Iron Therapy in Chronic Heart Failure - NHS Wales · Heart Failure anaemia pathophysiology- complex and multi-factorial * Ble Arch Intern Med 2005 165 2222-7. Iron deficiency in chronic

Iron Therapy in Chronic Heart Failure

Dr. Victor Sim MBBCh DGM MD FRCP

Consultant Physician

General Medicine and Geriatric Medicine

Topics to cover

• Anaemia and CHF

• Iron def with or without anaemia in CHF

• Therapeutic option for Iron def in CHF

Despite recent advances in HF management…..

Pharmacological therapy

• Loop Diuretic

• Digoxin

• ACEi (CONSENSUS 1987)

• Spironolactone

• Beta-blocker

• ARB

• Ivabradine

• Epleronone

• Perhexilene

Devices and Surgery

• CRT

• Revascularization

• ICD

• Valvular surgery/ intervention

• VAD

• Transplant

Morbidity and mortality in HF remain high!

Therapeutic targets

**Neurohormonal antagonists:ACEi; beta-blocker; ARB; aldosterone antagonists

Inotrope: Digoxin

Metabolic efficiency: Perhexilene

Heart rate control: Ivabradine

Correcting synchrony: CRT

Improving blood supply: revascularization

New novel therapy: correcting anaemia?

Anaemia and chronic heart failure:

Emerging concepts and therapeutic options

Prevalence of anaemia in chronic heart failure

Prevalence of Anaemia in HF

11. Anand I et al. Circulation 2005;112:1121–1127 12. Sharma R et al. Eur Heart J 2004;25:1021–1028 13. Anand I et al. Circulation 2004;110:149–154 14. Komajda M et al. Eur Heart J 2006;27:1440–144615. O’Meara et al Circulation 2006;113:986−994

1 2 3 4 5 6 7 8 913 14 14 1510,1

1

12

1. Cleland JG et al. Eur Heart J 2003;24:442−463 2. Komajda M et al. Eur Heart J 2003;24:464−474 3. Adams KF et al. Am Heart J 2005;149:209−216 4. Maggioni AP et al. J Card Fail 2005;11:91−985. Horwich TB et al. J Am Coll Cardiol 2002;39:1780−1786

6. Silverberg DS et al. J Am Coll Cardiol 2000;35:1737–1744 7. McClellan W et al. Curr Med Res Opin 2004;20:1501–15108. van Tellingen A et al. Neth J Med 2001;59:270−279

9. Ezekowitz JA et al. Circulation 2003;107:223-22510. Cohn JN et al. N Engl J Med 2001;345:1667–1675

7

Local data….

Prevalence of anamia in HF patients in

Cardiff and Vale UHB

43%

37%

26%

17%

7%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

<12.0 <11.5 <11.0 <10.5 <10.0

Haemoglobin (g/dl)

Mean age 81 yearsSim,Yousef, O’Mahony Tech Health Care 2009 17 377-385

1. Falk K et al. Eur J Heart Fail 2006;8:744−749; 2. Adapted from Kalra PR et al. Am J Cardiol 2003;91:888−891

Relationship of Exercise Intolerance

and Anaemia• In CHF, subjective experience of fatigue is associated with low

haemoglobin concentration (after adjustment for other cofactors)1

9

5

10

15

20

25

30

35

10 11 12 13 14 15 16 17

Hb (g/dL)Ref 2

Pe

ak

VO

2(m

L/k

g/m

in)

All patientsr= 0.36, p= 0.0004

Hb ≥≥≥≥13 g/dLr= -0.05, p= 0.7

Hb <13 g/dLr= 0.41, p= 0.014

Anaemia in HF Adversely Affects the

Outcome

• Meta-analysis, 34 studies, n=153,180 HF patients; anemics – 37%1

• Mortality: anemics – 46.8% vs non-anemics – 29.5%; OR=1.96 (1.74−2.21)1

• Anaemia independent risk of mortality; adjusted HR – 1.46 (1.26−1.69)1

1. Groenveld HF et al. J Am Coll Cardiol 2008;52:818−827; 2. O’Meara E et al. Circulation 2006;113:986−994

100

200

400

Pe

r 1

00

0 p

t-ye

ars

CV Non-CV

Reduced LVEF Preserved LVEFCV Non-CV

300

Hospital admission

50

100

150

Pe

r 1

00

0 p

t-ye

ars

CV Non-CV

Reduced LVEF Preserved LVEFCV Non-CV

Mortality

Anemics

Non-anemics

CHARM program2

10

• Kaplan-Meier analysis of all-cause mortality according to anaemia status1

Persistence of Anaemia in Ambulatory HF

Patients is Related to Poor Outcome

1. Tang WH et al. J Am Coll Cardiol 2008;51:569–576

0

20

40

60

80

100

18.6%

0 1 2 3 4 5

Log-rank p<0.0001Chi square= 227

Total baseline population (n=6159)

