered significant if there was, within or between-group analyses, a statistical confidence level of 95%.

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Results 

The starting sample consisted of 56 patients consecutively recruited during the follow-up study. A total of 5 patients died (3 in placebo group and 2 in treated group). Of 51 remaining patients, 37 were in NYHA class III, and 14 were in class IV. The mean NYHA class for group A before the study was 3.4 ± 0.4, and for group B, 3.6 ± 0.5. The main contributing factors to CHF were considered to be ischemic heart disease in 27 patients, whereas 16 patients displayed idiopathic dilatative cardiomyopathy (CDM), and 8 had cardiac hypertrophy due to hypertension. Before the study, the 2 groups displayed similar cardiac function, comorbidities, laboratory investigations, and similar therapy (Table I).

Table I. Clinical and laboratory characteristics of patients studied

Prior medical treatment with diuretics, ACE inhibitors, β blockers, and angiotensin receptor blockers was similar in the 2 groups. EF, Ejection fraction.

The patients in group A after 4 months (Table II) demonstrated an increase in LVEF with respect to baseline and to group B at the same period (30.1 ± 7.1 vs 32.3 ± 6.1 intragroup and 30.8 ± 5.6 intergroup, both P < .05); after 4 months, group A showed a significant reduction in left ventricular systolic diameter (LVSD; 49.5 ± 4.8 vs 48.3 ± 4.7 mm intragroup and 50.9 ± 4.8 mm intergroup, P < .02 and P < .01, respectively), left ventricular systolic volume (LVSV; 74.4 ± 19 vs 69.9 ± 16.1 mL/m² intragroup [P < .01] vs 71.8 ± 10.2 mL/m² intergroup [P < .02]), and left ventricular mass (LVM) between baseline and 4 months (197.6 ± 16.1 vs 194 ± 16.4 g/m², P < .05). No differences were seen for PAP, left ventricular diastolic diameter (LVDD), and left ventricular diastolic volume (LVDV).

Table II. Echocardiographic parameters in the 2 groups at baseline

Comparison of echocardiographic parameters after 4 months of treatment in EPO and placebo groups.

After 12 months (Table III), patients in group A demonstrated a decrease in LVSD and LVSV with a concomitant increase in LVEF compared with group B (LVSD, 46 ± 4.7 vs 51.6 ± 5.1 mm, P < .01; LVSV, 63.2 ± 17.1 vs 74.4 ± 10.7 mL/m², P < .001; LVEF, 36.8% ± 6.5% vs 29.5% ± 6.1%, P < .001). A significant reduction was seen in group A with respect to group B in LVDD and LVDV (LVDD, 66 ± 5.4 vs 68.8 ± 4.9 mm, P < .05; LVDV, 99.3 ± 16.8 vs 104.7 ± 15 mL/m², P < .01). Group B demonstrated more LV enlargement at 12 months than at baseline (LVDD at baseline, 67.5 ± 5.5 vs 68.8 ± 4.9 mm, P < .05; LVDV at baseline, 101.4 ± 14.1 vs 104.7 ± 15 mL/m² at 12 months, P < .05). In addition, LVM and PAP were reduced in group A with respect to baseline and group B LVM (197.6 ± 16.1 at baseline vs 186.1 ± 18.8 and 193.1 ± 10.9 g/m², P < .01; PAP, 39.6 ± 4.7 at baseline vs 33.8 ± 3.4 and 39 ± 4.7 mm Hg at 12 months, P < .01 ) (Table IV, Figure 1, Figure 2).

Table III. Comparison of echocardiographic parameters after 12 months of treatment in EPO and placebo groups

Table IV. Comparison of echocardiographic parameters in each group during follow-up period

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• Figure 1. 

  Mean LVEF values at start, 4 months, and 12 months of follow-up period in group A (EPO) and group B (placebo). Erythropoietin therapy improved LVEF after 12 months.

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• Figure 2. 

  Mean LVSV at start, 4 months, and 12 months of follow-up period in group A (EPO) and group B (placebo). Erythropoietin therapy reduced LVSV after 4 and 12 months.

