Inder S. Anand, MD, FRCP, D Phil, (Oxon.)

Professor of Medicine, Cardiovascular Division

University of Minnesota Medical School

Director of Heart Failure Clinic

VA Medical Center

Minneapolis and San Diego

Iron Deficiency and Heart Failure:

Iron supplements as a Treatment for Heart Failure

• Anemia and Iron deficiency (ID) are common comorbidities in HF

& often coexist. Together or independently they are associated

with worse symptoms and outcomes.

• Whether anemia or ID are just a marker of severe HF or

mediators of adverse outcomes, that need to be targeted has

been debated for long.

• Treating anemia in HF with erythropoiesis-stimulating agent does

not improve outcomes, may be deleterious and is not

recommended.

• Increasing data suggests that treating ID with IV iron improves

symptoms and exercise capacity, but long-term outcomes and

safety data are not yet available.

Heart Failure, Anemia and Iron Deficiency

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 100 to 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 with 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 with 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 a

Multi-ethnic community-based Southeast Asian controls and heart

failure population.

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

Absolute or Relative ID in Heart Failure is

Associated with Worse Outcomes

546 patients with stable HF; LVEF 26 ± 7%. Overall, absolute or relative ID was

present in 37% patients; 57% in those with anemia, 33% in those without anemia.

Absolute or Relative ID was present

in 37% all CHF patients (199/546)

20

40

60

% o

f C

HF

Patients

33%

Non

anemics

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.

In HF Iron Deficiency May be a More Important Prognostic Marker Anemia

Klip et al. Am Heart J 2013;165:575-582.e3.

International pooled cohort, 1,506 HF patients with and without ID and

anemia

Iron deficiency but not anemia remained an independent

predictor of mortality (HR] 1.42, 95% CI 1.14-1.77, p = .002)

Does Iron Replacement Therapy Help?

• Oral iron supplementation is standard therapy

for ID in non-HF patients; readily available,

inexpensive & effectively raises serum iron.

• In HF, iron is not absorbed well because of

elevated hepcidin, which inhibits iron absorption

• Oral iron is also associated with adverse GI

effects and not well tolerated.

• Few studies have investigated the effects of oral

iron in patients with ID and HF.

IRONOUT-HF (Iron Repletion Effects on Oxygen Uptake in Heart Failure)

• Phase 2 RCT, 225 patients with NYHA class II to IV HF

• Median LVEF, 25%

• Hb; 9 - 15 g/dL (men) or 9 - 13.5 g/dL (women) and ID

• Randomized: oral iron polysaccharide 150 mg BD/

placebo.

Primary Endpoint: • Change in peak VO2 from baseline at 16 weeks

Secondary Endpoints: • 6MWD, NT-proBNP levels and KCCQ QoL score

Lewis, GD et al.JAMA. 2017;317(19):1958-1966. doi:10.1001/jama.2017.5427

IRONOUT-HF (Iron Repletion Effects on Oxygen Uptake in Heart Failure)

Lewis, GD et al.JAMA. 2017;317(19):1958-1966. doi:10.1001/jama.2017.5427

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

• ↑ Exercise capacity (6MWT; Peak Vo2)

• Improved QoL scores

• Improved NYHA class • ↓ NT-proBNP level

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

• Because of small size - outcomes could not be

assessed

CV Deaths and CV Hospitalization Recurrent Event Analysis - 42% ↓

Meta-analysis of 4 RCT Comparing IV Ferric Carboxymaltose and Placebo HFrEF

Individual 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

Meta-analysis of 4 RCT using Similar Protocol as FAIR-HF of IV FCM in HFrEF

Individual patient data from 839 patients with HFrEF and ID

504 randomized to Ferric Carboxymaltose, 335 to placebo.

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

Recurrent Cardiovascular Outcomes

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

All Cause Mortality and Recurrent CV Hospitalization

Meta-analysis of 4 RCT using Similar Protocol of IV FCM in HFrEF

Individual patient data from 839 patients with HFrEF and ID

504 randomized to Ferric Carboxymaltose, 335 to placebo.

Deleterious Effects of Iron on the Body

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

• Human body is unable to excrete iron

• Under normal conditions, iron absorption is

reduced in the duodenum to prevent overload

• This protective mechanism is bypassed when

iron is given intravenously

• At higher TSAT, Reactive Oxygen Species are

formed - can mediate cell death in most organs

• Hence iron toxicity could be a major concern of

IV iron therapy

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.”

2017 - AHA/ACC Guidelines

Class IIb, Level of evidence BR recommendation:

2016 - ESC Guidelines

Class 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.

Conclusions

• Increasing hemoglobin in anemic patients with HF does

not appear to be a therapeutic target

• Use of IV iron in the management of absolute or

functional ID in HF patients with or without anemia,

appears promising, and could become a therapeutic

target.

• Long-term clinical studies are required to confirm that

treatment of ID improves outcomes. A number of large

RCT in patients with Acute and Chronic HFrEF and

HFpEF are underway to address these issues.

Personalized Algorithm for Management of Patients with HF and ID

Anand and Gupta 2020. Blood: /doi.org/10.1182/blood.2019004004

HFrEF (with Hb ≤15 g/dL,

LVEF ≤45% and NYHA II-IV)

HFpEF

No data yet for IV

iron. Enroll in ongoing

trials, if possible

Optimize heart failure management.

Chronic anemia*

Ferritin <100 mg/L or ferritin 100-300 mg/L with TSAT <20%

Yes No

Consider IV iron infusion**

Monitor cardiac status, Hb and iron indices – repeat

IV iron if necessary

Continue monitoring

clinical status, Hb and iron indices

No anemia

Check iron indices We recommend considering

judicious packed red cell transfusion with IV furosemide

to prevent fluid overload if Hb <7-8

g/dL. However, there are no

prospective data for red cell transfusion

*Hb <13 g/dL (men) Hb <12 g/dL (women)

**Dose based on Ganzoni formula

Identify and treat correctable as well as co-existing causes of anemia

Heart Failure

Acute anemia

Judicious packed red

cell transfusion

Hemodynamic instability or tissue hypoxia

or ongoing bleeding or Hb <7-8 g/dL

Yes No

Continue monitoring

clinical status and labs

Consider possibility of ID from bleeding, identify cause, treat

accordingly