Su

rviv

al

(%)

Years

Without anaemia (n=5101)

With anaemia (n=1058)

0

20

40

60

80

100

0 1 2 3 4 5

Log-rank p<0.0001Chi square= 81.2

6 month follow-up (n=1393)

Su

rviv

al

(%)

Years

Resolved anaemia (n=143)

No anaemia (n=860)

Incident anaemia (n=210)

Persistent anaemia (n=180)

12

Documented evaluation only in 3% of anaemic patients

Heart Failure anaemia pathophysiology

Cardiorenal anaemia syndrome

Heart Failure

CKDAnaemia

• Renal hypo-perfusion→ CKD

• Blunt EPO→ anaemia

• HF comorbities (↑ BP, DM)

• Inflammation

• ↓ EPO- anaemia

• Haemodilution- anaemia

• Hecipdin- Fe def anaemia

• Anorexia- malnutrition

• Tissue hypoxia

• ↑ sympathetic pathway

• ↑ Renin- angioten- aldo

• ↑ fluid retention and HF

symptoms

Other: Iron effects

Heart Failure anaemia(Anaemia of chronic disease)

Fe def anaemiaCKD

Renal anaemiaEPO def

Anaemia of chronic disease• Cytokines IL-6, IL-1, TNF-α• Hepcidin• Functional Fe def• Blunted EPO response/ relative EPO def • Apoptosis of erythroid progenitors• Inhibit erythropoiesis

Absolute Fe deficiency• Malnutrition• Malabsorption

• PPI• Phosphate binders• Cytokines/ Hepcidin

• GI loss• Anti-platelet• Anti-coagulant• GI pathlogy

EPO deficiency• CrCl < 30ml/min*• Cytokines

• ↓ Hepcidin secretion

Others• Haemodilution (CKD, Cytokines)• ACEi and ARB

• ↓ EPO

• ↓ erthyroid progenitor

Heart Failure anaemia pathophysiology- complex and multi-factorial

* Ble Arch Intern Med 2005 165 2222-7

Therapeutic options for anaemia in Chronic Heart Failure

Heart Failure anaemia(Anaemia of chronic disease)

Fe def anaemiaCKD

Renal anaemia

Anaemia of chronic disease• Cytokines IL-6, IL-1, TNF-α• Hepcidin• Functional Fe def• Blunted EPO response/ relative EPO def • Apoptosis of erythroid progenitors• Inhibit erythropoiesis

Absolute Fe deficiency• Malnutrition• Malabsorption

• PPI• Phosphate binders• Cytokines/ Hepcidin

• GI loss• Anti-platelet• Anti-coagulant• GI pathlogy

EPO deficiency• CrCl < 30ml/min*• Cytokines

• ↓ Hepcidin excretion

Others• Haemodilution (CKD, Cytokines)• ACEi and ARB

• ↓ EPO

• ↓ erthyroid progenitor

Heart Failure anaemia pathophysiology- complex and multi-factorial

* Ble Arch Intern Med 2005 165 2222-7

Iron deficiency in chronic heart failure

with and without anaemia

Iron

• All biological life on earth has iron

• Biological organisms- Fe+2 and Fe+3

• Iron content in human= 2.5 -4g (40-50mg per Kg body weight)

Iron and anaemia

Iron is a Vital Biometal Involved in Numerous

Physiological Processes

• Oxygen transport– The availability of iron is a

rate-limiting step in the formation of haemoglobin (Hb) and, therefore, red blood cells (RBCs)

• Oxygen conservation– Iron is a vital component of myoglobin, the

protein in muscle that conserves oxygen and assure the steady state in which inflow of oxygen into the myocyte equals

the rate of oxygen consumption.

