This document summarizes information on anemia in heart failure patients. Some key points: 1. The prevalence of anemia in heart failure patients ranges from 20-30% for outpatients to 30-40% for inpatients, depending on the definition and study. 2. Anemia is associated with worse prognosis and increased risk of hospitalization and mortality in heart failure patients. 3. Potential treatment options for anemia in heart failure include blood transfusions, erythropoietin-stimulating proteins (ESPs), and iron therapy. However, clinical trials of ESPs like darbepoetin alfa have not shown clear benefits. 4. The FAIR-HF trial found

1. Anaemia in Heart Failure
PRESENTER- DR ABHISHEK RATHORE
SJIC&R ,Bangalore

2. Introduction
 Anemia – poor prognosis in HF
 Anemia itself can cause HF (Hb < 5gm/dl)*, but
uncommon to be the sole mechanism.
 Elderly, IHD, Renal dysfunction and even General
population with anemia are at risk of HF.
 ESPs or iron therapy may have role in HF with
anemia.
*ACC/AHA 2005 Guideline update for diagnosis
and management of CHF in adults.

3. Potential Therapeutic Targets

4. Definition of Anemia
 WHO- Hb < 13g/dl (Men)
Hb < 12g/dl (Women)
 NKF criteria-
Hb < 12g/dl (Men and Postmenopausal
women)
Hb < 11g/dl (Premenopausal women)

5. Prevalence
 Depend on population studied and definition of
anemia used.
 ARIC (Atherosclerosis Risk in Communities)
study-
 A/c to WHO
 Age: 45-64 years
 N= 15,792
 9% patients were found Anemic.

6. ANCHOR study
N= 59,772
43% had anemia.
N= 12,065 (New onset heart
failure)
Prevalence- 17% Ezekowitz JA et al, Circulation.2003;107:223–5
AS GO et al, Circulation.2006;113:2713-23

7. Anemia in patients with heart failure
Hb = hemoglobin
Hct = hematocrit
HF = heart failure
The prevalence of anemia in heart failure patients is approximately:
– 30% for Inpatients
– 20% for Outpatients

8.  4 – 61% (Median 18%) by Tang and Katz from 15
papers.
 Circulation.2006;113:2454-61

9. The prevalence of anemia and the severity of heart
failure
Source: STAMINA Registry – 45 General Cardiologist sites, n=673, 12
Academic sites (incl. HF Specialists), n=337
2% 2%
4%6% 8%
29% 30%
40%
60%
12%
44%
11%
52%
19%
14%13%
29%
21%20%
56%
0%
10%
20%
30%
40%
50%
60%
70%
I (n=158) II (n=467) III (n=340) IV (n=25)
Patients
Hb<10g/dL (n=32) Hb<=11g/dL (n=97) Hb<=11.5g/dL (n=165) Hb<=12.0g/dL (n=244) Hb<=12.5g/dL (n=337)
NYHA Class

10. Mechanism of Anemia in HF
 Concominant CKD (in 40-50% patients)—M.C.
 Inflammation and Cytokine activation ( TNF-alpha, IL-6
and CRP)
 Aspirin usage (GI loss)
 ACE inhibitor and ARBs
 Decrease Fe absorption (Bowel edema, Inc Hepecidin)
 Hemodilution
 Nutritional

12. Type of Anemia
 M.C.- Normocytic normochromic
 Anand et al- Prevalence of Fe deficiency anemia-
5 to 21%#
 De Silva et al*. 43% pts had low serum iron or
ferritin, but only 6% had Microcytic anemia.
 Nanas JN et al$. Found depleted bone marrow
stores in 73% pts despite normal serum iron,
ferritin and EPO levels. #Anand IS.JACC.2008;52:501-11
*Am J Cardiol.2006;98:391-8
$ JACC.2006;48:285-9

