Inder S. Anand, MD, FRCP, D Phil, (Oxon.) Professor of Medicine, Cardiovascular Division

University of Minnesota Medical SchoolDirector of Heart Failure Clinic

VA Medical CenterMinneapolis and San Diego

Anemia and Iron Deficiency in Heart Failure:

Current Concepts and Emerging Therapy

Conflict of Interest Disclosure

Research Grant, Consultant Fees and Honoraria:

Amgen, AstraZeneca, ARCA, Boehringer Ingelheim, LivaNova, Novartis, Zensun

• Anemia and Iron deficiency (ID) are common comorbidities in HF & often coexist. Together or independently they are associated with worse symptoms, functional capacity and outcomes than in HF patients without anemia or ID.

• Mechanisms by which they worsens outcomes are unclear but appear to be multifactorial

• Whether anemia or ID are just a marker of severe HF or a mediator of adverse outcomes, to be targeted is debated?

• Treating anemia in HF with erythropoiesis-stimulating agent may improve functional capacity but not outcomes.

• Preliminary data suggests that treating ID with IV iron improves symptoms and exercise capacity, but longterm outcomes and safety data are not yet available

Heart Failure and Anemia

A Third of Stable Patients with Heart Failure have Anemia

Study N Anemia Definition PrevalenceAndrone 196 Hct <41% M, <38% F 61%Silverberg 142 Hb <12 g/dL 56%STAMINA-HFP 982 Hb <12 g/dL F, <13 g/dL M 33%UCLA Study 1061 Hb <12 g/dL F, <13 g/dL M 30%Val-HeFT 5010 Hb <12 g/dL F, <13 g/dL M 23%PRAISE 1130 Hct <37.6% 20%RENAISSANCE 912 Hb ≤12 g/dL 20%COPERNICUS 2286 Hb <12.5 g/dL 19%ELITE II 3044 Hb ≤12.4 g/dL 17%Szachniewicz 176 Hb <12 g/dL 17%IN-CHF 2411 Hb <11 g/dL F, <12 g/dL M 16%Tanner 193 Hb <12 g/dL 15%

Approximately the Patients Admitted with ADHF have Anemia

Study N Anemia Definition Prevalence

McClellan 663 Hct <40 70%Wexler 338 Hb <12 g/dL 52%Wisniacki 201 Hb <12 g/dL 50%

OPTIME-CHF 906 Hb <13 g/dL M <12 g/dL F 49%

Kosiborod 2281 Hct ≤37% 48%Herzog 152,584 ICD-9 codes 28%Euro HF Survey 9971 Hb <11 g/dL 21%Ezekowitz 12,065 ICD-9 codes 17%Cromie 269 Hb ≤11 g/dL 14%

Groenveld, H. F. et al. J Am Coll Cardiol 2008;52:818-827

Anemia Doubled Risk of Mortality: A meta-analysis of 33 studies

§ Kotecha D et al. Am Heart J 2011;161:822-831

Meta-analysis of 11 small Phase 2 RCTsEffect of ESA Therapy on All-Cause Mortality

338 Patients with Anemia and HFrEF

§ Kotecha D et al. Am Heart J 2011;161:822-831

Meta-analysis of 11 small Phase 2 RCTsEffect of ESA Therapy on Hospitalizations for Heart Failure

338 Patients with Anemia and HFrEF

NEJM 2013;368:1210-19

RED-HF was Phase-3 pivotal trial designed as the to evaluated the effects of treating anemia with the ESA darbepoetin alfa on

clinical outcomes in patients with heart failure with reduced Ejection Fraction (HFrEF) and anemia.

Median Hemoglobin Concentration (g/dL)

Placebo (n=1142)Darbepoetin alfa (n=1136)

9

10

11

12

16

15

14

13

17

Study Visit (Month)

Mon

thly

Med

ian

Hem

oglo

bin

(g/d

L)

BL 6 12 18 24 30 36 42 48 54 60

Number of Subjects1140 966 803 676 560 459 377 265 182 140 99

1133 959 827 673 569 465 372 289 208 158 115

RED-HF Trial

Swedberg K, et al. N Engl J Med 2013;368:1210-9.