• Energy generation– The electron transport chain relies on the

redox capability of iron to shuttle electrons and generate adenosine triphosphate(ATP) from adenosine diphosphate (ADP)

Hypothesis: iron deficiency = mitochondrial dysfunction

Cremonesi P et al. Pharmacol Toxicol 2002;91:97–102

H+ H+

H+H+

H+H+

3H+ 3H+

ADP ATP

H+

H+H+

H+3H+

H+e-

H2O

RBC

21

Iron Deficiency can Affect Oxygen Consumption

Haas JD & Brownlie T. J Nutr 2001;131(2 suppl 2):676S–690S; Dallman PR. J Intern Med 1989;226:367–372;Willis WT & Dallman PR. Am J Physiol 1989;257:C1080–1085

pVO2

ATPO2

Hb

Iron deficiency

Mitochondrion Oxidativephosphorylation

Aerobic enzymes

O2 utilizationO2 delivery

22

Importance of Iron

Essential for growth and function

• Oxygen uptake, storage

and metabolism

• Energy production/

Mitochondrial function

• Iron dependent

cofactor/enzyme/catalyst

• Synthesis and degradation

of CHO, lipids, RNA and

DNA

• Apoptosis

• LVH

• Cardiac fibrosis

Cells and organs Individuals• Exercise intolerance

• Cognitive impairment

• Increased morbidity

and mortality

Iron is particularly important in cells with high energy demand- eg cardiomyocytes

Andrews NEJM 1999 341 1986-95Cairo Gene Nutr 2006 1 25-39Zimmermann Lancet 2007 370 511-20

Iron deficiency in the absence of anaemia

• Iron def is a potent substrate for dyspnoea and exercise intolerance

• Predicts higher mortality

Brownlie Am J Clin Nute 2004;79:437-43; Verdon BMJ 2003;326:1124-7; Kovesdy Clin J Am Soc Nephrol 2009;4:435-41

Iron disorder in CHF Okonoko et al JACC 2011: 1241-51

• Iron def (TSAT<20%) is common 43%

• Deranged Iron haemostasis relate closely to worsening inflammation, disease severity, exercise intolerance, lower Hb and increase mortality.

• Iron def associated with lower peak VO2 and increase risk of death independent of Hb

• Non-anaemic iron def 2X increased risk of death than anaemic iron repleted subjects

Iron haemostasis disorders

• Confusion terms:

– Functional iron deficiency

– Absolute iron deficiency

– Storage iron deficiency

– Circulating iron deficiency

– Functioning iron deficiency

– Anaemia of chronic disease

– Iron- deficiency anaemia

+/- anaemia

Iron deficiency

Absolute iron deficiency +/- anaemia

• Storage iron deficiency• Iron- deficiency anaemia

Functional iron deficiency+/- anaemia

• Circulating iron deficiency• Functioning iron deficiency• Anaemia of chronic disease

Inflammation

Patients with CHF are more prone to develop absolute iron deficiency

Increased lossesReduced dietary intake

• Poor dietHalf of HF patients consumed less than half of the iron requirement

• CKD+HF → anorexia→ poor oral iron intake

• Reduce intestinal absorption• PPI

• Phosphate binder• Inflammation/ Hecidin

Gastrointestinal loss• Anti-platelet• Anti-coagulant• Impaired mucosal integrity

• Occult loss

Andrews NEJM 1999 341 1986-95

Macdougall Curr Med Res Opin 2010 26 473-82

Naito J Hypertension 2011 29 741-8

Hughes Nut Metab Cardiovas Dis 2011

Patients with CHF are more prone to develop functional iron deficiency

? The role of Hepcidin and other inflammatory molecules: TNF- alpha and IL-6

• reduce the release of iron from reticuloendothelial system• reduce iron absorption from intestine

Increase of Hepcidin in HF patients because:• Inflammation• Reduce GFR

Ganz Blood 2011 117 4425-33

Babitt Am J Kidney Dis 2010 55 76-41

Hepcidin and Iron Regulation

Hentze MW et al. Cell 2004;117:285–297

Macrophages and other memory cells (including liver)

Intestine cells (Enterocytes)

Macrophages

Produced

ChymeErythrocytes

↓↓↓↓O2 saturation

↑↑↑↑ Iron need

Iron status ↑↑↑↑Inflammation

Bonemarrow

Liver

32

Iron disorder in CHF Okonoko et al JACC 2011: 1241-51

Functional iron def is more prevalent than absolute iron def anaemia particularly in the early stage of disease, often the two conditions coexist