13. Prognostic significance of anemia in
HF
 Poor prognosis
 Increase mortality and hospitalisations

14. Study Design N Anemia Risk Assessment Limitations
Alexander1
Retrospective cohort
study of a population
based HF database
90,316
Anemia was an independent risk factor
of 1-year rehospitalization (RR 1.162;
95% CI: 1.134 to 1.191)
no confirmation of the HF
diagnosis; undercounts of minorities
and biased results.
Polanczyk2
Prospective, single
center, observational
study
205
Anemia was an independent predictor
of 3-month rehospitalization (p=0.002)
Too small of a population to resolve
a small difference in readmission
rates; role of confounding variables
due to lack of control
OPTIME-CHF3 Retrospective chart
review
906
Anemia was an independent predictor
of 60-day death or rehospitalization
(odds ratio of 0.89 per 1 g/dL increase
in hemoglobin; 95% CI: 0.82 to 0.97)
Anemia may have been caused by
hemodilution in hospitalized
patients
Kosiborod4
Retrospective chart
review 2,281
Patients had 2% higher risk of 1-year
rehospitalization for every 1% lower
hematocrit (95% CI: 1.01 to 1.03;
p=0.0002)
Lack of data on transfusions or
other treatments for anemia; study
generalizability to non-study
population
COPERNICUS5
Randomized,
double blind,
placebo controlled
trial
2,286
Anemia was an independent risk factor
for 1-year morbidity (HF hospitalization)
and mortality outcomes
-
Anemia is associated with increased risk for
hospitalization in heart failure patients
1Alexander M, et al. Am Heart J. 1999;137:919-927
2Polanczyk CA, et al. J Card Failure. 2001;7:289-298
3Felker GM, et al. Am J Cardiol. 2003;92:625-628
4Kosiborod M, et al. Am J Med. 2003;114:112-119
5Anker SD, et al. J Am Coll Cardiol. 2004;43(suppl A):Abstract 842-2

15. Hemoglobin and mortality in heart failure
patients

16.  Groenveld HF et al*. Anemia and mortality in
heart failure patients: a systematic review and
metaanalysis.
Meta-analysis of 34 studies, Includes
1,53,180patients
JACC.2008;52:817-28

17.  If Anemia as mediator of HF - T/t is beneficial
 If Anemia as marker of HF - Benefits limited
Should we treat anemia in a patient with
heart failure?

18. What is the rationale for anemia correction?
Potential Benefits
 Improved oxygen delivery
 Improved exercise
tolerance
 Attenuate adverse
remodeling
 Improved Quality of Life
 Antiapoptotic?
 Decrease in hosp./death?
Potential Risks
 Increased thrombosis
 Platelet activation
 Hypertension
 Endothelial activation
Adapted from Felker and O’Connor J Am Coll Cardiol. 2004;44:959-966.
Potential benefits and risks of treating anemia in HF:

19. Treatment options for anemia in
HF
 Blood transfusion
 ESPs
 Iron therapy

20. Blood Transfusion in HF
 The clinical utility in CV disease is controversial.
 “Transfusion Threshold”
Hematocrit < 30% in CV disease
Based on expert opinion
 May be considered as an acute treatment for severe
anemia.
 Not a strategy for the longterm management in CHF.

21. Saftey concern of ESP in variety of
anemic patients.
 1. In CKD

22. Pivotal Clinical Trials in CKD with Anemia
 NHCT(1998): National Hematocrit Cardiac
Trial---
N-1200, high hemoglobin was conferred with high death and the trial was
thereby prematurely stopped.
 Canadian Cardiac Trial(2005)---similar trial with very
similar observation.
 CREATE(2006): Cardiovascular Risk Reduction by Early Anemia
Treatment with Epoetin beta
 CHOIR(2006): Correction of Hemoglobin and Outcomes in Renal
Insufficiency
 TREAT(2009): Trial to Reduce Cardiovascular Events with Aranesp
Therapy.

23.  2. In Cancer patients (N=1473 pts)
Conclusion- DA not associated with significant reduction in transfu
also patients had shorter survival time.

