Silverberg 2005

TATM 2005;6(3):26-37
The Role of Anemia in the

Progression of Congestive Heart
Failure: Is There a Place for
Erythropoietin and Intravenous Iron?
SUMMARY
Despite all the advances in congestive heart failure (CHF), the mortality, morbidity
D ONALD S. S ILVERBERG , MD , FRCP(C) , 1

D OV W EXLER , MD , 2 A DRIAN I AINA , MD , 1
AND D ORON S CHWARTZ , MD 1
and the number of rehospitalizations in this condition is still very high, even if patients
are given the recommended CHF medications in the recommended doses. We found
that the majority of these refractory CHF patients were anemic, with hemoglobin
DEPARTMENT OF NEPHROLOGY
2
DEPARTMENT OF CARDIOLOGY - CHF CLINIC
1
concentrations less than 12 g/dL. In both uncontrolled and controlled studies, when
TEL AVIV SOURASKY MEDICAL CENTER

TEL AVIV, ISRAEL
we corrected their anemia with subcutaneous erythropoietin (EPO) and intravenous

iron sucrose, we found that their cardiac functional status and cardiac function
improved, their need for rehospitalization fell dramatically and their need for
diuretics improved greatly.Their renal function, which had been deteriorating rapidly
before correction of the anemia, generally stabilized or improved. Others subsequently
found, in controlled studies using EPO, that cardiac function, as judged by oxygen
Anemia
utilization during peak exercise, also improved, as did exercise capacity and quality
Congestive heart failure
of life. Subsequently, many others have examined this relationship of anemia to the
Chronic kidney
insufficiency
severity of CHF, the mortality rate and the hospitalization rate, and the great majority
Erythropoietin
have confirmed our findings. A randomized controlled double-blind study is now
Intravenous iron
being carried out on hundreds of severe, anemic CHF patients to ascertain the role
of anemia correction is in CHF. If it verifies the preliminary optimistic results
mentioned above, anemia management may become an important new therapy for the
prevention of progression of CHF and the associated renal failure.
Transfusion Alternatives in Transfusion Medicine
( Page
26
VOLUME 6 NUMBER 3 FEBRUARY 2005
Anemia in Congestive Heart Failure
Anemia is found in about a third of all cases of congestive heart

failure (CHF). One of the most common causes is likely chronic
kidney insufficiency (CKI) which is present in about half of all
cases of CHF. The CKI is likely due to the renal vasoconstriction
that often accompanies CHF and can cause long-standing renal
ischemia. This reduces the amount of erythropoietin (EPO)
produced in the kidney and leads to anemia. However, anemia
can occur in CHF without CKI and in these cases it is likely due
to excessive cytokine production (e.g., TNF- and IL-6) which
is common in CHF and can cause reduced EPO secretion,
interference with EPO activity in the bone marrow and reduced
release of iron from the reticuloendothelial system with
consequent reduced supply of iron to the bone marrow. The
anemia itself can worsen the cardiac function both because it
causes cardiac stress through tachycardia and increased stroke
volume and because it can also cause a reduced renal blood flow
and fluid retention, adding further stress to the heart. Longstanding anemia of any cause can result in left ventricular dilation
and hypertrophy which can lead to cardiac cell death through
apoptosis and worsen the CHF. Thus, a vicious circle is set up
wherein CHF causes anemia and the anemia causes more CHF;
both damage the kidneys, which worsens the anemia and the
CHF further. We have called this vicious circle the Cardio Renal
Anemia Syndrome. Patients with CHF who are anemic are often
resistant to all the CHF medications and end up being
hospitalized again and again. Many studies also show that they
die more rapidly than their non-anemic counterparts. They also
have more rapid deterioration of their renal function and may
end up on dialysis. There is now evidence from both uncontrolled
and controlled studies that early correction of the anemia of CHF
with subcutaneous EPO and, in some cases, with the addition
of intravenous (IV) iron improves shortness of breath and fatigue,
cardiac function, renal function and exercise capability, and
dramatically reduces the need for hospitalization. For all these
reasons it is not surprising that quality of life has also been shown
to improve. As both CHF and end-stage renal disease (ESRD)
are rapidly increasing in the community, the possibility that these
twin conditions can be improved by adequate treatment of
anemia holds up a new hope for slowing the progression of both
conditions.
Initial Observations on Anemia and CHF