Blood tests for iron deficiency

• Serum Iron• Total Iron Binding Capacity (TIBC)

– Elevated with inflammation (less cf Ferritin)– Reduced in malnutrition and chronic disease– Diurnal fluctuations (upto 70%)

• Transferrin Saturation= (Iron/ TIBC) X 100• Ferritin

– Iron storage, also in:• Inflammation

• Gender

• Ageing

– ? A level > 100 µg/ L excludes absolute Fe def*

• Serum transferrin receptor– More sensitive and specific assessment iron stores– Less affected by inflammation

• % hypochromic red cells

Suominen Arthritis Rheum 2000 43 1016-20 Skikne Blood 1990 75 321-4 Rimon Arch Intern Med 2002 `62 445-9

* Guyatt J Gen Intern Med 1992 7 145-53

Mixed absolute and functional iron def

Using serum transferrin receptor and % hypochromic red cells as gold standard for measuring circulating and functional iron

Defining Iron deficiency in CHF?

1. Ferritin <100, or

2. Ferritin 100-300 and TSAT <20%

• Predict worse outcomes• Diagnostic criteria used in

Interventional trials

Iron therapy in Chronic Heart Failure

Potential toxicity of IV Iron

IV Iron toxicity

Acute

Allergic hypersensitivity

Intermediate

Oxidative stress(surrogate markers)

Long term

?Infection?Mortality

Lim Neph Dial Transplant 1999 14 2680-7 Bailie HFA 2009

Where are the evidences of IV Iron therapy in HF?

Five published trials• Two uncontrolled studies• One un-blinded placebo-control• Two double blinded RCT (n=40; *n=459)

I.v. Iron Sucrose Improves Functional Capacity and

Quality of Life in Patients with CHF and Anemia

• Prospective, uncontrolled study with iron sucrose

• N=16 • Left ventricular ejection

fraction (LVEF) 26±13%• Hb ≤12 g/dL• Ferritin ≤400 ng/mL

Bolger AP et al. J Am Coll Cardiol 2006;48:1225–1227

MLWHF, Minnesota Living With Heart Failure; 6MWT, 6-minute walk test

MLWHF Score

33 ± 19→19 ± 14 (p=0.02)

6MWT

242 ±78→ 286 ±72 m(p=0.01)

R=0.56P=0.03

R=0.76P=0.002

Ch

an

ge

in

6M

WT

(m

)

Ch

an

ge

in

ML

WH

F q

ue

sti

on

na

ire

sc

ore 200

150

100

50

0

25

75

125

175

-25

-50

-75

-1 0 1 2 3-1 0 1 2 3

60

50

40

30

20

10

0

-10

-20

Change in Hb (g/dL)Change in Hb (g/dL)

49

• Uncontrolled prospective study IV Iron. N= 32, NYHA III (19) and IV (23)

• 100- 200mg IV Fe Sucrose per week 26 weeks (total 2800mg)

• Hb< 11g/dl

• Hb increased 10.1- 13.1

• Improved NYHA function and LV function (echocardiography)

• Randomised, open-label, observer-blind, IV Iron and placebo, N= 35

• Ferritin< 100 ug/L or Ferritin= 100-300 + TSat< 20%, Peak VO2< 18 ml/kg/min

• Anaemic< 12.5; non-anaemic= 12.5-14.5

• Improved Ferritin level and TSAT, but no increase in Hb;

• NYHA functional class mostly in anaemic group;

• Peak and total VO2 in aneamic group

I.v. Iron Sucrose Improves Iron Status in Patients with and without Anaemia

• Ferric Iron Sucrose in Heart Failure (FERRIC-HF)– Prospective randomized 2:1

controlled trial (RCT) in CHF

– n=35

– Iron deficiency• Ferritin <100 µg/L or

• Ferritin 100–300 µg/L and TSAT <20%

– Anemia• Hb <12.5 g/dL

Okonko DO et al. J Am Coll Cardiol 2008;51:103–112

Control I.v. iron

*P=0.001; **P<0.001

i.v. iron administration

improves iron status without an increase in Hb (increased TSAT and

ferritin)

0

10

20

30

40

50

Baseline Week 18

TS

AT

(%

)

*

0

100

200

300

400

500

Baseline Week 18

Fe

rrit

in(n

g/m

L)

**

52

I.v. Iron Sucrose Improves Peak VO2

in Anaemic Patients

-100

-50

0

+50

Data: mean±SD and treatment effect (95% CI)