Laboratory parameters showed a significant increase in Hb, Hct, and RBC levels in group A at 12 months after treatment with respect to baseline (12.4 ± 0.8 vs 10.4 ± 0.6 g/dL, P < .01; 36.4% ± 4% vs 30% ± 3%, P < .01; 4.2 ± 0.6 vs 3.3 ± 0.4 mil, P < .01). No significant differences in any blood parameters were seen for group B. The renal parameters, both serum creatinine and creatinine clearance, were not different in either group between the initial and the 12-month period. Plasma BNP levels before and after EPO therapy and in comparison with group B were significantly reduced in group A after 4 and 12 months (group A, 568 ± 320 pg/mL at time 0 vs 295 ± 198 pg/mL at 4 months, P < .01; group B, 585 ± 342 pg/mL at time 0 vs 496 ± 330 pg/mL at 4 months, P = NS; at 12 months, group A [322 ± 187 pg/mL] vs group B [535 ± 346 pg/mL], P < .001 between groups). There was a significant reduction in hospitalization in the EPO group with respect to placebo: hospitalizations occurred in 4 (15%) of 26 in group A and in 8 (32%) of 25 in group B (P < .01). The NYHA class was significant lower in group A with respect to placebo: 2.7 ± 0.5 versus 3.5 ± 0.5 (P < .05) (Table V).

Table V. B-type natriuretic peptide levels, hematological renal parameters, and cardiac events frequency during time periods in each group

At 12 months, an inverse correlation was observed between BNP and Hb levels in group A (r = 0.61; P < .01) but not in group B (Figure 3, A and B).

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• Figure 3. 

  Relationship between BNP and Hb levels after 12 months in 2 groups: in EPO-treated patients, BNP decreased together with Hb increase.

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Discussion 

In this study, we found that during a 1-year period, the anemic patients with CHF in whom the anemia was corrected had an improvement in LVEF, LVSD, LVSV, LVDD, LVDV, LVM, PAP, and BNP, whereas in the group who did not receive EPO, all these parameters either stayed the same or worsened. In the treated group (A), most of these changes were already apparent after the initial 4-month double-blind period of the study and continued to improve during the subsequent 8 months when the study continued but was not double-blind. In contrast, in the nontreated group (B), worsening of many of these parameters was often seen in the first 4 months, and this worsening continued during the subsequent 8 months. These results are consistent with many studies that have shown that anemia in CHF is associated with a higher mortality, morbidity, and rate of hospitalization, and more severe hemodynamic changes including higher right atrial pressure and pulmonary wedge pressure and progressive LV hypertrophy and dilation.¹, ², ³ They are also consistent with studies in which EPO therapy in CHF improves many parameters including NYHA, LVEF, oxygen utilization during exercise, exercise tolerance, and quality of life.¹, ², ³, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴ In hemodialysis patients with CHF, EPO treatment also leads to a reduction in LVM and an improved LVEF.¹⁹

The high serum creatinine in our study is consistent with the findings in other reports of anemia and CHF.⁶, ⁹, ¹¹, ¹³ Our patients had moderately severe renal failure. It may be that other studies that have not reported such a severe degree of renal failure have specifically removed anemic renal failure CHF patients from their study or selected milder forms of CHF in which renal function is better preserved; whereas our patients were all patients with severe CHF with NYHA III and IV. In addition, other studies where renal function has been better than ours studied younger patients. Our patients' mean age was around 73, and it is known that renal function is lower in the elderly.

In the 1 case-controlled non–placebo-controlled study of 16 anemic CHF cases that examined LV hypertrophy and dilation, these improved after correction of the anemia with EPO over 24 months but not in the 7 controls who did not receive EPO.¹⁰ The present study therefore represents the first double-blind placebo-controlled study that examined the effect of anemia correction in CHF on LV hypertrophy, LV dilation, and LVM. In a previous study involving some of the patients in this study,¹³ we showed that the NYHA, BNP, renal function, oxygen utilization during exercise, exercise tolerance, and BNP improved during the 4-month double-blind period and during the subsequent 8 month nonblinded period of the study as compared with a control group that did not receive EPO. In the present study, the BNP improved in a similar manner by 4 and 12 months, and the cardiac dimensions and PAP also improved. Because BNP is one of the most powerful markers of the adverse outcome in CHF, plasma lowering might indirectly signal an improvement in cardiac function and outcome in patients with this cardiorenal anemia syndrome. If our results will be confirmed in larger studies, EPO therapy might provide results similar to β-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers in anemic patients with CHF.

