Anemia Correction in Patients with CHF and CKD:
Can Early Use Erythropoietin Reverse Cardiovascular Disease Morbidity?
Mike Speckhart, MD
October 14, 2003
The incidences of kidney disease, cardiac disease and anemia are high and
continue to grow. As internal medicine providers we can expect patients with any or all
of these disease processes in our clinical practice. Anemia, cardiac disease and chronic
kidney disease are physiologically linked, and research is showing that early correction of
anemia with recombinant human erythropoietin can slow the development of heart failure
and progression to end-stage renal disease. This paper will discuss the epidemiological
association between anemia, cardiac disease, and chronic kidney disease. A proposed
mechanism of action linking all three disease process will be detailed. Although no large
clinical trials have been completed, the prospective studies where anemia management in
patients with chronic kidney disease has affected cardiovascular outcomes will be
II. Link between Cardiac Disease and Chronic Kidney Disease.
The link between cardiac disease and kidney disease is largely epidemiological.
Cardiovascular Disease (CVD) includes any of the following processes: coronary artery
disease, heart failure, cerebrovascular disease, and peripheral artery disease. CVD is the
leading cause of morbidity and mortality in patient with kidney disease, especially those
on dialysis. The risk factors for CVD of left ventricular hypertrophy (LVH), congestive
heart failure (CHF), and ischemic heart disease (IHD) are present in stages 1-4 of chronic
kidney disease (CKD). Also, the more traditional risk factors in CVD of diabetes,
hypertension, age, gender, dyslipidemia carry through as risk factors in CKD.
In epidemiological reviews, a concurrent presence of both CVD and CKD leads to
a poorer outcome. The higher stage of CKD portends a worse outcome as well. The
National Kidney Foundation has classified different levels of kidney disease as follows:
Table 1 summarizes the limited but consistent knowledge in linking CKD and CVD.
Table 1. CVD and CKD links.
•The prevalence of hypertension is high in CKD, ranging from 87% to 90%.
•At least 35% of CKD patients had evidence of IHD, angina, or myocardial infarction.
•The prevalence of LVH increases with each stage of CKD. At stage 5, approximately
75% of patients have LVH.
•Risk factors for LVH include elevated systolic blood pressure and anemia.
•↑NYHA cardiac class associated with ↑LVH, ↓GFR,↓Hgb.
•The presence of CVD predicts the faster decline in kidney function and need for dialysis.
•The mortality rate after MI is at least 50% higher in those with impaired kidney function
and on dialysis.
III. Link between Cardiac Disease and Anemia.
Multiple retrospective studies have shown the association of anemia and worse
outcomes in CVD specifically congestive heart failure (CHF). A less rigorous
association can be established between anemia and ischemic heart disease.
In a small review of 142 patients in a CHF clinic, 55% had Hgb < 12 g/dL. In
NYHA class IV patients, 79% had Hgb < 12 g/dL, while only 9% of class I patients had
Hgb < 12 g/dL. In a study of hospitalized patients, 66% of NYHA class IV patients had
Hgb < 12 g/dL. In the Study of Left Ventricular Dysfunction (SOLVD), 6563 patients
were retrospectively reviewed and survival rates were highest in patients with LV
dysfunction (with or without CHF) who had a hematocrit >40%. Progressively poorer
rates of survival were demonstrated in patients with lower hematocrit.[2,3] Thus an
apparent association between higher hematocrit and survival was present.
The largest study linking CKD, anemia and heart failure was the retrospective
review of 1 million Medicare recipients age >65. In the study, 26% of CHF patients
without anemia died over a two year period compared with 35% of CHF patients with
anemia. Of the CKD patients, only 16% without anemia died over two years compared
to 27% with anemia. Of the combined patients with both CHF and CKD, those without
anemia had a 38% death rate compared to 46% of those with anemia.
The Atherosclerosis Risk in Communities (ARIC) Study was a prospective cohort
study of 14410 patients. Of those patients, 1358 subjects were anemic (<13 g/dL males,
<12 g/dL females). There were a total of 549 CVD events (MI, angioplasty, CABG,
death secondary to heart disease) over the mean follow-up of 6.1 years in the entire
cohort. Anemia was independently associated with an increased risk of CVD event of
1.41 (CI [1.01, 1.95], p<0.04) in the entire cohort. The following figure shows the
presence of anemia as a risk factor for CVD survival in both men and women.
