Anaemia in Heart Failure

PRESENTER- DR ABHISHEK RATHORE SJIC&R ,Bangalore

IntroductionAnemia – 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.

Potential Therapeutic Targets

Definition of AnemiaWHO- Hb < 13g/dl (Men) Hb < 12g/dl (Women)

NKF criteria- Hb < 12g/dl (Men and

Postmenopausal women) Hb < 11g/dl (Premenopausal

women)

PrevalenceDepend on population studied and

definition of anemia used.

ARIC (Atherosclerosis Risk in Communities) study-

A/c to WHOAge: 45-64 yearsN= 15,792

9% patients were found Anemic.

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

Anemia in patients with heart failure

Hb = hemoglobinHct = hematocritHF = heart failure

The prevalence of anemia in heart failure patients is approximately:– 30% for Inpatients– 20% for Outpatients

4 – 61% (Median 18%) by Tang and Katz from 15 papers.

Circulation.2006;113:2454-61

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)

Pati

ents

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

Mechanism of Anemia in HFConcominant 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

Type of AnemiaM.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

Prognostic significance of anemia in HF

Poor prognosis

Increase mortality and hospitalisations

Study Design N Anemia Risk Assessment Limitations

Alexander1Retrospective cohort study of a population based HF database

90,316Anemia 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.

Polanczyk2Prospective, 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 chartreview 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

COPERNICUS5Randomized,double blind,placebo controlledtrial

2,286Anemia 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;137:919-9272Polanczyk CA, et al. J Card Failure. 2001;7:289-298

3Felker GM, et al. Am J Cardiol. 2003;92:625-6284Kosiborod 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

Hemoglobin and mortality in heart failure patients

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

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?

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:

Treatment options for anemia in HFBlood transfusion

ESPs

Iron therapy

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.

Saftey concern of ESP in variety of anemic patients.

1. In CKD

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.

2. In Cancer patients (N=1473 pts)

Conclusion- DA not associated with significant reduction in transfusions and also patients had shorter survival time.

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

Erythropoietin Stimulating Proteins in HF

STAMINA HeFT trial

Circulation. 2008;117:526-535

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;117:526-35

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 weeksHb rise Exercise

durationHb 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;117:526-535

RED-HF trial (Reduction of Events by Darbepoetin Alfa in Heart Failure)

March 28, 2013N Engl J Med 2013;368:1210-19

Darbepoetin alfa group (target hemoglobin 13.0 to 14.5 g/dL)N = 1200

Placebo groupN = 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 eventsStudy End September 1 2012

Began enrolling June 2006

Site Evaluation & Selection

Follow-up

RED-HF trial

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

2.4695% CI: (0.90,

4.02)

P = 0.011

Chan

ge fr

om B

asel

ine

in K

CCQ

Sy

mpt

om F

requ

ency

Sco

reDarbepoetin

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

0123456789

10

6.68

4.48

2.2095% CI: (0.65, 3.75)

P = 0.005

Chan

ge fr

om B

asel

ine

in K

CCQ

O

vera

ll Su

mm

ary

Scor

e

Placebo(n = 929)

Darbepoetin alfa

(n = 928)

Primary outcome: All cause death or first hospitalization for worsening heart failure

Years of Randomization

Prop

. of S

ubje

ct W

ith

Even

t (%

)

Subjects at risk:

11361142

975956

855818

712695

581591

473497

385395

281290

212211

161154

10192

Stratified Log-rank, p = 0.87

PlaceboDarbepoetin alfa

100

80

60

40

20

00 1 2 3 4 5

Selected adverse events of interestn (%)

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 support use of DA in HF.

IV Iron Therapy for anemia in HF

Table 1 Randomized, controlled studies with intravenous iron in patients with heart failure

FAIR-HF trial

Anker SD et al. N Engl J Med 2009;361:2436–48

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;361:2436–48

MethodStudy 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;361:2436–48

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;361:2436–48

Anker SD et al. N Engl J Med 2009;361:2436–48

Anker SD et al. N Engl J Med 2009;361:2436–48

Anker SD et al. N Engl J Med 2009;361:2436–48

Anker SD et al. N Engl J Med 2009;361:2436–48

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;361:2436–48

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;361:2436–48

CONFIRM HF Trial

A multi-centre, double-blind, placebo-controlled trial.N= 304 patientswith 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 adverse events were comparable between both groups.

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.

RECOMMENDATIONS

  

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

EPO recommendation

Values and Preferences:The recommendations against the use of erythropoiesis-stimulating agents (ESAs) were derived from robust data from RCTs.

RecommendationWe recommend erythropoiesis stimulating agents not be routinely used to treat anemia in HF (Strong Recommendation, High-Quality Evidence).

Take Home MessageAnemia 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 information and therapy guidelines.