Many animal studies have shown that EPO appears able to directly improve LV function even without increasing the Hb.²⁰, ²¹, ²³ It can induce myocardial neovascularization and prevent myocardial cell apoptosis, myocardial fibrosis, and oxidative stress in animal models secondary to myocardial infarction, CHF, or ischemic injury.²⁰, ²¹, ²², ²³ The beneficial effects of EPO appear to be confirmed by the BNP level reduction that we found in our study in the treated patients.

There has recently been considerable controversy about what should be the target Hb in CRI, and because many anemic patients with CHF have some degree of renal insufficiency, this controversy involves CHF as well. Some studies on correction of anemia with EPO in CRI (such as the recent CHOIR study²⁴) and in dialysis patients²⁵ have suggested that a target Hb of 12 g/dL is acceptable but that increasing it to 13 g/dL increases the cardiovascular risk. Some reviews²⁶, ²⁷ and a recent meta-analysis²⁸ agree with this opinion. However many other recent reviews have cast doubt on the conclusions of the CHOIR study,²⁹, ³⁰, ³¹ pointing out the small numbers studied, the lack of a double-blind study and placebo, the high dropout rate from noncardiovascular causes, the higher prevalence initially of cardiovascular disease and hypertension in the high Hb group, the small number of adverse vascular events in both the high and low Hb group, and other problems. Clearly well-powered double-blind placebo-controlled studies are needed to answer this controversy in CRI and CHF. The TREAT study in CRI²⁹ and the RED-HF study³⁰ in CHF are such studies and are now in progress. In any case, the mean Hb in our treatment group at the end of the study was only 12.4 ± 0.8 g/dL, which is less than the level of 13 g/dL, which has caused concern.

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Study limitations 

This single-center study was limited by its small sample size. The investigators were blinded to the study in the first 4 months; however, the 8-month additional period was unblinded, some results could have less statistical power and could not be easily biased by the investigator. In this study, the etiology of renal disease was not considered, and the impact of EPO therapy might differ on the basis of the type of anatomic kidney alterations. The Cockroft-Gault equation is based on ideal body weight, and this method was not validated on patients with CHF. It is likely that the baseline weight of some subjects was above their ideal weight due to fluid retention upon hospital admission. The study carries some limitations linked to noninvasive assessment of LV measures and systolic function; however, the LV volumes and LVEF have been measured with area-length formula that has demonstrated a good correlation with the ventriculography. Nevertheless, our results should be partially due to afterload reduction and heart rate slowing. The method used is especially limited for patients affected with atrial fibrillation (n = 14), we have tried to avoid these problems by making a mean of 5 measures.

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Conclusions 

Anemia in CHF has been related to adverse clinical outcomes, but little is known about the effects of its correction with EPO on cardiac dimensions and function. We showed that such correction leads to an improvement in LVEF, LVSD, LVSV, LVDD, LVDV, LVM, and PAP. This improvement in LV morphology and function was associated with a significant decrease in BNP levels.