In the year 2000 we published observations about the high
prevalence and severity of anemia in CHF and the marked
benefits of correcting this anemia with a combination of
subcutaneous EPO and IV iron which we gave as iron sucrose
(Venofer, Vifor International, St. Gallen, Switzerland).1 In 142
cases of CHF seen in a cardiac outpatient clinic devoted to CHF,
55.6% were found to have anemia as defined as a hemoglobin
(Hb) concentration of < 12 g/dL. The more severe the CHF, the
D O N A L D S S I LV E R B E R G et al.
more prevalent and severe was the anemia. Indeed, in the patients
with the most severe CHF (New York Heart Association [NYHA]
IV), 79.1% were anemic. We then treated 26 such anemic CHF
patients with the EPO and IV iron combination. They were
characterized by severe CHF which had not responded to
maximally-tolerated doses of the recommended CHF therapy
which consisted of angiotensin converting enzyme (ACE)
inhibitors, beta blockers, oral and IV furosemide, aldospirone,
digoxin, and long acting nitrates. Despite this aggressive therapy,
they were still grossly symptomatic with shortness of breath
and/or severe fatigue on minimal to no exertion (NYHA class IIIIV) and most had been in and out of the hospital on many
occasions in the previous year because of recurrent pulmonary
edema. Correction of the anemia to a Hb of > 12 g/dL with
weekly subcutaneous EPO and IV iron (as needed to maintain
iron stores) was associated with a marked and often dramatic
improvement in the NYHA functional class, with patients now
being able in many instances to return to work and to live quite
normal lives where they had previously been extremely limited.
These positive findings were accompanied by an improvement
in cardiac function as measured by the left ventricular ejection
fraction (LVEF), a marked reduction in the need for
hospitalization and in the doses of furosemide needed both
oral and IV. The serum creatinine, which had been rising steadily
in the period before the correction of the anemia, stabilized or
improved in the great majority of patients after anemia correction.
How Common Are Anemia and CKI in CHF?

Many other studies have appeared recently which have studied
this relationship between anemia and CHF (Tables 1-3). As seen
in Table 1 it would appear that about one-third of patients with
CHF have a Hb concentration below 12 g/dL. Also in Table 1,
in the many studies that have examined the relationship between
CHF and mean Hb concentration or hematocrit (Hct) and/or the
prevalence of anemia in CHF patients, there is a very wide
variation in prevalence of anemia from 2.72% to 61%!
However, examination of these studies shows that the anemia
was generally more common in the elderly, in diabetics, in those
with more severe renal damage or more severe CHF, more
common in those who were hospitalized than in those treated
in the community and more common in those in whom the
anemia was defined as a Hb level of < 12-13.5 g/dL rather than
< 11 g/dL. In some of the larger controlled intervention studies
of medications in CHF, patients with CKI or severe anemia were
specifically excluded, which could partially explain the low
prevalence of anemia in these studies. Some of these CHF studies
defined anemia as merely a recorded physician diagnosis of
anemia in the medical discharge chart without actual values of
Hb concentration being given,11,16 but some doctors may only
recognize the presence of anemia if it is very severe.43 There is
( Page
27
Table 1.
Prevalence of Anemia and Other Clinical Characteristics in Several Studies of In-Hospital and Outpatient Clinic CHF Patients
Reference
No. of
patients
Mean age
(years)
Criteria for anemia*
Silverberg et al.1
McClellan et al.2
Wisniacki et al.3
Chatterjee et al.4
Tanner et al.5
Horwich et al.6
Cromie et al.7
Maggioni et al.8
Szachniewicz et al.9
Anker et al.10
Ezekowitz et al.11
142
665
201
72
193
1061
269
2411
5010
176
29,302
70.1 11.1
75.7 10.9
> 65
53
54 11
52
NI
NI
NI
63 9
NI
Hb < 12
Hct < 36
Hb < 12
"moderate anemia"
Hb < 12
Hb < 12.3
Hb < 11
Hb < 11 F, Hb < 12 M
Hb < 11 F, Hb < 12 M
Hb 12
Not defined
Kalra et al.12
Golden et al.13
93
239
61.9 1
65.1
Hb < 13
Hct < 35%
Bolger et al.14
Herzog et al.15
157
112,4302
NI
65
Hb < 12.1
Not defined
Eznekowitz et al.16
12,065
Not defined
Androne et al.17
196
Median,
77.3 12
52 11
Hct < 38 F, Hct < 41 M
McClellan et al.18
1207
72.4 10.8
Hb 12
Trovato et al.19
Kosiborod et al.20
869
2281
63.25 10.65
79 8
Hct 37
Macin et al.21
Mozaffarian et al.22
Adams et al.23
335
1130
942
64
65 11
66
Hct < 37 F, Hct < 39 M

Hct < 37.6
Hb < 12
Stewart et al.24
Ryan et al.25
Nordyke et al.26,27
Felker et al.28
42,713
188
9107
949
NI
NI
74
65.3
NI
Hb < 11.5
Hb < 12
Hb < 13 M, Hb < 12 F
Uber et al.29
Ceresa et al.30
Bolger et al.31
Hussein et al.32
Abromeit et al.33
Anker et al.34
119
980
110
604
168
2286
NI
53 9.4
Hb < 12
Hb 12
Hb 12
62 11
Hct < 43
Hb < 12.5
Kalra et al.35
Ezekowitz et al.36
Cleland et al.37
Kerzner et al.38
Muster et al.39
Berry et al.40
531
791
46,788
373
1347
476
76 10
Hb < 13
Hb < 13 M, Hb < 12 F
Hb < 11
69.2
76 7.8
72 13
( Page
Hb M < 13, F < 11.5
28
Population studied
% anemic
Outpt. CHF clinic