IV. Link between Anemia and Chronic Kidney Disease.
Anemia has long been observed in patients with renal disease. Richard Bright
first made these observations in the 1830s. The etiology of this anemia has been
primarily attributed to a reduction in the production (decreased kidney mass) and activity
of erythropoietin. Other factors include deficiencies in substrates (iron, folate, B12,
carnitine), erythropoietin inhibitors (inflammatory states, hyperparathyroidism), blood
loss, and shortened red cell life span. The degree of anemia noted in individuals with
CKD is dependent upon the type of kidney disease.
The National Kidney Foundation has produced the KDOQI guidelines after
multiple reviews and a consensus opinion had determined the high level of evidence
linking anemia to CKD. Clinicians should begin to follow and manage patients with
anemia once the glomerular filtration rate < 60 ml/min. The parameters for anemia are as
follows: Hgb <11 g/dL in premenopausal or pre-pubertal females, and Hgb <12 g/dL in
adult males and post-menopausal females.
Figure 2. Anemia workup in chronic kidney disease regardless of cardiac status.
V. Mechanism of action.
A proposed mechanism of action linking cardiac disease, anemia, and chronic kidney
disease is shown in figure 2.
Beginning with anemia as a starting point, tissue hypoxia results from abnormal
levels of hemoglobin. Peripheral vasodilation occurs to compensate for locally low tissue
oxygenation levels. Vasodilation induces lower blood pressure. The body responds by
increasing sympathetic tone and thus decreasing renal blood flow. A low flow through
the renal arteries decreases glomerular volume. The increased sympathetic tone
independently induces the renin-angiotensin-aldosterone, which has been implicated in
inducing cardiac cell apoptosis. ADH is also released with resultant fluid retention.
Plasma volume increases as fluid is retained and is implicated in LV dilation leading to
LVH. Extreme LVH causes necrosis and apoptosis of myocardial cells resulting in CHF.
Cytokine levels such as tumor-necrosis factor alpha (TNFα) are increased in CHF and
have been implicated in development of anemia of chronic disease.
VI. Outcomes with increases in Hemoglobin.
To break this above cycle, various studies have challenged the hypothesis that
cardiovascular morbidity can be altered by increase hemoglobin levels using recombinant
human erythropoietin. Endogenous levels of erythropoietin are low in chronic kidney
disease patients. The studies reviewed have looked at cardiovascular outcomes in
predialysis patients and those with ESRD.
Most studies examining anemia therapy in predialysis kidney patients have been
small and lacking controls. In the studies by Hayashi et al, and Portoles et al, a
reversal of LVH was obtained by correcting anemia. Silverberg, et al., detailed below, in
an uncontrolled trial of 179 diabetic (type II) and nondiabetics with severe resistant
congestive heart failure demonstrated an improvement in cardiac and patient function
(NYHA class), an association with less frequent hospitalizations, less renal impairment
and less diuretic use in patients treated with EPO and Iron to maintain Hgb > 12.5 g/dL.
Study1. Silverberg et al. The effect of correction of anaemia in
diabetics and nondiabetics with severe congestive heart failure and
chronic renal failure by subcutaneous erythropoietin and intravenous
iron. Nephrology Dialysis Transplantation (2003) 18: 141-146.
In the Silverberg study, 95 patients without diabetes and 84
patients with diabetes were studied. All patients were treated by
cardiologist for at least 3 months in CHF clinic and were maximally
medicated with ACE inhibitors, beta-blockers, spironolactone, long acting
nitrates, digoxin and oral and iv furosemide. All had severe CHF as
judged by NYHA classes 3-4 despite medical management. All had levels
of hemoglobin of 9.5-11.5 g/dL on at least three consecutive visits over 3
week period. Secondary causes of anemia such as hypothyroidism and
deficiencies in B12 and folate were ruled out. All participants were given
a starting dose of 4000-5000 IU/week with increases to 10,000 IU/week to
maintain Hgb of 12.5 g/dL. IV Iron was given so that ferritin levels
would reach 500micrograms/dL/week. All doses of medications except
for furosemide were maintained. Patients were followed up weekly
initially, then every 2-4 weeks depending on status. CBC, BMP, and Iron
profile drawn each visit. HgbAIC was checked in diabetics every 3
months. Blood pressure was checked each visit. A MUGA scan was done
initially and then at 4-6 month intervals. Rate of GFR change during
anemia correction period was compared to rate of GFR change in the year
preceding anemia correction. The number of hospitalizations during the
anemia correction period were compared with a similar time period prior
to the study. Finally, a Visual Analogue Scale (VAS) was implemented to
assess the severity of the patients’ fatigue and/or shortness of breath at the
beginning and end of the study. The duration of the study was 11.8 +/- 8.2
months (range 5 -27 months)
Initial and final values were assessed by paired Student’s t-test,
with p<0.05 being considered significant. Analysis performed by SPSS
Results are summarized in Table 2.