24.  3. In Ischemic Stroke
 Ehrenreich H et al*- Recombinant human
erythropoietin in patients presenting in 6 hrs of
ischemic stroke had higher death rates.
*Stroke.2009;40:e647-e56

25. Erythropoietin Stimulating Proteins in
HF

26. STAMINA HeFT trial
Circulation. 2008;117:526-535

27. STAMINA HeFT trial
 Largest(319 pts) and longest (53 weeks)
completed study of ESP in HF patients.
 Patients with EF ≤40% , Hb ≥ 9g/dl and ≤ 12.5
g/dl were randomised.
 Target Hb was 14.0 ± 1.0 g/dl
Ghali JK et al.Circulation.2008;117:526

28.  Conclusion: Darbepoetin alfa not associated
with significant clinical benefits. DA was well
tolerated and effectively raised Hb. A trend of
lower risk of morbidity and mortality observed.
27 weeks 53 weeks
Hb rise Exercise
duration
Hb rise Deaths
Darbepoietin
group(n = 162)
1.8g/dl +57.3
secs +2.1g/dl
11(7%)
Placebo group(n =
157)
0.3g/dl +46.5
secs +0.5g/dl
18
(11%)
Circulation. 2008;117:526-53

29. RED-HF trial (Reduction of Events by
Darbepoetin Alfa in Heart Failure)
March 28, 2013
N Engl J Med 2013;368:1210-19

30. Darbepoetin alfa group (target hemoglobin 13.0 to 14.5 g/dL)
N = 1200
Placebo group
N = 1200
Study Population
•Hemoglobin 9 to
12 g/dL
•LVEF ≤ 35%
•NYHA Class II to IV
Approximately 620 global sites
1:1 randomization
Timelines
Event driven: ~1150 events
Study End September 1 2012
Began enrolling
June 2006
Site Evaluation &
Selection
Follow-up
RED-HF trial

31. KCCQ primary analysis: Change from baseline to
month 6
KCCQ Symptom Frequency Score
Mean Change From Baseline to Month 6
0
1
2
3
4
5
6
7
8
9
10
6.20
3.91
2.46
95% CI: (0.90, 4.02)
P = 0.011
ChangefromBaselineinKCCQ
SymptomFrequencyScore
Darbepoetin alfa
(n = 925)
Placebo
(n = 927)
Mixed effects model estimating treatment effect adjusted for region, type of device, and baseline KCCQ score;
scale scores range from 0 to 100, with higher scores indicating better functioning.
KCCQ Overall Summary Score
Mean Change From Baseline to Month 6
0
1
2
3
4
5
6
7
8
9
10
6.68
4.48
2.20
95% CI: (0.65, 3.75)
P = 0.005
ChangefromBaselineinKCCQ
OverallSummaryScore
Placebo
(n = 929)
Darbepoetin alfa
(n = 928)

32. Primary outcome: All cause death or first
hospitalization for worsening heart failure
Years of Randomization
Prop.ofSubjectWithEvent(%)
Subjects at risk:
1136
1142
975
956
855
818
712
695
581
591
473
497
385
395
281
290
212
211
161
154
101
92
Stratified Log-rank, p = 0.87
Placebo
Darbepoetin alfa
100
80
60
40
20
0
0 1 2 3 4 5

33. Selected adverse events of interest
n (%)
Darbepoetin alfa
(N = 1133)
Placebo
(N = 1140)
Risk difference
(95% CI) p-value
Ischaemic cerebrovascular
conditions
51 (4.5) 32 (2.8) 1.7 (0.2, 3.2) 0.031
Embolic and thrombotic
events
153 (13.5) 114 (10.0) 3.5 (0.9, 6.1) 0.009
Hypertension 81 (7.1) 69 (6.1) 1.1 (-0.9, 3.1) 0.292
Malignancies 69 (6.1) 68 (6.0) 0.1 (-1.8, 2.1) 0.900
Hypersensitivity reactions 99 (8.7) 96 (8.4) 0.3 (-2.0, 2.6) 0.787
Conclusion: Treatment with darbepoetin alfa did not
improve
clinical outcomes in patients with systolic heart failure
and mild to moderate anemia. Our findings do not

34. IV Iron Therapy for anemia in HF
Table 1 Randomized, controlled studies with intravenous iron in patients with heart failure

35. FAIR-HF trial
Anker SD et al. N Engl J Med 2009;361:243

36. FAIR HF Trial
 Aim
To determine whether treatment with IV iron (ferric
carboxymaltose) would improve symptoms in patients
who had HF, reduced LV function, and iron deficiency
either with or without anemia.
Anker SD et al. N Engl J Med 2009;361:243