13.0 (IQR 12.4-13.4)

11.5 (IQR 10.7-12.2)

n = 2,278

Primary Outcome: All-Cause Death or First Hospitalization for Worsening HF

Years From Randomization

Prop

. of S

ubje

ct W

ith E

vent

(%)

Subjects at risk:

1136 975 855 712 581 473 385 281 212 161 101

1142 956 818 695 591 497 395 290 211 154 92

Stratified Log-rank, p = 0.87

Placebo

Darbepoetin alfa

100

80

60

40

20

0

0 1 2 3 4 5

RED-HF Trial

Swedberg K, et al. N Engl J Med 2013;368:1210-9.

HR 1.01, 95% CI (0.90 to 1.13)

Adverse Events of Interest

RED-HF Trial

n (%)

Darbepoetin alfa

(N = 1133)Placebo

(N = 1140)Risk difference

(95% CI)p-

valueAny Event of Interest 660 (58.3) 662 (58.1) 0.2 (-3.9, 4.2) 0.93

Cardiac failure 438 (38.7) 459 (40.3) -1.6 (-5.6, 2.4) 0.43Ischaemic heart disease 155 (13.7) 164 (14.4) -0.7 (-3.6, 2.2) 0.63Cerebrovascular disorders 61 (5.4) 45 (3.9) 1.4 (-0.3, 3.2) 0.10Haemorrhagic cerebrovascular conditions 39 (3.4) 30 (2.6) 0.8 (-0.6, 2.2) 0.26

Ischemic cerebrovascular conditions 51 (4.5) 32 (2.8) 1.7 (0.2, 3.2) 0.03

Embolic and thrombotic events 153 (13.5) 114 (10.0) 3.5 (0.9, 6.1) 0.01

Arterial* 87 (7.7) 73 (6.4) 1.3 (-0.8, 3.4) 0.24Venous† 29 (2.6) 20 (1.8) 0.8 (-0.4, 2.0) 0.19

Hypertension 81 (7.1) 69 (6.1) 1.1 (-0.9, 3.1) 0.29Malignancies 69 (6.1) 68 (6.0) 0.1 (-1.8, 2.1) 0.90Hypersensitivity reactions 99 (8.7) 96 (8.4) 0.3 (-2.0, 2.6) 0.79

ESAs are the wrong agents to treat anemia or anemia is the wrong target?

If anemia is a valid target, is blood transfusion a better agent?

LOS=length of stay

Blood Transfusion is Associated With Increased Risk of Death And LOS of Hospitalization

Kao DP, et al. Am J Cardiol 2011;107:69-73.

Public discharge data from California on 596,456 patient admitted for heart failure (2000 to 2006).

Multiple Logistic Regression

Increasing hemoglobin or treating anemia in HF patients with ESA or blood

transfusions does not appear to be beneficial and may be deleterious

AHA/ACC Guidelines for the Treatment of Anemia in Patients with Heart Failure

HF guidelines recommend a diagnosticworkup to seek and treat correctable causes of

Anemia in patients with HF

Class III (no benefit), Level of evidence BR recommendation:

“In patients with HF and anemia, ESAs should NOT be used to improve morbidity and mortality.”

Yancy CW, et al. 2017 Circ. 2017;136:e137–e161.

How Could Treatment of Anemia be Harmful in Patients with Heart Failure?

• HF patients with anemia are vasodilated• Increasing hemoglobin causes vasoconstriction

• Increase in SVR is partly because of • Increase in viscosity• Decrease in NO availability

• Hemoglobin is a powerful sink for NO

• Hypertension

Vasodilation in Chronic Severe AnemiaIs Due to Increased Nitric Oxide Availability

Effect of L-NMMA on Forearm Blood Flow

Basal L-NMMA 4 mmol/min

L-NMMA 16 mmol/min

0

2

4

6

8

Fore

arm

Blo

od F

low

(mL/

min

/100

mL)

P=0.096

Normal subjects

Anand IS, et al. J Am Coll Cardiol. 1995;25:1402-1407.

Anemia Rx with rapid BT

P=0.0003

Untreated anemia

HR RAP PAP PAWP Mean BP CI SVRbeats/min mmHg mmHg mmHg mmHg L/min/m2 dynes.sec.cm-5

Before 86 3 11 5 74 4.9 796

After 68 1 8 4 94 3.5 1230

Hemodynamics of Chronic SevereAnemia Before and After Treatment

4.5 ± 0.5 units Hb 4.8 ± 0.7 to 9.6 ± 0.7 g/dL

Anand I, et al. J Am Coll Cardiol.1995;25:1402-1407.