+100

+150

Change in total pVO2

(mL/min)

+200

Delta96 (-12, 205)

-2

-1

0

+1

+2

+3

+4

Change peak pVO2

(mL/kg/min)

Delta2.2 (0.5, 4.0)

Exercise time(s)

Delta60 (-6, 126)

-160

-80

0

+80

+160

Okonko DO et al. J Am Coll Cardiol 2008;51:103–112 Data on file – Clinical Study Report

Control I.v. iron

53

P=NS (0.08)

P=0.01P=NS (0.08)

I.v. Iron Sucrose Improves New York Heart

Association Status in Patients with Anaemia

Okonko DO et al. J Am Coll Cardiol 2008;51:103–112

Anemic patients(p=0.048)

Non-anemic patientsTrend for improvement

(p=NS (0.08))

Total population (p=0.007)

-1

0

+1 +1 +1

-1 -1

Delta-0.6 (-0.9, -0.2)

0 0

Delta-0.5 (-1.0, 0)

Delta-0.6 (-1.3, 0.1)

Ch

an

ge

in

NY

HA

cla

ss

Control I.v. iron

54

• Placebo- controlled double blind, N= 40, follow up 6 months

• Hb< 12.5 g/dl for male; 11.5 g/dl for female

• Ferritin< 100ug/L +/- TSat< 20%; GFR< 90ml/min

• Hb; NYHA functional class; LVEF, 6MWT, hospitalization rate;

• MLHFQ; QOL; creatinine clearance; CRP; BNP;

• Reduced heart rate and diuretic need

I.v. Iron Sucrose Improves Kidney Function

in Patients with CHF and Iron Deficiency

Inclusion criteria:• 40 CHF outpatients, GFR ≤90 mL/min• LVEF ≤35%, Hb <12.5 (m)/<11.5 g/dL(f)• Ferritin <100 ng/mL and/or TSAT ≤20%

Toblli JE et al. J Am Coll Cardiol 2007;50:1657–1665

*P<0.01

Placebo (n=20)

I.v. iron (n=20)

NT

-pro

BN

P(p

g/m

L)

LV

EF

(%

)

*

Months

0 1 2 3 4 5 6 7

800

700

600

500

400

300

200

100

0

*

Months

0 1 2 3 4 5 6 7

45

40

35

30

25

20

15

10

5

0

* *

TS

AT

(%

)

Months

0 1 2 3 4 5 6 7

0.28

0.24

0.20

0.16

0.12

0.08

0.04

0.00

* * * *

0 1 2 3 4 5 6 7

* * * *

Cre

ati

nin

ecle

ara

nce

(mL

/min

)

60

50

20

10

0

40

30

Months

Treatment:

• 200 mg i.v. iron sucrose per week

• Weekly for 5 weeks then monthly• Duration: 6 months

Hospitalizations (secondary endpoint):

• I.v. iron: 0/20

• Control: 5/20*

56

Secondary endpoint

Anker et al. FAIR-HF Eur J Heart Failure 2009;11:1084-1091

• N= 459• LVEF average 32%• Ferritin< 100; Ferritin= 100-300 + % TSat< 20%• Hb= 9.5- 13.5 g/dL• Improved NYHA class functional class; Kansas City QOL; PGA;

6MWD; renal function; • Increase Hb and Ferritin levels• No difference in first hospitalisation for cardiovascular causes or

death• Early benefits• Benefit in both anaemic (9.5- 12) and non-anaemic (12.0- 13.5)

group• No adverse effects of the IV treatment comparing with placebo

Study Design (1/2)

• Statistical considerations:

– 90% power to detect a difference in PGA score means of 0.900

– 90% power to detect a difference in NYHA class means of 0.500

– All tested at 2-sided significance of 0.025

– Aimed to enroll: 442 patients

Anker SD et al. Eur J Heart Failure 2009;11:1084-1091

*total dose required for repletion calculated using the Ganzoni formula

Correction Phase* Maintenance Phase

RScreening

i.v. iron 200mg weekly

i.v. iron 200mg 4-weekly

normal saline weekly

normal saline 4-weekly

Week 26: safety

Week 24: PGA & NYHA

Ferric carboxymaltose n=304

Placebo n=155

60

Study Design (2/2)

• Main inclusion criteria:

– NYHA class II / III, LVEF ≤40% (NYHA II) or ≤45% (NYHA III)