55.6
In hospital
46.8
In hospital
49.8
Outpt. CHF clinic
38.9
Outpt. CHF clinic
15
Outpt. CHF clinic
25
In hospital
14.4
IN-CHF outpt. study
15.5
Val-HeFT outpt. study
9.9
Outpt. study
10.2
CHF pts admitted to
16.4
acute care hospitals
Ambulatory CHF male pts
39
Community based
27.6
CHF program
Stable CHF
29
5% sample of US
33.7
Medicare pts 65+
CHF patients admitted to
17
acute care hospitals
Pts referred
61
to heart transplant clinic
CKI in 267 medical practices.
50.3
Pts with s creat F 1.6-6 mg%
and M 2-6 mg%
In patients without CKI
Hospitalized CHF
48
Medicare pts 65+
Hospitalized with acute CHF
29.1
Outpt. study
20
STAMINA-HFP outpt.
24
CHF study
Hospital discharges
M 2.72, F 4..5
LVEF < 45% in CHF clinic
10.6
Hospitalized CHF patients
42.1
OPTIME hospitalized
49
CHF patients
NI
28
NI
19
Outpt. stable CHF
25.5
Outpt. CHF
21
58
COPERNICUS study
18.8
of severe CHF
Outpt. CHF clinic
36
Outpt. CHF clinic
39, M 40, F 35
In hospital CHF
21
Hospitalized CHF 65+
Hospitalized CHF
M 52, F 37
Mean Hb
Mean serum
creatinine
11.9 1.5
12.2
NI
13.5
14.0
13.6
NI
NI
NI
14 1.5
NI
1.6 1.1
1.5
NI
NI
1.34
1.4
NI
NI
NI
1.2 0.5
NI
13.7 0.2
NI
117 5
1.35 0.57
NI
NI
NI
NI
NI
NI
12.4 2.5 M,
11.9 1.7 F
12.1 1.7
1.65 1.4 M,
1.17 0.6 F
2.2 1.8
12.57 2.24
Median
Hct 38%
1.06 0.29
NI
13.9 1.7
13.2
1.5
1.4 0.5
1.3
NI
NI
NI
12.6 1.8
NI
NI
NI
1.5
13.2
NI
NI
NI
Hct 43 5
NI
NI
NI
NI
NI
112 59
NI
13.3
13.4 19
NI
11.8
11.9 1.89
M 12.5 1.9
F 12 1.9
105
NI
NI
1.8
GFR 58.2
NI
Berry et al.41
528
Wexler et al.42
Tang et al.43
338
2011
Wagoner et al.44
Hb M < 13, F < 11.5
Hospitalized CHF
76.2 9.9
Hb < 12
M Hb < 12, F < 11
In hospital
Ambulatory CHF patients
52.4
29
982
64 14
M < 13, F < 12
33
Brucks et al.45
137
66 13
M < 13, F < 12
45
Hct 37.1
Forman et al.46
1004
67.3
Hct < 30
STAMINA HFP
Out patient study
Outpt. CHF with
diastolic dysfunction
In hospital patients
12.0 1.8
M 14 1.8,
F 13 1.6
13.3 1.8
12.7
Witte et al.47
72.5
74.1
70.3
68 9.3
12.5
Urrutia et al.48
171
122
58
330
CHF syst dysfcn,

CHF diast dysfcn,
Control: no CHF
Outpt. clinic
35
33
6.9
30
Van der Meer et al.49
74
60 7
< 12
< 12
M 51, F 38 Hct M 39, F 37
13.1 1.7
13.2 1.7
13.9 1.0
32 12
Increased s
creat in 52%
1.7 1.1
NI
1.42
s creat
> 1.5-35.8%
12 53
107 43
84 14
S creat
> 2.5-6%
12.9
* Hemoglobin (Hb) concentration (g/dL) or hematocrit (%).

Abbreviations: CKI = Chronic kidney insufficiency; NI = No information available.
Table 2.
Summary of Studies Showing the Relationship Between Anemia and Mortality, Hospitalization, and Severity of CHF
Reference
Year of study No. of patients
Kannel50
1987
5209
Alexander et al.51
1999
Silverberg et al.1
Chatterjee et al.4
Polanczyk et al.52
Type of study
Follow-up Negative correlation

between NYHA
and anemia
30 years
NI
91422
Framingham
community study
Hospitalized CHF pts
12 months
NI
2000
2000
2001
142
72
205
Pts in special CHF outpt. clinic

Pts in special CHF outpt. clinic
NI
NI
3 months
yes
no
NI
Al-Ahmad et al.53
2001
6997
Mean
33.4 months
yes
Felker et al.28
2001
949
SOLVD controlled study

of ACE inhibitors in pts with
LVSD with or without CHF
OPTIME controlled study
of Milrinone in
hospitalized CHF patients
60 days
NI
Wisniacki et al.3
McClellan et al.2
2001
2002
201
665
NI
12 mo
yes
NI
Tanner et al.5
2002
193
Hospitalized CHF pts > 65