Cardiac Output Decreases With Increasing Hemoglobin in CKD Patients

Baseline (Hb = 8.5 g/dL)

[Hb] 10 (Hb = 10 g/dL)

[Hb] 14 (Hb = 14 g/dL)

Cardiac output (L/min)

7.0+0.6* 6.6+0.5* 5.2+0.3*

DBP (mmHg) 73+4 83+3* 81+6**

McMahon LP, et al. Nephrol Dial Transplant. 2000; 15: 1425-1430

Treatment with EPO Leads to development of HTN in Early Trials in CKD(> 10 mmHg increase in DBP)

Authors # Patients # DevelopingHypertension

% Hypertension

Samtleben, 1988 90 27 30

Akizawa, 1988 66 23 35

Eschbach, 1989 251 88 35

Sundal, 1989 150 48 32

Overall 557 186 33

• BP increased during first 4 months, not related to dose of EPO, rate of increase in Hgb or final Hgb achieved.

• SVR increased in all patients irrespective of an increase in BP.

Anand et al. Circulation 2005;112:1121-1127.

Hemoglobin and Blood Pressure in V-HeFT

Hemoglobin Diastolic BP(g/dL) (mmHg)

Hgb Q1, <12.8(n= 1226)

Hgb Q2, 12.8-13.71(n = 1139)

Hgb Q3, 13.71-14.7(n = 1292)

Hgb Q4, >14.7(n =1346)

Trend P-value <0.001 <0.001

15.4+0.7 78.1+10.4

14.1+0.3 76.7+10.2

72.4+10.4

13.2+0.3 74.8+10.5

11.8+0.8

Change in LVEF Vs. Change in Hemoglobin in Val-HeFT Trial

Anand et al. Circulation 2005;112:1121-1127.

Change in Median Hemoglobin (g/dL)

2.5

3.0

3.5

4.0

-1.7 -0.5 -0.1

Cha

nge

in L

V Ej

ectio

n Fr

actio

n (%

)

P=0.006

+0.5No change or increase in HgbDecrease in Hgb

• Correction of anemia and increase in Hgb in patients with

HFrEF is associated with vasoconstriction, decrease in cardiac output and ejection fraction and development of hypertension

• These hemodynamic changes are likely to be harmful to HF patients

• Anemia is most likely just markers of the severity, and of poor

prognosis in HF rather than a mediator of the disease

• Increasing hemoglobin in anemic patients with HF appears to

be a wrong therapeutic target irrespective of the agent used

Summary

Are there other targets or agents in patients with heart failure?

Absolute or Relative Iron Deficiency is Common in Heart Failure

Absolute Iron Deficiency:• When total body iron is decreased

Functional Iron Deficiency:• When total body iron is normal or increased but

inadequate to meet the needs of target tissues because of sequestration in the storage pool

In patients with HF, ferritin <100 μg/L or <300 μg/L if transferrin saturation (TSAT) is <20%

include patients with both absolute and functional ID

Iron Deficiency is Common in Heart Filure• 546 patients, stable HF; 55+11 y, 88% males, LVEF 26+7%, Iron def:

ferritin ,100 mg/L, or 100–300 mg/L,T-Sat <20%.

Jankowska et al. Eur Heart J. 2010:31;1872–1880

Iron Deficiency is Common in Heart Filure• 751 HF patients SHOP Study; age 62±12 y, 76% men, 65% Chinese,

24% Malay, 10% Indian and 601 controls; age 60±10 y, 50% men, 71% Chinese, 22% Malay, 7% Indian). ID: 100 mg/L, or 100–300 mg/L,T-Sat <20%.

§Yeo et al. Eur J Heart Failure 2014 16, 1125–1132; doi:10.1002/ejhf.161

SHOP (Singapore HF Outcomes and Phenotypes study) in aMulti-ethnic community-based Southeast Asian controls and heart

failure population.

Iron Deficiency is Common in Heart Filure• 751 HF patients SHOP study; age 62±12 y, 76% men, 65% Chinese,

24% Malay, 10% Indian and 601 controls; age 60±10 y, 50% men, 71% Chinese, 22% Malay, 7% Indian). ID: 100 mg/L, or 100–300 mg/L,T-Sat <20%.