37. Method
Study design: A randomized, double-blind, multicenter study.
Study population: N= 459 patients.
NYHA class II or III, a LVEF of 40–45% or less, a Hb from 9.5 to 13.5
g/dL and iron deficiency..
Treatment regimen: 4 ml Ferric carboxymaltose or saline was
administered. Weekly injections were continued until Fe was repleted(
usually within 8 weeks) and then at 4 weekly intervals upto 24 weeks.
End point: The primary end point was a self-reported Patient Global
Assessment (PGA) form and NYHA functional class in the 24th week.
Safety end points were serious and non-serious adverse effects,
hospitalization and death up to the 26th week of study.
The FAIR-HF trial
Anker SD et al. N Engl J Med 2009;361:243

38. Result
The evaluation of PGA forms showed much or moderate i.e., around 50%
improvement in the ferric carboxymaltose group as compared to the 28% in the
placebo group. 47% in the ferric carboxymaltose group had NYHA functional class I or
II as compared to 30% in the placebo group.
Anker SD et al. N Engl J Med 2009;361:243

39. Anker SD et al. N Engl J Med 2009;361:243

40. Anker SD et al. N Engl J Med 2009;361:243

41. Anker SD et al. N Engl J Med 2009;361:243

42. Anker SD et al. N Engl J Med 2009;361:243

43. The administration of ferric carboxymaltose in patients with chronic heart failure
and iron deficiency with or without anemia was beneficial.
Anker SD et al. N Engl J Med 2009;361:243

44. FAIR HF Trial
 Conclusion
Ferric carboxymaltose for a period of 24 weeks in patients with chronic
heart failure and Fe deficiency with or without anemia showed
improvement in the symptoms, functional capacity and the QoL.
No additional side-effects were observed during this time-span. This
treatment was beneficial to both patients with and without anemia.
Anker SD et al. N Engl J Med 2009;361:243

45. CONFIRM HF Trial

46.  A multi-centre, double-blind, placebo-controlled trial.
 N= 304 patients
 with LVEF ≤ 45%, elevated natriuretic peptides, and
Fe deficiency (ferritin <100 ng/mL or 100–300 ng/mL if
transferrin saturation ,20%).
 FCM, n = 152 or placebo (saline, n =152) for 52
weeks given.
 FCM significantly prolonged 6MWT distance,
improvement in NYHA class, PGA, QoL, and
Fatigue Score at Week 24 and was sustained to
Week 52.
 Treatment with FCM was associated with a
significant reduction in the risk of hospitalizations
for worsening HF [ P = 0.009]. The number of deaths
(FCM: 12, placebo: 14 deaths) and the incidence of

47. CONFIRM HF Trial
 Conclusion: Treatment of symptomatic, Fe-
deficient HF patients with FCM over a 1-year
period resulted in sustainable improvement in
functional capacity, symptoms, and QoL and may
be associated with risk reduction of
hospitalization for worsening HF.

48. RECOMMENDATIONS

49. Practical Tip: Symptomatic patients with low transferrin and/or ferritin levels
should be considered for supplementary iron therapy principally with a goal of
improving symptoms
Anemia recommendations
We suggest that for patients with documented iron deficiency, oral or
intravenous iron supplement be initiated to improve functional capacity (Weak
Recommendation, Low-Quality Evidence).
Values and Preferences:
The iron supplement recommendation was derived mostly from the experience
of clinicians, small clinical trials, and 2 large randomized controlled trials (RCTs).
Recommendation

50. EPO recommendation
Values and Preferences:
The recommendations against the use of erythropoiesis-stimulating agents
(ESAs) were derived from robust data from RCTs.
Recommendation
We recommend erythropoiesis stimulating agents not be routinely used to treat
anemia in HF (Strong Recommendation, High-Quality Evidence).

51. Take Home Message
 Anemia is a independent predictor of morbidity and
mortality of HF.
 Anemia has emerged as a possible treatment target in HF.
 ESPs is a major concern for safety in HF patients.
 ESPs should not be used routinely in HF.
 For patients with documented Fe deficiency, oral or
intravenous iron supplement may be initiated to improve
functional capacity.
 Larger controlled clinical trials are needed for further