Hospitalized CHF pts
in community hospitals
Tertiary CHF outpt. clinic
yes
Horwich et al.6
2002
1061
Mean 1.4
to 3.3 yrs in
NYHA I-IV,
respectively
Up to 5 yrs
Trovato et al.19
2002
869
Maggioni et al.8
2002
2411
University center for

heart transplant evaluation
with normal renal function
IN CHF Study: ambulatory
pts in clinical practice
Results
A low Hct was inversely correlated with

incidence of CHF
Anemia was an independent risk
factor for readmission and for death
Low hematocrit was an independent

predictor of rehospitalization
1% lower Hct was associated with
a 1.027% increase in mortality
Hb was an independent predictor of
events. Odds ratio for death and
rehospitalization was 0.89 for every
1 g/dL increase in Hb
Mortality was 50% higher for those with
Hct 40% compared to Hct < 30%
Rate of death or heart transplantation
was similar for all levels of Hb
yes
Relative risk of mortality was 1.131 for

every decrease of Hb of 1g/dL
yes
1 yr
yes
One year all cause mortality was

higher in anemic (25.8%) than
non-anemic (13.2%) pts. RR 1.59
( Page
29
Maggioni et al.8
2002
5010
Val-HeFT controlled
study of Valsartan in CHF
23 months
yes
Sharma et al.10
2004
3044
ELITE II controlled study

of Captopril vs. Losartan
24 mo
yes
Szachniewicz et al.9
2002
176
All CHF pts seen

in cardiology dept.
> 18 mo
yes
Ezekowitz et al.11
2002
29302
Hospitalized pts with CHF
1 yr
NI
Gilbertson et al.54,
and Herzog et al.15
2002
2002,
> 1.1 million

elderly
5% sample of
US Medicare pts 65+
2 yrs
NI
23-month all cause mortality was

higher in anemic (29.6%) than
non-anemic (18.5%) pts. RR 1.26
2-yr survival 85% in group with
Hb 14.5-15.4 and 75% in group
with Hb < 12 g/dL. RR 1.8
death: hazard ratio 2.6. 18-mo
survival was 67% in anemic and 87%
in non-anemic pts
1-yr survival 63.2% in anemic
and 71.6% in non-anemic group
No anemia,
CHF or CKD
Anemia
CHF
CHF + anemia
CKD
CKD + anemia
CHF + CKI
CHF + CKD
+ anemia
Kalra et al.12
2002
93
Ambulatory male CHF pts
NI
yes
Golden et al.13
2002
239
Community based CHF

program
23.114.2
months
NI
Mean 31
months
NI
yes
2002
157
Stable CHF
Mancini et al.55
2002
61
Severe CHF in clinic
Ezekowitz et al.16
2003
12065
Hospitalized patients with CHF
Median
573 days
NI
Androne et al.17
2003
114
Severe CHF in clinic
1 year
NI
Poole-Wilson et al.56
2003
3164
2003
2281
Median 46
months
12 mo
NI
Kosiborod et al.20
ATLAS CHF outpt.

clinic study
Hospitalized CHF pts 65+
NI
Kerzner et al.38
2003
373
25 months
no
Ezekowitz et al.36
2003
791
Outpatient CHF patients
Up to 12 years
NI
Stewart et al.24
2003
42713
CHF hospital discharges
2 years
NI
Nordyke et al.26,27
2003
9107
NI
NI
( Page
30
NI
ESRD %
7.7
0.1
16.6
26.1
34.6
16.
27.3
38.4
0.2
0.2
0.3
2.6
5.4
3.4
45.6
5.9
In patients with Hb < 13 g/dL Hb

was an independent predictor
of peak MVO2
Hospitalized
Mean hosp days
Mortality
Bolger et al.14
2-yr follow-up:
mortality %
Hct < 35
53%
7.84
15.1%
Hct > 42%

21.4%
1.48
3.6%
RR for mortality increased by 1.38 for

every 1 g/dL decrease in Hb
By univariate analysis Hct was a
predictor of survival
1-yr survival: 62% in anemics
and 73% in non-anemics; 5-yr survival:
41% in anemics and 50%
in non-anemics
1-yr survival: 41% in anemics
and 63% in non-anemics
Level of Hb inversely associated
with CHF deaths
Each 1 unit lower Hct value associated
with a 2% higher risk of 1 yr mortality
and rehospitalization
In patients < 75 years old and reduced
LVEF, Hb was an independent risk factor
for mortality with HR 0.8
Mortality risk:
Males HR 1.7 (p < 0.001),
Females HR 1.2 (p = 0.624; NS)
Anemia independent predictor of
mortality OR Males 1.36 Females 1.21
1 g/dL increase in Hb associated with
10.2% reduction in in-hospital mortality
risk, 5.1% reduction in length of
hospital stay, 5.3% reduction in
hospital charges
Anker et al.34
2003
2286
COPERNICUS severe One year

CHF patients
Jozwiak et al.57
2002
770
Mozaffarian et al.g
2003
1130
Hospitalized elderly
(age 65-102) CHF patients
PRAISE study < 30%
CHF IIIb and IV and LVEF
Macin et al.21
2003
330
Gregory et al.58
2003
6541
Kalra et al.35
2003
552
Ambulatory and hospitalized

CHF patients
Median
3 years
NI
Uber et al.29
2003
119
NI
NI
yes
NI
NI
NI
15 months
no
24 months
no
Hospitalized patients in SOLVD - 33.4 months