– Hb 95–135 g/L

– Iron deficiency: serum ferritin <100 µg/L or <300 µg/L, if TSAT <20%

• Main exclusion criteria:

– Uncontrolled hypertension, inflammation (CrP >20 mg/L)

– Significant liver or renal dysfunction

• Treatment adjustment algorithm:

– Interruption: Hb >160 g/L or ferritin >800 µg/L or

ferritin >500 µg/L, if TSAT >50%

– Restart: Hb <160 g/L and serum ferritin <400 µg/L and TSAT <45%

• Blinding:

– Clinical staff: unblinded and blinded personnel

– Patients: usage of curtains and black syringes for injections

Anker SD et al. Eur J Heart Failure 2009;11:1084-1091 61

Demographics (1/2)

FCM(N=304)

Placebo (N=155)

Age (years) 68 67

Gender (% female) 52 55

Ischemic etiology (%) 81 79

Diabetes (%) 31 24

LVEF (%) 32 33

SBP (mm Hg) 126 126

DBP (mm Hg) 77 76

ACEi/ARB (%) 92 91

Beta-Blocker (%) 86 83

Diuretics (%) 92 90


FCM (N=304)

Placebo (N=155)

NYHA class II, n (%) 53 (17.4) 29 (18.7)

NYHA class III, n (%) 251 (82.6) 126 (81.3)

6-min walk test distance (m)* 274 ± 105 269 ± 109

Hb (g/L)* 119 ± 13 119 ± 14

MCV (µm3)* 92 ± 8.1 92 ± 6.7

Serum ferritin (µg/L)* 53 ± 55 60 ± 67

TSAT (%)* 17.7 ±12.6 16.7 ± 8.4

CRP (mg/L)* 7.5 ± 5.3 9.1 ± 5.5

Creatinine (mg/dL)* 1.2 ± 0.6 1.2 ± 0.6

Estimated GFR (mL/min/1.73m2)*

64 ± 21 65 ± 25

Demographics (2/2)

*mean ± SD Anker SD et al. Eur J Heart Failure 2009;11:1084-109163

FCM

Placebo

I.v. FCM Improves Patient Global Assessment Scores

• FCM improved self-reported Patient Global Assessment (PGA) scores at week 24

• Odds ratio for better rank: 2.51 (95% CI 1.75,3.61), P<0.001

50% vs 27%


FCM

Placebo

*Adjusted for baseline

I.v. FCM Improves NYHA Functional Class

• FCM improved NYHA functional class at week 24

• Odds ratio for improvement by 1 class: 2.40 (95% CI 1.55,3.71), P<0.001*

47% vs 30%


I.v. FCM Improves Symptoms and Functional Capacity

Self-reported PGA Score NYHA Functional Score

Weeks after randomization Weeks after randomization


FCM

Number of patients 303 284 280 268

Distance (mean±SE) 274±6 294±7 312±6 313±7

Placebo


Distance (mean±SE) 269±9 269±10 272±10 277±10

Treatment effect (mean±±±±SE)

21±6 37±7 35±8

I.v. FCM Improves Exercise Capacity


FCM


Score (mean±SE) 52±1 62±1 65±1 66±1

Placebo


Score (mean±SE) 53±1 56±2 57±2 59±2

Treatment effect (mean±±±±SE)

6±1 8±2 7±2

I.v. FCM Improves Kansas City Cardiomyopathy

Questionnaire Scores


I.v. Iron Performs Better than Placebo

in all Patient Subgroups

Self-reported PGA score NYHA functional class


69

Patients with events (Incidence per 100-patient years at risk)

FCM (N=305)

Placebo (N=154)

P

Death 5 (3.4) 4 (5.5) 0.47

CV death 4 (2.7) 4 (5.5) 0.31

Death due to worsening HF 0 (0.0) 3 (4.1) -

First hospitalization 25 (17.7) 17 (24.8) 0.30

Hospitalization for any CV reason 15 (10.4) 14 (20.0) 0.08

First hospitalization for worsening HF 6 (4.1) 7 (9.7) 0.11

Any hospitalization or death 30 (21.2) 19 (27.7) 0.38

Hospitalization for any CV reason or death 20 (13.9) 16 (22.9) 0.14

First hospitalization for worsening HF or death

11 (7.5) 10 (13.9) 0.15

Safety Endpoints


Adverse events are classified by the Medical Dictionary for Regulatory Activities (MedDRA) and are reported by system organ class when they occurred for more than 4% of patients in total.