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References 

1. Lindenfeld JA. Prevalence of anemia and the effects on mortality in patients with heart failure. Am Heart J. 2005;149:391–401
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (174 KB)
   • CrossRef
2. Silverberg DS, Wexler D, Iaina A, et al. The interaction between heart failure and other heart disease and anemia. Semin Nephrol. 2006;26:296–333
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (223 KB)
   • CrossRef
3. Felker GM, Adams Jr KF, Gattis WA, et al. Anemia as a risk factor and therapeutic target in heart failure. J Am Coll Cardiol. 2004;44:959–966
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (134 KB)
   • CrossRef
4. Kannel W. Epidemiology and prevention of cardiac heart failure: Framingham Study insights. Eur Heart J. 1987;8(Suppl F):23–29
   • View In Article
5. Packer M, Cohn JN. Consensus recommendations for the management of chronic heart failure. Am J Cardiol. 1999;83:1A–38A
   • View In Article
   • Full-Text PDF (342 KB)
   • CrossRef
6. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, congestive heart failure improves cardiac and renal function, functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000;35:1737–1744
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (157 KB)
   • CrossRef
7. Cleland JGF, Coletta AP, Clark AL, et al. Clinical trials update from the European Society of Cardiology Heart Failure meeting and the American College of Cardiology: darbepoetin alfa study, ECHOS, and ASCOT-BPLA. Eur J Heart Fail. 2005;7:937–939
   • View In Article
   • MEDLINE
   • CrossRef
8. Bolger AP, Bartlett FP, Penston HS, et al. Intravenous iron alone for the treatment of anemia in patients with chronic heart failure. J Am Coll Cardiol. 2006;48:1225–1227
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (286 KB)
   • CrossRef
9. Silverberg DS, Wexler D, Blum M, et al. Effects of treatment with EPO beta on outcomes in patients with anaemia and chronic renal failure. Kidney Blood Press Res. 2005;28:41–47
   • View In Article
   • MEDLINE
   • CrossRef
10. Mishra TK, Mishra SK, Mohanty NK, et al. Prevalence, prognostic importance and therapeutic implications of anemia in heart failure. Indian Heart J. 2005;57:670–674
    • View In Article
    • MEDLINE
11. Silverberg DS, Wexler , Sheps D, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol. 2001;37:1775–1780
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (149 KB)
    • CrossRef
12. Mancini DM, Katz SD, Lang CC, et al. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation. 2003;21:294–299
    • View In Article
13. Palazzuoli A, Silverberg DS, Iovine F, et al. Erythropoietin improves anemia, exercise tolerance, and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia. Am Heart J. 2006;152:9–15
    • View In Article
14. Ponikowski P, Anker SD, Szachniewicz J, et al. Effect of darbepoetin alpha on exercise tolerance in anemic patients with symptomatic chronic heart failure. J Am Coll Cardiol. 2007;49:753–762
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (532 KB)
    • CrossRef
15. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41
    • View In Article
    • MEDLINE
    • CrossRef
16. Schiller NB, Shah PN, Crawford M, et al. Recommendations for quantification of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr. 1989;2:358–367
    • View In Article
    • MEDLINE
17. Devereux LB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986;57:450–458
    • View In Article
    • MEDLINE
    • CrossRef
18. Goodman DJ, Harrison DC, Popp RL. Echocardiographic features of primary pulmonary hypertension. Am J Cardiol. 1974;33:438–443
    • View In Article
    • Abstract
    • Full-Text PDF (2081 KB)
    • CrossRef
19. Hampl H, Hennig L, Rosenberger C, et al. Effects of optimised heart failure therapy and anemia correction with epoetin beta on left ventricular mass in hemodialysis patients. Am J Nephrol. 2005;25:211–220
    • View In Article
    • MEDLINE
    • CrossRef
20. Wright GL, Hanlon P, Amin K, et al. Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury. FASEB J. 2004;25:285–291
    • View In Article
21. van der Meer P, Lipsic E, Henning RH, et al. Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol. 2005;46:125–133
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (666 KB)
    • CrossRef
22. Ribatti D, Presta M, Vacca A, et al. Human erythropoietin induces a pro angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood. 1999;93:2627–2636
    • View In Article
    • MEDLINE
23. Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA. 2005;293:90–95
    • View In Article
    • CrossRef
24. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–2098
    • View In Article
    • CrossRef
25. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;39:584–590
    • View In Article
26. Strippoli GFM, Tognoni G, Navaneethan SK, et al. Haemoglobin targets: we were wrong, time to move on. Lancet. 2007;369:346–350
    • View In Article
    • Full Text
    • Full-Text PDF (72 KB)
    • CrossRef
27. Remuzzi G, Ingelfinger JR, et al. Correction of anemia—payoffs and problems. N Engl J Med. 2006;355:2144–2146
    • View In Article
    • CrossRef
28. Phrommintikul A, Haas SJ, Elsik M, et al. Mortality and target hemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet. 2007;369:381–388
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (132 KB)
    • CrossRef
29. Pfeffer MA. An ongoing study of anemia correction in chronic kidney disease. N Engl J Med. 2007;356:959–961
    • View In Article
    • CrossRef
30. van Veldhuisen DJ, McMurray JJV. Are erythropoietin stimulating proteins safe and efficacious in heart failure? Why we need an adequately powered randomized outcome trial. Eur Heart J. 2007;9:110–112
    • View In Article
    • MEDLINE
31. Levin A. Understanding recent haemoglobin trials in CKD: methods and lesson learned from CREATE and CHOIR. Nephrol Dial Transplant. 2007;22:309–312
    • View In Article
    • MEDLINE
    • CrossRef