Studies of Left Ventricular
Dysfunction - role of ACE inhibitor
2003
980
Outpatient CHF patients
3 years
NI
Abromeit et al.33
2003
168
NI
NI
NI
Li et al.59
2003
41,523
5% sample of US Medicare
population aged 67+ with CKI
NI
NI
Berry et al.40
2003
476
Hospitalized from
Emergency room
NI
NI
Zeidman et al.60
2004
367
McMurray et al.61
2004
2694
317 Patients admitted to hospital

NI
with Ischemic Heart Disease (IHD)
and anemia and 50 with IHD
without anemia
CHARM study of
Mean 37.7
Candesartan in CHF
months
Low Hb was an independent risk factor

for death and rehospitalization.
All-cause 1-year mortality was 23.2%
with Hb < 11 g/dL and 13.1%
with Hb 15.1-16.5 g/dL
OR for in hospital mortality
for anemia was 1.8
After adjustment for potential
confounders HR for mortality between
lowest and highest quintiles of Hct was
1.52. Within the lowest quintile of
Hct (< 37.5%) each 1% decrease in
Hct was associated with a 11% higher
risk of death
2-year survival 40% in anemics and
80% in non-anemics. Incidence of
refractory CHF during hospitalization
8.8% in anemics and 3.2% in
non-anemics (p = 0.04)
Hospitalization expenses for anemics
were 19.9% higher than for non
anemics when corrected for renal
function. Admissions per patient per
month were 0.96 if Hct < 33
and 0.59 if Hct > 36
Hazard ratio for mortality for anemia
was 0.92 (p = 0.001) in univariate
but only 0.98 (NS) by
multivariate analysis
50% of anemic patients and 15%
of non-anemics required hospitalization
NI
Ceresa et al.30
or emergency room visits. Lower

Hb was independently associated with
a high BNP level
Anemia was an independent predictor
of hard cardiac events. 39% of anemic
patients had hard cardiac events
compared to 27% of non-anemics
58% of patients with an elevated
CRP were anemic compared to only
32% of those with a normal CRP.
CHF present in 46% of CKI population.
36.8% of non-anemic CKI pts and
55.7% of anemic CKI patients had CHF
A higher Hb was positively associated
with in hospital survival OR
1.03 per g/dL
31% of those with anemia had CHF
compared to 18% of those
without anemia
NI
NI

outcomes in both preserved LVEF and
reduced LVEF and is of equal
prognostic significance in the two groups.
Low LVEF HR death 0.62 hosp 0.72
. Preserved EF HR death 0.63 hosp 0.62
( Page
31
Wagoner et al.44
2004
962
STAMINA Study
NI
Yes
Adams et al.62
2004
780
STAMINA study
NI
NI
O'Connor et al.63
2004
319
ACTIV study
NI
NI
Brucks et al.45
2004
137
Diastolic CHF
330 200
days
Yes
Butler et al.64
2004
382 pts ss
NI
NI
Forman et al.46
2004
1009
Case control study of 191 in

hospital CHF pts with worsening
renal function compared to
191 with stable renal function
In hospital CHF patients
NI
NI
Witte et al.45
2004
295
173 with syst CHF, 122

with diast CHF
NI
Yes
Van der Meer et al.49
2004
74
Controlled study with

15 controls
2.6 years
NI
OR for anemia increased 1.31 for every

NYHA class
Hb level was independently related
to QOL
Anemia showed a trend to
increased mortality
Anemia was independent risk factor
for less hospital free survival. There was
a trend for lower survival in anemics
(p = 0.09)
Anemia was independently related to
worsening renal function. OR of
Hct > 45 was 0.39
Anemic patients were significantly more
likely to develop worsening of renal
function than non-anemic patients
Anemic patients had a lower exercise
capacity and lower oxygen consumption
with exercise
Hb levels were independent
predictors of survival
Abbreviations: NI = no information available; QOL = Quality of Life; LVEF = Left Ventricular Ejection Fraction; LVSD = Left Ventricular Systolic Dysfunction; ESRD = End Stage Renal
Disease; NYHA = New York Heart Association functional class; RR = Relative Risk; HR = Hazard Ratio; OR = Odds Ratio; CKI = Chronic Kidney Insufficiency
Table 3.
Characteristics Associated With Anemia in CHF
Characteristics
References
Older age
1,2,3,9,16,18,26,35,39,40,42,101
Less smokers
9,22,101
Higher prevalence of diabetes
5,9,20,28,47,52,101,102
Elevated serum creatinine
1,17,18,19,24,32,39,41,42,105
Hyponatremia
20,21
hyperuricemia
12
lymphopenia
14,20,41
Elevated BNP
29,102
Evidence of iron deficiency
25,107
Reduced serum albumin
6,19,22,32
Reduced serum total protein
19
Reduced serum cholesterol
6,22,101
Elevated C Reactive Protein
33,107
Elevated serum TNF-
14
Inappropriately low erythropoietin levels
106,107
Reduced red cell mass
17
Increased plasma volume
17
Reduced Body Mass Index
5,6,19,30
More cardiovascular events
30
Higher right and left ventricular filling pressures
30
Increased pulmonary capillary wedge pressure
6
Abnormal A/E ratio
19,101
( Page
32
Reduced ejection fraction