§Yeo et al. Eur J Heart Failure 2014 16, 1125–1132; doi:10.1002/ejhf.161

SHOP (Singapore HF Outcomes and Phenotypes study) in aMulti-ethnic community-based Southeast Asian controls and heart

failure population.

Jankowska et al Eur Heart J (2010) 31, 1872–1880

Absolute or Relative Iron Deficiency is Common in Heart Failure

546 patients with stable HF; LVEF 26 ± 7%. Overall, absolute or relative ID was present in 37% patients; 57% in those with anemia, 32% in those without anemia.

Absolute or Relative ID was present in 37% all CHF patients (199/546)

20

40

60

% o

f CH

F P

atie

nts

32%

Nonanemics

57%

Anemic(Hb ≤ 12 g /dL)

ID was associated with death or Heart Tx independent of anemia (HR 1.58, 95% CI 1.14-2.17)

Jankowska EA, et al. Eur Heart J 2010;31:1872–80.

Iron Deficiency Decreass Exercise Performance• Iron important component of Hb, myoglobin and respiratory enzymes • Iron deficiency may decrease exercise capacity even before anemia• Iron deficiency alone has greater negative impact on exercise

capacity than anemia alone

Jankowska et al. Journal of Cardiac Failure 2011

Studies with Intravenous Iron in Heart FailureEfficacy of IV Iron Sucrose or Ferric Carboxymaltose Investigated in 5 RCT

Randomized Studies of the Effects of Intravenous Iron in Patients with Iron Deficiency with and without Anemia and Heart Failure. Author Study

Design Inclusion Criteria Patient (n) Follow-up

Duration Baseline Hb

(g/dL) Achieved Hb

(g/dL) Agents and dose

used Outcomes

Okonko 200818 FERRIC-HF

Randomized Observer-blinded Placebo-controlled

NYHA class II-III, anemic (Hb <12.5 g/dL) or non-anemic (Hb >12.5 g/dL) Ferritin <100 Pg/L or ferritin 100-300 Pg/L with TSAT <20% Peak VO2 <18 ml/kg/min

11 Control 24 IV iron sucrose

18 weeks Placebo 12.2 ± 1.0 IV iron sucrose 12.6 ± 1.2

Placebo 12.6 ± 1.2 IV iron sucrose 13.2 ± 1.1

200 mg weekly until ferritin >500 Pg/L, 200 mg monthly thereafter

n in Peak VO2 (P = 0.009) p in NYHA class (P <0.007)

Anker 200919 FAIR-HF

Randomized Double-blind Placebo-controlled

NYHA class II, LVEF <40% NYHA class III, LVEF <45% Hb 9.5-13.5 g/dL Ferritin <100 Pg/L or ferritin 100-300 Pg/L with TSAT<20%

155 Placebo 304 FCM

24 weeks Placebo 11.9 ± 1.4 FCM 11.9 ± 1.3

Placebo 12.5 ± 1.0 FCM 13.0 ± 1.0

200 mg weekly until ferritin >500 Pg/L, 200 mg monthly thereafter

PGA improved (P <0.001) nKCCQ QoL (P <0.001) n EQ-5D Score NYHA class improved n 6MWD

Beck-da-Silva 2013 20 IRON-HF

Randomized Double-blind Placebo-controlled

NYHA class II, LVEF <40% Anemia (Hb 9.0-12.0 g/dL) Ferritin <500 Pg/L and TSAT <20%

6 Placebo 10 IV iron sucrose 7 Oral iron

5 weeks to 3 months

Placebo 10.9 ± 0.7 Iron 11.2 ± 10.6

∆ Hb 1.04 in IV iron group; ∆ Hb 1.69 in oral iron group; ∆ Hb 1.1 in placebo group

Iron sucrose 200 mg/week x 5; Oral ferrous sulfate 200 mg tid for 8 weeks versus placebo

n Peak VO2 by 3.5 ml/kg/min in IV group p Peak VO2 by 0.86 in oral iron n Peak VO2 by 1.86 in placebo