Patients with events (Incidence per 100-patient years at risk)

FCM (N=305)

Placebo (N=154)

P

Cardiac disorder 38 (27.6) 33 (50.2) 0.01

Gastrointestinal disorder 24 (16.9) 5 (6.9) 0.06

General disorder or administration site condition 23 (16.2) 6 (8.3) 0.14

Injection site pain or discoloration 6 (4.1) 0 (0.0) -

Infection or infestation 50 (37.0) 24 (35.8) 0.97

Abnormal laboratory test, vital sign, physical finding 32 (23.0) 10 (14.0) 0.17

Nervous system disorder 22 (15.6) 14 (20.3) 0.44

Respiratory, thoracic or mediastinal disorder 9 (6.2) 10 (14.2) 0.06

Vascular disorder 20 (14.0) 11 (15.7) 0.80

No severe or serious hypersensitive reactions

Reported Adverse Events


Summaries

• Anaemia is common in CHF and associated with adverse morbidity and mortality

• Pathophysiology of anaemia is complex- main mechanisms are inflammation, Iron def and EPO def.

• Iron def with or without anaemia is common in CHF and associated adverse morbidity and mortality

• IV iron therapy seems to reduce symptoms, improve exercise tolerance and quality of life

What do the guidelines say?- all guidelines acknowledge the problems of anaemia, but

• ESC 2008- No proven effective treatments

• ACC/ AHA 2009- No recommendation

• NICE 2010- No mention of anaemia

• Update 2011 Cardiac Society of Australia and New Zealand- “Fe def should be looked for and treated to reduce symptoms and improve exercise tolerance and quality of life”

Practical points:Iron therapy in CHF

• Anaemia and iron def are under diagnosed, yet these conditions are assoc with high morbidity and mortality.

• Therefore: important to assess anaemia and iron status, particularly in those with refractory symptoms on optimal HF treatments

• Fe deficient- Ferritin <100 (possible absolute iron def) or Ferritin 100-300 and TSAT< 20% (likely functional iron def)

• Evidence of symptomatic benefits for IV Iron

• Hb< 13.5

Research project?

• Prevalence of iron def in real life population? Most published studies with mean age< 70 years

• The benefits of oral iron?

Thank You

Drueke 2006- CREATE

• ESA early treatment in patients with CKD and anaemia

• Trend toward increased mortality with a relative risk of 35% (p= 0.14) in the group attempting to normalise Hb levels (13- 15 g/dl)

Singh et al 2006- CHOIR

• N= 1432

• CKD and anaemia

• ESA

• Targeted to achieve Hb= 13.5 and Hb= 11.3

• Higher Hb group 35% increase in composite endpoints of death, MI, hospitalisation for HF and stroke (p= 0.03)

Pfeffer 2009- TREAT

• N= 4044

• DM II + CKD + anaemia (Hb<11)

• Neutral mortality (HR= 1.05; 95%Cl 0.92- 1.21; p=0.48)

• Neutral in worsening HF (HR= 0.89; 95% Cl 0.74- 1.08; p=0.24)

• Neutral Renal event

• Less blood transfusion in EPO treatment group

• Modest improvement in patient-reported fatigue in EPO group

• Increase stroke (HR=1.92; 95%Cl 1.38- 2.68; p<0.001)

Van Der Meer 2009- meta-analysis

• Seven randomised controlled trials

• N= 650

• Lower risk of hospitalisation (0.59; 95% Cl0.4-0.86; p=0.006)

• No difference in mortality (RR=0.69, 95%Cl 0.39-1.23; p=0.21)

• No difference in hypertension and venous thrombosis

Desai et al 2010- meta-analysis

• N= 2039

• Included TREAT HF patients

• Overall mortality RR= 1.03; 95%Cl 0.89-1.21; p= 0.68)

• Worsening HF RR= 0.95; 95%Cl 0.82-1.10; p=0.46)

NICE Guidance 2011Renal anaemia and ESA

• Treatment HB< 11g/dl or those with anaemic symptoms

• Target HB between 10-12 g/dl

Documents

Iron Therapy in Chronic Heart Failure - NHS Wales · Heart Failure anaemia pathophysiology- complex and multi-factorial * Ble Arch Intern Med 2005 165 2222-7. Iron deficiency in chronic