1,19,47
Greater Left Ventricular Mass Index
19
Greater atrial dimensions
19
Lower oxygen utilization (MVO2)
during maximal exercise
6,12,29,30,49,57,105
Peripheral hypoperfusion
21
Lower blood pressure
6
Higher heart rate
6,28
Higher NYHA
1,3,5,8,9,10,12,14,19,29,47,101,105
Lower quality of life
57,101,109
Higher percentage requiring diuretics
5,101
Higher diuretic dose
1,55,101
Higher percentage requiring digoxin
52
Higher percentage of resistant CHF
21
Greater long-term mortality
2,6,8,9,10,11,13,14,15,16,17,20,
21,22,24,27,28,34,35,36,38,45,46,48,49,50,51,99,102,106
More hospitalizations
13,20,28,29,34,45,46,52,102
Longer hospital stays
13,26,52
Greater in hospital mortality
26
Greater hospital costs
26,52
More require dialysis
48
also a wide variation in the mean serum creatinine or creatinine

clearance in the studies but it would appear that about half the
patients with CHF have a serum creatinine of 1.5 mg/dL or
higher or a creatinine clearance of 60 mL/min/m2, both
definitions fitting the criteria for moderate to severe CKI.
What Is the Significance of this Anemia

in CHF?
In Table 2 and 3 are listed many studies that have examined
the relationship between anemia and CHF severity,
hospitalization and mortality. Of 21 studies that looked at the
relationship between severity of CHF and anemia, 17 (81%)
showed that the presence of anemia was associated with a more
severe degree of CHF as judged by NYHA functional class. Of
the 33 studies that examined the relationship between mortality
and anemia in CHF, 31 (93.9%) showed a positive relationship,
one5 did not and one63 was borderline. In many of these studies,
these relationships between anemia and CHF were still
statistically significant by multivariate analysis where renal
function and age were also taken into consideration that is,
anemia was an independent risk factor for cardiac mortality.
Indeed, renal failure and anemia were found in some studies to
have an additive effect on mortality.2,53 In 9 studies that examined
the relationship between anemia and the number and/or duration
of hospitalizations (Tables 2 and 3), all 9 (100%) showed that
anemic patients were hospitalized more often and/or for a longer
period of time than non-anemics. In addition, in 2 studies, the
cost of hospitalization for anemic CHF patients was found to be
higher than for non-anemic CHF patients.26,58
Anemia was also found to be associated with an increased
tendency for the eventual development of CHF in the general
population in the Framingham study.50 In another study of elderly
patients with normal renal function,67 and in patients with
ischemic heart disease60 anemia increased the risk of developing
CHF. In elderly CHF patients anemia was also associated with a
greater chance of developing ESRD within 2 years.54 As seen in
Table 3, anemic CHF patients are older, less likely to be smokers
(perhaps because smokers are more likely to develop lung disease
with secondary polycythemia), and more likely to be diabetics.
They are more likely to have a reduced red cell volume, an
increased plasma volume and hyponatremia. They are more likely
to have hyperuricemia and lymphopenia. They are more likely
to have signs of malnutrition such as a lower body mass index
(BMI), reduced iron stores, serum albumin total protein and
serum cholesterol. They are more likely to have signs of
inflammation such as elevated serum C reactive protein (CRP)
and TNF-. They are more likely to have cardiovascular events,
signs of cardiac damage such as: left ventricular hypertrophy
(LVH), greater atrial dimensions, higher right and left ventricular
filling pressures, increased pulmonary capillary wedge pressure,
elevated brain natriuretic peptide (BNP), a useful test for