Ponikowski 201521 CONFIRM-HF

Randomized Double-blind Placebo-controlled

NYHA class II, LVEF <45% BNP >100 pg/mL, NT-proBNP >400 pg/mL, Hb <15 g/dL Ferritin <100 Pg/L or 100-300 Pg/L if TSAT <20%

152 Saline 152 FCM

52 weeks

Placebo 12.4 ± 1.3 FCM 12.37 ± 1.4

∆ Hb at 52 wks. 1.0 (FCM vs placebo; P <0.001)

FCM 500-2000 mg at baseline and week 6 then 500 mg at weeks 12, 24, & 36 if ID still present

PGA improved (P <0.001) n KCCQ QoL (P <0.001) n EQ-5D Score NYHA class improved n 6MWD

van Veldhuisen 201722 EFFECT-HF

Randomized controlled

NYHA class II-III, LVEF<45% BNP >100 pg/mL, NT-proBNP >400 pg/mL, Hb <15 g/dL Ferritin <100 Pg/L or 100-300 Pg/L if TSAT <20%, Peak VO2 10 to 20 ml/kg/min

86 Control 86 FCM

24 weeks Control 13 ± 1.5 FCM 12.9 ± 1.3

Control 13.2 ± 1.4 FCM 13.9 ± 1.3

FCM 500-1000 mg at baseline and week 6 based on weight and Hb then at week 12 if ID still present

∆ in Peak VO2 by -0.16 ml/kg/min in FCM and -0.63 ml/kg/min in control (P = 0.23) not imputed PGA improved (P <0.05) NYHA class improved (P <0.05)

6MWD, 6-minute walk distance; CrCl, creatinine clearance; CRP, C-reactive protein; Hb, hemoglobin; IV, intravenous; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NT-proBNP, N-terminal brain natriuretic peptide; NYHA, New York Heart Association; PGA, Patient’s Global Assessment; TSAT, Transferrin saturation; VO2, peak oxygen consumption.

• ↑ Exercise capacity (6MWT; Peak Vo2)• Improved QoL scores• Improved NYHA class

• ↑ LVEF• ↓ NT-proBNP level

Anand and Gupta Circulation. 2018;138:80–98

Meta-analysis of Trial of IV Iron in Heart FailureIndividual patient data from 4 RCTs comparing FCM with placebo in 839 patients with HFrEF and ID, 504 randomized to FCM and 335 to placebo.

Anker et al. Eur J Heart Fail. 2017; doi:10.1002/ejhf.823

CV Deaths and CV Hospitalization

Meta-analysis of Trial of IV Iron in Heart FailureIndividual patient data from 4 RCTs on 839 patients with HFrEF and ID.

504 randomized to FCM and 335 to placebo.

Anker et al. Eur J Heart Fail. 2017; doi:10.1002/ejhf.823

Recurrent Cardiovascular Outcomes

Meta-analysis of Trial of IV Iron in Heart FailureIndividual patient data from 4 RCTs comparing FCM with placebo in 839 patients with HFrEF and ID, 504 randomized to FCM and 335 to placebo.

Anker et al. Eur J Heart Fail. 2017; doi:10.1002/ejhf.823

All Cause Mortality and Recurrent CV Hospitalization

Guidelines for the Treatment of Iron Deficiency in Patients with Heart Failure

“In patients with NYHA class II and III HF and ID (ferritin <100 μg/L or 100–300 μg/L, TSAT <20%),

intravenous iron replacement might be reasonable to improve functional status and QoL.”

2107 - AHA/ACC GuidelinesClass IIb, Level of evidence BR recommendation:

2016 - ESC GuidelinesClass IIa, Level of Evidence A recommendation:

Yancy CW, et al. 2017 Circ. 2017;136:e137–e161.

Ponikowski, P et al. Eur Heart J. 2016;37:2129–2200.

ESC Guidelines for Treatment of Iron Deficiency in HF

von Haehling, S. et al. J Am Coll Cardiol HF. 2019;7(1):36–46.

Conclusions

• Increasing hemoglobin in anemic patients with HF does not appear to be a therapeutic target

• Treatment of absolute or relative iron deficiency in HF patients with or without anemia, using IV iron appears promising and could become a therapeutic target.

• Long-term clinical studies are required to confirm that treatment of iron deficiency, particularly in the non-anemic subjects, improves outcomes.