Increases in Hemoglobin to 12.5 g/dL in diabetics and nondiabetics
with resistant CHF and mild to moderate CKD improved the NYHA class
score, increased LVEF%, increased VAS score, decreased
hospitalizations, slowed GFR decline.
Strengths and Weakness
This paper was prospective and had reasonable entry criteria, good
follow-up and relevant endpoints. The number of patients was relatively
The study was uncontrolled and included some subjective data
(VAS score) in the analysis. Baseline GFRs were unknown.
Studies looking at anemia correction in hemodialysis patients have shown mixed
results. The Normalization of Hematocrit Trial was a prospective open label trial of 1233
hemodialysis patients with symptomatic heart disease or congestive heart failure
randomized to a hematocrit of 42 % or 30% with primary end point of length of time to
death or first nonfatal MI. The study was stopped early because of a 7% excess
mortality in the higher hematocrit group using intention to treat analysis.[11,12]
Study 2. Besarab A et al. The effects of Normal as Compared wit
Low Hematocrit Values in Patients with Cardiac Disease who are
Receiving Hemodialysis and Epoetin. New England Journal of
Medicine (1998) 339: 584-590.
This was a randomized, prospective, open-labeled trial of 1233
patients with congestive heart failure (need for hospitalization or
nonroutine ultrafiltration in prior 2 years) or ischemic heart disease
(angina, CAD documented by catheterization, or prior MI) who were
undergoing hemodialysis at 51 centers. All had hematocrit levels of 27 to
33% and had been receiving epoetin for four weeks prior to enrollment.
The patients were randomly assigned to one of two groups: a
normal hematocrit group that received epoetin to achieve hematocrit
values of 42%; the other group received epoetin to maintain hematocrit at
30%. Duration of enrollment was 3 years. Strict epoetin dosage applied.
After 29 months, the risk ratio for death in the high hematocrit
group was 1.3 (CI[0.9, 1.9]), and the study was halted.
Strengths and Weaknesses
This paper is often quoted in review of this topic because of its
significance in hemodialysis patients. Strengths were that the study was
randomized, prospective, had power, had excellent follow-up, and had
relevant patients with typical demographics. Weakness were that it was
open-label, there was an unexplained decline in dialysis clearance (Kt/V),
access thrombosis, and iron requirement.
Foley et al, investigated 146 hemodialysis patients with asymptomatic
cardiomyopathy and randomized them to hemoglobin of 10 or 13.5 g/dL with the primary
outcome being change of left ventricular mass index in those with LV hypertrophy and
change of cavity index in those with LV dilation. The study showed no regression of
established LV hypertrophy and dilation. Secondary outcomes that evaluated quality of
life such as improvements in fatigue, depression and relationships were significant with
higher hemoglobin levels. Mancini et al, showed improvement in exercise capacity in
patients with severe CHF after treatment with epoetin. 
The largest study to date analyzing the effect of anemia correction on
cardiovascular risk with patients not yet requiring renal replacement therapy is currently
ongoing. The Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin β
(CREATE) trial is in the enrollment stage. In this study approximately 600 patients with
moderate anemia (Hgb 11.0-12.5 g/dL) and CKD (GFR 15-35 ml/min) will be divided
into two groups: one receiving Epo therapy early with a goal Hgb 13-15 g/dL, the other
group receiving Epo only when Hgb <10.5 g/dL with a goal Hgb 10.5-11.5 g/dL. Left
Ventricular Mass Index (LVMI) measured by echocardiography will be the primary
efficacy variable. If there is significant difference after one year, the study will access
time to first cardiovascular event (CHF, sudden death, arrhythmia, MI, CVA, angina, or
PVD. Secondary objectives include progression of CKD and quality of life.
Studies showing association between anemia, heart failure, and chronic kidney
disease are well established. A logical mechanism of action linking the three disease
processes has been proposed. Trials with anemia normalization have shown wide
ranging cardiovascular outcomes. The data by Hayashi, Portoles, and Silverberg have
shown that correction of anemia early in kidney disease may provide improvement in
cardiac status. Other studies have shown improvement in quality of life and exercise
capacity. However, prolonged exposure to the uremic state present in advanced stages of
kidney disease may cause irreversible cardiac structural changes and may not be
favorable to anemia correction as seen in the Besarab study. More definitive studies,
such as CREATE, will hopefully provide answers perhaps justifying the secondary
prevention of cardiovascular disease by correction of anemia early in kidney disease.
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Sarnak MJ: Reduced Kidney Function and Anemia as Risk Factors for Mortality
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