diagnosing CHF, and evidence of both systolic dysfunction and
diastolic dysfunction. Clinically they are more likely to have a
higher heart rate, a lower blood pressure and signs of reduced
peripheral perfusion. They are more likely to require more
diuretics and in a higher dose, as well as more digoxin than nonanemics, that is, they are more resistant to medical therapy than
non-anemics. Their cardiac function as measured by oxygen
utilization during peak exercise (MVO2), their exercise duration
and distance walked in 6 minutes is low as is their quality of life.
Is this relationship between anemia and severity of CHF causal?
Is anemia really an important contributor to the production or
worsening of CHF or is it merely an innocent bystander? Is there
other evidence to suspect that anemia is an important contributor
to CHF?
There are several reasons to think that anemia may indeed be
a causal factor:
1. Treatment of anemic patients who have renal failure with
EPO has resulted in reduced LV mass,69-75 LV mass index
(LVMI),74-81 improved LVEF,1,69-71,74,75,82-86 and a reduction in
both LV end systolic volumes69,70,74,75,84,85 and LV end diastolic
volumes.69,70,74,75,84,85 In addition, in one study, treating the
anemia caused the LVH and LV diastolic volumes to
improve. When the EPO was stopped for a year, however,
both the LVH and LV end diastolic volume returned to their
previous levels.75
2. Treatment of the anemia with EPO in CKI patients before
dialysis has been associated with a reduction in
hospitalizations for CHF compared to those not treated,
both in American82,83 and European studies.90
3. In dialysis patients, the higher the Hb concentration the
lower the of mortality and hospitalization rate.91-93
4. Treatment of the anemia improves the CHF. As mentioned
initially, when we corrected the anemia in 26 severe CHF
patients, the CHF improved dramatically.1 In a subsequent
randomized controlled (but not double-blind) study,86 32
such resistant anemic CHF patients were assigned to 2
groups: 16 received the EPO/IV iron combination and the
other 16 did not. In the 16 who were treated, the anemia
improved and the NYHA and LVEF improved significantly,
the serum creatinine did not change, and the rate of
hospitalization fell significantly, as did the doses of oral and
IV furosemide. In the control group, the NYHA, LVEF,
hospitalization rate and dose of diuretics all worsened and
the serum creatinine increased significantly. No deaths
occurred in the treated group and 4 occurred in the nontreated group, all from progressive CHF. We have now
increased our experience to 12694 and 179 such patients87
and our results are similar. Our patients were asked on their
first visit and after a few months, when they had reached
the target Hb concentration of 12.5 g/dL, to assess their
fatigue and shortness of breath on a visual analogue scale
( Page
33
where 10 was the worst they could possibly feel and 0 the
best. Their mean score fell from 8.8 before intervention to
2.8 after correction of the anemia,95 a particularly striking
response in patients whose usual course is downhill. In
addition, the mean creatinine clearance, which had been
deteriorating at a rate of 1.12 1.3 mL/min/month in the
non diabetics was + 0.21 1.3 mL/min/month by the end
of the study (which lasted a mean of 11.8 8.2 months).87
The corresponding rates in the diabetics were - 1.18 1.49
mL/min/month and + 0.13 1.54 mL/min/month. The
similar rates of renal deterioration in non-diabetics and
diabetics suggests that it was not the diabetes alone that was
causing the deterioration but also the anemia and
uncontrolled CHF.
In a placebo-controlled trial,68 patients with severe CHF who
received EPO for three months had a significant improvement
in peak oxygen utilization (MVO2), MVO2 at the anaerobic
threshold, exercise duration in seconds and distance walked in
6 minutes. In the control group none of these changed
significantly. In the treated group the quality of life based on a
questionnaire showed improvement in the treated group and a
deterioration in the placebo group. A significant positive linear
correction was observed between the change in Hb level and the
change in peak MVO2. In those patients who had excessive
plasma volume, correction of the anemia reduced the plasma
volume to normal.
In a recent preliminary study of 84 patients with CHF and
anemia, correction of the anemia over a period of 15 months
with EPO and IV iron was associated with less hospitalizations
and less days spent in hospital, an improvement in renal
function66 and a reduction in diuretic dose.
How Does Anemia Cause CHF?

There are many ways in which anemia can cause CHF.95 The
lack of oxygen supply to the heart in the face of the increased
heart rate and stroke volume may cause ischemia and lead to
myocardial cell death. The red blood cells contain many
antioxidants and anemia is therefore, not surprisingly, associated
with an increase in oxidative stress96,97 which could cause damage
to the myocardial cells. Treatment of the anemia with EPO may
reduce the oxidative stress.96,97 There is even some in vitro evidence
that EPO itself may reduce oxidative stress unrelated to the effect
on anemia.98 Anemia causes tissue ischemia throughout the body
which causes peripheral vasodilatation and a lowering of the blood
pressure.99 The sympathetic system is activated which, in addition
to causing tachycardia and increased stroke volume also causes
renal vasoconstriction which can lead to salt and water retention.
The reduced renal blood flow activates the renin angiotensin
aldosterone system and antidiuretic hormone (ADH), causing
further renal vasoconstriction and salt and water retention. This
( Page
34
leads to peripheral edema and increased plasma volume (PV).

The increased PV causes ventricular dilation which puts a further
stress on the already stressed heart. Eventually LVH also occurs,
which can lead to myocardial cell death from necrosis and
apoptosis.100,101 This can lead to or worsen CHF.
EPO itself also has a direct effect both on the development of
cardiac muscle102 and on the degree of contractility.103 It may also
directly prevent cardiac myocyte apoptosis, stimulate blood vessel
production in the myocardium and improve endothelial cell
function.104 Therefore, lack of EPO itself could directly worsen
cardiac function even unrelated to the anemia.
What Is the Etiology of the Anemia in CHF?

One of the main causes of the anemia in CHF is most likely CKI
which is produced by the renal vasoconstriction leading to
prolonged renal ischemia. This causes renal damage and reduced
production of EPO in the kidneys. However, studies in animals
have shown that CHF itself may cause anemia.105 The damaged
heart may secrete excessive amounts of cytokines such as
TNF-106 which can cause anemia in 3 ways:107 by reducing EPO
production in the kidneys, by interfering with EPO activity at the
level of the bone marrow, and by inhibiting the release of iron from
the reticuloendothelial system so that the iron cannot get to the
bone marrow to be utilized in Hb production. Indeed it has
recently been shown that the higher the TNF- in CHF the lower
the Hb concentration.14 Many CHF patients take aspirin which
may cause blood loss in the gut. CHF patients often have
proteinuria, and EPO, iron and transferrin can all be lost in
significant amounts in the urine,108 also contributing to the anemia.
EPO production and utilization can be inhibited by ACE inhibitors
which can cause anemia.109 Finally, part of the anemia in CHF may
be due to hemodilution,17 but recent studies show that the majority
of anemic CHF patients actually have a reduced red cell volume.17
The Vicious Circle of CHF, CKI, and

Anemia The Cardio Renal Anemia
(CRA) Syndrome
A vicious circle appears to be present in CHF where CHF itself
causes both anemia and CKI. The CKI causes more anemia and
the anemia and CKI act back to further worsen the CHF which
then further worsens the anemia and CKI and so on (Figure 1).
We suggest calling this relationship the Cardio Renal Anemia
(CRA) syndrome.95 The importance of this concept is that if the
anemia is not treated in CHF patients there will likely be
resistance to any other form of CHF therapy and there will be
progression of both the CHF and the CKI. Thus correction of
anemia may therefore be crucial in the prevention of the
progression of both CHF and CKI.
Figure 1.
Conclusion
What Is the Attitude of Cardiologists

and Internists to Anemia in CHF
CHF has reached almost epidemic proportions and is a major

cause of hospitalization, morbidity and mortality in the
population.61 About 2% of the population has CHF and this rises
to about 5% in those above 65 and to about 10% of those above
80 years of age.99 It is the leading cause of admissions to medical
wards and is responsible for about 2% of the entire health
budget.61 Yet its prognosis has only improved slightly over the
last 50 years.110 One reason for this may be that the anemia, which
is commonly associated with this condition, has not been
recognized as important and therefore is not being treated. Largescale randomized double-blind placebo-controlled studies are
now in progress to give a definitive answer to the crucial question:
how important is anemia in CHF? If the preliminary data on the
great efficacy of EPO and IV iron are born out, correction of
anemia could have an enormous impact on the progression of
heart failure and renal failure while at the same time it could
markedly improve the patients' quality of life.
In a preliminary report from the Cleveland Clinic, 2,011

consecutive ambulatory patients with chronic stable heart failure
patients seen in tertiary care cardiology or internal medicine
clinics were studied.43 Anemia was defined as Hb 12 g/dL in
men and 11 g/dL in women. 29% of the cases developed
anemia at some time. Yet anemia was only recognized as a
diagnosis in 11.1% of cases seen by the internists and in 4.4%
of the cases seen by cardiologists. Diagnostic evaluation was only
performed in 6% of all patients and only 10% received medical
therapy for anemia. The conclusion of the investigators was that
anemia in ambulatory patients with CHF is underrecognized,
underdiagnosed and undertreated.
( Page
35
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TATM 2005;6(3):26-37

The Role of Anemia in the

D ONALD S. S ILVERBERG , MD , FRCP(C) , 1

TEL AVIV SOURASKY MEDICAL CENTER

we corrected their anemia with subcutaneous erythropoietin (EPO) and intravenous

Congestive heart failure

have confirmed our findings. A randomized controlled double-blind study is now

Transfusion Alternatives in Transfusion Medicine

VOLUME 6 NUMBER 3 FEBRUARY 2005

Anemia in Congestive Heart Failure

Anemia is found in about a third of all cases of congestive heart

Initial Observations on Anemia and CHF

How Common Are Anemia and CKI in CHF?

Transfusion Alternatives in Transfusion Medicine

VOLUME 6 NUMBER 3 FEBRUARY 2005

Anemia in Congestive Heart Failure

Criteria for anemia*

Hct < 38 F, Hct < 41 M

Hct < 37 F, Hct < 39 M

Transfusion Alternatives in Transfusion Medicine

Hb M < 13, F < 11.5

Outpt. CHF clinic

VOLUME 6 NUMBER 3 FEBRUARY 2005

Anemia in Congestive Heart Failure

Hb M < 13, F < 11.5

M < 13, F < 12

M < 13, F < 12

CHF syst dysfcn,

Van der Meer et al.49

M 51, F 38 Hct M 39, F 37

* Hemoglobin (Hb) concentration (g/dL) or hematocrit (%).

Year of study No. of patients

Follow-up Negative correlation

Pts in special CHF outpt. clinic

SOLVD controlled study

Hospitalized CHF pts > 65

University center for

A low Hct was inversely correlated with

Low hematocrit was an independent

Relative risk of mortality was 1.131 for

Transfusion Alternatives in Transfusion Medicine

One year all cause mortality was

VOLUME 6 NUMBER 3 FEBRUARY 2005

Anemia in Congestive Heart Failure

ELITE II controlled study

All CHF pts seen

Hospitalized pts with CHF

> 1.1 million

23-month all cause mortality was

Ambulatory male CHF pts

Community based CHF

Severe CHF in clinic

Hospitalized patients with CHF

Severe CHF in clinic

ATLAS CHF outpt.

Hospitalized CHF patients

Outpatient CHF patients

CHF hospital discharges

Hospitalized CHF patients

Transfusion Alternatives in Transfusion Medicine

VOLUME 6 NUMBER 3 FEBRUARY 2005

In patients with Hb < 13 g/dL Hb

Hct > 42%

RR for mortality increased by 1.38 for